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(12) United States Patent (10) Patent No.: US 7,795,436 B2 Chen Et Al

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(12) United States Patent (10) Patent No.: US 7,795,436 B2 Chen Et Al US007795436 B2 (12) United States Patent (10) Patent No.: US 7,795,436 B2 Chen et al. (45) Date of Patent: Sep. 14, 2010 (54) SUBSTITUTED TRICYCLIC 5,686,104 A 11, 1997 Mills et al. HETEROCYCLES AS SEROTONN 5,698,527 A 12, 1997 Kim RECEPTORAGONSTS AND ANTAGONSTS 5,712,396 A 1/1998 Magnin et al. 5,753,675 A 5/1998 Wattanasin (75) Inventors: Wenting Chen, Beijing (CN); Taekyu 5,770,615 A 6/1998 Cheng et al. Lee, Doylestown, PA (US) 5,776,983 A 7/1998 Washburn et al. 5.990,109 A 11/1999 Chen et al. (73) Assignee: Bristol-Myers Squibb Company, 6,043,265 A 3/2000 Murugesan et al. Princeton, NJ (US) 6,184,231 B1 2/2001 Hewawasam et al. 6,358,950 B1 3/2002 He et al. (*) Notice: Subject to any disclaimer, the term of this 6,362,180 B1 3/2002 Wilde et al. patent is extended or adjusted under 35 6,395,767 B2 5, 2002 Roblet al. U.S.C. 154(b) by 1056 days. (21) Appl. No.: 11/509,354 (Continued) (22) Filed: Aug. 24, 2006 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data DE 19622 222 12/1997 US 2007/OO4.9613 A1 Mar. 1, 2007 Related U.S. Application Data (Continued) (60) Provisional application No. 60/710,954, filed on Aug. OTHER PUBLICATIONS 24, 2005. Caplus English abstract Fuller Ray, 1976.* (51) Int. Cl. (Continued) CO7D 22 I/O (2006.01) A63/4.375 (2006.01) Primary Examiner Rita J Desai (52) U.S. Cl. ......................................... 546/79:514/290 (74) Attorney, Agent, or Firm Terence J. Bogie (58) Field of Classification Search ................... 546/79; (57) ABSTRACT 514/290 See application file for complete search history. The present application describes compounds, including all (56) References Cited pharmaceutically acceptable salts, prodrugs, Solvates and Ste U.S. PATENT DOCUMENTS reoisomers thereof, according to Formula I, pharmaceutical compositions, comprising at least one compound according 3,462.443 A 8/1969 Paragamian 3,674,836 A 7, 1972 Creger to Formula I and optionally at least one additional therapeutic 3,678,058 A * 7/1972 Ebnother et al. ............ 546,111 agent and methods of treating various diseases, conditions 3,983,140 A 9, 1976 Endo et al. and disorders associated with modulation of serotonin recep 4,027,009 A 5, 1977 Grier et al. tors such as, for example: metabolic diseases, which includes 4,231,938 A 11/1980 Monaghan et al. but is not limited to obesity, diabetes, diabetic complications, 4,346,227 A 8, 1982 Terahara et al. atherosclerosis, impared glucose tolerance and dyslipidemia; 4,379,785 A 4/1983 Weyer et al. central nervous system diseases which includes but is not 4,448,784. A 5/1984 Glamkowski et al. limited to, anxiety, depression, obsessive compulsive disor 4.450,171 A 5, 1984 Hoffman et al. der, panic disorder, psychosis, Schizophrenia, sleep disorder, 4,572,912 A 2f1986 Yoshioka et al. sexual disorder and social phobias; cephalic pain; migraine; 