SK99195A3 - Heteroaromatic compounds with antipsychotic effect - Google Patents

Abstract

The present invention relates to a group of piperazine and piperidine derivatives of formula (I), wherein Y is a heteroaryl group optionally substituted by one or more halogen, nitro, C1-6alkyl, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, hydroxy, S(O)nR<2> or S(O)nN(R<2>)2 where n is 0, 1 or 2, CN, CON(R<2>)2, COR<2>, CO2R<2>, CO-aryl, azido, -N(R<2>)2, -NR<2>N(R<2a>)2, -NR<2>N = C(R<2a>)2, -NR<2>(C = O)CH(N(R<2a>)2)R<2b>, -NR<2>(C = O)R<2a>, NR<2>CO2R<2a>, C1-6alkoxycarbonylamino or PhN = N; with the proviso that Y does not include benzisothiazolyls or benzisoxazolyis, V is O or S; Z is C1-8alkylene optionally interrupted by -O- or -S(O)n- where n is 0, 1 or 2, C2-8alkenylene or C2-8alkynylene; X is N, CR<3> or COR<3>; A is CR<4> or N; B is oxygen, NR<5> or S(O)n, where n is 0, 1 or 2; and R<1> is hydrogen or one or more halogen, hydroxy, nitro, CN, NR<6>2, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, or COR<6>, R, R<2>, R<2a>, R<2b>, R<3>, R<4>, R<5> and R<6>, are each hydrogen or C1-6alkyl; or a salt, solvate, N-oxide or physiologically functional derivative thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular in the treatment of psychotic disorders.

Description

Heteroaromatic compounds with antipsychotic effect

Technical field

The present invention relates to a class of piperazine and piperidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of psychotic diseases.

BACKGROUND OF THE INVENTION

Dopamine receptors acting via chemical information are known to be located in the corpus striatum and in the limbic region of the brain, and such receptors are classified as Dj and D ₂ based on receptor binding studies and the presence or absence of a positive association between receptor and adenylate cyclase activity. . Activation of D ₁ receptors is associated with stimulation of adenylate cyclase, whereas D ₂ mediates dopaminergic effects, so that it does not involve direct stimulation of this enzyme (see Kebabian and Calne, Nature 227, 93 (1979) and Harrold

Chem. 30, 1631 (1987)]. Although different features

D ₂ is not clearly separated, strong D ₂ receptor antagonism and antipsychotic Seeman, Pharmacol are expected. Rev. 32, 229 (1981), Seeman

Pharmacol. 34, 151 (1985), Creese et al., Science 192, 481 (1976) and Leysen in Clinical Pharmacology in Psychiatry: Neuroleptic and Antidepressant Research, eds. Usdin, Gram and Lingjaerde, Macmillan: Basingstoke, p. 35 to 52 (1982)).

5-Hydroxytryptamine (5-HT), acting via the chemical information pathway, is widely found in the central nervous system and is known to be related to behavioral regulation. A number of different 5-hydroxytryptamine receptors and receptor subtypes have been identified. In addition, in blocking D ₂ receptors, it is believed that 5-HT ₂ receptor antagonism is also required for an antipsychotic agent (see Janssen et al.,

J. Pharm. and Exper. Ther. 224 (2), 658 (1988)]. In particular, et al., J. Med. D ₁ receptors and correlation between activity (see et al., Biochem.

suggests that blocking the central dopamine D ₂ receptors can control the positive symptoms of schizophrenia (e.g. delirious images and hallucinations), while blocking 5-HT ₂ receptors can help to improve the negative symptoms of schizophrenia (e.g., apathy and social recession). It is also suggested that 5-HT ₂ receptor blocking results in a reduction in extrapyramidal side effects known to occur in the case of neuroleptically maintained therapy by many known antipsychotic agents.

Psychotropically acting benzisothiazoles and benzisoxazoles are described in U.S. Pat. No. 4,968,792; 0 357 134 and 0 196 132 and 0 511 610. Further antipsychotically active piperidines and piperazines are described in European Patent Specifications Nos. 0 329 168, 0 372 657 and 0 013 612 and also in U.S. Pat. 5,225 412.

SUMMARY OF THE INVENTION

We have now found a class of piperazine and piperidine derivatives which are potential dopamine D ₂ and / or 5-HT ₂ receptor antagonists and are therefore suitable for the treatment of psychotic disorders.

The present invention relates to a compound of formula I

Y

In which

Y represents a heteroalkyl group optionally substituted by one or more halogen atoms, nitro groups, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, aryloxy, arylalkyleneoxy groups having 1 to 6 carbon atoms in the alkylene moiety, hydroxy groups of the formula S (O) _n R ² or S (O) n N (R ² ) 2, wherein n is zero, the number 1 or 2,

CN, CON (R ²⁾ 2, COR ^2, CO 2 R ^2, CO-aryl, azido, -N (R ²⁾ 2, -NR ² -N (R ²⁾ 2, -NR ² N-C (R ^2a ) ₂ ,

-NR ² (C = O) CH [N (R ^2a ) 2] R ^2b , -NR ² (C = O) R ^2a , -NR ² CO ² R ^2a , C 1 -C 6 alkoxycarbonylamino or groups of the formula PhN = N, provided that Y does not include benzisothiazolyls or benzisoxazolyls,

V represents an oxygen atom or a sulfur atom,

Z comprises an alkylene group having 1 to 8 carbon atoms, which is optionally interrupted by an oxygen atom -O- or a group of the formula -S (O) _n -, where n is zero, the number 1 or 2, furthermore an alkenylene group having 2 to 8 atoms or a C 2 -C 8 alkynylene group, q 7

X is N, CR or COR

A includes CR ⁴ or N,

B comprises an oxygen atom, a group of formula NR ⁵ or S (O) _n , wherein n is zero, the number 1 or 2, and

R ¹ includes a hydrogen atom or one or more halogen, hydroxy, nitro, cyano, N (R ⁶ ) ₂ , C 1 -C 6 alkoxy, aryloxy, arylalkylene (C 1 -C 6) or COR ⁶ groups and

R 2, R ² , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ and R ⁶ herein and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each hydrogen or C 1-6 alkyl carbon atoms, a salt thereof, a solvate thereof or a physiologically acceptable functional derivative thereof.

The compounds of formula I may form solvates, particularly hydrates or partial hydrates, and all such solvates, including physiologically acceptable solvates, are also included within the scope of the invention.

The term - (R ^x ) y should indicate the presence of y variables R ^x , which are independently selected and therefore not necessarily identical.

As used herein, the term alkyl, in a group or part of a group, may have a straight or branched chain optionally substituted by one or more halogen, hydroxy, nitro, cyano, N (R ⁷ ) ₂ , alkoxy groups with 1 from 1 to 6 carbon atoms or groups of formula COR ⁷ , and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl. Alkyl groups are most preferably methyl or ethyl.

As used herein, the term alkylene refers to a straight, branched or cyclic alkylene group of 5 or 6 carbon atoms optionally substituted by one or more halogen, hydroxy, nitro, cyano, N (R ⁸ ) 2, (C 1 -C 6) alkoxy or COR ⁸ groups, and are, for example, methylene, ethylene, butylene, pentylene, hexylene, cyclohexylene or - (CH 2) _m -cycloalkyl- (CH ₂ ) - having 3 to 6 carbon atoms in a cycloalkyl moiety wherein m is 0 to 4. The cycloalkyl having 3 to 6 carbon atoms is primarily a cyclopropylene group.

As used herein, the term alkenylene refers to a straight, branched or cyclic alkenylene group of 4 to 8 carbon atoms optionally substituted by one or more halogen, hydroxy, nitro, cyano, N (R ⁹ ) ₂ , (C 1 -C 6) alkoxy or COR ⁹ groups such as ethenylene, propenylene, butenylene, pentenylene, hexenylene and the like.

As used herein, alkynylene refers to a straight or branched alkynylene group of 4 to 8 carbon atoms, optionally substituted by one or more halogen, hydroxy, nitro, cyano, N (R ¹⁰ ) ₂ , alkoxy, C 1 -C 6 carbon atoms or groups of formula COR ¹⁰ , such as ethynylene, propynylene, butinylene, pentinylene, hexinylene and the like.

As used herein, the term alkoxy refers to -O-alkyl, -O-alkenyl, or -O-alkynyl.

As used herein, the term heteroaryl refers to a monocyclic or bicyclic fused ring system containing 5 to 10 atoms, wherein one or more ring atoms are independently selected from nitrogen, oxygen or sulfur atoms.

The bicyclic heteroaryl groups may contain one of the rings which is fully or partially saturated.

As used herein, the term aryl refers to phenyl or naphthyl (naphthalene) which are optionally substituted with one or more halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, alkyl os lower alkylthio, or formula N (R) ₂ ·

As used herein, the terms aryloxy and arylalkyleneoxy having 1 to 6 carbon atoms in the alkylene moiety refer to -O-aryl and -O-alkylenearyl having 1 to 6 carbon atoms in the alkylene moiety, wherein aryl and alkyl are as previously defined .

As used herein, the term halogen refers to a fluorine, chlorine, bromine or iodine atom.

As used herein, the term "physiologically functional derivative" means any physiologically acceptable ester or salt of such an ester derived from a compound of Formula I or a compound which upon administration to a recipient is capable of providing (directly or indirectly) such a compound or its active metabolite or its active metabolite. Rest. Such physiologically functional derivatives may also be prodrugs of the compound of the invention and are considered to be within the scope of the invention.

The present invention encompasses all optical isomers of the compounds of Formula I and mixtures thereof including racemic mixtures. The invention also encompasses all geometric isomers of the compounds of formula I, including mixtures thereof.

The invention further provides compounds of formula I, and salts, solvates and physiologically functional derivatives thereof, wherein the nitrogen atom shown in formula I in the position adjacent to the substituent Z, which is part of a six-membered ring, is in its oxidized form as an N-oxide.

The present invention includes compounds of formula I in the form of their physiologically acceptable salts. Particularly suitable salts are acid addition salts, including those formed with both organic and inorganic acids. Such salts • yAyozExpExq oqoyE yÁyozExaq 'lÄuxypxouxqo' Yau -xyopux 'yÄyouxqoojpÄqEjqoq' TÄpxaÁdoyojÄd - [ÄuxiozEuxqo 'yÄuxp -xaxqjEu' ιλχοριιχ 'yÁuxzEXuq' yÄuxund 'yÄyozexozx ¹ yÁyozExqozx' [Äiozexq 'yÁyozEXO - [ÄTozppux' yÄuoxqzuoq 'yÄuoxq' YA- xnjozuoq 'TÄ.inj' yÁyozEpxuixzuoq 'yÁyozEpxuix' yÁyouxqoozx 'yÁyouxqo' TÁuxzepxjíÄd "THIS-IAD 'TÁyozpuÁd' yÁuxzEJÄd ¹ yÁuxpxuixxÄd 'TÄpxjÄd eye-jqez es Äuxdnxs OAoyÄXEojoqoq oupoqÄA xzpew • xyos qoÁAoxuouie qoÄu -uoquEAX nqexuouip e' (Exxpuoq pEyxxxdEU) uxuioz qoÄxoxyEXTE aoaox '(nxxpos pEyxxrdEU) aoaox ροΑχοχτρχτΕ of auauoAqÄA xyos nCnujqez xyos sxoxzpq eupoqÄA' uxusoníz qoAuqouipoxd axueqsxo nqouÁA eu p ^ .EAjznod nzoui ES oujopECxxd ΑχοχβοχοχζΑχ ns OXU ρχορχ 'zpq xyos ροχ x' oujoqpíxad ΑχοχβοχοχζΑί ouíeoAaz npnq Äzeq oupoqA • xuiezeq xuiAxoxueďuoue the χρρ xuiAxoxuEfixo with οχρ ououoax xyos nCnuuqpz es xtos pxoxzpq oupoqA xzpow 'nzoxEuAA rtqeszou IP eqnuuqez zoxqxsq ns and eojioza oqauooqoosA uxuopnyz xyos oxoxzpg (nqpupAq oqeuxEXOJEd oqoyp nqpupAq ιιιΑχ -qesAopeud) nqPAqos / xyos ouijoj οχοχχ o ns' and bojoza oqouooqoosA Äuxueonyz nqpszoj oqCoAS IP oCnuuqpz ζοχχχρχ zoypuÁA oquai pxqoyqoojpÁqxp oqeye pxuoyqooupÄq nojos and C p rtopoqÄA 's nouxxosÄx noupoqA' Azpq íoujoa ouiuoj o C Euoqx 'Äuxuaonyz Cousnysxud ηοχοχΕθπ ^ es .pqpjtÄA nzoui eoxozA oqouooqoosA uxusonyz xyos' CeAOuoxqozx AuxyosAx much CoAouojynsuozuoq AuxyosAx' CoAouojynsuonyoq d AuxyosAx • CeAouojynsueqo AuxyosAx 'CoAOuojynsueqoui AuxyosAx' CoAoqoo -χρχο ÄuxyosAx 'Coaouxoxeui AuxyesAx' CoAOXEuinj AuxyosAx 'Coaoxexo ÄuxyosÄx' CoAoupqueC AuxyesAx 'CsAoqoo AuxyosAx' CoAoqooronyj -xjq. ÄuxyosAx 'CoAouzouqouÄd AuxyosAx' Ceupoxyui AuxyosAx 'Coupox -ojsoj AuxyosAx' Couuxa ÄuxyosAx 'CoAouoxqxo AuxyosAx' Coaou -XS AuxyosAx 'CoAOXxpoAOUiouq AuxyosÄx' CoAOXjpoAOxoxqo AuxyesAx of ouoaoAqÄA xyos nCnujrqEZ xyos oupoqÁA οροχΕχ, uxusonyz qoAuqouipoxd xuoqsxp much oqo.xÄA XUD ^ es .EAXznod nzoui 'oujoqECxxd ΑχοχβοχοχζΑχ ns oxu ojoqx' xyos ροχ x 'oujoqEIxud ΑχοχβοχοχζΑχ ouľeoAaz npnq

More preferred heteroaryl groups are pyridyl, pyrrole, quinolyl, imidazolyl, furyl, thienyl, benzthienyl, indolyl, naphthiridinyl, quinazolinyl, tetrahydroquinolyl and indolinyl.

