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

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 composition 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

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

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)adamantyl; 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

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 pharmaceutically acceptable acid addition salts. [0025] In another class of compounds of this invention is a compound of the formula

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. [0026] In a preferred embodiment of this class is a compound of the formula

50 wherein

X is -OH, -OC(=O)(C2-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 55 p is 1; and

its pharmaceutically acceptable acid addition salts. [0027] More preferably, m is 3 and Y is 4-ﬂuoro.

4 EP 0 833 820 B1

[0028] Most preferably, X is 6-hydroxy, 6-OC(=O)NHbutyl, 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC(=O)adamantyl; and its pharmaceutically acceptable acid addition salts. [0029] In another preferred embodiment of this class are compounds of the formula

wherein 15

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; 20 m is 1, 2, 3 or 4; n is 1; and p is 1 or 2; and

its pharmaceutically acceptable acid addition salts. 25 [0030] More preferably, m is 3 and Y is 4-fluoro. [0031] Most preferably, X is 6-hydroxy, 6-OC(=O)NHbutyl, 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC(=O)adamantyl; and R1 is hydrogen or -C(=O)nonyl; and its pharmaceutically acceptable acid addition salts. [0032] Nonlimiting examples of compounds of the invention include: 30 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-5-hydroxy-1,2-benzisoxazole 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-4-hydroxy-1,2-benzisoxazole 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-7-hydroxy-1,2-benzisoxazole 35 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole hydrobromide 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole hydrochloride 3-[1-(4'-Fluorobenzoyl)butyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole 3-[1-(4'-Fluorobenzoyl)ethyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole 3-[1-(4'-Fluorobenzoyl)methyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole 40 Butyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Hexyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Dodecyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Octadecyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Decanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester 45 Dodecanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Hexadecanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Octadecanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Adamantane-1-carboxylic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Cyclohexylhexanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester 50 Cyclohexylcarboxylic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester Carbonic acid (3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)ester hexyl ester Carbonic acid (3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)ester dodecyl ester Carbonic acid (3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)ester octadecyl ester 3-[1-(4'-Fluorobenzoyl)propyl-4-homopiperazinyl]-6-hydroxy-1,2-benzisoxazole 55 Butyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-homopiperazin-1-yl]-1,2-benzisoxazol-6-yl ester Decanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-homopiperazin-1-yl]-1,2-benzisoxazol-6-yl ester Carbonic acid (3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]homopiperazin-1-yl]-1,2-benzisoxazol-6-yl)ester hexyl ester 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1H-indazole

5 EP 0 833 820 B1

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1H-indazole hydrochloride Butyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-yl ester Octadecanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-yl ester Carbonic acid (3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-yl)ester octadecyl ester 5 [0033] The compounds of the invention can be synthesized using one or more of the following general procedures described below. [0034] Throughout the description of the synthetic procedures, the notations X, Y, m, n and p have the respective meanings given above unless otherwise stated or indicated, R is (C1-C18)alkyl, (C6-C10)aryl, (C1-C12)alkylaryl, (C1- 10 C12)alkyl(C3-C8)cycloalkyl or (C3-C12)cycloalkyl, and other notations have the respective meanings defined in their first appearances. [0035] More particularly, as shown in Reaction Scheme A, the benzoxazoles are prepared from the chloro compound of Formula III, where X is alkoxy, by reaction with the cyclic amine of the formula IV to form the compound of Formula V where X is alkoxy. 15 [0036] The reaction is typically carried out neat in a sealed tube or under nitrogen at a temperature of from about 100°C to about 200°C, preferably from about 120°C to about 180°C, most preferably from about 130°C to about 150°C for from about 0.5 hour to about 100 hours, preferably from about 0.5 hours to about 8 hours, most preferably from about 0.45 hours to about 6 hours. [0037] The compound of Formula V is then reacted with the haloalkylphenone compound of Formula VI to provide 20 the compound of Formula VII wherein X is alkoxy. The reaction can be carried out in a polar non-protic organic solvent such as, for example, acetonitrile, at a temperature of from about 0°C to about 120°C, preferably from about 60°C to about 100°C, most preferably at about 80°C for from about 0.5 hours to about 24 hours, preferably for from about 1 hour to about 12 hours, most preferably for about 4 to 6 hours. The reaction is generally carried out in the presence of a base such as potassium or sodium carbonate and a catalyst such as potassium iodide. 25 [0038] The indazoles are prepared as shown in Reaction Scheme B, starting from the appropriate acetophenone of Formula IX wherein X is alkoxy which is oxidized to the corresponding carboxylic acid of Formula X wherein X is alkoxy under known conditions such as in the presence of sodium hydroxide and bromine.

6 EP 0 833 820 B1

55 [0039] The acid of Formula X wherein X is alkoxy is then treated with sulfonyl chloride and p-toluenesulfonhydrazide under known conditions to form the hydrazide of Formula XI which is further treated with sulfonyl chloride under known conditions to yield the chlorotosylhydrazone of Formula XII wherein X is alkoxy.

7 EP 0 833 820 B1

[0040] The chlorotosylhydrazone of Formula XII wherein X is alkoxy is reacted with the appropriate phenylpiperazinyl ketone of Formula XIII (prepared from the appropriate haloalkylphenone and piperazine under known conditions) to yield the hydrazono compound of Formula XIV wherein X is alkoxy. The reaction is typically carried out in an organic solvent at from about 0°C to about 50°C, preferably from about 10°C to about 35°C, most preferably at about room 5 temperature. [0041] The compound of Formula XIV is then heated in a polar non-protic solvent such as dimethylformamide for from about 1 hour to about 24 hours, more preferably from about 2 hours to about 12 hours, most preferably from about 3 hours to about 6 hours at a temperature of from about 35°C to about 125°C, more preferably from about 50°C to about 100°C, most preferably at about 90°C to yield the compound of Formula XV. 10 [0042] The compound of Formula XV is heated in the presence of hydrochloric acid to form the compound of Formula XVI wherein X is alkoxy. [0043] The compound of Formula XVI is alkylated under known conditions, such as with dimethylsulfate in the presence of a base such as potassium carbonate in a non-protic organic solvent to form the compound of Formula XVII. [0044] The compounds of Formula VII and XVII when X is alkoxy can be treated with acid such as, for example, 48% 15 hydrobromic acid to yield the corresponding hydroxy compounds of Formula VIII and XVIII. The reaction is typically carried out at reﬂux for from about 1 hour to about 12 hours, preferably from about 2 hours to about 4 hours.