4,639,436 A 1/1987 Junge et al. 4,681,893 A 7, 1987 Roth and gastrointestinal disorders using compounds according to 4,759,923 A 7, 1988 Buntin et al. Formula I 4,871,721 A 10, 1989 Biller 4,904,769 A 2f1990 Rauenbusch 4,924,024 A 5, 1990 Biller 5,006,530 A 4, 1991 Angerbauer et al. 5,011,930 A 4, 1991 Fujikawa et al. 5,177,080 A 1/1993 Angerbauer et al. 5,260,440 A 11/1993 Hirai et al. 5,273,995 A 12, 1993 Roth 5,354,772 A 10, 1994 Kathawala 5,385,929 A 1/1995 Bjorge et al. 5.447,954 A 9, 1995 Gribble et al. 5.488,064 A 1, 1996 Sher 5,491,134 A 2f1996 Sher et al. 5,541.204 A 7, 1996 Sher et al. 5,594,016 A 1/1997 Ueno et al. 5,612,359 A 3/1997 Murugesan 7 Claims, No Drawings US 7,795,436 B2 Page 2 U.S. PATENT DOCUMENTS that “Presqualene Pyrophosphate” is an Essential Intermediate on the Path to Squalene'. J. of the American Chemical Society, vol. 98(5), 6,399,609 B1 6, 2002 Wilde pp. 1291-1293 (1976). 6,414,002 B1 7/2002 Cheng et al. 6,414,126 B1 7/2002 Ellsworth et al. Costall, B. et al., “Detection of the Deuroleptic Properties of 6,448,261 Bl 9/2002 Bakthavatchalam et al. Clozapine, Sulpiride and Thioridazine'. 6,515,005 B2 2/2003 Dubowchik et al. Psychopharmacologia(Berl) vol.43, pp. 69-74 (1975). 6,515,117 B2 2/2003 Ellsworth et al. Cryan, J. et al., “Antidepressant-Like Behavioral Effects Mediated by 6,518,271 B1 2/2003 Gilligan et al. 5-Hydroxytryptamine Receptors'". The J. of Pharmacology and 6,521,636 B1 2/2003 Gilligan et al. Experimental Therapeutics, vol. 295(3), pp. 1120-1126 (2000). 6,525,056 B2 2/2003 Arvanitis et al. 6,573.287 B2 6/2003 Sulsky et al. Di Matteo, V. et al., “Role of 5-HT2C receptors in the control of 6,579,876 B2 6/2003 Gilligan et al. central dopamine function”. TRENDS in Pharmacological Sciences, 6,589,952 B2 7/2003 Bakthavatchalam et al. vol. 22(5), pp. 229-232 (2001). 6,630,476 B2 10/2003 Bakthavatchalam Egan, C. et al., "Agonist activity of LSD and lisuride at cloned 5HT 6,635,626 B1 10/2003 Barrish et al. and 5HT receptors'. Psychopharmacology, vol. 136, pp. 409–414 6,642,230 B2 11/2003 Wilde et al. (1998). 2004/O147539 A1 7/2004 Cook et al. Fitzgerald, L. et al., “High-Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5-HT, and FOREIGN PATENT DOCUMENTS 5-HT Receptors: Evidence Favoring the Ternary Complex and EP O 675 714 10, 1995 Two-State Models of Agonist Action”. J. of Neurochemistry, vol. 72, EP O 8184.48 1, 1998 pp. 2127-2134 (1999). EP O992 496 4/2000 Ghiselli, G., “The Pharmacological Profile of FCE 27677: A Novel EP 1 O22 272 T 2000 ACAT Inhibitor with Potent Hypolipidemic Activity Mediated by GB 2304 106 3, 1997 Selective Suppression of the Hepatic Secretion of ApoB-100-Con JP 52091867 * 5, 1976 taining Lipoprotein'. Cardiovascular Drug Reviews, vol. 16(1), pp. WO WO94, 15592 T 1994 16-30 (1998). WO WO97.21993 6, 1997 Glennon, R. et al., “I' Il-1-(2,5-Dimethoxy-4-iodophenyl)-2- WO WO97/35576 10, 1997 amino-propane: An Iodinated Radioligand that Specifically labels the WO WO97/48.701 12/1997 Agonist High-Affinity State of 5-HT Serotonin Receptors'. J. Med. WO WO99.00353 1, 1999 