PL176230B1 - Method of obtaining heteroarylpiperidinc compounds - Google Patents

Abstract

1. The method of producing hetero-aryl-piperidine compounds with the following general formula (1) IMAGE> where: Y refers to an atom of hydrogen or halogens; R1 refers to R20 R21 or R22, where: R20 refers to -(CH2)n-, where n is equal to 2,3,4 or 5, or refers to -(CH2)n'-, where n' is equal to 1, 2, 3,4 or 5; R21 refers to-CH2-CH=CH-CH2-, -CH2-CH=CH-CH2-CH2-, or -CH2-CH2-CH=CH-CH2- while the -CH=CH- bond is a cis or trans bond; R22 refers to R20 or R21, where one or more than one atom of coal in R20 or R21 is substituted with at least one linear C1-6 alkyl group; Y2 is selected from the group comprising: (2) where R3 refers to hydrogen or lower alkoxyl group, while R20 refers to -(CH2)n-; (3) where R4 refers to hydrogen or lower alkoxyl group, while R20 refers to -(CH2)n-; (4) where R4' refers to R4 or -C(=)-lower alkyl group, while R20 refers to -(CH2)n'-; (5) where either Xy or Xz refers to -C(=0)-, while the other refers to -CH2-; R5' refers to R4 or lower alkoxyl group, while R20 refers to -(CH2)n-; (6) where R4' refers to R4 or -C(=0)-lower alkyl group, while R20 refers to -(CH2)n-;

Description

The present invention relates to a process for the preparation of novel heterotripiperidine compounds. In particular, the invention relates to heterdaryl piperidine compounds having an aatypsychotic effect which are suitable for the preparation and use in antipsychotic drugs.

The treatment of patients with schizophrenia by administering neuroleptic drugs such as chlouopuomtnynα, haloperidol, sulpiride and chemically closely related compounds is widely used. While the symptoms of schizophrenia have been successfully managed, treatment with these drugs does not cure the psychotic patient, who will survive relapse after drug withdrawal. There is an ongoing need for antipsychotic drugs to treat psychosis.

Furthermore, some of the known neuroleptics have undesirable side effects. For example, side effects include so-called extrapyramidal symptoms such as stiffness and jitteriness, constant restless walking, and grimacing dyskinesia.

176 230 and involuntary movements of the face and limbs. Orthostatic hypotension is also usually present. There is therefore a need for antipsychotic drugs that produce less of the symptoms of common side effects or no side effects.

At the same time, there is a need for drugs with a different biological effect. For example, pain relief is the subject of human endeavors over the centuries, which led to the discovery of natural and synthetic painkillers. Nevertheless, to this day, people are looking for safe and effective painkillers.

EP publication 402 644 discloses heteroarylpiperidine and heteroarylpiperazine compounds of the following formula (R) m

\ - (CH ₂ ) _n O

These compounds are close to the piperidinyl derivatives of the invention wherein Y2 is

This structure is excluded from the definition of a Y ₂ substituent. The closest is the structure of formula (9), but the structure differs from the above-mentioned publication in that the substituent Q2 cannot be -O-. Accordingly, the above-cited publication does not disclose or suggest a method of preparing the compounds of the invention.

EP publication 314 098 discloses imide derivatives of the formula below

where A is carbonyl or sulfonyl; B is the structures disclosed on pages 2 and 3; W is a lower alkylene group, a lower alkenyl group, a lower alkynylene group, or a lower alkylene group substituted with a hydroxyl group; G is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxyl. These compounds are similar to the compounds of the invention where Y2 is

176 230

This structure is excluded from the definition of the substituent Y2. The closest structure is formula (7), but the structure of formula (7) differs from that disclosed in the above-mentioned publication in that the known structures do not allow B to be a phenyl group when A is a carbonyl group. Moreover, the definition of R 1 in formula (7) does not include hydrogen, which is required for the structure of one of the substituents R 1 or R 2. Thus, publication EP 314 098 also does not disclose or suggest a process for the preparation of the compounds of the invention.

The compounds of the invention are useful as antipsychotics and analgesics. These compounds can have a wide variety of substituents and chemical groups. As used herein, the term "lower" is used in connection with the description of a particular group and means that the group contains from 1 to 6 carbon atoms.

The term "alkyl" refers to a straight or branched saturated hydrocarbon group, for example methyl, ethyl, isopropyl, 2-butyl, neopentyl or n-hexyl.

The term "alkoxy" refers to a monovalent substituent consisting of an alkyl group linked through an ether oxygen atom and having a free bond on the oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy or pentoxy.

Unless otherwise specified, the term "halogen" refers to a member of the halogen family of the group consisting of fluorine, chlorine, bromine and iodine.

Throughout the description and complex claims, a given chemical formula or name should include all geometric, optical and steric isomers, if they exist.

A. The inventive process for preparing compounds

The present invention relates to a process for the preparation of heteroarylpiperidine compounds of the following general formula (1)

wherein

Y is hydrogen or halogen;

Rj is R2 ₀ , R21 or R22 where

R 20 is - (CH 2, - wherein n is 2,3,4, or 5, or

- (CH2 - where rf is 12,3,4 or 5 '

R21 is -CH2-Ch = CH-CH2-,

-CH2-CH = CH-CH2-CH2-, or

-CH2-CH2-CH = CH-CH2- wherein the bond -CH = CH- is cis or trans;

R22 is R20 or R21 in which one or more than one carbon atom of R 20 or R ₂ 1 is substituted by at least one linear alkyl group C;

Y2 is selected from the group consisting of:

(2)

where R ₃ is hydrogen or a lower alkoxy group and R 20 is - (CH 2), -;

176 230 (3)

wherein R ₄ is hydrogen or a lower alkoxy group and R 2 ₀ is - (CH 2) -; (4)

where R4 'is Rj or -C (= O) -loweralkyl and R20 is - (Cr) -'-; (5)

wherein one of Xy or X _z is -C (= O) - and the other is -CH2-; R 5 'is R ₄ or lower alkoxy group, and R20 is - (CH2>-;

(6)

ABOUT

-AND

H.

R wherein R ₄ 'is R ₄ or -C (= O) loweralkyl and R 20 is - (Ou) -; (7)

(R '% where R f is lower alkyl, lower alkoxy, halogen or nitro; q is 1 or 2; and R 20 is - (CH 4 -;

(9) (R),

-mO>

176 230 wherein Q 'is -S- or -NH-; R is hydrogen, lower alkoxy, lower alkoxy, hydroxy, or -C (= O) -alkyl; m is 1 or 2 and R ' _O is - (CHA-;

(10)

wherein R'o is - (CHA-;

(11) -O-R 12 wherein R ₁₂ is selected from hydrogen, loweralkyl, -C (^ = O) - (C ₁ _ ₁ 2 linear or branched alkyl) group or -C (= O) - NR ₁₃ R _14, wherein RMjest selected from hydrogen and alkyl groups C _M2; R ₁₄ is selected from hydrogen and Ο _μΐ2 alkyl groups, u R _m is - (CHAs (12) -1NR ₈ R ₁₉ where RM is selected from hydrogen, C1.12 straight or branched alkyl groups -C (= O) - O- (C1.12 alkyl), and groups -C (= O) - (C1.2 alkyl); u

RM is independently selected from straight or branched C ₁₄₂ alkyl groups, -C (= O) -O- (C 1-12 alkyl) groups and -C (= O) - (C 1-12 alkyl) groups, or the entire NR 1 R 6 moiety forms a ring structure selected from piperidinyl, morpholinyl or piperazinyl and R20 is - (CHA-;

(13) -S-RR wherein R ₁₂ 'is hydrogen, a lower alkyl group, or a -C (= O) alkyl group and R _M is - (CHA-;

all geometric, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salts thereof, characterized in that the compound is reacted

wherein Y is as hereinbefore defined, under the conditions of alkylation with a compound of formula (15) Hal (R ₁₎ - (Y ₂₎ wherein R 1 and Y 'May ąznaczenia previously defined and Hal is chlorine, bromine, j by or an equivalent leaving group is methanesulfonyloxy (mesyloxy).

The following compounds are obtained with particular preference by the process according to the invention described above

6-fluoro-3 - [1- [3 - [(5-methoxy-1H-indol-6-yl) oxy] propyl-4-piperidinyl] -1,2-benzisoxazole; 6-fluoro-3- [1- [3 - [(1 -H-indol-7-yl) oxy] propyl] -4-piperidinyl] -1,2-benzisoxazole hemifumarate;

6-b6 oro-3 [1- (3-hydroxy) propyl-4-piperidin; 6-bh] <1,2-benzis.oxazole;

6-fluoro-3 - [1- (2-pyrimidinoxy) propyl] -4-piperidinyl] -1,2-benzisoxazole fumarate;

6-aceto-2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidine] methyl-1,4-benzodioxane;

2- [4- (6-fluoro-1,2-benzisoxuzol-3-yl) -1-piperidinyl] methyl-1,4-benzodioxane;

2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-1,4-benzodioxane;

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6- (6- (4- (6-fiboro-1,2-benzocechol-3-yl) -1-piperidinyl] propokey] -7-meth4-cy-1-tztoclzn;

N-3- [4- (6-fluoro-1,2-benzisocechol-3-10) -1-aiaeoydy.nyi] propyl-6-caetyl-2-benzodk-folinone;

N- [4- [4- (6-fluoro-1,2-benkikokecko-6-yl) -1-piperidinyl] butyl] -phthalivide;

- [4- [3 - [4- (6-fluoro-1,2-benkikokeco-6-yl) -1-piperidinyl] thio-3-methocyphenyl] -ethanone;

- C4- [3- [4- (6-fluoro 1, OrOer 2: 1 - 2 - 4 - 6 - C 1) -1 - piperidase 1 d] propyl-ohmino-3-me-tocyphenyl] ethαnon;

- [4- [3- [4- (6-fluoro-1,2 ^ ^ O ^ - / 010-3-H] -1 epipeoyidinyl] poopyltin] -3 -hydrocyphenylen] etcnon;

2- [4e (6-fluo-1,2-benzisoxyc] 1r-6-yl) -1-pipoyidinyl] ethylb acetate fumcrcn; N- [2- (4e (6-fluoro-r, 2-benki2; okecko-3-yl) -1-piperinyl] ethyl] vorpholine; Ne [2- (4- (6-fluoro-1,2-benzicocechol-6-yl) ) -1-piperidinyl] ethylphthalide, fum-rcn 2e [4- (6-f] boron-1,2-benzisoxchol-3-yl) -1-piaeoyoyoyl] ethyl ether;

fumcrcn 4e [4e (6-fluoro-1,2-benzisocecco-6-yl) -r-pipzridinyl] bbtyl acetate; fumcrcn U2-fluoro-1,2ebznkizok-azo1oe3-i.I (r) -1-aipzryOyny1o] bbtcno1b; fumcrcn 2e [2- [4- (6eflboron, 2-benzoisoceco-6-yl) -1-epiρeridinyl] ethyl] -1β-dioxane; hewifbwcrcn 2- υ - ^ - ΑηοΓΟ-1 ^ -benzisoxchol-S-yl) -1 epiperidin1o] etcno1b; hewiftlwcran 2- [4- (6-ί '^ ι ^ ι ^) ^ <^ - 1,2-benzisoceczo1oe6-yl) -1 epipeoyidin1o] eth1quin; fumcrcn (S) - (+) e3e [4- (6-fluoro-1,2-benzisoceczo6-i10) -1-piperidinyl] -2-methyl-1e

-propanol;

difbm: crcl4e (6efluoΓ0-1.2bznzisoxico-6-yl) -re (3- (1-pipeoyidinyl) propy-10] piperidine;

ditu-rcn re (3eOimety1ocminopooay1o) -4- (6-fluoro-1,2-benzisox; cyclo-3-yl) aiperidine; fumcrcn (R) - (-) - 6e4 - [(6-fluoro-1'-benzisoxchol-1-yl) -1-aiperidinyl] -2-vetyl-1-aopcno1b;

6eflboro-6- [1- [6 - [(1Hemdo10-5-10) okey] propy-10-4-aiperidinyl] -1,2-benkozizocco1; 6-fluoro-6 - [1- [3 - [(1 Hemdo-4-clay) okey] aoopy10] -4-pipzoyidinyl] -1,2-bznzozizokeczo1; hewifUwcuan 6eflboro-3- [1e [(3e [(6-wet: oxy-1H-mdo1o-5eyl) okey] aropyl] e4epipeoydye nyl] -1,2-benzozizoecoolo;

fumcrcn 3 - [4- (6efluoIΌ-1,2-benzo-isoxo-3-yl) -1-epiperidinyl] -2,2-dimethyl-1-proacno;

fum-rcn thiooctc ^ u 2e (4- (6eflboro-1,2-benzosiphoxo-3-yl) -1-piperidinyl); Dc1ekw eaoeobem according to the invention is a process for the preparation of heteoacrylpipyridine compounds of the following general formula (16)

wherein

Y is hydrogen or halogen;

R1 is - (CH2), - wherein n is 2,3,4 or 5; its distinct geometric, optical, and stereoisOmers, or far-Baltic acceptable acid addition salts, characterized by the fact that a compound is decanted

176 230

wherein Y is as defined above, under alkylation conditions with N- (bromo) - (CH2) n-phthalimide in which n is as defined above.

A further process according to the invention is a process for the preparation of heteroarylpiperidine compounds of the following general formula (18)

wherein

Y is hydrogen or halogen;

R is R0, R21 or R5 where

R20 is - (CHR - wherein n is 2,3,4 or 5; R21 is -CR-CH = CH-CR-,

-CR-CH = CH-CR-CR-, or

-CR-CR-CH = CH-CR- wherein the bond -CH = CH- is cis or trans;

R22 is R20 or R21 wherein one or more hydrogen atoms of a carbon R20 or R2 _] is substituted with at least one C _w linear alkyl group;

Rn is selected from -C (= O) - (C1_ ₁₂ linear or branched alkyl), or -C (= O) -NR Ri4 _13, wherein R _N is selected from hydrogen and alkyl groups C1_ _12; R _M is selected from hydrogen and alkyl groups C _M 2, the all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salts, characterized in that a compound (19)

in which Y is as defined above, under alkylation conditions with a compound of formula (20)

Hal '- (C = O) - (C1_12 straight or branched alkyl), or with a compound (21) Hal' - (C = O) -NR ₃ R ₄ ;

or with a compound (22) (C1-12 straight or branched) alkyl-N = C = O wherein R _B and R are as previously defined and Hal 'represents chlorine or bromine.

