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||||I|IIII US005496957A United States Patent (19) 11 Patent Number: 5,496,957 Glennon 45) Date of Patent: Mar ||||I|IIII US005496957A United States Patent (19) 11 Patent Number: 5,496,957 Glennon 45) Date of Patent: Mar. 5, 1996 (54) TRYPTAMINE ANALOGS WITH 5-HT1D 131-178 (1991). SELECTIVITY Gomez-Jeria et al., "Quantum-Chemical Study of the Rela tion Between Electronic Structure and A2 in a Series of 75 Inventor: Richard A. Glennon, Richmond, Va. 5-Substituted Tryptamines.” Int'l Journal of Quantum Chemistry, vol. XXVIII, pp. 421-428 (1985). 73) Assignee: Virginia Commonwealth University, Gomez-Jeria et al., "Quantum Chemical Approach to the Richmond, Va. Relationship Between Molecular Structure and Serotonin Receptor Binding Affinity,” Journal of Pharmaceutical Sci (21) Appl. No.: 317,907 ences, vol. 73, No. 12, pp. 1725-1728 (1984). Gordeev et al., "Synthesis of 5-alkyltryptamines and 22) Filed: Oct. 4, 1994 5-alkyl-alpha-methyltryptamines,” Mosk. Khim.-Tekhnol. Inst., No. 70, 110-15 (1972). Related U.S. Application Data Hibert et al., "Serotonin (5-HT) Receptors,' Comprehensive 63) Continuation-in-part of Ser. No. 115,003, Sep. 1, 1993, Medicinal Chemistry, vol. 3, ed. Sammes P., pp. 567-600, abandoned. 1984. Hiemke et al., "Gas-Liquid Chromatographic Properties of (30) Foreign Application Priority Data Catecholamines, Phenylethylamines and Indolalkylamines Aug. 31, 1994 (WO WIPO ..................... PCT/CA94/00476 As Their Propionyl Derivatives,” Journal of Chromatogra phy, vol. 153, pp. 451-460 (1978). (51) Int. Cl. .................................. CO7D 209/04 Hino et al., "1-(1-Pyrrolin-2-yl)-3-carbolines. Synthesis 52 U.S. C. .............................................................. 548/491 of Eudistomins H, I, and P')," Chem. Pharm. Bull, vol. 37, 58) Field of Search ............................................... 548/491 No. 10, pp. 2596–2600 (1989). Landau et al., “Sensitivity of Sea Urchin Embryos to Cyto 56) References Cited toxic Neuropharmacological Drugs, The Correlations U.S. PATENT DOCUMENTS Between Activity and Lipophility of Indole and Benzole Derivatives,” Comp. Biochem. Physiol, vol. 69C, pp. 3,182,071 5/1965 Shavel et al. ........................... 260/319 359-366 (1981). 3,317,560 5/1967. Claassen ............................ 260/326.5 (List continued on next page.) FOREIGN PATENT DOCUMENTS 1137489 12/1982 Canada. Primary Examiner-Joseph K. McKane 0287468 10/1988 European Pat. Off. Attorney, Agent, or Firm-Foley & Lardner 0327426 8/1989 European Pat. Off.. 6404604 of 0000 Netherlands. 57) ABSTRACT 191564 of 0000 U.S.S.R. Described herein are tryptamine analogs that display high 859223 1/1961 United Kingdom. binding affinity and selectivity for the 5-HT1DB receptor, of 2186874 8/1987 United Kingdom................... 548/491 the formula: WO91/06537 5/1991 WIPO 92/14708 9/1992 WIPO .................................... 548/491 R2 (I) WO93/00333 1/1993 WIPO : / Ri N OTHER PUBLICATIONS N R3 Neth, Appl. 6,404,604, Chemical Abstract, vol. 64, No. 11180 (1965). N Soviet Union 191564, Abstract, 000530675 WPI Acc No.: R4 66-31247F/00 (1966). wherein Buznikov et al., "Sensitivity of Sea Urchin Early Embryos to Antagonists of Acetylcholine and Monoamines,” Experi R' represents a chain selected from Calkyl, mental Cell Research, vol. 86, pp. 317-324 (1974). Coalkoxy, C-11 alkanoyl and C7 loalkanoyloxy Buznikov et al., "The Sensitivity of