Most preferred heteroaryl groups are pyridyl, quinolyl, thienyl, benzthienyl, indolyl, tetrahydroquinolyl and indolinyl.

According to a preferred aspect of the present invention Y is substituted with n group of formula N (R) ₂ ·

According to another feature of the present invention, Y is a pyridine, thiophene or benzthiophene radical optionally substituted by a n group of formula N (R) ₂ ;

According to an even more preferred aspect of the present invention, R is hydrogen or methyl, Y is a pyridine, thiophene or benzthiophene radical optionally substituted with NH ₂ , NHMe or NHAc.

In the most preferred aspect of the invention R is H and Y is pyridine or thiophene radical which is substituted by the formula NH ₂ ·

According to a further preferred aspect of the present invention, V is preferably an oxygen atom, Z is an alkylene group having 1 to 6 carbon atoms, most preferably an alkylene group having 4 carbon atoms, B is a group of the formula -S-, NH or -O-, preferably a sulfur atom -S- or an oxygen atom -O- and most preferably a sulfur atom -S-. A is a group of formula CH or N, and most preferably N, and R ¹ is hydrogen or fluoro and most preferably hydrogen.

Preferred compounds of formula I include:

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide,

N- [4- / 4- (1,2-benzisothiazol-3-y1) -1-piperazinyl / butyl] -3-pyridinecarboxamide,

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide, tert-butyl-N- [4- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / buty1] karbamoy1] -3-tieny1] carbamate,

2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide,

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide,

4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide,

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4pyridinkarboxamid,

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide,

4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-thiophenecarboxamide,

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperazinyl / butyl] benzo [b] thiophene-2-carboxamide,

2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3tiofénkarboxamid,

N- [4- / 4- (1,2-benzisothiazol-3-y1) -1-piperazinyl / butyl] -8-quinolinecarboxamide;

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2,3,4-tetrahydro-8-quinolinecarboxamide,

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-1H-indole-7-carboxamide; and

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -lH-indole

7-carboxamide and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides.

More preferred compounds of formula I include:

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide,

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2tiofénkarboxamid,

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide and * N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides.

The most preferred compound of formula I is 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide and its physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides.

The salts of the compounds of formula I are preferably hydrochloride salts, solvates are preferably hydrates.

· * Χ

The compounds of formula I show a favorable pharmacological activity profile and are suitable for the treatment of a variety of conditions. For example, the compounds exhibit an anxiolytic, centrally acting muscle relaxant and have an antidepressant effect. They are also useful in the treatment of aggression associated with senile dementia, borderline personality disorders and as broad spectrum antiemetics. The compounds are particularly useful in the treatment of psychotic disorders such as schizophrenia.

Potential antipsychotic activity can be determined by the ability of the compound to block apomorphine-induced climbing of mice (see Ogren et al., Eur. J. Pharmacol. 12, 459 (1984), Iversen, Science 188, 1084 (1975) and Gudelsky and Moore, J Neural Transm., 38, 95 (1976)). The compound's tendency to induce catalepsy and its ability to block apomorphine-induced stereotypes is a measure of behavior that demonstrates the compound's ability to induce extrapyramidal side effects.

In general, the compounds of the formula are potential dopamine D ₂ and 5-HT ₂ receptor antagonists and have utility as antipsychotics. This activity profile is confirmed by the action of the compounds of formula (I) in the mouse climbing test and by the good ratio of the dose required for the test to that required to induce catalepsy.

The compounds of formula I are also potent 5-HT _1A receptor antagonists. This activity is associated with antidepressant and anxiolytic effects as well as a reduction in extrapyramidal side effects. The combination of strong antagonism of dopamine D ₂ receptor and antagonism of 5-HT ₂ receptor agonists of ^5-HT IA receptor which has been found in preferred compounds of formula I, a particularly advantageous profile of activity for antipsychotic agents and especially for drugs used for the treatment of schizophrenia.

In another aspect, the present invention also provides a method of treating or prophylaxis of a mammal, such as a human, in a disease selected from the group consisting of fatigue, muscle cramps, depression, senile dementia aggression, borderline personality disorders, vomiting and psychosis, or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof. A method for the treatment and prophylaxis of, in particular, psychotic diseases in a mammal comprises administering to the mammal an antipsychotically effective amount of a compound of formula I or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof. In particular, the invention provides such a method for the case where the psychotic disease is schizophrenia.

In yet another aspect, the present invention provides a compound of formula I or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof for use in therapy, in particular in the treatment or prophylaxis of psychotic diseases such as schizophrenia. The invention also relates to the use of a compound of formula I or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders such as schizophrenia.

While the compounds of this invention may be administered in the form of crude chemical compounds, it is preferable to present them as pharmaceutical compositions. In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof together with one or more pharmaceutically acceptable carriers therefor and optionally at least one other therapeutic agent. component. The carrier or carriers must be acceptable in the sense that they are compatible with the other ingredients of the formulation and have no deleterious effect on the patient.

Compositions of the invention include those suitable for oral, parenteral (including subcutaneous, transdermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration, although the most preferred mode may depend, for example, on the condition and diseases of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of the invention as defined herein, or a pharmacologically acceptable salt thereof, or solvate thereof, with a carrier, which comprises one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired composition.

Compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of active ingredient, such as powders or granules, as solutions or suspensions in an aqueous or non-aqueous liquid or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be presented in the form of a bite, medicament with syrup or paste.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made, in a suitable machine, by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, glidant, inert diluent, lubricant, surfactant or dispersing aid. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredients moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may, for example, contain antioxidants, buffers, bacteriostatic preparations and solutes which render the blood recipient isotonic, and aqueous and non-aqueous sterile suspensions which may contain, for example, suspending agents and thickeners. The compositions may be presented in single or multiple dose containers, for example, in sealed ampoules or vials, and may be stored under freeze-thaw conditions, requiring only the addition of a sterile liquid carrier, such as water, for immediate use. injections. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described above.

Compositions for transdermal administration can be delivered by passive diffusion or electrically assisted transfer, e.g., iontophoresis (see, for example, Pharmaceutical Research 3 (6), 318, (1986)), and typically take the form of an optionally buffered aqueous solution of a compound of Formula I or its a salt or an acid derivative thereof. Suitable formulations include citrates or bis / tris buffer (pH 6) or aqueous ethanol. Such compositions may optionally contain formulations inhibiting lysosomal absorption.

Formulations for rectal administration may be presented as a suppository containing conventional carriers, such as cocoa butter or polyethylene glycol.

Compositions suitable for topical administration in the mouth, for example for buccal or sublingual administration, include lozenges containing the active ingredient with a flavored base such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin or glycerin, or sucrose; acacia.

Preferred dosage unit formulations are those containing the active ingredient in an amount corresponding to the active ingredient

- 15 a dose as described below, or an appropriate proportion thereof.

It is to be understood that in addition to the ingredients explicitly mentioned above, the compositions of the present invention may also include other substances conventional in the art with respect to the type of composition concerned. For example, compositions suitable for oral administration may include flavoring agents.

The compounds of the invention are preferably used for the treatment of psychotic diseases such as schizophrenia by being administered orally or by injection (intraparenterally or subcutaneously). The exact amount of compound administered to a patient will depend upon the responsibility of the attending physician. However, the dosage employed will depend on a variety of circumstances, including the age and sex of the patient, the exact nature of the disease being treated and its severity. Also, the route of administration may vary according to the condition of the disease and its severity.

The compounds of this invention may conveniently be administered orally or by injection at a dosage ranging from 0.02 to 50.0 mg per kilogram of recipient body weight per day. The dosage range for an adult is generally within the range of

1.4 to 3500 mg per day, preferably in the range of 2.8 to 1750 mg per day, particularly preferably from 7 to 700 mg per day.

The present invention also provides methods of making compounds of Formula I and their physiologically acceptable salts, solvates, and physiologically functional derivatives thereof. In general, the compounds of formula (I) may be prepared by any method known in the art for the production of analogous compounds. In the description below, the groups Z, X, V, A, B, R, R ¹ , R ² , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ meanings ascribed to them under formula I unless otherwise stated.

According to the first general process A), the compounds of the formula I can be prepared by reacting a compound of the formula II (II)

with a compound of formula III

(III) in which

L is a leaving group such as a halogen atom such as a bromine, chlorine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group in the presence of a suitable solvent and a base.

The process can be carried out either at room temperature or at elevated temperature, such as from 60 to 140 ° C. Suitable solvents include N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene and the like. Suitable bases may be selected from organic bases such as triethylamine, pyridine and the like, from alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or from alkali metal hydrides such as e.g. sodium hydride, potassium hydride and the like.

According to the second general process B), compounds of formula I in which Z represents a group of formula - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ - may be prepared by reacting a compound of formula II with a compound of formula IV

(IV) in which

W ^- is a suitable anion such as derived from a halogen such as bromine or chlorine, sulfonic acid esters such as mesylate or tosylate, and

R ¹² is - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, in particular - (CH ₂ ) ₄ -.

The reaction conditions for this reaction may be the same as described for general process A) above. Additionally, a complexing agent such as 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) may be included.

According to a third general process C), the compounds of the formula I can be prepared by reacting a compound of the formula V

(V) in which

L is as defined above, a compound of formula VI

(VI)

The process can be carried out as described for general process A) above.

According to a fourth general process (D), compounds of formula I in which X is N may be prepared by reaction of a compound of formula VII

(VII) with a compound of formula VIII

R '(VIII) in which

L is as defined above.

The process can be carried out as described for general procedure A) above.

According to the fifth general process F), the compounds of the formula I can be prepared by reacting a compound of the formula IX

IN

in which

Ί

L is halo, for example chloro or bromo, methoxy, or hydroxy, or, when Y in Formula I is substituted with at least one of the positions ortho to the amide or thioamide group of the formula -NHR ^2, reacting a compound of formula IXa

(IXa) wherein p

Y, V and R have the meanings given above with the compound of formula X

(X) in a suitable organic solvent with or without the addition of a suitable base, at room temperature, below this temperature or at elevated temperature (e.g., from -30 to 140 ° C). Suitable solvents include Ν, Ν-dimethylformamide, acetonitrile, dichloromethane, benzene, toluene, tetrahydrofuran, xylene and the like. Suitable bases may be selected from organic bases such as triethylamine, pyridine and the like, alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or alkali metal hydrides such as sodium hydride , potassium hydride and the like. In addition, catalysts or coupling agents such as trimethyl aluminum, isobutyl chloroformate or 1,3-dicyclohexylcarbodiimide (DCC) may also be included in the reaction mixture.

When L is hydroxy and Y is substituted by a group of formula NHR attached to a carbonyl or thiocarbonyl group, the process can be carried out in the presence of refluxing silica in a solvent such as anhydrous pyridine (MJ Kornet, J. Heterocyclic. Chem. Chem. 29, 103 (1992)].

According to the sixth process G) the compounds of the formula I in which Y represents a thiophene group can be prepared by treating a compound of the formula Xa

IN

(Xa) with 1,4-dithien-2,5-diol (A. Walser et al., J. Het. Chem. 28, 1121 (1991)).

The compounds of formula I may also be prepared from other compounds of formula I. Examples of such interconversions are given below.

Compounds of formula I wherein Z is C 2 -C 8 alkylene can be prepared by reduction of a compound of formula I wherein Z is C 2 -C 8 alkenylene or C 2 -C 8 alkynylene. The reduction can be achieved by catalytic hydrogenation with hydrogen in the presence of a suitable catalyst such as palladium, platinum, nickel, rhodium and the like in a suitable solvent such as ethanol, tetrahydrofuran, methanol, ether, ethyl acetate, benzene, toluene, hexane and the like. The reaction may be carried out at atmospheric or elevated pressure and at room temperature or elevated temperature, such as at 20 to 100 ° C. partial reduction of the acetylene residue (-Csc-) to the alkylene group (-C = C-) can be carried out by reduction using a poisoned catalyst as a Lindlar catalyst.