176 230

With the particularly preferred process according to the invention described above, the following compounds are obtained;

4- [1 - 1 - fluoro-1,2-benzozisoxazole-3-yl) -1-piperidinyl] butyl decanoate phthimarate; 3 - [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1-piperidinyl] propyl decanoate fumarate; N, N-diethyl-4- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] butyl carbamate fumarate;

N-methyl-4- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] butyl carbamate fumarate;

2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl decanoate fumarate; N, N-diethyl-2- [4- (6-fluoro-1,2-benzosisox; azole-3-yl) -1-piperidinyl] ethyl carbamate fumarate;

Acetate fumarate (R &lt; 5 &gt; C - &lt; - &gt; -fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] -2-methyl-1-propyl;

A further process of the invention is a process for the preparation of heteroarylpiperidine compounds of the following general formula (23)

wherein

Y is hydrogen or halogen;

R 1 is R ₂ o, R ₂ 1 or R ₂₂ where

R ₂₀ is - (CH ₂ ) _n - wherein n is 2, 3, 4 or 5;

R ₂ 1 is -Ch ₂ -Ch = CH-Ch ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -, or

-CH2-CH2-CH = CH-CH2- wherein the -CH = CH- bond is cis or trans;

R22 is R20 or R21 wherein one or more carbon atoms

R20 1 or R ₂ is substituted by at least one linear alkyl C16

R18 and R) 9 are independently selected from -C (= O) -O- (C ₁ 12 alkyl), and -C (= O) - (C 12 alkyl);

all geometric, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salts, characterized by reacting compound (24)

wherein Y and R 1 are as defined above, at alkylation conditions with a compound of formula (25) toughened (CoO) - (Cu ₂ alkyl); or (26) Ηβ ^ Ο ^ ι-π alkyl) wherein Hal 'is chlorine or bromine.

176 230

The following compounds are particularly preferably obtained with the process according to the invention described above:

2- [4- (6-fluoro-1,2-benzosisoxazole-3-10) -1-piperidinyl] ethyl decanamide fumarate; 2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl acetamide fumarate; methyl 2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethylcarbamate fumarate;

A further process of the invention is a process for the preparation of heteroarylpiperidine compounds of the following general formula (27)

wherein

Y is hydrogen or halogen;

R1 is R20, R21 or R22 where

R20 is - (CHL), - wherein n is 2,3,4 or 5;

R21 is -Ch ₂ -Ch = CH-Ch ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -, or

-CH ₂ -CH ₂ -CH = CH-CH ₂ - wherein the -CH = CH- bond is cis or trans;

R 22 is R ₂ or by R 21 in which one or more than one carbon atom

R ₂ o or R ₂₁ is substituted with at least one linear C 1-6 alkyl group;

R _t 2 is selected from lower alkyl, lower alkoxy, halogen and nitro groups, p is 1 or 2;

all geometrical, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salts thereof, characterized by reacting compound (28)

wherein Y and R are as defined above, under alkylation conditions with an anhydride of formula

(29)

O or with phthalic acid of formula: (30)

wherein R and q are as previously defined.

The following compounds are particularly preferably obtained with the process according to the invention described above:

N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -4,5-dichlorophthalimide;

N- [2- [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1-piperidinyl yethyl] -3,6-dichlorophthalimide;

N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-pipyridinyl] ethyl] -4-chlorophthalimide; N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -3-fluorophthalimide; N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -4-fluorophthalimide; N-2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -4-methylphthalimide; N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -4-methoxyphthalimide;

N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -4-mtrophthalimide;

B. Preparation of intermediates

1. Preparation of 3- (1-disubstituted-4-piperidinyl) -1,2-benzisoxazoles

Compound of formula (14)

can be produced on the basis of several descriptions. For example, U.S. Patent No. 4,355,037 contains a detailed description of the compounds of formula (14) and methods for their preparation. Additional description of methods for the preparation of compounds of formula (14) can be found in U.S. Patent No. 4,327,103 and Strupczewski et al. J. Med. Chem., 28: 761: 769 (1985). Compounds of formula (14) can be used in the synthesis of the benzisoxazole substituted piperidines of the invention.

2. Produces 3- (unconditioned-4-pipe4ydynyy) -1,2 ~ ben2isotiazzli

Some 3- (4-piperidinyl) -1,2-benzisothiazoH can be used in the synthesis of heteroaryl piperidines, in particular the benzisothiazole of formula (17)

CH NH

S can be reacted with the described alkylating agent to provide the heteroaryl piperidines of the invention. The compounds of formula (17) and their methods of preparation are described in detail in US Patent No. 4,458,076.

3. Preparation of alkylating agents

Compounds described in Part A can be reacted with alkylating agents of the formula:

(15) Hal- (R 1) - (Y 2) to form heteroaryl piperidines.

The procedures for preparing the alkylating agents of Formula 15 are described in the following examples. These procedures can be used to prepare other alkylating agents for use in the present invention.

4. Alkylation of Heteroaryl Piperidines, The heteroaryl piperidines described in Part A can be reacted under the alkylation conditions described in Item 3 to provide compounds of the present invention. The reaction can be carried out by dissolving the reactants in an inert solvent such as dimethylformamide, acetonitrile or butanol and allowing the reactants to react at 50 ° C to the reflux temperature of the solvent in the presence of an acid acceptor such as a base. Examples of suitable bases are alkali metal carbonates such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction may be carried out in the presence or absence of a catalytic amount of an alkali metal iodide such as. potassium iodide or sodium iodide for a sufficient time to form the compound of formula (I) of the invention. Generally, the alkylation reaction takes from about 4 to about 16 hours depending on the activity of the reactants. The reaction temperature may vary from about 50 ° to about 120 ° C. The products can be isolated by treating the product with water, extracting the product into a water-immiscible organic solvent, washing, drying, and concentrating to give the free base, then converting the compound into an acid addition salt by conventional means.

5. Preparation of the acylating agent

The compounds described in parts -3, A4 or A5 can be reacted with acylating agents of the following formulas:

(twenty)

Hal '- (C = O) - (C112 straight or branched alkyl), (26)

HaT-CO— (C _r C ₁₂ ) aIkXi O (21)

HaT — C — NR, ₃ R ₁₄ Feb ^{13 14} O (22).

^(C 1-12 straight or branched) alkyl-N = C = O (29)

or

176 230

to give the heteroarylpiperidines obtainable by the process of the invention. Methods for preparing acylating agents are described in the chemical literature and in the following examples. These methods may be used to prepare other acylating agents for use in the process of the invention.

6. Acylation of heteroarylpyridines to provide compounds according to the invention.

The heteroarylpyridines described in parts A3, A4 and A5 can be acylated with the above-described acylating agent to provide compounds according to the invention. The reaction can be performed by dissolving the reagent in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, acetonitrile and allowing the starting compound to react at a temperature from room temperature (approximately 22 ° C) to the reflux temperature of the solvent. Typically, when an acid such as H-Hal is formed in the reaction, an acid acceptor, such as a base, is added to the reaction mixture. Examples of the suitable base include alkali metal carbonates such as potassium carbonate, sodium carbonate, or sodium bicarbonate; inorganic bases such as potassium hydroxide; organic bases such as triethylamine, and alkali metal alkoxylates such as potassium tert-butoxide. For acylations using phthalic acid, a coupling agent such as dicyclohexylcarbodiimide is added to complete the reaction. Typically, the acylation reaction is performed for from about 20 minutes to about 18 hours. The reaction temperature may vary from about room temperature (approximately 22 ° C) to the reflux temperature of the solvent. The resulting heteroaryl piperidines can be isolated by treating the reaction mixture with water, extracting the product into an organic solvent that is miscible with water, washing, drying and concentrating the organic solvent to isolate the product. The product may be further purified by crystallization or chromatography. If the product is a free base it may alternatively be further purified by conversion to the acid addition salt in a conventional manner.

The compounds of the present invention are useful in the treatment of psychoses due to their ability to elicit an antipsychotic response in mammals. Antipsychotic activity is determined in a mouse climbing test in a manner similar to that described by P. Protais et al., Psychopharmacol., 50: 1 (1976) and B. Costalla, Eur. J. Pharmacol., 50:39 (1978).

Male CK-1 (23-27) g mice were grouped under standard laboratory conditions. The mice were placed one at a time in wire cages (4 x 10) allowing them to adapt for an hour and explore the new environment. They were injected subcutaneously with apomorphine at a dose of 1.5 mg / kg, causing all mice to climb for 30 minutes. Compounds with antipsychotic activity. were tested, injected intraperitoneally or administered with food at various time intervals, e.g., 30 minutes, 60 minutes, prior to administration of apomorphine at a protective dose of 10-60 mg / kg.

176 230

To assess the climb, 3 readings at 10, 20 and 30 minutes were recorded according to the following scale:

The climbing behavior of mice with: rating 4 paws on the bottom (does not climb) 0 2 paws on the wall (on hind legs) 1 4 paws on the wall (climbs) 2

Mice stubbornly climbing prior to apomorphine injection were discarded.

With fully developed apomorphine climbing, animals hang from the cage walls in relative motionlessness for extended periods of time. In contrast, climbing associated with normal motor stimulation usually only takes a few seconds.

The climbing scores were individually summed (maximum score for mice: 6 in three readings) and the total sum of the controls (intraperitoneal vehicle - apomorphine subcutaneously) was taken as 100%).

Tables 1 and 1A show ED50 values with 95% confidence intervals calculated by linear regression analysis for certain novel compounds of the invention as well as standard antipsychotics.

Table 1

Relationship Mouse climbing test (ED 50 mg / kg, Dortenoid) 2- [4- (6-fluoro-1,2-beazi.z; oxstnol-3-yl) -1-piperOyaylo] eOyld-1,4-benneioxane (example 7) 0.29 6-fluoro-S - [1- (3-hydroxypropyl) -4-piperidyl] -2. , 2-beazinoxstnol (example 3) 4.1 decaaoaau fumarate 4- [4- (6-fluoro 2-beaninrxazol-3-yl) -1-nyljbutyl piperid (example 20) 3.31 N- [2- [4- (6-fluoro-1,2-beanisoxazol-3-yl) -2-piperdylylr] ethyl] phthalimide (example 16) 5.0 chlorprrmanynt (pattern) 1.3

Table 1A

Relationship Mouse climbing test (ED50 mg / kg, ip) 1 2 6-fluorr-3- [1- [3 - [(5-methxy-2H-mdol-6-yl) oxy) propyl] -4-pyridyl] -1,2-beazizrxazole (Example 1) 2.7 hemifUmaΓan6-flurrr-3- [1- [3 - [(1H-iadrlo-7-yl) oxy] propyl] -4-pipelidinyl] -1,2-beaninrxαnrlu (Example 2) 2.2 6-furrr-3- [2- [3 - [(1H-indol-5-yl) oxy] propyIo] -4-piperidinyl] -1,2- -benzizrkstnrl (Example 36) -100% in a dose of 1 dortrnewaowre 6-fluorr-3- [2- [3 - [(2H-iadrlo-4-yl) oxy] propyl] -4-piperidinyl] -1.2- -beazinrksαnol (Example 37) -90% at a dose of 10 i.p. hemifumίt'an6-flurro-3- [2- [3 - [(6-methoxy-2H-iaOolr-5-yl) oxy] propyl] -4-piperidinyl] -1,2-beanisrxαnrlu (Example 38) -100% in a dose of 1 i.p.

176 230

cont. Table 1A 1 2 6-fluoro-3- [1- (2-pyrimidinoxy) propyl] -4-piperidine- fumarate- Io] -1,2-benzisoxazole (Example 4) 0.23 6-aceto-2- [4- (6-fluoro-1,2-benzisoxazoy-3-yl) -1-piperidinyl] methyl-1,4-benzodioxane (Example 5) 13.69 2- [4- (6-fluoro-9,2-benzisoxazole-3-i-l) -1-piperidinyl) methyl-9,4-benzodioxane (Example 6) 6- [3- [4- (6-fluoro-9,2-benzisoxazoy-3-yl) -1-piperidinyl] propoxy] -7-methoxy-1-tetralone (Example 8) 4.9 2.3 N- [3- [4- (6-fluoro-9,2-benzisoxazole-3-yl) -1-piperidinyl] propy- Io] -6-acetyl-2-benzoxazolinone (Example 9) -15% at a dose of 20 i.p. N- [4- [4- (6-fluoΓO-9,2-benzisoxazole-3-10) -9-piperidinyl] butyl] - phthalimide (Example 10) -71% at a dose of 20 i.p. N- [2- [4- (6-fluoro-1,2-benzisothiazol-3-yl) -9-piperidinyl] ethyl] phthalimide (Example 43) 0.38 N- [2 - [^ - (^^: f ^^^ jro-1,2-b ^ nzizokisa ^ oily - ^: ^^^ l ^ o) -1-piperidinyl] ethyl-3,6- -dichlorophthalimide (Example 44) -15% at a dose of 20 i.p. N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -4- -chlorophthalimide (Example 45) 10.6 N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -9-piperidinyl] ethyl] -3- -fluorophthalimide (Example 46) 6 N- [2- [4- (6-fluoro-9,2-benzisoxazol-3-yl) -9-piperidinyl] ethyl] -4- -fluoroffalimide (Example 47) 1.3 N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -4-m.e- Tylophthalimide (Example 48) 0.67 N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -4-ni- trophthalimide (Example 50) 3.5 1- [4- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propy- Io] thio] -3-methoxyphenyl] ethanone (Example 11) -81% at a dose of 20 i.p. 1- [4- [3- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propylam- no] -3-methoxyphenyl] ethanone (Example 12) 0.26 2- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-1 -1,3-dioxane fumarate (example 24) 2.0 2- [4- (6-Fluoro-1,2-benzisoxazole-3-yl) -1-piperidine acetate fumarate- lo] ethyl (Example 14) 2.4

176 230

cont. Table 1A 1 2 2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidine acetate fumarate- lo] ethyl (Example 14) 2.4 methyl ether fumarate 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-pip- ridinyl] ethyl (Example 17) 62 4- {4- (6-f] uoro-1,2-benzisoxazol-3-yl) -1-piperidine acetate fumarate lo] butyl (Example 18) 1.36 4- [4- (6-fuoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] - fumarate butanol (Example 19) 0.81 3- [4- (6-Fluoro-1,2-lbenzisoxazol-3-yl) -1-piperidate decanoate fumarate nyl] propyl (Example 21) -46% at a dose of 10 i.p. N, N-diethyl-4l {4- (6-fluoro-1,2-lbenzisoxazol-3l-yl) -1-pi] p ^ ir < y &lt; y &lt; n &gt; ) 0.213 N-Methyl - N - [4- (6-fluoro-1, 2-benzisoxazole-3-yl) -1-piperidinyl] butyl carbamate fumarate (Example 23) 0.22 2- [4- (6-fluoro-1,2-benzisoxazole-3-clay) -1-piperidine hemifumarate- lo] ethanol (Example 25) 4.1 2l [4- (6l-fluoro-1,2-lbenzisoxazol-3-yl) -1-piperid- decanoate fumarate nyl] ethyl (Example 26) -28% o in a dose of 10 i.p. N, N-Diethyl-2- [4- (6-fluoro-1,2-benzisoxazole-3-yl) -1.-piperidium- fumarate nyl] ethyl carbamate (Example 27) 3.9 (S) - (+) - 3- [4- (6-f ^ uoi ^ i ^^ 1,2-benzisoxazole-3-iio) -1-piperidinyl] -2-me: t ^] ^^^ 1-propanol (Example 32) 7.9 (R) - (1) -3- [4- (6-fluoro-1'-benzisoxazol-S-yl) fumarate -! -piperidinyl] l2-methyl-1-propanol (Example 35) 1.7 (R) - (-) - 3L (4- (6-fluoro-1,2-lbenzisoxazol-3-yl) -1-piperidinyl] -2-methyl-1-propyl acetate fumarate (Example 39) 1.8 3- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] 1,2,2-dimethyl-1-propanol fumarate (Example 40) 6.3 4- [4- (6-fluorol, 1,2-benzisoxazol-3-yl) -1-piperidinyl) -2-methyl- fumarate lo, 4 -hydroxybutane (Example 51) 0.35 N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] - morpholine (Example 15) 3

