Patent Application
20100016285
The present invention relates to a medicine, in particular, a compound that modulates the function of having a transient receptor potential Vanilloid type I receptor (hereinafter referred to as “TRPV1 receptor”), in particular, to an N-(aryl)acetamide derivative having a heterocyclidene skeleton, a TRPV1 receptor antagonist comprising the derivative as an active ingredient, and an agent for preventing or treating diseases which cause pain and in which the TRPV1 receptor is involved, the preventive or treatable agent comprising the derivative as an active ingredient.
In a study related to the pain-producing mechanism, a receptor of capsaicin (8-methyl-N-vanillyl-6-nonenamide), which is a main pungent taste component of chili pepper, (TRPV1 receptor) was cloned in 1997 (Caterina M J, Schumacher M A, TomLinaga N, Rosen T A, Levine J D, and Julius D., Nature, Vol. 389, pp. 816-824, 1997). The TRPV1 receptor, which is a receptor that recognizes capsaicin, frequently expressed in primary sensory neurons involved in the sense of pain, and sensory afferent fibers containing C-fiber nerve endings. Thereafter, many TRP family receptors were cloned.
The structures of the TRP family receptors are similar to each other. The TRP family receptors each have a six transmembrane domain, and the N-terminal and the C-terminal of the molecule are disposed in a cell. In response to capsaicin stimulation, an acid (pH 6.0 or less), or heat (43° C. or higher), the TRPV1 receptor allows cations such as a calcium ion and a sodium ion to flow into a cell. Accordingly, considering the expression sites of the TRPV1 receptor and the action of capsaicine, a marked contribution of the TRPV1 receptor to the excitement of nerve was assumed. Furthermore, contributions of the TRPV1 receptor to living organisms have been elucidated from information disclosed in many previous reports. In particular, in a mouse in which the TRPV1 receptor has been deleted (TRPV1 knockout mouse), enhancement of heat sensitivity due to neuropathic pain is not observed, development of edema is suppressed in a Complete Freund's Adjuvant (CFA)-induced inflammatory pain model (Szabo A, Helyes Z, Sandor K, Bite A, Pinter E, Nemeth J, Banvolgyi A, Bolcskei K, Elekes K, and Szolcsanyi J, Journal of Pharmacology And Experimental Therapeutics, Vol. 314, pp. 111-119, 2005), and desensitization action by a TRPV1 receptor agonist disclosed in a previous report exhibits an analgetic effect in a neuropathic pain model and an inflammatory pain model, and thus, an involvement of the TRPV1 receptor in pain has been suggested (Rashid M H, Inoue M, Kondo S, Kawashima T, Bakoshi S, and Ueda H, Journal of Pharmacology And Experimental Therapeutics, Vol. 304, pp. 940-948, 2003).
Application of capsaicin causes a temporary acute pain, but then induces desensitization to cause an analgetic effect. On the basis of this characteristic, many TRPV1 receptor agonists, such as a capsaicin cream, have been under development as analgetic drugs (Saper J R, Klapper J, Mathew N T, Bapoport A, Phillips S B, and Bernstein J E, Archives of Neurology, Vol. 59, pp. 990-994, 2002).
Recently, it has been reported that, in dorsal root ganglion cells of a diabetic pain model rat induced by administering streptozotocin, depolarization due to capsaicin stimulation is accelerated, that is, the sensitivity of the TRPV1 receptor is enhanced. Thus, an involvement of the TRPV1 receptor in diabetic pain has been suggested (Hong S and Wiley J W, The Journal of Biological Chemistry, Vol. 280, pp. 618-627, 2005). In addition, it has been reported that the desensitization action of capsaicin, which is a TRPV1 receptor agonist, is effective for improving the bladder function, and thus, a contribution to urination has also been suggested (Masayuki Takeda and Isao Araki, Nippon Yakurigaku zasshi (Folia Pharmacologica Japonica), Vol. 121, pp. 325-330, 2003). Furthermore, contraction of bronchia caused by capsaicin stimulation, an inhibition effect of a TRPV1 receptor antagonist for this action, and the like have also been reported, and thus, an involvement in respiratory organs has also been suggested. It has been elucidated that the TRPV1 receptor is involved in various diseases. From the information described above, TRPV1 receptor modulators that modulate the function of the TRPV1 receptor have been expected to be useful.
Among such TRPV1 modulators, agonists that stimulate the TRPV1 receptor to induce desensitization and antagonists are expected to be useful in treating various diseases. Among these agonists and antagonists, since the agonists cause pain involving temporary acute stimulation and so forth, TRPV1 receptor antagonists that do not induce such excitation due to stimulation have attracted attention. Currently, compounds having a TRPV1 receptor antagonism are expected to be widely useful for, for example, analgetic drugs, therapeutic drugs for urinary incontinence, and therapeutic drugs for respiratory diseases.
Pain is defined as “an unpleasant, sensory and emotional experience that is caused by a substantial or latent lesion of a tissue, and a sensory and emotional experience that is described using such an expression”. Pain can be roughly divided into three categories: 1. nociceptive pain, 2. neuropathic pain, and 3. psychogenic pain.
The nociceptive pain is physiological pain caused by mechanical stimuli, thermal stimuli, or chemical stimuli. In general, the nociceptive pain acute pain and serves as a biosensor based on unpleasant sensory experiences to protect the body from danger. It has been thought that pain such as rheumatism is surely acute pain. However, a prolonged period from the onset thereof and the chronicity of inflammation bring about chronic pain.
Hyperalgesia to thermal to thermal stimuli or mechanical stimuli arises after tissue damage or during inflammation. The sensitization of receptors to a pain-inducing material and pain-inducing stimuli is reported in explanation of the hyperalgesia to thermal stimuli or mechanical stimuli. Examples thereof include sensitization of pain receptors due to inflammatory mediators occurring in local inflammation and a decrease in the pH therein, an increase in reactivity to bradykinin and histamine due to an increase in the temperature of local inflammation, and sensitization due to nerve growth factor (NGF) (reference: Kazuo Hanaoka, Itami-Kiso, Shindan, Chiryo-(Pain-Base, Diagnosis, and Therapy-), Asakura Shoten, 2004). Specific examples thereof include chronic rheumatism and knee osteoarthritis, which are typical examples. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for treatment of inflammatory pain due to pain chronic rheumatism and knee osteoarthritis for a long period of time. However, the use thereof is restricted because of side effects due to a disorder of apparatus digestorius and renal disorder. Furthermore, although cyclooxygenase-2-selective inhibitors (COX2 inhibitors) have been developed for reducing the side effects of NSAIDs, there is concern abut side effect that can lead to cardiac insufficiency which has become a social problem. Accordingly, an inflammatory pain therapeutic agent having higher efficacy in oral administration and having fewer side effects is required.
Postoperative pain is basically inflammatory pain which tissue damage accompanies, and includes factors of neurogenic pain factor derived from nerve injury. Postoperative pain is broadly divided into somatic pain and visceral pain. Somatic pain is further divided into superficial pain and deep pain. Among these, when severe postoperative pain is left untreated, nerve sensitization occurs; hence, pain is also evoked by innocuous stimuli, such as a touch and a press (allodynia). When such pain occurs, there are many intractable cases that cannot be controlled by nerve block therapy and the administration of drugs, such as NSAIDs, antiepileptic drugs, and opioid agonists. Furthermore, these drugs used have side effects. For example, the NSAIDs have side effects due to disorder of apparatus digestorius organs and renal disorder. In the antiepileptic drugs, carbamazepine and Phenyloin have side effects, such as tibutation, eruption, digestive symptoms, and cardiotoxicity; and Gabapentin has side effects such as somnolence and vertigo. The opioid agonists have side effects such as constipation. Accordingly, a postoperative pain therapeutic agent having higher efficacy and having fewer side effects is required.
Neuropathic pain is pain caused by primary damage of a certain portion in a neurotransmission system ranging from a periphery to center or caused by a malfunction thereof (Kenjiro Dan, Zusetsu Saishin Masuikagaku sirizu 4, Itamino rinsho (Textbook of anesthesiology 4, Fully illustrated) Chapter 1, 1998, Medical View Co., Ltd.).
Nerve injuries that cause neuropathic pain are typically external injuries or lesions on a peripheral nerve, a nerve plexus, or perineural soft-tissue. However, neuropathic pain is also caused by lesions on central somatosensory pathways (for example, ascending somatosensory pathways in spinal cord, brainstem, the thalamic or cortex level, and the like). For example, neuropathic pain is possibly caused by any of neurodegenerating diseases, osteolytic disease, metabolic disorder, cancer, infection, inflammation, after surgical operation, external injuries, radiotherapy, treatment using anticancer agents, and the like. However, the pathophysiological mechanism, or in particular, the molecular mechanism of the onset, has not yet been completely elucidated.
Allodynia is known as an example of an abnormal skin reaction characterizing neuropathic pain is allodynia. Allodynia is a state in which a person feels pain even with stimulation that would not result in normal person feeling pain. In allodynia, pain is evoked by tactile stimulus. That is, fundamental characteristics of allodynia are qualitative change in sensory responses and a low pain threshold. In postherpetic neuralgia, which is representative of neuropathic pain, it is confirmed that 87% of patients have allodynia. It is alleged that the strength of pain in postherpetic neuralgia is proportional to the degree of allodynia. Allodynia, which is a symptom that markedly constrains patients' freedom, draws attention as a therapeutic target of postherpetic neuralgia.
Herpes is a disease in which an infected herpes virus is neurons to cause onset, and 70% of herpes patients feel severe pain. This pain disappears as the disease is treated. However, about 10% of the patients suffers from so-called postherpetic neuralgia in which the pain remains for many years even after the disease is cured. On pathogenetic mechanism, it is said that the herpes virus proliferates again from a nerve ganglion, and nerve lesions generated during this proliferation accelerate reorganization of synapses, thus causing allodynia, which is neuropathic pain. In clinical settings, elderly people are more likely to develop the postherpetic neuralgia, and 70% or more of the cases of postherpetic neuralgia occur in patients 60 years old or older. Examples of a therapeutic agent used include anticonvulsant agents, non-steroidal anti-inflammatory agents, steroids, and the like, but there is no complete therapy (reference: Kazuo Hanaoka, Itami-Kiso, Shindan, Chiryo-(Pain-Base, Diagnosis, and Therapy-), Asakura Shoten, 2004).
Diabetic pain is broadly categorized into acute pain that occurs when hyperglycemia is rapidly remedied and chronic pain that occurs due to factors such as demyelination or nerve regeneration. Among these types of diabetic pain, the chronic pain is neuropathic pain due to inflammation of the dorsal root ganglion caused by a decrease in the bloodstream due to diabetes, and spontaneous firing of neurons and excitability caused by the subsequent regeneration of nerve fibers. Non-steroidal anti-inflammatory agents, antidepressant agents, capsaicin creams and the like are used for therapy. However, there is no perfect therapeutic agent for treatment of diabetic pain that can cure all the types of diabetic pain using a single agent (Reference: Iyaku no ayumi (Progress in Medicine)(Journal of Clinical and Experimental Medicine), Vol. 211, No. 5, 2004, Special feature “Itami shigunaru no seigyo kiko to saishin chiryo ebidensu” (“Control mechanisms of Pain Signal and Latest Evidence-based Therapy”)).
In neuropathic pain, analgesic treatment for patients who complain of a chronic pain symptom that interferes with their daily life directly improves the quality of life. However, it is believed that central analgetic agents represented by morphine, non-steroidal anti-inflammatory analgesic agents, and steroids are not effective against neuropathic pain. In practical pharmacotherapy, antidepressant agents such as amitriptyline; antiepileptic drugs such as Gabapentin, Pregabalin, carbamazepine, and phenyloin; and antiarrhythmic agents such as mexiletine are also used and prescribed for the treatment of neuropathic pain. However, it is known that these drugs have the following side effects: Amitriptyline causes side effects such as dry mouth, drowsiness, sedation, constipation, and dysuria. Carbamazepine and phenyloin cause side effects such as light-headedness, eruption, digestive apparatus symptoms, and cardiotoxicity. Gabapentin causes side effects such as somnolence and vertigo. Mexiletine causes side effects such as vertigo and digestive apparatus symptoms. These drugs, which are not specific neuropathic pain therapeutic agents, have poor dissociation between drug efficacy and side effect, thus, resulting in low treatment of satisfaction. Accordingly, a neuropathic pain therapeutic agent that exhibits a higher efficacy in oral administration and that have fewer side effects is required.
Recently, compounds having a TRPV1 receptor antagonism have been studied. Known heterocyclic compounds each having an amide bond are disclosed in, for example, PCT Publication No. 03/049702 pamphlet (Patent Document 1), PCT Publication No. 04/056774 pamphlet (Patent Document 2), PCT Publication No. 04/069792 pamphlet (Patent Document 3), PCT Publication No. 04/100865 pamphlet (Patent Document 4), PCT Publication No. 04/110986 pamphlet (Patent Document 5), PCT Publication No. 05/016922 pamphlet (Patent Document 6), PCT Publication No. 05/030766 pamphlet (Patent Document 7), PCT Publication No. 05/040121 pamphlet (Patent Document 8), PCT Publication No. 05/046683 pamphlet (Patent Document 9), PCT Publication No. 05/070885 pamphlet (Patent Document 10), PCT Publication No. 05/095329 pamphlet (Patent Document 11), PCT Publication No. 06/006741 pamphlet (Patent Document 12), PCT Publication No. 06/038871 pamphlet (Patent Document 13), and PCT Publication No. 06/058338 pamphlet (Patent Document 14). However, these patent documents have not handled the relationship of a TRPV1 inhibitor with the change in the body temperature as a problem to be solved. In addition, these patent documents do not disclose heterocyclidene acetamide derivatives.
Examples of the related art that disclose a compound having a heterocyclidene skeleton include that are PCT Publication No. 94/26692 pamphlet (Patent Document 15), PCT Publication No. 95/06035 pamphlet (Patent Document 16), PCT Publication No. 98/39325 pamphlet (Patent Document 17), PCT Publication No. 03/042181 pamphlet (Patent Document 18), Japanese Patent Application Laid-open No. 2001-213870 (Patent Document 19), PCT Publication No. 06/064075 pamphlet (Patent Document 20), PCT Publication No. 07/010,383 pamphlet (Patent Document 21), Journal of Heterocyclic Chemistry, Vol. 22, No. 6, pp. 1511-18, 1985 (Non-Patent Document 1), Tetrahedron Letters, Vol. 42, No. 18, pp. 3227-3230, 2001 (Non-Patent Document 2), and Chemical & Pharmaceutical Bulletin, Vol. 47, No. 3, pp. 329-339, 1999 (Non-Patent Document 3).
Patent Document 15 discloses, as a muscle relaxant, a compound with a structure which has a 1(2H)-benzopyran-4-ylidene skeleton or a 1,2,3,4-tetrahydro-4-quinolidene skeleton and in which a hydrogen atom, an alkyl group, or a cycloalkyl group is bonded to the N atom of the acetamide structure. However, a compound in which a substituted aryl group, heteroaryl group, or the like is bonded to the N atom is not disclosed. Patent Documents 16 to 18 disclose, as an arginine vasopressin antagonist or an oxytocin antagonist, a compound with a specific structure which has a 4,4-difluoro-2,3,4,5-tetrahydro-1(1H)-benzodiazepine skeleton and in which an aryl carbonyl group substituted an aryl is bonded to the N atom of the 1-position of the skeleton.
Patent Document 19 discloses, as a 2-(1,2-benzisothiazol-3(2H)-ylidene 1,1-dioxide) acetamide derivative used as a novel charge-control agent for a toner for electrostatography, a specific compound in which the N atom of the acetamide has a substituted phenyl group.
Patent Document 20 discloses, as an amide derivative of a 2,3-dihydro-1-oxo-1H-isoquinolin-4-ylidene used as a calpain inhibitor, a compound with a specific structure which has a sec-butyl group at the 3-position.
Patent Document 21 discloses a nobel heterocycliden acetamide derivatives used as the TRPV1 receptor antagonist. However, this patent document has no disclosure for the relationship of heterocyclidene acetamide derivatives with the change in the body temperature.
In a report related to the synthesis of an oxyindole derivative, Non-Patent Document 1 discloses 2-(1,2-dihydro-2-oxo-3H-indol-3-ylidene)-N,N-dimethyl-acetamide. However, a substituted aryl group or heteroaryl group, or the like is not bonded to the N atom.
Non-Patent Document 2 discloses, as a (1,2,3,4-tetrahydro-2-oxo-5H-1,4,-benzodiazepin-5-ylidene)acetamide derivative used for an N-methyl-D-aspartate (NMDA) antagonist, a compound with a specific structure in which a phenyl group is bonded to the N atom of the acetamide.
Non-Patent Document 3 discloses, as a (2,3,4,5-tetrahydro-1(1H)-benzodiazepin-5-ylidene)acetamide derivative used as a nonpeptide arginine vasopressin antagonist, a compound with a specific structure in which a 2-pyridylmethyl group is bonded to the N atom of the acetamide, and the benzodiazepine skeleton does not have a substituent.
Patent Documents 15 to 20 and Non-Patent Documents 1 to 3 disclose compounds each having a heterocyclidene skeleton, but the antagonism of the TRPV1 receptor is not disclosed or suggested.
It was reported that rise of body temperature was caused by administration of TRPV1 receptor antagonist (Journal of Medicinal Chemistry, Vol. 48, No. 6, pp. 1857-72, 2005 (Non-Patent Document 4), Society Neuroscience Abstruct, 30, Program No. 890.24, 2004 (Non-Patent Document 5), Journal of Neuroscience, Vol. 27, No. 13, pp. 3366-74, 2007 (Non-Patent Document 6)). In addition, there have been reported recently examples of a TRPV1 modulator that has no increase on body temperature in a rat (Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 1, pp. 218-29, 2008 (Non-Patent Document 7)). However, a compound has not been suggested that has a cyclidene skeleton as in the present invention.
In the development of pharmaceuticals, it is required to satisfy strict criteria for not only target pharmacological activity but also absorption, distribution, metabolism, excretion, and the like. With respect to drug interactions, desensitization or tolerance, digestive absorption in oral administration, the rate of transfer to a small intestine, the rate of absorption and first-pass effect, an organ barrier, protein binding, induction of a drug-metabolizing enzyme, an excretion pathway and body clearance, a method of administration (an application site, a method, and purpose), and the like, various agenda are required. However, a drug that satisfies these requirements is seldom discovered.
These comprehensive problems in drug development also exist for TRPV1 receptor antagonists, and TRPV1 receptor antagonists have not yet been released onto the market. More specifically, compounds having a TRPV1 receptor antagonism also include problems in terms of usefulness and safety. For example, these compounds have low metabolic stability and oral administration of these compounds is difficult; these compounds exhibit inhibitory activity of the human ether-a-go-go related gene (hERG) channel, which may cause arrhythmia, and pharmacokinetics of these compounds are not satisfactory. There are problems which will be understood at stages of clinical experiments. For instance, the change in the body temperature according to administering the TRPV1 receptor antagonist is suggested, and a prior art that has suggested possible compounds to solve such problem is only Non-Patent Document 7, in which some compounds of certain structures have been studied. However, it has never suggested a general chemical structure of the compounds. Accordingly, a compound has been desired that solves as many such problems as possible and further has high activity.
No prior art has been found that discloses a method of inducing compounds to solve such problems.
Accordingly, a compound in which these problems are solved and which has high activity has been desired.
In addition, a compound that causes fewer of the above-mentioned side effects than known drugs that are currently used in the treatment of pain including the above-described types of neuropathic pain has been desired.
(Patent Document 1) PCT Publication No. 03/049702 pamphlet
(Patent Document 2) PCT Publication No. 04/056774 pamphlet
(Patent Document 3) PCT Publication No. 04/069792 pamphlet
(Patent Document 4) PCT Publication No. 04/100865 pamphlet
(Patent Document 5) PCT Publication No. 04/110986 pamphlet
(Patent Document 6) PCT Publication No. 05/016922 pamphlet
(Patent Document 7) PCT Publication No. 05/030766 pamphlet
(Patent Document 8) PCT Publication No. 05/040121 pamphlet
(Patent Document 9) PCT Publication No. 05/046683 pamphlet
(Patent Document 10) PCT Publication No. 05/070885 pamphlet
(Patent Document 11) PCT Publication No. 05/095329 pamphlet
(Patent Document 12) PCT Publication No. 06/006741 pamphlet
(Patent Document 13) PT Publication No. 06/038871 pamphlet
(Patent Document 14) PCT Publication No. 06/058338 pamphlet
(Patent Document 15) PCT Publication No. 94/26692 pamphlet
(Patent Document 16) PCT Publication No. 95/06035 pamphlet
(Patent Document 17) PCT Publication No. 98/39325 pamphlet
(Patent Document 18) PCT Publication No. 03/042181 pamphlet
(Patent Document 19) Japanese Patent Application Laid-open No. 2001-213870
(Patent Document 20) PCT Publication No. 06/064075 pamphlet
(Patent Document 21) PCT Publication No. 07/010,383 pamphlet
(Non-Patent Document 1) Journal of Heterocyclic Chemistry, Vol. 22, No. 6, pp. 1511-18, 1985
(Non-Patent Document 2) Tetrahedron Letters, Vol. 42, No. 18, pp. 3227-3230, 2001
(Non-Patent Document 3) Chemical Pharmaceutical Bulletin, Vol. 47, No. 3, pp. 329-339, 1999
(Non-Patent Document 4) Journal of Medicinal Chemistry, Vol. 48, No. 6, pp. 1857-72, 2005
(Non-Patent Document 5) Society Neuroscience ABstruct, Program No. 890.20, 2004
(Non-Patent Document 6) Journal of Neuroscience, Vol. 27, No. 13, pp. 3366-74, 2007
(Non-Patent Document 7) Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 1, pp. 218-29, 2008
Under the above-described circumstances, a TRPV1 receptor modulator, in particular, a TRPV1 receptor antagonist that can be orally administered, that has high safety, and that has excellent effectiveness, an agent for preventing or treating diseases in which the TRPV1 receptor is involved, and in particular, an agent for preventing or treating pain have been desired. In the related art, amitriptyline causes side effects such as dry mouth, drowsiness, sedation, constipation, and dysuria; carbamazepine and phenyloin cause side effects such as eruption, digestive apparatus symptoms, and cardiotoxicity; gabapentin causes side effects such as somnolence and vertigo; mexiletine causes side effects such as vertigo and digestive apparatus symptoms; non-steroidal anti-inflammatory drugs cause side effects such as gastrointestinal damage; and COX2 inhibitors cause a side effect of heart failure; or problems to be confronted such as reduction of inhibitory action of an hERG current; improvement of metabolic stability or absorption; oral administrability; improvement of pharmacokinetics or solubility; and no cause of body temperature increase. Accordingly, there has been desired an agent that overcomes at least one of such problems, and can orally administered to mammals including humans, in particular, an agent for preventing or treating diseases in which the TRPV1 receptor is involved, in particular, an agent for preventing or treating pain, which has less body temperature change and is easy to use clinically.
The present invention provides a compound that modulates the function of a TRPV1 receptor, in particular, a heterocyclidene —N-(aryl)acetamide derivative represented by formula (I) where the benz ring (bicyclic ring system), which is condensed to nitrogen-containing ring (having, in particular, any of carbonyl group, sulfonyl group or oxygen atom), is bonded to amido-nitrogen atom, a pharmaceutically acceptable salt thereof, and a solvate thereof; a TRPV1 receptor modulator, in particular, a TRPV1 receptor antagonist, and an agent for preventing or treating pain, in particular, an agent for preventing or treating neuropathic pain, and an agent for preventing or treating inflammatory pain that contain the derivative as an active ingredient.
In order to solve the above problems and to obtain a compound that modulates the function of having a TRPV1 receptor having high safety and excellent effectiveness, the present inventors have conducted intensive studies and found that N-(aryl)-acetamide derivatives having a heterocyclidene skeleton represented by formula (I) where the benz ring (bicyclic ring system), which is condensed to nitrogen-containing ring (having, in particular, any of carbonyl group, sulfonyl group or oxygen atom), is bonded to amido-nitrogen atom and, pharmaceutically acceptable salts thereof, and solvates thereof have an excellent activity that modulates the function of the TRPV1 receptor, and the group of these compounds has at least one of features that the compounds have high metabolic stability, excellent oral absorbability, or do not cause the rise of body temperature (in particular, the change in the body temperature is very little). Accordingly, a pharmaceutical composition comprising one of the compounds as an active ingredient is promising as an agent for preventing or treating pain that can be orally administered, in particular, as an agent for preventing or treating neuropathic pain, or an agent for preventing or treating inflammatory pain,
The present invention provides a heterocyclidene-N-(aryl)acetamide derivative represented by formula (I) where the benz ring (bicyclic ring system, which is condensed to nitrogen-containing ring (having, in particular, any of carbonyl group, sulfonyl group or oxygen atom), is bonded to amido-nitrogen atom, a salt thereof, a pharmaceutical composition comprising the derivative or a salt thereof; and pharmaceutical use of the derivative or a salt thereof.
Embodiments of the present invention will now be described. In the description related to the compounds of the present invention, for example, the expression “C1-6” means, unless otherwise stated, “a linear or branched chain having 1 to 6 carbon atoms” for a linear group, and “the number of carbon atoms constituting a ring” for a cyclic group.
The molecular weight of a compound represented by formula (I) of the present invention is not particularly limited. However, the molecular weight is preferably 700 or less, and more preferably 550 or less. When the structure of a compound is specified in recent drug design, in addition to the basic skeleton having a pharmacological feature, a limitation such as that of the molecular weight is normally used as another significant limiting factor.
A first embodiment of the present invention is a compound represented by formula (I):
(wherein k, m, n, and p each independently represent an integer of 0 to 2; j and q represents an integer of 0 or 1; R1 represents a group selected from a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a protected or unprotected hydroxyl group, a protected or unprotected carboxyl group, a carbamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a C1-6 alkanoyl group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a sulfamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a cyano group, and a nitro group; R2 represents a group selected from a halogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, and an oxo group, or two geminal or vicinal R2 may bind to each other to form a C2-6 alkylene group, and form a cyclo ring group together with the carbon atom to which the two R2 are bonded or the cyclo ring group may form non-aromatic heterocyclic groups containing an oxygen atom or a nitrogen atom; X1 represents an oxygen atom, —NR3— (wherein R3 is a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)r— (wherein r is an integer of 0 to 2); X2 represents a methylene group, an oxygen atom, —NR3— (wherein R3 is a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group) or —S(O)r— (wherein r is an integer of 0 to 2); W represents a methylene group, a carbonyl group or a sulfonyl group; R7 represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group; R8, R9A and R9B each independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alkyl group, a protected or unprotected hydroxyl group, a protected or unprotected carboxyl group, a carbamoyl group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alkyl group, a C1-6 alkanoyl group, C1-6 alkylthio group, a C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, a sulfamoyl group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alkyl group, a cyano group or a nitro group; L1 and L2 each independently represent a single bond, a —CR9AR9B—, an oxygen atom; —NR10— (R10 represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted acyl group) or —S(O)t- (t is an integer of 0 to 2), the broken line in the ring containing X1 and X2 represents a condensation of two rings; Cycle moiety represents a five- or six-membered aryl ring or heteroaryl ring; and the solid line and the broken line between L1 and L2 is a single bond or double bond, and the wavy line represents an E-isomer or a Z-isomer), provided that when W represents a methylene group L1 is an oxygen atom and L2 is a —CR9AR9B—, and that each of (E)-2-(8-trifluoromethyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)-N-(3-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)acetamide;
Each of the groups in formula (I) used in the compound of embodiment [1] above will now be described specifically. In the following description, the expression “C1-6” means that the number of carbon atoms is in the range of 1 to 6. For example, a C1-6 alkyl group represents an alkyl group having 1 to 6 carbon atoms.
[1-1] In the compounds represented by formula (I), R1 is a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a protected or unprotected hydroxyl group, a protected or unprotected carboxyl group, a carbamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a C1-6 alkanoyl group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a sulfamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group, a cyano group, or a nitro group. Among these, a substituted or unsubstituted hydrocarbon group is preferred.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The “hydrocarbon groups” of the “substituted or unsubstituted hydrocarbon groups” include aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, and aryl groups. Among these, aliphatic hydrocarbon groups are preferred.
Examples of the “aliphatic hydrocarbon groups” in the “substituted or unsubstituted aliphatic hydrocarbon groups” include linear or branched hydrocarbon groups such as alkyl groups, alkenyl groups, and alkynyl groups.
Examples of the “alkyl groups” include C1-10 (more preferably C1-6) alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, 1-methyl-heptyl, and n-nonyl.
Examples of the “alkenyl groups” include C2-6 alkenyl groups such as vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, and hexenyl.
Examples of the “alkynyl groups”1 include C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, and hexynyl.
Examples of the “alicyclic hydrocarbon groups” include saturated and unsaturated alicyclic hydrocarbon groups such as cycloalkyl groups, cycloalkenyl groups, and cycloalkanedienyl groups.
Examples of the “cycloalkyl groups” include C3-9 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.
Examples of the “cycloalkenyl groups” include C3-6 cycloalkenyl groups such as 1-cyclopropen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, and 1-cyclohexen-1-yl.
Examples of the “cycloalkanedienyl groups” include C4-6 cycloalkanedienyl groups such as 2,4-cyclopentadien-1-yl and 2,5-cyclohexadien-1-yl.
Examples of the “aryl groups” include C6-14 aryl groups such as phenyl, naphthyl, biphenyl, 2-anthryl, phenanthryl, acenaphthyl, and 5,6,7,8-tetrahydronaphthalenyl; and partially hydrogenated fused aryl such as indanyl and tetrahydronaphthyl.
Examples of the heterocyclic groups of the “substituted or unsubstituted heterocyclic groups” in R1 include aromatic heterocyclic groups and saturated or unsaturated non-aromatic heterocyclic groups. Examples of the rings include five- to fourteen-membered rings, preferably five- to twelve-membered rings, containing at least one heteroatom (preferably, 1 to 4 heteroatoms) selected from N, O, and S in addition to the carbon atoms.
The “aromatic heterocyclic groups” include monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups. Preferably, the monocyclic aromatic heterocyclic groups each have a five- or six-membered ring. Examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,2,5-triazinyl, 1,3,5-triazinyl, and thiadiazinyl.
Preferably, the fused aromatic heterocyclic groups each have an eight- to twelve-membered ring. These groups include, for example, monovalent groups obtained by removing any hydrogen atom from a ring formed by condensing the above-mentioned five- or six-membered aromatic ring with one or a plurality of (preferably 1 to 2) aromatic rings (such as benzene rings).
Specific examples thereof include indolyl, isoindolyl, 1H-indazolyl, benzofuranyl(-2-yl), isobenzofuranyl, benzothienyl(-2-yl), isobenzothienyl, benzindazolyl, benzoxazolyl(-2-yl), 1,2-benzisoxazolyl, benzothiazolyl(-2-yl), 1,2-benzisothiazolyl, 2H-benzopyranyl(-3-yl), (1H-)benzimidazolyl(-2-yl), 1H-benzotriazolyl, 4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylizinyl, purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, (4,5,6,7-)tetrahydrothiazolo[5,4-c]pyridyl(−2-yl), (4,5,6,7-)tetrahydrothieno[3,2-c]pyridyl, (1,2,3,4-)tetrahydroisoquinolyl(−6-yl), thiazolo[5,4-c]pyridyl (−2-yl), pyrrolo[1,2-b]pyridazinyl, pyrazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, chromenyl (2H-chromenyl), 1H-pyrazolo[3,4-b]pyridyl, and [1,2,4]triazolo[1,5a]pyrimidinyl (Preferred embodiments are indicated in the parenthesis “( )”).
Examples thereof also include partially hydrogenated fused aromatic heterocyclic groups and the like, such as tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoazepinyl, tetrahydronaphthpyridinyl, tetrahydroquinoxalinyl, chromanyl, dihydrobenzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, dihydrobenzothiazolyl, 3,4-dihydro-2H-1,4-benzoxazinyl, isochromanyl, indolinyl, pteridinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 1,2,3,4-tetrahydro-1-methylquinolinyl, 1,3-dihydro-1-oxoisobenzofuranyl, and 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridyl.
Examples of the “non-aromatic heterocyclic groups” include three- to eight-membered saturated and unsaturated non-aromatic heterocyclic groups such as azetidinyl, oxiranyl, oxepanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, piperidyl, tetrahydropyranyl, piperazinyl, morpholinyl, oxazolinyl, thiazolinyl, thiomorpholinyl, oxepanyl and quinuclidinyl.
In the “substituted or unsubstituted C1-6 alkoxy group”, examples of the C1-6 alkoxy groups include a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, 3-pentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cyclopropylmethyloxy group, 1-cyclopropylethyloxy group, 2-cyclopropylethyloxy group, cyclobutylmethyloxy group, 2-cyclobutylethyloxy group, and cyclopentylmethyloxy group.
In the “substituted or unsubstituted C1-6 alkoxycarbonyl group”, examples of the C1-6 alkoxycarbonyl groups include a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclopropylmethyloxycarbonyl group, 1-cyclopropylethyloxycarbonyl group, 2-cyclopropylethyloxycarbonyl group, cyclobutylmethyloxycarbonyl group, 2-cyclobutylethyloxycarbonyl group and cyclopentylmethyloxycarbonyl group.
In the “amino group which is arbitrarily mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group”, the amino group which may be mono- or di-substituted with a C1-6 alkyl group means an amino group in which one or two hydrogen atoms of the amino group may be substituted with the above-mentioned “C1-6 alkyl group”. Specific examples thereof include an amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, and butylpropylamino group.
Examples of the protective group for the “protected or unprotected hydroxyl group” include alkyl protective groups such as a methyl group, tert-butyl group, benzyl group, trityl group, and methoxymethyl group; silyl protective groups such as a trimethylsilyl group and tert-butyldimethylsilyl group; acyl protective groups such as a formyl group, acetyl group, and benzoyl group; and carbonate protective groups such as a methoxycarbonyl group and benzyloxycarbonyl group.
Examples of the protective group for the “protected or unprotected carboxyl group” include alkylester protective groups such as a methyl group, ethyl group, tert-butyl group, benzyl group, diphenylmethyl group, and trityl group; and silyl ester protective groups such as a trimethylsilyl group and tert-butyldimethylsilyl group.
In the “carbamoyl group which is arbitrarily mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group”, the carbamoyl group which may be mono- or di-substituted with a C1-6 alkyl group means a carbamoyl group in which one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group may be substituted with the above-mentioned “C1-6 alkyl group”. Specific examples thereof include a carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group, isohexylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group, butylmethylcarbamoyl group, butylethylcarbamoyl group, and butylpropylcarbamoyl group.
Examples of the “C1-6 alkanoyl group” include a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, and hexanoyl group.
Examples of the “C1-6 alkylthio group” include a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, tert-pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethylpropylthio group, hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cyclopropylmethylthio group, 1-cyclopropylethylthio group, 2-cyclopropylethylthio group, cyclobutylmethylthio group, 2-cyclobutylethylthio group, and cyclopentylmethylthio group.
Examples of the “C1-6 alkylsulfinyl group” include a methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group, butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, isopentylsulfinyl group, tert-pentylsulfinyl group, neopentylsulfinyl group, 2-methylbutylsulfinyl group, 1,2-dimethylpropylsulfinyl group, 1-ethylpropylsulfinyl group, hexylsulfinyl group, cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, cyclopropylmethylsulfinyl group, 1-cyclopropylethylsulfinyl group, 2-cyclopropylethylsulfinyl group, cyclobutylmethylsulfinyl group, 2-cyclobutylethylsulfinyl group, and cyclopentylmethylsulfinyl group.
Examples of the “C1-6 alkylsulfonyl group” include a methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, tert-pentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1,2-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, hexylsulfonyl group, cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cyclopropylmethylsulfonyl group, 1-cyclopropylethylsulfonyl group, 2-cyclopropylethylsulfonyl group, cyclobutylmethylsulfonyl group, 2-cyclobutylethylsulfonyl group, and cyclopentylmethylsulfonyl group.
In the “sulfamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group”, the sulfamoyl group which may be mono- or di-substituted with a C1-5 alkyl group means a sulfamoyl group in which one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group may be substituted with the above-mentioned “C1-6 alkyl group”. Specific examples thereof include a sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoyl group, isobutylsulfamoyl group, pentylsulfamoyl group, isopentylsulfamoyl group, hexylsulfamoyl group, isohexylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, diisopropylsulfamoyl group, dibutylsulfamoyl group, dipentylsulfamoyl group, ethylmethylsulfamoyl group, methylpropylsulfamoyl group, ethylpropylsulfamoyl group, butylmethylsulfamoyl group, butylethylsulfamoyl group, and butylpropylsulfamoyl group.
Examples of the “substituents” of the “substituted or unsubstituted hydrocarbon group”, the “substituted or unsubstituted heterocyclic group”, the “substituted or unsubstituted C1-6 alkoxy group”, the “substituted or unsubstituted C1-6 alkoxycarbonyl group”, the “amino group which may be mono- or di-substituted with a substituted or unsubstituted C-6 alkyl group”, the “carbamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group”, or the “sulfamoyl group which may be mono- or di-substituted with a substituted or unsubstituted C1-6 alkyl group” in R1 include (a) alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and cycloalkenyl; (b) heterocyclic groups; (c) amino; (d) imidoyl, amidino, hydroxyl, thiol, and oxo; (e) halogen atoms such as fluorine, chlorine, bromine, and iodine, cyano, and nitro; (f) carboxyl; and (g) carbamoyl, thiocarbamoyl, sulfonyl, sulfinyl, sulfide, and acyl. Among (a) to (g) mentioned above, the groups except for (e) may further have a substituent. The above groups in R1 may be arbitrarily substituted with 1 to 5 such substituents as “substituent” of each of the “substituted or unsubstituted group” in R1. Examples of the substituents (a) to (g) will now be described specifically.
(a) The alkyl, alkenyl, alkynyl, aryl, cycloalkyl, and cycloalkenyl groups may be any of the “alkyl groups”, “alkenyl groups”, “alkynyl groups”, “aryl groups”, “cycloalkyl groups” and “cycloalkenyl groups” mentioned as examples of the “hydrocarbon group” for R. The preferred groups are C1-6 alkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C6-14 aryl groups, C3-7 cycloalkyl groups, and C3-6 cycloalkenyl groups.
These groups may further include an optional substituent RI (wherein RI represents a group selected from C1-6 alkoxy, C1-6 alkoxycarbonyl, carboxyl, carbamoyl which may be mono- or di-substituted with C1-6 alkyl, halogen, C1-6 alkyl, halogenated C1-6 alkyl, amino which may be mono- or di-substituted with C1-6 alkyl, C2-6 alkenoylamino, nitro, hydroxyl, phenyl, phenoxy, benzyl, pyridyl, oxo, cyano, and amidino).
(b) The heterocyclic group may be any of the “aromatic heterocyclic groups” and “non-aromatic heterocyclic groups” mentioned as examples of the “heterocyclic group” for R1. More preferably, the heterocyclic groups include (i) “five- or six-membered, monocyclic aromatic heterocyclic groups”, (ii) “eight- to twelve-membered, fused, aromatic heterocyclic groups”, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups” which contain 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to carbon atoms.