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[0045] The hydroxy compounds of Formula VIII and XVIII are treated with the appropriate isocyanate, carbamoylchlo- ride or carbonyldimidazole and an amine to obtain the corresponding compounds of Formula XIX and XX where R is

9 EP 0 833 820 B1

(C1-C18)alkyl or aryl(C1-C10)alkyl. The reaction is carried out in an inert organic solvent such as, for example, ethyl acetate for from about 0.5 hours to about 24 hours, optionally in the presence of a catalyst such as, for example, copper (I)chloride. [0046] Additionally, the hydroxy compounds of Formula VIII and XVIII are treated with an alkyl, aryl or aralkylcarbox- 5 ylic acid halide, such as for example, adamantanecarbonyl chloride or decanoyl chloride, under basic conditions known in the art to yield the corresponding alkoxy, aryloxy or aralkyloxy compounds of Formula XXI and XXII. [0047] The hydroxy compounds of Formula VIII and XVIII are also reacted under basic conditions known in the art with the appropriate chloroformate to yield the carbonate compounds of Formula XXIII and XXIV. [0048] In the case of the indazoles, the nitrogen at the 1-position of the indazole can also be substituted by means 10 known in the art. [0049] The preparation of the starting materials is known in the art. For example, the preparation of the compounds of Formula III is disclosed in WO 9412495A1. [0050] Selected compounds of the invention possess a hydroxyl or amine group attached to either an aliphatic or aromatic carbon capable of forming the highly lipophilic esters or amides of this invention The hydroxy group may 15 alternatively be acylated with a (C1-C18) alkoxycarbonyl chloride to form a highly lipophilic carbonate derivative or with a (C1-C18) carbamoylhalide to form a highly lipophilic carbamate derivative. Representatives of such alcohols and amines and their highly lipophilic derivatives are found in the Examples of this invention. [0051] It is known in the art that long acting derivatives of drugs may be obtained by such transformation. European Patent Publication No. 260,070 discloses the prolonged action of haloperidol decanoate ester. International Publication 20 No. WO 92/06089 discloses sustained release amide derivatives of sertindole. [0052] The compounds of the present invention are useful for treating psychoses by virtue of their ability to elicit an antipsychotic response in mammals. In particular, the present compounds are potent atypical antipsychotic agents, i. e. compounds which display a D2/5-HT2 affinity ratio of greater than 1. The compounds of the invention further show a reduced potential for extra pyramidal side effects (EPS) as evidenced by a large difference in ED50 for the Climbing 25 Mouse Assay (CMA) and the Apomorphine Induced Stereotypy in Rats Test (APO-S). [0053] It is known that it is possible to predict antipsychotic efficacy and potential side effect liability by observing the electrophysiological profile of a drug on the dopamine (DA) neurons in the mesolimbic (A10) and nigrostriatal (A9) regions, respectively, of the rat brain. Thus, it has been shown by utilizing extracellular single unit recording techniques that all compounds that were effective antipsychotics both classic and atypical, would cause, upon repeated adminis- 30 tration, a tonic depolarization inactivation of the A10 DA neurons. Such a result would support the hypothesis that the symptoms of schizophrenia are predominantly due to excess DA activity in the mesolimbic area of the brain. However, it has also been shown that classic antipsychotics, those known to have EPS liability, such as haloperidol, would additionally cause a depolarization inactivation of the DA neurons in the A9 area of the brain. As this area of the brain is linked to motor function, the inhibition of these neurons provided a rationale for the EPS liability of the typical antip- 35 sychotics. The compounds of the invention show a significant decrease in the number of spontaneously active DA neurons in the A10 area of the brain. However, similar to clozapine and unlike haloperidol, the compounds of the invention do not cause a decrease in the number of DA neurons in the A9 area. This result strongly suggests that the compounds should be effective antipsychotics with little propensity to cause EPS.

40 CLIMBING MOUSE ASSAY

[0054] Antipsychotic activity is determined in the climbing mice assay by a method similar to those described by P. Protais, et al., Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39 (1978). [0055] Subject CK-1 male mice (23-27 grams) are group-housed under standard laboratory conditions. The mice 45 are individually placed in wire mesh stick cages (4"x10") and are allowed one hour for adaption and exploration of the new environment. Then apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 30 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneally or given oral doses at various time intervals, e.g. 30 minutes, 60 minutes, etc. prior to the apomorphine challenge at a screening dose of 10-60 mg/kg. 50 [0056] For evaluation of climbing, 3 readings are taken at 10, 20, and 30 minutes after apomorphine administration according to the following scale:

Climbing Behavior Mice With: Score 4 paws on bottom (no climbing) 0 55 2 paws on the wall (rearing) 1 4 paws on the wall (full climb) 2

10 EP 0 833 820 B1

Mice consistently climbing before the injection of apomorphine are discarded. [0057] With full-developed apomorphine climbing, the animals are hanging on to the cage walls, rather motionless, over long periods of time. By contrast, climbs due to mere motor stimulation usually only last a few seconds. [0058] The climbing scores are individually totaled (maximal score: 6 per mouse over 3 readings) and the total score 5 of the control group (vehicle intraperitioneally, apomorphine subcutaneously) is set to 100%. ED50 values with 95% conﬁdence limits, calculated by a linear regression analysis, of some of the compounds of the present invention as well as reference standard antipsychotic agents are presented in Table 1.

TABLE 1 10 COMPOUND CLIMBING MOUSE ASSAY (ED50 mg/kg, ip) 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazine)-6-methoxy- 5.28 1,2-benzisoxazole comparative 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy- 0.4 15 1,2-benzisoxazole hydrobromide Clozapine (reference) 8.1 Haloperidol (reference) 0.11

20 APOMORPHINE STEREOTYPY INHIBITION IN RATS

Purpose:

[0059] To screen neurolepic compounds which act directly on the dopaminergic system by blocking the action of 25 apomorphine on postsynaptic dopamine receptors (Anden et al., 1967; Ernst, 1967).

Method:

[0060] The subjects are male Wistar rats (125-250 grams) housed under standard laboratory conditions. For a pri- 30 mary screen, a group size of six is used. Drug is administered one hour prior to scoring and the animals are placed in individual clear plastic cages (24 x 14 x 13 cm). The control group receives vehicle. Apomorphine is prepared at a concentration of 15 mg/10 ml in a 0.003% ascorbic acid stock solution prepared with 30 mg of ascorbic acid in 100 ml of 1% saline to increase the stability of the apomorphine while in solution. Apomorphine is admininistered at a dose of 1.5 mg/kg subcutaneously (s.c.) with a dosage volume of 1 ml/kg 50 minutes after test compound or vehicle adminis- 35 tration. Stereotypic behavior is noted 10 minutes later. Stereotypy occurs in a repetitive manner and is continuous for a 10 second period in the presence of white noise. Stereotypic behavior is defined as sniffing, licking or chewing behavior which occurs in a repetitive manner and is continuous for a 10-second period in the presence of white noise. The animal is considered protected if this behavior is interrupted. The percent effectiveness of a drug is determined by the number of animals protected in each group. 40 [0061] A dose-response is determined in the same manner as a primary screen except that a group size of 10 is used and the animals are dosed in a randomized manner. One group receives vehicle. ED50 values for inhibition of stereotypy are calculated by means of Litchfield and Wilcoxon Analysis. [0062] Compounds preventing the stereotypy behavioral response to apomorphine were verified to have postsynaptic dopamine receptor antagonist properties. 45 References:

[0063] Anden, N.E., Rubenson, A., Fuxe, K. and Kokfelt, T. evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol., 19: 627-629, 1967. 50 [0064] Ernst, A.M. Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychop- harmacologia (Berl.,) 10:316-323, 1967. [0065] The ED50 values are set forth in Table 2.

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TABLE 2 COMPOUND APOMORPHINE STEREOTYPY INHIBITION (ED50 mg/kg, ip or % inhibition) 5 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy- 0% at 4.0 mg/kg. 1,2-benzoisoxazole hydrobromide Clozapine >40 mg/kg. Haloperidol ED =0.6 mg/kg, ip. 10 50

D2/5-HT2 BINDING ASSAYS

3 H-Spiroperidol Binding to Striatal Membranes (D2-Dopaminergic Site) in Rats 15 [0066] Assays were run according to the method of Leysen et al. [1978]. Striatal membranes were incubated with 3H- spiroperidol (0.4nM) and various concentrations of test drug at 37°C for 10 minutes in 1 ml of 0.05 M Tris-HCl buffer, pH 7.7 containing 120 mM NaCl, 5 mM KCl, 2mM CaCl2, and 1 mM MgCl2. Nonspecific binding was determined in the presence of 2µM(+)-butaclamol. Bound ligand was separated by rapid filtration through Whatman GF/B filters. 20 3 H-Spiroperidol Binding to Cerebral Cortical membranes (5HT2 Site) in Rats

[0067] Assays were performed by a modification of the method of Peroutka and Snyder [1979]. Cortical membranes were incubated with 3H-spiroperidol (1.5 nM) and various concentrations of test drug at 37°C for 10 minutes in 1 ml of 25 0.05 M Tris-HCl buffer, pH 7.7 containing 120 mM NaCI, 5 mM KCI, 2 mM CaCl2, and 1 mM MgCl2. Nonspecific binding was determined in the presence of 5 µM methysergide. The incubation was terminated by rapid filtration through What- man GF/B filters. [0068] The results are set forth in Table 3.