Compounds of formula I which are optionally substituted with one or more hydroxy groups can be prepared from the corresponding methoxy derivatives by known methods [e.g., treatment with a Lewis acid such as boron tribromide or aluminum chloride in a solvent such as dichloromethane at room temperature (JFW). Mcomie and DE West, Org. Synth. Coll., Vol. V, 412 (1973), RD Dillard et al., J. Med. Chem., 34, 2768-2778 (1991)].

Compounds of formula I which are optionally substituted with one or more N (R ² ) 2 or NRN (R ² ) 2 groups may be prepared by hydrolysis of the corresponding alkoxycarbonylamino derivatives by known methods, for example by treating the (tert-butoxycarbonyl) amino derivative with an acid, such as trifluoroacetic acid, and a tert-butyl cation scavenger such as anisole or thiophenol in a solvent such as chloroform at room temperature (BF Lundt, Int. J. Prept. Protein Res. 12, 258 (1978)).

Compounds of formula I which are optionally substituted with one or more amino groups can also be prepared by reduction of the corresponding nitro derivatives by known methods [e.g. catalytic hydrogenation with hydrogen in the presence of a catalyst such as platinum, palladium or Raney nickel (Org. Synth. 49, 116/1969) (J. Med. Chem., 16, 1043 (1973), J. Org. Chem., 38, 60 (1973)).

Compounds of formula I which are optionally substituted with one or more groups of formula -NR ² (C = O) R ^2a , -NR ² CO ² R ^2a or -NR ² (C = O) CH [N (R ^2a ) 2] R ^2b , can be prepared by acetylating the corresponding amino derivatives by known methods (for example, treatment with an acid chloride such as acetyl chloride or ethyl chloroformate, and with an organic base such as triethylamine in a solvent such as dichloromethane).

Compounds of formula I wherein R is C 1 -C 6 alkyl may be prepared by alkylation of the corresponding secondary amide by known methods (e.g., treatment with a base such as sodium hydride in a suitable solvent such as dimethylformamide and then treatment with an alkylating agent, such as methyl iodide).

Compounds of formula I wherein V is sulfur can be prepared by treating a compound of formula I wherein V is oxygen with a sulfonating agent such as Lawesson's reagent, i.e. 2,4-bis (4-methoxyphenyl) -1 3-dithia-2,4-diphosphetane-2,4-disulfide, in a solvent such as. toluene, at

increased temperature (Synthesis, 941/1979 / Tetrahedron 35, 2433 / 1979 /). General compounds formula I, which ones They are possibly

substituted with one or more groups of the formula NHN = C (R ² ) ₂ can be prepared from the corresponding hydrazine derivatives and the corresponding ketones by known methods.

Compounds of formula I in which a nitrogen atom is oxidized to an N-oxide may be prepared by oxidizing compounds of formula I with an oxidizing agent such as m-chloroperoxybenzoic acid in a suitable solvent such as dichloromethane.

The compounds of formula (II) are either known compounds or can be prepared by conventional methods known in the art.

Compounds of formula III may be prepared either by alkylating a compound of formula VI with a compound of formula XI

L - Z - L (XI) in which

L is a leaving group such as a halogen atom such as a bromine, chlorine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy.

In some cases, for example, when both L groups are halogen and Z is R ¹² , especially when

represents a group of formula - (CH ₂ ) 2 to a compound of formula IV (1986)). -, the same reaction can lead (J. Med. Chem. 29, 359-369 Compounds of general formula V sa they can make alkylation

of the corresponding compound of formula II with a compound of formula XI. In another embodiment, a compound of formula V can be produced by converting a hydroxy group in a compound of formula XII

IN

R (XII) to a leaving group L as defined above by known methods. Conversely, the compound of formula (XII) can be produced by condensation of a compound of formula (XII)

IX with an amino alcohol XIII

H ₂ N - z - oh (XIII) or by treatment of a compound of formula

II with a compound of formula

L-Z-OH

This process can be carried out either at room temperature or at elevated temperature, such as from 60 to 140 C. Suitable solvents include N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene and the like. Suitable bases may be selected from organic bases such as triethylamine, pyridine and the like, i

25 alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or alkali metal hydrides such as sodium hydride, potassium hydride and the like.

Compounds of formula (VI) are known compounds or can be prepared by known methods such as:

when X is a nitrogen atom and A is a nitrogen atom and B is a sulfur atom, see Yevich et al., J. Med. Chem. 29, 359-369 (1986) and U.S. Pat. 4 590 196

when X is an atom carbon, means an atom nitrogen and B means atom sulfur, see U.S. Pat. 4,528,292, when X is an atom nitrogen, means an atom nitrogen and B means atom oxygen, see J. Med. Chem. 29, 359-369 / 1986 /. when X is an atom carbon, means an atom nitrogen and B means atom oxygen, see J. Med. Chem. 28, 761-769 / 1985 /.

when X is a nitrogen atom, A is a nitrogen atom and B is a sulfonyl, see J. Med. Chem. 34, 3316-3328 (1991), alternatively, these intermediates can be prepared by treating 3-chlorobenzisothiazole-1,1-dioxide (European Patent Application 0 196 096) with piperazine in a solvent such as toluene at elevated temperatures such as from 150 to 160 ° C when X represents a nitrogen atom, A represents a nitrogen atom and B represents a sulfinyl, see J. Med. Chem. 34, 3316-3328 (1991), when X represents a carbon atom, A represents a carbon atom and B represents a group of the formula NR ⁵ , see U.S. Pat. No. 4,335,127 and U.S. Pat. No. 4,710,500, when X is a nitrogen atom, A is a carbon atom, and B is a sulfur atom, intermediates can be prepared according to the reaction scheme shown below by heating appropriately substituted aminobenzo [b] thiophenes with piperazine in a solvent such as 1- methyl-2-pyrrolidinone. The desired aminobenzo [b] thiophenes can be prepared by treating the appropriately substituted 2-fluorobenzonitrile with the methylthioglycolate anion and then decarbomethoxylating the resulting benzo [b] thiophene

when X is a carbon atom, A is a carbon atom and B is a sulfur atom, see FR patent no. 2,253,519 (1975),

if X means • nitrogen atom, A means nitrogen atom and B means group of formulas NR ⁵ , see US U.S. Pat. 4 957 916. if X means atom alkyl, A means atom nitrogen and B means

a group of formula NR ^5, the intermediate may be prepared by deprotection of N-protected piperinylindazolov, obtained by reaction of an appropriately substituted 4- (2-fluoroaroyl) piperidine (J. Med. Chem. 28, 761/1985 /) with hydrazine at reflux temperature , than. n-butanol, under reflux, according to the following scheme:

P

H

when X is a carbon atom, A is a carbon atom and B is a sulfonyl, see JP patent no. 03264583 A 2, and when X is carbon, A is carbon and B is NR ^5, see DE-A. 3,500,898 A1.

Compounds of formula VII can be prepared by alkylating piperazine with a compound of formula V.

The compounds of formula (VIII) are known compounds or can be prepared by known methods, for example:

when L is a chlorine atom, A means nitrogen atom and B means atom sulfur, see U.S. Patent No. 4 590 196. when L is a chlorine atom, A means nitrogen atom and B means atom oxygen, see J. Med. Chem. 29, 359 (1986) a

when L represents a chlorine atom, A represents a nitrogen atom and B represents a sulphonyl, see European Patent Specification no. 0 196,096 A2.

Compounds of formula (IX) or (IXa) are either known compounds or can be prepared by known methods.

For example, compounds of formula IXa can be prepared by treating appropriately substituted 2-amino acids with phosgene or a phosgene substitute (e.g., trichloromethyl chloroformate) in a suitable solvent such as benzene or dioxane (J. Het. Chem. 12, 565 (1975), J. Am. Chem. Soc., 72, 4887 (1950), J. Org. Chem., 41, 2070 (1976). Compounds of formula IXa in which V represents an oxygen atom may be prepared by treatment of the appropriately substituted anhydrides of formula XIX

(XIX) with azidotrimethylsilane in a suitable solvent such as chloroform. The corresponding thioderivatives of the general formula (IXa) in which V represents a sulfur atom can be prepared by refluxing the corresponding oxo derivatives with phosphorous sulphide in xylenes.

Compounds of formula X in which R is hydrogen may be obtained by cleavage of the corresponding phthalimides of formula Xb

hydrazine hydrate in methanol. Compounds of formula Xb may be prepared by alkylating compounds of formula VI with compounds of formula XX

(XX) in which

Z and L are as defined above.

Compounds of formula XX are either commercially available or can be prepared by alkylating a phthalimide with a compound of formula XI.

Compounds of formula X wherein R is C 1 -C 6 alkyl may be prepared from compounds of formula Xc

in which it represents a protecting group, for example a trifluoroacetate residue, by removal of the protecting group by known methods, for example by treatment with an aqueous potassium carbonate solution.

Compounds of formula Xc in which R is C 1 -C 6 alkyl may be prepared from compounds of formula X in which R is hydrogen by protecting the amino group, for example by treatment with trifluoroacetamide, followed by alkylation of the resulting protected amine with an alkyl halide with 1 to 6 carbon atoms, for example methyl iodide.

Compounds of formula Xa may be prepared by coupling compounds of formula X with cyanoacetic acid in the presence of a suitable coupling agent such as 1,3-dicyclohexylcarbodiimide (DCC) in a suitable solvent such as dimethylformamide.

Biological data

A. Antipsychotic activity

Apomorphine antagonism (5 mg / kg subcutaneously) inducing climbing in mice is a measure of dopamine receptor antagonism in the mesolimbic region of the brain, and in turn reflects potential antipsychotic activity.

Compounds are administered orally to mice 1 hour before the start of the test. 3-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide (Example 5) antagonized apomorphine-induced climbing in mice at the ED _5Q = 5 7 mg / kg, po and 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide (Example 8) at ED 50 ' ^{9 '7} mg / kg (Costall B., RJ

Naylor and V. Nohria, Climbing Behavior Induced by Apomorphine in Mice: A Potential Model for Detection of Neueroleptic Activity, European Journal of Pharmacology 50, 39-50 (1978)).

Examples of pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions in which the active ingredient is a compound of formula (I) or a physiologically acceptable salt or solvate thereof, such as 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) (-1-piperazinyl / butyl) -2-pyridinecarboxamide. These examples are not intended to limit the invention.

A. Tablets

active substance 150 mg * lactose 200 mg * maize starch 50 mg * polyvinylpyrrolidone 4 mg * magnesium stearate 4 mg *

* Content shown on the tablet

The active ingredient is mixed with lactose and starch and then granulated with a solution of polyvinylpyrrolidone in water. The resulting granules are dried, mixed with magnesium stearate and compressed into tablets.

B. Injections

Injection I

The salt of the compound of this invention is dissolved in sterile water for injection.

Formulation II consisting of intravenous injections of the active substance 0.20 g sterile phosphate buffer, pH 9.0, pyrogen-free to 10 ml

The effective phosphate given volume is dissolved in most of up to 40 ° C, then made up into a filter into (type 1), which are sealed into vials.

the substance in the form of a buffer salt at 35 and filtered through a sterile microporous 10 ml sterile vial and capped

C. Capsule composition

Capsule composition

Compound I can be prepared by mixing the resulting mixture in two parts by mixing the ingredients and hard gelatin capsules.

a)

b)

c)

(d) the active ingredient lactose B. P.

Starch sodium glycolate Magnesium stearate, total

Capsule composition II

(a) the active substance

(b) Macrogel 4000 B.P.

total mq / capsule

250

143

420 mq / capsule

250

350

600

Capsules can be made by melting, dispersing the active ingredient in the melt and two-piece hard gelatin capsules.

B. P.,

Macrogel 4000 by filling the melt into

Capsule formulation III (controlled release capsule) mg / capsule

(a) the active substance 250

(b) microcrystalline cellulose125

(c) lactose B. P.125

(d) ethyl cellulose13 total 513

A controlled release capsule formulation is prepared by extruding the miscible ingredients (a) to (c) using an extruder, then spheronizing and drying the extrudate. The dried granules are then coated with the ethylcellulose mentioned under d) as the release controlling membrane and filled into two-piece hard gelatin capsules. .

Composition in the form of a syrup active substance

0.2500 g sorbitol solution

1.5000 g glycerol

1.0000 g sodium benzoate

0,0050 g flavor

0.0125 ml purified water up to 5.00 ml as needed

Sodium benzoate is dissolved in portions in purified water and sorbitol solution is added. The active substance is added to the solution and dissolved. The resulting solution is mixed with glycerol and then adjusted to the desired volume with purified water.