These groups may further include 1 to 3 optional substituents RII (wherein RII represents a halogen atom such as fluorine, chlorine, bromine, or iodine; a C1-6 alkyl group, a C1-6 alkanoyl group, or a benzoyl group).
(c) The “substituted or unsubstituted amino group” may be, for example, an amino group which may be mono- or di-substituted with a substituent RIII (wherein RIII represents a group selected from C1-6 alkyl, C1-6 alkanoyl, C2-6 alkenoyl, benzoyl, benzyl, phenyl, pyridyl which may be substituted with a group selected from C1-6 alkyl, halogen, and trifluoromethyl, and C1-6 alkoxycarbonyl which may be substituted with 1 to 5 halogen atoms), or three- to eight-membered monocyclic amino group which may be substituted with a group selected from C1-6 alkyl, C7-10 aralkyl, and C6-10 aryl.
(d) Examples of the substituents in “the substituted or unsubstituted imidoyl group, the substituted or unsubstituted amidino group, the substituted or unsubstituted hydroxyl group, and the substituted or unsubstituted thiol group” include RIII (wherein RIII represents a group selected from C1-6 alkyl, C1-6 alkanoyl, C2-6 alkenoyl, benzoyl, benzyl, phenyl, pyridyl which is arbitrarily substituted with a group selected from C1-6 alkyl, halogen, and trifluoromethyl, and C1-6 alkoxycarbonyl which may be substituted with 1 to 5 halogen atoms) described in (c) described above.
Accordingly, examples of (d) include C1-6 alkylimidoyl groups, a formimidoyl group, an amidino group, C1-6 alkoxy groups, a benzyloxy group, C1-6 alkanoyloxy groups, a phenoxy group, pyridyloxy groups which may be substituted with a group selected from C1-6 alkyl, halogen, and trifluoromethyl, and an oxo group.
Examples of (e) include halogen atoms such as fluorine, chlorine, bromine, and iodine; a cyano group; and a nitro group.
(f) The “substituted or unsubstituted carboxyl groups” include a carboxyl group, C1-6 alkoxycarbonyl groups, C7-12 aryloxycarbonyl groups, and C6-10 aryl-C1-4 alkoxycarbonyl groups. The aryl group in such (f) may be further substituted with a substituent RIV. RIV represents an amino group which may be mono- or di-substituted with a substituent RII′ (wherein RII′ represents a C1-6 alkyl group, a C1-6 alkanoyl group, or a benzoyl group); a halogen atom; a hydroxyl group; a nitro group; a cyano group; a C1-6 alkyl group which may be substituted with 1 to 5 halogen atoms; or an alkoxy group which may be substituted with 1 to 5 halogen atoms.
(g) Examples of “the substituted or unsubstituted carbamoyl group, the substituted or unsubstituted thiocarbamoyl group, the substituted or unsubstituted sulfonyl group, the substituted or unsubstituted sulfinyl group, the substituted or unsubstituted sulfide group, and the substituted or unsubstituted acyl group” include groups represented by —CONRgRg′, —CSNRgRg′, —SOy—Rg, or —CO—Rg, wherein Rg represents a hydrogen atom or a substituent RV (wherein RV represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, C7-10 aralkyl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the cycloalkyl, the aryl, the aralkyl, or the heterocyclic group may be further substituted with 1 to 5 substituents RIV of (f) described above); Rg′ is a hydrogen atom or a group selected from C1-6 alkyl groups, C3-6 cycloalkyl groups, and C7-10 aralkyl groups; and y is 0, 1, or 2.
[1-1-a] In the compounds represented by formula (I) of embodiment [1], examples of R1 preferably include halogen atoms, substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterocyclic groups, and substituted or unsubstituted C1-6 alkoxy groups. Examples of the “substituted or unsubstituted hydrocarbon group” and the “substituted or unsubstituted heterocyclic group” include (1) C1-10 alkyl groups; (2) C2-6 alkenyl groups; (3) C2-6 alkynyl groups; (4) C3-9 cycloalkyl groups; (5) C3-6 cycloalkenyl groups; (6) C4-6 cycloalkanedienyl groups; (7) C6-14 aryl groups; (8) heterocyclic groups each containing 1 to 4 hetero-atoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups; and (9) substituted or unsubstituted C1-6 alkoxy groups. Each of the groups in (1) to (9) may be either unsubstituted or substituted with 1 to 5 substituents in a class selected from (a-1) to (g-1) as described below.
The classes are as follows.
(a-1): Substituents include C1-6 alkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C6-14 aryl groups, C3-7 cycloalkyl groups, and C3-6 cycloalkenyl groups. These substituents may be further substituted with a substituent RI (wherein RI represents a group selected from C1-6 alkoxy, C1-6 alkoxycarbonyl, carboxyl, carbamoyl which is arbitrarily mono- or di-substituted with C1-6 alkyl, halogen, C1-6 alkyl, halogenated C1-6 alkyl, amino which is arbitrarily mono- or di-substituted with C1-6 alkyl, C2-6 alkenoylamino, nitro, hydroxyl, pyridyl, oxo, cyano, and amidino).
(b-1): Substituents are any one of heterocyclic groups of (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups which contain 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms. These heterocyclic groups may be further substituted with a substituent RII (wherein RII represents a group selected from halogen atoms such as fluorine, chlorine, bromine, and iodine; C1-6 alkyl, C1-6 alkanoyl, and benzoyl).
(c-1): Substituents in (c-1) include an amino group which may be substituted with a substituent RIII (wherein RIII represents a group selected from C1-6 alkyl, C-6 alkanoyl, C2-6 alkenoyl, benzoyl, benzyl, phenyl, pyridyl which may be substituted with a group selected from C1-6 alkyl, halogen, and trifluoromethyl, and C1-6 alkoxycarbonyl which may be substituted with 1 to 5 halogen atoms), or a three- to eight-membered monocyclic amino group which may be substituted with a group selected from C1-6 alkyl, C7-10 aralkyl, and C6-10 aryl.
(d-1): Substituents in (d-1) include an imidoyl group, an amidino group, a hydroxyl group, a thiol group, and an oxo group. These substituents may be substituted with groups selected from the substituents RIII described in (c-1) described above.
(e-1): Substituents in (e-1) include halogen atoms such as fluorine, chlorine, bromine, and iodine, a cyano group, and a nitro group.
(f-1): Substituents in (f-1) include a carboxyl group, C1-6 alkoxycarbonyl groups, C7-12 aryloxycarbonyl groups, and C6-10 aryl-C1-4 alkoxycarbonyl groups. The aryl groups in (f-1) may be further substituted with a substituent RIV′ (wherein RIV′ represents amino which may be mono- or di-substituted with groups selected from RIII described in (c-1) described above; C1-6 alkyl or C1-6 alkoxy which may be substituted with 1 to 5 halogen atoms; halogen atoms; hydroxyl; nitro; and cyano).
(g-1): Substituents in (g-1) include groups represented by —CONRgRg′, —CSNRgRg′, —CO—Rg, and —SO—Rg wherein Rg represents a hydrogen atom or a substituent RV (wherein RV represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, C7-10 aralkyl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, and the alkyl, the cycloalkyl, the aryl, the aralkyl, or the heterocyclic group may be further substituted with 1 to 5 substituents RIV of (f) described above); Rg′ is a hydrogen atom or a group selected from C1-6 alkyl groups, C3-6 cycloalkyl groups, and C7-10 aralkyl groups; and y is 0, 1, or 2.
In the groups listed in (a-1) to (g-1) described above, “particularly preferable groups” include substituents such as C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen atoms, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-alkoxy-C1-6 alkyl, carboxy-C6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, morpholinylcarbonyl, morpholinylsulfonyl, 5-trifluoromethylpyridin-2-yloxy, quinoxalin-2-yl, (pyridin-4-yl)methyl, 1,2,3-thiadiazolo-4-yl, 1H-pyrazolo-1-yl, 4-chlorophenyl, tetrahydrofuranyl and oxyranyl. The aromatic rings in these substituents may be further substituted with 1 to 5 substituents selected from halogen atoms, trifluoromethyl, cyano, hydroxyl, amino, nitro, carboxyl, carbamoyl, C1-6 alkyl, C1-6 alkoxy, mono/di C1-6 alkylamino, di-C1-6 alkylcarbamoyl, C1-6 alkoxycarbonyl, N—C1-6 alkylcarbamoyl, N,N-di C1-6 alkylcarbamoyl, and C2-6 alkenoylamino.
[1-1-b] Preferably, R1 is a halogen atom, and (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (7) a C1-4 aryl group, and (9) a C1-6 alkoxy group. Each group in (1), (2), (7), and (9) is arbitrarily substituted with 1 to 5 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
[1-1-c] More preferably, R1 is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), and a C1-6 alkyl group (in particular, C1-4 alkyl group) or C1-6 alkoxy group (in particular, C1-4 alkoxy group) which may be substituted with 1 to 5 halogen atoms.
[1-1-d] Further preferably, R1 is a halogen atom (particularly preferably, a fluorine atom or a chlorine atom), and a C1-4 alkyl group or C1-4 alkoxy group which is arbitrarily substituted with 1 to 5 halogen atoms. More specifically, examples thereof include a fluorine atom, a chlorine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, and tetrafluoroethoxy.
[1-1-e] Particularly preferably, R1 is a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy. Still more preferably, R1 is trifluoromethyl.
[1-2] In the compounds represented by formula (I) of embodiment [1], n is an integer of 0 to 2. Preferably, n is 1 or 2, and more preferably, n is 1.
The substitution position of R1 may be any position except for the condensation position of the five- or six-membered aryl ring or heteroaryl ring represented by “Cycle” in formula (I).
[1-2-1]
More preferably, when the “Cycle” is a six-membered ring, at least one of R1's is preferably bonded to the 4th position (A2) in the clockwise direction from the condensation position close to the carbon atom of the cyclidene in the partial structural formula (wherein each of A1 to A4 is either CH or N) below.
[1-2-1a]
For example, this position corresponds to the 7th position of a chroman ring, a pyridochroman ring, a 2,3-dihydroquinoline ring, or the like, which belongs to a skeleton in which m=1 and q=0, or an isochroman ring or the like, which belongs to a skeleton in which m=0 and q=1.
[1-2-1b]
This position corresponds to the 8th position of a 3,4-dihydrobenzo[b]oxepine ring or a 1,2,3,4-tetrahydrobenzo[b]azepine ring, which belongs to a skeleton in which m=2 and q=0, or a 3,4-dihydrobenzo[b]isooxepine ring or the like, which belongs to a skeleton in which m=1 and q=1.
[1-2-2]
When the “Cycle” is a five-membered ring, at least one of R1's is preferably bonded to the 3rd position (B2) in the clockwise direction from the condensation position close to the carbon atom of the cyclidene in the partial structural formula (wherein each of B1 to B3 is any one of CH, N, O, and S) below.
[1-2-2a]
For example, this position corresponds to the 6th position of a 2,3-dihydro-4H-pyrano[2,3b]pyrrole ring or a 2,3-dihydro-thieno[2,3-b]pyran ring, which belongs to a skeleton in which m=1 and q=0. This position corresponds to the 2nd position of a 5,6-dihydro-furo[2,3-b]pyran ring, which belongs to a skeleton in which m=1 and q=0.
In the all embodiments [1-2] to [1-2-2b], at least one of R1's is preferably a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy. More preferably, at least R1 bonded to A2 or B2 is a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy, and particularly preferably, trifluoromethyl.
[1-3] In the compounds represented by formula (I) of embodiment [1], R2 is a halogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, or an oxo group.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the “substituted or unsubstituted amino group” include amino groups which may be mono- or di-substituted with a substituent RIII (wherein RIII represents a group selected from C1-6 alkyl, C1-6 alkanoyl, C2-6 alkenoyl, benzoyl, and C1-6 alkoxycarbonyl which is arbitrarily substituted with 1 to 5 halogen atoms), or three- to eight-membered monocyclic amino group which may be substituted with a group selected from C1-6 alkyl, C7-10 aralkyl, and C6-10 aryl.
Aromatic rings of these substituents may further include 1 to 3 optional substituents selected from halogen atoms, trifluoromethyl, cyano, hydroxyl, amino, nitro, carboxyl, carbamoyl, C1-6 alkyl, C1-6 alkoxy, mono/di C1-6 alkylamino, di-C1-6 alkylcarbamoyl, C1-6 alkoxycarbonyl, N—C1-6 alkylcarbamoyl, N,N-di C1-6 alkylcarbamoyl, and C2-6 alkenoylamino.
The “substituted or unsubstituted hydrocarbon group” represents the same meaning as described in R1 of embodiment [1-1] described above. Examples of the “hydrocarbon group” include alkyl groups (for example, C1-10 (more preferably C1-6) alkyl groups), alkenyl groups (for example, C2-6 alkenyl groups), cycloalkyl groups (for example, C3-9 cycloalkyl groups), cycloalkenyl groups (for example, C3-6 cycloalkenyl groups), and aryl groups.
The “aromatic heterocyclic group” of the “substituted or unsubstituted aromatic heterocyclic group” represents the same meaning as described in R1 described above.
Substituents of these groups are the same groups as those listed as “particularly preferable groups” in the groups described in (a-1) to (g-1) in R1 described above.
[1-3-a] In the compounds represented by formula (I) of embodiment [1], R2 is preferably a fluorine atom, a chlorine atom, an amino group which is arbitrarily mono-substituted with a substituent RIII, a C1-6 alkyl group which is arbitrarily mono-substituted with a group selected from a C1-6 alkoxy, amino and mono/di C2-6 alkylamino, or a phenyl group. More preferably, R2 is a C1-6 alkyl group which is arbitrarily mono-substituted with a group selected from a C1-6 alkoxy, amino and mono/di C1-6 alkylamino (in particular, a C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, methoxymethyl, 2-methoxyethyl). Further preferably, R2 is methyl, ethyl, methoxymethyl.
[1-4] In the compounds represented by formula (I) of embodiment [1], p is an integer of 0 to 2. Preferably, p is 0 or 2 except cases raised in the following [1-4-a] to [1-4-c].
[1-4-a] However, in the compounds represented by formula (I), when R2 is a C1-6 alkyl group (in particular, a C-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl), p is preferably 1 or 2, and more preferably 2 and is bonded to geminal position. Alternatively, two geminal or vicinal R2 may bind to each other to form a C2-6 alkylene group respectively, and form a cyclo ring group together with the carbon atom to which the two R2 are bonded, or the cyclo ring group may form non-aromatic heterocyclic groups containing an oxygen atom or a nitrogen atom. Three to eight-membered rings are preferable. For example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, oxirane ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, aziridine ring, azetidine ring, pyrrolidine ring or piperazine ring can be formed.
[1-4-b] However, in the compounds represented by formula (I), when R2 is a fluorine atom, p is preferably 1 or 2, and more preferably 2.
[1-4-c] In the compounds represented by formula (I), when R2 is an amino group which may be mono-substituted with a substituent RIII or an oxo group, p is preferably 1 or 2, and more preferably 1.
[1-5] In the compounds represented by formula (I) of embodiment [1], m is 0 to 2, and preferably 1 or 2. In either case, the carbon atom or atoms located at the position corresponding to m may be substituted with R2.
[1-6] In the compounds represented by formula (I) of embodiment [1], X1 represents an oxygen atom, —NR3— (wherein R3 is a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)r— (wherein r is an integer of 0 to 2).
When R3 is a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterocyclic group, examples of the hydrocarbon group or the heterocyclic group include those listed in the “substituted or unsubstituted hydrocarbon groups” or the “substituted or unsubstituted heterocyclic groups”, respectively, in [1-1] mentioned above. These groups may be substituted with 1 to 3 “substituents” listed in (a) to (g).
When R3 is a “substituted or unsubstituted acyl group”, R3 is a group represented by —CO—Rg (wherein Rg is the same as the above) in (g) of [1-1] described above.
[1-6-a] In the compounds represented by formula (I) of embodiment [1], preferably, X1 is an oxygen atom or —NR3′— (wherein R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group all of which is defined in R3). More preferably, X1 is an oxygen atom.
[1-6-b] When X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ preferably include (1) C1-10 alkyl groups; (2) C2-6 alkenyl groups; (3) C2-6 alkynyl groups; (4) C3-9 cycloalkyl groups; (5) C3-6 cycloalkenyl groups; (6) C4-6 cycloalkanedienyl groups; (7) C6-14 aryl groups; and (8) heterocyclic groups each containing 1 to 4 hetero-atoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups, and each of the groups in (1) to (8) may be either unsubstituted or arbitrarily substituted with 1 to 5 substituents in a class selected from (a-1) to (g-1) described in [1-1-a] above.
When X1 is —NR3′—, examples of the “substituted or unsubstituted acyl group” of R3′ preferably include groups represented by —CO—Rg″ (wherein Rg″ represents a substituent RV (wherein RV represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, C7-10 aralkyl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the cycloalkyl, the aryl, the aralkyl, or the heterocyclic group may be further substituted with 1 to 5 substituents RIV of (f) described above).
[1-6-c] More preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (1′) C1-6 alkyl groups; (2′) C2-6 alkenyl groups; (41) C3-6 cycloalkyl groups; (7′) C6-14 aryl groups; and (8′) heterocyclic groups each containing 1 heteroatom or 2 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups, and each of the groups in (1′), (2′), (4′), (7′), and (8′) may be mono-substituted with a substituent in a class selected from the substituents (a-1) to (g-1) (in particular, the substituents listed as “particularly preferable groups” in (a-1) to (g-1)).
More preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted acyl group” of R3′ include groups represented by —CO—Rg′″ (wherein Rg′″ represents a substituent RV′ (wherein RV′ represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain 1 heteroatom or 2 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the cycloalkyl, the aryl, or the heterocyclic group may be further substituted with 1 to 5 substituents RIV of (f) described above).
[1-6-d] Further preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (1″) C1-6 alkyl groups; (4″) C3-6 cycloalkyl groups; (7″) C6-14 aryl groups; and (8″) heterocyclic groups each containing a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups, and each of the groups in (1″), (4″), (7″), and (8″) may be mono-substituted with a substituent in a class selected from the substituents (a-1) to (g-1) (in particular, the substituents listed as “particularly preferable groups” in (a-1) to (g-1)).
Further preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted acyl group” of R3′ include groups represented by —CO—Rg″″ (wherein Rg″″ represents a substituent RV″ (wherein RV″ represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the cycloalkyl, the aryl, or the heterocyclic group may be further substituted with 1 to 3 substituents RIV of (f) described above).
[1-6-e] Particularly preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (1′″) methyl and (1′″) ethyl, (4′″) cyclohexyl, (7′″) phenyl and (7′″) naphthyl (e.g., naphthalen-1-yl and naphthalen-2-yl), and (8′″) pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) which may be substituted with a halogen atom. More specifically, examples thereof include methyl, trifluoromethyl, ethyl, cyclohexyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, naphthalen-1-yl, naphthalen-2-yl, and 3-chloro-pyridin-2-yl.
Particularly preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted acyl group” of R3′ include groups represented by —CO—Rg′″″ (wherein Rg′″″ represents a substituent RV′″ (wherein RV′″ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heptyl, naphthyl, tetrahydropyran-4-yl, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), 2,2-dimethylpropyl, 2-methylpropyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,1-dimethylbutyl, 4,4-difluorocyclohexyl, 3-fluorocyclopentyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 4,4,4-trifluorobutyl, phenylmethyl, 1,1-difluoropropyl, and 1-fluoro-1-methylethyl; and the alkyl, the cycloalkyl, the aryl, or the heterocyclic group may be further substituted with a substituent RIV of (f) described above).
More specifically, examples of the groups represented by —CO-Rg′″″ include acyl groups which may be halogenated, such as acetyl, pentanoyl, 2-ethylbutanoyl, cyclohexanecarbonyl, 4-pyranoyl, benzoyl, nicotinoyl, cyclopentanecarbonyl, pentanoyl, cyclobutanecarbonyl, 3,3-dimethylbutanoyl, 3-methylbutanoyl, 4-methylpentanoyl, 3-methylpentanoyl, 2-methylpentanoyl, 2,2-dimethylpentanoyl, 4,4-difluorocyclohexanecarbonyl, 3-cyclopentanecarbonyl, 1-methylcyclopropanecarbonyl, 1-methylcyclobutanecarbonyl, 4,4,4-trifluorobutanoyl, 3,3,3-trifluoropropanoyl, 5,5,5-trifluoropentanoyl, 1-phenylacetyl, 2,2-difluorobutanoyl, and 2-fluoro-2-methylpropanoyl.
[1-7] X2 represents a methylene group, an oxygen atom, —NR4— (wherein R4 is a hydrogen atom, a C1-6 alkyl group (in particular, a C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl), or —S(O)r- (wherein r is an integer of 0 to 2).
[1-7-a] In the compounds represented by formula (I) of embodiment [1], X2 is preferably a methylene group or an —NH— group. More preferably, X2 is a methylene group.
[1-8] In the compounds represented by formula (I) of embodiment [1], r is an integer of 0 or 1. Preferably, r is 0.
[1-9] In the compounds represented by formula (I) of embodiment [1], examples of the Cycle moiety include the rings described as “aryl groups” in R1 and the five- to fourteen-membered rings, preferably five- to twelve-membered rings, containing at least one heteroatom (preferably, 1 to 4 heteroatoms) selected from N, O, and S in addition to the carbon atoms, which are described as “aromatic heterocyclic groups”.
[1-9-a] More preferably, examples of the Cycle moiety include monocyclic, five- or six-membered rings. A benzene ring and some of the groups described as examples of the monocyclic aromatic heterocyclic groups in R1 of embodiment [1-1] above correspond to such rings. Specific examples thereof include a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrrole ring, a thiophene ring, a furan ring, an Imidazole ring, a thiazole ring, and an isothiazole ring.
Regarding the condensation form of the monocyclic aromatic heterocyclic groups, at least one heteroatom is preferably located at positions selected from A1, A2, and A3, or B1, B2, and B3 in the following formulae. More preferably, at least one heteroatom is located at the position of A1 or B1.
[1-9-b] Zero to two R1's described above can be bonded to the Cycle moiety. More specifically, n represents an integer of 0 to 2. Preferably, n is an integer of 1 or 2, and more preferably, n is 1.
[1-9-c]
When n is 1, the substitution position of R1 corresponds to the 7th position of a chroman ring, a pyridochroman ring, a 2,3-dihydroquinoline ring, or the like, which belongs to a skeleton in which m=1 and q=0, or an isochroman ring or the like, which belongs to a skeleton in which m=0 and q=1. This position also corresponds to the 8th position of a 3,4-dihydrobenzo[b]oxepine ring or a 1,2,3,4-tetrahydrobenzo[b]azepine ring, which belongs to a skeleton in which m=2 and q=0, or a 3,4-dihydrobenzo[b]isooxepine ring or the like, which belongs to a skeleton in which m=1 and q=1. In the substitution positions of R1's, at least one of R1's is preferably a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy. More preferably, at least R1 bonded to A2 or B2 is a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy, and particularly preferably, trifluoromethyl.
[1-10] In the compounds represented by formula (I) of embodiment [1], j is 0 or 1, and preferably 0.
[1-11] In the compounds represented by formula (I) of embodiment [1], k is 0 to 2, and preferably 0 or 2, and more preferably 0.
When j or k is not 0 in the embodiments [1-10] and [1-11], i.e., when j=1 or k=1 or 2, carbon atoms defined by the number of j or k may be mono-substituted by the substituents indicated as “particularly preferable substituent” in the groups shown in (a-1) to (g-1) in the embodiment [1-a].
[1-12] In the compounds represented by formula (I) of embodiment (1), W represents a methylene group, a carboxyl group or a sulfonyl group. W represents preferably carboxyl group or a sulfonyl group. When w represents a methylene group, L1 is an oxygen atom and 2 is a —CR9AR9B—.
[1-13] In the compounds represented by formula (I) of embodiment [1], R7 represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted acyl group. When R7 is the substituted or unsubstituted hydrocarbon atom or the substituted or unsubstituted heterocyclic group, R7 has the same meaning with the “substituted or unsubstituted hydrocarbon group” and the “substituted or unsubstituted heterocyclic group” listed in the [1-1] mentioned above and these groups may be substituted by 1 to 3 “subsituents” listed in (a) to (g).
When R7 represents the “substituted or unsubstituted acyl group”, R7 means —CO—Rg (Rg has the same meaning mentioned above) of (g) in the [1-1] mentioned above.
[1-13-a] In the compounds represented by formula (I) of embodiment [1], R7 represents preferably a hydrogen atom, a substituted or unsubstituted hydrocarbon group, or a substituted or unsubstituted heterocyclic group.
[1-13-a-1] Examples of the “substituted or unsubstituted carbon hydrogen group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable R7 are:
(1) C1-10 alkyl group, (2) C2-6 alkenyl group or (3) C2-6 alkynyl group, (4) C3-9 cycloalkyl group, (5) C3-6 cycloalkenyl group, (6) C4-6 cylcoalcanedienyl group, (7) C6-14 aryl group, (8) any one of heterocyclic groups which contain 1 to 4 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom, the heterocyclic groups being selected from (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group. The above-mentioned (1) to (8) may be arbitrarily substituted with 1 to 5 substituents in the classes of the substitutents (a-1) to (g-1) in [1-1-a] mentioned above and the following.
[1-13-a-2] Preferable examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable R7 are: (1′) C1-10 alkyl group, (7′) C6-14 aryl group or (8′) any one of heterocyclic groups of (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
[1-13-b] In the compounds represented by formula (I) of embodiment [1], more preferably, R7 represents a hydrogen atom or (1′) C1-10 alkyl group, or (8′) any one of heterocyclic groups of (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
[1-13-c] In the compounds represented by formula (I) of embodiment [1], more preferably, R7 represents a hydrogen atom, or C1-6 alkyl group or tetrahydropyraniy (preferably teotrahydropyran-4-yl group) which may be mono- or di-substituted by a substituent such as halogen atom, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
[1-13-d] In the compounds represented by formula (I) of embodiment [1], particularly preferably, R7 represents a hydrogen atom, or C1-6 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxyl, mono/di C1-6 alkylamino, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
[1-13-d-1] Examples of the “C1-6 alkyl group” in the substituents of the particularly preferable R7 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec-butyl is preferable.
[1-13-e] In the compounds represented by formula (I) of embodiment [1], particularly preferably, R7 represents a hydrogen atom, or a methyl group, a ethyl group, a propyl group, isopropyl group, butyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl. More concretely, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl, sec-butyl, aminomethyl group, (2-)aminoethyl group, hydroxymethyl group, (2-)hydroxyethyl group, (3-)hydroxypropane-1-yl group, (4-)hydroxybuthyl group, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propane-2-yl group, 1-methyl-2-hydroxyethyl group, 2-hydroxy-propane-1-yl group, methoxyethyl group, (2-)ethoxyethyl group, (2-)N,N-dimethylaminoethyl group, (2-)N,N-diethylaminoethyl group, benzyl group, phenethyl group, oxiranylmethyl group, (2-)tetrahydrofuranylmethyl group etc. (Preferred embodiments are indicated in the parenthesis “( )”). The definition of R7 in the present embodiment [1-13-e] is the same as R7A described later in the present specification.
[1-14] In the compounds represented by formula (I) of embodiment [1], R8, R9A and R9B each independently represent a substituent arbitrarily selected from a hydrogen atom, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alky group, a protected or unprotected hydroxyl group, a protected or unprotected carboxyl group, a carbamoyl group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alky group, a C1-6 alkanoyl group, C1-6 alkylthio group, a C1-6 alkylsulfinyol group, C1-6 alkylsulfonyl group, a sulfamoyl group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alky group, a cyano group or a nitro group. Preferably, R8, R9A and R9B each independently represent a substituent selected from a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alky group, a protected or unprotected hydroxyl group. The definition of each substituent in R8, R9A and R9B has the same meaning as defined in the embodiment [1-1] mentioned above.
[1-14-a] In the compounds represented by formula (I) of embodiment [1], preferably, R8 represent a hydrogen atom, a substituted or unsubstituted C1-4 alky group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted C1-4 alkoxy group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-4 alkyl group. Example of non-aromatic substituents of “substituted or unsubstituted non-aromatic heterocyclic group” are azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, oxepanyl, thiomorpholinyl. These substituents arbitrarily substituted with 1 to 3 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
[1-14-a-1] Examples of more preferable R8 are a hydrogen atom, or a group selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an azetidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group or amino group which may be substituted by a substituted or unsubstituted C1-2 alkyl group. Each of these groups may be substituted by substituents such as C1-6 alkyl, halogen, amino, hydroxyl, C1-6 alkoxyl, mono-/di-C1-6 alkylamino, oxo which are listed in [1-1] mentioned above as “particularly preferable group”. Examples of substituents in “substituted or unsubstituted C1-2 alkyl” are halogen, amino, hydroxyl, C1-6 alkoxy, mono-/di-C1-6 alkylamino, oxo, 4-pyranoyl.
[1-14-a-2] Examples of further preferable R8 are, concretely, a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, 3-hydroxypropoxy group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, a 1-piperidinyl group, 4-oxo-1-piperidinyl group, a 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, a pyrrolidinyl group, a 3S-fluoro-pyrrolidinyl group, a 3S-hydroxypyrodinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group, a 2S-hydroxymethyl-pyrrolidinyl, a 2S-methoxymethyl-pyrrolidinyl group; an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-ethylmethylamino group, an N,N-bis(2-methoxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-(2-dimethylaminoethyl)amino, an N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl amino group, an N-methyl,N-(4-pyranoyl)amino.
[1-14-a-3] Particularly preferable R8 is hydrogen atom.
[1-14-b] In the compounds represented by formula (I) of embodiment [1], preferably, R9A and R9B are a substituent arbitrarily selected from the group of a hydrogen atom, a substituted or unsubstituted C1-4 alky group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, or an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-4 alky group. Non-aromatic substituents of the “substituted or unsubstituted non-aromatic heterocyclic group” have the same meaning as defined in the embodiment [1-1] mentioned above, and, for example, azetidinyl group, morpholinyl group, piperidinyl group, piperazinyl group, pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group and these substituents are arbitrarily substituted with 1 to 3 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
[1-14-b-1] R9A and R9B may be same or different, but more preferable R9A and R9B are a substituent selected from a group of a hydrogen atom, or a methyl group, an ethyl group, a methoxy group, an ethoxyl group, an azetidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group or amino group which may be substituted by a substituted or unsubstituted C1-2 alkyl group. These substituents are arbitrarily substituted with substituents listed as “particularly preferable substituent” in [1-1] mentioned above, for example, C1-6 alkyl, halogen, amino, hydroxyl, C1-6 alkoxyl group, mono-/di-C1-6 alkylamino, oxo. Examples of the substituents in “substituted or unsubstituted C1-2 alkyl” are halogen, amino, hydroxyl, C1-6 alkoxy, mono-/di-C1-6 alkylamino, oxo, 4-pyranoyl.
[1-14-b-2] Examples of further preferable R9A and R9B are, concretely, a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, a 1-piperidinyl group, 4-oxo-1-piperidinyl group, a 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, a pyrrolidinyl group, a 3S-fluoro-pyrrolidinyl group, a 3S-hydroxy-pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group, a 2S-hydroxymethyl-pyrrolidinyl, a 2S-methoxymethyl-pyrrolidinyl group; an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-ethylmethylamino group, an N,N-bis(2-methoxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-(2-dimethylaminoethyl)amino, an N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-(4-pyranoyl)amino.
[1-14-b-3] Particularly preferable R9A and R9B are hydrogen atom or methyl group when they are the; and one of them represents the hydrogen atom and the other presents a group (except the hydrogen atom) listed in [1-14-b-2] mentioned above.
[1-15] In the compound of formula (I) used for the compound of Embodiment [1], L1 and L2 each independently represent single bond, —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2), and L1 and L2 may be identical with or different from each other.
[1-15-a] Preferable L1 and L2 are as follows: in a case where L1 and L2 are identical with each other, they are selected from single bond or —CR9AR9B—, and in a case where L1 and L2 are different from each other, one is —CR9AR9B—, and the other is oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or S(O)t- (t is an integer of 0 to 2). When W represents a methylene group, L1 is an oxygen atom and L2 is a —CR9AR9B—.
[1-15-b] More preferable L1 and L2 are as follows: in a case where L1 is —CR9AR9B—, L2 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2). More preferable L1 and L2 are as follows: in a case where L2 is —CR9AR9B—, L1 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2). More specifically, in a case where the solid line and broken line between L1 and L2 are single bonds, the moiety of L1 and L2 can be represented by the following formula:
and it is more preferable that R9B is hydrogen atom. Further, in a case where the solid line and broken line between L1 and L2 are double bonds, the moiety of L1 and L2 can be represented by the following formula:
wherein L1′ and L2′ represent —CR9B═ or —N═.
[1-15-b-1] In these cases, preferable R9A and R9B can include hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperadinyl group, 4-methyl-piperadinyl group, pyrrolidinyl group, 3S-fluoro-pyrrolidinyl group, 3S-hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group, 2S-hydroxymethyl-pyrrolidinyl group, 2S-methoxymethyl-pyrrolidinyl group; N,N-dimethylamino group, N,N-diethylamino group, an N,N-ethylmethylamino group, N,N-bis(2-methoxyethyl)amino group, N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-cyclohexylamino group, N-methyl-N-(2-dimethylaminoethyl)amino group, N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-(4-pyranoyl)amino group, and the like that are mentioned in [1-14-b-2].
[1-15-c] Further preferable L1 and L2 are as follows: in a case where L2 is CR9AR9B—, L1 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2).
The solid line and broken line between L1 and L2 are single bonds or double bonds, the moiety of L1 and L2 can be represented by the following formula:
wherein L1′ represents —CR9B═ or —N═.
[1-15-c-1] In these cases, preferable R9A and R9B can include hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperadinyl group, 4-methyl-piperadinyl group, pyrrolidinyl group, 3S-fluoro-pyrrolidinyl group, 3S-hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group, 2S-hydroxymethyl-pyrrolidinyl group, 2S-methoxymethyl-pyrrolidinyl group; N,N-dimethylamino group, N,N-diethylamino group, an N,N-ethylmethylamino group, N,N-bis(2-methoxyethyl)amino group, N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-cyclohexylamino group, N-methyl-N-(2-dimethylaminoethyl)amino group, N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-(4-pyranoyl)amino group, and the like that are mentioned in [1-14-b-2].
More preferably R9B— in the L1 represents a hydrogen atom.
[1-15-d] Particularly preferable L1 and L2 are as follows: in a case where L1 is —CH2—, L2 is —CR9AH—, or L1 is —CH═, L2 is ═CR9A—. In this case, it is particularly preferable that R9A is morpholino group. For example, the solid line and broken line between L1 and L2 are single bonds or double bonds, and the moiety of L1 and L2 can be represented by the following formula:
[1-15-e] In L1 and L2, t is an integer of 0 to 2, and it is preferable that t is 0 or 2.
[1-15-f] In the L1 and L2, the case which represents the left partial structural formula in [ch.6] of the embodiment [1-10-b] is preferable, and particularly preferable L1 is —CH2— and L2 is —CH2— or —NH— in this case.
[1-16] In the compound of formula (I) used for the compound of Embodiment [1], R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group, or —S(O)t- (t is an integer of 0 to 2), which has the same meaning as that in the above-mentioned [1-13]. When R10 is the substituted or unsubstituted hydrocarbon atom or the substituted or unsubstituted heterocyclic group, R10 has the same meaning with the “substituted or unsubstituted hydrocarbon group” and the “substituted or unsubstituted heterocyclic group” listed in the [1-1] mentioned above and these groups may be substituted by 1 to 3 “subsituents” listed in (a) to (g).
When R10 represents the “substituted or unsubstituted acyl group”, R10 means —CO—Rg (Rg has the same meaning mentioned above) of (g) in the [1-1] mentioned above.
[1-16-a] In the compounds represented by formula (I) of embodiment [1], R10 represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group, or a substituted or unsubstituted heterocyclic group.
[1-16-a-1] Examples of the “substituted or unsubstituted carbonhydrogen group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable R10 are:
(1) C1-10 alkyl group, (2) C2-6 alkenyl group or (3) C2-6 alkynyl group, (4) C3-9 cycloalkyl group, (5) C3-6 cycloalkenyl group, (6) C4-6 cylcoalcanedienyl group, (7) C6-14 aryl group, (8) any one of heterocyclic groups of (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 4 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom. The above-mentioned (1) to (8) may be arbitrarily substituted with 1 to 5 substituents in the classes of the substitutents (a-1) to (g-1) in [1-1-a] mentioned above and the following.
[1-16-a-2] Preferable examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable 10 are: (1′) C1-10 alkyl group, (7′) C6-14 aryl group or (8′) any one of heterocyclic groups of (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
[1-16-b] In the compounds represented by formula (I) of embodiment [1], more preferably, R10 represents a hydrogen atom or (1′) C1-10 alkyl group, or (8′) any one of heterocyclic groups of (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
[1-16-c] In the compounds represented by formula (I) of embodiment [1], more preferably, R10 represents a hydrogen atom, or C1-6 alkyl group or tetrahydropyraniy (preferably teotrahydropyran-4-yl group) which may be mono- or di-substituted by a substituent such as halogen atom, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
[1-16-d] In the compounds represented by formula (I) of embodiment [1], particularly preferably, R10 represents a hydrogen atom, or C1-6 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxyl, mono/di C1-6 alkylamino, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
[1-16-d-1] Examples of the “C1-6 alkyl group” in the substituents of the particularly preferable R10 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-triethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec-butyl is preferable.
[1-16-e] In the compounds represented by formula (I) of embodiment [1], particularly preferably, R10 represents a hydrogen atom, or a methyl group, a ethyl group, a propyl group, isopropyl group, butyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl. More concretely, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl, sec-butyl, aminomethyl group, (2-)aminoethyl group, hydroxymethyl group, (2-)hydroxyethyl group, (3-)hydroxypropane-1-yl group, (4-)hydroxybuthyl group, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propane-2-yl group, 1-methyl-2-hydroxyethyl group, 2-hydroxy-propane-1-yl group, methoxyethyl group, (2-)ethoxyethyl group, (2-)N,N-dimethylaminoethyl group, (2-)N,N-diethylaminoethyl group, benzyl group, phenethyl group, oxiranylmethyl group, (2-)tetrahydrofuranylmethyl group etc. (Preferred embodiments are indicated in the parenthesis “( )”).
[1-16-f] Most preferable R10 includes hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group or methoxyethyl group.
[1-17] In the compounds represented by formula (I) in embodiment [1], solid line and broken line between L1 and L2 represents as a whole a single bond or a double bond, preferably a single bond.
[1-18]
In the compounds represented by formula (I) in embodiment [1], examples of group represented by formula (A) include more preferable group represented by formula (a).
(In formula (A), the definitions of k, j, t, W, R7, R8, R9A, R9B, R10, L1, and L2 are the same as those described in one of embodiments [1-10] to [1-17], and in formula (a), the definitions of k, j, t, W, R7, R8, R9A, R9B, R10, L1, and L2 are the same as those described in one of embodiments [1-10] to [1-17]).
