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  Tetracyclic azepinoindole compoundsUSPTO Application #: 20050282796Title: Tetracyclic azepinoindole compounds Abstract: wherein R1, R2, X and Y have any of the values defined in the specification, as well as pharmaceutical compositions comprising the compounds. The invention also provides therapeutic methods as well as processes and intermediates useful for preparing compounds of formula (I).
The present invention provides compounds of formula I: (end of abstract)
Agent: Warner-lambert Company - Ann Arbor, MI, US Inventors: Brad A. Acker, Michael D. Ennis, Kristine E. Frank, Jackson B. Hester, Eric Jon Jacobsen, Bruce N. Rogers, Susan L. Steele USPTO Applicaton #: 20050282796 - Class: 514215000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of One Nitrogen And Six Carbons, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Additional Hetero Atom In The Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20050282796. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIORITY OF INVENTION [0001] This application claims priority from U.S. Provisional Application No. 60/130,881, filed 23 Apr. 1999. FIELD OF THE INVENTION [0002] The present invention provides tetracyclic 1,2,3,4,5,6-hexahydroaze- pino-[4,5-b]indole derivatives having a ring connecting position 6 (N-6) and position 7 (C-7), and more specifically, provides compounds of formula (I) described hereinbelow. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired. BACKGROUND OF THE INVENTION [0003] Serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects. [0004] As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990). [0005] The major classes of serotonin receptors (5-HT.sub.1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects). [0006] For example, the 5-HT.sub.2 family of receptors is comprised of 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT.sub.2 subtypes. The 5-HT.sub.2B and 5-HT.sub.2A receptors are widely distributed in the periphery, while the 5-HT.sub.2C receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16, 105-110. [0007] Subtype 5-HT.sub.2A has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT.sub.2C has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmacologic role of the 5-HT.sub.2B receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40,2762-2769; J. R. Martin, et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., J. Med. Chem., 1998, 41,1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al., Neuropharmacology, 1999, 38, 415-423. [0008] U.S. Pat. No. 3,676,558, issued Jul. 11, 1972, discloses compositions comprising specific 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5- -b]indole compounds. The compositions are reported to be useful to suppress hunger in mammals. This patent also discloses a method for inducing anorexia in obese subjects to produce weight loss. The azepino[4,5-b]indole compounds disclosed in this patent lack the ring connecting the 6-position and the 7-position that is present in the compounds of the instant invention. [0009] U.S. Pat. No. 3,839,357, issued Oct. 1, 1974, discloses specific 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole compounds, which are reported to have sedative or tranquilizing action. The azepino[4,5-b]indole compounds disclosed in this patent also lack the ring connecting the 6-position and the 7-position that is present in the compounds of the instant invention. [0010] There is currently a need for pharmaceutical agents that are useful to treat diseases and conditions that are associated with 5-HT receptors. SUMMARY OF THE INVENTION [0011] In accordance with the present invention, novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. Thus, the present invention provides a compound of formula I: 2 [0012] wherein, [0013] each R.sub.1 is independently hydroxy, nitro, halo, cyano, trifluoromethyl, trifluoromethoxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy, aryl, heteroaryl, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, --S(O).sub.mR.sub.c, or --C(.dbd.O)NR.sub.aR.sub.b, wherein any C.sub.1-7alkyl, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, or C.sub.1-7alkanoyloxy of R.sub.1 is optionally partially unsaturated and is optionally substituted with aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, nitro, halo, cyano, C.sub.1-7alkoxy, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, C.sub.1-7alkanoyloxy, --S(O).sub.mR.sub.e, --S(O).sub.mNR.sub.aR.sub.b, NR.sub.cR.sub.d, or --C(.dbd.O)NR.sub.aR.sub.b; [0014] R.sub.2 is hydrogen, C.sub.1-7alkyl, C.sub.1-7alkanoyl, arylcarbonyl, aryl, (aryl)C.sub.1-7alkyl, C.sub.1-7alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or (aryl)C.sub.1-7alkoxycarbonyl; [0015] X and Y together are a 2, 3, or 4 membered saturated or partially unsaturated chain comprising one or more carbon atoms and optionally comprising one oxy (--O--), thio (--S--), sulfinyl (--SO--), sulfonyl (S(O).sub.2--), or NR.sub.f in the chain; wherein the chain is optionally substituted on each carbon with oxo (.dbd.O), thioxo (.dbd.S), --NR.sub.qR.sub.r, --S(O).sub.pR.sub.s, or --OR.sub.t, or with one or two substituents independently selected from the group consisting of C.sub.1-7alkyl, (C.sub.1-7alkoxy)C I .sub.7alkyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl, and (aryl)oxyC.sub.1-7alkyl; or wherein the chain is optionally substituted on a carbon with a 4, 5, or 6 membered spirocyclic carbon ring; or wherein the chain is optionally substituted on two adjacent atoms with a 2, 3, or 4 membered alkylene chain (e.g. --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) forming a ring that is fused to the ring comprising X and Y; [0016] each m is independently 0, 1, or 2; [0017] n is 0, 1, 2, or 3; [0018] p is 0, 1, or2; [0019] each R.sub.a and R.sub.b is independently hydrogen, C.sub.1-7alkyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl, or (heteroaryl)C.sub.1-7alkyl; or R.sub.a and R.sub.b together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; [0020] each R.sub.c and R.sub.d is independently hydrogen, C.sub.1-7alkyl, C.sub.1-7alkanoyl, C.sub.1-7alkoxycarbonyl, aryl, (aryl)C.sub.1-7alkyl, heteroaryl, (heteroaryl)C.sub.1-7alkyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; or R.sub.c and R.sub.d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; Continue reading... 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