Whole, Half and Quarter wherein said chain is optionally substituted by Sea Urchin Embryos to Cytotoxic Neuropharmacological hydroxyl, Calkyl or Calkoxy and wherein one of Drugs,” Comp. Biochem. Physiol, vol. 64C, pp. 129-135 the intervening carbons of said chain is optionally (1979). replaced with a heteroatom selected from oxygen, Glennon "Central Serotonin Receptors as Targets for Drug nitrogen and sulfur, Research,” Journal of Medicinal Chemistry, vol. 30, No. 1, R’ and Reach independently represent H or Calkyl; pp. 1-12 (1987). and Glennon et al., "Bufotenine Esters,” Journal of Medicinal R" represents H, C, alkyl, aryl or arylC alkyl; Chemistry, vol. 22, No. 11, pp. 1414-1416 (1979). Glennon et al., "5-HT Receptors: A Serotonin Receptor The compounds are useful as reagents for receptor identi Population for the 1990s,” DN&P vol. 6, No. 6, pp.390-405 fication and in receptor-based drug screening programs, and (Jul 1993). can also be used therapeutically to treat conditions for which Glennon et al., “5-HT Receptor Ligands-Update 1992,” administration of a 5-HT1D ligand is indicated, for example Current Drugs Ltd., pp. 1-45. in the treatment of migraine. Glennon, "Serotonergic Agents and CNS Receptors,” Advances in CNS Drug-Receptor Interactions, vol. 1, pp. 22 Claims, No Drawings 5,496,957 Page 2 OTHER PUBLICATIONS CA 64:11180g, Indolylalkylguanidines, Gloeilampenfab Morozovskaya et al., "O-acyl Derivatives of Serotonin,” rieken, (1966). Pharm. Chem. Journal, vol. 3, pp. 125-128 (1968). Gordeev, et al., "Synthesis of 5-alkyltryptamines and Sleight et al., "Identification of 5-hydroxytryptamine 5-alkyl-o-methyl tryptamines', p. 485, (1973). Receptor Agents. Using a Composite Pharmacophore Analy Suvorov, et al., "Indole Derivatives. XXII Improved sis and Chemical Database Screening,” Arch Pharmacology, Tryptamine Synthesis”, Zh Obshch Khim, vol. 34:1595, vol. 343, pp. 109-116 (1991). (1964). Strandtmann et al., "Acyltryptamines. II. Synthesis of Acyl Suvorov, et al., “Amino Acid And Peptide Derivatives Of tryptamines, Indazoles, and Azepinoindoles from the Biogenetic Amines. IX. Synthesis of O,N-amino Acid Acylphenylhydrazones of 2,3-Piperidinedione'." J. Med. Derivatives Of Serotonin And Their Mass Spectrometric Chem., vol. 6, pp. 719–721 (Nov. 1963). And Pharmacological Study', Zh Obshch Khim, vol. Suvorov et al., (Abstract) Zh. Obshch. Khim., vol. 46(5), 46(5):1165 (1976). 1165-75 (1976). Vasin et al., (Abstract) Radiobiologiya, vol. 24, No. 3, pp. Vasin, et al., “Role Of The Serotonin Hydroxyl Group In 411-414 (1984). Pharmacological And Radioprotectant Action Of Serotonin' Suvorov, et al., Chemical Abstract No. 70637p, Hetero Radiobiologiya, vol. 24(3):411, (1984). cycles, vol. 80, No. 13, Apr. 1, 1974. CA 101:146879u Role of... Serotonin. Vasin et al., p. 319, Street, et al., "Synthesis and Serotonergic Activity of 1984. 5-(Oxadiazolyl)tryptamines: Potent Agonists for 5-HT CA 1.14:22 1894u A new . sites. Boulenguez et al., pp. Receptors', J. Med. Chem., vol. 36:1529-1538 (1993). 147-148, 1991. 5,496,957 1 2 TRYPTAMINE ANALOGS WITH 5-HT1D In a further aspect, the present invention provides com SELECTIVITY positions containing the present compounds either for use as reagents for example in the identification of 5-HT1D recep This application is a CIP of application Ser. No. 08/115, tors or in screening for ligands of such receptor, or for use 003, filed Sep. 1, 1993, now abandoned. 