Lace-up active ingredient (63 μπι) * hard fat, B. P. (Witepsol H15 - Dynamite Nobel) total mq / suppositories

250

1770

The 2020 active substance is used as a powder in which at least 90% of the particles have a diameter of 63 μιη or less

One fifth of Witepsol H15 melts in a steam-coated pan at a maximum temperature of 45 C. C. The active ingredient is passed through a 200 mesh screen and added to the molten base with stirring, using a Silverson stirrer mounted with the cutting head, and stirring is continued until a smooth dispersion is obtained. The mixture is maintained at 45 ° C, the remaining Witepsol H15 is added to the suspension and mixed to ensure a homogeneous mixture. The whole suspension is passed through a 250 µm stainless steel sieve and allowed to cool to 40 ° C with continuous stirring. At 38-40 ° C, 2.02 g portions of the mixture are filled into suitable plastic molds, and Allow the laces to cool to room temperature.

F. Transdermal

Compositions suitable for transdermal administration may be presented as separate patches adapted to remain in close contact with the recipient's skin over an extended period of time. Such patches preferably contain the active ingredient

1) in a buffered aqueous solution, if any,

(2) dissolved in an adhesive substance; or

3) dispersed in the polymer.

A suitable concentration of active ingredient is about 1 to 20%, preferably about 3 to 15%. A specific embodiment is that the active ingredient is released from the patch by iontophoresis, as generally described in Pharmaceutical Research 3 (6), 318 (1986).

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples, which are not to be construed as limiting in any way.

s Experimental section

General information

Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Anhydrous solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, toluene, pyridine and dimethylsulfoxide (DMSO) were obtained from Aldrich Chemical Company in securely sealed containers. Triethylamine was distilled from calcium hydride before use. All reactions using compounds sensitive to air or moisture are carried out under a nitrogen atmosphere. Flash chromatography (W.

C. Still et al., J. Org. Chem. 43, 2923 (1978)) and flush chromatography are performed using EM Scienè silica gel 60 (with a grain size of 37 nm, 230-400 mesh ASTM). Thin-layer chromatography (TLC) is performed on Analtech silica gel FG TLC plates (250 μιη grain size). NMR spectra and ¹³ C NMR spectra are determined in a FT superconductor FT NMR spectrometer at 200, 300 and 500 MHz. Chemical shifts are expressed as deviation from trimethylsilane in ppm. Significant H NMR values are reported in order: multiplicity (s singlet, d doublet, t triplet, q quartet, m multiplet), number of protons and coupling constant, expressed in Hz. Elemental analyzes are performed on either Atlantic Microlab, Inc., Norcross Georgia or Gal Braith Laboratories, Inc.. Knoxville, Tennessee. Melting points are determined using a capillary temperature determination apparatus (Thomas Hoover) and are uncorrected.

The piperidine benzisothiazole intermediate 3- (1-piperazinyl) -1,2-benzisothiazole was prepared according to known methods (J. P. Yevich et al., J. Med. Chem. 29, 359-369 (1986)).

EXAMPLES

Example 1

a) Method for the preparation of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] phthalimide hydrochloride

3.50 g (0.0124 mmol, 1 L, 2.24 mL acetonitrile)

N- (4-bromobutyl) phthalimide, 2.72 g

Of 3- (1-piperazinyl) -1,2-benzisothiazole equivalent) triethylamine and 15.0 ml round-bottomed flask was heated (0.0124 ml)

1.0 equivalents) (0.0161 mol, 1.3 was added to orange at reflux for room temperature and the solution was washed dried with sulfate to give 5.48 g of light.

100 ml. Quenched with atmosphere and boiled is allowed to cool with methane. The organic is melted with potassium, steam, giving a crude bottom under nitrogen for 17 hours. The mixture was diluted with dichloromethane saturated with carbonate, filtered, and an off-white solid. This acetonitrile and dried in a vacuum oven to 4.35 g of brown powder. The hydrochloride is prepared by adding 1N ethereal hydrogen chloride and recrystallizing from 95% ethanol. 4.53 g of the title compound is obtained as an off-white powder, m.p. 258 DEG-260 DEG C. (dec.). Yield: 82%.

¹ H NMR (DMSO-d 6): δ 1.72 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.02 (broad doublet, 2, J = 13), 7), 7.44 (ddd, J = 8.1, 7.0, 1.1),

7.57 (ddd, 1, J = 8.1, 7.0, 1.0) 7.85 (m, 4), 8.09 (dd, 2, J = 8.0, 4.5), 11.18 (broad singlet, 1) ppm.

3Ί ¹³ C NMR (DMSO-d₆): δ 20.52, 25.25, 36.82, 46.30, 50.44,

54.98. 121.13, 122.98, 123.94. 124 , 56, 126.90, 128.06, 131.58, 134,33, 152 , 04, 162.16, 167.93. analysis for ^C 23 ^H 24 ^N 4 ° 2 ^N . HC1: calculated: 60.45% C, 5.51% H, 12 16 % N, found • 60.46% C, 5.55% H, 12 17 % N.

b) Process for the preparation of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole

2.62 g (1.5 equivalents) of 85% hydrazine hydrate (Aldrich Chemical Company) was added to a solution of 12.46 g (0.0296 mol).

2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] phthalimide in 30 mL of methanol. The reaction mixture is refluxed for

3.5 hours and then allowed to cool to room temperature. To the solution was added 59.0 mL of 1N hydrochloric acid, and the resulting white precipitate was filtered off and washed with water. The filtrate was basified by addition of 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and rotary evaporated. This gave 8.1 g of the title compound as an orange-brown oil. Yield: 94%.

This crude amine was used without further purification

c) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide hydrochloride

1.1 g (6.1 mmol) of nicotine chloride hydrochloride (Aldrich Chemical Company) was gradually added to an ice-cold solution of 1.8 g (6.0 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] with stirring t-1,2-benzisothiazole and 2.5 mL (17.9 mmol, 3 equivalents) of triethylamine in 25.0 mL of dichloromethane. The resulting suspension was allowed to stir at 0 ° C for 30 minutes and then at room temperature for 2 hours. The cloudy reaction mixture was diluted with dichloromethane (25.0 mL) and washed twice with saturated sodium bicarbonate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated on a rotary evaporator to give an off-white foam. The crude material was diluted with 20.0 mL of isopropanol, cooled rapidly in an ice bath, and treated dropwise with 6.0 mL of 1N ethereal HCl solution with rapid swirling. The mixture was diluted with 40 mL of ether and the resulting off-white solid was filtered and washed three times with 10 mL of ether each time. The salt was recrystallized from 95% ethanol to give 1.47 g of the title compound as off-white crystals having a melting point of 229-231 ° C. Yield: 57%.

¹ H NMR (DMSO-d ₆ ): δ 1.64 (m, 2), 1.81 (m, 2), 3.27 (m, 4), 3.47 (m, 2), 3.62 (broad doublet, 2, J = 11.5), 4.10 (broad doublet, 2, J = 11.3), 7.56 (m, 2), 7.62 (t, 1, J = 7, 6), 8.14 (t, 2, J = 6.8), 8.23 (d, 1, J = 6.2), 8.73 (d, 1, J = 4.5), 8, 81 (broad triplet, 1, J = 6.2), 9.05 (s, 1), 10.82 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.76, 27.33, 39.58, 47.53, 51.61,

56.25, 122.35, 124.57, 125.16, 125.78, 128.11, 129.28, 131.10,

136.15, 149.55, 152.88, 153.26, 163.39, 163.39, 165.92.

M + 1 (396).

mA / sec), m / z:

Mass spectrum (CI / CH3),

Analysis for ^C 21 ^H 25 ^N 5 ^OS . HC1: calculated: 58.39% C, 6,07% H, 16.21 % N, 7.42% S, 8.21 % Cl, found: 58.37% C, 6,12% H, 16.14 % N, 7.49% S, 8.14 % Cl.

Example 2

(a) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -

-1-piperazinyl / butyl] -4-pyridinecarboxamide

This compound was prepared as described in Example 1c) using 1.1 g (6.1 mmol) of isonicotinoyl chloride hydrochloride (Aldrich Chemical Company), 1.8 g (6.0 mmol) of 3- / 4- (4-aminobutyl) -1-piperazinyl / -1,2-benzisothiazole (Example 1 (b) and 2.5 mL (17.9 mmol, 3 equivalents) of triethylamine in 25.0 mL * dichloromethane) The crude hydrochloride was recrystallized from 95% ethanol to give 1.20 g of the title compound as off-white crystals, m.p. 238 DEG-240 DEG C. Yield: 46%.

^X H NMR (DMSO-d₆): δ 1.64 (m, 2), 1.80 (m, 2), 3.29 (m, 4), 3.46 (m, 2), 3.61 ( broad doublet, 2, J = 10.5), 4.10 (broad doublet, 2, J = 10.5), 7.49 (t, 1, J = 7.6), 7.62 (t, 1) , J = 7.6)

7.80 (d, 2, J = 5.8), 8.15 (t, 2, J = 6.7), 8.75 (d, 2, J = 5.8),

8.90 (broad triplet, 1, J = 5.5) 10.80 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.76, 27.24 , 39 68. 47.53, 51.61, 56.24, 122.36, 122.45. 125.17, 125.78, 128, 11 129.28, 142.56, « 151.30, 153.26, 163,39, 165.78. 4 weight spectrum (CI / _CH4, 50 mA / sec, m / z: M + (396).

Analysis for ^C 21 ^H 25 ^N 5 ^OS . HC1: calculated: 58.39% C, 6,07% H, 16.21 % N, 7.42% S, 8.21% Cl, found: 58.47% C, 6,11% H, 16.12 % N, 7.38% S, 8.15% Cl.

Example 3

a) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide hydrochloride ¹³ C NMR (DMSO-dg): δ 21.79, 27 , 54, 39.31, 47.51, 51.61,

56.32, 122.36, 123.02, 125.15, 125.78, 127.61, 128.10, 129.28,

138.94, 149.50, 151.16, 153.24, 163.37, 165.04.

Mass spectrum (CI / CH ₄ , 50mA / s, m / z: M + 1 (396)).

Analysis for ^C 21 ^H 25 ^N 5 ^OS . HC1: calculated: 58.39% C, 6,07% H, 16.21 % N, 7.42 % S, 8.21 % Cl, found: 58.10% C, 6,10% H, 16.04 % N, 7.39 % S, 8.09 % Cl.

Examples 4 and 5

a) A process for the preparation of 3-azaisate anhydride and 6-azaisate anhydride

A. A 2: 1 mixture of 3-azaisate anhydride and 6-azaisate anhydride was obtained from 11.4 g (76 mmol) of 2,3-pyridinecarboxylic acid anhydride (Aldrich Chemical Company), 11.4 ml (86 mmol). , 1.1 equivalents) of azidotrimethylsilane (Aldrich Chemical Company) and 500 ml of chloroform according to the method described by DJ Le Court and DJ Dewsbury in Synthesis 11, 972 (1982). The precipitate obtained from the reaction mixture is filtered and dried. 6.10 g of a 2: 1 mixture of the title compounds are obtained as a white solid, m.p. 207 DEG-210 DEG C. (dec.). Yield: 48%.

Ί

1 H NMR values for the 6-isomer (minor component) are shown in square brackets. @ 1 H NMR (DMSO-d6): .delta.7.29 (dd, 1, J = 4.9, 7.8), [7.53 (dd, 1, J = 1.5, 8.6)] , [7.69 (dd, 1, J = 4.5,

8.6)], 3.29 (dd, 1, J = 1.8, 7.8), [8.49 (dd, 1, J = 1.5, 4.5)],

8.64 (dd, 1, J = 1.8, 4.9), [11.53 (broad singlet, 1)] 12.53 (broad singlet, 1) ppm.

1.2 g (9.7 mmol) of picolinic acid (Aldrich Chemical Company) and 0.56 g (10.0 mmol) of potassium hydroxide are dissolved in 25.0 ml of distilled water. Water was evaporated on a rotary evaporator and the resulting white solid was treated with 25.0 mL of benzene. The solution was evaporated and dried under high vacuum. The resulting potassium salt was suspended in 15.0 mL of benzene and cooled in an ice bath.

1.0 ml (11.5 mmol) of oxalyl chloride was added dropwise to the obtained cold solution. The reaction mixture was allowed to warm to room temperature and then gradually warmed to gentle reflux. The resulting burgundy-black solution was cooled and added dropwise to a cold solution (bath consisting of ice and water) 3.0 g (10.0 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1, Of 2-benzisothiazole (Example 1 (b)) and 2.5 ml (17.9 mmol) of triethylamine in 10.0 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred overnight. The dark suspension was evaporated on a rotary evaporator to give a black oil. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated under reduced pressure. 5.01 g of a dark oil are obtained. The crude material was purified by flash chromatography on silica gel, using graduated chloroform, acetone and chloroform, acetone, to give 1.80 g of free methanol in the ratio of methanol to amine. Obtained by elution with the mixture

28 : 2: 1 to mixture 14 : 2: 1. This is how

The material is taken up in dichloromethane, hydrogen chloride and treated with 4.6 ml of a 1N ethereal solution diluted with ethyl acetate. The dark colored precipitate was filtered from solution and the filtrate was allowed to stand for 3 days. The crystals formed by standing are filtered and dried. 1.15 g of the title compound is obtained in the form of off-white crystals, m.p. 231 DEG-234 DEG C. Yield: 27% of theory.