176 230 cd. Table 1A

1 2 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-prperidecanamide decanamide fumarate nyl] ethyl (Example 29) -43% at a dose of 20 i.p. 2- [4- (6-Fluoro-1,2-benzisoxazole-3-yl) -1-prperidium acetamide fumarate nyl] ethyl (Example 30) 2.34 Methyl 2- [4- (6-fluoro-1'-benazoxazole-1-yl] -piperidinyl] ethylcarbamate fumarate (Example 31) 0.5 diffmarjn 4- (6-fluoro-1 ^ -benzisoxazole ^ -yl] -l-p-U-piperidine- Io) propylJpiperidine (Example 33) -33% at a dose of 20 i.p. 1- (3-dimethylaminopropyl) -4- (6-phloro-1,2-benzisocazole) difumarate N-yl-1-steridine (Example 34) -31% at a dose of 20 i.p. Chlorpromazine (standard) 1.3

The antipsychotic response is achieved when the compounds are administered to a patient in need of such treatment as effective orally, parenterally or intravenously from 0.01 to 50 mg / kg body weight per day. However, it should be understood that the dosage regimen of a particular patient should be tailored to the individual needs of the individual and the professional judgment of the person administering or supervising the administration of said compound. It should further be understood that the doses provided herein are exemplary only and do not in any way limit the scope or practice of the invention.

Some of the compounds of the invention are useful as analgesics due to their ability to relieve pain in mammals. Analgesic usefulness was demonstrated in the phenyl-β-quinone pain test in mice, standard in analgesic studies: Proc. Soc. Exptl. Biol. Med., 95: 729 (1957).

Analgesia is achieved when the compounds according to the present invention are administered to a patient in need of such treatment at an effective oral, parenteral or intravenous dose of 0.01 to 100 mg / kg body weight. However, it should be understood that the dosage regimen of a particular patient should be tailored to the individual's needs and the professional judgment of the person administering or supervising the administration of said compound. It should further be understood that the dosages provided herein are exemplary only and do not in any way limit the scope or practice of the invention.

Effective amounts of the novel compounds can be administered to the patient in several ways, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.

The compounds of the present invention which are effective as such may be prepared and administered in the form of their pharmaceutically acceptable acid addition salts for the purposes of imparting stability, facilitating crystallization, improving solubility, and the like. Preferred pharmaceutically acceptable acid addition salts include salts of mineral acids, e.g., hydrochloric, sulfuric, nitric, and the like, salts of monobasic carboxylic acids, e.g., acetic acid, propionic acid, and the like, salts of dibasic carboxylic acids, e.g., maleic acid, fumaric acid, and the like. the like, salts of tribasic carboxylic acids, e.g., carboxysuccinic, citric, and the like.

Effective amounts of the compounds can be administered orally, e.g. with an inert diluent or with an edible carrier. They can be closed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds according to the invention can be combined with ex

And used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending on the particular form and may conveniently be from 4% to about 70% by weight of the serving. The amount of active compound in such a composition is such as to achieve proper dosage. The recommended compositions and preparations are prepared so that a portion for oral administration contains 1.0-300 mg of active compound.

The tablets, pills, capsules and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin, a diluting agent 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 Sterotes, a lubricant such as colloidal silicon dioxide, and a sweetener such as sucrose, a flavoring agent such as mint, methyl salicylate, or orange essence. When the dose is in the form of a capsule, it may contain, in addition to the substances mentioned, a liquid carrier such as a vegetable oil. Other dosage forms may contain various substances to modify the physical dosage form, for example, coatings. Thus, tablets and pills may be coated with sugar, shellac or other edible coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, flavors. Materials used for these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the active compound of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but the amount may vary from 0.5 to about 50% by weight. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Recommended compositions and preparations are prepared such that a dose for parenteral administration contains from 0.5 to 100 mg of the active compound.

The solutions or suspensions may also contain the following ingredients; sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfide, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrate or phosphates, and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation can be contained in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

The following examples are for the purpose of illustration only and are not intended to limit the invention in any way. All temperatures are in degrees Celsius (° C) unless otherwise stated.

Example 1

6-fluoro-3- [1- [3 '- [(5-methoxy-1H-mdol-6-yl) oxy] propyl] -4-] piperidinyl] -1,2-benzisoxazole (A) 6- (3 -chloropropoxy) -5-methoxyindole

To a nitrogen hydride suspension (0.94 g, 19.6 mmol of a 50% oil suspension) in dimethylformamide (20 ml) stirred under nitrogen at -5 ° C, 5-methoxy-6-hydroxyindole (3.2 g , 19.6 mmol) dissolved in dimethylformamide (60 ml) so that the temperature does not exceed -2 °. After the addition was complete, the mixture was stirred at 0 ° for 45 minutes. Maintaining the temperature from -5 to 0 ° C, a solution of 1-bromo-3-chloropropane (3.1 g, 19.6 mmol) in dimethylformamide (15 ml) was slowly added. The mixture was stirred at room temperature under nitrogen for 21 hours. It was cooled in an ice bath and water was added to remove excess sodium hydride, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried with MgSO _4, and concentrated to yield 5.3 g of a dark oily liquid. This was combined with an additional sample, a total of 10.0 g, and purification by preparative HPLC (Waters Associates Prep LC / system 500) gave 5.1 g of a tan solid. A 2.5 g sample was recrystallized from isopropyl alcohol to give 1.1 g (30%) 6- (3-chloropropoxy) -4-methoxyindole as beige crystals, mp 73-75 ° C.

17 (5230

Analysis.:

Calculated for ^^ 0 ^ 2 60.13% C 5.89% H 5.84% N

Found: 60.26% C 5.86% Ή 5.77% N (B) 6-fluoro-3- [1- [3 - [(5-methoxy-1H-indol-6-yl) oxy] propyl] -4 -piperidinyl] 1,2-benzisoxazole

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (2.5 g, 11.5 mmol), 6- (3-chloropropoxy) -5-methoxyindole (2.5 g, 10.4 mmol), K2CO3 (1.6 g, 11.5 mmol), KI (200 mg), and acetonitrile (100 ml) were heated under reflux for 40 hours. The cooled reaction mixture was poured into water, washed with brine, dried over Mg2-4 and concentrated to give 4.0 g of a solid. The compound was recrystallized from ethanol to give 3.3 g of product. Recrystallization from ethanol (using carbon treatment) gave 2.9 g (66%) 6-yluoro-3- [1- [3 - {(5-methoxy-1H-indol-6-yl) oxy] propyl] - 4-piperidinyl | -1,2-benzisoxazole as a beige solid, mp 156-158 ° C.

Analysis:

Calculated for (^ 2 ^ 303: 68.07% C 64% H 9.92% N

Found: 67.89% C 6.07% H 9.91% N

Example 2 6-fluoro-3- [1- [3 - [(1H-indol-7-yl) oxy] propyl] -4-piperidinyl-1,2-benzisoxazole hemifumarate (A) 7- (3-chloropropoxy) indole

To a nitrogen hydride suspension (0.8 g, 0.017 mol 50% oil suspension) in dimethylformamide (20 ml) stirred under nitrogen, 7-hydroxyindole (2.1 g, 0.0157 mol) in dimethylformamide (20 ml) was added dropwise. . After the addition was complete, the mixture was stirred at room temperature for 0.5 hours and then cooled to 15 ° C. To the cooled solution was added dropwise 1-bromo-3-chloropropane (2.5 g, 0.0157 mol) in dimethylformamide (5 ml). The mixture was stirred at room temperature under nitrogen for 16 hours. It was then poured into water, followed by extraction with ethyl acetate. Ethyl acetate was washed with water, dried (MgSO 4), and concentrated to a dark brown oil. Flash chromatography on silica gel gave 7- (3-chloropropoxy) indole as a colorless oil, 1.0 g.

Analysis:

Calculated for C 11 H Cl NO 63.01% C 5.77% H 6.68% N

Found: 63.25% C 5.61% H 6.65% N (B) 6-fluoro-3- [1- [3 - [(1H-indol-7-yl) oxy] propyl] -4- hemifumarate piperidinyl] -1,2-benzisoxazole

Mixed mixture of 7- (3-chloropropoxy) indole (3.5 g, 0.017 mol), 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (3.5 g, 0.017 mol), K ₂ CO 3 (2.3 g) and acetonitrile (60 ml) was heated to reflux for 11 hours. The mixture was poured into water and extracted with ethyl acetate. Ethyl acetate was washed with water, dried (MgSO4) and concentrated to give a dark oil. The oil was flash chromatographed on silica gel. Concentration of the appropriate fractions yielded 3.0 g of a white, foamy material. The material was dissolved in ethyl acetate (75 mL) and fumaric acid (0.97 g, 0.083 mol) was added. The mixture was rapidly heated to reflux and stirred at room temperature for 1.5 hours. The resulting insoluble salt was collected to give 4.2 g of product. Recrystallization of the salt from dimethylformamide gave 3.1 g (36%) 6-fluoro-3- [1- [3 - [(1H-indol-7-yl) oxy] propyl] -piperidinyl] -1,2-benzisoxazole hemifumarate in white solid, mp 213-215 ° C.

Analysis:

Calculated for C25H26FN3O4: 6640% C 5.80% H 9.31% N

Found: 66.23% C 644% H 9.39% N

Example 3

6-fhioro-3- [1 - (3ehydeoxy) propy1oe-4-piaeryOyny1o] -r, 2-benkizoxcfol

Meal 6-fluoro-3- (4-piperidinyl) -r, 2-benziso] Cscfol (10.0 g, 0.045 mol),

K ₂ CO ₃ (10.0 g), 3-boomo-1-aooacno1b (7.3 g, 0.046 mol) and acetonitrile (200 ml) were heated under reflux for 3 hours. The meat was poured onto water and 7.1 g of a beige solid was collected. Filter the ecchloromethane with dichloromethane and, after concentration, collect 6.7 g of a crude solid. The solids were combined and triturated under the boiling point of ethyl acetate to give 8.0 g of 6eflbOuo-6- [1- (6-hydroxy) aIΌdust] e4-piaeryoyinyl] -1,2-benzisoxide as an off-white solid. A sample (4.0 g) was recovered from water with t-nole (charcoal treatment) to give 2.4 g (40%) of alcohol as a white solid, mp 140-142 ° C

Anclizc:

Calculated for dlc C1 ₅ H ₁₉ FN ₂ O2: 64.73% C 6.88% H 10.06% N

Found: 64.79% C 6.97% H 10.03% N

Example 4 fumcrcn 6-fluoro-3- (re (2-pioywiOynokey) propy1oee4-piperidinyl] -1,2-benzocaine

To the fresh suspension of 6eflboooe3- [r- (3-hyo-O-ox-ypropyl) -4-piperidinyl] -1,2-benzifoceco1b (3.6 g 0.013 mol) in tetoahydo-refraction (50 ml) was added dropwise bisivetylsilic acid (2.6 g 0.013 mol), decomposed in tetrahydrofurc (20 ml). Upon completion of the quintuple reaction, the reaction was brought to a cool room temperature for 5 minutes, followed by 2-ahloopyrividine (1.6 g, 0.014 mol). The whole was kept at room temperature for 4 hours, after which the thin-skin choomatdgocf method was performed, which ended the reaction incompleteness. An additional amount of sodium (0.5 g) was added and the reaction was allowed to run at room temperature for 4 hours. The mixture is exclusively water and organic dichloromethane. The ecetuakt was washed with (H 2 O), descaled (K ₂ CO ₃ ) and the rocuscckclnik was concentrated to give a wet solid. It was triturated with diethyl ether and the product isolated was collected with 1.0 g of the starting alcohol. The filtrate was concentrated to provide 3.8 g of a coke, yellow solid. This material was combined with 2.6 gf of other pofebizib and subjected to a sickness flash on a cofevionic gel, eluting first with ethyl acetate and then with 8% diethylavine in ethyl acetate. Concentration of the appropriate fractions gave 3.0 g of the desired compound in aoetαci yellow solid. The pofec-ftC was washed in fumaric acid with the acetone solution of fumaric acid, and then the pofec-ft was recirculated to water. It was combined with another sample, and the combined samples were subjected to a selective HPLC with nc coevion gel (eluting with 4.5% methanol in dichloromethane). The corresponding fractions were added to 1.6 g of the yellow solid duty. Fumcrcn was prepared yielding 2.1 g (16%) fumcrcn 6efluoro-3- [1e (2-airidinoxy) propyl] -4epipzryOyne] -1,2-benphysoxically, mp 184-186 ° C.

Anclizc:

Calculated for dlc C ₂ 3 H ₂₅ FN · R: 58.47% C 5.33% H 11.86% N

Found: 58.52% C 5.34% H 11.80% N

Example 5

6-cceto-2- [4- (6-fluoro-1,2-bznkifokecko1e3-yl) -1-piperidin-10] -v-ethyl-1,4-benzodiocecn (A) 6-cceto-2-vizyloxymethyl-1, 4-benzodioxin

6-Ceto-2-hydroxyethyl-1, 4-benzodio-cn (3.39 g, 16.3%) was depleted in trichlohydrate (100 ml). To mesyl chloride (2.5 g, 1.35 eq.) Was added toiethyltin (2.5 g) at 0 ° C. All for 2 hours at room temperature. Mieefinin was diluted, and the salt was ice-cold salt (150 ml), sodium bicarbonate and brine, o-bisphonium over magnesium salt, and concentrated to give 5.6 g of product. After being subjected to an NH ₂ column with a SiO ₂ column, 3.64 g (78% yield) of 6-caetOe2-oxymethyl-1 Abenzodioxene was obtained.

