BG99839A - Heteroaromatic compounds having antipsychotic effect - Google Patents

Abstract

The invention relates to a group of piperazine and piperidine derivatives of the formula wherein Y represents a heteroaryl group optionally substituted by one or more halogen atoms, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryloxy, aryl-C 1 -C 6 -alkyleneoxy (R 2) 2, COR 2, CO 2 R 2, CO-aryl, azido, -N (R 2) 2, ) 2, -NR 2 N (R 2a) 2, -NR 2 N = C (R 2a) 2, -NR 2 (C = O) CH 2 N 2 R 2b, -NR 2 C 2 O 2 R 2a, NR 2 CO 2 R 2a, alkoxycarbonylcarbonylamino or PhN = N, with the proviso that Y does not include benzisothiazolyl or benzisoxazolyl, V is 0 or S, Z is C1-8-alkylene optionally interrupted by -O- or -S (O) n-, n being 0 , 1 and and X is N, CR 3 or COR 3, A is CR 4 or N, B is O, NR 5 or S (O) n, n being 0, 1 or 2, and R 1 represents hydrogen or one or more halogen atoms, hydroxy, nitro, CN, N (R 6) 2, C 1-6 -alkoxy, aryloxy, aryl-C 1-6 -alkyleneoxy or COR 6 and R 1, R 2a, R4, R5 and R6 are each independently hydrogen or C1-6-alkyl. The invention also relates to a physiologically acceptable salt, solvate, N-oxide or physiologically active derivative of the compound, to a process for their preparation, to pharmaceutical compositions containing them, and to their therapeutic use, e.g. especially for the treatment of mental disorders.

Description

The present invention relates to a group of piperazine and Piperidine derivatives, a method for their preparation, pharmaceutical compositions containing them, and their therapeutic use, especially in the treatment of mental illness.

The receptors for the chemical dopamine receptor are known to be located in the striatum and in the limbic brain region and that such receptors are classified as Dpi D2 based on receptor binding studies and the presence or absence of a positive binding between the receptor and adenylate cyclase. Di-receptor activation is associated with adenylate cyclase stimulation, where the 1 2-receptor mediates dopaminergic effects that do not involve direct stimulation of this enzyme [see Ref. Kebabian & Caine, Nature, 227, 93 (1979) and Harrold et al., J. Med. Chem., 30, 1631 (1987)]. Although the separate functions of Dj- and Do · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · <

The receptors are not clearly distinguished, it is suggested that there is a strong correlation between the antagonism of D2-peuenmopa and the antipsychotic effect [cf. Seeman, Pharmacol. Rev., 32, 229 (1981). Seeman et al., Biochem. Pharmacol., 34, 151 (1985). Greece et al., 192, 481 (1976) in Leysen in Clinical Pharmacology in Psychiatry: Neuroleptic and Antdepressant Research: Eds. Usdin. Dahl. Gram and Lingjaerde.

Macmillian: Basingstoke, pp. 35-52 (1982)].

The chemical mediator 5-hydroxytryptamine (5-HT) is widespread in the central nervous system and is known to be involved in behavioral control. A large number of different 5-HT receptors and receptor subtypes have been identified. In addition to blocking D2-peuenmopume, it is recognized that 5-HT2 receptor antagonism in an antipsychotic agent is also desirable. In particular, it is recognized that blocking of central dopamine D2-peuenmopu may control the positive symptoms of schizophrenia (eg, delusions, hallucinations) while blocking

5-HT2 receptors can help to improve the negative symptoms of schizophrenia (eg apathy, withdrawal from society). It has been suggested that blocking the 5-HT2 receptor results in a decrease in extrapyramine side effects, which are known to occur when conducting neuroleptic supportive therapy with many of the known antipsychotic agents.

Psychotropic benzisothiazoles and benzisoxazoles are described in US 4,968,792, EP 0 357 134, EP 0 196 132 and EP 0 511 610. In addition, antipsychotic piperidines and piperazines are described in EP 0 329 168, EP 0 372 657, EP 0 013 612 and US 5 225 412.

A group of novel piperazine and piperidine derivatives has been discovered, which are potent dopamine D2-penenmopu antagonists ········:

· · · · · · · · · · · · ·:

The · and · or 5-HT2 receptors b are therefore psychiatric disorders.

