Patent Application
20090221611
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to substance P, the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively.
Tachykinin, and in particular substance P, antagonists are useful in the treatment of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity, including disorders of the central nervous system, nociception and pain, gastrointestinal disorders, disorders of bladder function and respiratory diseases.
The present invention is directed to certain hydropyranopyrrole compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.
In one aspect, the present invention is directed to compounds of the formula I:
wherein:
R is selected from the group consisting of:
wherein choices (1) through (8) are optionally substituted with 1 or 2 groups selected from
R1 is hydrogen or C1-3alkyl;
R2 is hydrogen, hydroxyl, methyl, —NH2 or —NHC(O)—O—C1-4alkyl;
X, Y and Z are independently selected from the group consisting of:
Within this aspect there is a genus of compounds the formula Ia:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
Within this aspect there is a genus of compounds wherein
the heterocycle of R is selected from the group consisting of
which may be substituted as defined above.
Within this aspect there is a genus of compounds wherein
the heteroaryl of R is selected from the group consisting of
which may be substituted as defined above.
Within this aspect there is a genus of compounds wherein X is fluorine, Y is hydrogen, and Z is hydrogen.
Within this aspect there is a genus of compounds wherein X is methyl, Y is hydrogen, and Z is hydrogen.
Within this aspect there is a genus of compounds wherein R is selected from the group consisting of:
wherein choices (1) through (5) are optionally substituted with 1 or 2 groups selected from
(2) CH3,
Within this aspect there is a genus of compounds wherein
An embodiment of the present invention includes compounds wherein X, Y and Z are hydrogen. An embodiment of the present invention includes compounds wherein X is fluorine, Y is hydrogen, and Z is hydrogen. An embodiment of the present invention includes compounds wherein X is 4-fluoro, Y is hydrogen, and Z is hydrogen. An embodiment of the present invention includes compounds wherein X is methyl, Y is hydrogen, and Z is hydrogen. An embodiment of the present invention includes compounds wherein X is 2-methyl, Y is hydrogen, and Z is hydrogen.
As used herein, “alkyl” as well as other groups having the prefix “alk” such as; for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C—C bond.
The term “cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, “cycloalkenyl” means carbocycles containing no heteroatoms and at least one non-aromatic C—C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term “aryl” unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.
The term “C0-C6alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent or a direct bond—depending on whether the alkyl is a terminus or a bridging moiety.
The term “hetero” unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloC5alkyl is a five membered ring containing from 5 to no carbon atoms.
Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
Examples of heterocyclic groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
The term “amine” unless specifically stated otherwise includes primary, secondary and tertiary amines.
The term “halogen” includes fluorine, chlorine, bromine and iodine atoms.
Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
There are several acceptable methods of naming the compounds discussed herein
For example, the above compound can be named as tert-butyl 4-{[(6S,7S)-7-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-6-(4-fluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}piperidine-1-carboxylate or (6S,7S)-7-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-6-(4-fluorophenyl)-3-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine tert-butyl carbamate. The core structure may be generally referred to as tetrahydrotriazolopyridine, perhydrotriazolopyridine, hydrotriazolopyridine, triazolopiperidine or fused triazole compounds.
As appreciated by those of skill in the art, halo or halogen as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C1-6, as in C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C1-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity. Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid hemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis. Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia, frequent urination and urinary incontinence, including the prevention or treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. The compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of the present invention are particularly useful in the prevention or treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. For example, the compounds of the present invention are of use optionally in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderate or highly emetogenic cancer chemotherapy, including high-dose cisplatin. Most especially, the compounds of the present invention are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram. Examples of such chemotherapeutic agents include alkylating agents, for example, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172]. A further aspect of the present invention comprises the use of a compound of the present invention for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of the present invention for blocking the phase-shifting effects of light in a mammal.
The present invention is further directed to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) (“DIMS”) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus, fibromyalgia, muscle pain, sleep apnea and restless legs and non specific REM disturbances as seen in ageing.