In formula (A) and (a), the substitution position of —NH— or R8 may be any position of carbon atoms of G1 to G4 represented in the partial structural formula (wherein each of G1 to G4 is CH) below. —NH— is preferably bonded to the 1st position (G4) or 3rd position (G2) in the clockwise direction from the condensation position close to the L1. When —NH— is bonded to the carbon atom of G2 position, R8 is preferably bonded to the carbon atom of G4 position.
Specific examples of formula (a) are those described in the embodiments of [1-10] to [1-17], more specifically, further preferable examples of each substituents are amino groups described below or formula (a1) to (a141).
(2,2-dimethyl-4H-benzo[1,4]oxazin-3-on-5-yl)amino group, (2,2-dimethyl-4H-benzo[1,4]oxazin-3-on-6-yl)amino group, (2,2-dimethyl-4H-benzo[1,4]oxazin-3-on-7-yl)amino group, (2,2-dimethyl-4H-benzo[1,4]oxazin-3-on-8-yl)amino group, (2-methyl-4H-benzo[1,4]oxazin-3-on-5-yl)amino group, (2-methyl-4H-benzo[1,4]oxazin-3-on-6-yl)amino group, (2-methyl-4H-benzo[1,4]oxazin-3-on-7-yl)amino group, (2-methyl-4H-benzo[1,4]oxazin-3-on-8-yl)amino group, (2-(2-hydroxyethyl)-4H-benzo[1,4]oxazin-3-on-5-yl)amino group, (2-(2-hydroxyethyl)-4H-benzo[1,4]oxazin-3-on-6-yl)amino group, (2-(2-hydroxyethyl)-4H-benzo[1,4]oxazin-3-on-7-yl)amino group, (2-(2-hydroxyethyl)-4H-benzo[1,4]oxazin-3-on-8-yl)amino group, (2H-benzo[b][1,4]thiazin-3(4H)-on-5-yl)amino group, (2H-benzo[b][1,4]thiazin-3(4H)-on-6-yl)amino group, (2H-benzo[b][1,4]thiazin-3(4H)-on-7-yl)amino group, (2H-benzo[b][1,4]thiazin-3(4H)-on-8-yl)amino group, (1-oxo-2H-benzo[b][1,4]thiazin-3(4H)-on-5-yl)amino group, (1-oxo-2H-benzo[b][1,4]thiazin-3(4H)-on-6-yl)amino group, (1-oxo-2H-benzo[b][1,4]thiazin-3(4H)-on-7-yl)amino group, (1-oxo-2H-benzo[b][1,4]thiazin-3(4H)-on-8-yl)amino group, (1,1-dioxo-2H-benzo[b][1,4]thiazin-3(4H)-on-5-yl)amino group, (1,1-dioxo-2H-benzo[b][1,4]thiazin-3(4H)-on-6-yl)amino group, (1,1-dioxo-2H-benzo[b][1,4]thiazin-3(4H)-on-7-yl)amino group, (1,1-dioxo-2H-benzo[b][1,4]thiazin-3(4H)-on-8-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-6-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinone-7-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (4-methyl-3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (4-methyl-3,4-dihydro-2(1H)-quinoxalinon-6-yl)amino group, (4-methyl-3,4-dihydro-2(1H)-quinoxalinon-7-yl)amino group, (4-methyl-3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (3-hydroxymethyl-3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (3-hydroxymethyl-3,4-dihydro-2(1H)-quinoxalinon-6-yl)amino group, (3-hydroxymethyl-3,4-dihydro-2(1H)-quinoxalinon-7-yl)amino group, (3-hydroxymethyl-3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinoxalinon-6-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinoxalinon-7-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (3,3-dimethyl-4-methyl-3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (3,3-dimethyl-4-methyl-3,4-dihydro-2(1H)-quinoxalinon-6-yl)amino group, (3,3-dimethyl-4-methyl-3,4-dihydro-2(1H)-quinoxalinon-7-yl)amino group, (3,3-dimethyl-4-methyl-3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (1,4-dihydro-2H-3,1-benzoxazin-2-on-5-yl)amino group, (1,4-dihydro-2H-3,1-benzoxazin-2-on-6-yl)amino group, (1,4-dihydro-2H-3,1-benzoxazin-2-on-7-yl)amino group, (1,4-dihydro-2H-3,1-benzoxazin-2-on-8-yl)amino group, (3,4-dihydro-1H-qunazolin-2-on-5-yl)amino group, (3,4-dihydro-1H-qunazolin-2-on-6-yl)amino group, (3,4-dihydro-1H-qunazolin-2-on-7-yl)amino group, (3,4-dihydro-1H-qunazolin-2-on-8-yl)amino group, (3-methyl-3,4-dihydro-2 (1H)quinazolinon-5-yl)amino group, (3-methyl-3,4-dihydro-2 (1H)quinazolinon-6-yl)amino group, (3-methyl-3,4-dihydro-2(1H)quinazolinon-7-yl)amino group, (3-methyl-3,4-dihydro-2(1H)quinazolinon-8-yl)amino group, (3-(2-hydroxyethyl)-3,4-dihydro-2(1H)quinazolinon-5-yl)amino group, (3-(2-hydroxyethyl)-3,4-dihydro-2(1H)quinazolinon-6-yl)amino group, (3-(2-hydroxyethyl)-3,4-dihydro-2(1H)quinazolinon-7-yl)amino group, (3-(2-hydroxyethyl)-3,4-dihydro-2(1H)quinazolinon-8-yl)amino group, (3-(2-methoxyethyl)-3,4-dihydro-2(1H)quinazolinon-5-yl)amino group, (3-(2-methoxyethyl)-3,4-dihydro-2(1H)quinazolinon-6-yl)amino group, (3-(2-methoxyethyl)-3,4-dihydro-2(1H)quinazolinon-7-yl)amino group, (3-(2-methoxyethyl)-3,4-dihydro-2(1H)quinazolinon-8-yl)amino group, (3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiazin-5-yl)amino group, (3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiazin-6-yl)amino group, (3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiazin-7-yl)amino group, (3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiazin-8-yl)amino group, (3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (1-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (1-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (1-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (1-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (2H-benzo[1,4]oxazin-3(4H)-on-5-yl)amino group, (2H-benzo[1,4]oxazin-3(4H)-on-6-yl)amino group, (2H-benzo[1,4]oxazin-3(4H)-on-7-yl)amino group, (2H-benzo[1,4]oxazin-3(4H)-on-8-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-5-yl)amino group, (3,4-dihydro-2(11)-quinoxalinon-6-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-7-yl)amino group, (3,4-dihydro-2(1H)-quinoxalinon-8-yl)amino group, (3,4-dihydro-4-methyl-2(1H)-quinoxalinon-5-yl)amino group, (3,4-dihydro-4-methyl-2(1H)-quinoxalinon-6-yl)amino group, (3,4-dihydro-4-methyl-2(1H)-quinoxalinon-7-y) amino group, (3,4-dihydro-4-methyl-2(1H)-quinoxalinon-8-yl)amino group, (3,4-dihydroquinolin-2(1H)-on-5-yl)amino group, (3,4-dihydroquinolin-2(1H)-on-6-yl)amino group, (3,4-dihydroquinolin-2(1H)-on-7-yl)amino group, (3,4-dihydroquinolin-2(1H)—on-8-yl)amino group, (1-methyl-3,4-dihydroquinolin-2(1H)-on-5-yl)amino group, (1-methyl-3,4-dihydroquinolin-2(1H)-on-6-yl)amino group, (1-methyl-3,4-dihydroquinolin-2(1H)-on-7-yl)amino group, (1-methyl-3,4-dihydroquinolin-2(1H)-on-8-yl)amino group, (3-(hydroxymethyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(hydroxymethyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(hydroxymethyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(hydroxymethyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinolinon-5-yl)-amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3,3-dimethyl-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-morpholinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-morpholinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-morpholinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-morpholinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-methyl-1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-methyl-1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-methyl-1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-methyl-1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N,N-dimethylamino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N,N-dimethylamino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N,N-dimethylamino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N,N-dimethylamino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N,N-diethylamino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N,N-diethylamino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N,N-diethylamino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N,N-diethylamino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N,N-(bis(2-methoxydiethyl)amino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N,N-(bis(2-methoxydiethyl)amino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N,N-(bis(2-methoxydiethyl)amino)-3,4-dihydro-2(1H)quinolinon-7-yl)amino group, (3-(N,N-(bis(2-methoxydiethyl)amino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N-methyl-N-(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N-methyl-N-(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N-methyl-N-(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N-methyl-N-(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-((S)-3-fluoropyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-((S)-3-fluoropyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-((S)-3-fluoropyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-((S)-3-fluoropyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-((S)-3-hydroxypyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-((S)-3-hydroxypyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-((S)-3-hydroxypyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-((S)-3-hydroxypyrrolidin-1-yl)-3,4-dihydro-2(1H) quinolinon-8-yl)amino group, (3-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2 (1H)-quinolinon-5-yl)amino group, (3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(3-thiazolidinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(3-thiazolidinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(3-thiazolidinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(3-thiazolidinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N-methyl-N-cyclohexylamino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N-methyl-N-cyclohexylamino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N-methyl-N-cyclohexylamino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N-methyl-N-cyclohexylamino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(1-piperazinyl)-3,4-dihydro-2 (1)-quinolinon-6-yl)amino group, (3-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)-amino group, (3-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-([1,4]oxepan-4-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-([1,4]oxepan-4-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-([1,4] oxepan-4-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-([1,4]oxepan-4-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-oxo-piperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-oxo-piperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-oxo-piperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-oxo-piperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-hydroxypiperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-hydroxypiperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-hydroxypiperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-hydroxypiperidin-1-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-thiomorpholinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-thiomorpholinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-thiomorpholinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-thiomorpholinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(1,1-dioxothiomorpholin-4-yl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(1,1-dioxothiomorpholin-4-yl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(1,1-dioxothiomorpholin-4-yl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(1,1-dioxothiomorpholin-4-yl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(4-methoxy-1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(4-methoxy-1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(4-methoxy-1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(4-methoxy-1-piperidinyl)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-((S)-3-methoxy-1-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-((S)-3-methoxy-1-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-((S)-3-methoxy-1-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-((S)-3-methoxy-1-pyrrolidinyl-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, ((S)-2-methyl-4H-benzo[1,4]oxadin-3-on-5-yl-amino group, ((S)-2-methyl-4H-benzo[1,4]oxadin-3-on-6-yl)amino group, ((S)-2-methyl-4H-benzo[1,4]oxadin-3-on-7-yl)amino group, ((S)-2-methyl-4H-benzo[1,4]oxadin-3-on-8-yl)amino group, ((R)-2-methyl-4H-benzo[1,4]oxadin-3-on-5-yl)amino group, ((R)-2-methyl-4H-benzo[1,4]oxadin-3-on-6-yl)amino group, ((R)-2-methyl-4H-benzo[1,4]oxadin-3-on-7-yl)amino group, ((R)-2-methyl-4H-benzo[1,4]oxadin-3-on-8-yl)amino group, (3-(4-morpholinyl)quinolin-2(1H)-on-5-yl)amino group, (3-(4-morpholinyl)quinolin-2(1H)-on-6-yl)amino group, (3-(4-morpholinyl)quinolin-2(1H)-on-7-yl)amino group, (3-(4-morpholinyl)quinolin-2(1H)-on-8-yl)amino group, 3-(1-azetidinyl)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, 3-(1-azetidinyl)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, 3-(1-azetidinyl)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, 3-(1-azetidinyl)-3,4-dihydro-2 (1H)-quinolinon-8-yl)amino group, (3-(N-methyl-N-(2-(dimethylamino)ethyl)amino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N-methyl-N-(2-(dimethylamino)ethyl)amino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N-methyl-N-(2-(dimethylamino)ethyl)amino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N-methyl-N-(2-(dimethylamino)ethyl)amino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N-methyl-N-(hydroxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N-methyl-N-(hydroxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N-methyl-N-(hydroxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N-methyl-N-(hydroxyethyl)amino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (3-(N-methyl-N-(4-tetrahydropiranyl)amino)-3,4-dihydro-2(1H)-quinolinon-5-yl)amino group, (3-(N-methyl-N-(4-tetrahydropiranyl)amino)-3,4-dihydro-2(1H)-quinolinon-6-yl)amino group, (3-(N-methyl-N-(4-tetrahydropiranyl)amino)-3,4-dihydro-2(1H)-quinolinon-7-yl)amino group, (3-(N-methyl-N-(4-tetrahydropiranyl)amino)-3,4-dihydro-2(1H)-quinolinon-8-yl)amino group, (2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-5-yl)amino group, (2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-6-yl)amino group, (2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-7-yl)amino group, (2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-8-yl)amino group.
Further preferable examples of each substituents are formula (a1) to (a141).
Preferably, each of the groups (a1) to (a141) in the embodiment of [1-18] may be either unsubstituted or substituted with 1 to 2 substituents in a class selected from (a-1) to (g-1) described in [1-1-a] above, or arbitrarily exchanged for any of the substituent in (a1) to (a114).
Particularly preferable substituents include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen atoms, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, morpholinylcarbonyl, morpholinylsulfonyl, 5-trifluoromethylpyridin-2-yloxy, quinoxalin-2-yl, (pyridin-4-yl)methyl, 1,2,3-thiadiazolo-4-yl, 1H-pyrazolo-1-yl, and 4-chlorophenyl. The aromatic rings in these substituents may be substituted with a halogen atom, trifluoromethyl, cyano, hydroxyl, amino, nitro, carboxyl, carbamoyl, C1-6 alkyl, C1-6 alkoxy, mono/di C1-6 alkylamino, di-C1-6 alkylcarbamoyl, C1-6 alkoxycarbonyl, N—C1-6 alkylcarbamoyl, N,N-di C1-6 alkylcarbamoyl, or C2-6 alkenoylamino.
[1-19] The wavy line to which “CO—NH” in formula (I) of the present invention is bonded represents a bond of an E-isomer (anti-isomer or trans-isomer) or a Z-isomer (syn-isomer or cis-isomer). This means that the compounds represented by formula (I) include E-isomers(anti-isomer or trans-isomer) and Z-isomers(syn-isomer or cis-isomer). The compounds represented by formula (I) are preferably E-isomers(anti-isomer or trans-isomer). Hereinafter, wavy lines in formulae in this description represent the same meaning.
[1-20] In the compounds represented by formula (I) in embodiment [1], the ring containing X1 and X2 is preferably five- to eight-membered, more preferably six- or seven-membered. The ring containing W is preferably five- to eight-membered, more preferably five- to seven-membered, and most preferably five- or six-membered. When L1 and L2 are both single bond, W connects to the phenyl ring.
In the compounds represented by formula (I), preferable compounds can be determined by optional combinations of [1-1] to [1-20] described above. Examples of the compounds having specific combinations are described in [1-21].
[1-21] In formula (I),
R1 is a halogen atom, and (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (7) a C6-14 aryl group, and (9) a C1-6 alkoxy group. Each group in (1), (2), (7), and (9) is arbitrarily substituted with 1 to 3 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
More preferably, R1 is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), and a C1-6 alkyl group (in particular, C1-4 alkyl group) or C1-6 alkoxy group (in particular, C1-4 alkoxy group) which may be substituted with 1 to 3 halogen atoms.
More specifically, examples thereof include a fluorine atom, a chlorine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, and tetrafluoroethoxy.
Particularly preferably, R1 is a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy. Still more preferably, R1 is trifluoromethyl.
n is an integer of 0 to 2. Preferably, n is 1 or 2, and more preferably, n is 1.
R2 is a halogen atom, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, or an oxo group.
R2 is preferably a fluorine atom, a chlorine atom, an amino group which is arbitrarily mono-substituted with a substituent RIII, a C1-6 alkyl group which is arbitrarily mono-substituted with a group selected from a C1-6 alkoxy, amino and mono/di C1-6 alkylamino, or a phenyl group. More preferably, R2 is a C1-6 alkyl group which is arbitrarily mono-substituted with a group selected from a C1-6 alkoxy, amino and mono/di C1-6 alkylamino (in particular, a C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, methoxymethyl, 2-methoxyethyl). Further preferably, R2 is methyl, ethyl, methoxymethyl.
p is an integer of 0 to 2. Preferably, p is 0 or 2. However, in the compounds represented by formula (I), when R2 is a C1-6 alkyl group (in particular, a C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl), p is preferably 1 or 2, and more preferably 2 and is bonded to geminal position.
Alternatively, two geminal or vicinal R2 may bind to each other to form a C2-6 alkylene group respectively, and form a cyclo ring group together with the carbon atom to which the two R2 are bonded, or the cyclo ring group may form non-aromatic heterocyclic groups containing an oxygen atom or a nitrogen atom. Three to eight-membered rings are preferable. For example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, oxirane ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, aziridine ring, azetidine ring, pyrrolidine ring or piperazine ring can be formed.
When β2 is a fluorine atom, p is preferably 1 or 2, and more preferably 2. When R2 is an amino group which may be mono-substituted with a substituent RIII or an oxo group, p is preferably 1 or 2. m is 0 to 2, and preferably 1 or 2.
X1 represents an oxygen atom, —NR3′— (wherein R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or preferably, X1 is an oxygen atom.
When X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (1′) C1-6 alkyl groups; (2T) C2-6 alkenyl groups; (4′) C3-6 cycloalkyl groups; (71) C6-14 aryl groups; and (8′) heterocyclic groups each containing 1 heteroatom or 2 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) “three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups, and each of the groups in (1′), (21), (4′), (7′), and (8′) may be mono-substituted with a substituent in a class selected from the substituents (a-1) to (g-1) (in particular, the substituents listed as “particularly preferable groups” in (a-1) to (g-1)).
Examples of the “substituted or unsubstituted acyl group” of R3′ include groups represented by —CO—Rg′″ (wherein Rg′″ represents a substituent RV′ (wherein RV′ represents C1-6 alky, C3-6 cycloalkyl, C6-10 aryl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain 1 heteroatom or 2 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the aryl, or the heterocyclic group may be further substituted with 1 to 5 substituents RIV of (f) described above).
Further preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (7″) C6-14 aryl groups and (8″) heterocyclic groups each containing a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms, the heterocyclic groups being selected from (i) five- or six-membered, monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered, fused aromatic heterocyclic groups, and (iii) three- to eight-membered, saturated or unsaturated, non-aromatic heterocyclic groups, and each of the groups in (7″) and (8″) may be mono-substituted with a substituent in a class selected from the substituents (a-1) to (g-1) (in particular, the substituents listed as “particularly preferable groups” in (a-1) to (g-1)).
Examples of the “substituted or unsubstituted acyl group” of R3′ include groups represented by —CO—Rg″″ (wherein Rg″″ represents a substituent RV″ (wherein RV″ represents C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or a heterocyclic group; the heterocyclic group is any one of (i) five- or six-membered monocyclic aromatic heterocyclic groups, (ii) eight- to twelve-membered fused aromatic heterocyclic groups, and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic groups which contain a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the carbon atoms; and the alkyl, the cycloalkyl, the aryl, or the heterocyclic group may be further substituted with 1 to 3 substituents RIV of (f) described above).
Particularly preferably, when X1 is —NR3′—, examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” of R3′ include (1′″) methyl and (1′″) ethyl, (4′″) cyclohexyl, (7′″) phenyl and (7′″) naphthyl (e.g., naphthalen-1-yl and naphthalen-2-yl), and (8′″) pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) which may be substituted with a halogen atom. More specifically, examples thereof include methyl, trifluoromethyl, ethyl, cyclohexyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, naphthalen-1-yl, naphthalen-2-yl, and 3-chloro-pyridin-2-yl.
Examples of the “substituted or unsubstituted acyl group” include groups represented by —CO—Rg′″″ (wherein Rg′″″ represents a substituent RV′″ (wherein RV′″ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), 2,2-dimethylpropyl, 2-methylpropyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,1-dimethylbutyl, 4,4-difluorocyclohexyl, 3-fluorocyclopentyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 4,4,4-trifluorobutyl, phenylmethyl, 1,1-difluoropropyl, and 1-fluoro-1-methylethyl; and the alkyl, the cycloalkyl, the aryl, or the heterocyclic group may be further substituted with a substituent RIV of (f) described above).
More specifically, examples of the groups represented by —CO—Rg′″″ include acyl groups which may be halogenated, such as acetyl, pentanoyl, 2-ethylbutanoyl, cyclohexanecarbonyl, 4-pyranoyl, benzoyl, nicotinoyl, cyclopentanecarbonyl, pentanoyl, cyclobutanecarbonyl, 3,3-dimethylbutanoyl, 3-methylbutanoyl, 4-methylpentanoyl, 3-methylpentanoyl, 2-methylpentanoyl, 2,2-dimethylpentanoyl, 4(4-difluorocyclohexanecarbonyl, 3-fluorocyclopentanecarbonyl, 1-methylcyclopropanecarbonyl, 1-methylcyclobutanecarbonyl, 4,4,4-trifluorobutanoyl, 3,3,3-trifluoropropanoyl, 5,5,5-trifluoropentanoyl, 1-phenylacetyl, 2,2-difluorobutanoyl, and 2-fluoro-2-methylpropanoyl.
X2 is preferably a methylene group or an —NH— group. More preferably, X2 is a methylene group.
r is an integer of 0 or 1. Preferably, r is 0.
Examples of the Cycle moiety include monocyclic, five- or six-membered rings. Specific examples thereof include a benzene ring, a pyridine ring, a thiophene ring.
Zero to two R1's described above can be bonded to the Cycle moiety. More specifically, n represents an integer of 0 to 2. Preferably, n is an integer of 1 or 2, and more preferably, n is 1.
When n is 1, the substitution position of R1 corresponds to the 7th position of a chroman ring, a pyridochroman ring, a 2,3-dihydroquinoline ring, or the like, which belongs to a skeleton in which m=1 and q=0, or an isochroman ring or the like, which belongs to a skeleton in which m=0 and q=1. This position also corresponds to the 8th position of a 3,4-dihydrobenzo[b]oxepine ring or a 1,2,3,4-tetrahydrobenzo[b]azepine ring, which belongs to a skeleton in which m 2 and q=0, or a 3,4-dihydrobenzo[b]isooxepine ring or the like, which belongs to a skeleton in which m=1 and q=1. In the substitution positions of R1's, at least one of R1's is preferably a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy. More preferably, at least R1 bonded to A2 or B2 is a fluorine atom, a chlorine atom, isobutyl, tert-butyl, trifluoromethyl, or tetrafluoroethoxy, and particularly preferably, trifluoromethyl.
j is 0 or 1, and preferably 0.
k is 0 to 2, and preferably 0.
When j or k is not 0, i.e., when j=1 or k=1 or 2, carbon atoms defined by the number of j or k may be mono-substituted by the substituents indicated as “particularly preferable substituent” in the groups shown in (a-1) to (g-1) in the embodiment [1-a].
W represents a methylene group, a carboxyl group or a sulfonyl group. W represents preferably carboxyl group or a sulfonyl group. When w represents a methylene group, L1 is an oxygen atom and L2 is a —CR9AR9B—.
R7 represents hydrogen, a substituted or unsubstituted hydrocarbon group, or a substituted or unsubstituted heterocyclic group.
Examples of the “substituted or unsubstituted carbonhydrogen group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable R7 are:
(1) C1-10 alkyl group, (2) C2-6 alkenyl group or (3) C2-6 alkynyl group, (4) C3-9 cycloalkyl group, (5) C3-6 cycloalkenyl group, (6) C4-6 cylcoalcanedienyl group, (7) C6-14 aryl group, (8) any one of heterocyclic groups of (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 4 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom.
The above-mentioned (1) to (8) may be arbitrarily substituted with 1 to 5 substituents in the classes of the substitutents (a-1) to (g-1) in [1-1-a] mentioned above and the following.
Preferable examples of the “substituted or unsubstituted hydrocarbon group” or the “substituted or unsubstituted heterocyclic group” raised as the preferable R7 are:
(1′) C1-10 alkyl group, (7′) C6-14 aryl group or (8′) any one of heterocyclic groups of (i) five- to six-membered monocyclic aromatic heterocyclic groups (ii) eight- to twelve-membered fused aromatic heterocyclic groups and (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
More preferably, W represents a hydrogen atom or (1′) C1-10 alkyl group, or (8′) any one of heterocyclic groups of (iii) three- to eight-membered saturated or unsaturated non-aromatic heterocyclic group which contain 1 to 2 heterocarbon atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom other than carbon atom which may be mono- or di-substituted by substituents in the classes of the substitutents (a-1) to (g-1) (especially, the substituents listed as “particularly preferable”).
Example of the “substituted or unsubstituted hydrocarbon group” raised as more preferable R7 is:
(1′) C1-6 alkyl group which may be mono-substituted by substituents in the classes of the substitutents (a-1) to (g-1) in [1-1-a] (especially, the substituents listed as “particularly preferable”).
More preferably, R7 represents a hydrogen atom, or C1-6 alkyl group or tetrahydropyraniy (preferably teotrahydropyran-4-yl group) which may be mono- or di-substituted by a substituent such as halogen atom, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
Particularly preferably, R7 represents a hydrogen atom, or C1-6 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxyl, mono/di C1-6 alkylamino, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl.
Examples of the “C1-6 alkyl group” in the substituents of the particularly preferable R7 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec-butyl is preferable.
Particularly preferably, R7 represents a hydrogen atom, or a methyl group, a ethyl group, a propyl group, isopropyl group, butyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl. More concretely, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl, sec-butyl, aminomethyl group, (2-)aminoethyl group, hydroxymethyl group, (2-)hydroxyethyl group, (3-)hydroxypropane-1-yl group, (4-)hydroxybuthyl group, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propane-2-yl group, 1-methyl-2-hydroxyethyl group, 2-hydroxy-propane-1-yl group, methoxyethyl group, (2-)ethoxyethyl group, (2-)N,N-dimethylaminoethyl group, (2-)N,N-diethylaminoethyl group, benzyl group, phenethyl group, oxiranylmethyl group, (2-)tetrahydrofuranylmethyl group etc. (Preferred embodiments are indicated in the parenthesis “( )”). The definition of R7 in this embodiment described as “Particularly preferably’ is the same as R7A described later in the present specification.
Preferably, R8, R9A and R9B each independently represent a substituent selected from a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-6 alky group, a protected or unprotected hydroxyl group. The definition of each substituent in R8, R9A and R9B has the same meaning as defined in the embodiment [1-1] mentioned above.
Preferably, R8 represents a hydrogen atom, a substituted or unsubstituted C1-4 alky group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted C1-4 alkoxy group, an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-4 alkyl group. Example of non-aromatic substituents of “substituted or unsubstituted non-aromatic heterocyclic group” are azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, oxepanyl, thiomorpholinyl. These substituents arbitrarily substituted with 1 to 3 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
Examples of more preferable R8 are a hydrogen atom, or a group selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an azetidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group or amino group which may be substituted by a substituted or unsubstituted C1-2 alkyl group. Each of these groups may be substituted by substituents such as C1-6 alkyl, halogen, amino, hydroxyl, C1-6 alkoxyl, mono-/di-C1-6 alkylamino, or oxo which are listed in [1-1] mentioned above as “particularly preferable group”. Examples of substituents in “substituted or unsubstituted C1-2 alkyl” are halogen, amino, hydroxyl, C1-6alkoxy, mono-/di-C1-6 alkylamino, oxo, 4-pyranoyl.
Examples of further preferable R8 are, concretely, a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, 3-hydroxypropoxy group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, a 1-piperidinyl group, 4-oxo-1-piperidinyl group, a 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, a pyrrolidinyl group, a 3S-fluoro-pyrrolidinyl group, a 3S-hydroxypyrodinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group, a 2S-hydroxymethyl-pyrrolidinyl, a 2S-methoxymethyl-pyrrolidinyl group; an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-ethylmethylamino group, an N,N-bis(2-methoxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-(2-dimethylaminoethyl)amino, an N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-(4-pyranoyl)amino.
Particularly preferable R8 represents hydrogen atom.
Preferably, R9A and R9B are a substituent arbitrarily selected from the group of a hydrogen atom, a substituted or unsubstituted C1-4 alky group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted C1-6 alkoxy group, or an amino group which may be mono- or di-substituted by a substituted or unsubstituted C1-4 alky group. Non-aromatic substituents of the “substituted or unsubstituted non-aromatic heterocyclic group” have the same meaning as defined in the embodiment [1-1] mentioned above, and, for example, azetidinyl group, morpholinyl group, piperidinyl group, piperazinyl group, pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group and these substituents are arbitrarily substituted with 1 to 3 substituents in a class selected from (a-1) to (g-1) in [1-1] described above (in particular, the substituents listed as “particularly preferable groups”).
R9A and R9B may be same or different, but more preferable R9A and R9B are a substituent selected from a group of a hydrogen atom, or a methyl group, an ethyl group, a methoxy group, an ethoxyl group, an azetidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group or amino group which may be substituted by a substituted or unsubstituted C1-2 alkyl group. These substituents are arbitrarily substituted with substituents listed as “particularly preferable substituent” in [1-1] mentioned above, for example, C1-6 alkyl, halogen, amino, hydroxyl, C1-6 alkoxyl group, mono-/di-C1-6 alkylamino, oxo. Examples of the substituents in “substituted or unsubstituted C1-2 alkyl” are halogen, amino, hydroxyl, C1-6 alkoxy, mono-/di-C1-6 alkylamino, oxo, 4-pyranoyl.
Examples of further preferable R9A and R9B are, concretely, a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, a 1-piperidinyl group, 4-oxo-1-piperidinyl group, a 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, a pyrrolidinyl group, a 3S-fluoro-pyrrolidinyl group, a 3S-hydroxy-pyrrolidinyl group, a thiazolinyl group, an oxepanyl group, a thiomorpholinyl group, a 2S-hydroxymethyl-pyrrolidinyl, a 2S-methoxymethyl-pyrrolidinyl group; an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-ethylmethylamino group, an N,N-bis(2-methoxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-(2-dimethylaminoethyl)amino, an N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, an N-methyl-N-(4-pyranoyl)amino.
Particularly preferable R9A and R9B are hydrogen atom or methyl group when they are the same; and one of them represents the hydrogen atom and the other presents a group (except the hydrogen atom) listed in [1-14-b-2] mentioned above.
L1 and L2 each independently represent single bond, —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2), and L1 and L2 may be identical with or different from each other.
Preferable L1 and L2 are as follows: in a case where L1 and L2 are identical with each other, they are each independently single bond or —CR9AR9B—, and in a case where L1 and L2 are different from each other, one is —CR9AR9B—, and the other is oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2). When w represents a methylene group, L1 is an oxygen atom and L2 is a —CR9AR9B—.
More preferable L1 and L2 are as follows: in a case where L1 is —CR9AR9B—, L2 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2). More preferable L1 and L2 are as follows: in a case where L2 is —CR9AR9B—, L1 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or —S(O)t- (t is an integer of 0 to 2).
More specifically, in a case where the solid line and broken line between L1 and L2 are single bonds, the moiety of L1 and L2 can be represented by the following formula:
and it is more preferable that R9B is hydrogen atom. Further, in a case where the solid line and broken line between L1 and L2 are double bonds, the moiety of L1 and L2 can be represented by the following formula:
wherein L1′ and L2′ represent —CR9B═ or —N═.
In these cases, preferable R9A and R9B can include hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperadinyl group, 4-methyl-piperadinyl group, pyrrolidinyl group, 3S-fluoro-pyrrolidinyl group, 3S-hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group, 2S-hydroxymethyl-pyrrolidinyl group, 2S-methoxymethyl-pyrrolidinyl group; N,N-dimethylamino group, N,N-diethylamino group, an N,N-ethylmethylamino group, N,N-bis(2-methoxyethyl)amino group, N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-cyclohexylamino group, N-methyl-N-(2-dimethylaminoethyl)amino group, N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-(4-pyranoyl)amino group, and the like that are mentioned in [1-14-b-2].
Further preferable L1 and L2 are as follows: in a case where L2 is —CR9AR9B—, L1 is —CR9AR9B—, oxygen atom, —NR10— (R10 represents hydrogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group), or S(O)t- (t is an integer of 0 to 2).
The solid line and broken line between L1 and L2 are single bonds or double bonds, the moiety of L1 and L2 can be represented by the following formula:
wherein L1′ represents —CR9B═ or —N═.
In these cases, preferable R9A and R9B can include hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4,4-difluoro-1-piperidinyl group, 1-piperadinyl group, 4-methyl-piperadinyl group, pyrrolidinyl group, 3S-fluoro-pyrrolidinyl group, 3S-hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group, 2S-hydroxymethyl-pyrrolidinyl group, 2S-methoxymethyl-pyrrolidinyl group; N,N-dimethylamino group, N,N-diethylamino group, an N,N-ethylmethylamino group, N,N-bis(2-methoxyethyl)amino group, N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-cyclohexylamino group, N-methyl-N-(2-dimethylaminoethyl)amino group, N-methyl-N-(2-hydroxyethyl)amino group, an N-methyl-N-(2-methoxyethyl)amino group, N-methyl-N-(4-pyranoyl)amino group, and the like that are mentioned in [1-14-b-2]. More preferably, R9B in L2′ is hydrogen atom.
Particularly preferable L1 and L2 are as follows: in a case where L1 is —CH2—, L2 is —CR9AH—, or L1 is —CH═, L2 is CR9A—. In this case, it is particularly preferable that R9A is morpholino group. For example, the solid line and broken line between L1 and L2 are single bonds or double bonds, and the moiety of L1 and L2 can be represented by the following formula:
In L1 and L2, t is an integer of 0 to 2, and it is preferable that t is 0 or 2.
In the L1 and 2, the case which represents the left partial structural formula in [ch.6] of the embodiment [1-10-b] is preferable, and particularly preferable L1 is —CH2— and L2 is —CH2— or —NH— in this case.
Preferable R10 includes a hydrogen atom, or C1-6 alkyl group or tetrahydropyraniy (preferably teotrahydropyran-4-yl group) which may be mono- or di-substituted by a substituent such as halogen atom, halogenated C1-6 alkyl, cyano, amino, hydroxyl, carbamoyl, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, mono/di C1-6 alkylamino, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoylamino, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carbamoyl-C1-6 alkyl, N—C1-6 alkylcarbamoyl-C1-6 alkyl, N,N-di C1-6 alkylcarbamoyl-C1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl and the like.
More preferable R10 includes a hydrogen atom, or C1-6 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxyl, mono/di C1-6 alkylamino, morpholino, piperazino, oxo, oxiranyl, or tetrahydrofuryl and the like.
“C1-6 alkyl group” in the substituents of the particularly preferable R10 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec-butyl is preferable.
Particularly preferably, R10 represents a hydrogen atom, or a methyl group, a ethyl group, a propyl group, isopropyl group, butyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl. More concretely, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl, sec-butyl, aminomethyl group, (2-)aminoethyl group, hydroxymethyl group, (2-)hydroxyethyl group, (3-)hydroxypropane-1-yl group, (4-)hydroxybuthyl group, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propane-2-yl group, 1-methyl-2-hydroxyethyl group, 2-hydroxy-propane-1-yl group, methoxyethyl group, (2-)ethoxyethyl group, (2-)N,N-dimethylaminoethyl group, (2-)N,N-diethylaminoethyl group, benzyl group, phenethyl group, oxiranylmethyl group, (2-)tetrahydrofuranylmethyl group etc. (Preferred embodiments are indicated in the parenthesis “( )”).
Most preferable R10 includes hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group or methoxyethyl group.
The arylamine group in formula (I) is represented by formula (A):
(wherein the definitions of k, j, t, W, R7, R8, R9A R9B, R10, L1 and L2 are the same as those described in one of embodiments [1-1] to [1-17]), and preferably, formula (a):
(wherein the definitions of k, j, t, W, R7, R8, R9A, R9B, R10, L1 and L2 are the same as those described in one of embodiments [1-10] to [1-17]), in formula (A) and formula (a), —NH— or R8 is bonded to the positions of G1 to G4 of the phenyl moiety described below. —NH— is preferably bonded to the first position (G4) or third position (G2) in the clockwise direction from the condensation position close to the L1. When —NH— is bonded to the G2 position, R8 is preferably bonded to the G4 position.
Preferable examples of each substituents are the as those described previously in embodiment of [1-10] to [1-17], more specifically, formula (a) represents formula (a1) to (a141) described below.
The wavy line to which “CO—NH” in formula (I) of the present invention bonded represents a bond of an E-isomer (anti-isomer or trans-isomer) or a Z-isomer (syn-isomer or cis-isomer). This means that the compounds represented by formula (I) include E-isomers(anti-isomer or trans-isomer) and Z-isomers(syn-isomer or cis-isomer). The compounds represented by formula (I) are preferably E-isomers(anti-isomer or trans-isomer). Hereinafter, wavy lines in formulae in this description represent the same meaning.
In the compounds represented by formula (I) in embodiment [1], the ring containing X1 and X2 is preferably five- to eight-membered, more preferably six- or seven-membered. The ring containing W is preferably five- to eight-membered, more preferably five- to seven-membered, and most preferably five- or six-membered. When L1 and L2 are both single bond, W connects to the phenyl ring.
Examples of preferable compounds include:
and the compound described below example 58-313; or
examples of pharmaceutically acceptable salts thereof, solvate thereof and optical isomers thereof.
More preferably, the compound of the group A, B, C or D described below.
The compounds of EXAMPLE 9, 13, 14, 15, 23, 26, 28, 30, 33, 34, 35, 40, 45, 53, 59, 64, 65, 74, 77, 81, 88, 89, 93, 94, 95, 107, 109, 110, 112, 113, 114, 115, 151, 154, 161, 180, 181, 182, 183, 196, 200, 210, 211, 212, 213, 305 and 311.
The compounds of EXAMPLE 61, 62, 73, 75, 76, 78, 79, 80, 82, 93, 96, 97, 117, 118, 119, 134, 136, 137, 138, 139, 140, 141, 152, 153, 162, 163, 176, 187, 188, 189, 191 and 193.
The compounds of EXAMPLE 66, 68, 69, 70, 84, 85, 87, 106, 108, 120, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 142, 143, 144, 145, 146, 147, 148, 149, 150, 156, 157, 158, 164, 167, 168, 172, 173, 174, 177, 179, 190, 200, 202, 203, 208, 209, 310, 312 and 313.
The compound of the group A or B is Further preferable, the compound of the group A is Particularly preferable. These preferable compounds of group A, B, C, or D also include pharmaceutically acceptable salts thereof, solvate thereof and optical isomers thereof.
[1-22] In the compounds represented by formula (I) in embodiment [1], examples of more preferable compounds include compounds represented by formula (I-A).
In the compounds represented by formula (I-A), A1, A2, A3 and A4 represents each independently —N═ or —CH═, and R1, R2, X1, X2, m, n, p, q, R7, R8, W, L1, L2, j, k, and t are the same as those described in one of embodiments [1-1] to [1-20], preferably the same as those described in [1-21]. The wavy line to which “CO—NH” in formula (I-A) of the present invention is bonded preferably represents a bond of an E-isomer (anti-isomer or trans-isomer). Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-A-1). When q is 1, the compounds can be represented by formula (I-A-2). Preferable formula (A) in formula (I-A), an arylamine group, is represented by formula (a) or (a1) to (a141) as those described in embodiment of [1-18].