30 TABLE 3

COMPOUND D2 IC50 5-HT2 IC50 D2/5-HT2 3-[1-(4'-Fluorobenzoyl)-propyl-4-piperazinyl]-6-hydroxy- 0.24 µM 0.045 µM 5.3 1,2-benzisoxazole hydrobromide

35 Clozapine 0.83 µM 0.05 µM 17 Haloperidol 0.018µM 0.17 µM 0.1

DOPAMINE NEURON SAMPLING

40 [0069] Dopamine Neuron Sampling. Male Wistar rats (280-360 grams) were used in this procedure. They were housed for at least 48 hours in a climate-controlled vivarium with food and water continuously available. Each rat was initially anesthetized with chloral hydrate (400 mg/kg ip) and maintained with additional injections as needed throughout the experiment. The animal was mounted in a stereotaxic apparatus (Kopf, model 900). The cranium was exposed., cleaned of connective tissue and dried. The skull overlying both the substantia nigra [A9:anterior (A) 3000-3400 mi- 45 crons, lateral (L) 1800-2400 microns from lambda] and the ventral tegmental area (A10: A 3000-3400 microns, L 400-1000 microns from lambda)47 was removed. Using the dura as a point of reference, a micropipette driven by a hydraulic microdrive was lowered through the opening in the skull at vertical 6000-8500 microns. Spontaneously firing dopamine neurons within both the substantia nigra and the ventral tegmental areas were counted by lowering the electrode into twelve separate tracks (each track separated from the other by 200 microns) in each region. The se- 50 quence of the tracks was kept constant, forming a block of tissue which could be repoducibly located from animal to animal. [0070] Extracellular neuronal signals were sampled using a single barrel micropipette approximately one micron at its tip, and filled with 2M NaCI saturated with 1% pontamine sky blue dye. Thein vitro impedance of this pipet (measured with a Winston Electronics Co., BL-1000 Micro Electrode Tester) was between 5 and 10 megaohms. Electrical potentials 55 were passed through a high-impedance preamplifier and the signal was sent to a window discriminator (WPI model 121) which converted potentials above background noise levels to discrete pulses of fixed amplitude and duration. Only cells whose electrophysiological characteristics matched those previously established for midbrain dopamine

12 EP 0 833 820 B1

neurons were counted. In an anesthetized rat, a neuron was considered to be dopaminergic if it displayed a triphasic postive-negative-postive spike profile of 0.4 to 1.5 microvolts amplitude and 2.5 milliseconds duration, firing in an irregular pattern of 3 to 9 Hz with occasional bursts characterized by progressively decreasing spike amplitude and increasing spike duration. 5 [0071] At the end of each experiment, the location of the last recorded track tip was marked by passing 25 micro- ampere cathodal current through the recording micropipette barrel for 15 minutes in order to deposit a spot of dye. The rat was sacrificed; the brain was then removed, dissected and frozen on a bed of dry ice. Frozen serial sections (20 microns in width) were cut, mounted, and stained with cresyl violet and examined using a light microscope. [0072] Animals pretreated with vehicle prior to neuronal sampling served as controls. Compounds were prepared 10 as percent base. Each compound was suspended in distilled water and one drop of Tween 80, and kept constantly agitated during dosing. All compounds were delivered at a dosage volume of 1 mg/kg by the intraperitoneal route. For animals used in the chronic single-unit, dopamine neuron sampling assay, the compounds were administered once a day for 21 days, and dopamine neuron sampling was begun two hours after the last dose on the 21 st day. Drug treatment groups were compared to vehicle groups with a one-way ANOVA with a post hoc Neuman-Keuls analysis 15 for significance. [0073] The results are set forth in Table 4.

TABLE 4 CHRONIC SINGLE DOPAMINE NEURON SAMPLING IN RATS 20 Compound % Change in A10 region % Change in A9 region 3-[1-(4'-Fluorobenzoyl)-propyl-4-piperazinyl]-6-hydroxy- -44.9 +1.4 1,2-benzisoxazole hydrobromide at 20 mg/kg, ip. Clozapine (atypical reference drug) -79 +37 25 Haloperidol (atypical reference drug) -35 -30

[0074] Antipsychotic response is achieved when compounds of the present invention are administered to a subject requiring such treatment as an effective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kg of body weight 30 per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the scope or practice of the invention. [0075] Effective amounts of the compounds of the present invention can be administered to a subject by any one of 35 several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. [0076] The compounds of the present invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility, and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, 40 for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, for example, acetic acid, propionic acid, and the like , salts of dibasic carboxylic acids, for example, maleic acid, fumaric acid, and the like; and salts of tribasic carboxylic acids, such as carboxysuccinic acid, citric acid, and the like. [0077] Effective quantities of the compounds of the invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purposes 45 of oral therapeutic administration, compounds of the invention can be incorporated with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations should contain at least 0.5% of active compound of the invention, but can be varied depending upon the particular form and can conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such a composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to 50 the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of the active compound of the invention. [0078] Tablets, pills, capsules, troches, and the like can also contain the following ingredients: a binder, such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient, such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch, and the like; a lubricant such as magnesium stearate or Sterores; a glidant 55 such as colloidal silicon dioxide; and a sweetening agent such as sucrose; or saccarin, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms can contain various materials

13 EP 0 833 820 B1

that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup can contain, in addition to the active compounds, sucrose as a sweetening agent and certain perservatives, dyes, colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. 5 [0079] For the purpose of parenteral therapeutic administrations, the active compound of the invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but can be varied between 0.5 and about 50% of the weight thereof The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound. 10 [0080] Solutions or suspensions can also include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; anti- bacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in 15 ampules, disposable syringes, or multiple dose vials made of glass or plastic. [0081] The highly lipophilic esters, amides, carbonates and carbamates of the present invention are capable of sustained release in mammals for a period of several days or from about one to four weeks when formulated and administered as depot preparations, as for example, when injected in a properly selected pharmaceutically acceptable oil. The preferred oils are of vegetable origin such as sesame oil, cottonseed oil, corn oil, coconut oil, soybean oil, olive 20 oil and the like, or they are synthetic esters of fatty acids and polyfunctional alcohols such as glycerol or propylene glycol. [0082] The depot compositions of the present invention are prepared by dissolving or suspending a highly lipophilic ester, amide, carbonate or carbamate of the instant invention in a pharmaceutically acceptable oil under sterile conditions. The oil is selected so as to obtain a release of the active ingredient over a desired period of time. The appropriate oil may easily be determined by consulting the prior art, or without undue experimentation by one skilled in the art. 25 [0083] An appropriate dose of a compound in accordance with this embodiment of the invention is from about 0.01 to 10 mg/kg of body weight per injection. Preferably, the depot formulations of this invention are administered as unit dose preparations comprising about 0.5 to 5.0 ml of a 0.1 to 20% weight/weight solution of compound in the oil. It is to be understood that the doses set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention. 30 [0084] Representative examples of compounds of the invention and of intermediates used in their synthesis are set forth in Table 5. The examples are for illustrative purposes only and are not to be construed as limiting the invention. All temperatures are given in degrees Centigrade (°C) unless indicated otherwise.