The particularly preferred embodiments of the instant invention are the treatment of emesis, urinary incontinence, depression or anxiety by administration of the compounds of the present invention to a subject (human or animal) in need of such treatment.
The present invention is directed to a method for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention is further directed to a method for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of the present invention or a composition comprising a compound of the present invention. As used herein, the term “treatment” or “to treat” refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate either the symptoms or underlying cause of the noted disease conditions, in a subject (human or animal) that suffers from that condition or displays clinical indicators thereof. The term “prevention” or “to prevent” refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate the risk or likelihood of occurrence of the noted disease conditions, in a subject (human or animal) susceptible or predisposed to that condition.
The compounds of this invention are useful for antagonizing tachykinins, in particular substance P in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assays.
Receptor Expression in COS: To express the cloned human neurokinin-1 receptor (NK1R) transiently in COS, the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, Conn.). The cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100 U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, N.Y.) in 5% CO2 at 37° C. for three days before the assay.
Stable Expression in CHO: To establish a stable cell line expressing the cloned human NK1R, the cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer supplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO media [10% fetal calf serum, 100 U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, Kans.), 0.7 mg/ml G418 (GIBCO)] in 5% CO2 at 37° C. until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NK1R was selected for subsequent applications such as drug screening.
Assay Protocol using COS or CHO: The binding assay of human NKIR expressed in either COS or CHO cells is based on the use of 125I-substance P (125I-SP, from DU PONT, Boston, Mass.) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NK1R. Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECLALTY MEDIA, Lavallette, N.J.) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 125I-SP binding (approximately 50,000 to 200,000 cells). In the binding assay, 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 125I-SP and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 4° C. or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which was pre-wetted with 0.1% polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity was determined by gamma counter. The activation of phospholipase C by NK1R may also be measured in CHO cells expressing the human NK1R by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells are seeded in 12-well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of 3H-myoinositol by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 0.1 mM with or without the test compound, and incubation is continued at 37° C. for 15 min. Substance P is added to the well at final concentration of 0.3 nM to activate the human NK1R. After 30 min of incubation at 37° C., the media is removed and 0.1 N HCl is added. Each well is sonicated at 4° C. and extracted with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1×8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter. In particular, the intrinsic tachykinin receptor antagonist activities of the compounds of the present invention may be demonstrated by these assays. The compounds of the following examples have activity in the aforementioned assays in the range of 0.05 nM to 10 μM. The activity of the present compounds may also be demonstrated by the assay disclosed by Lei, et al., British J. Pharmacol., 105, 261-262 (1992).
According to a further or alternative aspect, the present invention provides a compound of the present invention for use as a composition that may be administered to a subject in need of a reduction of the amount of tachykinin or substance P in their body.
The term “composition” as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
The compositions containing compounds of the present invention may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples in the pharmacy arts of unit dosage forms. The compositions containing compounds of the present invention may also be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms “administration of” or “administering a” compound should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individuals body in a therapeutically useful form and therapeutically effective amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories. The term “therapeutically effective amount” refers to a sufficient quantity of the compounds of the present invention, in a suitable composition, and in a suitable dosage form to treat or prevent the noted disease conditions.
The compounds of the present invention may be administered in combination with another substance that has a complimentary effect to the tachykinin and substance P inhibitors of the present invention. Accordingly, in the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid, such as dexamethasone, or GABAB receptor agonists, such as baclofen. Likewise, for the prevention or treatment of migraine a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), α-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof. For the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents. It will be appreciated that for the treatment or prevention of pain or nociception or inflammatory diseases, a compound of the present invention may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent.
It will be appreciated that when using any combination described herein, both the compound of the present invention and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a “fast dissolving oral formulation” is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds. By “reasonable period of time” is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The compounds of this invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level of the compounds of the present invention, or pharmaceutically acceptable salts thereof, is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day. The dosage range will generally be about 0.5 to 1000 mg per patient per day, which may be administered in single or multiple doses. Preferably, the dosage range will be about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day. Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg. Pharmaceutical compositions of the present invention may be provided in a formulation comprising about 0.5 mg to 1000 mg active ingredient; more preferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient. Specific pharmaceutical compositions for treatment or prevention of excess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg of active ingredient.