[1-23] In the compounds represented by formula (I) in embodiment [1], examples of more preferable compounds represented by formula (I-A) include compounds represented by formula (I-B).
In formula (I-B), A1 represents —N═ or —CH═, m′ is an integer of 1 or 2, the definitions in of R1, R2, X1, X2, m, n, p, q, R7, R8, W, L1, L2, j, k and t are the same as those described in one of embodiments [1-1] to [1-20]1, and preferably, the same as the definitions in embodiment [1-21]. The wavy line to which “CO—NH” in formula (I-B) of the present invention is bonded preferably represents a bond of an E-isomer (anti-isomer or trans-isomer). Here, m′ is an integer of 1 or 2. When m′ is 1, the compounds can be represented by formula (I-B-1). When m′ is 2, the compounds can be represented by formula (I-B-2). Preferable formula (A) in formula (I-B), an arylamine group, is represented by formula (a) or (a1) to (a141) as those described in embodiment of [1-18].
[1-24] In the compounds represented by formula (I) in embodiment [1], examples of more preferable compounds represented by formula (I-B) include compounds represented by formula (I-C).
In formula (I-C), R1A represents hydrogen or R1 described before, m′ is an integer of 1 or 2, and the definitions of R1, R2, X1, X2, R7, R8, W, L1, L2, j, k, and p are the same as those described in one of embodiments [1-1] to [1-20], and preferably, the same as the definitions in embodiment [1-21]. The wavy line to which “CO—NH” in formula (I-C) of the present invention is bonded preferably represents a bond of an E-isomer (anti-isomer or trans-isomer). Here, m′ is an integer of 1 or 2. When m′ is 1, the compounds can be represented by formula (I-C-1). When m′ is 2, the compounds can be represented by formula (I-C-2). Preferable formula (A) in formula (I-C), an arylamine group, is represented by formula (a) or (a1) to (a141) as those described in embodiment of [1-18].
In formula (I-C), formula (B):
(wherein, definitions of R1A, m′, R1, R2, X1, and X2 are the same as those described above), further preferable examples of each substituents are the same as those described previously in embodiment of [1-1] to [1-9], more specifically, formula (b1) to (b18) described below.
[1-25] In the compounds represented by formula (I) in embodiment [1], examples of more preferable compounds include compounds represented by formula (I-D).
In the compounds represented by formula (I-D), A1, A2, A3 and A4 represents each independently —N═ or —CH═, and R1, R2, X1, X2, m, n, p, q, R7, R8, W, L1, and L2 are the same as those described in one of embodiments [1-1] to [1-20], preferably the same as those described in [1-21], and the solid line and the broken line between L1 and L2 is a single bond or double bond.
The wavy line to which “CO—NH” in formula (I-D) of the present invention is bonded preferably represents a bond of an E-isomer (anti-isomer or trans-isomer). Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-D-1). When q is 1, the compounds can be represented by formula (I-D-2). Preferable in formula (I-D), an arylamine group is represented by formula (a1) to (a14) as those described in embodiment of [1-18].
[1-26] In the compounds represented by formula (I) in embodiment [1], examples of more preferable compounds include compounds represented by formula (I-E).
In the compounds represented by formula (I-E), R2A and R2B are, independently, a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom; X2A represents a methylene group, an ethylene group or —NH—, and q, R7, R8, W, L1, and L2 are the same as those described in one of embodiments [1-1] to [1-20], preferably the same as those described in [1-21], and the solid line and the broken line between L1 and L2 is a single bond or double bond.
The wavy line to which “CO—NH” in formula (I-E) of the present invention is bonded preferably represents a bond of an E-isomer (anti-isomer or trans-isomer). Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-E-1). When q is 1, the compounds can be represented by formula (I-E-2). Preferable in formula (I-E), an arylamine group is represented by formula (a1) to (a141) as those described in embodiment of [1-18].
[1-27] In the compounds represented by formula (I-A) in embodiment [1-22], examples of more preferable compounds represented by formula (I-F) include compounds represented by formula (I-A).
In the compounds represented by formula (I-F), wherein q is an integer of 0 or 1; R7A represents a hydrogen atom, or C1-4 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl;
WA represents a carbonyl group or a sulfonyl group;
L2A represents a methylene group, or —NH—;
X2A represents a methylene group, an ethylene group or —NH—;
R2A and R2B are, independently, a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom;
and q, WA, X2A, L2A, R2A and R2B are the same as q, W, X2, L2 and R2 described in one of embodiments [1-1] to [1-20], preferably the same as those described in [1-21].
Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-F-1). When q is 1, the compounds can be represented by formula (I-F-2).
[1-28] In the compounds represented by formula (I-F) in embodiment [1-27], examples of more preferable compounds represented by formula (I-G) include compounds represented by formula (I-F).
In the compounds represented by formula (I-G), wherein q is an integer of 0 or 1; R7A represents a hydrogen atom, or C1-4 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl;
X2A represents a methylene group, an ethylene group or —NH—;
R2A and R2B are, independently, a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom; Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-G-1). When q is 1, the compounds can be represented by formula (I-G-2).
[1-28-1] In a compound of formula (I-G), more preferably, R7A represents a hydrogen atom, or C1-4 alkyl group. Further preferably, R7A represents a C1-2 alkyl group, for example, a methyl group or an ethyl group.
[1-28-2] In a compound of formula (I-G), R2A and R2B, respectively, represent a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom.
As used herein, examples of the C1-2 alkoxy group may include a methoxy group or an ethoxy group. Examples of the C1-4 alkyl group may include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc.
In the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom”, the cyclic ring includes, specifically, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, etc.
[1-28-2-a] More preferably, R2A and R2B, independently to each other, are a hydrogen atom or a C1-2 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, and specifically, include a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group and an ethoxyethyl group. In addition, in the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom”, the cyclic ring is more preferably, for example, a cyclobutane ring, an oxetane ring, a tetrahydropyran ring, etc.
[1-28-2-b] Further preferably, R2A and R2B are the same, and are a hydrogen atom or a C1-2 alkyl group optionally substituted with a C1-2 alkoxy group, and specifically include, a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group and an ethoxyethyl group. In addition, in the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom,” the cyclic ring is further preferably, for example, a cyclobutane ring, a tetrahydropyran ring, etc.
[1-28-2-c] Particularly preferably, R2A and R2B are the same, and are a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group or a methoxyethyl group. In addition, particularly preferably, R2A and R2B, together with the carbon atom to which they are bound, form a 4- to 6-membered cyclic ring that may contain one oxygen atom, for example, a tetrahydropyran ring.
[1-28-3] In a compound of formula (I-G), X2A is a methylene group, an ethylene group or —NH—.
[1-28-3-a] Preferably, X2A represents is a methylene group, an ethylene group or —NH—.
[1-28-3-b] When q is 0, X2A is preferably a methylene group, an ethylene group or —NH—. In addition, when q is 1, X2A is preferably a methylene group.
[1-28-4] Among the compounds of formula (I-G) in Embodiment [1-28], examples of more preferable compounds include compounds of formulae (I-G-a) to (I-G-h).
[1-29] In the compounds represented by formula (I-F) in embodiment [1-27], examples of more preferable compounds represented by formula (I-H) include compounds represented by formula (I-F).
In the compounds represented by formula (I-H), wherein q is an integer of 0 or 1; R7A represents a hydrogen atom, or C1-4 alkyl group which may be mono- or di-substituted by a substituent such as amino, hydroxyl, C1-6 alkoxy, mono/di C1-6 alkylamino, phenyl; X2A represents a methylene group, an ethylene group or —NH—; R2A and R2B are, independently, a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom; Here, q is an integer of 0 or 1. When q is 0, the compounds can be represented by formula (I-H-1). When q is 1, the compounds can be represented by formula (I-H-2).
[1-29-1] In a compound of formula (I-H), more preferably, R7A represents a hydrogen atom, or C1-4 alkyl group. Further preferably, R7A represents a C1-2 alkyl group, for example, a methyl group or an ethyl group.
[1-29-2] In a compound of formula (I-H), R2A and R2B, respectively, represent a hydrogen atom or a C1-4 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, or R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom.
As used herein, examples of the C1-2 alkoxy group may include a methoxy group or an ethoxy group. Examples of the C1-4 alkyl group may include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc.
In the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom”, the cyclic ring includes, specifically, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, etc.
[1-29-2-a] More preferably, R2A and R2B, independently to each other, are a hydrogen atom or a C-2 alkyl group optionally substituted with a hydroxyl group or a C1-2 alkoxy group, and specifically, include a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group and an ethoxyethyl group. In addition, in the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom”, the cyclic ring is more preferably, for example, a cyclobutane ring, an oxetane ring, a tetrahydropyran ring, etc.
[1-29-2-b] Further preferably, R2A and R2B are the same, and are a hydrogen atom or a C1-2 alkyl group optionally substituted with a C1-2 alkoxy group, and specifically include, a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group and an ethoxyethyl group. In addition, in the case where “R2A and R2B, together with the carbon atom to which they are bound, may form a 4- to 6-membered cyclic ring that may contain one oxygen atom,” the cyclic ring is further preferably, for example, a cyclobutane ring, a tetrahydropyran ring, etc.
[1-29-2-c] Particularly preferably, R2A and R2B are the same, and are a hydrogen atom, a methyl group, an ethyl group, a methoxymethyl group or a methoxyethyl group. In addition, particularly preferably, R2A and R2B, together with the carbon atom to which they are bound, form a 4- to 6-metered cyclic ring that may contain one oxygen atom, for example, a tetrahydropyran ring.
[1-29-3] In a compound of formula (I-H), X2A is a methylene group, an ethylene group or —NH—.
[1-29-3-a] Preferably, X2A represents is a methylene group, an ethylene group or —NH—.
[1-29-3-b] When q is 0, X2A is preferably a methylene group, an ethylene group or —NH—. In addition, when q is 1, X2A is preferably a methylene group.
[2] A second embodiment of the present invention provides a pharmaceutical composition comprising the compounds represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof as an active ingredient.
More specifically, the following embodiments are preferred.
[2-1] An embodiment 2-1 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-A), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[2-2] An embodiment 2-2 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-B), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[2-3] An embodiment 2-3 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-C), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[2-4] An embodiment 2-4 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-D), (I-E), (I-F), (I-G) or (I-H), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[2-5] An embodiment 2-5 of the present invention provides a pharmaceutical composition comprising at least one of the compounds described as the preferable compounds in embodiment [1-21], pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[3] A third embodiment of the present invention provides a pharmaceutical composition comprising the compounds represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof as TRPV1 receptor antagonists.
More specifically, the following embodiments are preferred.
[3-1] An embodiment 3-1 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-A), pharmaceutically acceptable salts thereof, or solvates thereof as TRPV1 receptor antagonists.
[3-2] An embodiment 3-2 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-B), pharmaceutically acceptable salts thereof, and solvates thereof as TRPV1 receptor antagonists.
[3-3] An embodiment 3-3 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-C), pharmaceutically acceptable salts thereof, and solvates thereof as TRPV1 receptor antagonists.
[3-4] An embodiment 3-4 of the present invention provides a pharmaceutical composition comprising at least one of the compounds represented by formula (I-D), (I-E), (I-F), (I-G) or (I-H), pharmaceutically acceptable salts thereof, and solvates thereof as TRPV1 receptor antagonists.
[3-5] An embodiment 3-5 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds described as the preferable compounds in embodiment [1-21], pharmaceutically acceptable salts thereof, and solvates thereof as TRPV1 receptor antagonists.
In this description, in particular, in the third embodiment of the present invention, the “TRPV1 receptor antagonist” is an embodiment of a “TRPV1 receptor modulator”. The term “TRPV1 receptor modulator” means an agent comprising a compound that modulates the function of the TRPV1 receptor. More specifically, the term “TRPV1 receptor modulator” means an agent comprising a compound that suppresses activation of the TRPV1 receptor. The compound may be a compound (TRPV1 receptor antagonist) that binds to the TRPV1 receptor and that antagonizes an endogenous ligand, thereby suppressing activation of the TRPV1 receptor, or a compound (TRPV1 receptor agonist) that continuously activates the TRPV1 receptor and that desensitizes nerves in which the receptor is present, thereby suppressing activation of the receptor thereafter. Accordingly, the term “TRPV1 receptor modulator” is a generic name for the TRPV1 receptor antagonists and the TRPV1 receptor agonists.
Antagonists include neutral antagonists and inverse agonists, and agonists include full agonists and partial agonists. Partial agonists show the action of antagonists in some conditions.
The TRPV1 receptor modulator of the present invention is preferably a TRPV1 receptor antagonist. The TRPV1 antagonists of the present invention include neutral antagonists, inverse agonists and partial agonist. It is expected that the TRPV1 antagonist of the present invention has a promising effect of preventing or trating various diseases and conditions. Examples thereof include acute pain; chronic pain; neuropathic pain; fibromyalgia; postherpetic neuralgia; trigeminal neuralgia; lower-back pain; pain after spinal cord injury; leg pain; causalgia; diabetic neuralgia; pain caused by edema, burns, sprains, bone fractures, and the like; pain after surgical operations; scapulohumeral periarthritis; osteoarthritis; arthritis; rheumatic arthritis pain; inflammatory pain; cancer pain; migraines; headaches; toothaches; neuralgia; muscle pain; hyperalgesia; pain caused by angina pectoris, menstruation, and the like; neuropathy; nerve damage; neurodegeneration; chronic obstructive pulmonary disease (COPD); asthma; airway hypersensitivity; stridor; cough; rhinitis; inflammation of mucosa such as eyes; nervous dermatitis; inflammatory skin complaint such as psoriasis and eczema; edema; allergic diseases; gastroduodenal ulcer; ulcerative colitis; irritable colon syndrome; Crohn disease; urinary incontinence; urge urinary incontinence; overactive bladder; cystitis; nephritis; pancreatitis; uveitis; splanchnopathy; ischemia; apoplexy; dystonia; obesity; sepsis; pruritus; and diabetes. In particular, a promising effect for neuropathic pain, inflammatory pain, and urinary incontinence can be expected.
[4] A fourth embodiment of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds represented by formula (I), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
More specifically, the following embodiments are preferred.
[4-1] An embodiment 4-1 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds represented by formula (I-A), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[4-2] An embodiment 4-2 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds represented by formula (I-B), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[4-3] An embodiment 4-3 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds represented by formula (I-C), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[4-4] An embodiment 4-4 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds represented by formula (I-D), (I-E), (I-F), (I-G) or (I-H), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[4-5] An embodiment 4-5 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds described as the preferable compounds in embodiment [1-21], pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[5] A fifth embodiment of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds represented by formula (I), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
More specifically, the following embodiments are preferred.
[5-1] An embodiment 5-1 of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds represented by formula (I-A), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[5-2] An embodiment 5-2 of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds represented by formula (I-B), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[5-3] An embodiment 5-3 of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds represented by formula (I-C), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[5-4] An embodiment 5-4 of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds represented by formula (I-D), (I-E), (I-F), (I-G) or (I-H), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[5-5] An embodiment 5-5 of the present invention provides an agent for preventing or treating neuropathic pain comprising at least one of the compounds described as the preferable compounds in embodiment [1-21], pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[6] A sixth embodiment of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds represented by formula (I), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
More specifically, the following embodiments are preferred.
[6-1] An embodiment 6-1 of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds represented by formula (I-A), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[6-2] An embodiment 6-2 of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds represented by formula (I-B), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[6-3] An embodiment 6-3 of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds represented by formula (I-C), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[6-4] An embodiment 6-4 of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds represented by formula (I-D), (I-E), (I-F), (I-G) or (I-H), pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
[6-5] An embodiment 6-5 of the present invention provides an agent for preventing or treating inflammatory pain comprising at least one of the compounds described as the preferable compounds in embodiment [1-21], pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.
In any one of the second embodiment to the sixth embodiment, and preferable embodiments thereof, in the compounds represented by formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) or (I-H), preferable substituents and combinations thereof are described in the first embodiment.
[7] A seventh embodiment of the present invention provides a compound which is obtainable by the processes and identified with at least one of the analytical data of each example disclosed as EXAMPLE 1 through EXAMPLE 313, a salt thereof, and solvates thereof. The analytical data are listed in Table 11-13(LC-MS) and Table 46(LC-MS), Table 14-16(NMR) and Table 47(NMR) for final compounds, or in Table 17-18(NMR) and Table 48(NMR) for intermediates. The analytical date is preferably NMR.
[7-1] An embodiment 7-1 of the present invention provides a compound which is obtainable by the processes and identified with at least one of the analytical data of each example disclosed as EXAMPLE 30, 31, 32, 33, 34, 35, 42, 43, 44, 45, 46, 47, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58, a salt thereof, and solvates thereof. The analytical date is preferably NMR.
[7-2] An embodiment 7-2 of the present invention provides a pharmaceutical composition comprising at least one of the compounds of the embodiment 7, pharmaceutically acceptable salts thereof and solvates thereof as an active ingredient.
[7-3] An embodiment 7-3 of the present invention provides an agent for preventing or treating pain comprising at least one of the compounds of the embodiment 7, pharmaceutically acceptable salts thereof and solvates thereof as an active ingredient.
In the embodiments described in [1] to [7] of the present invention, compounds having TRPV1 receptor antagonistic activity (determined by, for example, experimental example (1)-(b-1) described below: a measurement of Ca-influx using FDSS-6000) of 1 μM or less, preferably 100 nM or less, and more preferably 30 nM or less in terms of an A2 value are preferably used.
In the embodiments described above, “agent” means improvement of disease or symptom, not only treatment of disease or symptom.
In all the above embodiments, when the term “compound” is used, the term also refers to pharmaceutically acceptable salts thereof. The compounds of the present invention may have an asymmetric carbon atom. Accordingly, the compounds of the present invention include mixtures of various stereoisomers, such as geometrical isomers, tautomers, and optical isomers, and isolated isomers. The isolation and the purification of such stereoisomers can be performed by those skilled in the art with a known technique such as optical resolution using preferential crystallization or column chromatography, or asymmetric synthesis.
The compounds represented by formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) and (I-H) of the present invention may form acid addition salts. Alternatively, these compounds may form salts with a base according to the type of substituent. These salts are not particularly limited as long as the salts are pharmaceutically acceptable salts. Specific examples of the salts include acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; an organic carboxylic acid such as an aliphatic monocarboxylic acid, e.g., formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, or mandelic acid, an aromatic monocarboxylic acid, e.g., benzoic acid or salicylic acid, an aliphatic dicarboxylic acid, e.g., oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, or tartaric acid, and an aliphatic tricarboxylic acid e.g., citric acid; an organic sulfonic acid such as an aliphatic sulfonic acid, e.g., methanesulfonic acid, ethanesulfonic acid, or 2-hydroxyethanesulfonic acid, or an aromatic sulfonic acid, e.g., benzenesulfonic acid or p-toluenesulfonic acid; or an acidic amino acid, e.g., aspartic acid or glutamic acid; salts with a metal such as an alkali metal, e.g., sodium or potassium, or an alkaline earth metal, e.g., magnesium or calcium; salts with an organic base such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, or ornithine; and ammonium salts.
These salts can be obtained by a known method, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and salts thereof can form solvates with a solvent such as water, ethanol, or glycerol.
The salts of a compound of the present invention include mono-salts and di-salts. The compounds of the present invention can form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.
Furthermore, the present invention includes hydrates, pharmaceutically acceptable various solvates, and crystal polymorphism of the compounds represented by formulae (I), (I-A), (I-B), (I-C), (1-D), (I-E), (I-F), (I-G) and (I-H) of the present invention. The present invention is not limited to the compounds described in examples below and includes all compounds represented by formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) and (I-H)of the present invention and pharmaceutically acceptable salts thereof.
[Process of producing compound of the present invention] Compounds represented by formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F) (I-G), (I-H), (I′), (I″), (I′″), (I″″), (II), (IV), (V), (V-a), (V-a-1), (V-a-2), (V-b), (VI), (VI-a), or (VIII) which is used in the present invention, and related compounds can be obtained by production processes described below. Each of reaction steps will now be described.
Unless otherwise stated, the reaction conditions employed in the production processes are as described below. The reaction temperature is in the range of −78° C. to the solvent-reflux temperature, and the reaction time is the time sufficient for required progress of the reaction. Examples of solvents which are inactive to the reaction include aromatic hydrocarbon solvents such as toluene, xylene, and benzene; polar solvents such as alcohols, e.g., methanol and ethanol, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and water; basic solvents such as triethylamine and pyridine; organic acidic solvents such as acetic acid; halogenated solvents such as chloroform, dichloromethane, and 1,2-dichloroethane; ethereal solvents such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and mixed solvents thereof, and the solvent used may be adequately selected according to the reaction conditions. Examples of bases include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and sodium hydrogencarbonate; and organic bases such as triethylamine, diethylamine, pyridine, N,N-dialkylanilines, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide. Examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. The solvents, the bases, and the acids are not necessarily limited to those mentioned above.
The compounds represented by formula (I) and salts thereof, which are the compounds of the present invention can be readily produced from known compounds or commercially available compounds by, for example, known processes described in published documents, and produced by production processes described below.
The present invention is not limited to the production processes described below.
The production processes will now be described in detail.
In the description below, unless otherwise stated, the definitions of R1, R2, R3, R7, R8, R9A, R9B, R10, X1, X2, X1′, m, m′, n, p, q, k, j, L1, L2, W and cycle in formulae of the compounds represented by formula (I), (I′), (I″), (I′″), (I″″), (II), (IV), (V), (V-a), (V-a-1), (V-a-2), (V-b), (VI), (VI-a), or (VIII) is the same as those in formula (I). R4 represents a hydrogen atom or a alkyl group; R5 represents an alkyl group, R6 represents a protective group such as an arylsulfonyl group, an acyl group, a carbamoyl group (for example, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), or a p-toluenesulfonyl group; R10′ represents the same substituents as R1, “a group: —NR11R11” represents a nitrogen containing group defined into R9A or R9B, formed a linear or branched chain, or cyclic ring. R12 represents an alkyl group. R13 represents a NO2 or NHCOOR5, Y and Z each represent a leaving group such as halogen; Y and Z each represent a leaving group such as halogen; and M represents a metal such as L1, Na, or K; r represents an integral number 1 or 2.
The production methods will now be described in detail. In the description below, the definitions of X2A, R7A, R2A, R2B and q in a compound represented by formula (I-G), formula (I-G-h), formula (XIII), formula (XIII-a), formula (XIII-b), formula (XIII-c) or formula (XIV), are the same as those in formula (I-G) unless otherwise stated. RA represents an alkyl group, RB represents hydrogen or an alkyl group, M represents a metal such as Li, Na, K, Zn, etc., X and Y represent a leaving substituent such as halogen, etc., and Me represents a methyl group.
A compound represented by formula (I) can be obtained by a condensation reaction of a carboxylic acid represented by formula (VIII) and an arylamine represented by formula (A-H) which described (A) in [1-18] above-mentioned.
And, formula (A-H) represents Q-NH2 (=formula (IX)) in reaction scheme and production processes described below.
<The case where q is 0 and X2 is CH2, and X1′ is O, N—R3, or S.>
When R4 is H (a hydrogen atom), a compound represented by formula (IV) can be produced by allowing a compound represented by formula (II) to react with a compound represented by formula (III-a) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using a solvent which is inactive to the reaction, such as methanol, ethanol, acetone, N,N-dimethylformamide, dioxane, tetrahydrofuran, or water, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
Alternatively, the compound represented by formula (IV) can be produced by conducting a reaction using a compound represented by formula (III-b) by a process similar to that described in published documents, for example, PCT Publication No. 01/036381 pamphlet, pp. 360-361, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate with a solvent which is inactive to the reaction, such as methanol, ethanol, acetone, N,N-dimethylformamide, dioxane, tetrahydrofuran, or water, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
When R4 is an alkyl group (e.g., a methyl group or an ethyl group), the compound represented by formula (IV) can be produced from an ester, produced by the same reaction as that conducted in the case where R4 is H, by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis TV, Acids, amino acids, and peptides, pp. 1-43, 1992, Maruzen Co., Ltd., in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate using water and a solvent which is inactive to the reaction, such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (V-a) can be produced by conducting a reaction using the compound represented by formula (IV) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, in a cyclization-dehydrating agent such as polyphosphoric acid (PPA), polyphosphoric acid ethyl ester (PPE), diphosphorus pentaoxide (P2O5), or Eaton's reagent (a mixture of methanesulfonic acid and phosphorus pentoxide) or, and in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., toluene or benzene in the presence of a cyclization-dehydrating agent described above at a temperature in the range of 0° C. to the solvent-reflux temperature. Alternatively, the compound represented by formula (V-a) can be similarly produced by conducting the reaction in the presence of a Lewis acid such as aluminum trichloride or tin tetrachloride in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (V-b) (wherein p represents 1 or 2) can be produced as follows. When R2 is a halogen atom, for example, a fluorine atom (F), the compound represented by formula (V-a) is converted to a trimethylsilyl enol ether by a process similar to that described in published documents, for example, Tetrahedron Letters, 25(51), pp. 5953-5956, 1984. The resulting compound is then treated by a process similar to that described in published documents, for example, Organic Letters, 1(10), pp. 1591-1594, 1998, in the presence of a fluorinating reagent such as xenon difluoride (XeF2), fluorine (F2), 1-fluoro-4-methyl-1,4-diazabicyclo[2,2,2]octane trifluoromethanesulfonate, N-fluoro-O-benzenesulfonimide, N-fluorobenzenesulfonimide, hypofluorous acid trifluoromethyl ether, or 1-fluoropyridine trifluoromethanesulfonate in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., toluene or benzene at a temperature in the range of −78° C. to the solvent-reflux temperature, thereby producing the compound represented by formula (V-b). When R2 is an amino group, the above-mentioned trimethylsilyl enol ether is allowed to react with sodium azide by a process similar to that described in published documents, for example, Tetrahedron, 51(41), pp. 11075-11086, 1995, in the presence of diammonium cerium hexanitrate in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., acetonitrile, or an aromatic hydrocarbon solvent, e.g., toluene or benzene to produce an azide compound. Subsequently, hydrogen gas is added to the azide compound by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 251-266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as palladium-carbon (Pd—C), Raney-Ni, or platinum oxide (PtO2) in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, a polar solvent, e.g., ethyl acetate or acetonitrile, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or an acid solvent, e.g., acetic acid at a temperature in the range of room temperature to the solvent-reflux temperature, thereby producing the compound represented by formula (V-b). When R2 is an hydroxy group, the above-mentioned trimethylsilyl enol ether is allowed to react with 3-chloroperbenzoic acid, aqueous hydrogen peroxide, by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 23, Organic synthesis V, Oxidative reaction, pp. 225-298, 1992, Maruzen Co., Ltd., in a solvent which is inactive to the reaction, such as water, an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, a halogenated solvents e.g., dichloromethane or chloroform, or an aromatic hydrocarbon solvent, e.g., toluene or benzene to produce an epoxy compound. Subsequently, the trimethylsilyl group is removed by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999, thereby producing the compound represented by formula (V-b).
A compound represented by formula (VI) can be produced by conducting a reaction using the compound represented by formula (V-a) or (V-b) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 19, Organic synthesis I, Hydrocarbons and halogenated compounds, pp. 53-298, 1992, Maruzen Co., Ltd., in the presence of a Wittig reagent or a Horner-Emmons reagent, such as (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, ethyl triphenylphosphoranylidene acetate, bis-2,2,2-trifluoroethoxy phosphinyl acetate, ethyl di-ortho-tolylphosphonoacetate, ethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, or ethyl 1-trimethylsilyl acetate, and a base such as sodium hydride, butyllithium, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or phosphazene base-P4-tert-butyl, using a solvent which is inactive to the reaction, such as methanol, ethanol, N,N-dimethylformamide, dioxane, tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (VIII-a) can be produced by conducting a reaction by the same process as that used in <Step 1> of (Reaction scheme) (in the case where R4 is an alkyl group (e.g., a methyl group or an ethyl group)) using the compound represented by formula (VI) and a compound represented by formula (VII).
A compound represented by formula (I″) can be produced by conducting a reaction using the compound represented by formula (VII-a) and a compound represented by formula (IX) (for example, a known amine) as follows. When the compound represented by formula (VIII-a) is a carboxylic acid, the compound represented by formula (I″) can be produced by allowing the compound represented by formula (VIII-a) to react with the compound represented by formula (IX) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodimide hydrochloride (WSC.HCl), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g., N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0° C. to the solvent-reflux temperature. When the compound represented by formula (VIII-a) is converted to an acid halide, the compound represented by formula (I″) can be similarly produced by conducting a reaction by a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 144-146, 1992, Maruzen Co., Ltd., in the presence of a base such as triethylamine or pyridine in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0° C. to the solvent-reflux temperature.
The compound represented by formula (V-a) or a compound represented by formula (VI-a) (a compound in which p is 0 in formula (VI)), which is an intermediate in the above reaction scheme, can also be produced by Production processes A to D described below. In the formulae, X1′ is O, N—R3, or S.
A compound represented by formula (A-III) can be produced by allowing a compound represented by formula (A-I) to react with a compound represented by formula (A-II) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-82, 1992, Maruzen Co., Ltd., in the presence of an acidic reagent such as hydrochloric acid, sulfuric acid, thionyl chloride, or acetyl chloride, using a solvent such as methanol, ethanol, or 2-propanol at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (A-IV) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (A-III) and a compound represented by formula (III-a).
The compound represented by formula (V-a) can be produced by conducting a reaction using the compound represented by formula (A-IV) by a process similar to that described in published documents, for example, Organic Reactions, 1, p. 274, 1942, in the presence of a basic reagent such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, or potassium hydroxide with a solvent which is inactive to the reaction, such as methanol, ethanol, dimethyl sulfoxide, benzene, toluene, or xylene at a temperature in the range of 0° C. to the solvent-reflux temperature, followed by a reaction in a mixed solvent containing a solvent which is inactive to the reaction, such as dimethyl sulfoxide, benzene, toluene, or xylene, and water or an acidic aqueous solution such as an aqueous hydrochloric acid solution or an aqueous acetic acid solution at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (B-II) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using a compound represented by formula (B-I) and a compound represented by formula (B-II).
A compound represented by formula (B-V) can be produced by allowing the compound represented by formula (B-III) to react with a compound represented by formula (B-IV) by a process similar to that described in published documents, for example, Tetrahedron Letters, 25(51), pp. 5953-5956, 1984, in the presence of a silylation agent such as tert-butyldimethylsilyl chloride (TBSCl) or tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and a base such as sodium hydride, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide using a solvent which is inactive to the reaction, such as a halogen-containing solvent, e.g., methylene chloride or chloroform, an ethereal solvent, e.g., dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
The compound represented by formula (V-a) can be produced by conducting a reaction using the compound represented by formula (B-V) by a process similar to that described in published documents, for example, Tetrahedron, 60(13), pp. 3017-3035, 2004, in the presence of a ruthenium catalyst such as benzylidene bistricyclohexylphosphineruthenium dichloride, tricyclohexylphosphine-1,3-bis-2,4,6-trimethylphenyl-4,5-dihydroimidazol-2-ylidene benzylideneruthenium dichloride, or ruthenium-1,3-bis-2,4,6-trimethylphenyl-2-imidazolidinylylidenedichloro-2-1-methylethoxy phenyl methylene with a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (C-III) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using a compound represented by formula (C-I) and a compound represented by formula (C-II).
A compound represented by formula (VI-a) (a compound in which p is 0 in formula (VI)) can be produced by conducting a reaction using the compound represented by formula (C-III) by a process similar to that described in published documents, for example, Tetrahedron Letters, 28(44), pp. 5291-5294, 1987, in the presence of a palladium catalyst such as palladium diacetate, tetrakis triphenylphosphine palladium, or tris dibenzylideneacetone dipalladium with a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (D-III) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using a compound represented by formula (D-I) and a compound represented by formula (D-II).
The compound represented by formula (VI-a) (the compound in which p is 0 in formula (VI)) can be produced by conducting a reaction using the compound represented by formula (D-III) by a process similar to that described in published documents, for example, Synlett, No. 6, pp. 848-850, 2001, in the presence of a palladium catalyst such as palladium diacetate, tetrakis triphenylphosphine palladium, or tris dibenzylideneacetone dipalladium, and a base such as silver carbonate with a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
Alternatively, the compound represented by formula (D-III), which is an intermediate, can be produced by the following process.
A compound represented by formula (D-V) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (D-I) and a compound represented by formula (D-IV).
The compound represented by formula (D-III) can be produced by the same process as that used in <Step 3> of (Production process B) using the compound represented by formula (D-V) and a compound represented by formula (D-VI).
A compound represented by formula (D-VIII) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (D-I) and a compound represented by formula (ID-VII).
A compound represented by formula (D-IX) can be produced by conducting a reaction using the compound represented by formula (D-VIII) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 159-266, 1992, Maruzen Co., Ltd., in the presence of a reducing agent such as diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis-2-methoxyethoxy aluminum hydride, or Raney-Ni-formic acid, with a solvent which is inactive to the reaction, such as diethyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, benzene, or toluene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
The compound represented by formula (D-III) can be produced by the same process as that used in <Step 4> of (Reaction scheme) using the compound represented by formula (D-IX).
A compound represented by formula (V-a-1), in which m′ is 1 and X1′ is NH in the compound represented by formula (V-a), or a compound represented by formula (V-a-2), in which m′ is 1 and X1′ is N—R3′ (wherein R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group which is defined in R3) in the compound represented by formula (V-a) can also be produced by Production process E below.
A compound represented by formula (E-III) can be produced by allowing a compound represented by formula (E-I) to react with a compound represented by formula (E-II) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 280-372, 1992, Maruzen Co., Ltd., using a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, or water, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
The compound represented by formula (V-a-1) (the compound in which X1′ is N—R3, R3 is H, and m′ is 1 in the compound represented by formula (V-a)) can be produced by the same process as that used in <Step 2> of (Reaction scheme) using the compound represented by formula (E-III).
The compound represented by formula (V-a-2) (compound in which X1/is N—R3′, R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group which is defined in R3, and m′ is 1 in the compound represented by formula (V-a)) can be produced using the compound represented by formula (V-a-1) and a compound represented by formula (E-V) (for example, a desired alkyl halide, acyl halide, aryl halide, or heteroaryl halide, wherein R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group which is defined in R3). For example, when R3′ is alkyl, the compound represented by formula (V-a-2) can be produced by conducting a reaction by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 280-372, 1992, Maruzen Co., Ltd., using a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature. When R3′ is acyl, the compound represented by formula (V-a-2) can be produced by the same process as that used in <Step 6> of (Reaction scheme). When R3′ is aryl or a heterocycle, the compound represented by formula (V-a-2) can be produced by conducting a reaction by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 187-243, 1992, Maruzen Co., Ltd., using a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
In the above reaction scheme, the compound represented by formula (VIII-a) can also be produced from a compound represented by formula (V) (including the compounds represented by formulae (V-a) and (V-b) in the reaction scheme) by Production process F below.
A compound represented by formula (X) can be produced by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols, pp. 82-94, 1992, Maruzen Co., Ltd., by allowing the compound represented by formula (Vb) to react with a Reformatsky reagent (a compound represented by formula (XII)), which is prepared from an α-haloacetate such as ethyl bromoacetate or tert-butyl bromoacetate in the presence of zinc, or by allowing the compound represented by formula (V) to react with a silyl acetate such as ethyl (trimethylsilyl)acetate in the presence of a base such as phosphazene base-P4-tert-butyl using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
The compound represented by formula (VI) can be produced by performing a reaction using the compound represented by formula (X) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 19, Organic synthesis I, Hydrocarbons, pp. 194-236, 1992, Maruzen Co., Ltd., in the presence of a dehydrating agent such as potassium hydrogensulfate; an inorganic acid, e.g., concentrated sulfuric acid; an organic acid, e.g., p-toluenesulfonic acid, methanesulfonic acid, or trifluoroacetic acid; thionyl chloride; or phosphorus oxychloride using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
The compound represented by formula (VIII-a) can be produced by conducting a reaction by the same process as that used in <Step 5> of (Reaction scheme) (in the case where R5 is an alkyl group (e.g., a methyl group or an ethyl group)) using the compound represented by formula (VI) and the compound represented by formula (VII). When R5 is a tert-butyl group, the compound represented by formula (VIII-a) can be produced by conducting a reaction using an acid such as hydrochloric acid or trifluoroacetic acid.
A compound represented by formula (XI) can be produced by conducting a reaction by the same process as that used in <Step 5> of (Reaction scheme) using the compound represented by formula (X) and the compound represented by formula (VII).
The compound represented by formula (VIII-a) can be produced by conducting a reaction by the same process as that used in <Step 2> of (Production process F) using the compound represented by formula (XI).
A compound represented by formula (I)-e-1, in which X1′ is N—R3, R3 is H, p is 0 and m′ is 1 in the compound represented by formula (I″) in the reaction scheme, and a compound represented by formula (I)-e-2, in which X1′ is N—R3′, R3′ is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group which is defined in R3, p is 0 and m′ is 1 in the compound represented by formula (I″), can also be produced by Production process G below.
A compound represented by formula (G-I) can be produced by introducing a protective group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a p-toluenesulfonyl group into the compound represented by formula (V-a-1) by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999.
A compound represented by formula (G-II) can be produced in accordance with the process described in <Step 1> of (Production process F) using the compound represented by formula (G-I).
A compound represented by formula (G-III) can be produced in accordance with the process described in <Step 3> of (Production process F) using the compound represented by formula (G-II) and the compound represented by formula (VII).
A compound represented by formula (G-IV) can be produced in accordance with the process described in <Step 6> of (Reaction scheme) using the compound represented by formula (G-III) and the compound represented by formula (IX).
A compound represented by formula (G-V) can be produced by the same process as that used in <Step 5> of (Production process F) using the compound represented by formula (G-TV).
The compound represented by formula (I)-e-1 can be produced by removing the introduced protective group from the compound represented by formula (G-V) by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999.
The compound represented by formula (I)-e-2 can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (I)-e-1.
A compound represented by formula (G-VI) can be produced by conducting a reaction as in <Step 5> of (Production process G) using the compound represented by formula (G-III).
The compound represented by formula (I)-e-1 can be produced by conducting a reaction as in <Step 4> of (Production process G) using the compound represented by formula (G-VI).
<In formula (I), the case where X1 is O, N—R3, or S (which is represented by X1′), X2 is CH2, and p is 0.>
A compound represented by formula (H-II) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using a compound represented by formula (H-I) and the compound represented by formula (C-II).
A compound represented by formula (H-III) can be produced by the same process as that used in <Step 2> of (Production process C) using the compound represented by formula (H-II).
Alternatively, the compound represented by formula (H-III) can be produced by the following process.
A compound represented by formula (H-IV) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (H-I) and the compound represented by formula (D-TI).
The compound represented by formula (H-III) can be produced by the same process as that used in <Step 2> of (Production process D) using the compound represented by formula (H-IV).
Furthermore, the compound represented by formula (H-IV), which is an intermediate, can be produced by the following process.
A compound represented by formula (H-VI) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (H-I) and a compound represented by formula (H-V).
The compound represented by formula (H-IV) can be produced by the same process as that used in <Step 3> of (Production process B) using the compound represented by formula (H-VI) and a compound represented by formula (H-VII).