The present invention provides a compound of formula (I), salt, solvate or physiologically active derivative thereof.

V l

Useful in treating

(I) where

Y represents a heteroaryl group optionally substituted by one or more halogen atoms, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, aryloxy, aryl-C 1 -C 4 -alkylene, hydroxy, S (O) _n R 2 or S (O ) _n (R 2) 2, where n is 0, 1 or 2, CN, CON (R 2) 2, COR 2, CO2 R 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 CO ₂ R _2a> C _r C ₆ alkoxycarbonylamino or PhN = N, provided that Y does not include benzisothiazolyls or benzisoxazolyls;

V represents O or S;

Ζ represents C 1-6 alkylene optionally interrupted by -O- or -S (O) _n -, where n is 0, 1 or 2, C 2-8 alkenylene or C 2-8 alkynylene;

X represents N, CR3 or COR3;

A represents CR ₄ or N;

B represents oxygen, NR5 or S (O) _n , where n is 0, 1 or 2; and R 1 represents hydrogen or one or more halogen atoms, hydroxy, nitro, CN, N (R 2) 2, C 1-6 alkoxy, aryloxy, apUA-C 1-6 alkyleneoxy, or COR 4,

R, R 2, R _2a , R 2b = R 3, ^r 4> R 5 and R 6 are R ₇ , R ₈ , R ₉ , R ₁₀ υ Rn below represent hydrogen or CAB alkyl.

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

The expression - (R _x ) y indicates the presence of y R _x variables, each selected independently and therefore not necessarily identical.

As used herein, alkyl as a group or part of a group may mean a linear or branched alkyl group optionally substituted by one or more halogen atoms, hydroxy, nitro, CN, N (R ₇ ) ₂ , C 1-4 alkoxy or COR ₇ , e.g. . methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl. The alkyl groups are preferably methyl or ethyl.

Used herein the term alkylene refers to a linear, branched or C ^ alkylene-cyclic group optionally substituted by one or more halogen atoms, hydroxy, nitro, CN, N (R _{8) 2,} Ci-b-alkoxy or COR _8, e.g. . methylene, ethylene, butylene, pentylene, hexylene, cyclohexylene or - (CH ₂ ) _m C 3-6 -cycloalkyl (CH ₂ ) _m , where m is 0 to 4, especially where C 3-6 -cycloalkyl is a cyclopropylene group.

The term alkenylene as used herein refers to a linear, branched or cyclic alkenyl group having 4 to 8 carbon atoms optionally substituted by one or more halogen atoms, hydroxy, nitro, CN, N (R ₉ ) ₂ , C 1-6 -alkoxy or COR ₉ , e.g. ethenylene, propenylene, butenylene, pentenylene, hexenylene and the like.

The term alkynylene as used herein refers to a linear or branched alkynyl group having 4 to 8 carbon atoms, optionally substituted by one or more halogen atoms, hydroxy, · · · · ·

· .. · 3 · · · · · · · · · · · · · ·:

refers to nitro, CN, N (Rio) 2, C1-6-alkoxy, or CORo, such as e.g. ethynylene, propynylene, butynylene, pentynylene, hexynylene U-like.

The term alkoxy as used herein refers to an -O-alkyl, -O-alkenyl or -O-alkynyl group.

As used herein, heteroaryl ^{1 is a} monocyclic or bicyclic fused ring system containing 5-10 atoms, where 1 or more ring atoms are independently selected from the group of nitrogen, oxygen or sulfur.

One of the rings of the bicyclic heteroaryl groups may be fully saturated or partially saturated.

The term aryl as used herein refers to phenyl, naphthalenyl optionally substituted by one or more halogen atoms, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio or N (Rn) 2 ·

The terms aryloxy and aryl-C 1-6 -alkyleneoxy as used herein refer to -O-aryl and -O-C 1-6 alkylenearyl group, where aryl and alkyl respectively have the meanings given above.

The term halogeno used herein refers to fluoro, chloro, bromo and iodo.

As used herein, a physiologically active derivative means any physiologically acceptable ester or salt of such an ester of a compound of formula (I) or a compound that is capable of providing (directly or indirectly) such compound or active metabolite or their radical. Such physiologically active derivatives may be prodrugs of the compound of the present invention and are considered to be within the scope of the invention.