176 230 (B) 6-aceto-2- [4- (6441-06:) - 4, Orbenz-zoxazol-3-yl) -1 -ldpe2ydpny Io] -mlOy-o- e, 4lOenzodioxane

A mixed mixture of 6-fluouo-3- (4-piper4d4a4l) -1,2-beaninoxazole (3.0 g, 13.6 mmol), K2CO3 (2 g, 14.5 mmol) and 6-aceto-2-mesylox-4-methyl-1, 4-bennodioxane (3.5 g, 12 mmol) in acetonitrile (100 ml) was heated to reflux for 3 hours. At the end of the reaction, the solvent was removed on the rotary evaporator. The residue was extracted with dichloromethane (350 ml) and the insolubles were filtered off. The dichloromethane solution was concentrated and the crude oil was purified by Flash chromatography. The product obtained weighed 3.38 g (59%). Recrystallization from ethanol gave 6-aceto-2- [4- (6-fluoro-1,2-benzisoxano-3-yl) -1-piperydya-4-yl] -meth-4l-1,4-beanooxaa as light yellow crystals (3.2 g), m.p. -123 ° C.

Analysis:

Calculated for C2 ₃ ^ I ₂₃ 3FN ₂ O4: 67.31% C 5.65% H 6.83% N

Found: 67.24% C 5.50% H 6.75% N

Example 6

2- [4- (6-fluoro-1,2-benzisoxαnol-3-yl) -1-piperidinylol-methyl-1,4-benndioxane

A mixed mixture of 6-fluoro-3 (4-pipeu4d4a4l) -1,2-beaninoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), and 2-methoxazole methyl-1,4 -benzodioxy saau (3.35 g, 13.7 mmol) in acetone (100 ml) was heated to reflux for 12 hours. At the end of the reaction, the insolubles were filtered off and washed with dichloromethane. The organic solution was concentrated .. The crude oil was purified by flash chromatography on a silica gel column. Crystallization from ethanol and petroleum ether gave 2- [4-06fluo-1,2beazinoxαnol-3-yl) 1piperOya4l] -methyl-2, Z-beanoOioxaa as off-white crystals, 2.22 g, mp 86-87 ° C.

Analysis:

Calculated for C21H21FN2O3: C 5.75% H 7.60% N

Found: 6833% C 5.75% H 7.51% N

Example 7

2- [4- (6-fluoro-1,2-beazisoxazol-3-clay) -1-piperidinyl ytyl- 2,4-benzodioxaa (A) 2-mesylox4et4l-1,4-benndioxaa

Triethylamine (0.12 mol, 10 ml) was added to 2-h-4-dioxyethyl-1,4-beanodioxaau (11.96 g) in dichloromethane (450 ml). Then mesyl chloride was added dropwise and the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the solution was washed with water, brine, and concentrated to give an oil which was purified by silica gel chromatography to give 2mez4loxyethyl-1,4-beanoylx, 17.8 g.

(B) 2 [4 (6-FluoΓO-2,2beazisoxαzol-3-yl) -2-pipelidinyl] ethyl-1,4-beanodioxaa

A mixture of 6-fluoro-3- (4-piper-4-dinyl) -1,2-baazisoxαzole (4.7 g, 21 mmol), K2CO3 (3.5 g, 25.4 mmol) and 2-mez4loxymethyl-1,4-bennioxane (5.5 g, 21.3 mmol) in acetoite: R 4Lu (250 ml) was heated to reflux for 3.5 hours. At the end of the reaction, the insolubles were filtered off. The solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated to an oil. The crude oil was purified by flash chromatography on a silica gel column. The obtained material was pre-crystallized with ethanol. Crystals of 2- [Z (6-fluoro-2,2-benzisoxίazol-3-yl) -2-piperyOya4lo] et4l-1,4-bennoioxaau, which weighed 3.8 g, 48%, mp 112-113 ° C.

Analysis:

Calculated for C22H23FN2O3: 69.09% C 6.06% H 7.32% N

Found: 69.17% C 6.02% H 7.31% N

176 230

Example 8

6- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] poly-pooxy] -7-methoxy-1-tetralone (A) 6- (3-Chloropropoxy) -7-m-ethoxy-1- tetralone

A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50, 4937) (1.5 g, 7.8 mmol), K2CO3 (1.7 g, 12.3 mmol) and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The mixture was cooled to room temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) in acetone (8 mL) was added dropwise. After the addition was complete, the mixture was stirred under a nitrogen atmosphere at reflux for 21 hours. It was then cooled to room temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to give 2.0 g of 6- (3-chloropropoxy) -7-methoxy-1-tetralone as an amber oil.

(B) 6- {3- {4- (6-fluoΓO-1,2-benzisoxazol-3-yl) -1-piperidinyl] propoxy] -7-methoxy-1-tetralone

A mixture of 6luoro-3- (4-piperidinyl) l1,2-benzisoxazole (0.78 g, 3.6 mmol), K2CO3 (0.60 g, 4.1 mmol) KI (100 mg), 6- (3l Chloropropoxy) -7-methoxy-1-tetralone (0.87 g, 3.2 mmol) and acetonitrile (50 ml) were stirred at reflux for 17 hours. The cooled mixture was poured into 100 ml of water and extracted with ethyl acetate. The acetate extract was washed with brine, dried over MgSO4 and concentrated to give 1.7 g of a brown oil. The oil was subjected to preparative HPLC (Waters Associates Prep LC / system 500) to yield 1.0 g of a light brown solid. These were combined with an additional sample (2.3 g in total) and recrystallized from ethanol to give 1.7 g of product. Subsequent recrystallization from ethanol gave 1.25 g (36%) of 6- {3- [4- (6-fluoro-l., 2-benzisoxazol-3-yl) -1 l-piperidinyl] propoxy] -7-methoxy-1-tetralone in as a beige powder, mp 129-131 ° C.

Analysis:

Calculated for 69.01% C 6.46% H 6.19% N

Found: 68.77% C 6.43% H 6.16% N

Example 9

Nl3- {4l (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propyl-6-acetyl-2-benzOl xazolinone (A) N-3l (chloropropyl) -2-benzoxazoline

To a stirred under nitrogen suspension of sodium hydride (7.8 g, 0.16 mol, washed with ether) in dimethylformamide (75 ml) was added dropwise 2-benzoxazohnone (20.0 g, 0.15 mol) dissolved in dimethylformamide (150 ml ). After the addition was complete, the mixture was stirred at room temperature for 30 minutes and then cooled to -5 ° C in an acetone-ice bath. A solution of 3-chloro-1-bromopropane (46.6 g, 0.30 mol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded 0 ° C). The mixture was allowed to come to room temperature and was stirred for 16 hours. It was then poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4) and the extract was concentrated to give 21.9 g of a tan solid. They were recrystallized from toluene with hexane to give N-3- (chforopropyl) -2-benzoxazolinone as large needles, 15.6 g, mp 264-266 ° C.

(B) N-3l (chloropropyl) -6-acetyl-2-benzoxazolinone

A mixture of N-3- (chloropropyl) -2-benzoxazoline (8.5 g, 0.04 mol), polyphosphoric acid (100 g) and acetic acid (2.4 g, 2.3 ml, 0.04 mol) was stirred and heated to 100 ° C for 2 hours. The hot solution was poured onto ice water to form a yellow gum. The mixture was extracted with dichloromethane and the insolubles were filtered off. The dichloromethane extract was washed with water, dried (K2CO3) and concentrated to give 6.4 g of a greenish solid. They were recrystallized from ethanol (95%) to give N13- (chloropropyl) -6-acetyl-2-benzoxazoline as a tan solid, 3.5 g, mp 100-103 ° C.

176 230 (C) N-3- [4-6-fluoro-Fl, o-benzisoxoxazol-3-ylol-1-piperpynyl] propyl-o-ace-y-o-2-thenzoxazolinone

A mixture of 6-fluoro-3- (4-pip2rpdpsρlo) -1,2-beszisoxazole (2.0 g, 0.009 mol), N-3- (chloropropyl) -6-acetyl-2-bexoxazolinos (2.4 g, 0.009 mol), K2CO3 (3.6 g), several crystals of KI and α-etonitrile (50 ml) were stirred and heated to reflux for 13 hours. The mixture was poured into water and the separated dark brown solid was collected to give 3.3 g of crude product. It was flash chromatographed using Waters Prep 500 HPLC. Concentration of the appropriate fractions gave 2.3 g of a yellow solid and recrystallization from ethyl acetate gave 1.2 g (31%) of N-3- [4- (6-fluoro-1,2-besisoxazol-3-yl) -1 -piperρ · dpnplo] propyl-y-acetplo-2-b2shoxozolinone, melting point 152-154 ° C.

Anolysis:

Calculated for ΟΟΡΝΡΝΡΝΡΝ: 65.89% C 9.61% N

Found: 65.67% C 5.48% H 9.52% N

Example 10

N- [4- [4- (6-fluoro-1,2-beshisoxazol-3-yl) -1-piperidinyl] butyl | -phthalimide

A mixture of 6-yluoro-3- (4-piperidinyl) -1,2-benzisoxazole (5.5 g, 25 mmol), 4-bromobutplophtholimide (8.0 g, 28.3 mol, 1.13 eq) in acetonitrile ( 100 ml) was heated to reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The orgasicsp solution was concentrated gradually allowing it to solubilize. Crude crystals (5.9 g) were collected. Purification was done by flash chromatography on silica gel. The product thus purified (3.8 g) was recrystallized from ethanol (70 ml) to obtain 2.48 g of N- [4- [4- (6-fluoro-1,2-beshisoxazo | e3-yl) -1-pip2rpdpsplo] butplo] phtholimide as white crystals, mp 144-146 ° C.

Analyze

ObliczonodlaC28H28FN ₃ O3: C 5.74% H 9.97% N

Found: C 5.74% H 9.84% N

Example 11

1- [4- [3- [4- (6efluoro-1,2-b2nzizok3ozole6-yl) -1-pip2rpdpsplo] propplo] thio] -6-methok3pfesplo] etason (A) 1- [4e [(3-chloropropplo) thio] -3-methok3pfesplo] ethanone

A mixture of 1- (4-thioe3-methoc3pfenplo) ethanos (10.0 g, 0.0549 mol), potassium carbonate (9.0 g, 0.0651 mol) and acetone (100 ml) was stirred at reflux under an atmosphere of nitrogen for 30 minutes. The mixture was cooled to room temperature and a solution of 1-bromo-3-chloropropane (6.5 ml, 9.5 g, 0.0604 mol) dissolved in acetone (25 ml) was added dropwise. After the addition was complete, the mixture was stirred under a nitrogen atmosphere at reflux for 17 hours. After the reaction was complete, the mixture was filtered and the filter cake was washed with acetone. The filtrate was concentrated to give an amber oil. The small sample was solidified by rubbing it with hot cyclohexane to obtain 1- (4- - [(3-chloropropplo) thio] -3-methoxspfesplo] ethosos in the form of a yellow solid, 11.7 g, melt temperature 53-35 ^o C.

(B) 1 - [4- [3- [4- (6-fluoro-1,2-beszisoxazol-3-yl) -1 epiρerpdpsplo] propplo] thio] -6-methoxspf2nplo] etason

A mixture of yefluoro-3- (4-piperidinyl) ~ 1,2-benzisoc3Ozole (3.0 g, 0.0136 mol), n- [4 - [(6-cMoropropplo) thio] -6-m2to-3pfenplo] 21aslos ( 3.5 g, 0.0136 mol), K 2 CO 3 (2.3 g, 0.0166 mol), KI (200 mg) and CH ₃ CN (100 ml) were stirred under reflux for 7.5 hours. and then left at room temperature for 65 hours. The reaction mixture was poured into water, and the aqueous mixture was extracted with ethyl acetate. The acetate extract was washed twice with water, once with brine, and dried over MgSO4. The solvent was removed under reduced pressure. pressure to give 6.8 g of a light brown oil. The sample was cleaned

176 230 by flash chromatography. Concentration of the appropriate fractions gave 3.0 g of product. Recrystallization from ethanol gave 2.4 g (41%) 1- [4- [3- [4- (6-fluoro-1,2-benzisoxazol-3-iio) -1-piperidinyl] propyio] thio] -3-methoxyphenyl] ethanone as a beige solid, mp 93-95 ° C.

Analysis:

Calculate C10H2C24H2 ₇ FN2O3S: 65.14% C 6.15% H 6.33% N

Found: 64.66% C 6.17% H 6.26% N

Example 12

1- [4- [3 - [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propylamino] -3-methoxyphenyl] ethanone

To a stirred suspension of sodium hydride (0.37 g, 0.007 mol 50% dispersion in oil) in dimethylformamide (20 ml) was added dropwise 1- [4- [3- [4- (6-fluoro-1,2-benzisoxazole-3) -yl) -1-piperidinio] propyioamino] -3-hydroxyphenyi] ethanone (2.9 g, 0.007 mol) dissolved in dimethylformamide (25 ml). The reaction mixture was stirred at room temperature for 30 minutes, then water was added. The resulting aqueous mixture was extracted with ethyl acetate, the extract washed with water, dried (MgSO4) and concentrated to give 4.9 g of a brown oil which solidified on standing. It was flash chromatographed on silica gel. The appropriate fractions were concentrated to give 2.7 g of the product, a yellow solid. Recrystallization from toluene with hexane gave 2.0 g (67%) of analytically pure 1- [4- [3 - ^^ (6 ^^^^ and ^ (^^ 1,2-benzisoxazol-3-yl) -1- piperidinio] propylamino] -3-methoxyphenyl] ethanol as a yellow solid, mp 96-98 ° C.

Analysis:

Calculated for C24H28FN3O3: 67.75% C 6.63% H 9.88% N

Found: 67.93% C 6.72% H 9.80% N

Example 13

9- [4- [3- [4- (6-fluo-1,2-benzisoxazol-3-iio) -1-piperidinyl] propyla.mmo] -3-hydroxyphenyl] ethanone

A mixture of N- [3- [4- (6-fluoro-1,2-benzisoxuzol-3-yl) -1-piperidinio] propyio-6-uceti-2-benzoxuzolinone (6.0 g, 0.014 mol) and 10% aq. sodium hydroxide solution (50 ml) was stirred under reflux for 40 minutes. Water was added and the reaction mixture was acidified with 5% hydrochloric acid. Saturated Na'CO3 solution was added until the foaming ceased. The aqueous mixture was extracted with dichloromethane. The dichloromethane extract was washed (water), dried (K2CO3) and concentrated to give 2.6 g of a sticky solid. The crude solid was treated with saturated NaHCO3 solution and extracted with dichloromethane. Dichloromethane was washed (brine then water) and dried (MgSO4). The organic extract was concentrated to give 2.4 g of a tan solid which was combined with another sample to give 5.0 g of product. This sample was flash chromatographed on silica gel. A small sample (0.25 g) was recrystallized from toluene to give 1- [4- [3 - [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinio] propylamino] -3-hydroxyphenylojetanone in brown solid, 0.15 g, mp 150-152 ° C.