^{Χ Η} NMR (DMSO-d₆): δ 1.61 (m, 2), 1.76 (m, 2), 3.18 to 3.38 (m, 8), 3.57 (m, 2), 4.10 (m, 2), 7.47 (tm, 1, J = 7.6), 7.61 (m,

2), 8.02 (m, 2), 8.12 (t, 2, J = 8.1), 8.65 (dt, 1, J = 4.7,

1.2), 8.92 (t, 1, J = 6.2), 10.30 (broad singlet, 1) ppm.

b) A process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide hydrochloride and 3-amino-N- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide

A. A 2: 1 mixture of 1.0 g (6.1 mmol) of 3-azaisate anhydride and 6-azaisate anhydride was added to a solution of 1.8 g (6.0 mmol) of 3- / 4- with stirring. (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 1 (b)) in 20.0 mL of tetrahydrofuran. The reaction mixture was allowed to stir under nitrogen at room temperature for 30 minutes. The solvent was removed by rotary evaporation and the resulting crude residue was purified by flash chromatography on silica gel eluting with 100% dichloromethane, dichloromethane / methanol in a ratio of:

98.5: 1.5, 97: 3 dichloromethane / methanol, and 97: 3 97: 3 finally dichloromethane: methanol. 1.48 g are obtained.

2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide as a foam (91% yield) and 0.54 g 3 amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide as a foam (yield: 66% of theory). The hydrochloride salts of each isomer were prepared independently by dissolving the free amine in 20.0 mL of dichloromethane, filtering the resulting solution, and treating the filtrate with 1 equivalent of 1 N ethereal HCl. The solutions were diluted with ethyl acetate and allowed to stir at room temperature for 1 hour. The resulting white crystals were collected by filtration in a vacuum oven to give the corresponding hydrochloride salts.

Example 4

2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide hydrochloride

TLC: silica gel, methanol: chloroform 1: 9 _(Rf = 0.25), m.p. 220-222 "C.

¹ H NMR (DMSO-d 6): δ 1.59 (m, 2), 1.75 (m, 2), 3.32 (m, 8),

3.57 (m, 2), 4.08 (m, 2), 6.60 (dd, 1, J = 4.8, 7.7), 7.10 (s, 2), 7.47 ( t, 1, J = 7.6), 7.60 (t, 1, J = 7.5), 7.93 (dd, 1, J =

0.8, 7.6), 8.07 (dd, 1, J = 1.3, 4.7), 8.12 (t, 2, J = 8.0), 8.54 (broad triplet, 1, J = 5.5), 10.55 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.84, 26.30, 38.45, 46.62, 50.71,

55.38, 110.97, 111.59, 121.51, 124.32, 124.94, 127.28, 128.45,

138.10, 149.18, 152.47, 158.05, 162.58, 167.33.

Mass spectrum (CI / CH3), 50mA / s, m / z: M + 1 (411).

Analysis for ^C 21 ^H 26 ^N 6 ^OS . HC1: calculated: 56,43 % C, 6,09% H, N, 18.80; S, 7.17; C1, 7.93 found: 56,36 % C, 6,14% H, N 18.75%, S 7.19%, 8.03% C1

Example 5

3-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide hydrochloride

TLC: silica gel, methanol / chloroform 1: 9 (Rf = 0.47), mp 238-240 ° C.

3.58

J = ¹ H NMR (DMSO-d ₆ ):

(m, 2), 4.08 (m,

1.4, 8.4), 7.24

2), (dd,

1.59 (m, 2), 1.74 (m,

6.84 (broad singlet,

1, J = 4.2, 8.4),

2),

2),

7.47

3.30

7.15 (tm, (m, 8), (dd, 1,

1, J =

8.0), 7.60 (tm, 1, J = 8.0), 7.79 (dd, 1, J = 1.4, 4.2), 8.12 (t, 2, J = 8) 2), 8.69 (broad triplet, 1, J = 6.2), 10.40 (broad singlet, 1) ppm.

13 ₍ 1 H NMR (DMSO-d 6): δ 20.77, 26.55, 37.68, 46.47, 50.56, 55.29. 121.27, 124.07, 124.53, 124.70, 127.02, 127.24, 128.19, 128.91. 135.49, 146.32, 152.17, 162.28, 167.56.

Mass spectrum (CI / CH ₄ , 50mA / s, m / z: M + 1 (411)).

Analysis for ^C 21 ^H 26 ^N 6 → ⁸ . H, 6.09; Found: C, 56.36; H, 6.12;

18.80% N, 7.17% S, 7.93% C1,

N, 18.70; S, 7.12; C1, 7.85.

Examples 6 and 7

a) Process for preparing 4-azaisate anhydride and 5-azaisate anhydride ml of anhydrous chloroform, 11.5 g (77.1 mmol) of 3,4-pyridinecarboxylic anhydride and 10.1 g (88.0 mmol, 1.14) of azidotrimethylsilane was placed in a 250 ml round bottom flask and placed under a nitrogen atmosphere. The resultant cream-colored suspension is gently warmed to initiate the reaction. The reaction is exothermic and nitrogen gas is released. After 10 minutes the evolution of nitrogen was stopped and the solution was further refluxed for 45 minutes. As the reaction proceeds, the solids dissolve to form a clear light yellow solution. The reaction mixture was allowed to cool to room temperature and 4.5 mL (77.1 mmol, 1 equivalent) of ethanol was added in one portion. Solids precipitated out of solution as soon as ethanol was added. The mixture was allowed to stir at room temperature for 15 minutes and the solids were filtered off, washed with chloroform and dried in a vacuum oven at room temperature. 12.6 g of a pale yellow powder are obtained. This material is mixed with 100 ml of acetonitrile and the undissolved powder is filtered off. The filtrate is refluxed for minutes. The solution was allowed to cool to room temperature and further cooled in an ice bath. The resulting solid was collected by filtration and the filtrate was 1.80 g yellow by titrating all boiling acetonitrile and the filtrate was evaporated. The title compound yielded 41% 1: 1 anhydride and was evaporated on a rotary powder. The second undissolved within 90 minutes.

thereby providing a solid proportion in the form

The mixture was further evaporated.

product of substances

Thus, 3.35 g of yellow solids are obtained while hot in 100 ml. Overall theories. The crude material is a mixture in the ratio of 4-azaisate acid to acid anhydride of the compounds

5-azaizate, as shown by the integration of the corresponding signals in the ¹ H NMR spectrum.

¹ H NMR (DMSO-d 6): δ 7.08 (d, 1, J = 5.6), 7.80 (dd, 1, J = 4.8, 0.7), 8.45 (d 1, J = 4.8), 8.54 (s, 1), 8.66 (d, 1, J =

5.6), 8.96 (s, 1), 12.08 (broad singlet, 2) ppm.

This material was used without further purification.

b) A process for the preparation of 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide dihydrochloride hydrate and 4-amino-N- [4] dihydrochloride - / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide

A. A mixture of 4.71 g (28.7 mmol) of an acid anhydride mixture

Of 4-azaisate and 5-azaisate anhydride in a ratio of 1: 1 are introduced into a solution of 8.33 g (28.7 mmol, 1 equivalent) with stirring.

3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 1 (b)) in 40.0 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to stir under a nitrogen atmosphere at room temperature for 1 hour. The solvent was removed on a rotary evaporator and the resulting crude residue was purified twice by flash chromatography on silica gel, once with 5: 95 methanol / dichloromethane containing 0.1% triethylamine as eluent, and once with methanol / dichloromethane. 3: 97 containing 0.1% triethylamine as eluent. 3.11 g are thus obtained

3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide, as a brown foam (26% yield), thin layer: silica gel, 95: 5 methanol / dichloromethane, Rf = 0.44) and 2.99 g

4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide, as an orange solid (24% yield), (chromatography TLC: silica gel, 95: 5 methanol / dichloromethane Rf = 0.32). The hydrochloride salts of each isomer are prepared independently by treatment with 1N ethereal hydrogen chloride solution. The salts are recrystallized from either ethanol, ether and ethyl acetate or 95% ethanol and dried in a vacuum oven.

Example 6

3-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide dihydrochloride hydrate ¹ H NMR (DMSO-d 6, 300 MHz): δ 1 61 (m, 2), 1.83 (m, 2), 3.25 (m, 6), 3.55 (m, 4), 4.06 (broad doublet, 2, J = 13.2) 7.46 (t, 1, J = 7.6), 7.59 (dt, 1, J = 8.1, 0.8), 8.04 (s, 2), 8.12 (t .

I, J = 8.1), 8.31 (s, 1), 9.24 (broad triplet, 1, J = 4.4),

II, 45 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6, 50.29 MHz): δ 20.73, 26.05, 38.47, 46.54, 50.64, 55.26, 121.51, 124.32, 124.93 , 126.48, 126.40, 127.02,

127.28, 128.44, 130.62, 146.83, 152.46, 162.59, 165.43.

Analysis for C ₂₁ H ₂ gNgOS. 2 HCl. 0.5 H ₂ 0: calculated: 51.22 % C, 5.94 % H, N, 17.07 17.07 % Cl, 14.40 % h ₂ o found: 51.02 % C, 6.05 % H, 16.98% N, 14.09 % Cl, 14,54 % h _2o .

Example 7

4-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide dihydrochloride

Mp 122-130 ° C.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.64 (m, 2), 1.79 (m, 2), 3.07 (m, 2), 3.30 (m, 8), 3 74 (broad singlet, 2), 6.93 (d, 1, J =

6.6), 7.48 (t, 1, J = 7.5), 7.61 (t, 1, J = 8.7.4), 8.12 (m, 1),

8.44 (broad doublet, 2), 8.74 (s, 1), 8.97 (broad triplet, 1,

J = 5.6), 12.40 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6, 50.29 MHz): δ 21.12, 26.07, 38.30, 46.95, 50.83, 55.51, 111.05, 111.14, 121.22 , 124.07, 124.64, 127.06,

128.13, 141.52, 142.36, 152.11, 157.68, 162.50, 165.22.

Analysis for ^C 21 ^H 26 ^N 6 ^OS · ^{2 HCl:} Calculated: C 52.17, H 5.84,

17.38% N, found:

% C, 52.25;% H, 6.17;

17.31% N.

Example 8

a) A method for producing hydrochloride

3-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide

2.83 g (9.75 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 1 (b)) and 50 ml of anhydrous chloroform are placed in a round-bottomed flask. 250 ml and stirred under a nitrogen atmosphere. To the reaction mixture, 9.8 mL (19.6 mmol, 2.01 equivalents) of trimethyl aluminum (Aldrich Chemical Company) was added dropwise as a 2 molar solution in toluene, and the resulting reaction mixture was stirred for 30 minutes. A solution of 1.66 g (10.56 mmol, 1.08 equivalents) of methyl [3-amino-2-thiophenecarboxylate] (Aldrich Chemical Company) in 25 mL of anhydrous chloroform was then added and the orange solution was heated for days. The reaction mixture was slowly added with hydrochloric acid. Value of potassium carbonate and acid by saturated funnel separator.

separated.

layer with 200 ml of water. The aqueous layers are

Add to the separatory funnel

The organic layers were combined twice and extracted at 45-50 ° C for 5 to 100 mL of cold 1 N pH of the mixture was adjusted to a mixture, transferred with chloroform, washed with chloroform each.

to

The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated. 6.53 g of crude material is obtained in the form of a thin dark brown-orange oil. The free base was purified by flash chromatography, eluting with dichloromethane followed by a 95: 5 mixture of dichloromethane and methanol to give 1.32 g of a brown solid. 1.32 g (3.06 mmol) of the free base was dissolved in dichloromethane and 3.06 g of ethereal hydrogen chloride solution from aqueous ethanol was added. The hydrochloride is recrystallized from the title compound as a brown solid, mp 230-232 ° C. Yield: 21%.

^X H NMR _(DMSO-d6): δ 1.54 (m, 2), 1.75 (m, 2), 3.26 (m, 6),

3.48 (m, 2), 3.61 (broad doublet, 2, J = 11.1), 4.10 (broad doublet, 2, J = 12.5), 6.42 (broad singlet, 1) 6.60 (d, J, J =

5.3), 7.40 (d, 1, J = 5.3), 7.55 (m, 2), 8.15 (broad triplet, 2, J = 6.9), 10.51 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6):

δ 21,65,

27.61, 38.86, 47.40, 51.48,

56.24, 102.19, 121.90, 122.16, 124.97, 125.62, 127.92, 128.59,

129.12, 153.06, 154.08, 163.18, 165.53.

Analysis for ^C 20 ^H 26 ^N 5 ^OS 2 · ^HCl: calculated: 53.14% C, 5.80% H, 15.49% N, found: 53.23% C, 5.86% H, 15.36 % N.

Example 9 (a) Method for the preparation of methyl [4 - [(tert-butoxycarbonyl) amino] -3-thiophenecarboxylate]

6.57 g (33.9 mmol) of methyl [4-aminothiophene-3-carboxylate] hydrochloride (Maybridge Chemical Company), 25 ml of 1,4-dioxane and 25 ml of 5% sodium carbonate solution were contacted in a flask with 500 ml round bottom and cooled in an ice bath. A solution of 18.6 g (85.2 mmol) is slowly added dropwise to the reaction mixture.