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

The invention further provides compounds of formula (I) and their salts, solvates and physiologically active derivatives, wherein the nitrogen atom shown in formula (I) adjacent to Z and forming part of the six-membered ring is in oxidized form as N-oxide .

The present invention includes compounds of formula (I) in the form of their physiologically acceptable salts. Suitable salts are especially acid addition salts, including those formed with organic and inorganic acids. Such acids are generally physiologically acceptable, although physiologically unacceptable acids may be used in the preparation and purification of the compound in question. Preferred salts include those formed from hydrochloric, sulfuric, citric, tartaric, phosphoric, milky, pyro-degraded, trifluoroacetic, acetic, succinic, oxalic, fumaric, maleic, oxalocetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic acid. Salts of the compounds of formula (I) can be prepared by reacting a suitable compound in the form of a free base with a suitable acid. The preferred salt is hydrochloride or dihydrochloride.

The present invention also encompasses compounds of formula (I) which are in the form of a salt / solvate (especially a hydrate or a partial hydrate).

Basic salts of the compounds of formula (I) are also included within the scope of the invention. Suitable base salts are those formed with organic and inorganic bases. Such basics • ·

are generally physiologically acceptable, although salts of physiologically unacceptable bases may be useful in the preparation and purification of the compound in question. Such preferred base salts include alkali metal salts (eg sodium), alkaline earth metals (eg magnesium), ammonium and quaternary ammonium salts.

Preferred heteroaryl groups are pyridinyl, pyrimidinyl, pyrazinyl, pyrazolinyl, pyrolinyl, pyridazinyl, quinolinyl, isoquinolinyl, imidazolinyl, benzyl, benzyl, benzyl, benzoyl, benzene quinazolinyl, pyrrolopyridinyl, tetrahydro-quinolinyl, indolinyl, quinoxalinyl, triazolyl or thiadiazolyl.

Particularly preferred heteroaryl groups are pyridinyl, pyrrolyl, quinolinyl, imidazolyl, furyl, thienyl, benzothienyl, indolyl, naphthyridinyl, quinazolinyl, tetrahydroquinolinyl and indolinyl.

The most preferred heteroaryl groups are pyridinyl, quinolinyl, thienyl, benzothienyl, indolyl, tetrahydroquinolinyl and indolinyl.

According to a preferred embodiment of the present invention Y is replaced by N (R2) 2 ·

In another preferred embodiment of the present invention Y represents pyridine, thiophene or benzthiophene optionally substituted with N (R2) 2 ·

According to a particularly preferred embodiment of the present invention R represents H or Me, Y represents pyridine, thiophene or benzthiophene optionally substituted with NH 2, NHMe or NHAc.

·· ···· • · ¹ ····· ··:: ·· ···

.. ·· ··.

·· **. · · ·. * • · · ζ · · ··.

· · · · · ·

According to a most preferred embodiment of the present invention, R represents Η, Υ represents pyridine or thiophene substituted with ΝΗ2.

According to another preferred embodiment of the present invention V is particularly O, Ζ is C 1-6 alkylene and preferably C 1-6 alkylene, B is -S-, ΝΗ or -O-, and especially -S- or -O- and preferably -S-; A is CH or N and preferably N, a is H or F and preferably H.

Preferred compounds of formula (I) are:

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-pyridine carboxamide;

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) butyl) carbamoyl) -3-thienyl) 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) -4piridinkarboksamid;

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-quinoline carboxamide;

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;

N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -1H-indole-7 carboxamide;

and their physiologically acceptable salts, solvates, physiologically active derivatives and N-okcugu.

Particularly preferred compounds of formula (I) are:

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;

N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3-pyridinecarboxamide;

and their physiologically acceptable salts, solvates, physiologically active derivatives and N-okcugu.

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 active derivatives and N-okcugu.

Salts of compounds of formula (I) are preferably HCl salts and solvates are predominantly hydrates.

• ·

The compounds of formula (I) exhibit a favorable pharmacological action profile and are useful in the treatment of many disease states. The compounds show e.g. anxiolytic central muscle relaxant and antidepressant activity. They are also useful in the treatment of senile dementia, borderline (intermediate) personality disorders and as a broad-spectrum antiemetic. The compounds are particularly useful in the treatment of psychiatric disorders such as schizophrenia.