Several methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. All 1H NMR spectra were obtained on instrumentation at a field strength of 400 or 500 MHz.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
To a round-bottom flask equipped with an argon-filled balloon was loaded 5.0 g (25.1 mmol) N-BOC 4-piperidone, 2.89 g sodium tert-butoxide (30.1 mmol), 0.056 g palladium acetate (0.30 mmol), and 0.183 g 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.5 mmol). 150 mL THF was added followed by the addition of 4-fluoro-1-bromobenzene. After 5 evacuation/argon cycles, the reaction was heated to 80° C. for 24 hr. After cooling to ambient temperature, the reaction mixture was quenched with a saturated (aqueous) solution of ammonium chloride, filtered through a pad of celite, and rinsed the pad with copious amounts of ethyl acetate. After separation of the layers, the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified on silica gel (1-15% EtOAc/hexanes linear gradient; then 15% EtOAc/hexanes). This provided 3.1 g of the title compound. 1H-NMR (CDCl3): δ 1.53 (s, 9H), 2.54-2.64 (m, 2H), 3.40-3.60 (m, 2H), 3.64-3.76 (m, 1H), 4.18-4.40 (m, 2H), 7.07 (dd, 2H, J=9, 9 Hz), 7.17 (dd, 2H, J=6, 9 Hz) ppm.
To a cooled (−78° C.) solution of 4.61 g (15.7 mmol) of the intermediate from Example 1 step A in 200 mL of diethyl ether was added a 1.0M solution of LAH (in THF). The reaction was stirred at this temperature for 7 hr at which time the reaction was quenched by the sequential addition of H2O (0.72 mL), 5N NaOH (0.72 mL) and H2O (2.16 mL). The mixture was allowed to warm to ambient temperature overnight. The reaction mixture was then filtered through a pad of celite, rinsed with copious amounts of EtOAc, concentrated in vacuo and the crude residue was purified on silica gel (eluted with a linear gradient from 10 to 40% EtOAc/hexane) which yielded 3.71 g of the more polar trans-diastereomer. Alternatively, the crude residue could be recrystallized from 20% EtOAc/hexanes to yield the pure trans-diastereomer. 1H-NMR (CDCl3): δ 1.50 (s, 9H), 2.05-2.12 (m, 1H), 2.58-2.66 (m, 1H), 2.70-3.00 (m, 3H), 3.85 (ddd, 1H, J=5, 11, 11 Hz), 4.00-4.30 (m, 2H), 7.05-7.12 (m, 2H), 7.24-7.30 (m, 2H) ppm.
A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then the mixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0° C. for 2 hr during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35° C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3″×10″ pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): δ: 1.74 (d, 3H, 6.5 Hz), 6.07 (q, 1H, 6.5 Hz), 7.82 (s, 1H), 7.86 (s, 2H), 8.40 (br. s, 1H) ppm.
To a cooled (−5° C.) solution of 9.0 g of the trans-racemic alcohol (30.05 mmol) from Step B in a 2:1 mixture of cyclohexane-1,2-dichloroethane (360 mL) was added 24.53 g of the (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (610 mmol) followed by the addition 54% (in diethyl ether) HBF4 (0.5 mL). After 18 hr, an additional 0.5 mL HBF4 was added and the reaction was maintained at −5° C. for an additional 6 hr at which time the reaction mixture was diluted EtOAc. The organics were washed with a saturated solution of NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (eluted using a linear gradient of 1 to 15% EtOAc/hexanes). This provided 3 g of the desired diastereomer and 4 g of the starting alcohol. 1H-NMR (CDCl3): δ 1.35 (d, 3H, J=7 Hz), 1.50 (s, 9H), 1.56-1.64 (m, 1H), 2.16-2.24 (m, 1H), 2.66-2.90 (m, 3H), 3.39 (ddd, 1H, J=5, 11, 11 Hz), 3.90-4.40 (m, 2H), 4.54 (q, 1H, J=7 Hz), 6.92 (dd, 2H, J=9, 9 Hz), 7.01 (dd, 2H, J=6, 9 Hz), 7.30 (s, 2H), 7.73 (s, 1H) ppm.
