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Ep 1204654 B1 Europäisches Patentamt *EP001204654B1* (19) European Patent Office Office européen des brevets (11) EP 1 204 654 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 307/79, C07D 405/04, of the grant of the patent: C07D 405/12, A61K 31/496, 23.07.2003 Bulletin 2003/30 A61P 3/04 (21) Application number: 00948745.5 (86) International application number: PCT/US00/19543 (22) Date of filing: 21.07.2000 (87) International publication number: WO 01/009111 (08.02.2001 Gazette 2001/06) (54) BENZOFURYLPIPERAZINES: 5-HT2C SEROTONIN RECEPTOR AGONISTS BENZOFURYLPIPERAZINE: 5-HT2C SEROTONINREZEPTOR AGONISTEN BENZOFURYLPIPERAZINES: AGONISTES DU RECEPTEUR 5-HT2C DE LA SEROTONINE (84) Designated Contracting States: • REINHARD, Matthew, Robert AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Indianapolis, IN 46229 (US) MC NL PT SE • THOMPSON, Dennis, Charles Indianapolis, IN 46217 (US) (30) Priority: 29.07.1999 US 146270 P • WINNEROSKI, Leonard, Larry, Junior Greenwood, IN 46142 (US) (43) Date of publication of application: • XU, Yanping 15.05.2002 Bulletin 2002/20 Fishers, IN 46038 (US) (73) Proprietor: ELI LILLY AND COMPANY (74) Representative: Vaughan, Jennifer Ann et al Indianapolis, Indiana 46285 (US) Eli Lilly and Company Limited Lilly Research Centre (72) Inventors: Erl Wood Manor • BRINER, Karin Windlesham, Surrey GU20 6PH (GB) Indianapolis, IN 46256 (US) • BURKHART, Joseph, Paul (56) References cited: Plainfield, IN 46168 (US) EP-A- 0 006 524 EP-A- 0 189 612 • BURKHOLDER, Timothy, Paul WO-A-95/11243 WO-A-97/08167 Carmel, IN 46032 (US) WO-A-97/36893 US-A- 5 698 766 • CUNNINGHAM, Brian, Eugene Indianapolis, IN 46237 (US) • KUIPERS W. ET AL: "N4-unsubstituted • FISHER, Matthew, Joseph n1-arylpiperazines as high-affinity 5-HT1A Mooresville, IN 46158 (US) receptor ligands" JOURNAL OF MEDICINAL • GRITTON, William, Harlan CHEMISTRY., vol. 38, no. 11, 26 May 1995 Zionsville, IN 46077 (US) (1995-05-26), pages 1942-1954, XP002153536 • MILLER, Shawn, Christopher AMERICAN CHEMICAL SOCIETY. Noblesville, IN 46060 (US) WASHINGTON., US ISSN: 0022-2623 • MULLANEY, Jeffrey, Thomas Indianapolis, IN 46236 (US) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 204 654 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 204 654 B1 Description [0001] The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a hetero- geneous population of at least seven receptor classes. The serotonin 5-HT2 class is further subdivided into at least 5 three subtypes, designated 5-HT2a,5-HT2b, and 5-HT2c. The 5-HT2c receptor has been isolated and characterized (Julius, et al., U.S. Patent No. 4,985,352), and transgenic mice lacking the 5-HT2c receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius, et al., U.S. Patent No. 5,698,766). Compounds selective for the 5-HT2c receptor would provide useful therapies for the treatment of seizure and eating disorders without the side effects associated with current therapies. 10 [0002] WO 97/36893 relates to a group of piperazine and piperidine compounds having high affinity for both the dopamine D2 and serotonin 5-HT1A receptors. EP 0189612 relates to piperazine derivatives which may be used in pharmaceutical compositions having a psychotropic activity, due to their antiagressive and antipsychotic activity. J. Med. Chem., 1995, Vol.38, No 11, 1942-1954 describes the structural requirements for high 5-HT1A affinity in a series of aryl-substituted N'-phenylpiperazines. US 5,698,766 relates to a transgenic mouse model useful in the testing of 15 drugs for their efficacy in the treatment of eating disorders and epilepsy. [0003] The present invention provides compounds of Formula I: 20 25 30 where: A is a piperazine of formula: 35 40 R is hydrogen, halo, trifluoromethyl or C1-C6 alkyl; 45 1 R is hydrogen, halo, trifluoromethyl, phenyl, or C1-C6 alkyl; 2 3 4 R ,R , and R are independently hydrogen, halo, dihalomethyl, trifluoromethyl, 1,1-difluoroethy-1-yl, cyano, C1-C4 9 alkoxy, C1-C4 alkoxycarbonyl, C1-C6 alkyl, -C(O)NHR ,orC1-C6 alkyl substituted with a substituent selected from the group consisting of halo, C1-C4 alkoxy and hydroxy. 