The potential antipsychotic effect can be evaluated by the ability of the compound to block apomorphine-induced climbing in the mouse [see Ogren et al., Eur. J. Pharmacol. 12, 459 (1984), Iversen, Science, 188, 1084 (1975) in Gudelsky & Moore, J. Neural. Transm., 38, 95 (1976)]. The tendency of a compound to induce catalepsy and its ability to block apomorphine-induced stereotypes are behavioral criteria that demonstrate the potential of the compound to induce extrapyramidal side effects.

The compounds of formula (I) are effective antagonists of gonaMUH-Dg-peuenmopume and S-HTg-peuenmopume and are useful as antipsychotic agents. This action profile is confirmed by the efficacy of the compounds of formula (I) in the mouse climbing assay and by good dose ratios effective in this assay relative to the dose required for induction of catalepsy.

The compounds of formula (I) are also effective antagonists of the 5-HT1d receptor. This action is associated with antidepressant and anxiolytic effects, as well as a decrease in extrapyramidal side effects. The combination of effective dopamine-Oo-receptor antagonism and b-HT3-receptor antagonism with 5-HT1d-receptor agonism, which is detected in compounds of formula (I), is a particularly favorable activity profile for an antipsychotic agent and a special drug for the treatment of schizophrenia.

According to another embodiment, the present invention provides a method of treating or preventing mammals, e.g. people with the following diseases:

anxiety, muscle spasm, depression, senile dementia aggression, borderline personality disorders, vomiting (emesis) and psychosis, which includes administering to a mammal an effective amount to treat a compound of formula (I) or a physiologically acceptable salt, solvate or physiologically active derivative. In particular, a method of treating or preventing a mammal with a mental illness, which comprises administering an effective amount for antipsychotic treatment of a compound of formula (I) or a physiologically acceptable salt, solvate or physiologically active derivative or N-oxide thereof. In particular, the invention provides such a method for treating the mental illness of schizophrenia.

According to yet another embodiment, the present invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof, or a physiologically active derivative, or an N-okcug is an application for the treatment, especially treatment, or prophylaxis of a mental illness such as schizophrenia. The invention also provides the use of a compound of formula (I), or a physiologically acceptable salt thereof, or a solvate thereof, for the manufacture of a medicament for treating or preventing a mental illness such as schizophrenia.

It may be possible to administer the compounds of the present invention as a crude chemical, but it is recommended that they be presented as a pharmaceutical composition. In another embodiment, the present invention provides a pharmaceutical

a composition comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof, or a physiologically active derivative, or an N-oxide with one or more pharmaceutically acceptable carriers and optionally one or more therapeutically active ingredients. The carriers should be acceptable in the sense that they are compatible with the other ingredients of the composition and not interfere with their recipient.

The compositions include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous), rectal and topical (including dermal, oral, and sublingual) administration, although the most appropriate route will depend e.g. of the recipient's condition and illness. For convenience, the compositions may be in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of coupling a compound of the present invention, as defined herein, either on a pharmaceutically acceptable salt or solvate thereof (active ingredient) with a carrier consisting of one or more excipients. Typically, the compositions are prepared by uniformly and completely mixing the active ingredient with liquid carriers or finely dispersed solid carriers or both, and then, if necessary, preparing the preparation in the desired form.

The compositions of the present invention suitable for oral administration as single doses may be in the form of capsules, wafers or tablets, each containing a specified amount of the active ingredient: in the form of powder or granules, in the form of a solution or suspension in water, or non-aqueous liquid, either in the form of an oil-in-water emulsion or in water in

butter. The active ingredient may also be in the form of a pill or an electronics or paste.

One tablet may be prepared by compression or casting, optionally with one or more excipients. Compressed tablets may be prepared by compressing the active ingredient in bulk in suitable machines, such as e.g. powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. The molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or sliced and may be formulated to provide a slow or controlled release of the active ingredient.

Compositions for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solubles that make the composition isotonic with the blood given to the recipient and aqueous and non-aqueous sterile suspensions, which may include suspending agents. . The compositions may be in single or multiple dose packages, e.g. sealed ampoules or vials and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g. water for injections just before use. Injectable solutions without prior preparation and suspensions may be prepared from sterile powders, granules and tablets as described above.