14 EP 0 833 820 B1

15 EP 0 833 820 B1

EXAMPLES

10 EXAMPLE 1 (COMPARATIVE)

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-methoxy-1,2-benzisoxazole

a. 6-Methoxy-3-(1-piperazinyl)-1,2-benzisoxazole hemihydrate 15 [0085] A mixture of 3-chloro-6-methoxy-1,2-benzisoxazole (3.0 g) and piperazine (6.0 g) was heated to 140°C over 4 hours in a sealed tube and then cooled to room temperature. The contents of the tube were dissolved in MeOH and further diluted with EtOAc (1L). The precipitate was ﬁltered and the ﬁltrate dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 30% MeOH/EtOAc provided a residue upon evaporation (3.6 g, 20 m.p. 79-80 C).

ANALYSIS:

Calculated for C12H15N3O2 0.5H2O 59.49%C 6.65%H 17.34%N 25 Found 59:25%C 6.28%H 17.30%N

b. 3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-methoxy-1,2-benzisoxazole

[0086] To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (5.0 g, 21.4 mmol) in acetonitrile (25 30 ml) was added K2CO3 (3.6 g, 25.7 mmol), KI (0.4 g, 2.1 mmol) and 4-chloro-4'-fluorobutyrophenone (5.2 g, 25.7 mmol) under N2. The reaction mixture was heated at reflux for 5 hours and allowed to cool to room temperature. The material was diluted with EtOAc, washed with water and brine, dried with MgSO4, and concentrated in vacuo. The material was flashed chromatographed (silica gel) eluting with 3:2 EtOAc/heptane affording the pure free base of the product.

35 ANALYSIS:

Calculated for C22H24N3O3F 66.48%C 6.09%H 10.57%N Found 66.32%C 6.00%H 10.45%N

40 EXAMPLE 2

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole

[0087] A solution of 3-[1-(4'-ﬂuorobenzoyl)propyl-4-piperazinyl]-6-methoxy-1,2-benzisoxazole (3.5 g, 8.8 mmol) and 45 48% hydrobromic acid was heated at 120°C for 4 hours. The reaction mixture was neutralized with saturated Na2CO3 solution, extracted with EtOAc, and the organic phase was dried (MgSO4) and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 5% MeOH/CH2Cl2, concentration of the desired fractions and recrystallization from EtOAc provided the product as an off-white solid (0.5 g, 15%, m.p. 181-182°C).

50 ANALYSIS:

Calculated for C21H22N3O3F 65.78%C 5.78%H 10.96%N Found 65.52%C 5.89%H 10.76%N

16 EP 0 833 820 B1

EXAMPLE 3

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole hydrobromide

5 [0088] A solution of ethereal hydrobromic acid was added to a solution of 3-[1-(4'-ﬂuorobenzoyl)propyl-4-piperazinyl]- 6-hydroxy-1,2-benzisoxazole (0.31 g, 0.8 mmol) in 50% CH3CN/EtOAc and chilled to 0°C for 1 hour. The precipitate was ﬁltered under N2 and dried in vacuo to afford the hydrobromide salt as a white solid (0.3 g, 81%, m.p. 260-261°C).

ANALYSIS: 10 Calculated for C21H22N3O3F HBr 54.32%C 4.99%H 9.05%N Found 54.75%C 5.05%H 9.04%N

EXAMPLE 4 15 Carbonic acid (3-[4-[4-(4-ﬂuorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl)ester hexyl ester

[0089] To a suspension of the compound of Example 3 (7.6 g, 16.4 mmol) in EtOAc (200 ml) was added NaHCO3 (sat., 100 ml) at room temperature. After stirring over night, the solids were removed via filtration and the two-phase 20 filtrate was transferred to a separatory funnel. The layers were separated and the organic phase was dried over Na2SO4. Filtration and concentration of the filtrate gave 2.9 g (47%) of the compound of Example 2. [0090] This free amine (0.50 g, 1.31 mmol) was suspended in anhydrous THF (25 ml), under nitrogen, and treated with hexyl chloroformate (97%, 0.27 ml, 1.57 mmol). Milled potassium carbonate (0.22 g, 1.57 mmol) was then added and the reaction mixture was allowed to stir for eighteen hours. The solids were removed via filtration and washed with 25 DCM. The combined filtrates were concentrated to give the crude product which was purified via flash column chromatography (silica gel, ethyl acetate). Concentration of the desired fractions gave 0.51 g (76%) of the product as a light brown solid, m.p. 77-80°C.

ANALYSIS: 30 Calculated for C28H34FN3O5 65.74%C 6.70%H 8.21%N Found 65.80%C 6.74%H 8.04%N

EXAMPLE 5 35 Adamantane-1-carboxylic acid 3-[4-[4-(4-ﬂuorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester

[0091] The compound of Example 2 (0.50 g, 1.31 mmol) was suspended in acetonitrile (15 ml), under nitrogen, and 40 treated with K2CO3 (0.20 g, 1.44 mmol). 1-Adamantanecarbonyl chloride (0.30 g, 1.44 mmol) was then added and the reaction mixture was allowed to stir for sixty hours. The solids were removed via filtration and washed with DCM. The combined filtrates were concentrated to give the crude product which was purified via flash column chromatography (silica gel, ethyl acetate). Concentration of the desired fractions gave 0.52 g (73%) of the product as a white solid, m. p. 157-158°C. 45 ANALYSIS:

Calculated for C32H36FN3O4 70.44%C 6.65%H 7.70%N Found 70.29%C 6.62%H 7.54%N

50 EXAMPLE 6

Decanoic acid 3-[4-[4-(4-ﬂuorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester

[0092] The compound of Example 2 (0.60 g, 1.57 mmol) was suspended in acetonitrile (15 ml), under nitrogen, and 55 treated with K2CO3 (0.24 g, 1.73 mmol). Decanoyl chloride (0.36 ml, 1.73 mmol) was then added and the reaction mixture was allowed to stir for sixty hours. The solids were removed via ﬁltration and washed with DCM. The combined ﬁltrates were concentrated to give 0.80 g (95%) of the desired product as a brown solid, m.p. 69-71°C.

17 EP 0 833 820 B1

ANALYSIS:

Calculated for C31H40FN3O4 69.25%C 7.50%H 7.82%N 5 Found 69.28%C 7.71%H 7.76%N

EXAMPLE 7

Butyl carbamic acid 3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester 10 [0093] The compound of Example 2 (0.50 g, 1.31 mmol) was suspended in anhydrous THF (25 ml), under nitrogen, and treated with butyl isocyanate (0.18 ml, 1.57 mmol). Milled potassium carbonate (0.22 g, 1.57 mmol) was then added and the reaction mixture was allowed to stir for eighteen hours. The solids were removed via filtration and washed with DCM. The combined filtrates were concentrated to give the crude product which was purified via flash 15 column chromatography (silica gel, ethyl acetate). Concentration of the desired fractions gave 0.40 g (63%) of the product as a light brown solid, m.p. 137-141°C.