Analysis:

Calculated for C23H26FN3O3: 67.14% C 6.37% H 10.21% N

Found: 67.54% C 6.58% H 9.95% N

Example 14 2- [4- (6-fluoro-1,2-benzisoxuzol-3-yl) -1-piperidinyl] ethyl acetate fumarate

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol) and 2-bromoethyl acetate (4 g, 26 , 5 mmol) in acetonitrile (50 ml) was heated to reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered off and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on the rotary evaporator to give an oil. The oily product was purified by flash chromatography column (60g S1O2, eluting with MeOH, 2% -4% in DCM). The pure product thus obtained weighed 4.43 g. The oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The salt crystallized at room temperature to give 3.44 g (57%), mp 154-155 ° C.

Analysis:

Calculated for C 1 ₆ H ₁₉ FN ₂ O ₃ and R 2: 56.86% C 5.49% H 6.63% N

Found: 56.75% C 5.41% H 6.54% N

Example 15

N- [2- [4- (6-fluoro-1'-benzisoxazol-1-yl) -1-piperidinyl] ethyl] morpholine

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-bjnzisoxazolf (3.0 g, 13.6 mmol), 2-chlorotylmorpholine hydrochloride (4.46 g, 29.7 mmol) and RCO ₃ (7 , 3 g, 2.2 eq.) In acetonitrile (60 ml) was heated to reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to give an oil (about 7.1 g). Purification on a silica gel column (5 g, S1O2, eluting with MeOH with DCM) gave a solid product weighing 4 g. Recrystallization from hot ethanol gave 2.1 g (48%), mp 131-132 ° C.

Analysis:

Calculated for C ₁₈ H ₂₄ FN ₃ O ₂ : 64.84% C 7.26 ·% _H 12.66% N

Found: 64.80% C 7.00% H 12/77% N

Example 16

N- [2- [4- (6-f ^^ and ^^ o-1,2-benzisoxa: sol-3 - ^] ^, o) ^ 1-piperidinyl] ethyl] phthalimide

A mixture of 6-Ωuoro-3- (4-piperγidinyl) -1,2-bjnzisoxazolf (5.15 g, 23.4 mmol), K2CO3 (4.2 g, 30.4 mmol) and 2-bromoethylphthalimide (7.13 g, 28 mmol) in acetonitrile (250 ml) was heated to reflux for 3.5 hours. Solids and solvent were removed. The residue was purified by flash chromatography (S1O2, 110 g, elution with 2-4% CH ₃ OHzDCM). The product thus obtained weighed 7.8 g (84%). Part of the material was recrystallized to give 2.35 g of off-white crystals, mp 148-149 ° C.

Analysis:

Calculated for C22H20FN3O3: 67.17% C 5.12% H 12.68% N

Found: 67.01% C 5.20% H 12.77% N

Example 17 2- [4- (6-Fluoro-1l2-benzisoxazol-3-yl) -1-piperidinyl] yyl methyl ether fumarate

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (3.75 g, 17 mmol), K2CO3 (3 g, 21.7 mmol) and methyl bromoethyl ether (2.84 g, 20 mmol) 4 mmol) in acetonitrile (150 ml) was heated to reflux for 3.5 hours. The reaction mixture was cooled. The solids were removed and washed with DCM. The organic solution was concentrated to an oil (7 g). Purification by flash chromatography column (S1O2.45g, eluting with methanol / DCM) gave a light yellow oil (4g, 87%) as the product. The oil was dissolved in ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, mp 157-158 ° C.

Analysis:

Calculated for C 5 H ₁₉ FN2O2 · C4H4O4: C 5.88% H 7.10% N

Found: C 5.94% H 6.94% N

176 230

Example 18 4- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butyl acetate fumarate A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (9 , 5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol) and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated under reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packing with Sorbsil C30, 100 g silica gel, eluting with DCM, increasing the methanol content from 2 to 4%). The substance thus purified weighed 12.92 g (89%). A small sample was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to give white crystals, 1.8 g, mp 142-143 ° C.

Analysis:

Calculated for CUH23FN2O3C4H4O4: 58.66% C 6.04% H 6.22% N

Found: 58.56% C 6.00% H 6.3% N

Example 19 4- [4- (6-fuoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butanol fumarate 4- [4- (6-fluoro -, 2-benzisoxazol-3-yl) acetate mixture ) --- piperidinyl] butyl (11.5 g, 34.4 mmol), 15% NaOH (100 ml) and ethanol (100 ml) were heated to reflux under reflux for 4 hours. After cooling to room temperature, the base was neutralized with HCl to pH = 7. The solution was concentrated to low volume (about 50 mL) and extracted with DCM. The DCM solution was washed with salt and dried over MgSO ₄ . The solvent was concentrated to obtain approximately 10 g of crude oil. Purification by flash chromatography (Sorbsil C30, 100 g, eluting with MeOH: DCM, 3 L) gave 9.8 g of a white solid. The test sample was prepared by treating the free base (2.0 g) with fumaric acid (780 mg, 1.0 eq.) In ethanol. Crystals were collected and dried, 1.5 g, mp 131-132 ° C.

Analysis:

Calculated for C ^ R ^ FlNA · C4H4O4: 58.82% C 6.17% H 6.86% N Found: 58.81% C 6.37% H 6.66% N

Example 20 4- [4- (6-Fluoro -, 2-benzisoxazol-3-yl) -1-piperidinyl] butyl decanoate fumarate To a mixture of 4- [4- (6 "fuoro-1,2-benzisoxazol-3- clay) -1-piperidinyl] butanol (2.0 g,

6.84 mmol), triethylamine (1.0 g, 10 mmol) in DCM (70 ml) was added dropwise at room temperature decanoyl chloride (1.7 g, 8.9 mmol). The mixture was stirred for 1 hour then concentrated to give a crude solid. It is extracted with ethyl acetate and the insoluble salts are filtered off. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil C30, 30 g, eluting with a mixture of MeOH and DCM). The obtained oil (2.5 g, 81%) was converted to the fumarate with fumaric acid (650 mg, 1.0 eq.) In ethanol. Crystals collected, 2.5 g, mp -09-1-4 ° C.

Analysis:

Calculated from CRR? FN ^ - C4RO4: 64.04% C 7.70% H 4.98% N Found: 64.30% C 7.86% H 4.78% N

Example 21 3 - [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propyl decanoate fumarate To a mixture of 3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propanol (1.81 g,

6.5 mmol), triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added dropwise at room temperature decanoyl chloride (1.5 g, 7.8 mmol). The mixture was stirred for 20 minutes then concentrated to give a crude solid. They were extracted with EtOAc (20 ml) and the insoluble salts were filtered off. EtOAc was removed. The crude oil was purified by flash chromatography (Sorbsil C30, 30 g, eluting with a mixture of MeOH and DCM). The obtained oil (2.54 g, 90%) was converted to fumarate with fumaric acid (670 mg) in ethanol. The collected crystals weighed 1.61 g, mp 100-102 ° C.

Analysis:

Calculated for C2 ₅ H ₂₇ FN2O3- C4H4O4: 63.52% C 7.54% H 541% N Found: 63.63% C 7.74% H 5.00% CN

Example 22 N, N-diethyl-4- [4- (6-nuoro-1-ι2-bennisoxazol-3-yl) -1-piperidyl] butyl carbamate fumarate

To a mixture of 4- [4- (6-l'luoro-2,2-beanisoxanol-3-yl) -1-pipeuyd4a4l] butaaol (1.55 g,

5.3 mmol), potassium t-butoxide (750 mg, 6.7 mmol) in THF (100 ml) was added dropwise at room temperature diethyl carbamyl chloride (900 mg, 6.63 mmol). The mixture was stirred for 2 hours then the solvent was removed. The residue was extracted with DCM. The DCM solution was washed with brine and dried over MgSO4. The solution was concentrated. The product was purified by flash chromatography (SiO2, 14g, eluted with 2% MeOH in DCM) to yield 1.84g of an oil. - This oil was dissolved in ethanol (about 5 mL) and treated with a solution of fumaric acid (850 mg, 1.0 eq.) In ethanol. Crystallization was induced with a small amount of isopropyl ether, yielding 2.09 g, mp 152-153 ° C.

Analysis:

Calculated for C21H30FN3O3C4H4O4: 59.16% C 6.75% H 8.28% CN

Found: 59.17% C 6.84% H 841% N

Example 23 N-methyl-Z- [4- (6-fluorr-1,2-benzisoxazol-3-clay) -1-piperidinyl] butyl carbamate fumarate

To a mixture of 4- [Z- (6-fluoro-2ι-2-beanisoxazol-3-yl) -1-prperidinyl] butyral (2ι84 g,

6.3 mmol), K2CO3 (850 mg) in chloroform, methyl isocyanate (448 mg, 7.7 mmol and 360 mg, 6.2 mmol) were added dropwise in two portions. The mixture was filtered and concentrated to a crude oil. The product was purified by flash chromatography (SiO2, 11 g, eluting with 2% CH ₃ OH in DCM) to give a pale yellow oil (2.05 g, 93%). This oil was dissolved in ethanol and treated with a fumaric acid solution (800 mg, 1.0 eq.). Crystallization was induced with drops of isopropyl ether. Weight: 1.36 g, mp 96-98 ° C.

Analysis:

Calculated for C ^ FN-A- C4H4O4: 56.76% C 6.06% H 9.022 /% _N

Found: 56.27% C 6.03% H CN

Example 24 2- [2- [4- (6-fluoro-1,2-beazisoxstzol-3-yl) -1-piper4din4-yl] ethyl] -1ι3-dioxaau A mixture of 6-fluorr-3 (4-piper4dinyl) -1 , 2-beazisoxazole (2.0 g, 9.1 mmol), K2CO3 (1.5 g, 10.9 mmol) and bromoethyl-1,3-dioxaau (2.1 g, 10.7 mmol) in acetonitrile ( 50 ml) was heated to reflux for 3 hours. At the end of the reaction, insolubles were filtered off, washed with DCM and the filtrate was evaporated. The crude mixture was purified by flash chromatography on a silica gel column (Sorbsil C30, 25g, eluting with DCM and MeOH (1-3%) in DCM. Fractions containing pure product were combined to yield 3.13g of an oil. The oil was treated with fumaric acid ( 1.0 g) in ethanol Crystals collected, 3.98 g (77%), mp 161-162 ° C,

Analysis:

Calculated for C ₁₈ H23FN2O3-C4H4O4: 58.6% C 6.04% H 6.22% N

Found: 55.9% C 5.96% H 6.20% CN

176 230

Example 25 htmifumerate 2- [4- (6-fluoro-1,2-benzisocazol-3-yl) -1-piaeridin-1o] etαno1b (A) acetate 2- [4- (6efluoro-1,2-benziso] k-ίCfrl -3-yl) -1-piaeoyidinyl] ethyl

2- [4- (6-fluoro-1,2-benzisox; cfol-3-yl) -1-epiaeryidinyl] ethylbate acetate was obtained in pofykle 14.

(B) hewifUwcocn 2- [4- (6-fluolΌ-1,2ebznzizokecfo1-3-yl) -1-piaeryidin1o] etcno1u

2- [4- (6-Flboron, 2-belphifocechol-3-yl) -1-piaeoyidin1oeety1b acetate (10.58 g, 34.6 lb),

15% N-OH (100 ml) and ethanol (100 ml) was heated to reflux for 4 hours. The solution was cooled (about 5 ° C) and neutralized with HCl to a pH of about 7. The ethanol was bubbled under pressure. Aqueous solution with NCHCO3 desiccant and DCM extraction (2 x 200 L). The DCM solution was washed with brine and dried with ncd of MgSO4, left oop to give a white body, 6.88 g (75%). A sample (2.03 g) was diluted in ethanol and treated with fumaric acid (660 g, 1.0 eq.). Crystallization was induced by the isopropyl ether sponge to give off white crystals, 1.43 g, tewp. mp 159-161 ° C

Anclizc:

Calcd CnHpFNĄ · dlc 0,5C4H ₄ O4: 59.62% C 5 ° C 94% H% N 8,559

Found: 59.55% C 5.995 /% H 8 ^^ 5% N

Example 26 fumcrcn dec-ni-nium 2- [4e (6ef1uooo-1,2-benzisoxazo1e3-10) -1-piperidinyl] ethylene

Misszcnina 2e (4e (6-fluoro-1,2-benzisoxa: fol-3-yl) -1-piperidin1o] zt-no1u (1.6 g, 5 wmol) and triethyltin (800 g, 8 wmol) in chloroform (100 ml ) was treated with OzCiIu chloride (1.3 g, 7.2 mmol) dropwise at room temperature. The mixture was suspended for 4 hours. The Rofpb-phase agent was removed by slaking the crude solid. Only a small amount of DCM (15 ml) and concentrated, the solution was concentrated, the crystallization was induced with additional drops of ether, yield 1.97 g, mp 109-110 ° C, for example.

Ancliza:

Calculated for dlc C24H35FN ₂ O3 C4H4O4: 62.90% C 7.355% _H 5.22% N

Znelzziono: 62.93% C 7.30% _H 5/4% n

Example 27 lumcrcn kcrb-mini-nb NN-diethyl ^ - [4- (6-fluoro-1,2-benkizokeefol-3-yl) -1-piperidinyl] ethyl

For suspension 2e (4e (6ef'1boro-1,2-benzisoxazole-3-yl) -1-piperOynyl] etcno1 (1.6 g, 6 w mol) and potassium t-butno1-nb (850 mg, 7, 6mmol) in THF (100L) Add dropwise at room temperature diethyl chloride (1.03mg, 7.5mmol) The mixture was suspended for 4 hours The core of the crude solid was then concentrated. was purified by flash column chromatography vet (Sorbsil C30, 25 g, trituration with a mixture of DCM and MeOH). This rock-solid product, a light oil (2.2 g, 91%), was dissolved in ethanol and treated with a solution of fumaric acid (690 mg, 1 0.0 eq-) in ethanol (15 wl) Crystallization after cooling to dc2c 2.15 g of white crystals, mp 133-135 ° C

Anclizc:

Calculated for dlc C ^ IFNA. C4H4O4: 57.61% C 6.31% H 8.76% N

Found: 57.49% C 6.25% H 8.54% N

Example 28 hzmifumarcn 2- 1,2-benzisoc-ezo-1-3-yl) -1-piperidinyl yethyl amine (A) phthalimite- 2- [4- (6-fluorOfl, Ooden2zo tnsazo 1-eailo) -1-pyridinyl] yly1o

2- [4- (6-Fluoro-1,2-benkizoxyphol-3-yl) -1-piperidinyl] ethyl phelimide was prepared as in the box in Figure 16.