Sodium periodate (1.13 g, 5.29 mmol) was stirred vigorously in 20 mL H2O followed by the addition of RuO2 hydrate (29 mg, 0.22 mol) for 5 minutes. A solution of the intermediate from Example 1 step D (567 mg, 1.05 mmol) in 10 mL EtOAc was added dropwise. The reaction was stirred an additional 3 hr. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified on silica gel (eluted using a linear gradient of 15 to 35% EtOAc/hexanes). This furnished 300 mg of the title compound.
The intermediate from Example 1 step E was dissolved in 5 mL EtOAc followed by the addition of a saturated solution of HCl (in EtOAc). The mixture was allowed to age for 3 hr at ambient temperature. The volatiles were removed in vacuo and the crude residue was purified on silica gel (eluted using a linear gradient of 1 to 10% methanol/DCM). This furnished 220 mg of the title compound. 1H-NMR (CD3OD): δ 1.34 (d, 3H, J=7.0 Hz), 2.48 (dd, 11, J=9, 18 Hz), 2.96 (dd, 1H, J=6, 18 Hz), 3.06 (ddd, 1H, J=7, 10, 10 Hz), 3.30-3.34 (m, 2H), 3.92 (ddd, 1H, J=6, 8, 10 Hz), 4.71 (q, 1H, J=7 Hz), 6.91 (dd, 2H, J=9, 9 Hz), 7.14 (dd, 2H, J=6, 9 Hz), 7.52 (s, 2H), 7.78 (s, 1H).
The intermediate from Example 1 step F (30 mg, 0.066 mmol) was dissolved in 2 mL DCM followed by the addition of trimethyloxonium tetrafluoroborate (11 mg, 0.075 mmol). The reaction was allowed to age for 2 hr. The volatiles were removed in vacuo and the product was used without purification.
The intermediate from Example 1 step G was dissolved in 2 mL EtOH followed by the addition of acetic hydrazide (15 mg, 0.202 mmol). The reaction was heated to 75° C. overnight. The volatiles were removed in vacuo and the crude residue was purified on silica gel (5% methanol/DCM). This furnished the title compound. 1H-NMR (CD3OD): 1.38 (d, 3H, J=7 Hz), 2.37 (s, 3H), 2.97 (dd, 1H, J=9, 17 Hz), 3.41, ddd, 1H, J=6, 11, 11 Hz), 3.60 (dd, 1H, J=5, 17 Hz), 3.99 (dd, 1H, J=11, 13 Hz), 4.09 (ddd, 1H, J=6, 9, 9 Hz), 4.20 (dd, 1H, J=6, 13 Hz), 4.80 (q, 1H, J=7 Hz), 6.94 (dd, 2H, J=9, 9 Hz), 7.17 (dd, 2H, J=6, 9 Hz), 7.54 (s, 2H), 7.80 (s, 1H). MS (M+H)+ 488.
To a solution of the intermediate from Example 1 step F (272 mg, 0.6058 mmol) in 10 mL THF was added the Belleau reagent (385 mg, 0.7269 mmol). The mixture was allowed to age at ambient temperature. The reaction was quenched with H2O. The aqueous layer was extracted several time with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered through a fritted funnel. The volatiles were remover in vacuo and the crude residue was purified on silica gel (eluted with 10-30% EtOAc/hexanes). This furnished 165 mg of the title compound. MS (M+H)+ 466.
To a solution of the intermediate from Example 2 step A (165 mg, 0.3548 mmol) in 5 mL THF was added a 60% dispersion in oil of sodium hydride (28 mg, 0.7097 mmol). After 20 min, iodomethane (100 mg, 0.7097 mmol) was added. The volatiles were removed in vacuo and the crude residue was used without purification.