Chem., vol. 31, pp. 5-7 (1988). WO WOOOO1389 1, 2000 Greene, T. et al., “Protective Groups in Organic Synthesis »s 2 fed WO WOOO152O1 3, 2000 WO WOOO.30665 6, 2000 Edition, pp. 309-405 (1991). WO WOOO,38722 T 2000 Grottick, A.J. et al., “Activation of 5-HT, receptors reduces the WO WOOOf 3907 7 T 2000 locomotor and rewarding effects of nicotine'. Psychopharmacology, WO WOOO,50574 8, 2000 vol. 157, pp. 292-298 (2001). WO WOO2/O76973 10, 2002 Grottick, A.J. et al., “Studies to Investigate the Role of 5-HT WO WOO2/O836.36 10, 2002 Receptors on Cocaine- and Food-Maintained Behavior'". The J. of WO WOO3,O72197 9, 2003 Pharmacology and Experimental Therapeutics, vol. 295(3), pp. 1 183-1191 (2000). Hara, S., “Ileal Na+/bile acid cotransporter inhibitors'. Drugs of the OTHER PUBLICATIONS Future, vol. 24(4), pp. 425-430 (1999). Arnt, J., “Pharmacological Specificity of Conditioned Avoidance Hoffman, B. et al., “Distribution of serotonin 5-HT receptor mRNA Response Inhibition in Rats: Inhibition by Neuroleptics and Corre in adult rat brain, FEBS Letters, vol. 247(2), pp. 453-462 (1989). lation to Dopamine Receptor Blockade'. Acta pharmacol. et toxicol., Hollenbaugh, D. et al., “Cleavable CD40Ig fusion proteins and the vol. 51, pp. 321-329 (1982). binding to sgp39'. J. of Immunological Methods, vol. 188, pp. 1-7 Berridge, M. et al., “Lithium amplifies agonist-dependent (1995). phosphatidylinositol responses in brain and salivary glands'. Hollenbaugh, D. et al., “The human T cellantigen gp39, a member of Biochem. J., vol. 206, pp. 587-595 (1982). the TNF gene family, is a ligand for the CD40 receptor: expression of Biller, S. et al., “Isoprenoid (Phosphinylmethyl) phosphonates as a soluble form of gp39 with B cell co-stimulatory activity”. The Inhibitors of Squalene Synthetase'. J. of Medicinal Chemistry, vol. EMBO Journal, vol. 11(12), pp. 4313-4321 (1992). 31(10), pp. 1869-1871 (1988). Horlick, R. et al., “Rapid Generation of Stable Cell Lines Expressing Biller, S. et al., “Squalene Synthase Inhibitors'. Current Pharmaceu Corticotropin-Releasing Hormone Receptor for Drug Discovery'. tical Design, vol. 2, pp. 1-40 (1996). Protein Expression and Purification, vol. 9, pp. 301-308 (1997). Buchwald, S. et al., “A Highly Active Catalyst for Palladium-Cata lyzed Cross-Coupling Reactions: Room-Temperature Suzuki Cou Hoyer, D. et al., “VII. International Union of Pharmacology Classi plings and Amination of Unactivated Aryl Chlorides'. J. Am. Chem. fication of Receptors for 5-Hydroxytryptamine (Serotonin)”, Phar Soc., vol. 120, pp. 3722-3723 (1998). macological Reviews, vol. 46(2), pp. 157-203 (1994). Capson, T., "Synthesis and Evaluation of Ammonium Analogs of Kinbara, K. et al., “Chiral discrimination upon crystallization of the Carbocationic Intermediates in Squalene Biosynthesis'. Disserta diastereomeric salts of 1-arylethylamines with mandelic acid or tion, Univ. of Utah, Abstract, Table of Contents, pp. 16, 17.40-43-48 p-methoxymandelic acid: interpretation of the resolution efficiencies 51 (1987).
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