176 230 (B) hemifumarate 2a [4- (2-fiuoro-1,2rbenzizbk.nazol-3ailol-3 - {lo) e1 \ ^^; ^^ ieyyj] e ^ nylaenin ^ Phthalimide mixture 2- {4- (refluoro -1,2-benzisoxazol-3-i10) -1 epipkyidine] kty1o (4.6 g, 11.7 mmol) and hydrazine monohydrate (1.17 g, 23.4 mmol) in methanol (50 ml) was heated to reflux overnight. At the end of the reaction the methanol was removed leaving a crude solid. They were mixed with water (150 ml) and acidified with HCl to pH = 2. The insolubles were filtered off. The aqueous solution was basified with 50% NaOH and extracted with DCM (2 x 250 mL). The DCM solution was washed with brine and dried over MgSO4. The solvent was removed to give a colorless oil, 2.12 g. This was treated with fumaric acid (935 mg, 1.0 eq.) In ethanol. Salt crystallized, 0.99 g, mp 198-200 ° C. A second crop, 0.73 g (mp 198-200 ° C) was then collected.

Analysis:

Calculated for C ^ F ^ O 0.5C4H4O4: 59.80% C 6.27% H 11.07% N Found: 59.51% C 6.35% H 11.33% N

Example 29 2- {4- (6-fluoro-1,2-bknziaoxazole3-i1o) -1-epiperidinyl] enylu decanamide fumarate for a mixture of 2- {4- (6-fluoro-1,2-ibetnaisoxaaol-3-yl) -1epipkyidinyl ] ethyl4mine (1.49 g,

5.5 mmol) and triethylamine (1.0 g, 10 mmol) in chloroform (50 ml) were added decanoyl chloride (1.26 g, 6.6 mmol) at room temperature. The mixture was stirred for 3 hours at room temperature. The solvent was removed leaving a crude solid. They were purified by flash chromatography (SiO2.20 g, eluting with a solution of MeOH (0-3%) in DCM). The pure fractions were collected and concentrated to give 2.3 g of an oil. This oil was converted to fumarate by treatment with fumaric acid (655 mg) in ethanol. The ethanol was concentrated to low volume and 3 volumes of isopropyl ether were added. The mixture was stirred overnight to effect crystallization. The solid collected, 1.83 g (60.5%), mp 108-110 ° C.

Analysis:

Calculated for C ₂ 4H36FN3O2C4H4O4: 63.02% C 7.56% H 7.7% N Found: 62.22% C 7.58% H 7.66% N

Example 30 2- {4- (6-fluoro-1,2-belnzisoxazol-3-yl) -1-piperidinyl] tetamide acetamide fumarate For a mixture of 2- {4e (6efluoro-1,2-benziaoxαΌl-3-clay) - 1-epiperidinyl] ethyl4mine (2.56 g, 9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 mL) were added acetyl chloride (1.0 g, 12.7 mmol) dropwise at a temperature of room. The mixture was stirred for 4 hours at room temperature. It was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The oil was purified by flash chromatography on a silica gel column (SiO ₂ , 20 g, eluting with a solution (0-2%) CH3OH in DCM). The pure product obtained weighed 1.36 g (46%). It was converted to fumarate by treatment with fumaric acid (517 mg) in ethanol. Recrystallization from ethanol gave white crystals weighing 1.53 g, mp 132-133 °%

Analysis:

Calculated for CUH20FN3O2C4H4O4: 57.000% C 5.74% H 9.97% N Found: 57.05% C 5.85% H 9.95% N

Example 31 2e {4e (refluoro-1,2-oxo-azo-3-yl) -1-epipkyydinyl] methyl-kyl-carbam. Nil fumarate

A mixture of 2e {4e (6ef1uoyoe1,2-bknziaox4ao1-3-yl) -1-piperidin1o] -ethylamine (2.0 g,

7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treated dropwise with ethyl chloroformate (860 mg, 9.12 mmol) at room temperature. The mixture was stirred for 1 hour. It was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The oil was purified by column flash chromatography

176 230 with silica gel (28 mg Sorbsil C-30, eluting with DCM and MeOH / DCM). The resulting pure oil weighed 2.34 g. It was converted to fumarate by treatment with fumaric acid (814 mg, 1.0 eq.) In ethanol. Crystallization was induced by adding a drop of isopropyl ether, yield 2.31 g, mp Ϊ63-165 ° Ο.

Analysis:

Calculated for C ^ F ^ O. • C4H4O4: 54.92% C 5.53% H 9.61% N

Found: 54.49% C 5.45% H 9.24% N

Example 32 (S) - (+) - 3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] -2-methyl-1-propanol fumarate

A mixture of 4- (8-fluoro-1,2-benzisoxazol-3-yl) -1-piperidine (7.2 g, 32.7 mmol), (S) - (+) - 3-bromo-2-methyl- 1-Propanol (5.0 g, 32.6 mmol), RCO, (7.19 g, 52 mmol) vacetomtril (250 ml) was heated under reflux overnight. The insolubles were filtered off. The solvent was removed under reduced pressure and the crude residue was purified by silica gel column chromatography (SiO2, 84 g, eluting with 1% CH3OH in DCM) to obtain the target compound as an off-white solid. A 1.7 g sample was converted to fumarate by treatment with fumaric acid (710 mg) in ethanol. Recrystallization from ethanol gave 1.74 g of white crystals, mp 119-121 ° C.

Analysis:

Calculated for C20H25FN2O6 58.82% C 6.17% H 6.86% N

Found: 58.81% C 6.24% H 6.76% N

Example 33 diffmaπm4- (6-fluoro-1,2-benzisoxazol-3-yl) -1- [3- (1-piperidinyl) propyl] piperidine

A mixture of 4- (6-bh ^ ^ o: ^ i ^ ^ 1,2-benzisox ^ ol-3-yl) pip ^ iridine (3.0 g, 13.6 mmol), N- (3-chloropropyl) hydrochloride piperidine (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), and tetrabutylammonium bisulfate (interfacial transport catalyst, 2.3 g) in acetonitrile (100 mL) and water (15 mL) were heated to reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by chromatography on a silica gel column (55 g, Sorbsil C-30, eluting with 2% CH ₃ OH: 0.5% DEA in DCM). The thus purified oil (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. A solid was collected, 3.1 g, mp 178-181 ° C. Recrystallization from ethanol gave 2.28 g of white crystals, mp 190-192 ° C.

Analysis:

Calculated for C20H24FN3O · 2C4H4O4. 58.22% C 6.28% H 7.27% N

Found: 58.39% C 6.36% H 7.34% N

Example 34 1- (3-Dimethylaminopropyl) -4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidine difumarate

A mixture of 8-fluoro-3- (4-piperidinct) -1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6 , 2 g, 45 mmol) and tetrabutylammonium bisulfate (interfacial transport catalyst, 1.5 g) in acetonitrile (100 mL) and water (50 mL) was heated at 60 ° C overnight. The aqueous phase was separated and the acetonitrile was removed under reduced pressure. The residue was extracted with DCM. The organic solution was washed with water and brine, and dried over MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq.) In dilute ethanol. Crystals collected, 2.53 g, mp 192-194 ° C. Recrystallization from ethanol gave 2.08 g of white crystals, mp 194-195 ° C.

176 230

Analysis:

Calculated for C ^^ F ^ O · 2C4H4O4: 55.86% C 6.00% H 7.82% N

Found: 56.111% C 5.94% H 7.86% N

Example 35 (R) - (-) - 3 - [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] -2-methyl-1-propanol fumarate

A mixture of 4- (6-fluorυ-1,2-benzisoxuzol-3-yl) -9-piperidine (14.5 g, 65 mmol), K2CO3 (10 g, 72 mmol), (R) - (-) - 3 -bromo-2-methyl-1-propanol (10 g, 65.3 mmol) and tetrabutylammonium bisulfate (1.27 g, interfacial transport catalyst) in acetonitrile (300 mL) and H'O (5 mL) was heated to reflux under reflux for 6 hours. The mixture was cooled and the solvent removed on the rotary evaporator. The residue was extracted with methylene chloride (DCM) and the insolubles were filtered off. After concentrating the extract, the crude product was purified by flash chromatography on a silica gel column (SiO ', 150 g, eluting with DCM, 11,: 2% CH ₃ OH in DCM, 1.61). The purified material weighed 17 g (89%). A test sample was prepared by treating a sample (2.28 g) with fumaric acid (953 mg) in ethanol. Crystals were formed on adding the isopropyl ether. These were collected and dried, 1.84 g, m.p. H4-115 ^OC .

Elemental analysis:

Calculated for C ^ F ^ O 'C4H4O4: 58.82% C 647% H 6.86% N

Found: 58.488% _{c 6.0} g% _H 6.57% _N

Example 36

6-fluoro-3- [1- [3 - [(1H-indol-5-yl) oxy [propyl] -4-piperidinio] -1,2-benzisoxazes: ol

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (2.6 g, 11.8 mmol), K ₂ CO 3 (1.6 g, 11.6 mmol), KI (200 mg) , 5- (3-chloropropoxy) indole (2.2 g, 10.5 mmol) and CH ₃ CN (100 ml) were stirred at reflux under nitrogen for 18 hours. The cooled mixture was poured into H'O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed twice with H'O, twice with brine, and after drying with MgSO4, the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates Prep LO / system 500 using 2 silica gel columns eluting with 4% MeOH-CH'Cl ') to give 2.65 g (65%) of a beige solid. Recrystallization from ethanol yielded 2.2 g (54%) of a beige powder. MP 998-121 C. ^θ

Analysis:

Calcd for C2 ^ H24FN ₃ O ': C 70.21% 6115% H 10.68% N

Found: 6 ^f 9 ^ 0% Q 6211% H 10.78% N

Example 37

6-fluoro-3- [1- [3 - [(1H-indol-4-yl) oxy] propyl] -4-piperidinyl] -1,2-benzisoxuzole

A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4- (3- chloropropoxy) indole (3.0 g, 14 mmol) and CH3CN (100 ml) were stirred at reflux under nitrogen for 7 hours and at room temperature for 68 hours. It was refluxed again for 5 hours at which time TLC thin layer chromatography showed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the mixture was stirred under reflux for 17 hours. The cooled mixture was poured into H'O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H'O, saturated NaCl solution, and after drying with MgSO4, the solvent was removed to give 5.7 g of a beige solid. The product was purified by preparative HPLC (Waters Associates Prep LC / system 500 utilizing 2 silica gel columns, eluting with 4% _MeOH-CH2 Cl2 to give 3.4 g (61%) beżo40

176,230 of a solid. Two more recrystallizations from EtOH to the bottom 2.3 g (41%) of white powder, mp 129-131 ° C.

Analyze:

Calculated for Ci ₃ H28FN3O2: 70.21% C ό ,, ή, όΗ 10.68% N

Found: 69.90% C 6.5% H 10.65% N

Example 38 y-fluoro-3 - [1- [3 - [(6-methoxy-1H-indol-ithoxypropyl] 1 -piperidinyl] -1,2-b2-shisoc3azole hemifumarate

A mixture of 6-Πuoro-3- (4-piperidioxazole) -1,2-b2-isoxazole (3.0 g, 14 mmol), 5- (3-chloropropox3p) -6-methoc3pindole (3.0 g, 13 mmol), K ₂ C (O (2.1 g, 14 mmol), KI (200 mg) and C'TJ ₃ CN (150 ml) were stirred at reflux under nitrogen for 48 hours. The cooled mixture was poured into H ₂ O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H 2 O and brine and dried with sodium MgSO 4. Removal of the solvent in vacuo gave 5.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates Prep LC / 500 system with 2 silica gel columns eluting with 2% .ENH-EtOAc to give 2.5 g (47%) of a beige solid Recrystallization from EtOH gave 2.0 g of an off-white powder A sample of 1.8 g (4 mmol) was dissolved in warm EtOAc and fumaric acid (0.5 g, 4 mmol) was added. The mixture was stirred at about 40 ° C for 30 minutes and allowed to cool gradually to room temperature. n was collected and dried to give 2.0 g. The product was recrystallized from EtOH to give 1.5 g (25%) of a light beige powder, mp 186-188 ° C

Analysis:

Calculation for CirHi ₈ FN3O3: 64.84% C 5.87% H 8.37% N

Found: 64.22% C 5.85% H 8.55% N

Example 39 (R) - (-) - 3- [4- (6-fluoro-E2-benzisoc3azoE3-yl) -1-piperidpnplo] -2-metplo-1-propyl acetate fumarate

To a mixture of (R) - (-) - 3- [4- (6-fluoro-1,2-beszizok3azol-3-yl) -1-pip2rpdpnplo] -2-methyl-1-proposol (3.2 g, 11 mmol), triethylamine (3.2 g, 11 mmol) in DCM (100 ml) was added dropwise acetyl chloride (890 mg, 11.3 mmol) at 0 ° C. The mixture was stirred at room temperature for 4.5 hours. The solvent was removed on a rotary evaporator. Triethylamine hydrochloride was filtered using a small volume of DCM. The crude product was dissolved in DCM was purified by flash chromatography on a column (SiO2, 30 g; eluted with DCM and 1% _CH3 OH in DCM). The purified oil weighed 2.11 g (58%). The oil was treated with a solution of fumaric acid (695 mg, 1.0 eq) in ethanol to give the fumarate. Recrystallization from ethanol and isopropyl ether gave white crystals, 2.09 g, mp 118-120 ° C.

Analysis:

Calculation for · C8H8O8: 58.66% C 6.04% H 6.22% N

Found: 58.53% C 6.76% H 6.91% N

Example 40 3- [4- (6-Πιιοιό-1,2-benziz; ok3azol-3-yl) -1-pipelidinyl] -2,2-dimethyl-1-propanol fumarate

A mixture of 4- (y-fluoro-1,2-benzisoxazol-3-yl) -1-piperpdρnρ (3.0 g, 13.6 mmol), K ₂ CQ3 (12.5 g, 17.5 mmol), 3 -bromo-2,2-dimethyl-1-propanol (3 g, 21 mmol, 1.5 eq.), tetrabutylammonium bisulfate (1 g, interfacial transport catalyst) in water (5 mL) and a-2tositIplu (150 mL) was heated at reflux temperature for 43 dsi. Thin layer chromatography showed a small spot of the expected product. A mixture of 2N-sodium EtOAc (400 ml) and washed with brine. The organism solution was dried and concentrated to a dark brown mixture. The crude mixture was carefully purified by flash chromatography (SiO ₂ , 95 g to give a dried crude product, 260 mg, (6%) as an oil. The oil was converted to fumarate by treatment with fumaric acid (98.5 mg, 1.0 eq.) In ethanol Recrystallization from ethanol with ether gave 210 mg of white crystals, mp 144-145 ° C.