To a solution of the intermediate from Example 2 (0.3548 mmol) in 2.5 mL EtOH was added ethyl carbamate (1.42 mmol). The mixture was allowed to age for 2 hr at ambient temperature and then heated to reflux for 18 hr. The volatiles were removed in vacuo and the crude residue was purified on silica gel (eluted with EtOAc). This furnished the title compound. 1H-NMR (CDCl3): 1.43 (d, 3H, J=7 Hz), 2.85 (dd, 1H, J=7, 17 Hz), 3.04 (dd, 1H, J=5, 17 Hz), 3.31 (ddd, 1H, J==6, 8, 8 Hz), 3.76 (dd, 1H, J=8, 13 Hz), 3.83 (ddd, 1H, J=5, 8, 8 Hz), 4.05 (dd, 1H, J=6, 13 Hz), 4.63 (q, 1H, J=7 Hz), 7.00-7.15 (m, 2H), 7.20-7.24 (m, 2H) 7.51 (s, 2H), 7.83 (s, 1H), 9.37 (bs, 1H). MS (M+H)+ 490.
To a solution of the intermediate from Example 1 step F (97 mg, 0.2156 mmol) in 5 mL DCM was added trimethyloxonium tetrafluoroborate (48 mg, 0.3233 mmol). The reaction was allowed to age for 5 hr. The volatiles were removed in vacuo and the product was used without purification. The crude residue was dissolved in 5 mL EtOH followed by the addition of hydrazine hydrate (55 mg, 1.0780 mmol). The reaction was allowed to stand at ambient temperature. The volatiles were removed in vacuo. The excess hydrazine was removed by azeotropic removal using toluene. The crude residue was used without purification. The crude amidine was dissolved in 5 mL acetonitrile followed by the addition of chloroacetyl chloride (49 mg, 0.4312 mmol). The reaction mixture was heated to 75° C. for 15 hr. After cooling to ambient temperature, the reaction was diluted with DCM and washed sequentially with a saturated solution of NaHCO3 and brine. The organic fraction was dried over Na2SO4, filtered through a filtered funnel, and concentrated in vacuo. The crude residue was purified on silica gel (gradient elution 1-10% methanol/DCM). This furnished 65 mg of the title compound.
To a solution of the intermediate from step A (20 mg, 0.0383 mmol) in 3 mL ethanol was added 5 equivalents of pyrrolidine (14 mg, 0.1916 mmol). The reaction was heated to 75° C. for 2 hr. The reaction was cooled to ambient temperature and diluted with EtOAc. The mixture was washed with a saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a filtered funnel, and concentrated in vacuo. The crude residue was purified on silica gel (gradient elution 0-4% methanol/DCM). This furnished the title compound. MS (M+H)+ 557.
To the intermediate from Example 3 step A (27 mg, 0.0582 mmol) was added EDC (34 mg, 0.1746 mmol), DMAP (7 mg, 0.0582 mmol) and pyroglutamic acid (23 mg, 0.1746 mmol). The mixture was dissolved in 2.0 mL DCM. The reaction was aged for 15 hr. The mixture was diluted with DCM and washed sequentially with 1M HCL a saturated solution of NaHCO3, and brine. The organic extracts were dried over Na2SO4, filtered through a filtered funnel, and concentrated in vacuo. The crude residue was purified on silica gel (gradient elution 0-4% methanol/DCM). This furnished 7 mg of the title compound 1H-NMR (CD3OD): 1.40 (d, 3H, J=6 Hz), 2.30-2.70 (m, 4H), 3.02 (dd, 1H, J=9, 17 Hz), 3.44 (dddd, 1H, J=6, 6, 11, 11 Hz), 3.67 (ddd, 1H, J=2, 5, 17 Hz), 4.02-4.18 (m, 2H), 4.33 (ddd, 1H, J=6, 13, 19 Hz), 4.84 (q, 1H, J=6 Hz), 4.80-5.50 (m, 1H), 6.80-7.03 (m, 2H), 7.15-7.25 (m, 2H), 7.58 (s, 2H), 7.82 (s, 1H). MS (M+H)+ 557.
