Patent Grant
8623863
This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2009/060762, filed Oct. 15, 2009, which claims priority under 35 U.S.C. §119(e) from U.S. Ser. No. 61/196,848, filed Oct. 21, 2008.
The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999, 98, 437-451). Orexins have also been indicated as playing a role in arousal, reward, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.
Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumour/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.
The present invention is directed to disubstituted azepan and oxazepan amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
The present invention is directed to compounds of the formula I:
wherein:
An embodiment of the present invention includes compounds of the formula Ia:
wherein B, W, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ib:
wherein B, W, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ic:
wherein B, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ic':
wherein B, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ic″:
wherein B, R1d, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Id:
wherein B, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Id′:
wherein B, R1a, R1b, R1c, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Id″:
wherein B, R1a, R1b, R1c, R2a, R2b, R2e and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ie:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ie′:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ie″:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula If:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula If′:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula If″:
wherein B, R1a, R1b, R2a, R2b, R2c and R3 are defined herein; or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds wherein A is selected from the group consisting of: phenyl, pyrazolyl, and thiazolyl. An embodiment of the present invention includes compounds wherein A is phenyl. An embodiment of the present invention includes compounds wherein A is heteroaryl. An embodiment of the present invention includes compounds wherein A is pyrazolyl. An embodiment of the present invention includes compounds wherein A is thiazolyl.
An embodiment of the present invention includes compounds wherein B is independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein B is quinoline. An embodiment of the present invention includes compounds wherein B is isoquinoline. An embodiment of the present invention includes compounds wherein B is pyridine.
An embodiment of the present invention includes compounds wherein W is —CH2—. An embodiment of the present invention includes compounds wherein W is —O—.
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R1a, R1b and R1c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R1c is hydrogen and R1a and R1b are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R1c is hydrogen, R1b is hydrogen or methyl, and R1a is selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R1c is hydrogen, R1b is hydrogen or methyl, and R1a is triazolyl. An embodiment of the present invention includes compounds wherein R1c is hydrogen, R1b is hydrogen or methyl, and R1a is 2-(1,2,3-triazolyl).
An embodiment of the present invention includes compounds wherein R2a, R2b and R2c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R2a, R2b and R2c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R2a, R2b and R2c are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R2c is hydrogen, and R2a and R2b are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R2c is hydrogen, and R2a and R2b are independently selected from the group consisting of:
An embodiment of the present invention includes compounds wherein R3 is hydrogen, C1-6alkyl or C3-6cycloalkyl. An embodiment of the present invention includes compounds wherein R3 is other than hydrogen. An embodiment of the present invention includes compounds wherein R3 is C1-6alkyl. An embodiment of the present invention includes compounds wherein R3 is C3-6cycloalkyl. An embodiment of the present invention includes compounds wherein R3 is methyl or ethyl. An embodiment of the present invention includes compounds wherein R3 is methyl. An embodiment of the present invention includes compounds wherein R3 is in the trans configuration on the azepan ring relative to the substituent at the 6-position. An embodiment of the present invention includes compounds wherein R3 is in the cis configuration on the azepan ring relative to the substituent at the 6-position. An embodiment of the present invention includes compounds wherein R3 is in the R configuration on the azepan ring. An embodiment of the present invention includes compounds wherein the substituent at the 6-position of the azepan ring is in the R configuration. An embodiment of the present invention includes compounds wherein the group at C6 is in the R configuration on the azepan ring.
An embodiment of the present invention includes compounds wherein R4 is hydrogen or C1-6alkyl. An embodiment of the present invention includes compounds wherein R4 is hydrogen or methyl. An embodiment of the present invention includes compounds wherein R4 is hydrogen. An embodiment of the present invention includes compounds wherein R5 is hydrogen or C1-6alkyl. An embodiment of the present invention includes compounds wherein R5 is hydrogen or methyl. An embodiment of the present invention includes compounds wherein R5 is hydrogen.
Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric 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 scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. For example, Formula I shows the structure of the class of compounds without specific stereochemistry. When the compounds of the present invention contain one chiral center, the term “stereoisomer” includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures.
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.
As appreciated by those of skill in the art, halogen or halo 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 “heterocycle” as used herein includes both unsaturated and saturated heterocyclic moieties, wherein the unsaturated heterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, and wherein the saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.
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. Particular embodiments include 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′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, 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. Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I 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 enantiomers or diastereomers thereof.
The subject compounds are useful in a method of antagonizing orexin receptor activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of orexin receptor activity. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof for use in medicine. The present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing orexin receptor activity or treating the disorders and diseases noted herein in humans and animals.
