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(12) United States Patent (10) Patent No.: US 8,362,009 B2 Bergman Et Al

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(12) United States Patent (10) Patent No.: US 8,362,009 B2 Bergman Et Al USOO8362009B2 (12) United States Patent (10) Patent No.: US 8,362,009 B2 Bergman et al. (45) Date of Patent: Jan. 29, 2013 (54) SUBSTITUTED DIAZEPAN OREXIN (52) U.S. Cl. ........................................ 514/218: 540/575 RECEPTOR ANTAGONSTS (58) Field of Classification Search .................. 514/218; 54.0/575 (75) Inventors: Jeffrey M. Bergman, Sellersville, PA See application file for complete search history. (US); Paul J. Coleman, Wallingford, PA (US); Christopher D. Cox, Harleysville, (56) References Cited PA (US); Anthony J. Roecker, North U.S. PATENT DOCUMENTS Wales, PA (US) 5,932,571 A 8/1999 Maynard et al. 7,812,031 B2 10/2010 Aranyi et al. (73) Assignee: Merck Sharp & Dohme Corp., 7,951,797 B2 5/2011 Breslin et al. Rahway, NJ (US) 2003/0225065 A1 12/2003 Jacobsen et al. 2004, OO19039 A1 1/2004 Dorwald et al. (*) Notice: Subject to any disclaimer, the term of this 2007/0043037 A1 2/2007 Aranyi et al. patent is extended or adjusted under 35 2008/0132490 A1 6/2008 Bergman et al. U.S.C. 154(b) by 227 days 2009, O124603 A1 5/2009 Brashear et al. M YW- y yS. 2009,0192143 A1 7, 2009 Cox et al. 2009/02398.43 A1 9, 2009 Coleman et al. (21) Appl. No.: 12/739,304 FOREIGN PATENT DOCUMENTS (22) PCT Filed: Oct. 27, 2008 WO WO2005075458 8, 2005 WO WO2007 126935 11, 2007 (86). PCT No.: PCT/US2O08/O12182 WO WO2O080O8518 1, 2008 S371 (c)(1) OTHER PUBLICATIONS (2), (4) Date: Apr. 22, 2010 Supplementary European Search Report for EP08 84 5507, Jun. 30, 2011. (87) PCT Pub. No.: WO2009/058238 Primary Examiner — Brenda Coleman PCT Pub. Date: May 7, 2009 (74) Attorney, Agent, or Firm — J. Eric Thies; Gerard M. (65) Prior Publication Data Devlin US 2010/0256121 A1 Oct. 7, 2010 (57) ABSTRACT The present invention is directed to diazepan compounds Related U.S. Application Data which are antagonists of orexin receptors, and which are useful in the treatment of neurological and psychiatric disor (60) Provisional application No. 61/000,760, filed on Oct. ders and diseases in which orexin receptors are involved. The 29, 2007. invention is also directed to pharmaceutical compositions (51) Int. Cl comprising these compounds and the use of these compounds A. iP l3/00 (2006.01) and compositions in the treatment of Such diseases in which A6 IK3I/55 (2006.01) orexin receptors are involved. CO7D 243/06 (2006.01) 10 Claims, No Drawings US 8,362,009 B2 1. 2 SUBSTITUTED DIAZEPAN OREXN haemorrhage; ulcers; allergies; benign prostatic hypertrophy; RECEPTOR ANTAGONSTS chronic renal failure; renal disease; impaired glucose toler ance; migraine; hyperalgesia; pain; enhanced or exaggerated CROSS REFERENCE TO RELATED sensitivity to pain such as hyperalgesia, causalgia, and allo APPLICATIONS dynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; This application is a U.S. National Phase application under arthritic pain; sports injury pain; pain related to infection e.g. 35 U.S.C. S371 of PCT Application No. PCT/US2008/ HIV, post-chemotherapy pain; post-stroke pain; post-opera 012182, filed Oct. 27, 2008, which claims priority under 35 tive pain; neuralgia; emesis, nausea, vomiting; conditions U.S.C. S 119(e) from U.S. Ser. No. 61/000,760, filed Oct. 29, 10 associated with visceral pain such as irritable bowel syn 2007. drome, and angina; migraine; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal BACKGROUND OF THE INVENTION from narcotics; sleep disorders; sleep apnea; narcolepsy; The orexins (hypocretins) comprise two neuropeptides 15 insomnia; parasomnia, jet lag syndrome; memory disorders; produced in the hypothalamus: the orexin A (OX-A) (a 33 and neurodegenerative disorders including noSological enti amino acid peptide) and the orexin B (OX-B) (a 28 amino acid ties such as disinhibition-dementia-parkinsonism-amyotro peptide) (Sakurai T. et al., Cell, 1998,92, 573-585). Orexins phy complex; pallido-ponto-nigral degeneration; epilepsy; are found to stimulate food consumption in rats suggesting a seizure disorders and other diseases related to general orexin physiological role for these peptides as mediators in the cen system dysfunction. tral feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998,92, 573-585). Orexins regulate SUMMARY OF THE INVENTION states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac patients The present invention is directed to diazepan compounds (Chemelli R. M. et al., Cell, 1999, 98,437-451). Orexins have 25 which are antagonists of orexin receptors, and