ANALYSIS: Calculated for C H FN O 64.72%C 6.48%H 11.61%N 20 26 31 4 4 Found 64.29%C 6.83%H 11.77%N

EXAMPLE 8 (PREPARATIVE)

25 3-(1-homopiperazinyl)-6-methoxy-1,2-benzisoxazole

[0094] 3-Chloro-6-methoxy-1,2-benzisoxazole (5.0 g, 27.2 mmol) and homopiperazine (8.2 g, 81.6 mmol) were combined and mechanically stirred under N2 at 140°C for 45 minutes. The reaction mixture was cooled to room temperature, dissolved with EtOAc (500 ml), and the solution was washed with water, brine, dried over MgSO4, and concentrated 30 in vacuo. Flash column chromatography (silica gel, 20% MeOH/CH2Cl2) provided the product, 2.0 g, m.p. 74-75°C.

ANALYSIS:

Calculated for C13H17N3O2 63.14%C 6.93%H 16.99%N Found 62.88%C 6.85%H 16.81%N 35

EXAMPLE 9

1-(4-Fluorophenyl)-4-[4-[6-hydroxy-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one hydrochloride hydrate 40

a. 4-[4[N-(p-Toluenesulfonylhydrazono)-2-ﬂuoro-4-methoxyphenylmethyl]-piperazin-1-yl]-1-(4-ﬂuorophenyl)butan- 1-one

[0095] To a stirred solution of alpha-chloro-2-fluoro-4-methoxy benzaldehyde, 1-p-toluenesulfonylhydrazone (4.6 g, 45 12.8 mmol) in chloroform (20 ml) was added a solution of 1-(4-fluorophenyl)-4-piperazin-1-yl-butan-1-one (3.2 g, 12.8 mmol) in chloroform (20 ml) and allowed to stir at ambient temperature under nitrogen for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was flash chromatographed eluting with 3:2 CH2Cl2/EtOAc to afford the product, 2.5 g, mp = 66-67°C. 50 ANALYSIS:

Calculated for C29H32N4O4F2S 61.04%C 5.65%H 9.82%N Found 60.74%C 5.53%H 9.69%N

55 b. 1-(4-Fluorophenyl)-4-[4-[6-methoxy-1-toluene-4-sulfonyl)-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

[0096] To a stirred solution of the compound of Example 9a (2.5 g, 4.4 mmol) in N,N-dimethylformamide (10ml) was

18 EP 0 833 820 B1

added K2CO3 (1.2 g, 8.8 mmol) under N2. The reaction was heated to 90°C for 3 hours. The reaction mixture was then cooled, diluted with with ethyl acetate, washed with brine (6 times), dried over Na2SO4, and concentrated in vacuo. The residue was ﬂash chromatographed eluting with 3:2 CH2Cl2/EtOAc to afford the product, 2.3 g, mp = 120-121°C.

5 ANALYSIS

Calculated for C29H31N4O4FS 63.26%C 5.67%H 10.17%N Found 62.99%C 5.71%H 9.86%N

10 c. 1-(4-Fluorophenyl)-4-[4-[6-methoxy)-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

[0097] A mixture of the compound of Example 9b (1 g, 1.8 mmol) and 30 ml of 12M hydrochloric acid was heated at 90°C for 1 hour under nitrogen. The reaction mixture was cooled, diluted with EtOAc, and neutralized with Na2CO3 (sat'd). The organic layer was separated and the aqueous layer was extracted again with EtOAc. The organic layers 15 were combined, dried over Na2SO4 and evaporated to afford 0.65 g of the desired product, mp = 157-162°C.

d. 1-(4-Fluorophenyl)-4-[4-[6-methoxy)-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

[0098] To a mixture of the compound of Example 9c (0.45 g, 1.13 mmol) and potassium hydroxide (0.19 g, 3.4 mmol) 20 in 40 ml of acetone, there was added dimethylsulfate (0.14 g, 0.11 ml, 1.13 mmol) and the mixture was reﬂuxed for three hours. The reaction mixture was cooled, diluted with methylene chloride and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was ﬂash chromatogtaphed. Elution with 5% MeOH/CH2Cl2 gave 0.4 g of the product, mp = 103-104°C.

25 e. 1-(4-Fluorophenyl)-4-[4-[6-hydroxy)-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one hydrochloride hydrate

[0099] To 48% hydrobromic acid (20 ml) was added the compound of Example 9d (0.40 g, 1.0 mmol) and the mixture was heated to 110°C under N2 for four (4) hours. Then the mixture was cooled and diluted with EtOAc and neutralized with saturated Na2CO3 solution and extracted with additional EtOAc. The organic layers were combined, dried over 30 Na2SO4 and concentrated in vacuo. The residue was ﬂash chromatographed (silica gel, 3% MeOH/CH2Cl2 to yield a white solid which was dissolved in EtOAc and acidiﬁed with ethereal hydrochloride acid to afford the salt, 0.30 g, mp=243-244°C.

ANALYSIS 35 Calculated for C22H25N4O2F•HCl•H2O 58.60%C 6.26%H 12.40%N Found 58.60%C 6.06%H 12.36%N

Claims 40 1. A compound of the formula

50 wherein

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; 55 Y is H, 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;

19 EP 0 833 820 B1

m is 1, 2, 3 or 4; n is 1 or 2; and p is 1 or 2;

5 and its pharmaceutically acceptable acid addition salts.

2. The compound of Claim 1 of the formula

15 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; 20 Y is hydrogen, halogen, triﬂuoromethyl, (C1-C6)alkoxy, cyano or nitro; m is 1, 2, 3 or 4; and p is 1 or 2; and

its pharmaceutically acceptable acid addition salts. 25 3. The compound of Claim 2 of the formula

35 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 or halogen; 40 m is 1, 2, 3 or 4; and p is 1; and

its pharmaceutically acceptable acid addition salts.

45 4. The compound of Claim 1 which is a compound of the formula

wherein 55

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;

20 EP 0 833 820 B1

m is 1, 2, 3 or 4; and p is 1 or 2; and

its pharmaceutically acceptable addition salts. 5 5. The compound of Claim 4 of the formula

15 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 or halogen; 20 m is 1, 2, 3 or 4; and p is 1; and

its pharmaceutically acceptable acid addition salts.

25 6. The compound of Claim 1 of the formula

35 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; 40 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 p is 1 or 2; and

its pharmaceutically acceptable acid addition salts. 45 7. The compound of Claim 6 of the formula

wherein

21 EP 0 833 820 B1

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; 5 m is 1, 2, 3 or 4; and p is 1; and

its pharmaceutically acceptable acid addition salts.

10 8. The compound of Claim Claim 1 of the formula

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)cycloalkyl; Y is hydrogen, halogen, triﬂuoromethyl, (C1-C6)alkoxy, cyano or nitro; 25 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

30 its pharmaceutically acceptable acid addition salts.

9. The compound of Claim 8 of the formula

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- 45 cloalkyl; 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; n is 1, and 50 p is 1 or 2; and

its pharmaceutically acceptable acid addition salts.

10. The compound of claim 7 or 8 wherein m is 3 and Y is 4-ﬂuoro. 55 11. The compound of Claim 10 wherein X is 6-hydroxy, 6-OC(=O)NHbutyl, 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC (=O)adamantyl; and R1 is hydrogen or -C(=O)nonyl; and its pharmaceutically acceptable acid addition salts.