2.51 equivalents) of di-tert-butyl dicarbonate (Aldrich Chemical Company) in 25 mL 1,4-dioxane. The ice bath was removed and the reaction mixture was allowed to warm to room temperature for 18 hours. Another portion (3.86 g, 17.7 mmol, 0.52 equivalents) of di-tert-butyl dicarbonate in 10 mL of 1,4-dioxane was added and the reaction mixture was stirred at room temperature for 26 hours. The reaction mixture was then transferred to a separatory funnel. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed twice with water, dried over magnesium sulfate, filtered and evaporated. A red-brown liquid is obtained. The crude material was partially purified by flash chromatography eluting with a gradient of 100 to 95% hexanes and 0 to 5% ethyl acetate. A colorless liquid is obtained. The title compound precipitates upon standing. 2.09 g of the desired product are obtained having a melting point of 100-102 ° C. Yield: 24%.

^X H NMR (DMSO-d₆, 60 ° C): δ 1.48 (s, 9), 3.84 (s, 3), 7.53 (d, 1, J = 3.5), 8.32 (d, 1, J = 3.5), 9.01 (broad singlet, 1) ppm.

¹³ C NMR (CDCl ₃ ): δ 28.69, 52.27, 80.94, 107.74, 121.74,

132.96, 137.74, 153.49, 184.78.

Analysis for C ₁₁ H ₁₅ NO ₄ S: Calculated: 51.35% C, 5.88% H 5.44% N Found: 51.28% C, 5.90% H, 5.48% N.

b) Process for preparing 4 - [(tert-butoxycarbonyl) amino] -3-thiophenecarboxylic acid

2.08 g (8.08 mmol) of methyl [4 - [(tert-butoxycarbonyl) amino] -3-thiophenecarboxylate], 40 ml of 95% ethanol and 10 ml of 50% sodium hydroxide solution are introduced into a round-bottomed flask. volume of 500 ml and heated at 45 ° C for 1 hour. The reaction mixture was allowed to cool and the pH was adjusted to 2 by addition

1-normal hydrochloric acid. The reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. A white solid is obtained. The material obtained is dried for the second time as described above and then dried in a vacuum oven. This gives 1.83 g of the title compound as a white solid, m.p. 167-168 ° C (vigorous gas evolution). Yield: 93%.

¹ H NMR (DMSO-d ₆ ): δ 1.50 (s, 9), 7.54 (broad doublet, 1,

J = 3.3), 8.32 (d, J, 3.5), 9.31 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 28.85, 81.07, 108.30, 122.83, 134.94,

137.35, 152.89, 166.20.

Calculated for ^C io ^h 13 ^N0 4 ^S: Calculated: 49.37% C, 5.39% H 5.76% N Found: 49.30% C, 5.44% H, 5.72% N.

c) Process for the preparation of tert-butyl [N- [4- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] -3-thienyl] carbamate]

1.49 g (6.12 mmol) of 4 - [(tert-butoxycarbonyl) amino] -3-thiophenecarboxylic acid, 2.09 g (7.20 mmol, 1.18 equivalents) of 3- [4- (4-aminobutyl)] 1-piperazinyl-1,2-benzisothiazole (Example 1 (b)) and 20 ml of anhydrous N, N-dimethylformamide are combined in a 500 ml round bottom flask. A solution of 1.60 g (7.75 mmol, 1.27 equivalents) of 1,3-dicyclohexylcarbodiimide (Aldrich Chemical Company) in 5 mL of anhydrous N, N-dimethylformamide was added dropwise and the solution was stirred under nitrogen for 15 minutes. . To the solution was then added 1.0 g (7.40 mmol, 1.21 equivalents) of 1-hydroxybenzotriazole hydrate (Aldrich Chemical Company), and the reaction mixture was stirred under a nitrogen atmosphere for 2.75 days. The suspension was filtered, the filtrate was evaporated to an orange oil. The crude free base was dissolved in dichloromethane and the solution was transferred to a separatory funnel. The organic phase is washed with saturated sodium bicarbonate solution. The organic layer obtained was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated. An orange oil is obtained. The free base was partially purified by flash chromatography with dichloromethane followed by a 96: 4 mixture of dichloromethane and methanol as eluent. A cloudy orange oil is obtained. The oil was dissolved in dichloromethane, filtered and evaporated to give a less cloudy oil. The crude free base was dissolved in ethyl acetate, filtered and evaporated. 2.73 g of the free base are obtained in the form of a clear orange solution. Yield: 86%. A portion of the free base is isolated as the hydrochloride after recrystallization from ethanol. The title compound is mp 116-119 ° C.

¹ H NMR (DMSO-d 6): δ 1.44 (s, 9), 1.60 (m, 2), 1.78 (m, 2),

3.29 (m, 6), 3.44 (tm, 2, J = 12.1), 3.57 (d, 2, J = 11.9), 4.05 (d, 2, J = 13) 4), 7.45 (t, 1, J = 7.6), 7.49 (broad singlet, 1), 7.58 (t, 1, J = 7.5), 8.09 (d, 1, J = 8.2), 8.12 (d, 1, J =

8.4), 8.35 (d, 1, J = 3.4), 8.82 (broad triplet, 1, J = 5.6), 10.17 (s, 1), 10.63 (broad) singlet, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.58, 27.02, 28.89, 38.89, 47.36, 51.47, 56.06, 80.62, 107.69, 122.16, 124.85, 124.97, 125.59, 127.93, 129.09, 129.35, 137.81, 153.01, 153.09, 163.18, 164.89.

Analysis for ^C 25 ^H 33 ^N 5 ^S 2 ° 3 ^'HC1' Calculated: 52.66% C, 6.36% H Found: 52.76% C, 6.36% H, ^H2 °:

N, 12.28; H ₂ O, 3.16%;

12.38% N, 2.90% H ₂ 0th

Example 10

a) A method for producing hydrochloride

4-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-thiophenecarboxamide

3.13 g (6.07 mmol) of tert-butyl [N- [4- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl]] carbamoyl] -3-thienylcarbamate] (Example 9 (c)), 24 ml trifluoroacetic acid (EM Science),

6.4 ml of anhydrous anisole (Aldrich Chemical Company) and 50 ml of anhydrous chloroform were mixed in a 250 ml round-bottom flask and stirred at room temperature under nitrogen for 20 minutes. Thin layer chromatography showed the reaction was complete. The reaction mixture was evaporated to give an orange liquid. The crude material was dissolved in dichloromethane and transferred to a separatory funnel. The organic phase is washed with saturated sodium bicarbonate solution and separated.

The aqueous layer was extracted with dichloromethane.

The organic layers were combined, dried over magnesium sulfate, filtered and evaporated to give an orange liquid. The crude free base was purified by flash chromatography with dichloromethane and then 96: 4 dichloromethane / methanol as eluent. It will be obtained

1.57 g of the free base in the form of a pale orange oil. Dissolve 1.40 g (3.37 mmol) of the free base in ethyl acetate and add 3.4 mL (1.0 equivalents) of 1 N ethereal HCl.

The hydrochloride is filtered off and dried

1.01 g of the title compound, m.p. 204 DEG-37%.

form of whitish solid

206 ° C. Yield from ¹ H NMR (DMSO-d ₆ ): δ 1.58 (m, (m, 10), 4.04 (m, 2), 5.80 (broad (ddd, 1, J = 1.0, 7.0.

8.03 (d, 1, J = 3.5), (broad triplet, 1 J = 5.5) ppm.

3.3), 7.49

7.0, 8.1),

6.8), 8.40

2), 1.79 singlet, 8.1),

2), 3.00

6.10 (d,

7.62 (ddd, J)

8.15 (wide triplet, (m,

2),

- 3,80

1, J = 1.0,

2, J = ¹³ C NMR (DMSO-d6): δ 21.70, 27.29, 38.70, 47.46, 51.51,

56.16, 97.85, 122.18, 124.98, 125.59, 125.87, 127.93, 128.16,

129.09, 148.60, 153.06, 163.24, 165.04.

Analysis for ^C 20 ^H 25 ^N 5 ^OS 2 · ^HCl: calculated: 53.14% C, 5.80% H, 15.49% N, found: 53.20% C, 5.84% H, 15.34 % N.

Example 11

a) Method for the preparation of methyl [3-aminobenzo [b] thiophene-2-carboxylate]

This compound was prepared according to the method of J. R. Beck (J. Org. Chem. 37, 3224 (1972)) using 50.0 g (0.338 mol) of 2-nitrobenzonitrile (Aldrich Chemical Company).

33.2 mL (36.4 g, 1.11 equivalents) of methylthioglycolate (Aldrich Chemical Company), 400 mL of Ν, Ν-dimethylformamide and 37.4 g of potassium hydroxide in 187 mL of water. This afforded 36.1 g of the title compound as a light beige solid. Yield: 52%.

¹ H NMR (CDCl ₃ ): δ 3.90 (with, 3), 5.92 (broad singlet, 2), 7.37 (ddd, 1, J = 1.3) 7.0. 8,2) , 7.48 (ddd, 1, J = 1.5, 7.0, 8,2) 7.64 (ddd, J) 0.8. 1,5. 8,0), 7.74 (ddd, J, 0.8 = 0.8)

1.2, 8, Ο ppm.

b) Process for the preparation of 3-amino-N- [4- / 4- (1,2-benzoisothiazol-3-yl) -1-piperazinyl / butyl] benzo [b] thiophene-2-carboxamide hydrochloride

2.6 g (8.96 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl-1,2-benzisothiazole (Example 1 (b)) and 20 ml of anhydrous chloroform are introduced into a round-bottomed flask. volume of 100 ml and stirred under a nitrogen atmosphere. A solution was slowly added to the reaction mixture

4.6 ml (9.2 mmol, 1.03 equivalents) of trimethyl aluminum (Aldrich Chemical Company), as a 2 molar solution in toluene, and the light yellow solution was stirred under a nitrogen atmosphere for 20 minutes. An additional portion of 4.6 mL (9.2 mmol, 1.03 equivalents) of trimethyl aluminum and a solution of 1.86 g (8.98 mmol, 1 equivalents) of methyl [3-aminobenzo [b] thiophene] are then added to the reaction mixture. -2-carboxylate] in 10 ml of anhydrous chloroform and stirred under nitrogen at room temperature for 30 minutes. The gold-yellow solution was heated at 40 ° C for 4 days. Oil purchase! The dark orange solution was allowed to cool. To the slightly warm reaction mixture was slowly added 50 mL of 1N hydrochloric acid. The acidic reaction mixture was heated at 40 ° C for 30 minutes. The reaction mixture was allowed to cool and saturated potassium carbonate solution was added. The reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. The crude material was obtained as an orange liquid. The free base was purified by flash chromatography eluting with a gradient of 100 to 95% dichloromethane and 0 to 5% methanol. 1.14 g of the free base is obtained in the form of an orange oil. Yield: 27%. Dissolve 1.05 g (2.25 mmol) of the free base in ethyl acetate and add 2.25 mL (1.0 equivalent) of the resulting solution.

1-normal ethereal hydrogen chloride. The hydrochloride is recrystallized from aqueous ethanol. There was obtained 0.82 g of the title compound as a beige solid, m.p.

242 to 244 ’C. Yield: 48%.

¹ H NMR (DMSO-d 6): δ 1.58 (m, 2), 1.76 (m, 2), 3.10-3.50 (m, 8), 3.59 (broad doublet, 2, J = 11.2), 4.08 (broad doublet, 2, J = 13.4), 7.07 (broad singlet, 2), 7.38 (ddd, 1, J = 1.1, 7.1 , 8.1), 7.47 (tm, 2, J = 7.6), 7.60 (ddd, 1, J = 1.1, 7.1, 8.2), 7.68 (broad triplet 1, J = 5.6), 7.83 (d, 5.3), 8.03 (d, 1, J = 7.9), 8.12 (t, 2, J = 8.3) , 10.39 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 21.61, 27.61, 39.10, 47.33, 51.40,

56.16, 99.33, 122.16, 123.48, 123.94,

124.75, 124.98, 125.59,

127.93, 128.49,

129.08, 133.38,

137.89.

148.29, 153.09, 163.20,

166.12.

Analysis for ^C 24 ^H 27 ^N 5 ^0S 2 * ^HC1: Calculated: 57.41% C, 5.62% H, 13.95% N Found:

% C, 57.42;% H, 5.68;

13.94% N.