A compound represented by formula (H-IX) can be produced by the same process as that used in <Step 1> of (Reaction scheme) using the compound represented by formula (H-I) and a compound represented by formula (H-VIII).
A compound represented by formula (H-X) can be produced by the same process as that used in <Step 6> of (Production process D) using the compound represented by formula (H-IX).
The compound represented by formula (H-IV) can be produced by the same process as that used in <Step 4> of (Reaction scheme) using the compound represented by formula (H-X).
<In formula (I) the case where X1 is Or N—R3, or S (which is represented by X1′), X2 is CH2, q is 0, m is 1, R2 is alkyl, and p is 2.>
A compound represented by formula (I-II) can be produced by conducting a reaction using a compound represented by formula (I-I) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 46(13), pp. 2683-2696, 2003, in the presence of methyllithium (MeLi) with a solvent which is inactive to the reaction, such as diethyl ether, 1,2-dimethoxyethane, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (I-IV) can be produced by reacting the compound represented by formula (I-II) with a compound represented by formula (I-III) by a process similar to that described in published documents, for example, Journal of Heterocyclic Chemistry, 32, pp. 1393-1395, 1995, in the presence of a base such as pyrrolidine, piperazine, morpholine, triethylamine, N,N-diisopropylethylamine, or pyridine using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature. In the formulae, each of R2′ and R2″ is an alkyl group such as methyl, ethyl, propyl, or isopropyl, and R2′ and R2″ may be the same or independent each other. R2′ and R2″ may form a ring such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the ring may include a heteroatom such as S, O, or N.
A compound represented by formula (I-V) can be produced by conducting a reaction using the compound represented by formula (I-IV) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 25, Organic synthesis VII, Synthesis using organometallic reagent, pp. 59-72, 1992, Maruzen Co., Ltd., in the presence of vinyl magnesium chloride or vinyl magnesium bromide with a solvent which is inactive to the reaction, such as diethyl ether, 1,2-dimethoxyethane, dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (I-VI) can be produced by conducting a reaction using the compound represented by formula (I-V) by a process similar to that described in published documents, for example, Tetrahedron Letters, 30(9), pp. 1033-1036, 1989, in the presence of an oxidizing agent such as pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), or chromium oxide (CrO3) with a solvent which is inactive to the reaction, such as dichloromethane, 1,2-dichloroethane, or benzene, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (I-VII) can be produced by conducting a reaction using the compound represented by formula (I-VI) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 23, Organic synthesis V, Oxidative reaction, pp. 472-513, 1992, Maruzen Co., Ltd., in the presence of an oxidizing agent such as sodium hypochlorite or calcium hypochlorite with a solvent which is inactive to the reaction, such as dichloromethane, 1,2-dichloroethane, acetonitrile, or water, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (I′″) can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (I-VII) and the compound represented by formula (IX).
Alternatively, the compound represented by formula (I-VII), which is an intermediate, can be produced by the following process.
A compound represented by formula (I-IX) can be produced by a process similar to that described in <Step 1> of (Production process F) using the compound represented by formula (I-IV).
A compound represented by formula (I-X) can be produced by the same process as that used in <Step 4> of (Production process F) using the compound represented by formula (I-IX).
The compound represented by formula (I-VII) can be produced by the same process as that used in <Step 2> of (Production process F) using the compound represented by formula (I-X).
<In formula (I), the case where X1 is O, N—R3, or S (which is represented by X1′), X2 is NH, m is 1, R2 is alkyl, q is 0 and p is 2.>
A compound represented by formula (J-II) can be produced by a process similar to that described in <Step 6> of (Reaction scheme) using a compound represented by formula (J-I).
A compound represented by formula (J-IV) can be produced by allowing the compound represented by formula (J-II) to react with a compound represented by formula (J-III) by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999. In the formulae, each of R2′ and R2″ is an alkyl group such as methyl, ethyl, propyl, or isopropyl, and R2′ and R2″ may be the same or independent each other. R2′ and R2″ way form a ring such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the ring may include a heteroatom such as S, O, or N.
A compound represented by formula (J-V) can be produced by conducting a reaction using the compound represented by formula (J-IV) by a process similar to that described in published documents, for example, Bulletin des Societes Chimiques Belges, 87, p. 229, 1978, in the presence of the Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) with a solvent which is inactive to the reaction, such as toluene, benzene, xylene, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, or hexamethylphosphoric triamide, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (J-VII) can be produced by allowing the compound represented by formula (J-V) to react with a compound represented by formula (J-VI) by a process similar to that described in published documents, for example, Synlett, No. 11, pp. 1117-1118, 1996, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, or N,N-dimethylaminopyridine using a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, or chloroform, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (I″″) can be produced by conducting a reaction using the compound represented by formula (J-VII) by a process similar to that described in published documents, for example, Synlett, No. 11, pp. 1117-1118, 1996, in the presence of a phosphine reagent such as triphenylphosphine or tributylphosphine; a phosphite reagent such as trimethyl phosphite, triethyl phosphite, tripropyl phosphite, or tributyl phosphate; and a base such as triethylamine, N,N-diisopropylethylamine, or N,N-dimethylaminopyridine at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (J-X) can be produced by the same process as that used in <Step 4> of (Production process J) using the compound represented by formula (J-V) and a compound represented by formula (J-IX).
A compound represented by formula (J-XI) can be produced by the same process as that used in <Step 5> of (Production process J) using the compound represented by formula (J-X).
A compound represented by formula (J-XII) can be produced by the same process as that used in <Step 5> of (Reaction scheme) using the compound represented by formula (J-XI).
A compound represented by formula (I″″) can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (J-XII) and the compound represented by formula (IX).
<In formula (I), the case where X1 is O, N—R3, or S (which is represented by X1′), X2 is NH, m is 2, q is 0 and p is 0.>
A compound represented by formula (K-II) can be produced by the same process as that used in <Step 1> of (Production process A) using the compound represented by formula (K-I), and t-BuOH.
A compound represented by formula (K-IV) can be produced by the same process as that used in <Step 2> of (Production process A) using the compound represented by formula (K-II), and (K-III).
A compound represented by formula (K-V) can be produced by the same process as that used in <Step 6> of (Production process G) using the compound represented by formula (K-IV).
A compound represented by formula (K-VI) can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (K-V).
A compound represented by formula (K-VII) can be produced by the same process as that used in <Step 3> of (Production process J) using the compound represented by formula (K-VI).
A compound represented by formula (K-X) can be produced by the same process as that used in <Step 4> of (Production process J) using the compound represented by formula (K-VII), and (K-IX).
A compound represented by formula (I″″) can be produced by the same process as that used in <Step 5> of (Production process J) using the compound represented by formula (K-X).
A compound represented by formula (K-XII) can be produced by the same process as that used in <Step 4> of (Production process J) using the compound represented by formula (K-VII), and (J-IX).
A compound represented by formula (K-XIII) can be produced by the same process as that used in <Step 5> of (Production process J) using the compound represented by formula (K-XII).
A compound represented by formula (K-XIV) can be produced by the same process as that used in <Step 5> of (Reaction scheme) using the compound represented by formula (K-XIII).
A compound represented by formula (I″″) Can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (K-XIV).
An amine parts represented by formula A-H(=Q-NH2) can be produced by below process.
<In formula A-H, the case where j=0, k=0, L1=O, W═CO>
A compound represented by formula (L-III) can be produced by allowing a compound represented by formula (L-I) to react with a compound represented by formula (L-II) by a process similar to that described in published documents, for example, Bioorganic and Medicinal Chemistry, 10(8), pp. 2663-2669, 2002, in the presence of a base such as sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium hydroxide, cesium carbonate, or potassium fluoride using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide, acetone, 4-methyl-2-pentanone, 2,6-dimethylheptanone, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (L-IV) can be produced by conducting a reaction using the compound represented by formula (L-III) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 159-266, 1992, Maruzen Co., Ltd., in the presence of a catalyst such as palladium-carbon (Pd—C), Raney-Ni, platinum oxide (PtO2), or dichloro triphenyl phosphine ruthenium, under hydrogen atmosphere, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, a polar solvent, e.g., ethyl acetate or methyl acetate, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
And alternatively, a compound represented by formula (L-IV) can be produced by using Fe, or Sn, in hydrochloric acid or acetic acid, at a temperature in the range of 0° C. to the solvent-reflux temperature. Further more, a compound represented by formula (L-IV) can be produced also by using sodium borohydride in the presence of Lewis Acid, e.g., Nickel(II)chloride (NiCl2), Tin(II) chloride (SnCl2) using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (L-V) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (L-I).
A compound represented by formula (L-VI) can be produced by the same process as that used in <Step 1> of (Production process L) using the compound represented by formula (L-V) and (L-II),
A compound represented by formula (L-VI) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (L-III).
A compound represented by formula (L-VII) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (L-VI).
<In formula A-H, the case where j=0, k=0, L1=NR10, NH, or S, W═CO>
A compound represented by formula (M-III) can be produced by allowing a compound represented by formula (M-I) to react with a compound represented by formula (M-II) by a process similar to that described in published documents, for example, Journal of the Chemical Society, Perkin Transactions I, (3), pp. 681-689, 1988, in the presence of a base such as sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium hydroxide, cesium carbonate, or potassium fluoride using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide, acetone or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (M-IV) can be produced by the same process as that used in <Step 6> of (Production process L) using the compound represented by formula (M-III).
A compound represented by formula (M-V) can be produced by conducting a reaction using the compound represented by formula (M-III) by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 32(1), pp. 23-30, 1989, in the presence of sodium sulfide/Sulfur using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., acetonitrile, N,N-dimethylformamide, dimethylsulfoxide or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (M-VI) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (M-V).
A compound represented by formula (M-VII) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (M-VI).
<In particularly, the case where L1=NCOR10′, W═CO>
A compound represented by formula (M-VIII) can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (M-VI).
A compound represented by formula (M-IX) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (M-VI).
<In formula A-H, the case where L1═S(O)t, t=1 or 2 W═CO>
A compound represented by formula (N-II) can be produced by the same process as that used in <Step 6> of (Reaction scheme) using the compound represented by formula (N-I).
A compound represented by formula (N-III) can be produced by conducting a reaction using the compound represented by formula (N-II) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series) 4th edition, 23, Organic synthesis V, Oxidative reaction, pp. 472-513, 1992, Maruzen Co., Ltd., in the presence of a peroxyacid such as m-chloro perbenzoic acid, peracetic acid, trifluoromethyl peracetic acid, hydrogen peroxide, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
<In formula A-H, the case where j=0, k=0, L2=O, W═CO>
A compound represented by formula (O-II) can be produced by conducting a reaction using the compound represented by formula (O-I) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 234-245, 1992, Maruzen Co., Ltd., in the presence of a borane reagent such as borane-tetrahydrofurane complex (BH3-THF), borane-dimethylsulfide complex (BH3-Me2S) using a solvent which is inactive to the reaction, such an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, a halogenated solvent, e.g., dichloromethane or chloroform, a polar solvent, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (O-III) can be produced by conducting a reaction using the compound represented by formula (O-II) by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 25(6), pp. 735-742, 1982, in the presence of a carbonylation reagent such as urea, 1,1-carbonylbis-1H-imidazole, triphosgen and a base such as sodium hydride, lithium hydroxyde, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or a polar solvent, e.g., N,N-dimethylformamide or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (O-IV) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (O-III).
A compound represented by formula (O-V) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (O-IV)
<In formula A-H, the case where j=0, k=0, L2═NR10, W═CO>
A compound represented by formula (P—I) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (O-II)
A compound represented by formula (P-II) can be produced by conducting a reaction using the compound represented by formula (P-I) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 21, Organic synthesis III, aldehyde, ketone, and quinone, pp. 1-148, 1992, Maruzen Co., Ltd., in the presence of a oxidant such as pyridinium chlorochromate (PCC), activated manganese dioxide (MnO2), Dess-Martin reagent using a solvent which is inactive to the reaction, such a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
After the compound represented by formula (P-II) and (P-III) are converted to an imine, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature, A compound represented by formula (P-IV) can be produced by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 23(12), pp. 1405-1410, 1980 in the presence of a reductive reagent such as sodium borohydride using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (P-V) can be produced by the same process as that used in <Step 3> of (Production process O) using the compound represented by formula (P-IV).
A compound represented by formula (P-VI) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (P-V).
<In formula A-H, the case where j=0, k=0, L2═NR10, W═SO2>
A compound represented by formula (Q-I) can be produced by conducting a reaction using the compound represented by formula (P-IV) by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 44(12), pp. 1847-1852, 2001, in the presence of a sulfonylation reagent such as sulfamide using a solvent which is inactive to the reaction, such as a basic solvent e.g., triethylamine, N,N-diisopropylethylamine, pyridine or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (Q-II) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (Q-I).
<In formula A-H, the case where j=0, k=0, L1-L2=—CH2CH(NR11R11)— or L1-L2=—CH═C(NR11R11)—, W═CO>
A compound represented by formula (R-II) can be produced by the same process as that used in <Step 4> of (Reaction scheme) using the compound represented by formula (R-I).
<Step 2> (In the case where R13NHCOOR5)
A compound represented by formula (R-IV) can be produced by allowing a compound represented by formula (R-II) to react with a compound represented by formula (R-II) by a process similar to that described in published documents, for example, Tetrahedron, 60(2), pp. 383-387, 2004, in the presence of a Lewis Acid such as aluminum(III) chloride, titanium(IV) chloride, tin(IV) chloride, lithium perchlorate using a solvent which would not take part in the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (R-V) can be produced, first, by conducting a reaction of deprotection using the compound represented by formula (R-IV) and acid catalyst by a process similar to that described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999., then, by the same process as that used in <Step 2> of (Production process L).
A compound represented by formula (R-VI) can be produced by conducting a reaction using the compound represented by formula (R-V) by a process similar to that described in published documents, for example, Heterocyclic Communications, 11(6), pp. 485-490, 2005, in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone using a solvent which would not take part in the reaction, such as an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or a polar solvents e.g., acetonitril or a mixed solvent thereof at a temperature in the range of 0<C to the solvent-reflux temperature.
A compound represented by formula (R-VII) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (R-V).
A compound represented by formula (R-VIII) can be produced by the same process as that used in <Step 4> of (Production process R) using the compound represented by formula (R-VII).
<Step 7> (In the case where R13═NO2)
A compound represented by formula (R-IX) can be produced by the same process as that used in <Step 2> of (Production process R) using the compound represented by formula (R-II).
A compound represented by formula (R-X) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (R-IX).
A compound represented by formula (R-XI) can be produced by the same process as that used in <Step 4> of (Production process R) using the compound represented by formula (R-X).
A compound represented by formula (R-XII) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (R-X).
A compound represented by formula (R-XIII) can be produced by the same process as that used in <Step 4> of (Production process R) using the compound represented by formula (R-XII).
Regarding the Production process R, the original products, such as EXAMPLE 30 of the basic patent application JP2007-014372, obtained from the series of 2,4-dinitrocinnamate through the step 7 and step 8 (originally step 2 and step 3 or step 4 of the Production process R in the basic application) have been reassigned and confirmed this time as alpha(α)-addition products. This addition position corresponds to the 3-position of the 3,4-dihydro-2(1H)-quinolinone ring. From the view point, the reassigned EXAMPLES are No. 30, 31, 32, 33, 34, 35, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58.
During the investigation of the step 7, since the Michael reaction seemed to undergo in the step, the inventors misassigned the addition position as beta(β), which corresponds to 4-position of the 3,4-dihydro-2(1H)-quinolinone ring. Then, the inventors happened to recognize a literature*1 which reports that “ethyl 2-nitrocinnamate undergoes standard β-addition, however, ethyl 2,4-dinitrocinnamate undergoes α-addition” and tried the reassignment of the original products. *1: Canadian J. of Chemistry (2002), 80(2), 192-199 (Scheme 4/Procedure E)
Since the misassignment took place in a series of intermediates, the assignment of the positions of a series of following final products were also affected. Therefore, all wrong description “4-” should be reassigned as true position “3-” of the 3,4-dihydro-2(1H)-quinolinone ring in the chemical structures or chemical names of the above series of intermediates and related final products. For example, regarding the EXAMPLE 30, the addition position of 4-morpholinyl group has been reassigned from 4-(4-morpholinyl) to 3-(4-morpholinyl) in this application. The same reassignments have been done in the chemical structure or partial structure of related intermediates as formula 30-3 or (a27). The reassignments in the other EXAMPLES have also been done in the same way.
As the above explanation, there were the series of misassignments in the examples of basic patent application JP 2007-014372. And in the present application, these examples are described with reassigned results. However, there is no substantial difference as real products between the products or intermediates of above mentioned EXAMPLES described in the specifications of both patent applications, that is apparent since the analytical data are really identical.
<In formula A-H, the case where j=0, k=0, L1-L2═CH═NR11R11, W═CO>
A compound represented by formula (S-I) can be produced by the same process as that used in <Step 1> of (Production process A) using the compound represented by formula (O-I′), and an alcoholic solvent, e.g., methanol, ethanol, t-butanol, benzylalcohol.
A compound represented by formula (S-II) can be produced by conducting a reaction using the compound represented by formula (S-I) by a process similar to that described in published documents, for example, European Journal of Medicinal Chemistry, 40(9), pp. 897-907, 2005, in the presence of acetic anhydride using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (S-III) can be produced by conducting a reaction using the compound represented by formula (S-II) by a process similar to that described in published documents, for example, European Journal of Medicinal Chemistry, 40(9), pp. 897-907, 2005, in the presence of basic reagent such as sodium hydride, butyllithium, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (S-IV) can be produced by conducting a reaction using the compound represented by formula (S-III) and phosphoryl chloride by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(7), pp. 1347-1351, 1988, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (S-VI) can be produced by allowing a compound represented by formula (S-IV) to react with a compound represented by formula (S-V) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(7), pp. 1347-1351, 1988, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g., acetonitril, N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (S-VII) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (S-VI).
A compound represented by formula (S-VIII) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (S-VI).
A compound represented by formula (S-TX) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (S-VIII).
<In formula A-H, the case where j=0, k=0, L1-L2═CH2CH2, R8═NR11R11, W═CO>
A compound represented by formula (T-III) can be produced by allowing a compound represented by formula (T-I) to react with a compound represented by formula (T-II) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 280-372, 1992, Maruzen Co., Ltd., in the presence of a basic reagent such as sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium hydroxide, cesium carbonate, or potassium fluoride, using a solvent which is inactive to the reaction, such as acetonitrile, dioxane, tetrahydrofurane, benzene, toluene, dimethylsulfoxide, N,N-dimethylformamide, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (T-IV) can be produced by conducting a reaction using the compound represented by formula (T-III) and nitrating reagent such as nitric acid, nitric acid/sulfonic acid, nitric acid/acetic anhydride, potassium nitrate/sulfonic acid, sodium nitrate/sulfonic acid, potassium nitrate/acetic anhydride, nitric acid/trifluoromethanesulfonic acid by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 394-405, 1992, Maruzen Co., Ltd., at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (T-V) can be produced by conducting a reaction using potassium iodide and the diazo compound which converted from a compound represented by formula (T-IV) with sodium nitrite/sulfuric acid/acetic acid, by a process similar to that described in published documents, for example, Tetrahedron, 61(52), pp. 12300-12338, 2005, at a temperature in the range of 0° C. to room temperature.
A compound represented by formula (T-VI) can be produced by the same process as that used in <Step 2> of (Production process D) using the compound represented by formula (T-V).
A compound represented by formula (T-VII) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (T-VI).
A compound represented by formula (T-VIII) can be produced by conducting a reaction of deprotection using the compound represented by formula (T-VII) and acid catalyst such as 48% hydrobromide/acetic acid, aluminum (III) chloride by a process similar to that described in published textbooks, for example, Green et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999.
A compound represented by formula (T-IX) can be produced by conducting a reaction using the compound represented by formula (T-VIII) and trifluoromethanesulfonic acid anhydride, or trifluoromethanesulfonic acid chloride by a process similar to that described in published documents, for example, Synthesis, (4), pp. 547-550, 2005, in the presence of the basic reagent such as triethylamine, N,N-diisopropylethylamine, pyridine using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (T-XI) can be produced by allowing a compound represented by formula (T-IX) to react with a compound represented by formula (T-X) by a process similar to that described in published documents, for example, Synlett, (12), pp. 1400-1402, 1997, using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g., acetonitril, N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
<In formula A-H, the case where j=1, k=0, L1-L2═CH2, W═CO>
A compound represented by formula (U-II) can be produced by the same process as that used in <Step 3> of (Production process E) using the compound represented by formula (U-I).
A compound represented by formula (U-IV) can be produced by allowing a compound represented by formula (U-II) to react with a compound represented by formula (U-III) by a process similar to that described in published documents, for example, Synthesis, (7), pp. 534-537, 1981, in the presence of Tin(IV) chloride using a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (U-V) can be produced by conducting a reaction using the compound represented by formula (U-IV) by a process similar to that described in published documents, for example, Tetrahedron Letters, 28(21), pp. 2399-2402, 1987, in the presence of a catalyst such as Raney-Ni, under hydrogen atmosphere, in a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, a polar solvent, e.g., ethyl acetate or methyl acetate, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (U-VI) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (U-V).
<In formula A-H, the case where j=0, k=0, L1=L2≠O, NR, S(O)t=0˜2, W═CO>
A compound represented by formula (V-II) can be produced by the same process as that used in <Step 2> of (Production process T) using the compound represented by formula (V-I).
A compound represented by formula (V-III) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (V-II).
<In formula A-H, the case where j=1, k=0, L1=L2═CHr=1˜2, W═CO>
A compound represented by formula (W-II) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (W-I).
A compound represented by formula (W-III) can be produced by the same process as that used in <Step 2> of (Production process T) using the compound represented by formula (W-II).
A compound represented by formula (W-IV) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (W-III).
<In formula A-H, the case where j=0, L1-CH2, L2=bond, W═CO>
A compound represented by formula (X-III) can be produced by allowing a compound represented by formula (X-I) to react with a compound represented by formula (X-II) by a process similar to that described in published documents, for example, PCT WO 2005/044802 in the presence of a basic reagent such as sodium ethoxide, sodium methoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, a polar solvent, e.g., N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (X-V) can be produced by allowing a compound represented by formula (X-III) to react with a compound represented by formula (X-IV) by a process similar to that described in published documents, for example, Synth Commun, 7, pp. 409, 1977, in the presence of a acid catalyst such as Trifluoroacetic acid, trifluoroborate-diethylether complex, Lanthanum(III)chloride, p-toluenesulfonic acid, using a solvent such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, an ethereal solvent, at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (X-VI) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (X-V).
A compound represented by formula (X-VII) can be produced by conducting a reaction using the compound represented by formula (X-VI) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, reduction, sugar, and labeled compound, pp. 159-266, 1992, Maruzen Co., Ltd., in the presence of a reducing agent such as lithium aluminumhydride (LiAlH4), borane-tetrahydrofurane complex (BH3-THF)), borane-dimethylsulfide complex (BH3-Me2S), sodium bis(2-methoxyethoxy)aluminumhydride, using a solvent such an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (X-VIII) can be produced by the same process as that used in <Step 6> of (Production process G) using the compound represented by formula (X-VII).
<In formula A-H, the case where j=0, k=0, W═SO2>
A compound represented by formula (Y-II) can be produced by conducting a reaction using the compound represented by formula (Y-I) by a process similar to that described in published documents, for example, Bioorganic and Medicinal Chemistry, 10(11), pp. 3529-3544, 2002, in the presence of sodium thiosulfate, or sodium sulfite using a solvent such as an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound represented by formula (Y-III) can be produced by conducting a reaction using the compound represented by formula (Y-II) by a process similar to that described in published documents, for example, Bioorganic and Medicinal Chemistry, 10(11), pp. 3529-3544, 2002, in the presence of phosphorous pentachloride, phosphoryl chloride, or chlorine gas using a solvent such as ethereal solvent, e.g., diethyl ether or tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or a polar solvent, e.g., N,N-dimethylformamide, acetic acid, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature,
A compound represented by formula (Y-IV) can be produced by the same process as that used in <Step 2> of (Production process L) using the compound represented by formula (Y-III).
The compounds of formula (I-G) and salts thereof, which are the compounds of the present invention can be readily produced from known compounds or commercially available compounds by, for example, known processes described in published documents, and produced by production processes described below.
However, the present invention is not limited to the production methods described below.
The production methods will now be described in detail.
In the description below, the definitions of X2A, R7A, R2A, R2B and q in a compound represented by formula (I-G), formula (I-G-h), formula (XIII), formula (XIII-a), formula (XIII-b), formula (XIII-c) or formula (XIV), are the same as those in formula (I-G) unless otherwise stated. RA represents an alkyl group, RB represents hydrogen or an alkyl group, M represents a metal such as Li, Na, K, Zn, etc., X and Y represent a leaving substituent such as halogen, etc., and Me represents a methyl group.
A compound represented by formula (I-G) is produced by a condensation reaction between a carboxylic acid represented by formula (XIII) and an amine represented by formula (XIV).
A compound of formula (I-G) can be produced using a compound of formula (XIII) and a compound of formula (XIV) in accordance with a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 191-309, 1992, Maruzen Co., Ltd., by performing the reaction in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodimide hydrochloride (WSC.HCl), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), in a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, a polar solvent, e.g., N,N-dimethylformamide, or an alcoholic solvent, e.g., methanol, ethanol, or 2-propanol, in the presence or absence of a base such as triethylamine or pyridine at a temperature in the range of 0° C. to the solvent-reflux temperature. In addition, when the compound represented by formula (XIII) is converted to an acid chloride, the compound represented by formula (I-G) can be similarly produced by conducting a reaction in accordance with a process similar to that described in, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 144-146, 1992, Maruzen Co., Ltd., in the presence of a base such as triethylamine or pyridine in a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent, e.g., toluene or benzene, or a polar solvent, e.g., N,N-dimethylformamide at a temperature in the range of 0° C. to the solvent-reflux temperature.
In addition, particularly, when q=0 and X2A═NH in the above-described formula (I-G), a compound represented by formula (I-G-h) is produced by a transfer reaction (Reaction formula B).
A compound of formula (XVI) can be produced using a compound of formula (XV) in accordance with a process similar to Reaction formula A.
A compound of formula (XVIII) can be produced using a compound of formula (XVI) and a compound of formula (XVII) by introducing a dialkyl group such as a dimethyl group, a diethyl group and a cycloalkyl group, i.e., R2A and R2B groups by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999.
A compound of formula (XIX) can be produced using a compound of formula (XVIII) in accordance with a process similar to that described in published documents, for example, Bull. Soc. Chim. Belg., 87, p. 229, 1978, by performing the reaction in the presence of the Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) with a solvent which is inactive to the reaction such as toluene, benzene, xylene, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, or hexamethylphosphoric triamide, or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (XXI) can be produced using a compound of formula (XIX) and a compound of formula (XX) in accordance with a process similar to that described in published documents, for example, Synlett, No. 11, pp. 1117-1118, 1996, by performing the reaction in the presence of a base such as triethylamine, N,N-diisopropylethylamine, or N,N-dimethylaminopyridine using a solvent which is inactive to the reaction such as acetonitrile, 1,4-dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, or chloroform, or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (I-G-h) can be produced using a compound of formula (XXI) in accordance with a process similar to that described in published documents, for example, Synlett, No. 11, pp. 1117-1118, 1996, by performing the reaction in the presence of a phosphine reagent such as triphenylphosphine or tributylphosphine; a phosphate reagent such as trimethyl phosphite, triethyl phosphite, tripropyl phosphite, tributyl phosphate, etc.; and a base such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaminopyridine, etc. at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (XIII) in the above-mentioned reaction can be produced by (Production process AA) to (Production process CC) below, and a compound of formula (XIV) by (Production process DD) or (Production process EE).
<When g=0, R2A═R2B═H and X2A═CH2CH2, or q=0, R2A═R2B═H and X2A═CH2 in the above-described formula (XIII)>
A compound of formula (AA-III) can be produced using a compound of formula (AA-I) and a compound of formula (AA-II) in accordance with a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, by performing the reaction in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. using a solvent which is inactive to the reaction such as methanol, ethanol, acetone, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (AA-IV) can be produced using a compound of formula (AA-III) in accordance with a process similar to that described in published documents, for example, Synlett, No. 6, pp. 848-850, 2001, by performing the reaction in the presence of a palladium catalyst such as palladium diacetate (II), tetrakis triphenylphosphine palladium, trisdibenzylideneacetone dipalladium, etc. and silver carbonate, etc. with a solvent which is inactive to the reaction such as acetonitrile, 1,4-dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<When RA is an alkyl group such as methyl, ethyl, etc.>
A compound of formula (XIII-a) can be produced using a compound of formula (AA-IV) in accordance with a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-43, 1992, Maruzen Co., Ltd., by performing the reaction in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. using water and a solvent which is inactive to the reaction such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
<When RA is a tert-butyl group>
A compound of formula (XII)-a) can be produced using a compound of formula (AA-IV) by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis (the United States), 3rd edition, 1999, by performing the reaction in the presence of an acidic reagent such as formic acid, hydrochloric acid, sulfuric acid and p-toluenesulfonic acid using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol and ethanol, an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane, water, etc., or a mixed solvent thereof, at a temperature in the range of 0° C. to the solvent-reflux temperature.
In addition, a compound of formula (AA-III), which is an intermediate, can be produced according to a method below.
A compound of formula (AA-VI) can be produced using a compound of formula (AA-I) and a compound of formula (AA-V) in the same manner as in <Step 1> of (Production process AA).
A compound of formula (AA-III) can be produced using a compound of (AA-VI) and a compound of formula (AA-VII), by a process similar to that described in published documents, for example, Tetrahedron, 60(13), pp. 3017-3035, 2004, by performing the reaction in the presence of a ruthenium catalyst such as benzylidene bistricyclohexyl phosphine ruthenium dichloride, tricyclohexyl phosphine-1,3-bis-2,4,6-trimethylphenyl-4,5-dihydroimidazol-2-ylidene benzylidene ruthenium dichloride, ruthenium-1,3-bis-2,4,6-trimethylphenyl-2-imidazolidinylylidene dichloro-2-1-methylethoxyphenyl methylene, etc. with a solvent which is inactive to the reaction such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, etc., or an aromatic hydrocarbon solvent, e.g., benzene, toluene, xylene, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (AA-IX) can be produced using a compound of formula (AA-I) and a compound of formula (AA-VIII), in the same manner as in <Step 1> of (Production process AA).
A compound of formula (AA-X) can be produced using a compound of formula (AA-IX) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, Reduction, Sugars, and Labeled Compounds, pp. 159-266, 1992, Maruzen Co., Ltd., by performing the reaction using a reducing agent such as diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy) aluminum hydride, Raney-Ni-formic acid, etc. with a solvent which is inactive to the reaction such as diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, benzene, toluene, etc., or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound of formula (AA-III) can be produced using a compound of formula (AA-X) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 19, Organic synthesis 1, Hydrocarbons and halogenated compounds, pp. 53-298, 1992, Maruzen Co., Ltd., by performing the reaction in the presence of a Wittig reagent or a Horner-Emmons reagent such as (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, ethyl triphenylphosphoranylidene acetate, bis-2,2,2-trifluoroethoxyphosphinyl acetate, ethyl di-ortho-tolylphosphonoacetate, ethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, ethyl 1-trimethylsilyl acetate, etc. and a base such as sodium hydride, butyl lithium, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, phosphazene base-P4-tert-butyl, etc. using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, etc., a polar solvent, e.g., N,N-dimethylformamide, etc., an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, etc., or an aromatic hydrocarbon solvent, e.g., benzene, toluene, xylene, etc., or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
(Production Process BB) <When q=0, X2A═CH2 and R2A═R2B═H in the above-described formula (XIII)>
A compound represented by formula (BB-IV) can be produced by allowing a compound represented by formula (BB-I) to react with a compound represented by formula (BB-II) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. using a solvent which is inactive to the reaction such as methanol, ethanol, acetone, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature. Alternatively, a compound represented by formula (BB-IV) can be produced by conducting a reaction using a compound represented by formula (BB-I) and a compound represented by formula (BB-III) in accordance with a process similar to that described in published documents, for example, PCT Publication No. 01/36381 pamphlet, pp. 360-361, reference example 12, by performing the reaction in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. using a solvent which is inactive to the reaction such as methanol, ethanol, acetone, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
<Step 1> <When R8 is an alkyl group such as methyl, ethyl, etc.>
A compound represented by formula (BB-IV) can be produced from an ester, produced by the same reaction as that conducted <in the case where RB═H> by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 22, Organic synthesis IV, Acids, amino acids, and peptides, pp. 1-43, 1992, Maruzen Co., Ltd., in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. using water and a solvent which is inactive to the reaction such as methanol, ethanol, 2-propanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (BB-V) can be produced by conducting a reaction using the compound represented by formula (BB-IV) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 31(1), pp. 230-243, 1988, in a cyclization-dehydrating agent such as polyphosphoric acid (PPA), polyphosphoric acid ethyl ester (PPE), diphosphorus pentaoxide (P205), Eaton's reagent (a mixture of methanesulfonic acid and diphosphorus pentoxide), etc., or in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform, an ethereal solvent, e.g., diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., toluene or benzene in the presence of a cyclization-dehydrating agent described above at a temperature in the range of 0° C. to the solvent-reflux temperature. Alternatively, the compound represented by formula (BB-V) can be similarly produced by conducting the reaction in the presence of a Lewis acid such as aluminum trichloride or tin tetrachloride in a solvent which is inactive to the reaction, such as a halogenated solvent, e.g., dichloromethane or chloroform at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (BB-VI) can be produced by conducting a reaction using the compound represented by formula (BB-V) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 19, Organic synthesis I, Hydrocarbons and halogenated compounds, pp. 53-298, 1992, Maruzen Co., Ltd., in the presence of a Wittig reagent or a Horner-Emmons reagent, such as (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, ethyl triphenylphosphoranylidene acetate, bis-2,2,2-trifluoroethoxy phosphinyl acetate, ethyl di-ortho-tolylphosphonoacetate, ethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, or ethyl 1-trimethylsilyl acetate, and a base such as sodium hydride, butyllithium, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or phosphazene base-P4-tert-butyl, using a solvent which is inactive to the reaction, such as an alcoholic solvent, e.g., methanol or ethanol, a polar solvent, e.g., N,N-dimethylformamide, an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (XIII-b) can be produced using a compound represented by formula (BB-VI), by conducting a reaction in the same manner as in <Step 3> of (Production process AA).
A compound represented by formula (BB-VIII) can be produced by a process similar to that described in published documents, for example, Synthetic Communications, 35(3), pp. 379-387, 2005, by allowing the compound represented by formula (BB-V) to react with an alkyllithium reagent (formula (BB-VII)) which is prepared from lithium diisopropylamide and an acetic ester, by allowing the compound represented by formula (BB-V) to react with a Reformatsky reagent (formula (BB-VII)) which is prepared from an α-haloacetate ester such as ethyl bromoacetate or tert-butyl bromoacetate in the presence of zinc, or by allowing the compound represented by formula (BB-V) to react with a silyl acetate ester such as ethyl(trimethylsilyl)acetate in the presence of a base such as phosphazene base-P4-tert-butyl, using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., 1,4-dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of 78° C. to the solvent-reflux temperature.
The compound represented by formula (BB-VI) can be produced by performing a reaction using the compound represented by formula (BB-VIII) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 19, Organic synthesis I, Hydrocarbons, pp. 194-236, 1992, Maruzen Co., Ltd., in the presence of a dehydrating agent such as potassium hydrogensulfate; an inorganic acid, e.g., concentrated sulfuric acid; an organic acid, e.g., p-toluenesulfonic acid, methanesulfonic acid, or trifluoroacetic acid; thionyl chloride; or phosphorus oxychloride using a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., 1,4-dioxane or tetrahydrofuran, or an aromatic hydrocarbon solvent, e.g., benzene, toluene, or xylene, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound represented by formula (BB-IX) can be produced using a compound represented by formula (B-VIII), by conducting a reaction in the same manner as in <Step 3> of (Production process AA).
A compound represented by formula (XIII-b) can be produced using a compound represented by formula (BB-IX), by conducting a reaction in the same manner as in <Step 6> of (Production process BB).
(Production Process CC) <When q=0 and X2A═CH2 in the above-described formula (XIII)>
A compound represented by formula (CC-II) can be produced by conducting a reaction using a compound represented by formula (CC-I) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 46(13), pp. 2683-2696, 2003, in the presence of methyllithium (MeLi) with a solvent which is inactive to the reaction, such as diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, or tetrahydrofuran, or a mixed solvent thereof at a temperature in the range of −78° C. to the solvent-reflux temperature.
A compound of formula (CC-IV) can be produced using a compound of formula (CC-II) and a compound of formula (CC-III) by a process similar to that described in published documents, for example, Journal of Heterocyclic Chemistry, 32, pp. 1393-1395, 1995, by performing the reaction in the presence of a base such as pyrrolidine, piperazine, morpholine, triethylamine, N,N-diisopropylethylamine, pyridine, etc. using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature. In the formulae, R2A and R2B are a C1-5 linear or branched alkyl group, respectively, and the alkyl group may be substituted with 1 to 5 groups optionally selected from amino groups optionally substituted with 1 or 2 substituents optionally selected form the group of a halogen atom, a hydroxyl group, a C1-2 alkyl group, a C1-2 alkoxyl group, a C1-3 alkyl group, etc., or R2A and R2B, together with the carbon atom to which they are bound respectively, may form a C3-6 cyclocyclic group, and one carbon atom in the cyclocyclic group may be substituted with one oxygen atom or nitrogen atom <the nitrogen atom may be substituted with a C1-3 linear or branched alkyl group optionally substituted with 1 to 3 substituents optionally selected form the group of a halogen atom, —OH, —OCH3 or —OCF3>.
A compound of formula (CC-V) can be produced using a compound of formula (CC-IV) in the same manner as in <Step 5> of (Production process BB).
A compound of formula (CC-VI) can be produced using a compound of formula (CC-V) in the same manner as in <Step 3> of (Production process AA).
A compound of formula (XIII-c) can be produced using a compound of formula (CC-VI) in the same manner as in <Step 6> of (Production process BB).
A compound of formula (CC-VII) can be produced using a compound of formula (CC-V) in the same manner as in <Step 6> of (Production process BB).
A compound of formula (XIII-c) can be produced using a compound of formula (CC-VII) in the same manner as in <Step 3> of (Production process AA).