To a solution of 1-acetyl-4-piperidinecarboxylic acid (1.71 g, 10 mmol) in 20 mL diethyl ether was added an excess of 2.0 M trimethylsilyldiazomethane. The volatiles were removed in vacuo. The crude residue was triturated to high purity with diethyl ether.
To a solution of the intermediate from step A (950 mg, 5.13 mmol) in 20 mL methanol was added hydrazine (10.26 mmol). The reaction was heated to reflux for 2 days. The volatiles were removed in vacuo. The crude residue was triturated to high purity with diethyl ether. 1H-NMR (CD3OD): 1.55-1.85 (m, 4H), 2.12 (s, 3H), 2.45 (dddd, 1H, J=4, 4, 12, 12 Hz), 2.69 (ddd, 1H, J=3, 13, 13 Hz), 3.16 (ddd, 1H, J=3, 12, 15 Hz), 3.80-4.02 (m, 1H), 4.50-4.58 (m, 1H).
The intermediate from Example 1 step G was treated with the intermediate from step B according to the general protocol found in Example 1 step H. 1H-NMR (CD3OD): 1.39 (d, 3H, J=6 Hz), 1.58-2.06 (m, 5H), 2.10-2.13 (m, 3H), 2.72-2.80 (m, 1H), 2.95-3.02 (m, 1H), 3.05-3.15 (m, 1H), 3.18-3.27 (m, 1H), 3.38-3.46 (m, 1H), 3.60-3.68 (m, 1H), 3.80-4.25 (m, 2H), 4.26-4.32 (m, 1H), 4.50-4.62 (m, 1H), 4.78-4.86 (m, 1H), 6.94-6.99 (m, 2H), 7.16-7.22 (m, 2H), 7.56 (s, 2H), 7.82 (s, 1H). MS (M+H)+ 599.
To a solution of 6-chloronicotinic acid (2.5 g, 15.9 mmol) in 50 mL methanol was added an excess of 2.0 M trimethylsilyldiazomethane. The volatiles were removed in vacuo. The crude residue was purified on silica gel (eluted with 10-20% EtOAc/hexanes). This furnished 2.4 g of the title compound.
The intermediate from step A (2.4 g, 14 mmol) was combined with Cl2Pd(Ph3P)2 (493 mg, 0.70 mmol) and dissolved in 50 mL toluene followed by the addition of tributyl(1-ethoxyvinyl)tin (6.34 g, 17.5 mmol). The reaction was heated to 105° C. for 6 hr. The reaction mixture was cooled to ambient temperature then filtered through a pad of celite. After removal of the volatiles in vacuo, the crude enol-ether was treated with a 2:1 mixture of methanol/concentrated HCl (15 mL) and allowed to age for 4 hr. The reaction mixture was diluted with EtOAc and H2O and basified by the slow addition of solid Na2CO3. The layers were separated and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered through a filtered funnel, and concentrated in vacuo. The crude residue was purified on silica gel (5-20% EtOAc/hexanes). This furnished the title compound.
The intermediate from Example 24 step B (100 mg, 0.5556 mmol) was combined with 10% Pd/C (100 mg) and di-tert-butyl dicarbonate (363 mg, 1.6667 mmol) in 5 mL methanol. The reaction was stirred under 1 atm hydrogen for 2 days. The crude reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude residue was purified on silica gel (eluted with 70% EtOAc/hexanes). This finished the title compound.
The intermediate from step C was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. MS (M+H)+ 601.
Pyrrolidine (267 mg, 3.67 mmol) was dissolved in 10 mL DCE followed by the addition of 4 angstrom molecular sieves, ethyl 4-oxocyclohexanecarboxylate (500 mg, 2.94 mmol), catalytic acetic acid and sodium triacetoxyborohydride (2500 mg, 11.76 mmol). The reaction was allowed to age at ambient temperature for 24 hr. The reaction was quenched with a saturated NaHCO3 and extracted several times with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel, and concentrated in vacuo. The product was carried on without purification. 1H-NMR (CD3OD): 1.20-1.30 (m, 3H), 1.40-1.70 (m, 3H), 1.70-2.40 (m, 9H), 2.60-2.92 (m, 2H), 3.10-3.20 (m, 4H), 4.08-4.20 (m, 2H).
The intermediate from step A was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. MS (M+H)+ 625.
Methyl 4-piperidinecarboxylate (300 mg, 2.1 mmol) was dissolved in 10 mL DCM followed by the addition of methylisocyanate (180 mg 3.2 mmol). The reaction was allowed to age at ambient temperature for 24 hr. The reaction was quenched with a saturated NaHCO3 and extracted several times with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel, and concentrated in vacuo. The crude residue was purified on silica gel (1-8% methanol/DCM). This provided 347 mg of the title compound. 1H-NMR (CD3OD): 1.56 (dddd, 2H, J=5, 12, 12, 12 Hz), 1.85-1.94 (m, 2H), 2.58 (dddd, 1H, J=4, 4, 11, 11 Hz), 2.72 (s, 3H), 2.88-2.93 (m, 2H), 3.67 (s, 3H), 3.89-3.93 (m, 2H).
The intermediate from step A was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. 1H-NMR (CD3OD): 1.38 (d, 3H, J=7 Hz), 1.67 (dddd, 1H, J=4, 13, 13, 13 Hz), 1.79 (dddd, 1H, J=4, 13, 13, 13 Hz), 1.92 (dd, 2H, J=15, 15 Hz), 2.72 (s, 3H), 2.75-3.05 (m, 4H), 3.41 (ddd, 1H, J=6, 11, 11 Hz), 3.62 (dd, 1H, J=6, 17 Hz), 4.00-4.14 (m, 4H), 4.27 (dd, 1H, J=4, 13 Hz), 4.81 (q, 1H, J=7 Hz), 6.95 (dd, 2H, J=9, 9 Hz), 7.18 (dd, 2H, J=6, 9 Hz), 7.55 (s, 2H), 7.81 (s, 1H). MS (M+H)+ 614.
Methyl 4-piperidinecarboxylate (300 mg, 2.1 mmol) was dissolved in 10 mL DCM followed by the addition of triethyl amine (636 mg, 6.3 mmol), and dimethylcarbamoyl chloride (271 mg, 2.5 mmol). The reaction was allowed to age at ambient temperature for 24 hr. The reaction was quenched with a saturated NaHCO3 and extracted several times with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel, and concentrated in vacuo. The crude residue was purified on silica gel (1-8% methanol/DCM). This provided 367 mg of the title compound
The intermediate from step A was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. 1H-NMR (CD3OD): 1.38 (d, 3H, J=7 Hz), 1.70-2.00 (m, 4H), 2.80-3.05 (m, 10H), 3.42 (ddd, 1H, J=6, 11, 11 Hz), 3.62 (dd, 1H, J=6, 17 Hz), 3.73 (dd, 2H, J=10, 10 Hz), 4.06 (dd, 1H, J=13, 13 Hz), 4.12 (ddd, 1H, J=6, 10, 10 Hz), 4.28 (dd, 1H, J=6, 13 Hz), 4.82 (q, 1H, J=6 Hz), 6.95 (dd, 2H, J=9, 9 Hz), 7.18 (dd, 2H, J=5, 9 Hz), 7.55 (s, 2H), 7.81 (s, 1H). MS (M+H)+ 628.
The intermediate from Example 6 step B (220 mg, 1.22 mmol) was dissolved in 10 mL methanol followed by the addition of sodium borohydride (55 mg, 1.47 mmol) in a single portion. The reaction was allowed to age at ambient temperature for 1 hr. The reaction was quenched with a saturated H2O and extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel, and concentrated in vacuo. The crude residue was purified on silica gel (1-8% methanol/DCM). This provided 367 mg of the title compound. 1H-NMR (CDCl3): 1.56 (d, 3H, J=7 Hz), 3.99 (s, 3H), 4.06 (bs, 1H), 4.98 (q, 1H, J=7 Hz), 4.12 (d, 1H, J=8 Hz), 8.33 (dd, 1H, J=2, 8 Hz), 9.17 (d, 1H, J=4 Hz).
The intermediate from step A was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. MS (M+H)+ 595.
To a suspension of 2-hydroxy-5-pyrazinecarboxylic acid (500 mg, 3.6 mmol) in 20 mL toluene were added sequentially s drops DMF and thionyl chloride (1.7 g, 14.3 mmol). The reaction was heated to reflux for 2 hr. The reaction was cooled to ambient temperature followed by the addition of 4 mL methanol. The reaction was allowed to age for 15 hr. The reaction was diluted with a 1:1 hexanes/EtOAc. The brown solid was filtered and the volatiles were removed in vacuo. This provided 472 mg of the title compound. 1H-NMR (CDCl3): 4.08 bs, 3H), 8.74 (s, 1H), 9.12 (s, 1H).
The intermediate from step A (200 mg, 1.16 mmol) was dissolved in 8 mL THF followed by the sequential addition of triethylamine (234 mg, 2.32 mmol) and pyrrolidine (413 mg, 5.8 mmol). The reaction was allowed to age at ambient temperature for 2 hr. The volatiles were removed in vacuo and the crude residue was purified on silica gel (eluted with 50% EtOAc/hexanes). 1H-NMR (CDCl3): 2.00-2.20 (m, 4H), 3.40-3.80 (m, 4H), 3.98 (s, 3H), 7.93 (s, 1H), 8.84 (s, 1H).
The intermediate from Example 46 step A was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. MS (M+H)+ 621.
To a suspension of 2,4-dichloropyrimidine (1170 mg, 7.86 mmol) in 30 mL methanol were added sequentially triethylamine (1908 mg, 8.01 mmol) and methyl 4-piperidinecarboxylate (900 mg, 6.3 mmol). The reaction was heated to reflux for 15 hr. The reaction was cooled to ambient temperature and partitioned between H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel, and concentrated in vacuo. The crude residue was purified on silica gel (eluted with 30% EtOAc/hexanes). This provided 930 mg of the title compound. 1H-NMR (CDCl3): 1.72-1.83 (m, 2H), 2.00-2.07 (m, 2H, 2.65 (dddd, 1H, J=4, 4, 12, 12 Hz), 3.14 (ddd, 2H, J=3, 12, 14 Hz), 3.74 (s, 3H), 6.42 (d, 1H, J=7 Hz), 8.05 (d, 1H, J=7 Hz).
The intermediate from step A (200 mg, 1.16 mmol) was combined with 200 mg 10% Pd/C in 20 mL methanol. The reaction was stirred under 1 atm of hydrogen for 2 hr. The reaction was filtered through celite and rinsed with methanol. The volatiles were removed in vacuo and the crude residue was triturated with diethyl ether. This provided 750 mg of the title compound.
The intermediate from step B was subjected to the general reactions for the preparation of the acyl hydrazides and further transformation to the triazoles found in Example 5 steps B and C. 1H-NMR (CD3OD): 1.38 (d, 3H, J=7 Hz), 1.70-1.90 (m, 2H), 2.00-2.80 (m, 2H), 2.98 (dd, 1H, J=9, 17 Hz), 3.02-3.12 (m, 2H), 3.16 (dddd, 1H, J=4, 4, 12, 12 Hz), 3.42 (ddd, 1H, J=6, 10, 10 Hz), 3.63 (dd, 1H, J=5, 12 Hz), 4.04-4.15 (m, 2H), 4.31 (dd, 1H, J=6, 13 Hz), 4.82 (q, 1H, J=7 Hz), 6.80 (d, 1H, J=7 Hz), 6.96 (dd, 2H, J=9, 9 Hz), 7.19 (dd, 2H, J=6, 9 Hz), 7.55 (s, 2H), 7.82 (s, 1H), 8.10 (d, 1H, J=7 Hz), 8.44 (s, 1H). MS (M+H)+ 635.
Using the procedures similar to those described above the following Examples as shown in the Table were prepared in racemic form (mixture) or as a single enantiomer by separation by chiral chromatography.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US07/00434 | 1/5/2007 | WO | 00 | 6/26/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60757941 | Jan 2006 | US |