Example 12

a) Process for the preparation of 2-cyano-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] acetamide

2.23 g (7.69 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl-1,2-benzisothiazole (Example 1 (b)), 0.76 g (8.93 mmol, 1), 16 equivalents) of cyanoacetic acid (Aldrich Chemical Company) and 20 ml of Ν, Ν-dimethylformamide are placed in a 250 ml round-bottom flask and stirred under a nitrogen atmosphere. A solution of 1.86 g (9.01 mmol, 1.17 equivalents) of 1,3-dicyclohexylcarbodiimide (Aldrich Chemical Company) in 5 mL of Chemical, Ν-dimethylformamide was added dropwise to the reaction mixture. To the reaction mixture was added 1.24 g (9.18 mmol, 1.19 equivalents) of 1-hydroxybenzotriazole hydrate (Aldrich Chemical Company) and the resulting mixture was allowed to stir at room temperature under a nitrogen atmosphere for 23 hours. The suspension is filtered off and the solid is washed with N, N-dimethylformamide. The filtrate was evaporated to give an orange oil. The crude free base was dissolved in ethyl acetate and filtered. The filtrate was loaded directly onto a silica gel column and partially purified by flash chromatography, eluting with a gradient of 90-80% ethyl acetate and 10-20% methanol. 2.92 g of crude compound are obtained in the form of an orange oil. The crude free base was dissolved in dichloromethane and washed with saturated potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. This gives 1.93 g of the title compound as a light beige solid. Yield: 70%.

¹ H NMR (CDCl 3): δ 1.63 (broad triplet, 4, J = 3.3), 2.74 (broad triplet, 2, J = 6.7), 2.69 (broad triplet, 4 J = 4.9), 3.36 (m, 2), 3.37 (s, 2), 3.57 (broad triplet, 4, J = 4.9), 6.66 (broad singlet, 1) ), 7.36 (ddd, 1, J = 1.2, 7.0, 8.1), 7.47 (ddd, 1, J = 1.2, 6.9, 8.2), 7, 82 (dt, 1, J = 7.8, 1.1), 7.91 (dm, 1, J = 8.0) ppm.

b) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzoisothiazol-3-yl) -1-piperazinyl / butyl] -3-thiophenecarboxamide

1.83 g (5.12 mmol) of 2-cyano-N- [4- / 4- (1,2-benziosothiazol-3-yl) -1-piperazinyl / butyl] acetamide, 1.79 g (11.8 g) mmol, 2.30 equivalents) 1,4-dithien-2,5-diol (Aldrich Chemical Company), 1.70 mL (1.23 g, 12.2 mmol, 2.38 equivalents) triethylamine and 30 mL ethanol is placed in a 500 ml round bottom flask and heated at 60-65 ° C under nitrogen for 3 hours. The oil bath was removed and the reaction mixture was allowed to cool. Water and dichloromethane were added to the reaction mixture and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried with magnesium sulfate, filtered and evaporated to give a red-brown residue. The crude free base was partially purified by flash chromatography eluting with a mixture of 100 to 98% ethyl acetate and 0 to 2% methanol. A partially solidifying orange oil is obtained. The free base was dissolved in ethyl acetate and filtered. The filtrate was partially evaporated to give a suspension. The light brown solid was filtered to give 0.239 g of the title compound, m.p. 155-159 ° C (dec.). Yield: 11%.

NMR (CDCl ₃ ): δ 1.68 (broad singlet, 4), 2.48 (broad singlet, 2), 2.68 (broad singlet, 4), 3.42 (m, 2), 3.58 ( broad singlet, 4), 5.84 (broad singlet, 1), 6.07 (broad singlet, 2),

6.23 (d, 1, J = 5.8), 6.71 (broad doublet, 1, J = 5.8), 7.35 (ddd, 1, J = 1.1, 7.0, 8 1), 7.46 (ddd, 1, J = 1.1, 7.0, 8.1), 7.81 (d, 1, J = 8.2), 7.90 (d, 1, J = 8.2 ppm.

¹³ C NMR (DMSO-d 6): δ 23.80, 27.47, 38.26, 49.61, 52.53,

57.61, 105.69, 107.55, 121.09, 124.22, 124.43, 127.40, 127.89,

152.06, 161.05, 163.52, 165.45.

Analysis for ^C 20 ^H 25 ^N 5 ^OS 2 · ^{3/20 C} 4 ^H 8 ° 2 · ° ^'3H 2 ^0: Calculated: 56.98% C, 6.22% H, 16.13% N Found: H, 6.15; N, 16.26.

Example 13

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -8-quinolinecarboxamide hydrochloride

W ml of anhydrous N, N-dimethylformamide, 1.04 g (6.01 mmol) of 8-quinolinecarboxylic acid (Aldrich Chemical Company), 0.898 g (6.65 mmol, 1.11 equivalents)

1-hydroxybenzotriazole (Aldrich

Chemical Company) and 1.75 g (6.03 mmol, 1 equivalent)

(aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example

3- / 4- (41 (b)) was mixed in a 250 mL round bottom flask. The reaction mixture was cooled in an ice bath and stirred under a nitrogen atmosphere. A solution of 1.37 g (6.64 mmol, 1.10 equivalents) of 1,3-dicyclohexylcarbodiimide (Aldrich Chemical Company) in 12 mL of anhydrous N, N-dimethylformamide was added dropwise to the reaction mixture. Remove the ice bath and stir the reaction mixture at room temperature for hours. The suspension was evaporated under reduced pressure to give the crude material

57 was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, filtered and evaporated to give a mixture of finely dispersed solids in an orange oil. Ethyl acetate was added to the mixture and the suspension was filtered. The filtrate was evaporated to give 2.98 g of the crude compound as an orange oil. The crude material was purified by flash chromatography with dichloromethane, dichloromethane / methanol (99: 1) and dichloromethane / methanol (97: 3) as eluent. The appropriate fractions were combined, evaporated, redissolved in dichloromethane and treated with 3.28 mL (1.0 equivalent) of ethereal hydrogen chloride. The solvent was evaporated under reduced pressure. The resulting hydrochloride was dissolved in methanol and the solution was filtered through a folded filter paper directly into rapidly stirred ethyl acetate. The resulting suspension was filtered to give 0.265 g of the title compound as a light beige solid. The filtrate was evaporated and the residue was recrystallized from methanol. A second crop of 0.447 g is obtained. A total of 0.712 g of the title compound having a melting point of 187-189 ° C was obtained. The overall yield corresponds to 25% of theory.

³ H NMR (DMSO-d ₆ ): δ 1.68 (m, 2), 1.91 (m, 2), 3.10-3.42 (m, 4), 3.56 (m, 6) 4.03 (broad doublet, 2, J = 11.8), 7.43 (t, 1, J = 7.5), 7.56 (t, 2, J = 7.6), 7.65 (dd, 1, J = 4.3, 8.3),

7.72 (t, 1, J = 7.7), 8.09 (t, 2, J = 7.7), 8.17 (d, 1, J =

8.1), 8.54 (dm, 2, J = 7.6), 9.09 (dd, 1, J = 1.4, 4.1), 10.87 (broad triplet, 1, J = 5.5), 11.55 (broad singlet, 1) ppm.

55.59, ¹³ C NMR (DMSO-d6)

121.52, 121.90,

21.24.

26.95.

124.35, 124.94,

128.56.

129.67, 132.38,

132.72, 138.30,

38.85, 46.72, 50.82,

126.66, 127.31, 128.44,

144.99, 150.82, 152.43,

162.60.

165.41

Example 14

a) A process for the preparation of 1,2,3,4-tetrahydro-8-quinolinecarboxylic acid

This compound was prepared by the method of G. M. Coppola (J. Heterocyclic Chem., 15, 645 (1978)) using

1.73 g (9.99 mmol) of 8-quinolinecarboxylic acid (Aldrich Chemical Company), 0.182 g of platinum oxide hydrate (EM Science) and 30 ml of ethanol. The mixture was hydrogenated in a Parr hydrogenator at 50 psi for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated. This gives 1.76 g of the title compound as a yellow solid, m.p. 158-160 ° C (melting point 165-167 ° C according to literature). Yield: 99%.

¹ H NMR (DMSO-d 6): δ 1.77 (quintet, 2, J = 5.9), 2.69 (t, 2, J = 6.2), 3.33 (t, 2, J = 5.5), 6.36 (t, 1, J = 7.5), 7.00 (d, 1, J = 7.0), 7.54 (d, 1, J = 8.0) ppm .

¹³ C NMR (DMSO-d 6): δ 21.46, 28.33, 41.68, 109.59, 114.17,

122.73, 130.58, 134.54, 149.13, 171.24.

Analysis for ^C io ^H 2 II ^N0: Calculated: 67.78% C, 6.26% H 7.90% N Found: 67.56% C, 6.32% H, 7.85% N.

b) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2,3,4-tetrahydro-8-quinolinecarboxamide

This compound was prepared according to the method described in Example 13 (a) using 1.06 g (5.98 mmol) of acid.

1,2,3,4-tetrahydro-8-quinolinecarboxylic acid, 0.90 g (6.66 mmol,

1.1 equivalents) 1-hydroxybenzotriazole hydrate (Aldrich Chemical Company), 1.47 g (7.12 mmol, 1.2 equivalents) 1,3-dicyclohexylcarbodiimide (Aldrich Chemical Company), 1.82 g (6.27 mmol) , 1.05 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 1 (b)) and anhydrous Ν, Ν-dimethylformamide. The reaction mixture was allowed to stir at room temperature for 18 hours, evaporated under reduced pressure and the crude was partitioned between dichloromethane and saturated sodium bicarbonate solution. The finely dispersed solids are filtered off and the filtrate is evaporated to give the crude free base. This material was purified by flash chromatography as described in Example 13 (a). The pure free base weighing 2.28 g (5.07 mmol) was dissolved in dichloromethane and 5.07 mL (1.0 ether of hydrogen chloride was added to the solution. The solvent and the resulting hydrochloride were dissolved equivalent) of the 1N was evaporated under reduced pressure. in methanol. The solution is filtered through a folded filter paper directly into rapidly stirred ethyl acetate. The suspension is filtered to give 0.28 g of the title compound, m.p. 9%.

in the form of an orange-beige solid

138-142 ° C. Yield corresponds to ¹ H NMR (DMSO-d 6): δ 1.55 (m, 2), 1.77 (m, 4), 2.69 (t, 2, J = 6.0), 3.21 (m .Delta., 3.47 (t, 2, J = 12.9), 3.56 (d, 2, J =

11.6), 4.05 (d, 2, J = 13.4), 4.46 (broad singlet, 1), 6.44 (t, 1, J = 7.5), 6.96 (d 1, J = 7.0), 7.37 (d, 1, J = 7.8), 7.46 (t, 1, J = 7.5), 7.58 (t, 1, J = 7.5), 8.11 (t, 2, J = 8.2), 8.32 (broad triplet, 1, J = 5.3), 10.91 (broad singlet, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.54, 21.86, 27.43, 28.27, 39.11,

41.75, 47.56, 51.64, 56.34, 115.14, 115.19. 122.37, 123.35,

125.15, 125.78, 127.35, 128.10,

163.35, 170.20.

Analysis for ^c 25 ^H 31 ^N 5 ^O 5 ^S. H, 6.55. Found: C, 58.81;

1.23 % h ₂ °, 58,47 % C, 6.62% H, 0.85 % h ₂ °.

129.29, 132.84, 146.19, 153.26,. 0.35 H ₂ 0:

13.72% N, 10.41% Cl,

N 13.43, Cl 10.18,

Example 15

a) A process for the preparation of 2- (2,3-dihydro-1H-indol-1-yl) glyoxyloyl chloride

This compound was prepared according to the procedure of W. J. Welstead et al. (J. Med. Chem. 22, 1074 (1979) 0, with modifications. A 2-liter, 3-necked round bottom flask is introduced

102.1 g (0.804 mol) of oxalyl chloride (Aldrich Chemical Company) and 400 ml of anhydrous dichloromethane. The flask used is equipped with a mechanical stirrer, dropping funnel and nitrogen inlet.

A solution of 48.0 g (0.43 mol) of indoline in 350 ml of anhydrous dichloromethane was added dropwise to the reaction mixture with stirring over 2 hours. The resulting reaction mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. The resulting red-brown solution was evaporated and diethyl ether was added to the residue. The suspension is filtered and the filtrate is evaporated. 56.75 g of acid chloride are obtained in the form of a yellow-green solid. Yield: 68%. The crude acid chloride was used without further purification.

^X H NMR (DMSO-d₆): δ 3.19 (t, 2, J = 8.3), 4.17 (t, 2, J = 8.3), 7.12 (t, 1, J = 6.9), 7.24 (t, 1, J = 7.1), 7.33 (d, 1,

J = 7.0), 8.01 (d, J, 7.6) ppm.

* b) A process for preparing 4,5-dihydropyrrolo [3,2,1-hi] indoline-1,2-dione

12.7 g (95.2 mmol, 5.0 equivalents) of aluminum chloride (Aldrich Chemical Company) and 4.00 g (19.1 mmol) of 2- (2,3-dihydro-1H-indol-1-yl)) - (glyoxyloyl) chloride is introduced into a 300 ml round bottom flask equipped with a mechanical stirrer and nitrogen inlet. The mixture was rapidly heated to 100-120 ° C and allowed to stir for 20 minutes. Oil purchase! is removed and the mixture is allowed to cool to room temperature. The resulting solid is triturated with a spatula and added to 600 ml of ice water. The aqueous mixture was stirred for 1 hour and then extracted with chloroform. The organic layer was dried (MgSO 4) and evaporated to give an oily red residue.