A compound of formula (DD-II) can be produced using a compound of formula (DD-I) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 24(6), pp. 742-748, 1981, by performing the reaction in the presence of alkyl amine (R7ANH2) using an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc., a polar solvent which is inactive to the reaction such as N,N-dimethylformamide, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (DD-III) can be produced using a compound of formula (DD-II) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 28(10), pp. 1387-1393, 1985, by performing the reaction in the presence of trifluoroacetic acid and sodium hydroborate using an ethereal solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc. at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound represented by formula (DD-IV) can be produced by conducting a reaction using the compound represented by formula (DD-III) by a process similar to that described in published documents, for example, Journal of Medical Chemistry, 25(6), pp. 735-742, 1982, in the presence of a carbonylation reagent such as urea, 1,1′-carbonylbis-1H-Imidazole, triphosgen using a base such as sodium hydride, lithium hydroxyde, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine and a solvent which is inactive to the reaction, such as an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or a polar solvent, e.g., N,N-dimethylformamide or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (XIV) can be produced using a compound of formula (DD-IV) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 26, Organic synthesis VIII, Asymmetric synthesis, Reduction, Sugars, and Labeled Compounds, pp. 159-266, 1992, Maruzen Co., Ltd., by performing the reaction in the presence of a catalyst such as palladium-carbon (Pd—C), Raney-Ni, dichlorotris(triphenylphosphine)ruthenium, etc. under hydrogen atmosphere using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, etc., an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc., a polar solvent, e.g., ethyl acetate, methyl acetate, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature. Alternatively, a compound of formula (XIV) can be produced by performing the reaction in the presence of Fe or Sn, in conc. hydrochloric acid or acetic acid, at a temperature in the range of 0° C. to the solvent-reflux temperature. In addition, a compound of formula (XIV) can also be produced in the presence of Lewis Acid, e.g., Nickel chloride (NiCl2), Tin chloride (SnCl2), etc. and a sodium borohydride using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, etc., an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (EE-I) can be produced using a compound of formula (DD-I) by a process similar to that described in published documents, for example, Journal of Medicinal Chemistry, 33(1), pp. 434-444, 1995, by performing the reaction in the presence of iron (Fe) and hydrochloric acid using a solvent which is inactive to the reaction such as an alcoholic solvent, e.g., methanol, ethanol, 2-propanol, etc., 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (EE-II) can be produced using a compound of formula (EE-I) in the same manner as in <Step 2> of (Production process DD).
A compound of formula (EE-IV) can be produced using a compound of formula (EE-II) by a process similar to that described in published documents, for example, Tetrahedron Letters, 36, pp. 6373-6374, 1995, by performing the reaction in the presence of a nosylation reagent (formula (EE-III)) such as 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, etc., and a basic reagent such as potassium carbonate, etc., using a solvent which is inactive to the reaction such as an aromatic hydrocarbon solvent, e.g., benzene, toluene, xylene, etc., an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, etc., a halogen solvent, e.g., methylene chloride, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (EE-V) can be produced using a compound of formula (EE-IV) and a benzyl alcohol such as veratryl alcohol (DMB-OH) by a process similar to that described in published documents, for example, Tetrahedron Letters, 36, pp. 6373-6374, 1995, by performing the reaction in the presence of a reagent such as azodicarboxylic acid diethyl (DEAD) and triphenylphosphine, using a solvent which is inactive to the reaction such as an aromatic hydrocarbon solvent, e.g., benzene, toluene, xylene, etc., an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, etc., a halogen solvent, e.g., methylene chloride, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (EE-VI) can be produced using a compound of formula (EE-V) by a process similar to that described in published documents, for example, Tetrahedron Letters, 36, pp. 6373-6374, 1995, by performing the reaction in the presence of a reagent such as benzenethiol and thioglycolic acid, and a basic reagent such as lithium hydroxide monohydrate and potassium carbonate using a solvent which is inactive to the reaction such as an aromatic hydrocarbon solvent, e.g., benzene, toluene, xylene, etc., an ethereal solvent, e.g., 1,4-dioxane, tetrahydrofuran, etc., a halogen solvent, e.g., methylene chloride, etc., or a mixed solvent thereof at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (EE-VII) can be produced using a compound of formula (EE-VI) in the same manner as in <Step 3> of (Production process DD).
A compound of formula (EE-IX) can be produced using a compound of formula (EE-VII) and a compound of formula (EE-VIII) by a process similar to that described in published documents, for example, Jikken Kagaku Koza (Experimental Chemistry Series), 4th edition, 20, Organic synthesis II, Alcohols and amines, pp. 280-372, 1992, Maruzen Co., Ltd., by performing the reaction in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate, using an ethereal solvent, e.g., diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc., a hydrocarbon solvent, e.g., benzene, toluene, etc., a polar solvent, e.g., acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, etc., or a mixed solvent thereof at a temperature in the range of room temperature to the solvent-reflux temperature.
A compound of formula (EE-X) can be produced using a compound of formula (EE-IX) by a process similar to that described in published documents, for example, the Journal of Organic Chemistry, 62(16), pp. 5428-5431, 1997, by performing the reaction in the presence or the absence of anisole using a strong acid solvent such as trifluoroacetic acid and sulfuric acid at a temperature in the range of 0° C. to the solvent-reflux temperature.
A compound of formula (XIV) can be produced using a compound of formula (EE-X) in the same manner as in <Step 4> of (Production process DD).
When the compound synthesized by any of the above-described production processes has a reactive group such as a hydroxyl group, an amino group, or carboxyl group, as a substituent, the compound can be produced by appropriately protecting the reactive group with a protective group in the production processes and then removing the protective group in an appropriate stage. The processes of the introduction and the removal of such a protective group are appropriately selected according to the type of group to be protected or the type of protective group. The introduction and the removal of the protective group can be performed by a process described in published textbooks, for example, Greene et al., Protective Groups in Organic Synthesis, (the United States), 3rd edition, 1999.
The compound of the present invention can be used in combination with other drugs.
Examples of the drugs include acetaminophen and aspirin; opioid agonists, e.g., morphine; gabapentin; pregabalin; antidepressant drugs such as duloxetine and amitriptyline; antiepileptic drugs such as carbamazepine and phenyloin; antiarrhythmic drugs such as mexiletine, which are alternatively used and prescribed for neuropathic pain; NSAIDs such as diclofenac, indomethacin, ibuprofen, and naproxen; and anti-inflammatory drugs such as COX-2 inhibitors, e.g., Celebrex; NR2B antagonists; bradykinin antagonists; and anti-migraines. Among these, preferable examples of the drugs include morphine, gabapentin or Pregabalin, diclofenac, and Celebrex.
In addition to the use of the compound of the present invention in combination with other drugs, the compound of the present invention can be performed in combination with other treatments. Examples of the other treatments include acupuncture, laser therapy, and nerve block therapy.
For diseases or conditions in which TRPV1 is involved other than pain, the compound of the present invention can be used in combination with drugs used in the corresponding field. For example, for chronic rheumatic arthritis, the compound of the present invention can be used in combination with generally used NSATDs, disease-modifying antirheumatic drugs (DMARDs), anti-TNF-α antibodies, soluble TNF-α receptors, steroids, imnunosuppressants, or the like. For COPD or allergic diseases, the compound of the present invention can be used in combination with general therapeutic agents such as β2-receptor agonists or steroids. For an overactive bladder or urinary incontinence, the compound of the present invention can be used in combination with an anticholinergic drug.
When the compound of the present invention is used for treating the above diseases and conditions in combination with an existing drug, the dosage of the existing drug can be decreased, and thus, side effects of the existing drug can be reduced. The method of using the drugs in combinations is not limited to the above-mentioned diseases and conditions, and the drugs used in combinations are not limited to the above compounds listed as examples.
When the compound of the present invention is used in combination with another drug, the drugs may be prepared separately or as a medical mixture. In the case of separate dosing, both drugs may be administered at the same time. Alternatively, one drug may be administered in advance, and another drug may then be administered some time later.
A medicine of the present invention is administered in the form of a pharmaceutical composition.
It is sufficient that the pharmaceutical composition of the present invention contains at least one compound represented by formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I′), (I″), (I′″), or (I″″). The pharmaceutical composition of the present invention is prepared by being combined with pharmaceutically acceptable additives. In more detail, the compound of the present invention may be appropriately combined with the following additives to prepare various formulations. Examples of the additives include excipients (for example, lactose, sucrose, mannitel, crystalline cellulose, silicic acid, corn starch, and potato starch); binders (for example, celluloses (hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC)), crystalline cellulose, sugars (lactose, mannitel, sucrose, sorbitol, erythritol, and xylitol), starches (corn starch and potato starch), a-starch, dextrine, polyvinylpyrrolidone (PVP), macrogol, and polyvinyl alcohol (PVA)); lubricants (for example, magnesium stearate, calcium stearate, talc, and carboxymethyl cellulose); disintegrants (for example, starches (corn starch and potato starch), sodium carboxymethyl starch, carmellose, carmellose calcium, crosscarmellose sodium, and crosspovidone); coating agents (for example, celluloses (hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC)), aminoalkyl methacrylate copolymer E, and methacrylic acid copolymer LD); plasticizers (for example, triethyl citrate, and macrogol); masking agents (for example, titanium oxide); colorants; flavoring agents; antiseptics (benzalkonium chloride and parahydroxybenzoates); isotonic agents (for example, glycerol, sodium chloride, calcium chloride, mannitol, and glucose); pH adjusting agents (sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, and a buffer solution such as a phosphate buffer); stabilizers (for example, sugars, sugar alcohols, and xanthan gum); dispersion agents; antioxidants (for example, ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, and dl-α-tocopherol); buffers; preservatives (for example, paraben, benzyl alcohol, and benzalkonium chloride); aromatics (for example, vanilin, 1-menthol, and rose oil); dissolution aids (for example, polyoxyethylene hardened castor oil, Polysorbate 80, polyethylene glycol, phospholipid cholesterol, and triethanolamine); absorption accelerators (for example, sodium glycolate, disodium edetate, sodium caprate, acylcarnitines, and limonene), gelation agents; suspending agents; emulsifying agents; and suitable additives and solvents which are normally used.
Such formulations include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, plasters, suppositories, injections, troches, liquids, spirits, suspensions, extracts, and elixirs. These formulations may be administered to a patient by oral administration, subcutaneous administration, intramuscular administration, intranasal administration, percutaneous administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, subdural administration, intraventricular administration, intrarectal administration, inhalation, or the like.
The dosage of the compound of the present invention is usually in the range of 0.005 mg to 3.0 g per day for an adult, preferably 0.05 mg to 2.5 g, and more preferably 0.1 mg to 1.5 g. The dosage may be appropriately increased or decreased in accordance with the progress of the disease and administration routes.
The entire quantity may be orally or parenterally given in one dose or given in two to six doses, or may be continuously administered by intravenous drip or the like.
The present invention will now be described more specifically using experimental examples. However, the present invention is not limited to these experimental examples.
(a) Establishment of a Transformed CHO Cell Line Expressing Human and Rat TRPV1
Human and rat vanilloid receptor 1 (hTRPV1 and rTRPV1) cDNA was cloned from human brain and rat dorsal root ganglion, respectively. The cloned TRPV1 cDNA was incorporated in a pCAGGS vector. The vector was introduced to a CHO-K1 cell line, thus performing transformation. Clones obtained by limiting dilution were stimulated with capsaicin. Clones with a high responsiveness were selected using an increase in the Ca concentration as an indicator. The selected clones were used for the following experiment.
(b-1) Measurement of Ca Influx using FDSS-6000
The transformed CHO cells expressing human or rat TRPV1 were seeded in a 96-well plate (with black walls and transparent bottoms, manufactured by Greiner) at a density of 40,000 cells per well. The cells were cultured at 37° C. in 5% CO2 atmosphere for one night. A loading solution of FLIPR Calcium 3 assay kit (manufactured by Molecular Devices Corporation) containing 2.5 mmol/L of probenecid was then added to each of the wells in the same amount as the culture medium, and the cells were cultured at 37° C. for 60 minutes. For three minutes after the cells were stimulated with capsaicin (1 nmol/L to 1 μmol/L), the change of the intracellular Ca concentration was measured using FDSS-6000 (λex: 480 nm, λem: 540 μm, manufactured by Hamamatsu Photonics K.K.). The integrated values of the increase rate of the intracellular Ca concentration were calculated for a group treated with the compounds of the present invention and a group treated with a vehicle, thus allowing capsaicin concentration-reaction curves to be obtained. A concentration (A2 value) of each of the compounds of the present invention, at which the capsaicin concentration-reaction curve obtained when the cells were treated with the vehicle was shifted two times rightward, was calculated. The inhibitory effects of the test compounds were compared using this value as an indicator.
In Table 1, compounds of the present invention having an A2 value of less than 100 nM are represented by A, and compounds having an A2 value of 100 nM or more are represented by B. When the A2 values of the compounds of the present invention were measured by the above-described method, the compounds have a potency of 1 μM or less.
(b-2) Measurement of Ca Influx using FDSS-6000
The transformed CHO cells expressing human or rat TRPV1 were inoculated in a 96-well plate (with black walls and transparent bottoms, manufactured by Greiner) at a density of 40,000 cells per well. The cells were cultured at 37° C. in 5% CO2 atmosphere for one night. A loading solution of FLIPR Calcium 3 assay kit (manufactured by Molecular Devices Corporation) containing 2.5 mmol/L of probenecid was then added to each of the wells in the same amount as the culture medium, and the cells were cultured at 37° C. for 60 minutes. For three minutes after the cells were stimulated with capsaicin (10 nmol/L), the change of the intracellular Ca concentration was measured using FDSS-6000 (λex: 480 nm, λem: 540 nm, manufactured by Hamamatsu Photonics K.K.). The integrated values of the increase rate of the intracellular Ca concentration were calculated for a group treated with the compounds of the present invention and a group treated with a vehicle. Then, the concentration of the compound of the present invention was calculated that inhibits 50% of the intracellular Ca concentration increase induced by capsaicin (IC50). Using this value as the index, inhibitory effects of the test compounds were compared. In addition, when IC50 value in human TRPV1 was less than 100 nmol/L, it was shown as A in Table 1C. When IC50 value of the compound of the present invention is measured according to the above-mentioned method, it has strong degree of at least 1 μmol/L or less.
A CFA-induced rat inflammatory pain model is prepared by a general method, for example, the method used by Pomonis J D et al. (The Journal of Pharmacology and Experimental Therapeutics, Vol. 306, pp. 387-393). More specifically, 150 μL of CFA diluted to 50% with physiological saline is administered into the sole of a rat's paw, thus inducing inflammation.
A compound of the present invention is orally administered to rats one day or one week after the administration of CPA. Thereby, a decrease in the threshold of pain is suppressed, that is, the effectiveness as a therapeutic agent for inflammatory pain is verified.
A CFA-induced rat inflammatory pain model is prepared by a general method, for example, the method used by Pomonis J D et al. (The Journal of Pharmacology and Experimental Therapeutics, Vol. 306, pp. 387-393). More specifically, 50 μL of 100% CFA is administered into the sole of a rat's paw, thus inducing inflammation.
Oral administration of the compound of the present invention to rats two days or one week after the CFA administration suppresses a decrease in the threshold of pain, which shows the effectiveness of the compound of the present invention as a therapeutic agent for inflammatory pain.
A compound of the present invention is orally administered to rats in a Chung's model, a Seltzer's model, or a STZ-induced diabetic pain model. Thereby, a decrease in the threshold of pain is suppressed, that is, the effectiveness as a therapeutic agent for neuropathic pain is verified.
Mouse PQ (Phenyl-p-quinone) writhing is prepared, e.g., by a method of Mustafa A A et al. (General Pharmacology, Vol. 23: 1177-1182). Specifically, phenyl-p-quinone diluted with physiological saline is administered into the peritoneal cavity of the mouse, and the number of mouse behaviors such as body extending, twisting and rolling up, is recorded over a certain period.
Administration of the compound of the present invention into a mouse before the administration of phenyl-p-quinone, reduced the number of mouse behaviors such as body extending, twisting and rolling up after the administration of phenyl-p-quinone, which shows effectiveness of the compound of the present invention.
When a compound of the present invention is orally administered to rats at a single dosage of 30 mg/kg, no rat dies and a remarkable abnormal behaviour of the rat is not observed. Thus, the safety of the present invention is verified.
(6) hERG Inhibitory Test by Patch-Clamp Method
An effect on hERG (a human ether-a-go-go related gene) channel is measured with fully-automated patch-clamp system (PatchXpress 7000A; molecular device). To confirm the hERS IKr current in the cell, a depolarization pulse is applied while membrane potential is hold at −80 mV. After the generated current is stabilized, a test compound is added to a perfusate. The effect of the test compound on the hERS channel is confirmed on the basis of the change in tail current induced by applying depolarization pulses having a voltage of −50 mV for 0.2 seconds and +20 mV for 5 seconds and subsequent repolarization pulse having a voltage of −50 mV for 5 seconds. The stimulus is given once every 12 seconds. The measurement is performed at room temperature. The hERG channel inhibitory activity is calculated as the ratio of the tail current 5 minutes after adding the test compound to the maximum tail current before addition of the test compound. Calculation of this inhibitory activity enables to estimate the induction of QT prolongation and subsequent fatal adverse events (ventricular tachycardia and sudden death and like) by drugs.
For example, after a single oral administration of a compound of the present invention to 5- or 6-week-old male SD rats, time-course of plasma concentration is studied. Bioavailability is high, and the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increase almost in proportion to the doses, and the linear relationship between the dose and the plasma concentration is verified. Inhibitory effects on human drug-metabolizing enzymes are measured and verified. Moreover, using liver microsomes of humans, monkeys, dogs, and rats, metabolic stability is examined. Therefore, it is clarified whether a compound receives first pass effect in the liver or not.
A test compound was orally administered to rats at single doses of 3, 10 and 30 mg/kg. Then rectal temperature was measured 30, 60 and 120 minutes after administration.
Effects on rectal temperature in rats were shown in Table 1A.
Effects on rectal temperature can be observed using various animals as appropriate other than rats. The examples of various animals include Rodents (e.g., hamsters, mice, guinea pigs), Insectivores (e.g., house musk shrews), Duplicidentatas (e.g., rabbits), Carnivora (e.g., dogs, ferrets, minks, cats), Perissodactyls (e.g., horses), Artiodactyls (e.g., pigs, cattle, goats, sheep), Primates (e.g., various monkeys, chimpanzees). Further, effects on body temperature can be observed with humans.
Compound A: 4-(3-trifluoromethylpyridine-2-yl)-N-(5-trifuluoromethylpiridine-2-yl)-1-piperadinecarboxamide
Compound B: (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxine-6-yl)acrylamide
Compound C: N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide(*)
Title: The capsaicin receptor TRPV1: Is it a pain transducer or a regulator of body temperature?
Authors: N. R. GAVVA;
Compound D: (E)-2-(8-trifluoromethyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)-N-(3-hydroxy-1,2,3,4-tetrahydroquinolin-5-yl)acetamide (EXAMPLE 68 described in WO2007/010383)
1)from published information (Non-Patent Document 4 or 5)
Differences of the mean value between a group treated with test substance and a vehicle-treated group were calculated at all measuring points and, based on the maximum absolute value of differences, changes in rectal temperature were divided into the following three categories:
−: the maximum value was less than 0.5 degree Celsius
+: the maximum value was more than 0.5 degree but less than 1.0 degree Celsius
++: the maximum value was more than 1.0 degree Celsius
A test compound was administered to rats into tail veins at single dose of 1 mg/kg. Then rectal temperature was measured 15, 30 and 60 minutes after administration. Thus effects on rectal temperature were observed and the results are shown in Table 1D.
A test compound was orally administered to rats at single dose of 10 mg/kg. Then rectal temperature was measured 30, 60 and 120 minutes after administration. Thus, effects on rectal temperature were observed and the results are shown in Table 1D.
Effects on rectal temperature can be observed using various animals as appropriate other than rats. The examples of various animals include Rodents (e.g., hamsters, mice, guinea pigs), Insectivores (e.g., house musk shrews), Duplicidentatas (e.g., rabbits), Carnivora (e.g., dogs, ferrets, minks, cats), Perissodactyls (e.g., horses), Artiodactyls (e.g., pigs, cattle, goats, sheep), Primates (e.g., various monkeys, chimpanzees). Further, effects on body temperature can be observed with humans,
1)Reference information (Non-Patent Document 4 or 5)
Differences of the mean value between a group treated with test substance and a vehicle-treated group were calculated at all measuring points and, based on the maximum absolute value of differences, changes in rectal temperature were divided into the following three categories:
−: the maximum value was less than 0.5 degree Celsius
+: the maximum value was more than 0.5 degree but less than 1.0 degree Celsius
++: the maximum value was more than 1.0 degree Celsius
The above results show that the compound of the present invention had an antagonism to the TRPV1 receptor. Furthermore, an analgetic effect is observed in the inflammatory pain model and the neuropathic pain model in vivo. In addition, no particular effect is observed in the safety test, which demonstrated the low toxicity of the present invention.
Furthermore, preferable compounds of the present invention have high metabolic stability and satisfactory pharmacokinetics. In addition, these compounds have advantage in solubility and do not cause the rise of body temperature (in particular, the change in the body temperature is very little) by the dose of pharmaceutical activity.
Accordingly, the compound of the present invention serves as a TRPV1 receptor modulator, in particular, a TRPV1 receptor antagonist and is expected as a preventive or therapeutic agent for preventing or treating pain, in particular, as a preventive or therapeutic agent for preventing or treating inflammatory pain or neuropathic pain.
It is expected that the compound of the present invention has a promising effect of preventing or treating the above various diseases and conditions. More specifically, the compound of the present invention can be used for treating acute pain; chronic pain; neuropathic pain; fibromyalgia; postherpetic neuralgia; trigeminal neuralgia; lower-back pain; pain after spinal cord injury; leg pain; causalgia; diabetic neuralgia; pain caused by edema, burns, sprains, bone fractures, and the like; pain after surgical operations; scapulohumeral periarthritis; osteoarthritis; arthritis; rheumatic arthritis pain; inflammatory pain; cancer pain; migraines; headaches; toothaches; neuralgia; muscle pain; hyperalgesia; pain caused by angina pectoris, menstruation, and the like; neuropathy; nerve damage; neurodegeneration; chronic obstructive pulmonary disease (COPD); asthma; airway hypersensitivity; stridor; cough; rhinitis; inflammation of mucosa such as eyes; nervous dermatitis; inflammatory skin complaint such as psoriasis and eczema; edema; allergic diseases; gastroduodenal ulcer; ulcerative colitis; irritable colon syndrome; Crohn disease; urinary incontinence; urge urinary incontinence; overactive bladder; cystitis; nephritis; pancreatitis; uveitis; splanchnopathy; ischemia; apoplexy; dystonia; obesity; sepsis; pruritus; and diabetes. In particular, a promising effect for neuropathic pain, inflammatory pain, and urinary incontinence can be expected.
Examples of pharmaceutical compositions of the present invention will be described below.
The above ingredients are weighed and then mixed homogeneously. The resulting mixture is compressed to prepare a tablet having a weight of 150 mg.
The above ingredients are weighed. Hydroxypropylmethyl cellulose and Macrogol 6000 are then dissolved in water, and titanium oxide is dispersed in the solution. The resulting liquid is coated on the surfaces of 300 g of the tablets prepared in Formulation example 1 to form a film. Thus, film-coated tablets are obtained.
The above ingredients are weighed and then mixed homogeneously. Subsequently, 300 mg of the resulting mixture is filled in an appropriate hard capsule with a capsule enclosing device, thus allowing a capsule to be prepared.
The above ingredients are weighed. The compound of Example 16, lactose, and corn starch are then mixed homogeneously, and an aqueous solution of hydroxypropyl cellulose is added to the mixture. Granules are produced by a wet granulation method. Talc is then homogeneously mixed with the granules. Subsequently, 200 mg of the resulting mixture is filled in an appropriate hard capsule, thus allowing a capsule to be prepared.
The above ingredients are weighed and then mixed homogeneously. Thus, 20% powder medicine is prepared.
The above ingredients are weighed. The compound of Example 38, lactose, crystalline cellulose, and partially α-converted starch are then homogeneously mixed, and an aqueous solution of hydroxypropyl cellulose (HPC) is added to the mixture. Granules or fine granules are produced by a wet granulation method. The granules or fine granules are dried, thus allowing a granular medicine or a fine granular medicine to be prepared.
The above ingredients are weighed. The compound of Example is then mixed with other ingredients and dissolved. A proper amount of purified water is added so that the total weight reaches 50 g, thus allowing a cream formulation to be prepared.
The compound of Example 50 is sufficiently ground with a mortar to prepare a fine powder. The powder is then formed into a suppository having a weight of 1 g by a fusion method.
The present invention will now be described in more detail using examples, but the present invention is not limited to the examples.
The measurement of nuclear magnetic resonance (NMR) spectrum was performed using a JEOL JNM-LA300 FT-NMR (manufactured by JEOL Ltd.) or a JEOL JNM-EX270 FT-NMR (manufactured by JEOL Ltd.). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters FractionLynx MS system (manufactured by Waters Corporation). A SunFire column (4.6 mm×5 cm, 5 μm) (manufactured by Waters Corporation) was used. Acetonitrile and a 0.05% aqueous acetic acid solution were used as the mobile phase. The analysis was performed under the following gradient conditions: acetonitrile:0.05% aqueous acetic acid solution=1:9 (0 minutes), 9:1 (5 minutes), and 9:1 (7 minutes).
In the following example 302 to 316, the measurement of nuclear magnetic resonance (NMR) spectrum was performed using JEOL JNM-EX270 FT-NMR (manufactured by JEOL Ltd.), JEOL JNM-ECX300 FT-NMR (manufactured by JEOL Ltd.) or JEOL JNM-ECX400 FT-NMR (manufactured by JEOL Ltd.). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters FractionLynx MS system (manufactured by Waters Corporation). A SunFire column (4.6 mm×5 cm, 5 μm) (manufactured by Waters Corporation) was used. Acetonitrile and a 0.05% aqueous acetic acid solution were used as the mobile phase. The analysis was performed under the following gradient conditions: acetonitrile:0.05% aqueous solution of acetic acid=1:9 (0 minute), 9:1 (5 minutes), and 9:1 (6 minutes). Discover S-class microwave synthesis system (manufactured by SEM Corporation) was used as microwave reaction system.
A toluene (200.0 mL) solution of 3-trifluoromethylphenol (16.6 g) was added dropwise to a toluene (300.0 mL) suspension of sodium hydride (7.1 g) under ice cooling. The reaction solution was stirred at the same temperature for 30 minutes, and iodine (26.0 g) was then added thereto. The solution was stirred at room temperature for 12 hours. Subsequently, 3 N hydrochloric acid was added to the solution so that the pH of the solution was adjusted to 2. The solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (30.8 g) was obtained as pale yellow oil.
Potassium carbonate (52.8 mg), 6-bromo-2-hexenoic acid methyl ester (57.5 mg), and 18-crown ether-6 (a catalitic amount) were added to an N,N-dimethylformamide (10.0 mL) solution of the compound (100.0 mg) prepared in <Step 1> of Example 1. The reaction solution was stirred at room temperature for 12 hours. Water was added to the solution, and the solution was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (66.0 mg) was obtained as colorless oil.
Palladium acetate (3.7 mg), triphenylphosphine (8.6 mg), and silver carbonate (45.0 mg) were added to a tetrahydrofuran (1.0 mL) solution of the compound (65.0 mg) prepared in <Step 2> of Example 1. The reaction solution was refluxed under heating for eight hours in a nitrogen stream. The reaction solution was subjected to Celite filtration. Water was then added to the solution, and the solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title compound (47.0 mg) was obtained as colorless crystals.
Water (1.0 mL) and lithium hydroxide (33.5 mg) were added to a tetrahydrofuran (5.0 μL) solution of the compound (160.0 mg) prepared in <Step 3> of Example 1, and the reaction solution was then refluxed under heating for six hours. The solvent was distilled off under reduced pressure. The reaction solution was then neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Ethyl acetate was added to the residue to solidify the resulting product. The title compound (120.0 mg) was obtained as colorless crystals.
Sodium carbonate (2.75 g) and chloroform (10.0 mL) solution of 2-bromoisobutyryl bromide (2.24 g) were added to a chloroform (40.0 mL) solution of 2-amino-4-nitrophenol (1.0 g) under ice cooling. The reaction solution was stirred at same temperature to room temperature overnight. The reaction mixture was filtered, and the solvent was then distilled off under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50.0 mL), and sodium carbonate (1.03 g) was added to the solution, then stirred under heating at 80° C. for 2 hours. The mixture was left to cool, water was then added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 100:0 to 70:30). The title compound (0.98 g) was obtained as a pale brown solid.
10% Pd—C (100 mg) was added to tetrahydrofuran:methanol-1:1 (50 mL) solution of the compound (500.0 mg) prepared in <Step 5> of Example 1 was stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. n-Hexane and diethyl ether were added to the residue to solidify the resulting product. The title compound (380.0 mg) was obtained as a pale brown solid.
Oxalyl chloride (0.07 mL) and N,N-dimethylformamide (one drop) were added to a methylene chloride (5.0 mL) solution of the compound (110.0 mg) prepared in <step 4> of Example 1. The mixture was stirred at room temperature for 2 hours. The solvent was then distilled off under reduced pressure. A methylene chloride (5.0 mL) and pyridine (0.1 mL) solution of the compound prepared in <step 6> of Example 1 was added dropwise to the residue which was dissolved in methylene chloride (2.0 mL), and then stirred at room temperature for 2 hours. The reaction solution was neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (100.0 mg) was obtained as a white solid.
The title compound (28.0 g) was obtained as a white solid from 2-amino-4-nitrophenol (20.0 g) and diethyl 2-bromo-2-methylmalonate (6.2 mL) by the same process as that used in <Step 5> of Example 1.
The title compound (420.0 mg) was obtained as a pale brown solid from the compound (500.0 mg) prepared in <Step 1> of Example 2 by the same process as that used in <Step 6> of Example 1.
The title compound (140.8 mg) was obtained as a white solid from the compound (140.0 mg) prepared in <Step 2> of Example 2 by the same process as that used in <Step 7> of Example 1.
The title compound (18.0 g) was obtained as a pale brown solid from 2-amino-4-nitrophenol (20.0 g) and α-bromo-γ-butyrolactone (23.6 g) by the same process as that used in <Step 5> of Example 1.
The title compound (2.5 g) was obtained as a white solid from the compound (3.0 g) prepared in <Step 1> of Example 3 by the same process as that used in <Step 6> of Example 1.
The title compound (13.0 mg) was obtained as a white solid from the compound (50.0 mg) prepared in <Step 2> of Example 3 by the same process as that used in <Step 7> of Example 1.
Mercaptoacetic acid ethyl ester (5.0 g) and triethylamine (5.3 μL) were added to a tetrahydrofuran solution of 2,4-dinitrofluorobenzene (5.5 mL) and stirred at room temperature for 5 hours. Ice water was added to the reaction solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (5.0 g) was obtained as a yellow solid.
Ethyl acetate (20.0 mL) and acetic acid (20.0 mL) solution of the compound (5.0 g) prepared from <step 1> in example 4 was added to water (20.0 mL) and acetic acid (1.0 mL) suspension of iron powder (13.0 g) and then stirred under heating at 80° C. for 4 hours. The mixture was left to cool. The mixture was filtered and extracted with ethyl acetate. The organic layer was sequentially washed with water, aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue to solidify the resulting product. The title compound (2.1 g) was obtained as a pale brown solid.
The title compound (440.0 mg) was obtained as a pale yellowish-white solid from the compound (300.0 mg) prepared in <Step 2> of Example 4 by the same process as that used in <Step 7> of Example 1.
m-Chloroperbenzoic acid (39.7 mg) was added to the methylene chloride (5.0 mL) solution of the compound (100.0 mg) prepared from <step 3> in example 4, and the mixture was stirred. After consumption of starting compound, aqueous sodium sulfite solution was added to the mixture and extracted with ethyl acetate. The organic layer was sequentially washed with aqueous sodium sulfite solution and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue to solidify the resulting product. The title compound (42.0 mg) was obtained as a pale yellowish-white solid.
m-Chloroperbenzoic acid (127.1 mg) was added to the methylene chloride (5.0 mL) solution of the compound (100.0 mg) prepared from <step 3> in example 4, and the mixture was stirred at room temperature overnight. Aqueous sodium sulfite solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with aqueous sodium sulfite solution and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue to solidify the resulting product. The title compound (42.0 mg) was obtained as a pale yellowish-white solid.
Sodium hydrogen carbonate (4.15 g) and glycine ethyl ester hydrochloride (3.79 g) were added to aqueous ethanol (100.0 mL) solution of 2,4-dinitrochlorobenzene (5.0 g), and refluxed for 4.5 hours. The mixture was left to cool. The solvents were distilled off under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 85:15). The title compound (3.2 g) was obtained as a yellow solid.
The title compound (260.0 mg) was obtained as a brown solid from the compound (300.0 mg) prepared in <Step 1> of Example 7 by a process similar to the process used in <Step 6> of Example 1.
The title compound (25.0 mg) was obtained as a white solid from the compound (50.0 mg) prepared in <Step 2> of Example 7 by the same process as that used in <Step 7> of Example 1.
Formalin (11.4 mg) was added to a water solution (0.5 mL) of sulfuric acid (0.18 g) under ice cooling. The compound (30.0 mg) prepared in <step 3> of Example 7 and tetrahydrofuran solution of sodium borohydride (13.6 mg) were added dropwise to the mixture at the same temperature and the mixture was stirred at same temperature for 5 minutes. Water was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue to solidify the resulting product. The title compound (21.0 mg) was obtained as a pale yellowish-white solid.
The title compound (1.0 g) was obtained as a yellow solid from 2,4-dinitrofluorobenzene (1.0 g) and (DL)-serine methyl ester hydrochloride (0.84 g) by a process similar to the process used in <Step 1> of Example 7.
The title compound (100.0 mg) was obtained as a black solid from the compound (200.0 mg) prepared in <Step 1> of Example 9 by a process similar to the process used in <Step 6> of Example 1.
The title compound (5.0 mg) was obtained as a pale brown solid from the compound (110.0 mg) prepared in <Step 2> of Example 9 by a process similar to the process used in (Step 7> of Example 1.
The title compound (1.37 g) was obtained as a yellow solid from 2,4-dinitrofluorobenzene (1.0 g) and 2-methyl-alanine methyl ester hydrochloride (0.83 g) by a process similar to the process used in <Step 1> of Example 7.
The title compound (470.0 mg) was obtained as a brown solid from the compound (500.0 mg) prepared in <Step 1> of Example 10 by the same process as that used in <Step 6> of Example 1.
The title compound (120.0 mg) was obtained as a pale yellow solid from the compound (340.0 mg) prepared in <Step 2> of Example 10 by the same process as that used in <Step 7> of Example 1.
The title compound (10.0 mg) was obtained as a pale yellowish-white solid from the compound (32.0 mg) prepared in <Step 3> of Example 10 by the same process as that used in Example 8.
Sodium hydride (0.9 g) and carbonyldiimidazole (1.8 g) were added to a tetrahydrofuran (50.0 mL) solution of 2-amino-4-nitrobenzyl alcohol under ice cooling, and refluxed for 6 hours. The mixture was left to cool. Aqueous saturated ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (1.2 g) was obtained as a white solid.
The title compound (39.3 mg) was obtained as a white solid from the compound (100.0 mg) prepared in <Step 1> of Example 12 by the same process as that used in <Step 6> of Example 1.
The title compound (20.0 mg) was obtained as a white solid from the compound (28.0 mg) prepared in <Step 2> of Example 12 by the same process as that used in <Step 7> of Example 1.
Borane-tetrahydrofuran complex (1.0 M solution of tetrahydrofuran) (2.2 mL)was added to a tetrahydrofuran (6.0 mL) solution of 2-amino-4-nitrobenzamide (100.0 mg) and refluxed for 2 hours. The mixture was left to cool. Methanol was then added to the mixture and neutralized with 10% hydrogen chloride in methanol. The solvents were distilled off under reduced pressure. A solution of 1 N aqueous sodium hydroxide solution was added to the residue and was extracted with methylene chloride. The organic layer was washed with saturated saline solution, and dried over anhydrous sodium sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (92.1 mg) was obtained as an orange solid.
The title compound (75.4 mg) was obtained as a yellow solid from the compound (80.0 mg) prepared in <Step 1> of Example 13 by a process similar to the process used in <Step 1> of Example 12.
The title compound (44.8 mg) was obtained as a pale brown solid from the compound (50.0 mg) prepared in <Step 2> of Example 13 by the same process as that used in <Step 6> of Example 1.
The title compound (56.2 mg) was obtained as a white solid from the compound (40.0 mg) prepared in <Step 3> of Example 13 by a process similar to the process used in <Step 7> of Example 1.
Manganese dioxide (1.0 g) was added to a methylene chloride (30.0 mL) solution of 2-amino-4-nitrobenzyl alcohol (500.0 mg), and was stirred at room temperature for 2 hours. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The title crude compound (456.0 mg) was obtained as a reddish-orange solid.
Methylamine (10 M solution of methanol) (0.6 mL) was added to a methanol (1.0 mL) solution of the compound (100.0 mg) prepared in <Step 1> of Example 14, and the reaction mixture was stirred at room temperature overnight. Sodium borohydride (22.7 mg) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was then distilled off under reduced pressure. 1 N aqueous sodium hydroxide solution was added to the mixture, the mixture was extracted with ethyl acetate. The Organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The title compound (123.0 mg) was obtained as brown oil.
The title compound (40.0 mg) was obtained as a yellow solid from the compound (110.0 mg) prepared in <Step 2> of Example 14 by a process similar to the process used in <Step 1> of Example 12.
The title compound (34.0 mg) was obtained as a white solid from the compound (50.0 mg) prepared in <Step 3> of Example 14 by the same process as that used in <Step 6> of Example 1.
The title compound (52.5 mg) was obtained as a white solid from the compound (30.0 mg) prepared in <Step 4> of Example 14 by a process similar to the process used in <Step 7> of Example 1.
The title compound (112.0 mg) was obtained as a yellow solid from 2-hydroxyethylamine (72.1 pt) by the same process as that used in <Step 2> of Example 14.
tert-butyldimethylsilyl chloride (110.0 mg), imidazole (96.7 mg) and 4-dimethylaminopyridine (5.8 mg) were added to a N,N-dimethylformamide (5.0 mL) solution of the compound (100.0 mg) prepared in <Step 1> of Example 15, and the mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; methylene chloride:methanol=100:0 to 95:5). The title compound (145.0 mg) was obtained as yellow amorphous.
The title compound (252.0 mg) was obtained as a yellow solid from the compound (500.0 mg) prepared in <Step 2> of Example 15 by a process similar to the process used in <Step 1> of Example 12.
The title compound (191.0 mg) was obtained as a white solid from the compound (190.0 mg) prepared in <Step 3> of Example 15 by the same process as that used in <Step 6> of Example 1.
The title compound (174.0 mg) was obtained as a white solid from the compound (180.0 mg) prepared in <Step 4> of Example 15 by a process similar to the process used in <Step 7> of Example 1.
The title compound (50.0 mg) was obtained as a white solid from deprotection of the compound (100.0 mg) prepared in <Step 5> of Example 15 by using acid catalyst.
The title compound (391.0 mg) was obtained as a yellow oil from 2-methoxyethylamine (0.31 mL) by the same process as that used in <Step 2> of Example 14.
The title compound (105.0 mg) was obtained as a yellow solid from the compound (200.0 mg) prepared in <Step 1> of Example 16 by a process similar to the process used in <Step 1> of Example 12.
The title compound (63.0 mg) was obtained as a pale green solid from the compound (86.0 mg) prepared in <Step 2> of Example 16 by the same process as that used in <Step 6> of Example 1.