The subject treated in the present methods is generally a mammal, such as a human being, male or female. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need thereof.
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, 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. 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.
The utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R antagonists may be readily determined without undue experimentation by methodology well known in the art, including the “FLIPR Ca2+ Flux Assay” (Okumura et al., Biochem. Biophys. Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2 receptor antagonistic activity of the compounds of the present invention was determined in accordance with the following experimental method. For intracellular calcium measurements, Chinese hamster ovary (CHO) cells expressing the rat OX1 receptor or the human OX2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist. For each antagonist, IC50 value (the concentration of compound needed to inhibit 50% of the agonist response) is determined. Alternatively, compound potency can be assessed by a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant (Ki) is determined in membranes prepared from CHO cells expressing either the orexin-1 (OX1) or orexin-2 (OX2) receptor. The intrinsic orexin receptor antagonist activity of a compound which may be used in the present invention may be determined by these assays.
In particular, the compounds of the following examples had activity in antagonizing the rat orexin-1 (OX1) receptor and/or the human orexin-2 (OX2) receptor in the aforementioned assays, generally with an IC50 of less than about 50 μM. Many of compounds within the present invention had activity in antagonizing the rat orexin-1 (OX1) receptor and/or the human orexin-2 (OX2) receptor in the aforementioned assays with an IC50 of less than about 100 nM. Compounds of the present invention also have activity in the radioligand binding assay, generally with a Ki <100 nM against the orexin-1 (OX1) and/or the orexin-2 (OX2) receptor. Additional data is provided in herein. Such a result is indicative of the intrinsic activity of the compounds in use as antagonists of orexin-1 (OX1) receptor and/or the orexin-2 (OX2) receptor. The present invention also includes compounds within the generic scope of the invention which possess activity as agonists of the orexin-1 (OX1) receptor and/or the orexin-2 (OX2) receptor. With respect to other azepane compounds, the present compounds exhibit unexpected properties, such as with respect to increased potency, oral bioavailability, metabolic stability, and/or selectivity.
The orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, including one or more of the following conditions or diseases: sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, conditions due to drugs which cause reductions in REM sleep as a side effect; fibromyalgia; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; increasing learning; augmenting memory; increasing retention of memory; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related disorders including overeating and bulimia nervosa, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy; diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; 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, mood disorders due to a general medical condition, and substance-induced mood disorders; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, addictive feeding, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache.
Thus, in specific embodiments the present invention provides methods for: enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of the present invention.
The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to the patient, e.g., humans and elderly humans, to obtain effective antagonism of orexin receptors. The dosage range will generally be about 0.5 mg to 1.0 g. per patient per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated. However, the combination therapy may also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is contemplated. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered in combination with other compounds which are known in the art to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
In another embodiment, the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: insulin sensitizers including (i) PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like); (iii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics, such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH2); (c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like; (e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers/sequestrants, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iii) proliferator-activater receptor α agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterol acyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists as described in WO 97/36579 by Glaxo; (g) PPARδ agonists; (h) PPAR α/δ agonists, such as muraglitazar, and the compounds disclosed in U.S. Pat. No. 6,414,002; and (i) anti-obesity agents, such as (1) growth hormone secretagogues, growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, and L-163,255; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB1 receptor antagonists or inverse agonists, such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104; (9) melanin-concentrating hormone (MCH) receptor antagonists; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda); (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin receptor antagonists, such as SB-334867-A, and those disclosed in patent publications herein; (13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline; (14) melanocortin agonists, such as Melanotan II; (15) other Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R-1065; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1); 26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, aminone, milrinone, cilostamide, rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (29) ghrelin receptor antagonists; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed in Pept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophic factors), such as GI-181771 (GlaxoSmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron); (35) monoamine reuptake inhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, MK-431, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444; (46) dicarboxylate transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate transporter inhibitors; (49) Metformin (Glucophage®); and (50) Topiramate (Topimax®); and (50) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP), and other Y4 agonists such as 1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381, and pharmaceutically acceptable salts thereof; (55) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitor such as BVT 3498, BVT 2733; (58) a minorex; (59) amphechloral; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane; (79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87) phytopharm 57; and (88) zonisamide.
In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
In another embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents; beta-secretase inhibitors; gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonists; or neuronal nicotinic agonists.
In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexyl)hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.
In another embodiment, the subject compound may be employed in combination with acetophenazine, alentemol, benzhexyl, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.
In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with thesubject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
In another embodiment, the subject compound may be employed in combination with an anoretic agent such as a minorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; selective serotonin reuptake inhibitor (SSRI); halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptble salts thereof.
In another embodiment, the subject compound may be employed in combination with 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, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the 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. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
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.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DBAD: di-tert-butylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMSO: dimethylsulfoxide; EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et3N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovine serum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide; MTBE: methyl tert-butyl ether; SOCl2: thionyl chloride; CDI: carbonyl diimidazole; rt: room temperature; HPLC: high performance liquid chromatography; T3P: 1-propylphosphonic anhydride. The compounds of the present invention can be prepared in a variety of fashions.
In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes and examples may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
As shown in Reaction Scheme I, cyclic ketones can undergo the Schmidt reaction to provide azepanones (A-1). A-1 can be protected by alkylation with benzyl bromide to afford A-2. Carboxylation of A-2 can be accomplished through treatment of the lithium enolate with methyl cyanoformate to generate A-3. Reduction of the ester and amide functionalities with lithium aluminum hydride can proceed to give A-4. Mitsunobu coupling with substituted phenols can furnish ethers A-5. Removal of the benzyl protecting group under hydrogenation conditions can produce amines A-6, which can undergo coupling with substituted benzoic acids using EDC to provide amides A-7.
Reaction Scheme II illustrates an alternative method for the preparation of substituted amides B-2. Amines A-6 can be coupled with 2-iodobenzoic acids using EDC to provide B-1. Palladium-catalyzed cross coupling reaction of B-1 with organostannanes under Stille conditions can afford amides B-2.
A cooled (0° C.) suspension of NaH (2.414 g, 60.4 mmol) in THF (200 ml) was treated with a solution of 1-1 (5.94 g, 52.5 mmol) in THF (200 ml). The mixture was warmed to RT and stirred overnight. The mixture was filtered though celite and the filtrate concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) to yield 1-2 as a white solid. Data for 1-2: LRMS m/z (M+H): 203.96.
A cooled (−78° C.) solution of 1-2 (2 g, 9.84 mmol) in Et2O (50 ml) was treated with LDA (9.84 ml, 19.68 mmol) and stirred for 1 h. The mixture was treated with dimethyl carbonate (1.658 ml, 19.68 mmol), warmed to RT and stirred overnight. The mixture was quenched with 1N HCl and extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 60% EtOAc in Hex) to yield a 1:1 mixture of 1-3 and starting material as a tan oil. Data for 1-3: LRMS m/z (M+H): 262.1.
A solution of 1-3 (1.52 g, 5.82 mmol) in THF (35 ml) was treated slowly with lithium aluminum hydride (12.65 ml, 29.1 mmol). After stirring at RT for 30 min, the solution was cooled to 0° C. and treated dropwise with 1.1 mL of water, 1.1 ml of 15% NaOH, and 3.3 mL of water successively. Sodium sulfate was added to the mixture. After stirring overnight at RT, the mixture was filtered and the filtrate was concentrated to yield 1-4 as a colorless oil. Data for 1-4: LRMS m/z (M+H): 220.1.
A solution of 1-4 (500 mg, 2.280 mmol), 3-methyl-4-fluorophenol (288 mg, 2.280 mmol), and tiphenylphosphine-resin bound (1.060 g @ 2.15 mmol/g) in DCM (20 ml) was treated with DIAD (0.443 ml, 2.280 mmol). The mixture was stirred overnight at RT, filtered, and the filtrate was concentrated. The crude material was purified by gradient elution on silica gel (0 to 50% EtOAc in Hex) to yield 1-5 as a pale yellow oil. Data for 1-5: LRMS m/z (M+H): 328.2.
A solution of 1-5 (226 mg, 0.690 mmol) in MeOH (5 ml) was treated with 10 mol % palladium hydroxide on carbon (48.5 mg, 0.069 mmol). The flask was evacuated and backfilled with H2(g) three times and stirred under a H2(g) atmosphere (1 atm) at RT for 30 min. The mixture was filtered though a syringe filter and the filtrate was concentrated to yield 1-6. Data for 1-6: LRMS m/z (M+H): 238.1.
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in water with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid 1-5, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for 1-7: 1HNMR (500 MHz, DMSO-d6)d 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
A solution of 1-6 (164 mg, 0.691 mmol) in DMF (4 ml) was treated with 1-7 (154 mg, 0.760 mmol), EDC (159 mg, 0.829 mmol), HOBT (127 mg, 0.829 mmol), and TEA (0.289 ml, 2.073 mmol). After stirring at RT for 30 min, the mixture was diluted with EtOAc, washed with water (3×s) and once with brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) to yield 1-8 as a pale yellow oil. Data for 1-8: LRMS m/z (M+H): 423.1.