The residue was triturated with acetone and filtered. This afforded 0.71 g of the title compound as a red solid, mp 203-207 ° C. According to the literature (W. J. Welstead et al., J. Med. Chem., 22, 1074 (1979)) the melting point is 206-208 ° C. Yield: 22%.

¹ H NMR (DMSO-d ₆ ): δ 3.36 (t, 2, J = 7.9), 4.06 (t, 2, J = 7.9), 6.95 (t, 1, J = 7.5), 7.24 (d, 1, J = 7.6), 7.46 (d, 1,

J = 7.1) ppm ¹³ C NMR (DMSO-d 6): δ 31.35, 46.88, 113.03, 122.72, 124.74,

126.22, 134.16, 156.45, 160.67, 184.70.

Analysis for CioH ₇ N0 _2: calculated: 69.36% C, 4.07% H 8.09% N Found: 69.09% C, 4.10% H, 8.00% N.

c) A method for producing indoline-7-carboxylic acid

A solution of 1.82 g of sodium hydroxide in 20.2 ml of water and 1.0 g (5.8 mmol) of 4,5-dihydropyrrolo [3,2,1-hi] indoline-1,2-dione was contacted in 100 ml round-bottomed flask and stirred at room temperature for 30 minutes. A solution of hydrogen peroxide (consisting of 1.82 mL of 30% hydrogen peroxide in 18.2 mL of water) was added dropwise to the reaction mixture and allowed to stir for 3.5 hours. The reaction mixture was transferred to a separatory funnel and washed with benzene. The aqueous layer was separated and the pH was adjusted to 6-7 by the addition of 1N hydrochloric acid. The solution was extracted with chloroform. The pH of the aqueous layer was adjusted to pH 4-5 by addition of 1N hydrochloric acid and extracted with an additional portion of chloroform. The organic layers were dried over magnesium sulfate, filtered and evaporated to give a gold brown solid. The crude material was triturated with 3: 1 benzene / isooctane. This gives 0.54 g of the title compound as a brown solid, mp 164-166 ° C. [References (W. J. Welstead et al., J. Med.

Chem., 22, 1074 (1979), mp 164-168 ° C.]

Yield: 57%.

¹ H NMR (DMSO-d 6): δ 2.93 (t, 2, J = 8.6), 3.55 (t, 2, J =

8.6), 6.44 (t, 1, J = 7.0), 7.13 (d, 1, J = 6.9), 7.36 (d, 1, J = 7.5) ppm ¹³ C NMR (DMSO-d 6): δ 28.19, 46.70, 107.95, 115.49, 128.14,

128.43, 131.26, 154.48, 168.73.

H, 5.56; N, 8.58. Found: C, 65.98; H, 5.51; N, 8.48.

d) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-1H-indole-7-carboxamide

This compound was prepared according to the method described in Example 13 (a) using 0.86 g (5.27 mmol) of indoline-7-carboxylic acid, 1.60 g (5.51 mmol, 1.05 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 1 (b)), 0.78 g (5.77 mmol, 1.10 equivalents) of 1-hydroxybenzotriazole hydrate (Aldrich Chemical Company) ), 1.35 g (6.54 mmol, 1.24 equivalents)

1,3-dicyclohexylcarbodiimide and anhydrous Ν, Ν-dimethylformamide. The reaction mixture was allowed to stir at room temperature for 24 hours and then the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was filtered to remove insoluble material. The filtrate was washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO 4), filtered and evaporated. 3.12 g of crude compound are obtained, which is in the form of an orange oil. The crude material was purified by flash chromatography, eluting with ethyl acetate / methanol (99: 1). Appropriate fractions were combined, evaporated, redissolved in dichloromethane, filtered and re-evaporated. This gives 0.96 g of the title compound as an orange oil. Yield: 42%.

^X H NMR (DMSO-d₆): δ 1.51 (m, 4), 2.36 (t, 2, J - 6.4), 2.56 (br t, 4, J = 4.5), 2.89 (t, 2, J = 8.6), 3.22 (broad quartet, 2, J = 6.0), 3.41 (broad triplet, 4, J = 4.5), 3.51 (t, 2, J = 8.6), 6.45 (t, 1, J = 7.5), 6.54 (s, 1), 7.07 (d, 1, J = 7.2) 7.35 (d, 1, J = 8.1), 7.41 (tm, 1, J = 7.5), 7.53 (tm, 1, J = 7.5), 8.02 ( d, 1, J = 8.1), 8.03 (d, 1, J = 8.2), 8.11 (t, 1, J = 5.6) ppm

Example 16

a) A method for producing 1H-indole-7-carboxylic acid

This compound was prepared by the method of R. Ikan and E. Rapaport (Tetrahedron 23, 3823, (1967)) using 3.0 g (18.4 mmol) of indoline-7-carboxylic acid (Example 15 (c)). , 0.75 g of 10% palladium on carbon (Aldrich Chemical Company) and 150 ml of xylenes. The reaction mixture was heated for 4 hours. The hot solution was filtered through a pad of celite and the filtrate was evaporated. It will be obtained

1.55 g of the title compound as a red-beige solid, m.p. 202-204 ° C. Yield: 52%. (In the literature, the compound has a melting point of 202 ° ^{C.); H} NMR (DMSO-d₆): δ 6.52 (dd, 1, J = 2.0, 3.0), 7.08 (t, 1, J = 7.7), 7.35 (t, 1, J = 2.8) 7.74 (dd, 1, J = 1.2, 7.5), 7.81 (d, 1, J = 7) 9), 11.05 (s, 1), 12.98 (broad singlet, 1) ppm ¹³ C NMR (DMSO-d 6): δ 101.80, 113.83, 118.70, 124.13, 125 , 97, 127.16, 129.61, 134.90, 168.31.

b) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1H-indole-7-carboxamide

This compound was prepared according to the method described in Example 13 (a) using 1.32 g (8.19 mmol) of 1H-indole-7-carboxylic acid, 2.47 g (8.51 mmol, 1.04) equivalents) 3- / 4- (464

(aminobutyl) -1-piperazinyl / -1,2-benzisothiazole (Example 1 (b)),

1.20 g (8.88 mmol, 1.08 equivalents) of 1-hydroxybenzotriazole hydrate (Aldrich Chemical Company), 1.87 g (9.06 mmol, 1.1 equivalents) of 1,3-dicyclohexylcarbodiimide (Aldrich Chemical Company) and anhydrous Ν, Ν-dimethylformamide. The reaction mixture was allowed to stir at room temperature for 16 hours and then the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and the resulting suspension was filtered. The filtrate was washed with saturated sodium bicarbonate solution and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and evaporated to give the crude product as an orange oil. The crude free base was purified by flash chromatography using ethyl acetate, ethyl acetate / methanol (99: 1) and ethyl acetate / methanol (97: 3) as eluent. This gave 3.27 g of the title compound as a yellow oil. Yield: 92%.

^T H NMR (DMSO-d₆): δ 1.57 (m, 4), 2.39 (t, 2, J = 6.9), 2.57 (br t, 4, J = 4.5), 3.35 (m, 2), 3.42 (broad triplet, 4, J = 4.5), 6.46 (t, 1, J = 2.9), 7.04 (t, 1, J = 7.6), 7.32 (t, 1, J = 2.9), 7.41 (tm, 1, J = 7.6) 7.53 (tm, 1, J = 7.8), 7 64 (d, 1, J = 7.5), 7.70 (d, 1, J = 8.1), 8.02 (d, 1, J = 8.1),

8.03 (d, 1, J = 8.2), 8.53 (t, 1, J = 5.6), 11.13 (s, 1) ppm

Claims (14)

PATENT CLAIMS A compound of formula I wherein: Y represents a heteroalkyl group optionally substituted by one or more halogen atoms, nitro groups, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, aryloxy, arylalkyleneoxy groups having 1 to 6 carbon atoms in the alkylene moiety, hydroxy groups of the formula S (O) _n R ^2, S (O) n n (R ²⁾ 2, wherein n is zero, 1 or 2. CN, CON (R ²⁾ 2, COR ^2, CO 2 R ^2, CO-aryl, azido, -N (R ²⁾ 2, -NR ² -N (R ²⁾ 2, -NR ² N-C (R ^2a ) ₂ , -NR ² (C = O) CH [N (R ^2a ) 2] R ^2b , -NR ² (C = O) R ^2a , -NR ² CO ² R ^2a , C 1 -C 6 alkoxycarbonylamino or groups of the formula PhN = N, provided that Y does not include benzisothiazolyls or benzisoxazolyls, is an oxygen atom or a sulfur atom, Z comprises an alkylene group having 1 to 8 carbon atoms, which is optionally interrupted by an oxygen atom -O- or a group of the formula -S (O) _n -, where n is zero, the number 1 or 2, furthermore an alkenylene group having 2 to 8 atoms a C 2 -C 8 alkynylene group, X is N, CR ³ or COR ³ A is CR ⁴ or N, B is O, ^NR5 or S (0) _n wherein n is zero, 1 or 2, and R ¹ represents a hydrogen atom or one or more halogen, hydroxy, nitro, cyano, N (R ⁶ ) ₂ , alkoxy of 1 to 6 carbon atoms, aryloxy, arylalkyleneoxy of 1 to 6 carbon atoms or COR ⁶ and R, R ^2, R ^2a, R ^2b, R ^3, R ^4, R ⁵ and R ⁶ each are hydrogen or alkyl having 1 to 6 carbon atoms, or a salt, solvate, N-oxide or physiologically functional derivative thereof . The compound, salt, solvate, N-oxide or derivative of claim 1, wherein the heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridazinyl, quinolyl, isoquinolyl, imidazolyl, benzimidazolyl, furyl, benzofuryl , thienyl, benzthienyl, indazolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, purinyl, triazinyl, indolyl, naphthiridinyl, quinazolinyl, pyrrolopyridinyl, Tetrahydroquinolyl, indolinyl, quinoxalinyl, triazolyl or thiadiazolyl. A compound, salt, solvate, N-oxide or derivative according to any one of claims 1 and 2, wherein the heteroaryl group is n substituted by a group of formula N (R) ₂ · A compound, salt, solvate, N-oxide or derivative according to any one of claims 1 to 3, wherein the heteroaryl group is a pyridine, thiophene or benzthiophene radical which is optionally substituted with NH ₂ , NHMe or NHAc and R represents a hydrogen atom or methyl. A compound, salt, solvate, N-oxide or derivative according to any one of claims 1 to 4, wherein R is a hydrogen atom and the heteroaryl group is a pyridine or thiophene radical which is substituted with a group of formula NH ₂ . 6. Compounds: N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide, tert-butyl-N- [4- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butylcarbamoyl] -3-thienylcarbamate, 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide, 4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-pyridinecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide, 4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-thiophenecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzo [b] thiophene-2-carboxamide, 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-thiophenecarboxamide, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -8-quinolinecarboxamide; N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2,3,4-tetrahydro-8-quinolinecarboxamide; N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-1H-indole-7-carboxamide; and N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1H-indole-7-carboxamide and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides. 7. Compounds: 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide and N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridine, carboxamide and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides. 8. 3-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide and its physiologically acceptable salts, solvates, physiologically functional derivatives and N- oxides. A process for preparing a compound of formula I i in which Y, W, Z, X, A, B, R, R ^1, R ^2, R ^2a, R ^2b, R ^3, R ⁴ , R ⁵ and R ⁶ have the meanings defined in any one of claims 1 to 9, and a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof, characterized in that a compound of formula II is reacted ΊΟ In γ ^ 'ΝΗ R (II) with a compound of formula III (III) wherein: L is a leaving group, reacting a compound of formula II with a compound of formula IV (IV) wherein: W is a suitable anion and R ¹² represents a group of formula - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, reacting a compound of formula V V λ γ- ^ Ν Z — L R in which L is a leaving group, with a compound of formula VI (V), (VI) reacting a compound of formula VII IN R r ~ \ (NH1) with a compound of formula VIII (VIII) wherein: L is as defined above. reacting a compound of formula IX In (IX) in which L ¹ represents a halogen atom, a methoxy group, or a compound of formula IXa or hydroxy- (IXa) in which: Y, W and ^R2 are as defined above, with a compound of the formula X / H (x) reacting a compound of formula Xa with 1,4-dithiane-2,5-diol, reducing a compound of formula I wherein Z is (C 2 -C 8) alkenylene or (C 2 -C 8) alkynylene; or 10th subjecting to hydrolysis the corresponding alkoxycarbonylamino derivative of a compound of formula I, which is optionally substituted with one or more -N (R) ₂ or -NRN (R ² ) ₂ groups. A compound of formula I, according to claim 1, or a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof for use in therapy. 11. Use in the treatment of any of the following compounds or their physiologically acceptable salts, solvates, N-oxides or physiologically functional derivatives: 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ylic-2-pyridinecarboxamide, 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-thiophenecarboxamide, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-pyridinecarboxamide and N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-pyridinecarboxamide and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides. Use of a compound of formula I according to claim 1, or a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof for the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders. The use of claim 12, wherein the psychotic disorder is schizophrenia. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof.