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Benzisoxazole and Indazole Derivatives As Europäisches Patentamt *EP000833820B1* (19) European Patent Office Office européen des brevets (11) EP 0 833 820 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07D 261/20, C07D 231/56, of the grant of the patent: A61K 31/42, A61K 31/50, 14.02.2001 Bulletin 2001/07 A61K 31/415 (21) Application number: 96915782.5 (86) International application number: PCT/US96/06851 (22) Date of filing: 14.05.1996 (87) International publication number: WO 96/39397 (12.12.1996 Gazette 1996/54) (54) BENZISOXAZOLE AND INDAZOLE DERIVATIVES AS ANTIPSYCHOTIC AGENTS BENZISOXAZOL- UND INDAZOL- DERIVATE ALS ANTIPSYCHOTIKA DERIVES DE BENZISOXAZOLE ET D’INDAZOLE UTILISES COMME AGENTS NEUROLEPTIQUES (84) Designated Contracting States: (74) Representative: VOSSIUS & PARTNER AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC Siebertstrasse 4 NL PT SE 81675 München (DE) Designated Extension States: AL LT LV SI (56) References cited: EP-A- 0 302 423 EP-A- 0 402 644 (30) Priority: 06.06.1995 US 470400 WO-A-94/12495 DE-A- 3 247 530 US-A- 4 954 503 (43) Date of publication of application: 08.04.1998 Bulletin 1998/15 • JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 3, 1 March 1986, pages 359-369, (73) Proprietor: Aventis Pharmaceuticals Inc. XP000561328 YEVICH J P ET AL: "SYNTHESIS Bridgewater, NJ 08807-0800 (US) AND BIOLOGICAL EVALUATION OF 1-(1,2-BENZISOTHIAZOL-3-YL)- AND (72) Inventors: (1,2-BENZISOXAZOL-3-YL)PIPERAZINE • PALERMO, Mark, G., Building 20, DERIVATIVES AS POTENTIAL ANTIPSYCHOTIC Netcong, NJ 07857 (US) AGENTS" • MARTIN, Lawrence, L. Lebanon, NJ 07857 (US) Remarks: • NEMOTO, Peter, A. The file contains technical information submitted Westminster, CO 80234 (US) after the application was filed and not included in this specification 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 0 833 820 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 833 820 B1 Description [0001] This invention relates to heteroarylpiperazines having antipsychotic activity and to their use as antipsychotic drugs. 5 [0002] The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpro- mazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses. 10 [0003] Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, and tardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severe manifestations of these common side effects. 15 [0004] In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without the side effects previously mentioned. [0005] DE-A-3 247 530, US-A-4 954 503, EP-A-0 402 644 and J. Med. Chem., 29, 359-69, 1986 disclose piperazine derivatives having antipsychotic activity. 20 [0006] This invention relates to a compound of the formula 25 wherein 30 X is -OH, -OC(=O)(C1-C18)alkyl, -OC(=O)(C6-C10)aryl, -OC(=O)(C1-C12)alkyl(C6-C10)aryl, -OC(=O)NH(C1-C18) alkyl, -OC(=O)(C1-C12)alkyl(C3-C8)cycloalkyl, -OC(=O)O(C1-C18)alkyl, or -OC(=O)-(C3-C12)cycloalkyl; Y is hydrogen, halogen, trifluoromethyl, (C1-C6)alkoxy, cyano or nitro; Z is O or NR1; 35 R1 is hydrogen, (C1-C6)alkyl, formyl, -C(=O)(C1-C18)alkyl, or -C(=O)O(C1-C18)alkyl; m is 1, 2, 3 or 4; n is 1 or 2; and p is 1 or 2; and 40 its pharmaceutically acceptable acid addition salts; pharmaceutical compositions containing these compounds and their use as antipsychotic agents, particularly in the treatment of schizophrenia. The compounds of the invention are atypical antipsychotic agents. [0007] This invention also provides compounds which are suitable for acylation with (C1-C18)carboxylic acids or reactive functional derivatives thereof to form highly lipophilic esters, amides and carbamates, which compounds are 45 also compounds of this invention. Such selected compounds possess a hydroxyl group attached to either an aromatic carbon atom capable of forming the highly lipophilic esters of the invention or a secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of the invention. The secondary nitrogen atom may alternatively be acylated with a (C1-C18)alkoxy-carbonyl chloride to form a highly lipophilic carbamate derivative of the invention. 50 [0008] The invention also provides for the highly lipophilic compounds which provide long acting pharmaceutical effects when administered in the form of depot preparations. [0009] This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composi- tion is an antipsychotic composition comprising a compound of the invention in an amount sufficient to produce an 55 antipsychotic effect. [0010] In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention. [0011] Further, this invention provides a method of sustained release of a pharmaceutically effective amount of a 2 EP 0 833 820 B1 lipophilic compound of the invention in the form of a depot preparation. [0012] Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and the appended claims. [0013] The term (C1-C18)alkyl shall mean a straight or branched alkyl group, for example, methyl, ethyl, n-propyl, 5 isopropyl, tert-butyl, n-butyl, isobutyl, sec-butyl and straight and branched chain pentyl, hexyl, heptyl, decyl, undecyl, dodecyl, etc. up to an 18 carbon chain length. [0014] The term halo or halogen shall mean fluorine, chlorine, bromine or iodine. [0015] The term (C3-C12)cycloalkyl shall mean monocyclo and polycyclo alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl and the like. 10 [0016] The term (C6-C10)aryl shall mean aromatic carbocyclic rings such as benzene and naphthalene. [0017] Throughout the specification and the appended claims, a given formula or name shall encompass all stereo, optical, enantiomeric and tautomeric isomers where such isomers exists. [0018] In one class of compounds of this invention is a compound of the formula 15 20 wherein X is -OH, -OC(=O)(C1-C18)alkyl, -OC(=O)NH(C1-C18)alkyl, -OC(=O)O(C1-C18)alkyl or -OC(=O)-(C3-C12)cy- 25 cloalkyl; Y is hydrogen, halogen, trifluoromethyl, (C1-C6)alkoxy, cyano or nitro; Z is O or NR1; R1 is hydrogen, (C1-C6)alkyl, formyl, -C(=O)(C1-C18)alkyl or -C(=O)O(C1-C18)alkyl; m is 1, 2, 3 or 4; 30 n is 1 or 2; and p is 1 or 2; and its pharmaceutically acceptable acid addition salts. [0019] In a preferred embodiment of this class is a compound of the formula 35 40 wherein 45 X is -OH, -OC(=O)(C1-C18)alkyl, -OC(=O)NH(C1-C18)alkyl, -OC(=O)O(C1-C18)alkyl or -OC(=O)-(C3-C12)cycloalkyl; Y is hydrogen or halogen; m is 1, 2, 3 or 4; and p is 1; and 50 its pharmaceutically acceptable acid addition salts. [0020] More preferably, m is 3 and Y is 4-fluoro. [0021] Most preferably X is 6-hydroxy, 6-OC(=O)NHbutyl, 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC(=O)ada- mantyl; and its pharmaceutically acceptable acid addition salts. [0022] In another preferred embodiment of this class is a compound of the formula 55 3 EP 0 833 820 B1 5 wherein 10 X is -OH, -OC(=O)(C1-C18)alkyl, -OC(=O)NH(C1-C18)alkyl, -OC(=O)O(C1-C18)alkyl or -OC(=O)-(C3-C12)cycloalkyl; Y is hydrogen or halogen; R1 is hydrogen, (C1-C6)alkyl, formyl, -C(=O)(C1-C18)alkyl, or -C(=O)O(C1-C18)alkyl; m is 1, 2, 3 or 4; and 15 p is 1; and its pharmaceutically acceptable acid addition salts. [0023] More preferably, m is 3 and Y is 4-fluoro. [0024] Most preferably, X is 6-hydroxy, 6-OC(=O)NHbutyl, 20 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC(=O)adamantyl; and R1 is hydrogen or -C(=O)nonyl; and its pharmaceuti- cally acceptable acid addition salts. [0025] In another class of compounds of this invention is a compound of the formula 25 30 wherein X is -OH, -OC(=O)(C1-C18)alkyl, -OC(=O)NH(C1-C18)alkyl, -OC(=O)O(C1-C18)alkyl or -OC(=O)-(C3-C12)cycloalkyl; Y is hydrogen, halogen, trifluoromethyl, (C1-C6)alkoxy, cyano or nitro; 35 Z is O or NR1; R1 is hydrogen, formyl, (C1-C6)alkyl, -C(=O)(C1-C18)alkyl, or -C(=O)O(C1-C18)alkyl; m is 1, 2, 3 or 4; and p is 1 or 2; and 40 its pharmaceutically acceptable addition salts.
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