The title compound (66.0 mg) was obtained as a pale yellow solid from the compound (56.0 mg) prepared in <Step 3> of Example 16 by a process similar to the process used in <Step 7> of Example 1.
Sulfamide (170.0 mg) was added to a pyridine (6.0 mL) solution of the compound (100.0 mg) prepared in <Step 1> of Example 13, and the mixture was refluxed for 6 hours. The mixture was left to cool. Water was then added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The title compound (120.0 mg) was obtained as brown solid.
The title compound (57.4 mg) was obtained as a black solid from the compound (75.0 mg) prepared in <Step 1> of Example 17 by the same process as that used in <Step 6> of Example 1.
The title compound (61.0 mg) was obtained as a white solid from the compound (50.0 mg) prepared in <Step 2> of Example 17 by a process similar to the process used in <Step 7> of Example 1.
The title compound (53.8 mg) was obtained as a pale yellow amorphous from 5-amino-3,4-dihydro-2(1H)-quinolinone (60.0 mg) by a process similar to the process used in <Step 7> of Example 1.
The title compound (24.0 mg) was obtained as pale yellow amorphous from 1-(2-tert-butyldimethylsiloxyethyl)-5-nitro-3,4-dihydro-2(1H)-quinolinone (40.0 mg) by the same process as that used in <Step 6> of Example 1.
The title compound (27.0 mg) was obtained as a white amorphous from the crude compound (24.0 mg) prepared in <Step 1> of Example 19 by a process similar to the process used in <Step 7> of Example 1.
The title compound (10.0 mg) was obtained as a white amorphous from the crude compound (27.0 mg) prepared in <Step 2> of Example 19 by the same process as that used in <Step 6> of Example 15.
The title compound (150.0 mg) was obtained as a yellow amorphous from 2,6-dinitrochlorobenzene (2.0 g) and glycolic acid ethyl ester (1.12 mL) by a process similar to the process used in <Step 1> of Example 7.
The title compound (43.0 mg) was obtained as a yellow solid from the compound (150.0 mg) prepared in <Step 1> of Example 20 by the same process as that used in <Step 6> of Example 1.
The title compound (50.0 mg) was obtained as a pale yellow solid from the compound (43.0 mg) prepared in <Step 2> of Example 20 by a process similar to the process used in <Step 7> of Example 1.
The title compound (180.0 mg) was obtained as a yellow solid from 2,6-dinitrochlorobenzene (200.0 mg) and glycine ethyl ester hydrochloride (150.0 mg) by a process similar to the process used in <Step 1> of Example 7.
The title compound (120.0 mg) was obtained as a brown solid from the compound (180.0 mg) prepared in <Step 1> of Example 21 by the same process as that used in <Step 6> of Example 1.
The title compound (89.0 mg) was obtained as a pale yellow solid from the compound (120.0 mg) prepared in <Step 2> of Example 21 by a process similar to the process used in <Step 7> of Example 1.
The title compound (19.0 mg) was obtained as a pale yellow solid from the compound (30.0 mg) prepared in <Step 3> of Example 21 by the same process as that used in Example 8.
Sodium hydride (550.0 mg) was added to an N,N-dimethylformamide (20.0 mL) solution of 3-hydroxybenzotrifluoride (2.0 g), and the reaction solution was stirred at room temperature for one hour. β-Propiolactone (1.0 mL) was added thereto, and the solution was stirred at room temperature for 2.5 hours. Water was then added to the solution, and the pH was adjusted to 2 with 2 N hydrochloric acid. The solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the residue to perform crystallization. The title compound (2.2 g) was obtained as colorless crystals.
The compound (4.7 g) prepared in <Step 1> of Example 23 was dissolved in polyphosphoric acid (100 g), and the reaction solution was stirred at an outer temperature in the range of 100° C. to 120° C. for one hour. The reaction solution was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=10:1). The title compound (4.2 g) was obtained as colorless crystals.
A tetrahydrofuran (10 mL) solution of triethyl phosphonoacetate (8.5 mL) was added to a tetrahydrofuran (30.0 mL) suspension of 60% sodium hydride (1.7 g) at an inner temperature of 20° C. or lower, and the reaction mixture was then stirred at room temperature for one hour. A tetrahydrofuran (10 mL) solution of the compound (4.2 g) prepared in <Step 2> of Example 23 was added to the mixture under ice cooling, and the mixture was then stirred overnight at room temperature. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 10:1). The title compound (1.4 g) was obtained as colorless crystals.
The title compound (0.35 g) was obtained as colorless crystals from the compound (1.0 g) prepared in <Step 3> of Example 23 by the same process as that used in <Step 4> of Example 1.
The title compound (175.8 mg) was obtained as a pale yellowish-white solid from the compound (240.0 mg) prepared in <Step 4> of Example 23 by the same process as that used in <Step 7> of Example 1.
Methyllithium (1.0 M diethyl ether solution, 98.0 mL) was added to a tetrahydrofuran (60.0 mL) solution of 4-trifluoromethylsalicylic acid (6.0 g) under ice cooling, and the reaction solution was stirred at room temperature for two hours. Trimethylsilyl chloride (37.0 mL) and 1 N hydrochloric acid (100 mL) were added to the reaction solution under ice cooling. The reaction solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (5.86 g) was obtained as pale yellow oil.
Acetone (3.3 mL) and pyrrolidine (3.7 mL) were added to a methanol (140.0 mL) solution of the compound (5.71 g) prepared in <Step 1> of Example 24, and the reaction solution was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure. A 10% aqueous citric acid solution (50.0 mL) and water (50.0 mL) were added to the residue, and the resulting solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (6.27 g) was obtained as orange oil.
Vinyl magnesium chloride (38.0 mL) was added to a tetrahydrofuran (120.0 mL) solution of the crude compound (6.14 g) prepared in <Step 2> of Example 24 under ice cooling, and the reaction solution was stirred at room temperature for five hours. Water was added to the reaction solution, and the reaction solution was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (2.35 g) was obtained as a yellow oil.
Pyridinium dichromate (5.22 g) was added to a dichloromethane (35.0 mL) solution of the compound (1.89 g) prepared in <Step 3> of Example 24 and molecular sieves 4A (10.0 g) under ice cooling, and the reaction solution was stirred at room temperature for two hours. Diethyl ether was added to the reaction solution, and the reaction solution was subjected to Celite filtration. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (440 mg) was obtained as a yellow oil.
Sodium hydrogenphosphate (180 mg), 2-methyl-2-butene (0.63 mL), and water (2.0 mL) were added to a tert-butanol (8.0 mL) solution of the compound (400 mg) prepared in <Step 4> of Example 24. Sodium hypochlorite (400 mg) was added to the reaction solution under ice cooling, and the reaction solution was stirred at the same temperature for two hours. The reaction solution was neutralized with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (477 mg) was obtained as colorless crystals.
The title compound (138.6 mg) was obtained as a pale yellowish-white solid from the compound (260.0 mg) prepared in <Step 5> of Example 24 and 7-amino-3,4-dihydroquinolin-2(1H)-one (100.0 mg) by the same process as that used in <Step 7> of Example 1.
The title compound (156.0 mg) was obtained as a pale yellow amorphous from the compound (100.0 mg) prepared in <Step 5> of Example 24 and 7-amino-1-methyl-3,4-dihydro-2(1H)-quinolinone hydrochloride (150.0 mg) by the same process as that used in <Step 7> of Example 1.
2,2-Dimethoxypropane (24.0 mL) and concentrated sulfuric acid (2.0 mL) were added to a chloroform (200 mL) solution of 2-hydroxy-4-trifluoromethylbenzamide (10.0 g), and the reaction solution was refluxed under heating for 3 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and collected by filtration of the suspension. The title compound (9.52 g) was obtained as a white solid.
The Lawesson's reagent (7.85 g) was added to a toluene (200 mL) solution of the compound (9.52 g) prepared in <Step 1> of Example 26, and the reaction solution was refluxed under heating for one hour. The reaction solution was left to cool and was then purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 88:12 to 80:20). The title compound (9.72 g) was obtained as a yellow solid.
4-(4,6-Dimethoxy-1,3,5-triadine-2-yl)-4-methylmorpholinium chloride (7.88 g) was added to a methanol (190 mL) solution of 7-amino-3,4-dihydroquinoline-2(1H)-one (3.08 g) and bromoacetic acid (3.17 g), and the mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure. Water was added to the residue. The precipitate was collected by filtration and washed with water. Ethanol was added to the mixture. After azeotropic removal water, ethyl acetate was added to the residue and collected by filtration of the suspension. The title compound (4.98 g) was obtained as a pale brown solid.
Potassium carbonate (0.39 g) was added to a N,N-dimethylformamide (20.0 mL) solution of the compound (1.00 g) prepared in <Step 2> of Example 26 and the compound (1.09 g) prepared in <Step 3> of Example 26, then stirred under heating at 80° C. for one hour. Water was added to the mixture, and the resulting solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Diethyl ether was added to the residue and collected by filtration of the suspension. The title compound (1.58 g) was obtained as a pale off-white solid.
N,N-Diisopropylethylamine (1.50 mL) and triphenylphosphine (1.36 g) were added to the compound (0.80 g) prepared in <Step 4> of Example 26, and the reaction mixture was subjected to microwave irradiation at 180° C. for one hour. The reaction mixture was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=50:50 to 0:100). The title compound (0.22 g) was obtained as a yellow amorphous.
A solution of tetrahydrofuran (50 mL) of N,N′-dicyclohexylcarbodiimide (11.0 g) was added dropwise to a tetrahydrofuran (50 mL) suspension of 2-hydroxy-4-trifluoromethylbenzoic acid (10.0 g), tert-butanol (92.8 mL) and 4-(N,N-dimethylamino)pyridine (0.24 g), and stirred at room temperature for 64 hours. The precipitate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (8.18 g) was obtained as colorless oil,
Cesium carbonate (11.4 g) was added to a N,N-dimethylformamide (50 mL) solution of the compound (4.58 g) prepared in <Step 1> of Example 27 and 2-(tert-butoxycarbonylamino)ethyl bromide (4.70 g), and the mixture was stirred under heating at 80° C. for one hour. Water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (7.78 g) was obtained as a colorless oil.
Trifluoroacetic acid (50 mL) was added to a mixture of the compound (3.54 g) prepared in <Step 2> of Example 27 and anisole (0.95 mL), and stirred at 50° C. for 30 minutes. Trifluoroacetic acid was distilled off under reduced pressure. The residue was dissolved in acetonitrile (175 mL), Benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (7.72 g) and diisopropylethylamine (4.68 mL) were sequentially added to the mixture and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 67:33 to 0:100). The title compound (0.94 g) was obtained as colorless amorphous.
The title compound (0.67 g) was obtained as a milky white solid from the compound (0.94 g) prepared in <Step 3> of Example 27 by the same process as that used in <Step 2> of Example 26.
The title compound (0.40 g) was obtained as an off-white solid from the compound (0.24 g) prepared in <Step 4> of example 27 and the compound (0.29 g) in <Step 3> of Example 26 by the same process as that used in <Step 4> of Example 26.
The title compound (80 mg) was obtained as a milky white solid from the compound (0.20 g) prepared in <Step 5> of Example 27 by the same process as that used in <Step 5> of Example 26.
Lithium hexamethyldisilazide (1.0 M, tetrahydrofuran solution) (53.0 mL) was added dropwise to a tetrahydrofuran (100.0 mL) solution of β-hydroxypropanoic acid methyl ester (2.50 g) at −50° C., and the reaction mixture was stirred at the same temperature for 30 minutes. Benzyl bromide (2.86 μL) was added to the mixture. The mixture was stirred at −20° C. for one hour. Aqueous saturated ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (2.0 g) was obtained as colorless oil.
A mixed acid of fuming nitric acid (0.5 mL) and concentrated sulfuric acid (1.0 mL) was added dropwise to a concentrated sulfuric acid (1.5 mL) solution of the compound (0.4 g) prepared in <Step 1> of Example 28 under ice cooling, and the mixture was stirred at room temperature for one hour. Ice was added to the mixture and diluted with water. The mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (0.3 g) was obtained as colorless oil.
The title compound (125.0 mg) was obtained as a pale brown solid from the compound (0.4 g) prepared in <Step 2> of Example 28 by the same process as that used in <Step 6> of Example 1.
The title compound (54.0 mg) was obtained as a pale yellowish-white solid from the compound (120.0 mg) prepared in <Step 3> of Example 28 by a process similar to the process used in <Step 7> of Example 1.
The title compound (350.0 mg) was obtained as a pale yellow solid from 2,2-dimethyl-3-phenylpropanoic acid (290.0 mg) by a process similar to the process used in <Step 2> of Example 28.
Concentrated sulfuric acid (3.0 mL) was added dropwise to a ethanol (50.0 mL) solution of the compound (350.0 mg) prepared in <step 2> of Example 29 under ice cooling, and the mixture was refluxed for 18 hours. The mixture was left to cool. The solvent was distilled off under reduced pressure. Ice was added to the residue and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (330.0 mg) was obtained as colorless oil.
The title compound (120.0 mg) was obtained as a pale yellow solid from the compound (330.0 mg) prepared in <Step 2> of Example 29 by a process similar to the process used in <Step 6> of Example 1.
The title compound (65.0 mg) was obtained as a pale yellowish-white solid from the compound (41.9 mg) prepared in <Step 3> of Example 29 by a process similar to the process used in <Step 7> of Example 1.
Ethyl(triphenylphosphoranylidene)acetate (46.6 g) was added to a toluene (300.0 mL) solution of 2,4-dinitrobenzaldehyde (25.0 g), and the reaction mixture was refluxed under heating for two hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. A diethyl ether was added to the residue, and then the formed triphenylphosphine oxide was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0˜80:20). The title compound (26.0 g) was obtained as a yellow solid.
A morpholine (1.0 g) and a lithium perchlorate (0.8 g) were added to a tetrahydrofuran (10.0 mL) solution of the compound (2.0 g) prepared in <Step 1> of Example 30, and the mixture was stirred at room temperature for two days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0˜80:20). The title compound (2.2 g) was obtained as a yellow oil.
The title compound (800.0 mg) was obtained as a pale yellow-white solid from the compound (2.15 g) prepared in <Step 2> of Example 30 by the same process as that used in <Step 6> of Example 1.
The title compound (190.0 mg) was obtained as a pale yellow-white solid from the compound (100.0 mg) prepared in <Step 3> of Example 30 by the same process as that used in <Step 7> of Example 1.
The title compound (116.0 mg) was obtained as a pale yellow-white solid from 7-amino-3-(1-piperidinyl)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (176.0 mg) was obtained as a pale yellow-white solid from 7-amino-3,4-dihydro-3-(4-methyl-1-piperazinyl)-2(1H)-quinolinone (140.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (46.0 mg) was obtained as a pale yellow-white solid from the compound (100.0 mg) prepared in <Step 3> of Example 30 by the same process as that used in <Step 7> of Example 1.
Optical resolution of the compound (20 mg) obtained in Example 30 was performed by preparative chromatography (column; CHIRALPAK AS (2.0 cm×25.0 cm) manufactured by Daicel Chemical Industries Ltd., eluate; n-hexane:ethanol 50:50, flow rate; 15.0 mL/min, UV; 254 nm). Accordingly, enantiomers of the title compound were obtained as a first fraction (5.5 mg, white solid, 99.8% ee, retention time: 6.4 minutes; Example 34) and a second fraction (3.3 mg, white solid, 97.9% ee, retention time: 7.8 minutes; Example 35).
A diethyl oxalate (48.2 g) and sodium ethoxide (11.2 g) were added to a ethanol (300.0 mL) solution of 2,6-dinitrotoluene (30.0 g), and the mixture was stirred at 40° C. for four hours. The reaction mixture was cooled to room temperature. A 1N hydrochloric acid was added to the mixture, and the solvent was distilled off under reduced pressure. The residual aqueous solution was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=80:20˜70:30). The title compound (31.1 g) was obtained as a pale red solid.
A triethylorthoformate (9.6 mL) and trifluoroborane diethyl ether complex (2.4 mL) were added to an ethanol (16.2 mL) solution of the compound (5.4 g) prepared in <Step 1> of Example 36, and the mixture was refluxed under heating for three days. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The mixture was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0˜50:50). The title compound (1.45 g) was obtained as a yellow solid.
The title compound (220.0 mg) was obtained as a yellow solid from the compound (1.4 g) prepared in <Step 2> of Example 36 by the same process as that used in <Step 6> of Example 1.
A lithium aluminium hydride (140.0 mg) was added to the tetrahydrofuran (4.0 mL) solution of the compound (180.0 mg) prepared in <Step 3> of Example 36, and the mixture was refluxed under heating for thirty minutes. The reaction mixture was cooled to room temperature. Water and 1N sodium hydroxide were added to the mixture, and diluted with tetrahydrofuran. The insoluble matter was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 100:0˜70:30). The title compound (214.4 mg) was obtained as a pale brown solid.
The title compound (300.0 mg) was obtained as a white solid from the compound (150.0 mg) prepared in <Step 4> of Example 36 by the same process as that used in <Step 7> of Example 1.
The title compound (24.0 mg) was obtained as a white solid from the compound (50.0 mg) prepared in <Step 5> of Example 36 by the same process as that used in <Step 6> of Example 15.
The title compound (5.5 g) was obtained as an orange solid from 3,4-dihydro-8-hydroxy-2(1H)-quinolinone (5.0 g) prepared by a process similar to the process used in <step 2> of Example 28.
A potassium carbonate (220.0 mg) and a 3-bromo-1-tert-butyldimethylsiloxypropane (350.0 mg) were added to a N,N-dimethylformamide (4.0 mL) solution of the compound (300.0 mg) prepared in <Step 1> of Example 37, and the mixture was stirred at 100° C. for one hour. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with methylene chloride. The organic layer was washed with water, saturated sodium hydrogencarbonate and a saturated saline solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=80:20˜70:30). The title compound (214.4 mg) was obtained as a brown solid.
The title compound (150.8 mg) was obtained as a brown oil from the compound (210.0 mg) prepared in <Step 2> of Example 37 by the same process as that used in <Step 6> of Example 1.
The title compound (126.1 mg) was obtained as a brown oil from the compound (130.0 mg) prepared in <Step 3> of Example 37 by the same process as that used in <Step 7> of Example 1.
The title compound (86.8 mg) was obtained as a white solid from the compound (120.0 mg) prepared in <Step 4> of Example 37 by the same process as that used in <Step 6> of Example 15.
The title compound (2.2 g) was obtained as a yellow oil from the compound (1.5 g) prepared in <Step 1> of Example 14 and benzylamine (1.1 mL) by the same process as that used in <Step 2> of Example 14.
The title compound (711.0 mg) was obtained as a yellow solid from the compound (1.0 g) prepared in <step 1> of Example 38 by a process similar to the process used in <step 1> of Example 12.
The title compound (57.3 mg) was obtained as a white solid from the compound (60.0 mg) prepared in <Step 2> of Example 38 by the same process as that used in <Step 6> of Example 1.
The title compound (67.0 mg) was obtained as a pale green solid from the compound (50.0 mg) prepared in <Step 3> of Example 38 by the same process as that used in <Step 7> of Example 1.
A sodium hydride (10.2 mg) and a methyl iodide (53.2 μL) were added to a N,N-dimethylformamide (2.0 mL) solution of the compound (100.0 mg) prepared in <Step 2> of Example 38, and the mixture was stirred at room temperature for two hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate, n-hexane:ethyl acetate=100:0˜80:20). The title compound (42.0 mg) was obtained as a yellow amorphous.
The title compound (37.0 mg) was obtained as a pale yellow amorphous from the compound (42.0 mg) prepared in <Step 1> of Example 39 by the same process as that used in <Step 6> of Example 1.
The title compound (22.0 mg) was obtained as a pale yellow amorphous from the compound (38.0 mg) prepared in <Step 2> of Example 39 by the same process as that used in <Step 7> of Example 1.
The title compound (15.2 g) was obtained as a yellow oil from a 2,4-dinitrofluorobenzene (4.7 mL) and (DL)-O-(tetrahydro-2H-pyran-2-yl)serine ethyl ester by a process similar to the process used in <step 1> of Example 7.
The title compound (300.0 mg) was obtained as a brown solid from the compound (1.0 g) prepared in <Step 1> of Example 40 by the same process as that used in <Step 6> of Example 1.
The title compound (320.0 mg) was obtained as a pale yellow solid from the compound (210.0 mg) prepared in <Step 2> of Example 40 by the same process as that used in <Step 7> of Example 1.
The title compound (260.0 mg) was obtained as a pale yellow-white solid from the compound (320.0 mg) prepared in <step 3> of Example 40 by a process similar to the process used in <Step 6> of Example 15.
The title compound (23.0 mg) was obtained as a pale yellow solid from the compound (50.0 mg) prepared in <Step 4> of Example 40 by a process similar to the process used in Example 8.
The title compound (79.5 mg) was obtained as a pale brown solid from a 7-amino-3-(N,N-dimethylamino)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (10.5 mg) was obtained as a pale yellow solid from a 7-amino-3-(N,N-diethylamino)-3,4-dihydro-2(1H)-quinolinone (60.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (37.5 mg) was obtained as a yellow solid from a 7-amino-3-(N,N-bis(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (48.4 mg) was obtained as a white solid from a 7-amino-3-(N-methyl-N-(2-methoxyethyl)amino)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (66.7 mg) was obtained as a white solid from a 7-amino-3-(pyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinone (70.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (56.1 mg) was obtained as a white solid from a 7-amino-3-((3S)-fluoropyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (43.5 mg) was obtained as a yellow solid from a 7-amino-3-((3S)-tert-butyldimethylsiloxypyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinone (180.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (12.5 mg) was obtained as a white solid from a 7-amino-3-((2S)-tert-butyldimethylsiloxymethylpyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (39.9 mg) was obtained as a pale yellow solid from a 7-amino-3-((2S)-methoxymethylpyrrolidin-1-yl)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (8.3 mg) was obtained as a pale yellow amorphous from a 7-amino-3-(N-methyl-N-cyclohexylamino)-3,4-dihydro-2(1H)-quinolinone (68.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (4.3 mg) was obtained as a pale yellow solid from a 7-amino-3-(1-ethoxycarbonyl-4-piperazinyl)-3,4-dihydro-2(1H)-quinolinone (120.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (62.9 mg) was obtained as a white solid from a 7-amino-3-([1,4]oxazepan-4-yl)-3,4-dihydro-2(1H)-quinolinone (100.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (260.4 mg) was obtained as a white solid from a 7-amino-3-(4-thiomorpholinyl)-3,4-dihydro-2(1H)-quinolinone (200.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (207.5 mg) was obtained as a white solid from a 7-amino-3-(4-methoxy-1-piperidinyl)-3,4-dihydro-2(1H)-quinolinone (150.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (158.0 mg) was obtained as a white solid from a 7-amino-3-((3S)-methoxypyrrolidin-1-yl))-3,4-dihydro-2(1H)-quinolinone (130.0 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
The title compound (17.5 mg) was obtained as a brown solid from a 7-amino-3-(4-(N-methyl-N-(4-tetrahydropyranyl)amino)-3,4-dihydro-2(1H)-quinolinone (14.5 mg) prepared in the same process as that used in Example 30 by a process similar to the process used in <step 7> of Example 1.
2,3-dichloro-5,6-dicyano-p-benzoquinone (36.7 mg) was added to a acetonitrile (2.0 mL) solution of the compound (40.0 mg) prepared in <Step 3> of Example 30, and the mixture was refluxed for ten minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; ethyl acetate:methanol=100:0˜90:10). The title compound (6.0 mg) was obtained as a pale brown solid.
The title compound (2.6 mg) was obtained as a yellow amorphous from the compound (6.0 mg) prepared in <Step 1> of Example 58 by a process similar to the process used in <step 7> of Example 1.
The title compound (130.4 mg) was obtained as an orange solid from 2,4-dinitrobenzeneethansulfonyl chloride (510.0 mg) synthesized in accordance with the process described in PCT Publication No. 97/044345 pamphlet prepared in a process similar to the process used in <step 2> of Example 4.
The title compound (36.4 mg) was obtained as a pale yellow amorphous from the compound (72.8 mg) prepared in <Step 1> of Example 59 by a process similar to the process used in <step 7> of Example 1.
The title compound (25.7 g) was obtained as yellow oil from the compound (44.5 g) prepared in <Step 1> of Example 24 and 3-pentanone (36.6 mL) by a similar to the process used in <Step 2> of Example 24.
n-Butyllithium (1.59 M, n-hexane solution, 128.0 mL) was added to a tetrahydrofuran (500.0 mL) solution of diisopropylamine (30.0 mL) at an outer temperature −78° C., and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (21.0 mL) was added to the mixture, and the mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran (500.0 mL) solution of the compound (29.2 g) prepared in <Step 1> of Example 60 was added dropwise to the mixture at the same temperature, and the mixture was stirred at the same temperature for 20 minutes and room temperature for 90 minutes. Water was added to the mixture under ice cooling. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
The title crude compound (36.3 g) was obtained as a white solid.
The title compound (31.1 g) was obtained as yellow oil from the crude compound (36.0 g) prepared in <Step 2> of Example 60 by the same process as that used in <Step 4> of Example 1.
Concentrated sulfuric acid (24.9 mL) was added to a toluene (1.5 L) solution of the compound (31.1 g) prepared in <Step 3> of Example 60, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture under ice cooling. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 25:75). The title compound (9.1 g) was obtained as a white solid.
The title compound (165 mg) was obtained as a white solid from the compound (100.0 mg) prepared in <Step 4> of Example 60 by a similar to the process used in <Step 7> of Example 1.
The title compound (38.0 mg) was obtained as a white solid from (E)-2-(7-trifluoromethyl-spiro[chroman-2,1′-cyclobutan]-4-ylidene)acetic acid (75.5 mg) prepared by the way described in PCT Publication No. 07/010,383 pamphlet by a similar to the process used in <Step 7> of Example 1.
The title compound (2.2 g) was obtained as brown oil from the compound (1.5 g) prepared in <Step 1> of Example 24 and 1,3-dimethoxyacetone (950.0 mg) by a similar to the process used in <Step 2> of Example 24.
The title compound (1.65 g) was obtained as brown oil from the compound (2.2 g) prepared in <Step 1> of Example 62 by the same process as that used in <Step 2> of Example 60.
The title compound (1.28 g) was obtained as brown oil from the compound (1.5 g) prepared in <Step 2> of Example 62 by the same process as that used in <Step 4> of Example 1.
The title compound (365.0 mg) was obtained as a white solid from the compound (1.1 g) prepared in <Step 3> of Example 62 by the same process as that used in <Step 4> of Example 60.
The title compound (17.5 mg) was obtained as a pale yellow-white solid from the compound (60.0 mg) prepared in <Step 4> of Example 62 by a similar to the process used in <Step 7> of Example 1.
The title compound (9.0 g) was obtained as a yellow solid from the compound (5.8 g) prepared in <Step 1> of Example 24 and tert-butoxycarbonyl-3-oxoazetidine (5.35 g) by a similar to the process used in <Step 2> of Example 24.
The title compound (3.79 g) was obtained as yellow oil from the compound (14.8 g) prepared in <Step 1> of Example 63 by the same process as that used in <Step 3> of Example 23.
The title compound (1.98 g) was obtained as a pale orange solid from the compound (4.1 g) prepared in <Step 2> of Example 63 by a similar to the process used in <Step 4> of Example 1.
The title compound (19.3 mg) was obtained as yellow solid from the compound (50.0 mg) prepared in <Step 3> of Example 63 by the same process as that used in <Step 7> of Example 1.
4 N hydrogenchloride in 1,4-dioxane (5.0 mL) was added to a solution of 1,4-dioxane (5.0 mL) solution of the compound (270.0 mg) prepared in <Step 4> of Example 63, and the mixture was stirred at room temperature overnight. 4 N aqueous sodium hydroxide solution was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. Methanol was added to the residue to solidify the resulting product. The title compound (121.0 mg) was obtained as a yellow solid.
36% Formalin solution (11.2 μL) and sodium triacetoxyborohydride (28.7 mg) were added to a mixture of 1,2-dichloroethane (10.0 mL) and N,N-dimethylformamide (10.0 mL) of the compound (40.0 mg) prepared in <Step 5> of Example 63, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the reaction solution was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. n-Hexane and diethyl ether were added to the residue to solidify the resulting product. The title compound (33.1 mg) was obtained as a white solid.
The title compound (150.0 mg) was obtained as dark yellow oil from 7-trifluoromethyl-thiochroman-4-on (250.0 mg) prepared by the way described in Experienta (30(5), 452-455, 1974.) by a similar to the process used in <Step 2> of Example 60.
The title compound (139.0 mg) was obtained as an orange solid from the compound (150.0 mg) prepared in <Step 1> of Example 64 by the same process as that used in <Step 4> of Example 1.
The title compound (20.0 mg) was obtained as a white solid from the compound (139.0 mg) prepared in <Step 2> of Example 64 by the same process as that used in <Step 4> of Example 60.
The title compound (29.0 mg) was obtained as a pale orange solid from the compound (27.7 mg) prepared in <Step 3> of Example 64 by a similar to the process used in <Step 7> of Example 1.
The title compound (6.8 mg) was obtained as a pale yellow solid from the compound (0.15 g) prepared in <Step 3> of Example 30 by a similar to the process used in Example 26.
The title compound (99.8 mg) was obtained as a pale yellow solid from (E)-(8-trifluoromethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-ylidene)acetic acid (117 mg) prepared by the way described in PCT Publication No. 07/010,383 pamphlet by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from a known arylamine represented by formula (IX) described above and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from a arylamine represented by formula (IX) described above prepared by the same process as that used in Example 30 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
1 N tetrahydrofuran (63.40 mL) solution of lithium hexamethyldisilazide was added to a tetrahydrofuran (60.0 mL) solution of 3-hydroxypropanoic acid methyl ester (3.00 g) at −50° C., and the reaction mixture was stirred at −20° C. for 30 minutes. The mixture was cooled to −50° C., and then a tetrahydrofuran (6.00 mL) solution of 2,4-dinitrobenzaldehyde (5.65 g) was added dropwise thereto. The mixture was stirred at room temperature for one hour. Water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=90:10, 50:50 to 0:100). The title compound (1.26 g) was obtained as pale orange oil.
The title compound (0.23 g) was obtained as a brown solid from the compound (3.00 g) prepared in <Step 1> of Example 93 by a similar to the process used in <Step 6> of Example 1.
The title compound (42.8 mg) was obtained as a pale yellow solid from the compound (50.0 mg) prepared in <Step 2> of Example 93 and the compound (71.56 mg) prepared in <Step 4> of Example 1 by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from the compound in <Step 2> of Example 93 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
Bromine (1.75 mL) was added to a pyridine (44.0 mL) solution of 1,2-dihydro-7-nitro-2-oxo-3-quinolinecarboxylic acid (4.00 g) at 0° C., and the mixture was stirred in the range of 100° C. to 120° C. for 1.5 hours. The mixture was left to cool. Subsequently, 1 N hydrochloric acid was added thereto so that the solution became acidic. The precipitate was collected by filtration and washed with water. The title compound (2.78 g) was obtained as a brown solid.
Ethylmethylamine (0.16 mL)was added to a N,N′-dimethylimidazolidinone (1.0 mL) solution of the compound (50.0 mg) prepared in <Step 1> of Example 97, and the mixture was heated at 120° C. for 18 hours in sealed tube. The mixture was left to cool. Water was added to the mixture. The resulting precipitate was collected by filtration. An acetic acid (1.0 mL) and ethyl acetate (1.0 mL) mixed solution of the collected solid was added to an acetic acid (1.0 mL) suspension of iron powder (0.10 g) at 80° C. The mixture was refluxed for one hour. After cooling, the mixture was subjected to Celite filtration. The filtrate was neutralized with aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (33.0 mg) was obtained.
The title compound (34.3 mg) was obtained as a pale yellow solid from the compound (40.00 mg) prepared in <Step 2> of Example 97 and the compound (48.17 mg) prepared in <Step 4> of Example 1 by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from a arylamine represented by formula (IX) described above prepared by a similar to the process used in Example 58 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from 6-amino-4-(2-tert-butyldimethylsiloxyethyl)-4H-benzo[1,4]oxazin-3-one prepared from 6-nitro-4H-benzo[1,4]-oxazin-3-one by a similar to the process used in Example 39 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from 6-amino-2-(2-tert-butyldimethylsiloxyethyl)-4-methyl-4H-benzo[1,4]oxazin-3-one prepared from 2-(2-hydroxyethyl)-6-nitro-4H-benzo[1,4]-oxazin-3-one by a similar to the process used in <Step 2> of Example 15 and Example 39 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
10% hydrogen chloride in methanol (50.0 mL) was added to a methanol (150 mL) solution of 2,4-dinitrophenylacetic acid (25.0 g), the resulting mixture was refluxed for 5 hours. The mixture was left to cool. The solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was sequentially washed with aqueous saturated sodium hydrogencarobonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The title crude compound (28.6 g) was obtained as pale orange oil.
A tetrahydrofuran (150.0 ml) solution of the compound (27.10 g) prepared in <Step 1> at Example 109 was added dropwise to a tetrahydrofuran (150.0 mL) susupension of sodium hydride (13.54 g) and iodomethane (35.12 μL) over a period of 30 minutes at 0° C. The mixture was stirred at room temperature for 2 hours and refluxed for 6 hours. The mixture was left to cool. Aqueous saturated ammonium chloride solution was added to the mixture, and then was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate 100:0, 95:5 to 90:10). The title compound (6.3 g) was obtained as pale orange oil.
The title compound (1.3 g) was obtained as a brown solid from the compound (6.30 g) prepared in <Step 2> of Example 109 by a similar to the process used in <Step 6> of Example 1.
The title compound (91.9 mg) was obtained as pale white solid from the compound (50.0 mg) prepared in <Step 3> of Example 109 and the compound (0.12 g) prepared in <Step 5> of Example 24 by the same process as that used in <Step 7> of Example 1.
The compounds described blow were prepared from the compound prepared in <Step 3> of Example 109 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from arylamine represented by formula (IX) described above prepared by a similar to the process used in Example 14 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from arylamine, represented by formula (IX) described above prepared by a similar to the process used in Example 38 and Example 39, and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from 5-amino-3,4-dihydro-1H-quinazolin-2-one prepared by a similar to the process used in Example 13 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1
The compounds described blow were prepared from 5-amino-3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazine prepared by a similar to the process used in Example 17 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from arylamine represented by formula (IX) described above prepared by a similar process used in <Step 1> of Example 38 and Example 17, and the compound prepared in <Step 5> of Example 24 by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from the compound prepared in <Step 1> of Example 59 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described blow were prepared from the compound prepared in <Step 1> of Example 59 by a similar to the process used in Example 26.
The compounds described blow were prepared from 5-amino-2,2-dioxy-3,4-dihydro(1H)-2,1-benzothiazine prepared by a similar to the process used in Example 59 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
Potassium carbonate (1.63 mg) and iodomethane (3.04 mg) were added sequentially to a N,N-dimethylformamide (1.00 mL) solution of the compound (5.00 mg) prepared in example 189, and the mixture was stirred at room temperature for three hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent; n-hexane:ethyl acetate 50:50) to give title compound (4.6 mg) as a white solid.
The compounds described below were prepared from the compound prepared in Example 190 or the compound prepared in Example 191 by a similar to the process used in Example 198.
A tetrahydrofuran (14.0 mL)-ethanol (7.0 at) solution of 6-chloro-8-nitro-4H-benzo[1,4]oxazin-3-one (0.40 g) was added dropwise to a water (21.0 mL) solution of sodium hydrosulfite (4.90 g) at 0° C. The mixture was stirred at same temperature for one hour, and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with saturated saline solution, and dried over anhydrous sodium sulfate. The solvent distilled off under reduced pressure to give the title compound (0.24 g) as a pale brown solid.
The title compound (81.0 mg) was obtained as a yellow solid from the compound (50.0 mg) prepared in <Step 1> of Example 201 and the (E)-2-(7-trifluoromethyl-spiro[chroman-2,1′cyclobutane]-4-ylidene)acetic acid (79.12 mg) by the same process as that used in <Step 7> of Example 1.
The compounds described blow were prepared from arylamine represented by formula (IX) described above prepared from 6-chloro-8-nitro-4H-benzo[1,4]oxazin-3-one by a similar to the process used in Example 39 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
10% hydrochloric acid methanol solution (112 μL) was added to a dichloromethane (6.0 mL)-methanol (6.0 mL) solution of the compound (0.14 g) prepared in <step 4> of example 30, and the mixture was stirred at room temperature for three hours. The solvent was distilled off under reduced pressure. Ether was added to the residue, and solidified to give title compound (131 mg) as a pale yellow solid.
The title compound (141 mg) was obtained as a pale yellow solid from the compound (0.14 g) prepared in <Step 4> of Example 30 and the methanesulfonic acid (310 μL) by a similar to the process used in Example 210.
The title optically active compounds were obtained from the enantiomers (each enantiomer; 1.20 g) prepared by chiral resolution of the compound prepared in <step 3> of Example 30 and the compound (1.39 g) prepared in <Step 5> of Example 24 by a similar to the process used in Example 34 and 35.
The compound of Example 212 (1.95 g, pale yellow powder, 100% ee, retention time 9.4 minutes)
The compound of Example 213 (2.02 g, pale yellow powder, 99.6% ee, retention time 15.6 minutes)
The optical purities were determined by HPLC analysis using chiral column chromatography (column: CHIRALCEL OJ-H (0.46×25.0 am) manufactured by Daicel Chemical Industries, Ltd., solvent: n-hexane:ethanol=50:50, flow rate: 1.0 L/min, UV: 254 nm).
The title compound (94.0 mg) was obtained as an orange solid from the 8-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one (0.18 g) by the same process as that used in <Step 1> of Example 13.
The title compound (24.7 mg) was obtained as a pale yellow solid from the compound (30.0 mg) prepared in <Step 1> of Example 214 and the compound (57.4 mg) prepared in <Step 4> of Example 60 by the same process as that used in <Step 7> of Example 1.
The compound described blow was prepared from arylamine represented by formula (IX) described above prepared by a similar to the process used in Example 214 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <Step 7> of Example 1.
The compounds described below were prepared from known arylamine represented by formula (IX) described above and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from the compound prepared in <step 4> of Example 62 and an arylamine [formula (IX) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from the compound prepared in <step 3> of Example 63 and an arylamine [formula (IX) described above] used in Examples described above by a similar to the process used in <step 4>, <step 5> and <step 6> of Example 63.
The compounds described below were prepared from the compounds prepared in Example 194, Example 195, Example 196, Example 197 and Example 233 by a similar to the process used in Example 198.
Diethyl azodicarboxylate (40% in toluene solution)(72.7 μL) was added to a tetrahydrofuran (3.0 mL) solution of the compound (40.0 mg) prepared in Example 196, 2-(t-butyldimethylsiloxy)ethyl alcohol (28.5 mg) and triphenylphosphine (42.4 mg), and the mixture was stirred at room temperature for three hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=5:1) to give the title compound (32.4 mg) as a colorless amorphous.
The title compound (20.5 mg) was prepared as a white solid from a compound (31.4 mg) prepared in <step 1> of Example 246 by a similar to the process used in <step 6> of Example 15.