22 EP 0 833 820 B1

12. The compound of Claim 3 or 5 wherein m is 3 and Y is 4-ﬂuoro.

13. The compound of Claim 12 wherein X is 6-hydroxy, 6-OC(=O)NHbutyl, 6-OC(=O)Ohexyl, 6-OC(=O)nonyl, or 6-OC (=O)adamantyl; and its pharmaceutically acceptable acid addition salts. 5 14. The compound of Claim 13 which is 3-[1-(4'-ﬂuorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole,

3-[1-(4'-fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole hydrobromide, carbonic acid (3-[4- [4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl) ester hexyl ester, 10 adamantane-1-carboxylic acid 3-[4-[4-(4-fluoro-phenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester, decanoic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester, or butyl carbamic acid 3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl ester.

15 15. The compound of Claim 11 which is 1-[(4-ﬂuorophenyl)-4-[4-(6-hydroxy)-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]- butan-1-one.

16. A pharmaceutical composition which comprises the compound of any of Claims 1 to 15 and a pharmaceutically acceptable carrier. 20 17. An antipsychotic composition which comprises the compound of any of Claims 1 to 15 in an amount sufﬁcient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

18. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically 25 effective amount of the compound of any of Claims 1 to 15 wherein the compound contains a hydroxy group or amino group which has been acylated.

19. The composition of Claim 18 wherein the hydroxy or amino group is acylated with an (C4-C18)alkanoyl group or an (C4-C18)alkoxycarbonyl group. 30 20. The composition of Claim 18 which contains a pharmaceutically acceptable oil.

21. The composition of Claim 20 wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, olive oil and esters of fatty acids and polyfunctional alcohols. 35 22. A depot composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of any of Claims 1 to 15.

23. Use of a compound according to any one of Claims 1-15 for the manufacture of a medicament for the treatment 40 of psychoses or for providing a long acting antipsychotic effect.

24. A process for preparing a compound of claim 1 wherein Z is O and its pharmaceutically acceptable acid addition salts, comprising reacting a compound of the formula: 45

wherein X and n are deﬁned as above, with a compound of the formula:

23 EP 0 833 820 B1

wherein halo is Br or Cl, and Y, m and p are deﬁned as above, in a polar non-protic organic solvent in the presence of a base and a catalyst.

10 25. A process for preparing a compound of claim 1 wherein Z is NH and its pharmaceutically acceptable acid addition salts, comprising treating a compound of the formula:

wherein Ts is tosylate and X, Y, m, n and p are deﬁned as above, with concentrated HCI.

26. A process for preparing a compound of claim 1 25 wherein X is -OH and Z is O and its pharmaceutically acceptable acid addition salts, comprising heating a compound of the formula:

35 wherein

X is -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, and Y, m, n and p are deﬁned as above, 40 with 48% HBr.

Patentansprüche 45 1. Verbindung der Formel

55 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)(C6-C10)-Aryl-, -O-C(=O)(C1-C12)-Alkyl-(C6-C10)-

24 EP 0 833 820 B1

aryl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)-(C1-C12)-Alkyl-(C3-C8)-cycloalkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

Y ein Wasserstoff-, Halogenatom, eine Triﬂuormethylgruppe, einen (C1-C6)-Alkoxyrest, eine Cyano- oder Ni- 5 trogruppe darstellt;

Z ein Sauerstoffatom oder einen Rest NR1 bedeutet;

R1 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, eine Formylgruppe, einen -C(=O)(C1-C18)-Alkyl- oder -C(=O) 10 O(C1-C18)-Alkylrest darstellt;

m 1, 2, 3 oder 4 ist;

n 1 oder 2 ist; und 15 p 1 oder 2 ist;

und ihre pharmazeutisch verträglichen Säureadditionssalze.

20 2. Verbindung nach Anspruch 1 der Formel

30 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

35 Y ein Wasserstoff-, Halogenatom, eine Triﬂuormethylgruppe, einen (C1-C6)-Alkoxyrest, eine Cyano- oder Nitro- gruppe darstellt;

m 1, 2, 3 oder 4 ist; und

40 p 1 oder 2 ist; und

ihre pharmazeutisch verträglichen Säureadditionssalze.

3. Verbindung nach Anspruch 2 der Formel 45

in der

55 X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

Y ein Wasserstoff- oder Halogenatom darstellt;

25 EP 0 833 820 B1

m 1, 2, 3 oder 4 ist; und

p 1 ist; und

5 ihre pharmazeutisch verträglichen Säureadditionssalze.

4. Verbindung nach Anspruch 1, die eine Verbindung der Formel

ist, in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder 20 -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

Y ein Wasserstoff-, Halogenatom, eine Triﬂuormethylgruppe, einen (C1-C6)-Alkoxyrest, eine Cyano- oder Nitro- gruppe darstellt;

25 m 1, 2, 3 oder 4 ist; und

p 1 oder 2 ist; und

ihre pharmazeutisch verträglichen Additionssalze. 30 5. Verbindung nach Anspruch 4 der Formel

40 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

45 Y ein Wasserstoff- oder Halogenatom darstellt;

m 1, 2, 3 oder 4 ist; und

p 1 ist; und 50 ihre pharmazeutisch verträglichen Säureadditionssalze.

6. Verbindung nach Anspruch 1 der Formel

26 EP 0 833 820 B1

10 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

15 Y ein Wasserstoff-, Halogenatom, eine Triﬂuormethylgruppe, einen (C1-C6)-Alkoxyrest, eine Cyano- oder Ni- trogruppe darstellt;

R1 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, eine Formylgruppe, einen -C(=O)(C1-C18)-Alkyl- oder -C(=O) O(C1-C18)-Alkylrest bedeutet; 20 m 1, 2, 3 oder 4 ist; und

p 1 oder 2 ist; und

25 ihre pharmazeutisch verträglichen Säureadditionssalze.

7. Verbindung nach Anspruch 6 der Formel

in der

40 X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest darstellt;

Y ein Wasserstoff- oder Halogenatom bedeutet;

45 R1 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, eine Formylgruppe, einen -C(=O)(C1-C18)-Alkyl- oder -C(=O) O(C1-C18)-Alkylrest darstellt;

m 1, 2, 3 oder 4 ist; und

50 p 1 ist; und

ihre pharmazeutisch verträglichen Säureadditionssalze.

8. Verbindung nach Anspruch 1 der Formel 55

27 EP 0 833 820 B1

10 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest bedeutet;

15 Y ein Wasserstoff-, Halogenatom, eine Triﬂuormethylgruppe, einen (C1-C6)-Alkoxyrest, eine Cyano- oder Ni- trogruppe darstellt;

R1 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, eine Formylgruppe, einen -C(=O)(C1-C18)-Alkyl- oder -C(=O) O(C1-C18)-Alkylrest bedeutet; 20 m 1, 2, 3 oder 4 ist;

n 1 oder 2 ist; und

25 p 1 oder 2 ist; und

ihre pharmazeutisch verträglichen Säureadditionssalze.

9. Verbindung nach Anspruch 8 der Formel 30

40 in der

X die Gruppe -OH, einen -OC(=O)(C1-C18)-Alkyl-, -OC(=O)NH(C1-C18)-Alkyl-, -OC(=O)O(C1-C18)-Alkyl- oder -OC(=O)-(C3-C12)-Cycloalkylrest darstellt;

45 Y ein Wasserstoff- oder Halogenatom bedeutet;

R1 ein Wasserstoffatom, einen (C1-C6)-Alkylrest, eine Formylgruppe, einen -C(=O)(C1-C18)-Alkyl- oder -C(=O) O(C1-C18)-Alkylrest darstellt;

50 m 1, 2, 3 oder 4 ist;

n 1 ist; und

p 1 oder 2 ist; und 55 ihre pharmazeutisch verträglichen Säureadditionssalze.