which are also been indicated as playing a role in arousal, reward, learn useful in the treatment or prevention of neurological and ing and memory (Harris, et al., Trends Neurosci., 2006, 29 psychiatric disorders and diseases in which orexin receptors (10), 571-577). Two orexin receptors have been cloned and are involved. The invention is also directed to pharmaceutical characterized in mammals. They belong to the Superfamily of compositions comprising these compounds and the use of G-protein coupled receptors (Sakurai T. et al., Cell, 1998,92, 30 these compounds and compositions in the prevention or treat 573-585): theorexin-1 receptor (OX or OX1R) is selective for ment of such diseases in which orexin receptors are involved. 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 DETAILED DESCRIPTION OF THE INVENTION which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor 35 The present invention is directed to compounds of the as the two Subtypes of orexin receptors. formula I: Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disor I der; affective neurosis; depressive neurosis; anxiety neurosis: 40 R4 R O dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; R's ) é l Schizophrenia; manic depression; delirium; dementia; severe R2-N N RI mental retardation and dyskinesias Such as Huntington's dis R12 R7 ease and Tourette syndrome; eating disorders such as anor 45 R11 R8 exia, bulimia, cachexia, and obesity; addictive feeding behav R10 R9 iors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, Vomiting, nausea; asthma; cancer, Parkinson's disease; Cushing's syndrome? wherein: disease; basophile adenoma; prolactinoma; hyperprolactine 50 R" is selected from the group consisting of: mia; hypophysis tumour/adenoma; hypothalamic diseases; (1) phenyl, where the phenyl is substituted with R', R' inflammatory bowel disease; gastric diskinesia; gastric and R', and ulcers; Froehlich's syndrome; adrenohypophysis disease; (2) napthyl, where the napthyl is substituted with R', R' hypophysis disease; adrenohypophysis hypofunction; and R': adrenohypophysis hyperfunction; hypothalamic hypogo 55 (3) heteroaryl, where the heteroaryl is substituted with R", nadism; Kallman’s syndrome (anosmia, hyposmia); func RandR; tional or psychogenic amenorrhea; hypopituitarism; hypo R’ is heteroaryl, where the heteroaryl is substituted with R', thalamic hypothyroidism; hypothalamic-adrenal R° and R? dysfunction, idiopathic hyperprolactinemia; hypothalamic R. R. R. R. R. and R are independently selected disorders of growth hormone deficiency; idiopathic growth 60 from the group consisting of deficiency; dwarfism; gigantism; acromegaly; disturbed bio (1) hydrogen, logical and circadian rhythms; sleep disturbances associated (2) halogen, with diseases such as neurological disorders, neuropathic (3) hydroxyl, pain and restless leg syndrome; heart and lung diseases, acute (4) —(C=O), O, C-alkyl, where m is 0 or 1, n is 0 or and congestive heart failure; hypotension; hypertension, uri 65 1 (wherein if m is 0 or n is 0, a bond is present) and where nary retention; osteoporosis; angina pectoris; myocardinal the alkyl is unsubstituted or substituted with one or more infarction; ischemic or haemorrhagic stroke; Subarachnoid substituents selected from R', US 8,362,009 B2 3 4 5 —(C=O),f O, C-cycloalkyl,3-6 y where the 8) —(C—O)—O-heterocycle,f y where the heterocycley is cycloalkyl is unsubstituted or substituted with one or unsubstituted or substituted with one or more substitu more substituents selected from R', ents selected from R'', (6) —(C=O), Calkenyl, where the alkenyl is unsub- (9)-(C=O), NR'R'', stituted or substituted with one or more substituents 5 (10) - S(O), NR'R'', selected from R', 11) S(O) R'? (7) —(C=O), Calkynyl, where the alkynyl is unsub- 8. k s stituted or substituted with one or more substituents (13) CN. and selected from R', (14) NO (8) —(C=O) O-phenyl or —(C=O) O-napthyl, 10 R'' is selected2s from the group consisting of: where the phenyl or napthyl is unsubstituted or substi- (1) hydroxyl, tuted with one or more substituents selected from R', (9) —(C=O), O-heterocycle, where the heterocycle is (2) halogen, unsubstituted or substituted with one or more substitu- (3) Calkyl, ents selected from R', 15 (4) —C-cycloalkyl, (10)–(C=O), NR'R'', wherein RandR'' are inde- (5) —O—Calkyl, pendently selected from the group consisting of (6) —O(C=O) Calkyl, (a) hydrogen, (7) - NH Calkyl, (b) Calkyl, which is unsubstituted or substituted with (8) phenyl, one or more substituents selected from R', 20 (9) heterocycle, (c) Calkenyl, which is unsubstituted or substituted (10)
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