Transdermal delivery compositions may be administered by passive diffusion or by electrical transport, e.g. iontophoresis • ·

[see e.g. Pharmaceutical Research 3 (6), 318 (1986)] and are usually the nog form of an optionally buffered aqueous solution of a compound of formula (I) or a salt or acid derivative thereof. Suitable compositions include citrate or bis / tris buffer (pH 6) or ethanol / water. Such compositions may optionally contain a lysosomal absorption inhibitor.

Formulations for rectal administration may be in the form of suppositories with conventional carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration, e.g. by mouth or sublingually include suction pills containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those that contain an effective dose, as cited below, or a suitable portion thereof, of the active ingredient.

It is understood that in addition to the ingredients specifically mentioned above, the compositions of this invention may include other agents of a conventional kind, e.g. compositions suitable for oral administration may include flavoring agents.

The compounds of the invention are preferably used to treat psychiatric disorders such as schizophrenia by oral administration or by injection (intra-parenteral or subcutaneous). The exact amount of compound administered to the patient is determined by the treating physician. However, the dose administered will depend on a number of factors such as the age and gender of the patient, the type and extent of the disease. The Input Scheme may also • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Vary depending on the condition and its degree of M SLH3 W VUULL VH4 / ·

The compounds of the invention are usually administered orally or by injection at doses of 0.02 to 50.0 mg / kg per day. The adult dosage will generally range from 1.4 to 3500 mg / day and preferably between 2.8 and 1750 mg / day, in particular from 7 to 700 mg / day.

The present invention also provides methods for preparing compounds of formula (I) and its physiologically acceptable salts and solvates and its physiologically active derivatives. Typically, the compounds of formula (I) may be prepared by any method for preparing analogous compounds known in the art. In the description below, the groups Z, X, V, A, B, R, Ri, R ₂ , R _2a , Rat »R3>&5>&6> R &&9>& 10 ^and R11 have the meanings given by formula (I), unless otherwise stated.

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

(III) · · · · · · · · · · · · · · · · · · · · · · ·

· · · · · · · · · · · · · · · · · · · Where L is a leaving group, e.g. halogen such as bromine, chlorine or iodine, alkyl- or arylsulfonyloxy such as methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a suitable solvent and base.

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

etc.

According to the second general method (B), compounds of formula (I) wherein Z is - (CH2) 4 ~ or - (CH2) 5- can be prepared by reacting a compound of formula (II) with a compound of formula (IV )

(IV) wherein W 'is a suitable anion such as halogen, e.g. bromine or chlorine, sulfonic acid esters such as mesylate or tosylate, and R] 2 ^is

- (CH2) 4- or - (CH2) 5-, especially - (R 2) 4-- The reaction conditions may be the same as those described above for general method (A).

Additionally, a complexing agent such as 1,4,7,10,13,16-hexaoxacyclooctatecan (18-crown-6) may be included.

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

(V) where L has the meaning given above with a compound of formula

(VI)

The method can be carried out according to the description of general method (A) given above.

According to the fourth general method (D), the compounds of formula (I) in which X is N can be obtained by reacting a compound of formula (VII)

with a compound of formula (VIII)

(VII)

(VUI) where L has the meaning given above.

The method may be carried out according to the description of general method (A) given above.

According to the sixth general method (F), compounds of formula (I) can be prepared by reacting compounds of formula (IX) ν

A

Y Lj (ix) where Ι χ is halogen (e.g. Cl, Br), OMe or OH, or when Υ in a compound of formula (I) will be substituted at least one of the orthos with amide or thioamide with -NHR by reacting a compound of formula (1Xa)

V

(1Xa) and where Υ, V and R2 have the meanings given above with a compound of formula (X)

in a suitable organic solvent is either without the addition of a suitable base at or below room temperature (eg -30 ° C to +140 ° C). Suitable solvents are N, N-dimethylformamide, acetonitrile, dichloromethane, benzene, toluene, tetrahydrofuran, xylene, etc., and suitable bases may be selected from organic bases such as triethylamine, pyridine, etc., carbonates or bicarbonates alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc., or alkali metal hydrides such as sodium hydride, potassium hydride, etc. Catalysts or binders such as trimethylammonium may also be included. isobutyl chloroformate or 1,3-dicyclic lohexylcarbodiimide (DDC).