10. Verbindung nach Anspruch 7 oder 8, wobei m 3 ist, und Y eine 4-Fluorgruppe bedeutet.

28 EP 0 833 820 B1

11. Verbindung nach Anspruch 10, wobei X eine 6-Hydroxy-, 6-OC(=O)NH-Butyl-, 6-OC(=O)O-Hexyl-, 6-OC(=O)-No- nyl- oder 6-OC(=O)-Adamantylgruppe darstellt; und R1 ein Wasserstoffatom oder eine -C(=O)-Nonylgruppe bedeutet; und ihre pharmazeutisch verträglichen Säureadditionssalze.

5 12. Verbindung nach Anspruch 3 oder 5, wobei m 3 ist, und Y eine 4-Fluorgruppe darstellt.

13. Verbindung nach Anspruch 12, wobei X eine 6-Hydroxy-, 6-OC(=O)NH-Butyl-, 6-OC(=O)O-Hexyl-, 6-OC(=O)-No- nyl- oder 6-OC(=O)-Adamantylgruppe bedeutet; und ihre pharmazeutisch verträglichen Säureadditionssalze.

10 14. Verbindung nach Anspruch 13, die

3-[1-(4'-Fluorbenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazol,

3-[1-(4'-Fluorbenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazolhydrobromid, 15 Kohlensäure-(3-[4-[4-(4-ﬂuorphenyl)-4-oxobutyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)esterhexylester,

Adamantan-1-carbonsäure-3-[4-[4-(4-ﬂuorphenyl)-4-oxobutyl]piperazin-1-yl]-1,2-benzisoxazol-6-ylester,

20 Decansäure-3-[4-[4-(4-ﬂuorphenyl)-4-oxobutyl]piperazin-1-yl]-1,2-benzisoxazol-6-ylester oder

Butylcarbaminsäure-3-[4-[4-(4-ﬂuorphenyl)-4-oxobutyl]piperazin-1-yl]-1,2-benzisoxazol-6-ylester ist.

15. Verbindung nach Anspruch 11, die 1-[(4-Fluorphenyl)-4-[4-(6-hydroxy)-1-methyl-1H-indazol-3-yl]piperazin-1-yl] 25 butan-1-on ist.

16. Arzneimittel, das die Verbindung nach einem der Ansprüche 1 bis 15 und einen pharmazeutisch verträglichen Träger umfasst.

30 17. Antipsychotisches Arzneimittel, das die Verbindung nach einem der Ansprüche 1 bis 15 in einer zur Erzeugung einer antipsychotischen Wirkung ausreichenden Menge und einen pharmazeutisch verträglichen Träger umfasst.

18. Depotarzneimittel, das einen pharmazeutisch verträglichen Träger und eine therapeutisch wirksame Menge der Verbindung nach einem der Ansprüche 1 bis 15 umfasst, wobei die Verbindung eine acylierte Hydroxyl- oder 35 Aminogruppe enthält.

19. Mittel nach Anspruch 18, wobei die Hydroxyl- oder Aminogruppe mit einem (C4-C18)-Alkanoyl- oder (C4-C18)- Alkoxycarbonylrest acyliert ist.

40 20. Mittel nach Anspruch 18, das ein pharmazeutisch verträgliches Öl enthält.

21. Mittel nach Anspruch 20, wobei das Öl aus Kokosnussöl, Erdnussöl, Sesamöl, Baumwollsamenöl, Maisöl, Soja- bohnenöl, Olivenöl und Fettsäureestern und polyfunktionellen Alkoholen ausgewählt ist.

45 22. Depotarzneimittel, das einen pharmazeutisch verträglichen Träger und eine therapeutisch wirksame Menge der Verbindung nach einem der Ansprüche 1 bis 15 umfasst.

23. Verwendung einer Verbindung nach einem der Ansprüche 1-15 zur Herstellung eines Medikaments zur Behand- lung von Psychosen oder zur Bereitstellung einer antipsychotischen Langzeitwirkung. 50 24. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, wobei Z ein Sauerstoffatom darstellt, und ihrer pharmazeutisch verträglichen Säureadditionssalze, umfassend die Umsetzung einer Verbindung der Formel:

29 EP 0 833 820 B1

in der X und n wie vorstehend deﬁniert sind, mit einer Verbindung der Formel:

in der HaI ein Brom- oder Chloratom bedeutet, und Y, m und p wie vorstehend deﬁniert sind, in einem polaren, aprotischen, organischen Lösungsmittel in Gegenwart einer Base und eines Katalysators.

20 25. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, wobei Z die Gruppe NH darstellt, und ihrer pharmazeutisch verträglichen Säureadditionssalze, umfassend die Behandlung einer Verbindung der Formel:

30 in der Ts Tosylat bedeutet, und X, Y, m, n und p wie vorstehend deﬁniert sind, mit konzentrierter HCl.

26. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, wobei X die Gruppe -OH darstellt, und Z eine Sau- erstoffatom bedeutet, und ihrer pharmazeutisch verträglichen Säureadditionssalze, umfassend das Erhitzen einer 35 Verbindung der Formel:

45 in der

X einen -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- oder -OC(=O)-(C3-C12)- Cycloalkylrest darstellt, und Y, m, n und p wie vorstehend deﬁniert sind, 50 mit 48 %iger HBr.

Revendications 55 1. Composé de formule

30 EP 0 833 820 B1

10 où

X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)-aryle en C6-C10, -OC(=O)-alkyle en C1-C12-aryle en C6-C10, -OC(=O)NH-alkyle en C1-C18, -OC(=O)-alkyle en C1-C12-cycloalkyle en C3-C8, -OC(=O)O-alkyle en C1- C18 ou -OC(=O)-cycloalkyle en C3-C12 ; 15 Y est H, halogène, triﬂuorométhyle, alcoxy en C1-C6, cyano ou nitro ; Z est O ou NR1 ; R1 est l'hydrogène, alkyle en C1-C6, formyle, -C(=O)alkyle en C1-C18 ou -C(=O)O-alkyle en C1-C18 ; m est 1, 2, 3 ou 4 ; n est 1 ou 2 ; et 20 p est 1 ou 2 ;

et ses sels d'addition d'acide pharmaceutiquement acceptables.

2. Composé selon la revendication 1 de formule 25

35 où

X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18, -OC(=O)O-alkyle en C1-C18 ou -OC(=O)- cycloalkyle en C3-C12 ; Y est l'hydrogène, halogène, triﬂuorométhyle, alcoxy en C1-C6, cyano ou nitro ; 40 m est 1, 2, 3 ou 4 ; et p est 1 ou 2 ; et

ses sels d'addition d'acide pharmaceutiquement acceptables.

45 3. Composé selon la revendication 2, de formule

55 où

X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18, -OC(=O)O-alkyle en C1-C18 ou -OC(=O)-

31 EP 0 833 820 B1

cycloalkyle en C3-C12 ; Y est l'hydrogène ou halogène ; m est 1, 2, 3 ou 4 ; et p est 1 ; et 5 ses sels d'addition d'acide pharmaceutiquement acceptables.

4. Composé selon la revendication 1 qui est un composé de formule

où

20 X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18 ; -OC(=O)O-alkyle en C1-C18 ou -OC(=O)- cycloalkyle en C3-C12 ; Y est l'hydrogène, halogène, triﬂuorométhyle, alcoxy en C1-C6, cyano ou nitro ; m est 1, 2, 3 ou 4 ; et p est 1 ou 2 ; et 25 ses sels d'addition pharmaceutiquement acceptables.

5. Composé selon la revendication 4, de formule

où 40

X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18 ; -OC(=O)O-alkyle en C1-C18 ou -OC(=O)- cycloalkyle en C3-C12 ; Y est l'hydrogène ou halogène ; m est 1, 2, 3 ou 4 ; et 45 p est 1 ; et

ses sels d'addition d'acide pharmaceutiquement acceptables.

6. Composé selon la revendication 1 de formule 50

32 EP 0 833 820 B1

où

15 X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18 ; -OC(=O)O-alkyle en C1-C18 ou -OC (=O)-cycloalkyle en C3-C12 ; Y est l'hydrogène, halogène, triﬂuorométhyle, alcoxy en C1-C6, cyano ou nitro ; R1 est l'hydrogène, alkyle en C1-C6, formyle, -C(=O)-alkyle en C1-C18 ou -C(=O)O-alkyle en C1-C18 ; m est 1, 2, 3 ou 4 ; et 20 p est 1 ou 2 ; et

ses sels d'addition d'acide pharmaceutiquement acceptables.

7. Composé selon la revendication 6 de formule 25

où

40 X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18 ; -OC(=O)O-alkyle en C1-C18 ou -OC (=O)-cycloalkyle en C3-C12 ; Y est l'hydrogène ou halogène ; R1 est l'hydrogène, alkyle en C1-C6, formyle, -C(=O)-alkyle en C1-C18 ou -C(=O)O-alkyle en C1-C18 ; m est 1, 2, 3 ou 4 ; et 45 p est 1 ; et

ses sels d'addition d'acide pharmaceutiquement acceptables.

8. Composé selon la revendication 1 de formule 50

33 EP 0 833 820 B1

où

ses sels d'addition d'acide pharmaceutiquement acceptables.

25 9. Composé selon la revendication 8 de formule

où 40

X est -OH, -OC(=O)-alkyle en C1-C18, -OC(=O)NH-alkyle en C1-C18 ; -OC(=O)O-alkyle en C1-C18 ou -OC (=O)-cycloalkyle en C3-C12 ; Y est l'hydrogène ou halogène ; R1 est l'hydrogène, alkyle en C1-C6, formyle, -C(=O)-alkyle en C1-C18 ou -C(=O)O-alkyle en C1-C18 ; 45 m est 1, 2, 3 ou 4 ; n est 1 ; et p est 1 ou 2 ; et

ses sels d'addition d'acide pharmaceutiquement acceptables. 50 10. Composé selon la revendication 7 ou 8, où m est 3 et Y est 4-ﬂuoro.

11. Composé selon la revendication 10, où X est 6-hydroxy ; 6-OC(=O)NHbutylc, 6-OC(=O)O-hexyle, 6-OC(=O)nonyle ou 6-OC(=O)adamantyle et R1 est l'hydrogène ou -C(=O)nonyle ; et ses sels d'addition d'acide pharmaceutique- 55 ment acceptables.

12. Composé selon la revendication 3 ou 5 où m est 3 et Y est 4-ﬂuoro.

34 EP 0 833 820 B1

13. Composé selon la revendication 12, où X est 6-hydroxy, 6-OC(=O)NHbutyle, 6-OC(=O)Ohexyle, 6-OC(=O)nonyle ou 6-OC(=O)adamantyle ; et ses sels d'addition d'acide pharmaceutiquement acceptables.

14. Composé selon la revendication 13 qui est le 3-[1-(4'-ﬂuorobenzoyl)propyl-4-pipérazinyl]-6-hydroxy-1,2-benzi- 5 soxazole,

le bromhydrate de 3-[1-(4'-fluorobenzoyl)propyl-4-pipérazinyl]-6-hydroxy-1,2-benzisoxazole, l'hexylester de carbonate de (3-[4-[4-(4-fluorophényl)-4-oxo-butyl]-pipérazin-1-yl]-1,2-benzisoxazol-6-yle), l'adamantane-1-carboxylate de 3-[4-[4-(4-fluoro-phényl)-4-oxo-butyl]-pipérazin-1-yl]-1,2-benzisoxazol-6-yle, 10 le décanoate de 3-[4-[4-(4-fluorophényl)-4-oxo-butyl]-pipérazin-1-yl]-1,2-benzisoxazol-6-yle ou le butylcarbamate de 3-[4-[4-(4-flurophényl)-4-oxo-butyl]-pipérazin-1-yl]-1,2-benzisoxazol-6-yle.

15. Composé selon la revendication 11 qui est la 1-[(4-ﬂuorophényl)-4-[4-(6-hydroxy)-1-méthyl-1H-imidazol-3-yl]-pi- pérazin-1-yl]-butan-1-one. 15 16. Composition pharmaceutique qui comprend le composé selon l'une quelconque des revendications 1 à 15 et un support pharmaceutiquement acceptable.

17. Composition neuroleptique qui comprend le composé selon l'une quelconque des revendications 1 à 15 en une 20 quantité sufﬁsante pour produire un effet neuroleptique, et un support pharmaceutiquement acceptable.

18. Composition pharmaceutique retard qui comprend un support pharmaceutiquement acceptable et une quantité thérapeutiquement efﬁcace du composé selon l'une quelconque des revendications 1 à 15 où le composé contient un groupe hydroxyle ou un groupe amino qui a été acylé. 25 19. Composition selon la revendication 18 où le groupe hydroxyle ou amino est acylé avec un groupe alcanoyle en C4-C18 ou un groupe alcoxy en C4-C18-carbonyle.

20. Composition selon la revendication 18 qui contient une huile pharmaceutiquement acceptable. 30 21. Composition selon la revendication 20 où l'huile est choisie dans le groupe consistant en l'huile de coprah, l'huile d'arachide, l'huile de sésame, l'huile de coton, l'huile de maïs, l'huile de soja, l'huile d'olive et les esters d'acides gras et d'alcools polyfonctionnels.

35 22. Composition retard qui comprend un support pharmaceutiquement acceptable et une quantité thérapeutiquement efﬁcace du composé selon l'une quelconque des revendications 1 à 15.

23. Utilisation d'un composé selon l'une quelconque des revendications 1 à 15 pour la fabrication d'un médicament pour le traitement des psychoses ou pour produire un effet neuroleptique de longue durée. 40 24. Procédé pour préparer un composé selon la revendication 1 où Z est O et ses sels d'addition d'acide pharmaceutiquement acceptables comprenant la réaction d'un composé de formule :

où X et n sont déﬁnis comme ci-dessus, avec un composé de formule :

35 EP 0 833 820 B1

où halo est Br ou Cl, et Y, m et p sont déﬁnis comme ci-dessus, dans un solvant organique polaire aprotique en 10 présence d'une base et d'un catalyseur.

25. Procédé pour préparer un composé selon la revendication 1, où Z est NH et ses sels d'addition d'acide pharmaceutiquement acceptables comprenant le traitement d'un composé de formule :

où Ts est tosylate et X, Y, m, n et p sont déﬁnis comme ci-dessus, avec HCl concentré.

26. Procédé pour préparer un composé selon la revendication 1, où X est -OH et Z est O et ses sels d'addition d'acide 30 pharmaceutiquement acceptables comprenant le chauffage d'un composé de formule :

où

X est -OC(=O)-alkyle en C1-C18, -OC(=O)-aryle en C6-C10 ; 45 -OC(-O)-alkyle en C1-C12-aryle en C6-C10, -OC(=O)NH-alkyle en C1-C18, -OC(=O)-alkyle en C1-C12-cycloalkyle en C3-C8, -OC(=O)O-alkyle en C1-C18 ou -OC(=O)-cycloalkyle en C3-C12 ; et Y, m, n et p sont déﬁnis comme ci-dessus avec HBr à 48 %.