5 pharmaceutically to treat conditions where a 5-HT1D ligand This invention relates to tryptamine analogs having 5-HT is indicated. receptor binding activity, and to their production and use. The invention is now described in greater detail with reference to the accompanying FIG. 1, which illustrates the BACKGROUND TO THE INVENTION stimulatory effect of a compound of the invention on cells O presenting the 5-HT1D receptor. Through its interaction with receptors borne on neuronal and other cells, 5-hydroxytryptamine (5-HT, serotonin), exerts various physiological effects. Imbalances in this inter DETALED DESCRIPTION OF THE INVEN action are believed responsible for such conditions as anxi TION AND PREFERRED EMBODIMENTS ety, depression, hallucination, migraine, chemotherapy-in 15 duced nausea, and for disorders in sexual activity, The present invention provides tryptamine analogs that cardiovascular activity and thermoregulation, among others. bind with relative high affinity and selectivity to the 5-HT1D From an improved understanding of the 5-HT receptor receptor. Compounds having this desirable combination of population, it is apparent that these effects are mediated properties are tryptamine analogs in which the 5-position is selectively through individual types and sub-types of 5-HT 20 substituted by a group, designated R', having a length in the receptors. range from 8 to 11 atoms. Migraine, for example, has been treated with ergotamine, In particular and with reference to Formula I, the group R' dihydroergotamine and methysergide, all of which act at can be selected from linear C-11 alkyl, C3-alkanoyl, 5-HT1 type receptors. Their use is associated with undesir Coalkoxy in which the ether oxygen is attached at the able side effects, however, likely because they interact also 25 5-position, and Coalkanoyloxy in which the ester oxygen with various other 5-HT receptor types. An improved side is attached at the 5-position. These groups suitably have a effect profile is seen with the more recently marketed chain length of 8-11, and most suitably of 8, 9 or 10 atoms. tryptamine analog known as sumatriptan, which binds some In specific embodiments of the invention, R is what selectively at the 5-HT1 receptor sub-type known as Coalkoxy, preferably C. galkoxy and most preferably 5-HT1D (see Glennon and Westkaemper, DN&P, 1993, 6 30 Coalkoxy (nonyloxy). (6):390). The alkyl, alkoxy, alkanoyl or alkanoyloxy chain consti Given the physiological and clinical significance of the tuting R' can be substituted by one or more e.g. up to 4 5-HT1D receptor, it would be desirable to provide com substituents, suitably 1 or 2 substituents, selected from pounds capable of binding tightly and selectively to this hydroxyl; linear or branched chain Calkyl such as methyl, receptor, for medical use for example to treat indications 35 ethyl, propyl (n- and i-), butyl (n-, i- and t-); and linear or such as migraine and others for which administration of a branched chain Calkoxy such as methoxy, ethoxy, pro 5-HT1D ligand is indicated, and also for research and poxy (n- and i-) and butoxy (n-, i- and t-). In specific diagnostic use for example to identify these receptors and to embodiments, R is the group 8-hydroxyoctyloxy or the screen for drug candidates. group 7,7-dimethyloctyloxy. 40 A substituent may be conjugated to any one of the carbons SUMMARY OF THE INVENTION within the carbon chain of the group constituting R'.
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