Methanesulfonic acid (15 mL) was added to a solution of 2-methylcyclohexanone (2-1, 6.00 g, 53.5 mmol, 1 equiv) in DME (20 mL) at −40° C. Sodium azide (8.69 g, 134 mmol, 2.50 equiv) was added in four equal portions over 1 h as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and ethyl actetate (4×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 7-methylazepan-2-one (2-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.50 (br s, 1H), 3.50 (m, 1H), 2.43 (m, 2H), 2.05-1.30 (m, 6H), 1.21 (d, 3H,J=7.1 Hz).
Sodium hydride (95%, 1.74 g, 68.7 mmol, 1.15 equiv) was added to a solution of 7-methylazepan-2-one (2-2, 7.60 g, 59.8 mmol, 1 equiv) in THF (150 mL) at 0° C. and the resulting mixture was warmed to 23° C. and stirred for 20 h. Benzyl bromide (7.82 mL, 65.7 mmol, 1.10 equiv) was added followed by 2 drops of water, and the resulting mixture was stirred at 23° C. for 20 h. Excess sodium hydride was quenched carefully with water and the mixture was concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 100% EtOAc) to give 1-benzyl-7-methylazepan-2-one (2-3) as a colorless oil. LRMS m/z (M+H) 218.2 found, 218.2 required.
To a solution of lithium diisopropylamide in THF (1.8 M, 10 mL, 18 mmol, 1.3 equiv) freshly prepared at −78° C. was added a solution of 1-benzyl-7-methylazepan-2-one (2-3, 3.8 g, 18 mmol, 1.0 equiv) in THF (10 mL) was added. The reaction mixture was warmed to 0° C. and stirred for 1 h, then cooled to −78° C. HMPA (3.0 mL, 17 mmol, 0.99 equiv) was added followed by methyl cyanoformate (1.8 mL, 23 mmol, 1.3 equiv). After stirring 10 minutes at −78° C. the mixture was partitioned between water (40 mL) and diethyl ether (2×40 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield methyl 1-benzyl-7-methyl-2-oxoazepane-3-carboxylate (2-4). LRMS m/z (M+H) 276.2 found, 276.2 required.
To a solution of methyl 1-benzyl-7-methyl-2-oxoazepane-3-carboxylate (2-4, 3.8 g, 14 mmol, 1.0 equiv) in THF (70 mL) at 0° C. under nitrogen was added solid lithium aluminum hydride (2.6 g, 69 mmol, 5.0 equiv) and the resulting mixture was stirred at 0° C. for 1.5 hours. Excess LAH was quenched with water (2 mL) and 15% aqueous sodium hydroxide solution (2 mL). The mixture was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield (1-benzyl-7-methylazepan-3-yl)methanol (2-5) as a clear oil. 1H NMR (400 MHz, CDCl3) 7.36 (m, 5H), 3.68-1.49 (m, 18H). LRMS m/z (M+H) 234.3 found, 234.2 required.
A mixture of (1-benzyl-7-methylazepan-3-yl)methanol (2-5, 500 mg, 2.1 mmol, 1.0 equiv), 4-fluoro-3-methylphenol (300 mg, 2.4 mmol, 1.1 equiv), and PS-triphenyl phosphine resin (1.2 g, 2.4 mmol, 1.1 equiv) in dichloromethane (25 mL) was treated with DIAD (0.46 mL, 480 mg, 2.4 mmol, 1.1 equiv) and the resulting suspension was stirred for 16 hours at 23° C. The mixture was filtered and filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-1-benzyl-2-methylazepane (2-6) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 6.86 (m, 1H), 6.55 (m, 2H), 3.72-1.75 (m, 20H). LRMS m/z (M+H) 342.3 found, 242.2 required.
A mixture of 6-[(4-fluoro-3-methylphenoxy)methyl]-1-benzyl-2-methylazepane (2-6, 250 mg, 0.74 mmol, 1.0 equiv) and Pearlman's catalyst (wet 20% Pd(OH)2/C) (78 mg, 0.11 mmol, 0.15 equiv) in methanol (30 mL) was stirred under a hydrogen balloon for 1 hour at 23° C. The suspension was filtered and the filtrate was concentrated to give 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7). δ 6.90 (m, 1H), 6.71 (m, 2H), 3.72-1.75 (m, 19H). LRMS m/z (M+H) 252.3 found, 252.2 required.
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7, 50 mg, 0.20 mmol, 1.0 equiv) in DMF (3 mL) was treated with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (45 mg, 0.22 mmol, 1.1 equiv), EDC (46 mg, 0.24 mmol, 1.2 equiv), HOBT (37 mg, 0.24 mmol, 1.2 equiv) and triethylamine (83 ul, 60 mg, 0.60 mmol, 3.0 equiv) and the resulting mixture was stirred at 23° C. for 16 hours. The mixture was filtered and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]azepane (2-8). δ 7.95-6.14 (m, 8H), 4.97-0.65 (m, 21H). LRMS m/z (M+H) 437.4 found, 437.2 required.
The following compounds were prepared by using the corresponding phenols and carboxylic acids as described above.
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7, 120 mg, 0.48 mmol, 1.0 equiv) in DMF (5 mL) was treated with 2-iodo-5-methylbenzoic acid (140 mg, 0.52 mmol, 1.1 equiv), EDC (110 mg, 0.57 mmol, 1.2 equiv), HOBT (88 mg, 0.57 mmol, 1.2 equiv) and triethylamine (0.20 mL, 140 mg, 1.4 mmol, 3.0 equiv) and the resulting mixture was stirred at 23° C. for 16 hours. The mixture was filtered and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-1-(2-iodo-5-methylbenzoyl)-2-methylazepane (3-1). δ 7.87 (m, 1H), 7.10 (m, 6H), 6.43 (m, 1H), 4.79-1.04 (m, 19H). LRMS m/z (M+H) 496.2 found, 496.1 required.
A mixture of 6-[(4-fluoro-3-methylphenoxy)methyl]-1-(2-iodo-5-methylbenzoyl)-2-methylazepane (3-1, 50 mg, 0.10 mmol, 1.0 equiv), tetrakis(triphenyl phosphine)palladium (35 mg, 0.030 mmol, 0.30 equiv) and 2-tributylstannylthiazole (94 mg, 0.25 mmol, 2.5 equiv) in toluene (1 mL) was heated at 100° C. for 1 hour. The reaction was cooled and filtered. The filtrate was concentrated and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]azepane (3-2). δ 7.96-6.14 (m, 8H), 4.77-0.88 (m, 21H). LRMS m/z (M+H) 496.2 found, 496.1 required.
The following compounds were prepared by using the corresponding stannanes as described above.
Methanesulfonic acid (20 mL) was added to a solution of 3-methyltetrahydro-4H-pyran-4-one (4-1, prepared by the method of Smith, A. B. et al. J. Am. Chem. Soc. 1991, 113, 2071, 3.00 g, 26.3 mmol, 1 equiv) in DME (30 mL) at −40° C. Sodium azide (5.13 g, 79.0 mmol, 3.00 equiv) was added in four equal portions over 30 min as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and a solution of 10% n-propanol in ethyl actetate (2×400 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-1,4-oxazepan-5-one (4-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.73 (br s, 1H), 3.97 (ddd, 1H,J=12.4, 5.6, 2.8 Hz), 3.83 (d, 1H,J=12.2 Hz), 3.76 (m, 1H), 3.66 (dd, 1H,J=12.4, 10.8 Hz), 3.35 (dd, 1H, J=12.2, 8.2 Hz), 2.89 (ddd, 1H,J=15.8, 10.8, 2.8 Hz), 2.54 (dd, 1H,J=15.8, 5.6 Hz), 1.15 (d, 3H,J=7.1 Hz).
Sodium hydride (95%, 553 mg, 21.9 mmol, 1.15 equiv) was added to a solution of 3-methyl-1,4-oxazepan-5-one (4-2, 2.46 g, 19.0 mmol, 1 equiv) in DMF (40 mL) at 0° C. and the resulting mixture was stirred for 20 min. Benzyl bromide (2.49 mL, 20.9 mmol, 1.10 equiv) was added and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.05 (d, 1H,J=14.6 Hz), 4.17 (d, 1H,J=14.6 Hz), 4.00 (ddd, 1H,J=12.5, 6.1, 3.3 Hz), 3.80 (dd, 1H,J=12.8, 4.0 Hz), 3.56 (dd, 1H,J=12.5 Hz), 3.42 (d, 1H,J=12.8 Hz), 3.31 (m, 1H), 3.02 (ddd, 1H,J=15.0, 11.9, 3.4 Hz), 2.75 (ddd, 1H,J=16.2, 4.9, 1.2 Hz), 1.31 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 220.3 found, 220.1 required.
A solution of lithium diisopropylamide in THF (0.101 M, 100 mL, 10.1 mmol, 1.30 equiv) freshly prepared at −78° C. was added via cannula to a solution of 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3, 1.71 g, 7.80 mmol, 1 equiv) in THF (100 mL) at −78° C. and the resulting mixture was stirred for 20 min. HMPA (1.36 mL, 7.80 mmol, 1.00 equiv) was added followed by methyl cyanoformate (1.24 mL, 15.6 mmol, 2.00 equiv). The resulting mixture was warmed to 0° C., stirred for 20 min, and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4) as a mixture of diastereomers (colorless oil). LRMS m/z (M+H) 278.2 found, 278.1 required.
A solution of LAH in THF (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added to a solution of methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4, diastereomeric mixture, 600 mg, 2.16 mmol, 1 equiv) in THF (30 mL) at −78° C. and the resulting mixture was warmed to 23° C. and stirred for 60 h. Additional LAH solution (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added and the mixture was heated at 60° C. for 4 h. The mixture was cooled to 0° C. and excess LAH was quenched with 100 uL of H2O, followed by 100 uL of 15% aqueous sodium hydroxide solution, and lastly 300 uL of H2O. The mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated and the residue purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to afford (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5) as a mixture of diastereomers (TFA salts). 1H NMR (300 MHz, CD3OD) δ 7.62-7.45 (m, 5H), 4.70-4.30 (br m, 2H), 4.10-3.75 (br m, 3H), 3.65-3.30 (br m, 6 H), 2.45 (m, 1H), 1.45 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 236.3 found, 236.2 required. The TFA salts were free based by elution through an ion exchange column (Strata™ X-C, water loading, washing with CH3OH followed by elution of free base with 5% NH4OH in methanol).
Diisopropyl azodicarboxylate (40 uL, 0.20 mmol, 1.2 equiv) was added to a suspension of (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5, 40 mg, 0.17 mmol, 1 equiv), 4-fluoro-3-methylphenol (26 mg, 0.20 mmol, 1.2 equiv), and polystyrene-supported triphenylphosphine resin (250 mg, 0.51 mmol, 3.0 equiv) in anhydrous dichloromethane (30 mL) at 23° C. The mixture was stirred for 20 h, then filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide 4-benzyl-6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-6) as a ˜1:1 mixture of diastereomers (colorless oil). 1H NMR (300 MHz, CDCl3, reported for a single diasteromer) δ 7.38-7.19 (m, 5H), 6.85 (ddd, 1H,J=12.5, 9.2, 3.7 Hz), 6.53 (m, 2H), 3.97-3.50 (m, 6H), 3.08 (m, 1H), 3.00 (dd, 1H,J=14.0, 4.0 Hz), 2.90 (d, 1H,J=13.7 Hz), 2.82 (dd, 1H,J=14.0, 3.0 Hz), 2.60 (d, 1H,J=13.7 Hz), 2.44 (m, 1H), 2.21 (s w/small splittings, 3H), 1.08 (d, 3H,J=6.7 Hz). LRMS m/z (M+H) 344.4 found, 344.2 required.
A suspension of 4-benzyl-6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-6, 36 mg, 0.11 mmol) and Pearlman's catalyst (wet 20% Pd(OH)2/C, 100 mg) in methanol (20 mL) was stirred under a hydrogen balloon at 23° C. for 2 h. The mixture was filtered and the filtrate concentrated to give 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7) as a ˜1:1 mixture of diastereomers (colorless oil). LRMS m/z (M+H) 254.3 found, 254.2 required.
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7, 13 mg, 0.051 mmol, 1 equiv), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (16 mg, 0.077 mmol, 1.5 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 15 mg, 0.077 mmol, 1.5 equiv), 1-hydroxybenzotriazole (12 g, 0.077 mmol, 1.50 equiv) and triethylamine (21 uL, 0.15 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (100% hexanes initially, grading to 40% hexanes in EtOAc) to provide 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-oxazepane (4-8) as a mixture of diastereomers. LRMS m/z (M+H) 439.0 found, 439.2 required.
Similarly, 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-oxazepane (4-9) was prepared by coupling 4-7 with 2-(2H-1,2,3-triazol-2-yl)benzoic acid under the conditions used to prepare 4-8.
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/US2009/060762 | 10/15/2009 | WO | 00 | 4/20/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/048017 | 4/29/2010 | WO | A |
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