Analysis:

Calculated for C1 ₇ H ₂ 3FN ₂ O ₂ -C ₄ H4O4: 59/00% C 6.44% H 6.63% N Found: 59.52% C 6.38% H 6.52% N

Example 41 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl thioacetine fumarate To a 0 ° C stirring solution of triphenylphosphine (13.3 g, 0.05 mol) in THF (150 ml) was added diisopropyl azodicarboxylate (10.2 ml, 0.05 mol) dropwise. After stirring at 0 ° C for 0.5 h, a solution of 6-fluoro-3- [1- (2-hydroxyethyl) -4-piperidinyl] -1,2-benzisoxazole (8.5 g, 0.032 mol) was added dropwise and thioacetic acid (10.2 mL, 0.14 mol) in DMF (35 mL). The mixture was stirred at room temperature for 16 hours then concentrated at 60 ° C under reduced pressure to give a red oil. The oil was triturated with H ₂ O and flash chromatographed on silica gel, eluting first with CH ₂ Cl ₂ then 10% MeOH in CRCfy. The appropriate fractions were concentrated to give 16.5 g of an oil. The oil was triturated with Et ₂ O and the solid (reaction by-products) was filtered off. The filtrate was treated with fumaric acid (4.3 g) to give 7.2 g of the fumaric salt of the desired product as an off-white solid. The salt was recrystallized from EtOAc and twice from EtOH to give 1.0 g (7%) of the thioacetate as an off-white solid, mp 118-120 ° C.

Example 42

N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-4,5-dichlorophthalimide. Mixture 2- [4- (6-fluoro -, 2- benzisoxazol-3-yl) --- piperidinyl] ethylamine (2.83 g,

10.7 mmol) and 4,5-dichlorophthalic anhydride (2.56 g, 10.7 mmol, 1.1 eq.) In methylene chloride (100 mL, DCM) was stirred for 2 hours, whereupon a white solid precipitated. and thin layer chromatography showed disappearance of the starting material. The solvent was removed and the crude solid was loaded onto a flash chromatography column (28 g, SiO ₂ , Sorbsil C-30, eluting with 1% MeOH in DCM, 0.5% NH ₄ OH added at the end of elution). The substance thus purified weighed 2.26 g and was in the form of white crystals. Recrystallization twice from plenty of hot ethanol (400 mL) gave 1.57 g of shiny white crystals, mp 132-134 ° C.

Analysis:

Calcd for C22H1 ₈ Cl ₂ FN3O3: 57.16% C 3.92% H 9 () 9% N

Found: 57.13% C 3.63% H 8.933% N

Example 43

N- [2- [4- (6-Fluoro -1,2-benzisothiazol-3-yl) -1-piperidinyl] ethyl] phthalimide

A mixed mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisothiazole (4.72 g, 0.02 mol), potassium carbonate (4.14 g, 0.03 mol) and N- (2-bromoethyl) Phthalimide (6.35 g, 0.025 mol) in 200 ml of acetonitrile was heated to reflux for 4 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N- [2- [4- (6-fluoro-1,2-benzisothiazol-3-yl) -1-piperidinyl] ethyl] phthalimide

Example 44

N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -3,6-dichlorophthalimide. Mixture 2- [4- (6-fluoro -, 2 -benzisoxazol-3-yl) --- piperidinyl-ethylamine (2.44 g,

9.24 mmol) and 3,6-dichlorophthalic anhydride (2.01 g, 9.27 mmol) in dichloromethane (DCM, 50 mL) was stirred at room temperature for 1 hour. A white solid precipitated and the thin layer chromatography of the reaction mixture showed no amine. Chap42

The solvent was removed and the white solid slightly soluble in DCM was loaded onto a flash chromatography column (SiO 2.30 g) and eluted with a solution of 1% CH ₃ OH in DCM. The desired product thus obtained weighed 2.29 g (54%). Recrystallization from hot ethanol gave 2.15 g of white crystals, mp 163-164 ° C.

Analysis:

Calculate O 2 C ₂₂ H 1 _g Cl ₂ FN ₃ O ₃ : 57ι29% C 3.92% H 9.09% N

Found: 87ι26% C 3.64% H 9.13% N

Example 45

N- [2- [4- (6-fluoro-1,2-benzinoxanol-3-yl) -1-piper-4-n-4-yl] ethyl] -4-chloudfotlimld. Mixture 2 [4 (9-fluoro-1,2-benzidxazol-O-11) -2pipery0yaylo] ethyltmlay (2.63 g,

0ι31 mol) and 4-chlorophthalic anhydride (1.82 g, 3ι32 mol) in dichloromethane (WO ml) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography. The product was further purified by recrystallization to yield N- [2- [4 (6-fluoro-1ι2-beazinoc, saz.ol-3-yl) -1-pipeuydyal-4l] ethyl] 4-chlorophthalimide.

Example 46

N- [2- [4- (6-O uoro-1 ι2benninoxanol-3-yl) -1 piperid4nylO] ethyl] 3-fluorophthalimide Mixture 2 [4 (6-fluoro-2ι2-be.azisoxazol-3-yl) -1- piperdya4l] ethldamine (2.37 g,

8.98 mmol), 3-fluorophthalic acid (1.82 g, 9.9 mmol) and 0-cyclohex-4lcarbodiimim (DCC, 5.5 g, 22.7nunol, 2.6 equiv. In units of diChoromeeotae (DCM, 255 ml). tempeeraurze room temperature for 18 go0nia. Filter ^ AA ^ Oc saaee. Rozwóc orgMcerny aatżóono. the residue was purified on a flash column (SiO2, 50 g; eluted with 1% CH ₃ OH: 99% DCM 1,41,2-6% CH ₃ OH: DCM, 11) The desired product so obtained weighed 2.64 g (71%) and was in the form of an off-white solid Recrystallization from hot ethanol gave 1.41 g of white crystals, mp 142-143 ° C.

Analysis:

Calculated for C 16JJ / N-A: 64.22% C 4.66% H104P / N

Found: 64.11% C 4.70% H 10.44% N

Example 47 [244- (6 - (6-10-1'-benzisoxazole-S-yl) -1pipero 4n4] ethyl-4-fluouophthalimide Mixture of 2- [4 (6-fluoro-1ι2-benzisoxazrl-3-yl) -2-piperid4nyl] ethylamy (2.63 g,

0.01 mol) and 4-fluorophthalic anhydride (1.83 g, 3 ι 311 mol) in dichloromethane O 2 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residual solid was purified by flash chromatography. The product was further purified by recrystallization to yield N- [2 [Z (6-fluoro-1,2-beazisoxazol-3-yl) -1-piper-4-din-4-yl] ethyl-4-fluouo αlimide.

Example 48

N- [2- [4- (6-fluoro-2ι2-benzisoxazol-3-yl) -1-piper4dyn4-yl] et4-4-methylphthalimium Mixture of 2- [4- (9-fluoro-1,2-bennisoxazdl-3-yl) -2-piperinyl] et4lamm4 (2.44 g,

9.24 mmol), 4-me4 ^/ lophthalene anhydride (1.7 g, 10.8 mmol) and dicyclohexylcarbodiimide (2.1 g, 1.0 mmol) and dichloromethane (DCM, 100 ml) was stirred at for 2 hours The solid was filtered off. The DCM solution was concentrated to a crude solid. It was purified on a flash chromatography column (35 g, SiO ₂ , Sorbsil C-30, eluting with 1% CH ₃ OH in 99% DCM). The substance thus purified weighed 1.0 g (26%) and was in the form of a white solid. Recrystallization from hot ethanol gave 665 mg of crystals, mp 138-243 ° C.

Analysis:

Calculated for C23H22FN3O3: 67.80% C 5444% H

Found: 67.67% C 5.48% H 1130% N

176 230

Example 49

N- [2e {4e (6-fluoro-1,2ebknaiaox4aol-3-i1o) -1epiperidinyl] ktyl2e4emctoxyph4limide

A mixed mixture of 2- {4- (6efluoro-1,2-be.nziaoxazole-3-10) -1-piperidinyl] ethylamine (2.63 g, 0.01 mol) and 4-methoxyphthalic anhydride (1.78 g, 0.01 01 mol) in dichloromethane (100 ml) was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure and the residual material was purified by flash chromatography. The product was further purified by recrystallization to yield N- {2- {4e (6efluoro-1,2ebenaiaox4zol-3-yl) -1-piperidinyl [ethyl-4-meth2xyphthalimide.

Example 50

N- {2- {4- (6-fluoro-1,2ebknaiaoxaao1e3ei1o) -1-epiperidinyl] ethyl-4-nitrophthalimide

A mixed mixture of 2- ^ - (8-fluoro-1,2-benzisox; 4aol-3-ίlo) e1-piperidinylo] enylamine (2.63 g, 0.01 mol) and 4eniththyl anhydride (1.93 g, 0.01 mol) ) in dichloromethane (200 ml) was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure and the residual material was purified by flash chromatography. The product was further purified by recrystallization of Ne {2e {4e (6-fluoro-1,2-benaiaoxaau-1-3-yl) -1-epipcridin-10] ethyl-4-enitroph41imide.

Example 51 fumarate 4e {4e (r-fluoro-1,2ebknziaoxazo1e3-10) -1epipkyydinyl] -2-methyloe2hydroxybutane

To a solution of 3- [4- (6-fluoro-1,2-benzisoxaau-1-3) e 1-pipy dynyl] propionate (3.21 g, 10 mmol) in tetrahydrofuran (THF, 100 mL) was added dropwise overnight. 15 minutes at room temperature under nitrogen methylmagnesium bromide (10 ml, 30 mmol, 3M solution in ether). The resulting mixture was stirred for 16 hours. Hydro1ia2wan2 is then slowly aq. NH4CL. The THF solution is diluted with EtOAc (300 mL) then washed with water and brine. The organic solution was separated and dried over MgSO ₄ . After removal of the solvent, the crude product was purified by flash chromatography (25 g, SiO2, eluting with 1% CH3OH: 99% DCM). The material so obtained weighed 2.36 g (77%) and was in the form of white crystals. It was converted to fumarate by treatment with fumaric acid (895 mg) in ethanol. Recrystallization from ethanol gave white crystals, 2.47 g, mp 156-158 °%

Analysis:

Calculated for C1 ₇ H2 ₃ FN ₂ O ₂ · C4H4O4: 59.70% C 6.44% H 6.63% N

Found: 59.40% C 6.27% H 6.28% N

The subject of the invention is therefore a group of chemical compounds capable of causing antipsychotic effects, which may also have a beneficial effect on the negative symptoms of schizophrenia. In addition, many of these compounds have a tendency to extrapyramidal side effects in mammals.

176 230

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Claims (10)