5 6 7 8 R ,R ,R , and R are independently hydrogen, C1-C6 alkyl, phenyl, benzyl, hydroxymethyl, halomethyl, dihalom- 50 ethyl, trihalomethyl, or benzyloxymethyl; R5' is hydrogen or methyl, provided that R5' may be methyl only when R5 is other than hydrogen; or R5 and R5', together with the carbon atom to which they are attached, form a cyclopropyl moiety; R6' is hydrogen or methyl, provided that R6' may be methyl only when R6 is other than hydrogen; or R6 and R6', together with the carbon atom to which they are attached, form a cyclopropyl moiety; 55 R7' is hydrogen or methyl, provided that R7' may be methyl only when R7 is other than hydrogen; or R7 and R7', together with the carbon atom to which they are attached, form a cyclopropyl moiety; R8' is hydrogen or methyl, provided that R8' may be methyl only when R8 is other than hydrogen; or R8 and R8', together with the carbon atom to which they are attached, form a cyclopropyl moiety; 2 EP 1 204 654 B1 9 R is C1-C8 alkyl where the alkyl chain is optionally substituted with a substituent selected from the group consisting of phenyl and pyridyl; or pharmaceutically acceptable acid addition salts thereof subject to the following provisos: 5 2 3 4 a) when R ,R , and R are all selected from the group consisting of hydrogen, trifluoromethyl, cyano, C1-C4 alkoxy, 6 7 or C1-C4 alkyl, neither R nor R may be selected from the group consisting of hydrogen and C1-C6 alkyl unless: 1. R is halo; 10 2. R1 is halo or phenyl 3. R6' or R7' is methyl; or 4. R5 or R8 are other than hydrogen; b) when R, R1, and two of R2,R3, and R4 are hydrogen and one of R2,R3,orR4is selected from the group 15 consisting of fluoro, chloro, bromo, methyl, or methoxy, at least one of R5,R6,R7,orR8must be other than hydrogen; c) when R1 is bromo or R is methyl, at least one of R2, R3, and R4 must be other than hydrogen; and d) no more than two of R5, R6, R7, and R8 may be other than hydrogen. [0004] This invention also provides a pharmaceutical formulation which comprises, in association with a pharma- 20 ceutically acceptable carrier, diluent or excipient, a compound of Formula I. [0005] The present invention provides a use of a compound of Formula I for increasing activation of the 5-HT2C receptor in mammals.The present invention also provides a use of a compound of Formula I for treating obesity in mammals. [0006] A further embodiment of this invention is a use of a compound of Formula I for increasing activation of the 25 5-HT2C receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erec- 30 tile difficulty, anorexia nervosa, disorders of sleep, autism, anxiety, seizure disorders, and mutism. Any of these uses employ a compound of Formula I. [0007] This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of obesity. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of obesity containing a compound of Formula I. Furthermore, this invention includes a method for the treatment of obesity 35 which comprises administering an effective amount of a compound of Formula I. [0008] The general chemical terms used in the formulae above have their usual meanings. For example, the term "alkyl" includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term "alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. The term "acyl" includes such groups as formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, and the like. The term "halo" includes fluoro, chloro, 40 bromo and iodo. [0009] The term "C1-C6 alkyl substituted with a substituent selected from the group consisting of C1-C4 alkoxy and hydroxy" means a branched or linear alkyl group substituted in the carbon chain with one or two substituents inde- pendently selected from hydroxy or C1-C4 alkoxy. [0010] The term "C1-C8 alkyl where the alkyl chain is optionally substituted with a substituent selected from the group 45 consisting of phenyl and pyridyl" means a branched or linear alkyl group which may be substituted in the carbon chain with a phenyl or pyridinyl ring. [0011] Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the 50 free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
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