The compounds described below were prepared from the compounds prepared in Example 196 by a similar to the process used in Example 246.
The compounds described below were prepared from the compounds prepared in Example 233 by a similar to the process used in Example 246.
The compounds described below were prepared from 5-nitro-3,4-dihydro-2(1H)-quinolinone by a similar to the process used in Example 39.
The compound described below was prepared from 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine by a similar to the process used in Example 8 and <step 6> of Example 1.
The compounds described below were prepared from an arylamine [formula (IX) described above] synthesized from 2-(2-hydroxyethyl)-6-nitro-2H-benzo[1,4]oxazin-3(4H)-one in a similar to the process used in <step 2> of Example 15 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from 8-nitro-2H-benzo[1,4]oxazin-3(4H)-one by a similar to the process used in Example 39.
The compounds described below were prepared from 8-amino-4-(2-hydroxyethyl)-2H-benzo[1,4]oxazin-3(4H)-one by a similar to the process used in Example 214.
The title compound (2.98 g) was prepared as a pale orange solid from a compound (6.0 g) prepared in <step 1> of Example 24 and tetrahydropyran-4-one (3.24 g) by a similar to the process used in <step 2> of Example 24.
The title compound (2.40 g) was prepared as a yellow oil from a compound (1.60 g) prepared in <step 1> of Example 269 by a similar to the process used in <step 2> of Example 60.
The title compound (1.48 g) was prepared as a pale yellow solid from a compound (2.09 g) prepared in <step 2> of Example 269 by a similar to the process used in <step 4> of Example 1.
The title compound (1.22 g) was prepared as a white solid from a compound (1.48 g) prepared in <step 3> of Example 269 by a similar to the process used in <step 4> of Example 60.
The title compound (31.0 mg) was prepared as a white solid from a compound (78.9 mg) prepared in <step 4> of Example 269 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from known arylamine represented by formula (IX) described above and a compound prepared in <Step 4> of Example 269 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from arylamine [formula (IX) described above] used in Examples described above and a compound prepared in <step 4> of Example 269 by a similar to the process used in <step 7> of Example 1.
The compound described below was prepared from 5-amino-2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazine prepared in a similar to the process used in Example 59 and (E)-(8-trifluoromethyl-3,4-dihydrobenzo[c]oxepin-5(1H)-ylidene)acetic acid (117 mg) prepared by the way described in PCT Publication No. 07/010,383 pamphlet by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from the compounds prepared in Example 281, Example 238 and Example 282 by a similar to the process used in <step 1> of Example 39.
2-nitrobenzenesulphonyl chloride (0.70 g) and triethylamine (0.63 mL) were added sequentially to a dichloromethane (50 mL) solution of 2-amino-6-nitrobenzylamine (0.50 g) at ice-cooled, and the mixture was stirred at room temperature for three hours. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution sequentially, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was solidified with n-hexane/diethyl ether to give the title compound (840 mg) as a yellow solid.
The title compound (0.66 g) was prepared as a yellow solid from the compound (0.84 g) prepared in <step 1> of Example 285 by the same process as that used in <step 1> of Example 198.
Lithium hydroxide monohydrate (0.29 g) and thioglycolic acid (0.24 mL) were added sequentially to a N,N-dimethylformamide (5 mL) solution of a compound (0.66 g) prepared in <step 2> of Example 285. The reaction mixture was stirred at room temperature for one hour. A 1 N aqueous sodium hydroxide solution was added to the mixture, and extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and saturated saline solution sequentially, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (0.31 g) as a yellow solid.
The title compound (0.20 g) was prepared as a yellow solid from the compound (0.29 g) prepared in <step 3> of Example 285 by a similar to the process used in <step 1> of Example 12.
The title compound (0.16 g) was prepared as a brown solid from the compound (0.20 g) prepared in <step 4> of Example 285 by a similar to the process used in <step 6> of Example 1.
The title compound (54.1 mg) was prepared as a white solid from the compound (30 mg) prepared in <step 5> of Example 285 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from the compound prepared in <step 5> of Example 285 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
The title compound (2.63 g) was prepared as a yellow solid from the compound (2.00 g) prepared in <step 1> of Example 285 and veratryl alcohol (1.43 g) by a similar to the process used in <step 1> of Example 246.
The title compound (0.66 g) was prepared as a yellow solid from the compound (1.04 g) prepared in <step 1> of Example 288 by a similar to the process used in <step 3> of Example 285.
The title compound (0.62 g) was prepared as pale red solid from the compound (0.95 g) prepared in <step 2> of Example 288 by a similar to the process used in <step 1> of Example 12.
Potassium carbonate (0.36 g) and methyl iodide (0.16 mL) were added to N,N-dimethylformamide (8.0 mL) solution of the compound (0.30 g) prepared in <Step 3> of Example 288, and the mixture was stirred at 40° C. for three hours. Then, potassium carbonate (0.36 g) and methyl iodide (0.16 mL) were added to the solution, and the mixture was stirred at 40° C. for three hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Trifluoroacetic acid (4.0 mL) was added to the residue, and the mixture was stirred at room temperature for four and a half hours. 1 N sodium hydroxide solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 10% Pd—C (30 mg) was added to methanol (8.0 mL) solution of the residue was stirred under hydrogen atmosphere at room temperature for one hour. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; dichloromethane:methanol=9:1). The title compound (60.0 mg) was obtained as a white solid.
The title compound (3.9 mg) was prepared as a white solid from the compound (17.0 mg) prepared in <step 4> of Example 288 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from the compound prepared in <step 6> of Example 288 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
Acetic anhydride (6.2 mL) was added to 2-amino-4-nitrobenzoic acid methyl ester (2.84 g). The reaction solution was stirred at 90° C. for three hours. The mixture was left to cool. The appeared solid was filtered and washed with diethyl ether. The title compound (2.03 g) was obtained as a pale yellow solid.
Potassium hexamethyldisilazane (0.5M, toluene solution, 88.2 mL) was added dropwise to a tetrahydrofuran (126.0 mm) solution of the compound (3.0 g) prepared in <step 1> of Example 292 under ice cooling. The reaction solution was stirred at room temperature for three hours. 1 N aqueous hydrochloric acid was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was washed by mixed solvents (dichloromethane:methanol=90:10). The title compound (0.96 g) was obtained as a brown solid.
Phosphoryl chloride (1.3 mL) was added to the compound (0.95 g) prepared in <step 2> of Example 292. The reaction solution was refluxed for 30 minutes. The mixture was left to cool. 1 N aqueous sodium hydroxide was added to the mixture, the mixture was extracted with dichloromethane. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Concentrated hydrochloric acid (15.0 mL) was added to the residue. The reaction solution was refluxed for four hours. The mixture was left to cool. Water was added to the mixture, the appeared solid was filtered. The title compound (437.0 mg) was obtained as a pale yellow solid.
Morpholine (0.4 L) was added to a N,N-dimethylformamide (4.5 mL) solution of the compound (0.1 g) prepared in <step 3> of Example 292. The reaction solution was stirred at 100° C. for one hour. The mixture was left to cool. Saturated aqueous ammonium chloride solution was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Dichloromethane was added to the residue to solidify the resulting product. The title compound (78.2 mg) was obtained as a pale yellow solid.
The title compound (45.0 mg) was obtained as a pale yellow solid from the compound (60.0 mg) prepared in <Step 4> of Example 292 by the same process as that used in <Step 6> of Example 1.
The title compound (65.0 mg) was obtained as a pale yellow solid from the compound (50.0 mg) prepared in <Step 5> of Example 292 by the same process as that used in <Step 7> of Example 1.
The title compound (2.08 g) was prepared as a red-brown oil from the compound (6.09 g) prepared in <step 1> of Example 24 and oxetan-3-one (2.15 g) by a similar to the process used in <step 2> of Example 24.
The title compound (0.15 g) was prepared as a pale yellow oil from the compound (0.50 g) prepared in <step 1> of Example 293 by a similar to the process as that used in <step 3> of Example 23.
The title compound (0.10 g) was prepared as a yellow solid from the compound (0.14 g) prepared in <step 2> of Example 293 by a similar to the process used in <step 6> of Example 15.
The title compound (8.0 mg) was prepared as a white solid from the compound (20.0 mg) prepared in <step 3> of Example 293 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from known arylamine represented by formula (IX) described above and a compound prepared in <Step 3> of Example 293 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from arylamine [formula (IX) described above] and a compound prepared in <step 3> of Example 293 by a similar to the process used in <step 7> of Example 1.
The compounds described below were prepared from 5-amino-1-ethyl-3,4-dihydro-2(1H)-quinazolinone prepared in a similar to the process used in Example 288 and a carboxylic acid [formula (VIII) described above] used in Examples described above by a similar to the process used in <step 7> of Example 1.
To a suspension of sodium hydride (7.1 g) in toluene (300.0 mL), a solution of 3-trifluoromethyl phenol (16.6 g) in toluene (200.0 mL) was dropped under ice-cooling. After stirring at the same temperature for 30 minutes, iodine (26.0 g) was added thereto. After stirring at room temperature for 12 hours, an aqueous solution of 3N hydrochloric acid was added to pH=2. The reaction solution was extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (30.8 g) as pale yellow oil.
To a solution of the compound (60.0 g) obtained in <Step 1> of (Example 302) in acetone (250.0 mL), potassium carbonate (31.7 g), 4-bromobutyronitrile (31.5 g) and potassium iodide (3.5 g) were added, and the reaction solution was heated to reflux for 4 hours. After the mixture was left to cool, the reaction solution was filtered to remove the insoluble, and washed with acetone. The filtrate and the washed liquid were concentrated, added with water, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (72.4 g) as pale yellow oil.
To a solution of the compound (100.0 g) obtained in <Step 2> of (Example 302) in toluene (600.0 mL), diisobutylaluminium hydride (toluene solution, 341.0 mL) was dropped at −78° C., and the reaction solution was stirred at the same temperature for 30 minutes, and at room temperature for 1 hour. The reaction solution was added with an aqueous solution of 0.5N sulfuric acid (1.4 L)/extracted with hexane, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give an intermediate (aldehyde) as a pale yellow liquid. To a solution of the obtained aldehyde in tetrahydrofuran (1.0 L), diethylphosphonoethyl acetate (25.8 g) was added, and a suspension of potassium hydroxide (7.9 g) in tetrahydrofuran (200.0 ml) was added under ice-cooling, and the reaction solution was stirred at room temperature for 8 hours. The reaction solution was added with water, extracted with hexane, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (111.6 g) as pale yellow oil.
To a solution of the compound obtained in <Step 3> of (Example 302) (48.4 g) in tetrahydrofuran (500.0 ml), palladium acetate (2.8 g), triphenylphosphine (5.9 g) and silver carbonate (31.2 g) were added, and the reaction solution was heated to reflux for 15 hours under nitrogen atmosphere. The reaction solution was filtered with celite, and added with water. The reaction solution was extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (15.7 g) as a white solid.
To a solution of the compound obtained in <Step 4> of (Example 302) (10.2 g) in methanol (56.0 mL) was added an aqueous solution of 2N sodium hydroxide (28.0 μL), and the reaction solution was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure and the reaction solution was neutralized with an aqueous solution of 1N hydrochloric acid. The obtained solid was filtered, and washed with n-hexane, to give the titled compound (8.2 g) as a white solid.
To a solution of 2,6-dinitrobenzonitrile (Alfa Aesar) (10.8 g) in N,N-dimethylformamide (50.0 mL) was added methylamine (40% aqueous solution) (17.4 mL), and the reaction solution was stirred at 50° C. for 40 minutes. The reaction solution was poured into iced water. The precipitate was filtered, sequentially washed with water and n-hexane, and dried under reduced pressure, to give the titled compound (9.4 g) as a brownish-red solid.
To a suspension of sodium hydroborate (10.0 g) in tetrahydrofuran (100.0 mL) was dropped trifluoroacetic acid (20.0 ml) at 0° C. To this solution, a suspension of the compound obtained in <Step 6> of (Example 302) (9.4 g) in tetrahydrofuran (100.0 mL) was dropped over 20 minutes, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated, the obtained residue was added with water, and washed with dichloromethane. The aqueous layer was alkalified with an aqueous solution of 1N sodium hydroxide, and extracted with dichloromethane. The organic layer was sequentially washed with an aqueous solution of 2N sodium hydroxide, an aqueous solution of 1N sodium hydroxide and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (6.5 g) as brownish-red oil.
To a solution of the crude compound obtained in <Step 7> of (Example 302) (6.5 g) in dichloromethane (160.0 mL), pyridine (8.7 mL) and 1,1′-carbonylbis-1H-imidazole (11.6 g) were added, and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated, and the obtained residue was washed with diethyl ether, and dried under reduced pressure, to give the titled compound (4.6 g) as an ocher solid.
To a solution of the compound obtained in <Step 8> of (Example 302) (4.6 g) in tetrahydrofuran (500.0 mL), tin chloride (II) dihydrate (29.8 g) was added, and the reaction solution was heated to reflux for 7.5 hours. After the mixture was left to cool, the reaction solution was added with an aqueous solution of 2N sodium hydroxide to pH=10, and filtered with celite. The filtrate was extracted with ethyl acetate, and the organic layer was sequentially washed with an aqueous solution of 1N sodium hydroxide and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; ethyl acetate:methanol=100:0 to 70:30), to give the titled compound (1.8 g) as a pale yellow solid.
To a solution of the carboxylic acid obtained in <Step 5> of (Example 302) (75.0 mg) in dichloromethane (3.0 mL), oxalyl dichloride (50.0 μL) and N,N-dimethylformamide (1 drop) were added, and the reaction solution was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (3.0 mL). The reaction solution was dropped to a solution of the amine obtained in <Step 9> of (Example 302) (40.0 mg) in pyridine (0.1 mL) under ice-cooling, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was neutralized with an aqueous solution of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was added with dichloromethane to solidify it, to give the titled compound (62.0 mg) as a white solid.
To a solution of 4-trifluoromethylaniline (10.0 mL) in tetrahydrofuran (50.0 mL), di-tert-butyldicarbamate (30.0 mL) was added, and the reaction solution was heated to reflux for 10 hours. The solvent was removed by distillation under reduced pressure, and the obtained residue was solidified with water, and washed with hexane, to give the titled compound (18.7 g) as a colorless crystal.
To a solution of the compound obtained in <Step 1> of (Example 303) (18.5 g) in tetrahydrofuran (190.0 mL), tetramethylethylene diamine (32 mL) and n-butyl lithium (131.0 mL) were added at −78° C. The temperature was elevated to −30° C., and, at the same temperature, the reaction solution was stirred for 5 hours. The temperature was adjusted to −78° C. again, and dry ice (32.0 g) was added. The temperature was elevated to room temperature, and the reaction solution was stirred for 12 hours. The reaction solution was neutralized with an aqueous solution of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, and then cried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:methanol=100:0 to 90:10), to give the titled compound (18.7 g) as a white solid.
To a solution of the compound obtained in <Step 2> of (Example 303) (26.0 g) in ethanol (230.0 mL), an aqueous solution of 1N hydrochloric acid (60 mL) was added, and the reaction solution was heated to reflux for 3 hours. The reaction solution was neutralized with an aqueous solution of 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (13.2 g) as a yellow crystal.
To a suspension of the compound obtained in <Step 3> of (Example 303) (13.0 g) in conc. hydrochloric acid (15.0 mL) and water (80.0 mL), sodium hypochlorite (5.3 g) dissolved in water (12.0 mL) was dropped under ice-cooling. The reaction solution was stirred at the same temperature for 30 minutes, added with an aqueous solution of potassium iodide (21.0 g) dissolved in water (30.0 mL) and conc. sulfuric acid (5.0 μL), and stirred at 100° C. for 2 hours. The reaction solution was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of saturated sodium sulfite and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (19.1 g) as a yellow crystal.
To a solution of the compound obtained in <Step 4> of (Example 303) (17.2 g) in tetrahydrofuran (50.0 mL) was added boran-tetrahydrofuran solution (120.0 mL) under ice-cooling, and the reaction solution was stirred at room temperature for 3 hours. Water (200.0 mL) was added thereto, and the solvent was removed by distillation under reduced pressure. The obtained residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (16.0 g) as a yellow crystal.
To a solution of the compound obtained in <Step 5> of (Example 303) (16.0 g) in diethyl ether (130.0 mL) was added phosphorus tribromide (5.0 mL) under ice-cooling, and the reaction solution was stirred for 12 hours at room temperature. The reaction solution was added with water (200.0 mL), and extracted with diethyl ether. The organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (16.0 g) as a yellow crystal.
To a solution of 3-buten-1-ol (5.2 mL) in tetrahydrofuran (200.0 mL) was added sodium hydride (2.3 g) under ice-cooling, and the reaction solution was stirred at the same temperature for 30 minutes. The compound obtained in <Step 6> of (Example 303) (14.8 g) and n-tetrabutylammonium iodide (1.5 g) were added thereto, and the reaction solution was stirred for 12 hours at room temperature. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 95:5), to give the titled compound (13.9 g) as yellow oil.
To a solution of the compound obtained in <Step 7> of (Example 303) (12.8 g) and tert-butylacrylate (52.7 mL) in dichloromethane (180.0 mL), tricyclohexylphosphine-1,3-bis-2,4,6-trimethylphenyl-4,5-dihydroimidazol-2-ylidene benzylidene ruthenium dichloride (second generation Grubbs reagent) (1.5 g) was added, and the reaction solution was stirred for 4 hours at 40° C. The sol-vent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 98:2), to give the titled compound (11.9 g) as pale yellow oil.
From the compound obtained in <Step 8> of (Example 303) (11.8 g), palladium acetate (1.7 g), triphenylphosphine (4.1 g) and silver carbonate (7.1 g), the titled compound (7.6 g) was obtained as yellow oil in the same manner as in <Step 4> of (Example 302).
The compound obtained in <Step 9> of (Example 303) (7.5 g) was dissolved in formic acid (100.0 mL), and the reaction solution was stirred for 2 hours. To the reaction solution was added water (300.0 mL), and the precipitate was filtered, and dried under reduced pressure to give the titled compound (5.5 g) as a colorless crystal.
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 10> of (Example 303) and the amine obtained in <Step 9> of (Example 302).
To an aqueous solution of 3-trifluoromethyl phenol (25.0 g) in 2N sodium hydroxide (120.0 mL) was dropped 3-chloropropionic acid (25.0 g). With pH maintained to 10 or more using an aqueous solution of 5N sodium hydroxide, the reaction solution was heated to reflux for 1 hour. After the mixture was cooled to room temperature, the reaction solution was washed with diethyl ether. The reaction solution was acidified using an aqueous solution of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and n-hexane was added to the obtained residue to crystallize it, to give the titled compound (6.1 g) as a colorless crystal.
To a solution of 3-trifluoromethyl phenol (2.0 g) in N,N-dimethylformamide (20.0 mL), sodium hydride (0.6 g) was added, and the reaction solution was stirred at room temperature for 1 hour. β-propiolactone (1.0 mL) was added thereto, and the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was added with water, adjusted to pH=2 using an aqueous solution of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and n-hexane was added to the obtained residue to crystallize it, to give the titled compound (2.2 g) as a colorless crystal.
To methanesulfonic acid (18.0 g) was added diphosphorus pentoxide (2.0 g) portionwise, and the reaction solution was stirred at room temperature for 2.5 hours. The compound obtained in <Step 1-A, B> of (Example 304) (2.0 g) was added over 10 minutes at 70-80° C. of the outside temperature. The reaction solution was stirred at the same temperature for 30 minutes, left to cool, and was poured into iced water (100.0 mL). The reaction solution was extracted with ethyl acetate, and the combined organic layers were sequentially washed with water, saturated sodium bicarbonate solution, water and saturated saline. The organic layers were dried with sodium sulfate anhydride, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=95:5), to give the titled compound (1.7 g) as a yellow solid.
Zinc (0.3 g) was suspended in tetrahydrofuran (4.0 mL), and a solution of the compound obtained in <Step 2> of (Example 304) (0.5 g) and bromoethyl acetate (0.6 g) in toluene (8.0 mL) were dropped thereto at 70° C. of the outside temperature. The reaction solution was heated to reflux for 30 minutes, and zinc (0.3 g) and bromoethyl acetate (0.6 g) were added thereto. The reaction solution was heated to reflux for 30 minutes, and left to cool, and an aqueous solution of 1N hydrochloric acid was added to the reaction solution. After separation of the layers, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and washed with saturated saline. The organic layers were dried with sodium sulfate anhydride, and concentrated under reduced pressure, to give the titled compound (0.7 g) as brown oil.
From the compound obtained in <Step 3> of (Example 304) (0.7 g), the titled compound (0.6 g) was obtained as a dark orange amorphous in the same manner as in <Step 5> of (Example 302).
The compound obtained in <Step 4> of (Example 304) (120.0 mg) was suspended in toluene (1.0 mL), conc. sulfuric acid (1 drop) was added thereto, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added with water, and extracted with ethyl acetate. The organic layers were combined, and washed with saturated saline. The organic layers were dried with sodium sulfate anhydride, and concentrated under reduced pressure. The organic layers were triturated with diethyl ether/n-hexane, and filtered, to give the titled compound (22.0 mg) as pale yellow powders.
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 5> of (Example 304) and the amine obtained in <Step 9> of (Example 302).
To a solution of 4-trifluoromethylsalicylic acid (80.0 g) in tetrahydrofuran (780.0 mL) was added methyl lithium (1.6 M diethyl ether solution, 800.0 mL) under ice-cooling, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was poured into iced water. Under ice-cooling, conc. hydrochloric acid (135.0 mL) was added thereto. The reaction solution was extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled compound (68.0 g) as pale yellow oil.
To a solution of the compound obtained in <Step 1> of (Example 305) (50.0 g) in methanol (900.0 mL), acetone (28.8 mL) and pyrrolidine (32.7 mL) were added, and the reaction solution was stirred for 12 hours at room temperature. The solvent was removed by distillation under reduced pressure, and the obtained residue was added with an aqueous solution of 10% citric acid (420.0 mL) and water (420.0 mL). The reaction solution was extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (50.4 g) as brown oil.
To a solution of N,N-diisopropylamine (45.0 mL) in tetrahydrofuran (600.0 mL) was dropped n-butyl lithium (1.6 M n-hexane solution) (200.0 mL) at −78° C. of the outside temperature over 30 minutes. The reaction solution was stirred at the same temperature for 30 minutes, dropped with ethyl acetate (31.5 mL), and stirred further for 30 minutes. Furthermore, a solution of the compound obtained in <Step 2> of (Example 305) (40.0 g) in tetrahydrofuran (200.0 mL) was dropped over 20 minutes, and the reaction solution was stirred at −78° C. for 1.5 hours. The reaction solution was poured into water (1.0 L), and extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (49.0 g) as orange oil.
To a solution of the compound obtained in <Step 3> of (Example 305) (90.0 g) in dichloromethane (1.4 L), trifluoroacetic acid (101.0 mL) was dropped at 0° C. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was added with water, and extracted with dichloromethane. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 99:1 to 50:50), to give the titled compound (46.5 g) as pale yellow oil.
To a solution of the compound obtained in <Step 4> of (Example 305) (46.2 g) in ethanol (590.0 mL), an aqueous solution of 1N sodium hydroxide (293.0 mL) was added. The reaction solution was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the obtained residue was added with an aqueous solution of 1N hydrochloric acid to pH=1, and extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was recrystallized from n-hexane, to give the titled compound (22.1 g) as a colorless crystal.
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 5> of (Example 305) and the amine obtained in <Step 9> of (Example 302).
From 2,6-dinitrobenzonitrile (13.0 g), the titled compound (2.7 g) was obtained as a brown solid in the same manner as in (Example 302, Step 6˜9).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 5> of (Example 302) and the amine obtained in <Step 1> of (Example 306).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 10> of (Example 303) and the amine obtained in <Step 1> of (Example 306).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 5> of (Example 304) and the amine obtained in <Step 1> of (Example 306).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 5> of (Example 305) and the amine obtained in <Step 1> of (Example 306).
From the compound obtained in <Step 1> of (Example 305) (44.5 g) and 3-pentanone (36.6 mL), the titled compound (25.7 g) was obtained as a white solid in the same manner as in <Step 2> of (Example 305).
From the compound obtained in <Step 1> of (Example 310) (29.2 g), the titled crude compound (36.3 g) was obtained as a white solid in the same manner as in <Step 3> of (Example 305).
From the compound obtained in <Step 2> of (Example 310) (36.0 g), the titled compound (31.1 g) was obtained as pale yellow oil in the same manner as in <Step 5> of (Example 305).
From the compound obtained in <Step 3> of (Example 310)
g), the titled compound (9.1 g) was obtained as a white solid in the same manner as in <Step 4> of (Example 305).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 4> of (Example 310) and the amine obtained in <Step 1> of (Example 306).
From the compound obtained in <Step 1> of (Example 305) (15.7 g) and 1,3-dimethoxyacetone (10.0 g), the titled compound (24.2 g) was obtained as black oil in the same manner as in <Step 2> of (Example 305).
From the compound obtained in <Step 1> of (Example 311)
g), the titled crude compound (27.5 g) was obtained as black oil in the same manner as in <Step 3> of (Example 305).
From the compound obtained in <Step 2> of (Example 311) (27.5 g), the titled compound (30.0 g) was obtained as a black solid in the same manner as in <Step 5> of (Example 305).
From the compound obtained in <Step 3> of (Example 311) (25.5 g), the titled compound (7.0 g) was obtained as a white solid in the same manner as in <Step 4> of (Example 305).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 4> of (Example 311) and the amine obtained in <Step 1> of (Example 306).
From the compound obtained in <Step 1> of (Example 305) (15.0 g) and tetrahydro-4-pyran-4-one (8.1 g), the titled compound (20.0 g) was obtained as black oil in the same manner as in <Step 2> of (Example 305).
From the compound obtained in <Step 1> of (Example 312) (12.0 g), the titled crude compound (16.1 g) was obtained as red oil in the same manner as in <Step 3> of (Example 305).
From the compound obtained in <Step 2> of (Example 312) (16.0 g), the titled compound (13.4 g) was obtained as a red solid in the same manner as in <Step 5> of (Example 305).
From the compound obtained in <Step 3> of (Example 312) (13.4 g) the titled compound (5.5 g) was obtained as a white solid in the same manner as in <Step 4> of (Example 305).
The title compound was obtained in the same manner as in <Step 10> of (Example 302) from the carboxylic acids obtained in <Step 4> of (Example 312) and the amine obtained in <Step 1> of (Example 306)
To a solution of 4-trifluoromethylsalicylic acid (5.0 g) in toluene (50.0 mL) were added thionyl chloride (2.7 mL) and N,N-dimethylformamide (0.1 mL), and the reaction solution was heated to reflux for 30 minutes. After being left to cool, the reaction solution was dropped to ammonia water (50.0 mL) under ice-cooling, and the reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was adjusted to pH=3 with conc. hydrochloric acid, and extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 50:50), to give the titled compound (1.8 g) as a flesh-colored crystal.
To a solution of the compound obtained in <Step 1> of Example 313 (1.8 g) in chloroform (20.0 mL) were added 2,2-dimethoxypropane (4.3 mL) and conc. sulfuric acid (0.4 mL), and the reaction solution was heated to reflux for 8 hours. The reaction solution was neutralized with an aqueous solution of saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 50:50), to give the titled compound (1.1 g) as a pale yellow crystal.
To a solution of the compound obtained in <Step 2> of Example 313 (1.1 g) in toluene (58.0 mL), Lawesson's reagent (1.2 g) was added, and the reaction solution was heated to reflux for 1 hour. The reaction solution was left to cool, and purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=90:10 to 88:12), to give the titled compound (1.4 g) as a yellow crystal.
To a solution of the amine obtained in <Step 9> of (Example 302) (0.2 g) and bromoacetic acid (0.2 g) in methanol (5.0 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (0.4 g), and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was added with water, and the precipitate was filtered, washed with water, and subjected to ethanol azeotropy. The obtained residue was suspended in diethyl ether, and filtered, to give the titled compound (0.3 g) as a pale peach solid.
To a suspension of the compound obtained in <Step 3> of Example 313 (0.3 g) and the compound obtained in <Step 4> of Example 313 (0.3 g) in 1,4-dioxane (15.0 mL), triethylamine (0.4 mL) was added, and the reaction solution was heated to reflux for 1 hour. The reaction solution was added with water, and the precipitate was filtered, washed with water, and subjected to ethanol azeotropy. The obtained residue was suspended in diethyl ether, and filtered, to give the titled compound (0.4 g) as a white solid.
To a suspension of the compound obtained in <Step 5> of Example 313 (0.3 g) in chlorobenzene (1.2 mL) were added triphenylphosphine (0.6 g) and N,N-diisopropylethylamine (1.2 mL), and the reaction solution was heated using a microwave reactor at 180° C. for 1 hour as sealed. The reaction solution was added with water, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=90:10 to 0:100) and thin layer preparative chromatography (developing solvent; n-hexane:ethyl acetate=1:2), to give the titled compound (7.1 mg) as a pale yellow solid.
(Alternative synthesis of the compound of Example 312, step 9)
To a solution of 2,6-dinitrobenzonitrile (25.8 g) in methanol (450.0 mL) and 1,4-dioxane (280.0 mL), hydrochloric acid (100.0 mL) and Fe (22.0 g) were sequentially added under heating to reflux, and the reaction solution was stirred at the same temperature for 1.5 hours. An aqueous solution of 2N hydrochloric acid was added thereto at room temperature, and the reaction solution was filtered with celite. The filtrate was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (10.4 g) as a yellow solid.
To a suspension of sodium hydroborate (10.9 g) in tetrahydrofuran (70.0 mL) were sequentially added trifluoroacetic acid (22.0 mL) and a solution of the compound obtained in <Step 1> of (Example 314) (9.4 g) in tetrahydrofuran (140.0 mL) under ice cooling. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous solution of 1N sodium hydroxide (1.0 L), added with ethyl acetate (500.0 mL), and stirred for 1.5 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (9.2 g) as a dark violet solid.
To a solution of the compound obtained in <Step 2> of (Example 314) (0.5 g) in dichloromethane (50.0 mL) were sequentially added 2-nitrobenzenesulfonyl chloride (0.7 g) and triethylamine (0.6 mL) under ice-cooling, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was added with an aqueous solution of saturated sodium bicarbonate, extracted with dichloromethane, and the organic layer was sequentially washed with water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, and the obtained residue was solidified with n-hexane/diethyl ether, to give the titled crude compound (0.8 g) as a yellow solid.
To a solution of the compound obtained in <Step 3> of (Example 314) (2.0 g) and veratryl alcohol (1.43 g) in tetrahydrofuran (100.0 mL) were sequentially added triphenylphosphine (3.0 g) and diethyl azodicarboxylate (40% toluene solution) (5.3 mL) under ice-cooling, and the reaction solution was stirred at room temperature for 12 hours. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified with silica gel column chromatography (eluting solution; n-hexane:ethyl acetate=100:0 to 50:50), to give the titled compound (2.6 g) as a yellow solid.
To a solution of the compound obtained in <Step 4> of (Example 314) (1.0 g) in N,N-dimethylformamide (6.0 mL) were sequentially added lithium hydroxide monohydrate (0.4 g) and thioglycolic acid (0.3 mL) and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added with an aqueous solution of 1N sodium hydroxide, extracted with ethyl acetate, and the organic layer was sequentially washed with an aqueous solution of 1N sodium hydroxide, water and saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure, to give the titled crude compound (0.7 g) as a yellow solid.
To a solution of the compound obtained in <Step 5> of (Example 314) (1.0 g) in 1,2-dichloroethane (30.0 mL) were added triethylamine (1.3 mL) and 1,1′-carbonylbis-1H-imidazole (1.0 g), and the reaction solution was heated to reflux for 3 hours. After being left to cool, the precipitated solid was filtered, washed with dichloromethane, and dried under reduced pressure, to give the titled compound (0.6 g) as a pale red solid.
To a solution of the compound obtained in <Step 6> of (Example 314) (0.3 g) in N,N-dimethylformamide (8.0 mL) were added potassium carbonate (0.8 g) and methyl iodide (0.4 mL), and the reaction solution was stirred at 40° C. for 6 hours. The reaction solution was added with water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure. To the obtained residue was added trifluoroacetic acid (4.0 mL), and the reaction solution was stirred at room temperature for 4.5 hours. The reaction solution was added with an aqueous solution of 1N sodium hydroxide, extracted with ethyl acetate, and the organic layer was washed with saturated saline, and then dried with sodium sulfate anhydride. The solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in methanol (8.0 mL), added with 10% palladium-carbon (Pd—C) (30.0 mg), and the reaction solution was stirred at room temperature for 1 hour under hydrogen atmosphere. 10% palladium-carbon (Pd—C) was filtered with celite. The solvent was distilled off under reduced pressure to produce the residue, which was purified with silica gel column chromatography (eluting solution; dichloromethane:methanol=90:10), to give the titled compound (60.0 mg) as a pale yellow solid.
(Alternative synthesis of the compound of Example 306, step 1)
From the compound obtained in <Step 6> of (Example 314) (0.3 g), the titled crude compound (16.8 mg) was obtained as a brown solid in the same manner as in <Step 7> of (Example 314).
To a solution of 4-Trifluoromethyl-2-hydroxybenzoic acid (80.0 g) in dry THF (780.0 mL) was added dropwise MeLi (1.6M Et2O solution, 780.0 mL) using a cannula at −50° C. under N2 gas atmosphere. Then the reaction mixture was stirred at room temperature for 3 h. As the reaction did not complete, the mixture was cooled to −50° C. again and additional MeLi (1.6M Et2O solution, 100.0 mL) was added to the mixture using a cannula. Then the resulting mixture was stirred at room temperature for 2 h. Then the reaction mixture was poured into a mixture of ice and water (1.0 L). The pH of the aqueous layer was adjusted to 5 by adding conc. HCl (135.0 mL) very carefully. Then the whole was extracted with ethylacetate. The combined organic layers were washed with brine, dried, filtered, and concentrated in vacuo to give the titled compound (76.8 g) as pale yellow oil.
To a solution of the compound obtained in <Step 1> of (Example 316) (90.0 g) in MeOH (1.2 L) was added cyclobutanone (53 mL) and pyrrolidine (59 mL). The reaction mixture was stirred at 50° C. for 5 h. As the reaction did not complete, additional cyclobutanone (13 mL) and pyrrolidine (15 mL) were added to the reaction mixture. Then the mixture was stirred over night. Then the mixture was concentrated in vacuo. To the residue was added 1N HCl, and the whole was extracted with ethylacetate. The organic layers were washed with brine, dried, filtered, and concentrated in vacuo to give the titled compound (134 g) as brown oil.
To a solution of diisopropylamine (86.4 mL) in dry THE (1.1 L) was added n-BuLi (1.63M n-hexane solution, 361.3 mL) at −78° C. under N2 gas atmosphere. The reaction mixture was stirred at the same temperature for 0.5 h, and then a mixture of dry ethylacetate (60.0 mL) and dry THE (250 mL) was added dropwise to the reaction mixture at the same temperature. After stirring for 1 h, a solution of the compound obtained in <Step 2> of (Example 316) (79.0 g) in dry THF (250.0 μL) was added dropwise to the mixture at the same temperature, and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched by water (1 L), and the whole was stood at room temperature. Then the mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried, filtered, and concentrated in vacuo to give the titled compound (92.3 g) as reddish brown oil.
To a solution of the compound obtained in <Step 3> of (Example 316) (92.3 g) in EtOH (630.0 mL) was added 1N NaOHaq (630.0 mL) at room temperature. Then the reaction mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo, and conc. HCl (70.0 mL) was carefully added to the residue at 0° C. (pH was adjusted to 2). The resulting mixture was extracted with ethylacetate. The organic layers were washed with brine, dried, filtered, and concentrated in vacuo to give the titled compound (86.6 g) as reddish brown gum.
The compound obtained in <Step 4> of (Example 316) (86.6 g) was dissolved into toluene (1.7 L) by warming with a steam bath, then to the mixture was carefully added conc. H2SO4 (73.0 mL). The reaction mixture was stirred at room temperature for 5 h. Then the mixture was quenched with water at 0° C., and the whole was extracted with diethylether. The organic layers were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by a short column (eluted by h-hexane:ethylacetate=2:10:100) to give crude compound, which was triturated in n-hexane diethylether (4:1) to give the titled compound (13.4 g) as pale yellow solids. (*The mother liquid contained higher amount of the target compound.)
NMR data (δ: ppm): 300 MHz
(DMSO-d6) 7.96 (1H, d, J=8 Hz), 7.27-7.16 (2H, m), 6.59 (1H, s), 3.36 (2H, s), 2.30-2.11 (2H, m), 2.10-1.96 (2H, m), 1.92-1.75 (1H, m), 1.72-1.55 (1H, m).
LCMass (M-1)+: 297 (Retention time: 5.22 min)
The structures of the compound synthesized in Examples 1 to 301 are shown in [Ch.64]-[Ch.83]. The data of liquid chromatography-mass spectrometry (LC-MS) of these examples are shown in [Table 11]-[Table 13]. The NMR data of typical compounds are shown in [Table 14]-[Table 16] (300 MHz: no mark, 270 MHz: marked with *, 400 MHz: marked with **). The structures of the intermediate compounds are shown [Ch.84]-[Ch.85]. The NMR data of these intermediate compounds are shown in [Table 17]-[Table 18] (300 MHz: no mark, 270 MHz: marked with *). The “A” described in [Ch.84]-[Ch.85] correspond to the amine parts of each Example.
The structures of the compound synthesized in Examples 302 to 313 are shown in [Ch.92], and the structures of the intermediates synthesized in Examples 302 to 316 are shown in [Ch.93]. (for example, “Example 1-1” represent the compound synthesized in <Step 1> of (Example 1).)
The data of liquid chromatography-mass spectrometry (LC-MS) of Example 302 to 313 are shown in [Table 46]. The NMR data of the examples and intermediates are shown in [Table 47] and [Table 48] (No mark and the marks * and ** in Tables 47 and 48 represent 400 MHz, 300 MHz and 270 MHz, respectively), and for example, “Example 1-1” represent the compound synthesized in <Step 1> of (Example 1).
[Ch. **] mean a figure included in the general formulae, the reaction scheme or the structures of Example in the specification. And
[Table **] mean a table that the pharmacological data, spectral data or combination of chemical structures are shown in the specification.
The “**” mean a Serial number that was sequentially fixed from page 1 of the specification.
In the compound represented by formula (I) shown below, the compounds (Compound No. 1-2538 in Table; Compound No. 1-2538) by combined with the each groups shown by a group (a group: a1-a11) and b group (b group: b1-b18) can be synthesized as well as the above example.
The compound represented by formula (I) can be synthesized by combing arbitrarily the groups selected from the below R1, R2, X1, X2 etc., and the compounds of the combination shown by below table are preferred.
The specific example of a group (a1-a141) and b group (b1-b18) in the table are shown in the below Chemical formulae, a1-a141 b1-b18.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2007-014372 | Jan 2007 | JP | national |
| 2008-190338 | Jul 2008 | JP | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP2008/051471 | Jan 2008 | US |
| Child | 12507861 | US |