Patent claims 1. A method of producing heteroarylpiperidine compounds of the following general formula nym (1) Y— / \ N- (Ri> - (Y2) wherein Y is hydrogen or halogen; Ri is R20, R ₂ and or R22 where R ₂₀ is - (CH ₂ ) _n - wherein n is 2, 3, 4, or 5, or - (CH 2 6 where n 'is 1,2, 3,4, or 5; R21 is -CH ₂ -CH = CH-CH ₂ -, -CH ₂ -CH = CH-CH ₂ -CH ₂ -, or -CH2-CH2-CH = CH-CH2- where the bond -CH = CH- is cis or trans; R22 is R21 or R2 ₀ in which one or more than one carbon atom of R 2 _0, or R ₂₁ is substituted by at least one linear alkyl Cl; Y2 is selected from the group consisting of: (2) wherein R ₃ is hydrogen or a lower alkoxy group, and R ₂ o is - (CH 2) n-; (3) wherein R4 is hydrogen or lower alkoxy, and R20 is - _(CH2) n-; (4) Rip ABOUT 176 230 wherein R4 'is R4 or a group -C (=) - lower alkyl, and R ₂₀ is - (CH ₂₎ n'-; (5) wherein one of X or _X is -C (= O) - and the other is -CH ₂ -; R 'is R 4 or a lower alkoxy group and R ₂₀ is - (OH 5 -; (6) R4 wherein R4 'is R4 or -C (= O) loweralkyl and R2 ₀ is - (CH2 _n -; (7) wherein R4 is lower alkyl, lower alkoxy, halogen or nitro; q is 1 or 2 and R20 is - (CH2nS (9) (R) _m -MO wherein Q2 is -S- or -NH-; R is hydrogen, lower alkoxy, lower alkoxy, hydroxy, or -C (= O) -alkyl; m is 1 or 2 and R20 is - (CH2 _n -; (10) wherein R20 is - (CRR; (11) -OR] 2 wherein R ₁₂ is selected from hydrogen, lower alkyl, -C (= O) - (C _{1. I} 2 straight or branched alkyl), or -C (= O) -NR ₁₃ R ₁₄ , wherein R 3 is selected from hydrogen or Ο _{µΐ 2} alkyl groups; R ₁₄ is selected from hydrogen and alkyl groups, C _M2, and R ₂₀ is - (CH 2) _n -; (12) -NR ₁₈ R ₁₉ wherein RMjest selected from hydrogen, straight or branched alkyl groups Cu2 group -C (= O) -O- (C _M 2 alkyl), and -C (= O) - (C _W 2 alkyl); and RM is independently selected from straight or branched C _H 2 alkyl groups, -C (= O) -O- (C 12 alkyl) groups and -C (= O) - (C 1-12 alkyl) groups, or the entire NR 5 R 6 moiety forms the structure a ring selected from piperidinyl, morpholinyl or piperazinyl and R20 is - (CH2 _n -; (13) -S-R 1 where R 5 'is hydrogen, a lower alkyl group, or a -C (= O) -alkyl group and R 20 is - (CH 2) _n -; all geometric, optical and stereoisomers or pharmaceutically acceptable acid addition salts thereof, characterized by reacting compound (14) wherein Y is as defined above, under alkylation conditions, with a compound of formula (15) Hal- (R ^) - (Y2) where Ri and Y 'are as previously defined and Hal is chlorine, bromine, iodine or an equivalent leaving group which is methanesulfonyloxy (mesyloxy). 2. The method according to p. 6. A process as claimed in claim 1, characterized in that in the preparation of 6-fluoro-3 - [1- [3 - [(5-methoxy-1H-indol-6-yl) oxy] propyl-4-piperidinyl) -1,2-benzisoxuzole the reaction of the compound of formula (15) being 6- (3-chloropropoxy) -5-methoxyindole. 3. The method according to p. The method of claim 1, wherein for the production of 1 ^ ΐΏΪί ^: ώΜ & ^ η 6-fluoro-3- [1- [3 - [(1H-indol-7-yl) oxy] propyl] -4-piperidinyl] -1,2-benzisoxazole, a compound of formula (15) being 7- ( 3-chloropropoxy) -1H-indole. 4. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 6-fluoro-3- [1- (3-hydroxy) propyl-4-piperidinyl] -1,2-benzisoxazole, a compound of formula (15) being 3-bromine is reacted. 1-propanol. 5. The method according to p. 2. The process of claim 1, wherein in the preparation of 6-fluoro-3- [1- (2-pyrimidinoxy) propyl] -4-piperidinyl] -1,2-benzisoxuzole fumarate, a compound of formula (15) being 2-chloropyrimidine is reacted. . 6. The method according to p. 6. The process of claim 1, wherein in the preparation of 6-aceto-2- [4- (6-fluoro-1,2-benzisoxuzole-3-yl) -1-piperidine] -methyl-1,4-benzodioxane, the reaction is a compound of formula (15) being 6-aceto-2-mesyloxymethyl-1,4-benzodioxane. 7. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 2- [4- (6-fluoro-1,2-benzisoxazole-3-yl) -1-piperidinyl] -methyl-1,4-benzodioxane, a compound of formula (15) is administered to the reaction. ) which is' -methanesulfonyloxymethyl-M-benzodioxane. 8. The method according to p. The process of claim 1, wherein in the preparation of 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-1,4-benzodioxun, a compound of formula (15) is reacted being 2-mesyloxyethyl-1,4-benzodioxane. 9. The method according to p. 6. A process as claimed in claim 1, characterized in that in the preparation of 6- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propoxy] -7-methoxy-1-tetralone, the reaction is the compound of formula (15) being 6- (3-chloropropoxy) -7-methoxy-1-tetralone. 176 230 10. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of N-3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinylpropyl-6-acetyl-2-benzox; of formula (15) being N- (3-chloropropyl) -6-acetyl-2-benzoxazolinone. 11. The method according to p. The process of claim 1, wherein in the preparation of N- [4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butyl] -phthalimide, a compound of formula ( 15) which is 4-bromobutylphthalimide. 12. The method according to p. 7. A process as claimed in claim 1, wherein the compound is reacted in the preparation of 1- [4- [3- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] thio-3-methoxyphenyl] -ethanone. of formula (15) being 1- [4 - [(3-chloropropyl) thio] -3-methoxyphenyl] ethanone. 13. The method according to zasitrz. 7. A process as claimed in claim 1, wherein the compound of any of the preceding claims is reacted in the preparation of 1- [4- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-pipcridinyl] propylamino] -3-methoxyphenyl] ethanone. formula (15) being N- (3-chloropropyl) -6-acetyl-2-benzoxazolinone. 14. The method according to p. The process of claim 1, wherein the compound is reacted in the preparation of 1- [4- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propylamino] -3-hydroxyphenyl] ethanone. of formula (15) being N- (3-chloropropyl) -6-acetyl-2-benzoxazolinone. 15. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidin.y] o] ethyl acetate fumarate, a compound of formula (15) is reacted being 2-bromoethyl acetate. 16. The method according to p. The process of claim 1, wherein in the preparation of N- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] morpholine, a compound of formula (15) is reacted which is 2-chloroethylmorpholine. 17. The method according to p. The process of claim 1, wherein in the preparation of N- [2- [4- (6-fluoro-1,2-benzis.oxazol-3-yl) -1-piperidinyl] ethylphthalimide, a compound of formula (15) is reacted which is 2-bromoethylphthalimide. 18. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 2- [4- (6-fluoro-1,2-benzisoxazole-3-10) -1-pipcridinyl] ethyl methyl ether fumarate, a compound of formula (15) which is a methyl ether is reacted bromoethyl. 19. The method according to p. 4. The process of claim 1, wherein in the preparation of 4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butyl acetate fumarate, the compound of formula (15) being a 4- acetate is reacted. bromobutyl. 20. The method according to p. The process of claim 1, for the production of fumarate 1,2-benzisoxazole-3-yl) -1-piperidinyl] butanol is reacted and the compound of formula (15) being 4-bromobutyl acetate. 21. The method of p. 2. The process of claim 1, wherein in the preparation of 2- {4- (6-fluoro-1,2-benzisoxazole-3-yl) -1-piperidinyl yethyl] -1,3-dioxane fumarate, a compound of formula (15) being bromoethyl-1,3-dioxane. 22. The method according to p. 2. A process as claimed in claim 1, characterized in that in the preparation of 2- [4- (6-fuoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethanol hemifumarate, a compound of formula (15) being 2- acetate is reacted. bromoethyl. 23. The method according to p. 2. The process of claim 1, wherein the compound of formula (15) being 2-bromoethylphthalimide is reacted in the preparation of 2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethylamine hemifumarate. 24. The method according to p. A process as claimed in claim 1, characterized in that, in the preparation of (S) - (+) - 3- {4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-pyridinyl] -2-methyl-1- ρropanol is reacted with a compound of formula (15) which is (S) - (+) - 3-bromo-2-methyl-1-propanol. 176 230 25. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 4- (6-fluoro-1,2-benzisoxazol-3-yl) -1- [3- (1-piperidinyl) propyl] piperidine diiumarate, a compound of formula (15) is reacted being N- (3-chloropropyl) piperidine. 26. The method according to p. 3. The process of claim 1, wherein in the preparation of 1- (3-dimethylaminopropyl) -4- (6-fluoro-1,2-benzisoxazole-3-yl) piperidine difUmaran, a compound of formula (15) being 3-dimethylaminopropyl chloride is reacted . 27. The method according to p. A process as claimed in claim 1, characterized in that for the preparation of (R) - (-) - 3 - [4- (6-fluoro-1,2-benzisoxazole-3-yl) -1-piperidinyl] -2-methyl-1 - fumarate propanol, a compound of formula (15) which is (R) - (-) - (3-bromo-2-methyl-1-propanol) is reacted. 28. The method according to p. 6. A process as claimed in claim 1, characterized in that in the preparation of 6-fluoro-3 - [1- [3 - [(1H-indole-5-yl) -oxy] propyl] -4-piperidinyl] -1,2-benzozisoxazole, the compound of formula (15) being 5- (3-chloropropoxy) indole. 29. The method according to p. 6. A process as claimed in claim 1, wherein the compound is reacted in the preparation of 6-fluoro-3- [1- [3 - [(1H-indol-4-yl) oxy] propyl] -4-piperidinyl] -1,2-benzosisoxazole. of formula (15) being 4- (3-chloropropoxy) indole. A method according to claim 3. The process of claim 1, wherein 6-fluoro-3- [1- [3 - [(6-methoxy-1H-indol-5-yl) oxy] propyl] -4-piperidinyl] -1,2- hemifumarate is prepared. Benz, ozixazole, a compound of formula (15) being 5- (3-chloropropoxy) -6-methoxyindole is reacted. 31. The method according to p. A process as claimed in claim 1, characterized in that in the case of the preparation of the fumarate 3 - [4- (6-fluoro-1,2-benzozizoxazole-3-yl) -1-piperidinyl] -2,2-dimethyl-1-propanol is reacted the compound of formula (15) being 3-bromo-2,2-dimethyl-1-propanol. 32. The method according to p. 2. The process of claim 1, wherein in the preparation of 2- [4- (6-fluoro-1,2-benzozisoxazol-3-yl) -1-piperidinyl] ethyl thioacetate fumarate, the compound of formula (15) being a 2- acetate is reacted. bromoethyl. 33. A method for the preparation of heteroarylpiperidine compounds of the following general formula (16) in which Y is hydrogen or halogen; R _t is - (CH 3 - wherein n is 2,3,4 or 5; all geometric, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salts, characterized by reacting compound (17) wherein Y is as defined above, under the conditions of alkylation with N- (bromo) - (CH2) _n -phthalimide in which n is as defined above. 176 230 34. A process for the preparation of heteroarylpiperidine compounds of the following general formula (18) (18) in which Hydrogen atom, orthorium; Ri is R20, R21 or R22 where R 20 is - (CH 2 - wherein n is 2,3,4 or 5; R21 is -CH2-Ch = CH-CH2-, -CH2-CH = CH-CH2-CH2-, or -CH2-CH2-CH = CH-CH2- wherein the bond -CH = CH- is cis or trans; R22 is R21 or R2 ₀ in which one or more than one carbon atom of R20 or R21 is substituted with at least one linear alkyl group C; R ₁ 2 ^L is selected from -C (= O) - {C _in 2 linear or branched alkyl), or -C (= O) -NR Ri4 _3, wherein R ₁₃ is selected from hydrogen and alkyl groups C _M2; R _w is selected from hydrogen and C 1-6 alkyl groups, all geometric, optical and stereo isomers thereof, or pharmaceutically acceptable acid addition salts, characterized by reacting compound (19) wherein Y is as defined above under the conditions alkylation with a compound of formula (20) H'al '- (C = O) - (C ₁₂ straight or branched alkyl), or with Compound (21) Hal' - (C = O) -NR ₃ R _4; or with a compound (22) (Cm straight or branched kU ^ N ^^ _N, wherein R and R14 are as previously defined and Hal 'represents chlorine or bromine. 5. The method according to p. The process of claim 34, wherein decanoyl chloride compound of formula (20) is reacted in the preparation of decaaiaau 4- [4- (6-fluoro-2,2-beazoziadksαzold-3-yl) -2-piperOynyld] butyl fumarate. 36. The method according to replace. The process of claim 34, wherein in the preparation of 3- [4- (6-fluoro-2,2-beazoaizdxazdld-3-yl) -2-piperOyayId] prdpyl decanoate fumarate, the compound of formula (20), which is a decane chloride, is reacted. lu. 37. The method according to p. 34. A process according to claim 34, characterized in that in the preparation of N, N-Oiethyl-4- [4- (6-: fludro-1,2-beazdzizdxaaold-3-yl) -1-piperOynyl-butyl], a compound of formula (21) is reacted. ), which is Oietyldkarbtmdil chloride. 176 230 38. The method according to p. The process of claim 34, wherein in the preparation of N-methyl-4- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] butyl carbamate fumarate, the compound of formula (22) is reacted being methyl isocyanate. 39. The method of p. The process of claim 34, wherein the compound of formula (20), which is decanoyl chloride, is reacted in the preparation of 2- [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1-piperidinyl] ethyl decanoate fumarate. 40. The method according to p. The process of claim 34, wherein in the preparation of N, N-diethyl-2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl carbamate fumarate, a compound of formula ( 21) which is carbamoyl chloride. 41. The method according to p. 34. A process as claimed in claim 34, characterized in that for the preparation of (R) - (-) - 3 - [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1-piperidinyl] -2-methyl-1-acetate fumarate -propyl, a compound of formula (20) is reacted which is acetyl chloride. 42. A process for the preparation of heteroarylpiperidine compounds of the following general formula (23) in which Y is a hydrogen or halogen atom; R1 is R20, R21 or R2 ₂ where R20 is - (CH2) _n - wherein n is 2, 3,4 or 5; R ₂₁ is -CH ₂ -CH = CH-CH2-, -CH ₂ -CH = CH-CH2-CH2-, or -CH ₂ -CH ₂ -CH = CH-CH2- wherein the -CH = CH- bond is cis or trans; R22 is R20 or R21 in which one or more than one carbon atom of R 20 or R ₂ 1 is substituted by at least one linear alkyl group C; Ri9 and Rj8 are independently selected from the group - C (= O) -O- (C _M2 alkyl), and -C (= O) - _(CM 2 alkyl); all geometric, optical and stereoisomers, or pharmaceutically acceptable acid addition salts thereof, characterized by reacting compound (24) wherein Y and R1 are as above-mentioned under the conditions of closure with the compound of formula (25) H al ' ^, - (C = O) - (C1-12 alkyl); or (26) H 13 C O '- (C = O) R - O- (C 1-12 alkyl) wherein Hal' is chlorine or bromine. 43. The methods of Cs, characterized in that in the case of wdkboyamu fumufum C, 2- [4- (6-tborz-1,2-benzosisoxchol-3-yl) -1-pyearidinyl] ztylb, a compound of formula (25) being decanoyl chloride. 176 230 44. The method of p. 42. A process according to claim 42, wherein the acetyl chloride compound of formula (25) is reacted in the preparation of 2- [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1-piperidinyl] ethyl acetamide fumarate. . 45. The method of p. 42. The process of methyl 2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethylcarbamate fumarate, wherein the methyl chloroformate compound of formula (26) is reacted . 46. A process for the preparation of heteroarylpiperidine compounds of the following general formula (27) (27) in which Y is hydrogen or halogen; R1 is R20, R2i, or R22 where R20 is - (CRR wherein n is 2,3,4, or 5; R21 is -Clf-ClUCH-dR, -CH ₂ -CH = CH-CH ₂ -CH 2 -, or -CH ₂ -CH ₂ -CH = CH-CH2- wherein the -CH = CH- bond is cis or trans; R22 is R20 or R 1 ₂ in which one or more than one carbon atom of R20 or R21 is substituted with at least one linear alkyl group R ,; R12- is selected from lower alkyl, lower alkoxy, halogen and nitro groups, p is 1 or 2; all geometric, optical and stereoisomers thereof, or pharmaceutically acceptable acid addition salts thereof, characterized by reacting compound (28) wherein Y and R1 are as defined above, under alkylation conditions with an anhydride of formula (29) ABOUT 176 230 or with a phthalic acid of formula: wherein R and q are as previously defined. 47. The method of p. 46, characterized in that in the preparation of N- [2- [4- (6-fluoro-2,2-beazoninoxazole-3-ίlo) -2-piperyOynyl] ethyl] -4,5-dichlorophthalimide, the compound of formula (29) is reacted being 4,5-dichldroftalic anhydride. 48. 46, characterized in that in the preparation of N- [2- [4- (6-fluoro-1,2-benzosisoxazol-3-yl) -1-piperidinyl] ethyl] -3,6-OichOdophthalimide, the compound of of formula (29) being 3,6-0ichldrdphthalic anhydride. 49. The method of p. 46, characterized in that in the case of N- [2- [4- (6-fluoro-2,2-beanoziz.oxazol-3-yl) -1-piperidinyl] ethyl] -4-chlorophthalimide, the compound of formula (29) is reacted being 4-chocduoftaldehyde anhydride. The method of claim 50 46, characterized in that in the preparation of N- [2- [4- (6-fluoro-1,2-beazozinoxazol-3-yl) -1-piperoynyl] ethyl] 3-fluorophthimide, the compound of formula (30) is reacted which is with 3-fludrophthalic acid. 51. The method of p. 46, characterized in that in the preparation of N- [2- [4- (6-fluoro-1,2-beanonisoxazol-3-yl) -1-piperidinyl] ethyl] 4-fluoro-alimino, the compound of formula (29) is reacted which is 4-fluordphthalic anhydride. 52. The method of p. 46, characterized in that in the preparation of N-2 [4- (6-fluoro-1,2-benzozinoxαzol3yl) -1-piperidinyl] ethyl] -4-methylphthalimide, the compound of formula (29) being the anhydride 4- methylphthalic. 53. The method of p. 46, characterized in that in the case of the preparation of N- [2- [4- (6-flurro-1,2-beazozisoxanrld-3-yl) -1-pipel'-ynyl] eOyl] 4-methoxyphthalimide, a compound of formula (29) is reacted ) which is 4-methoxyphthalic anhydride. 54. The method according to replaces 46, characterized in that in the preparation of N- [2- [4- (6-fluoro-1,2-benzosisoxazole-3-yl) -1piperoynyl] ethyl] -4-α10ifttlimide, the compound of formula ( 29), which is 4n0rof0α0ic anhydride.