When L is OH and замест is substituted by an NHR group adjacent to the carbonyl or thiocarbonyl group, the process may be carried out in the presence of silicon tetrachloride in a reflux solvent such as anhydrous pyridine. [Comet, M. J, J. Heterocyclic Chem., 29, 103 (1982)].

According to the seventh general method (G), compounds of general formula (I), wherein Y is a thiophene group, can be obtained by treating a compound of formula (Xa)

· · · · · · · ·

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

Compounds of formula (I) may also be prepared from other compounds of formula (I). Examples of such internal transformations are given below.

Compounds of formula (I) wherein Z is C 2-8 alkylene can be prepared by reducing a compound of formula (I) wherein Z is C 2-8 alkenylene or C 2-8 alkynylene. The reduction can be carried out by catalytic hydrogenation with hydrogen in the presence of a suitable catalyst such as palladium, platinum, nickel, rhodium, etc. 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 at room temperature or at elevated temperature from 20 to 100 ° C. Partial reduction of acetylene (-C = C-) to alkylene (-C-C-) can be achieved by reducing the use of a poisonous catalyst as a Lindlar catalyst.

The compounds of formula (I) optionally substituted by one or more hydroxy groups may be prepared by known methods from the corresponding methoxy derivatives. [e.g. by treatment with Awis acids such as boron tribromide or aluminum trichloride in a solvent such as dichloromethane, at room temperature, Mcomie, J.F.W. and West, D. E., Org. Synth. Coll. Vol. V, 412 (1973), Dillard, R.D. et al., J. Med. Chem., 34, 1768-2778 (1991)].

• · · · · · · · · · · · · · · · · · ·

Compounds of formula (I) optionally substituted by one or more N (R-2) 2 or NRN (R2) 2 can be prepared by hydrolysis of the corresponding alkoxycarbonylamino derivatives, by known methods, butoxycarbonyl) amino derivative with an acid such as trifluoroacetic acid and substance that removes tert-butyl ···· · · · · · · · · · · · · · by treating (mpemation as anisole or thiophenol, in a solvent such as chloroform, at room temperature [Lundt. B. F., Int. J. Prept. Protein Res., 12, 258 (1978)].

Compounds of formula (I) optionally substituted by one or more INS groups may also be prepared by reduction of the corresponding nitroconductors by known methods [e.g. by catalytic hydrogenation with hydrogen, with a catalyst e.g. platinum, palladium, formerly 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 by one or more -NR 2 (C = O) R 2a, -NR 4 CO 3 α or NR ₂ (C = O) CH (NR ₂ a) 2R 2b may be obtained by acetylation of the corresponding amino derivatives by known methods, [e.g. by treatment with acid chloride such as acetyl chloride or ethyl chloroformate and an organic base such as triethylamine in a solvent such as dichloromethane].

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

Compounds of formula (I) wherein V represents sulfur can be prepared by treating compounds of formula (I) where V represents oxygen with a sulfonating agent such as · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Lawesson reagent [(2,4-bis-4-methoxyphenyl) -1,3-dithia-2,4diphosphetane-2,4-disulfide] in a solvent such as toluene at elevated temperature [Synthesis, 941 (1979); Tetrahedron, 35, 2433 (1979).

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

The compounds of formula (I), where nitrogen is oxidized to Noxide, can be prepared by oxidizing compounds of formula (I) with an oxidizing agent such as t-chloroperoxybenzoic acid in a suitable solvent such as dichloromethane.

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

The compounds of formula (III) can be prepared by alkylating a compound of formula (VI) with a compound of formula (XI)

L - b --- L (XI) wherein L represents a leaving group such as e.g. halogen such as bromine, chlorine or iodine, alkyl or arylsulfonyloxy such as methanesulfonyloxy or p-toluenesulfonyloxy.

In some cases, e.g. both L-groups are halogen and Z is B 2, especially (CH 2, the same reaction can give a compound of formula (IV) [J. Med. Chem., 29, 359-369 (1986)].

The compounds of formula (V) can be prepared by alkylating a suitable compound of formula (II) with a compound of formula (XI). Alternatively, the compound of formula (V) can be prepared by converting the hydroxyl group by known methods to a compound of formula (XII) ·· (xi) defined above.

· · · · · · · · · · · · · · · · · · · · · ·

in the leaving group L with significance,

The compound of formula (XII) can be obtained by condensation of a compound of formula (IX) with an amino alcohol of formula (XIII).

h ₂ n --- Z ---- OH (XIII) or by treating a compound of formula (II) with a compound of formula LZ-OH. The reaction may be carried out either at room temperature or at elevated temperature such as e.g. 60 ° C to 140 ° C. Suitable solvents are N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene, etc., and suitable bases may be selected from organic bases such as triethylamine, pyridine, etc., carbonates or bicarbonates of alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc. or alkali metal hydrides such as sodium hydride, potassium hydride, etc.

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

when X = N, A = NuB = S: Yevich et al., J. Med. Chem., 29, 3559-69 (1986). US 4 590 196; when X = C, A = N in B = S: US 4 528 292; when X = N, A = NuB = O: J. Med. Chem, 29, 359-69 (1986); when X = C, A = NuB = O: J. Med. Chem, 28, 761-69 (1985);

when

X = N, A = NuB = SO

2 ·

J. Med. Chem., 34, 3316-3328 (1991). Alternatively, these intermediates can be obtained by treating 3chlorobenzisothiazole-1,1-dioxide (Eur. Pat. Appl. 0 196 096) with piperazine in a solvent such as toluene at elevated temperature such as 150160 ° C.

when X = N, A = N and B = S (O):

J. Med. Chem., 34, 3316-3328 (1991);

when X = C, A = C in B ^ NRj:

US 4 335 127,

US 4 710 500;

when X = N, A = C and B = S:

can be prepared according to the following reaction scheme: by heating suitably substituted aminobenzo [b] thiophenes with piperazine in a solvent such as 1-methyl-2-pyrrolidinone. The necessary aminobenzo [b] thiophenes can be obtained by treating appropriately substituted 2-fluorobenzonitrile with the methyl thioglycolate anion, followed by decarbomethoxylation of the benzo [b] thiophene obtained:

when X = C, A = CuB = S:

· · · · · · · · · ·. · ·. · · · · · · ···· ·· ··· j. ·· * ··· ··· • · · · · · · 25 ……….

FR 2 253 519 when, where they can be obtained by deprotecting N protected piperinylindazoles, obtained by the reaction of suitably substituted 4- (2-fluoroaryl) piperidine [J. Med. Chem., 28, 761 (1985)] with reflux hydrazine in a solvent such as n-butanol according to the following scheme:

when X = C, A = C, and B = S () 2

JP 03264583 A2;

when X = C, A = C, and B = NRs

DE 3 500 898 Al;

The compounds of formula (VII) can be prepared by alkylation of piperazine with a compound of formula (V).

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

when L = C1, A = NuB = S US 4 590 196; when L = C1, A = N in B = O J. Med. Chem., 29, 359 (1986); when L = C1, A = NuB = SO ₂ EP 0 196 096 A2

· «· · · · ·

• ·

The compounds of formula (IX) or (1Xa) are known or can be prepared by known methods.

The compounds of formula (1Xa) e.g. may be obtained by treating suitably substituted 2-amino acids with a phosgene or a phosgene substituent (eg trichloromethylchloroformate) 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) wherein V represents an oxygen atom may also be prepared by treating suitably substituted anhydrides of formula (XIX) with azidotrimethylsilane in a suitable solvent such as chloroform. The corresponding thio-derivatives of formula (IXa), wherein V represents a sulfur atom, can be obtained by treating the corresponding oxo-derivatives with phosphorus pentasulfide in xylene under reflux.

Oh

about (XIX)

The compounds of formula (X) wherein R = H can be obtained by cleavage of the corresponding phthalimides is formula (Xb) O

R1 (XB)

with hydrazine hydrate in methanol. The compounds of formula (Xb) can be prepared by alkylating compounds of formula (VI) with

(XX) where Z and L have the meanings given above.

The compounds of formula (XX) are either commercially available or can be prepared by alkylation of phthalimides with a compound of formula (XI).

The compounds of formula (X), wherein N = C 1-5 -alkyl can be obtained from compounds of formula (Xc)

(Xc) where P represents a protecting group, e.g. trifluoroacetate, by removing the protecting group by known methods, e.g. with aqueous potassium carbonate solution.

Compounds of formula (Xc), wherein N = C 1-6 -alkyl can be prepared from compounds of formula (X), wherein R = H by protecting the amino group, e.g. such as trifluoroacetamide, followed by alkylation of the obtained protecting amine with C1-6-alkyl halide, e.g. methyl iodide.

·· ····

The compounds of formula (Xa) may be prepared by coupling the compounds of formula (X) with cyanoacetic acid in the presence of a suitable binding agent such as e.g. 1,3cyclohexylcarbodiimide (DCC) in a suitable solvent such as N, N-dimethylformamide. I

Biological data

A. Antipsychotic

The antagonism of apomorphine-induced climbing in mice (5 mg / kg s.c.) is a criterion for dopamine receptor antagonism in the mesolimbic brain region and in turn indirectly affects the potential antipsychotic effect.

The compounds were administered to the mice orally 1 hour prior to counting. 3-amino-N- (4- (4- (1,2-benzoisothiazol-3-yl) -1-piperazinyl) butyl-2-pyridinecarboxamide (Example 5) antagonized mouse-induced climbing of apomorphine at ED5q = 5.7 mg / kg p. and 3aMUHO-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl-2-thiophenecarboxamide (Example 8) - at ED 5q = 9.7 mg / kg p.o. [ Costall V., Naylor R.J. and Nohria, V. Climbing Behavior Induced by Apomorphine in Mice: A Potential Model for the Detection of Neuroleptic Activity, European Journal of Pharmacology, 50, 339-50 (1978)].

pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions wherein the active substance is a compound of formula (I) or a physiologically acceptable salt or solvate thereof, e.g. the compound • ·

3-Amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl-2-pyridinecarboxamide) These examples do not limit the invention.

A. Lactose tablets corn starch polyvinylpyrrolide he magnesium stearate

150 mg)

200 mg) mg) mg) mg)) = tablet content

The active substance is mixed with lactose and starch and granulated with a solution of polyvinylpyrrolidone in water. The resulting granules were dried, mixed with magnesium stearate and compressed to form tablets.

B. Injectable solutions

Injection solution

The salt of a compound of the invention is dissolved in sterile water to form an injection solution.

Composition II for intravenous injection active substance 0. 20 g sterile, pyrogen-free phosphate buffer (pH 9.0) up to 10 ml

The active substance in the form of salt was dissolved in a large portion of the phosphate buffer at 35-40 ° C, then made up to volume and filtered through a sterile microporous filter in a sterile 10 ml vial (type I), which was closed with a sterile stopper. and is sealed.

C. Capsule formulations • · • ·

Capsule composition I

Composition I can be obtained by mixing the ingredients and filling two hard gelatin capsules with the mixture obtained.

(a) Active substance (b) Lactose BP

mg / capsule

250

143 (c) starch sodium glycolate 25 (g) magnesium stearate

(Capsule composition II (a) active substance (b) Macrogel 4000 BP mg / capsule

250

350

600

The capsules can be prepared by melting the Macrogel 4000 BP, dispersing the active substance in a melter, and filling two-part hard gelatin capsules with the mixture.

Capsule composition III (controlled release capsules) (a) active substance (b) microcrystalline cellulose (c) lactose B.P.

(d) ethylcellulose mg / capsule

250

125

125

513

The controlled release capsule composition can be prepared by extruding the ingredients of mixture (a) to (c) using an extruder, then obtaining a granular material and drying. The dried beads are coated with ethylcellulose (d), which • ·

•• lx ··· ·· ·· ·· ··· 31

serves as a controlled release membrane and is filled into two-part hard gelatin capsules.

D. Syrup composition

active substance solution of sorbitol glycerol sodium benzoate flavoring purified water q.s. to 0. 2500г 1. 5000г 1. ООООг 0. 0050г 0. 0125ml 5.0ml

Sodium benzoate was dissolved in some of the purified water and a solution of sorbitol was added. The active substance is added and dissolved. The resulting solution was mixed with glycerol and then made up to volume with purified water.

F. Composition for suppositories

active substance (63 ml) * BP solid (Witepsol H15 - Dynamit Nobel - mg / suppository 250 1770 2020

* The active substance is used as a powder in which at least 90% of the particles are 63 mm in diameter or less.

One-fifth of Witepsol H15 is melted in a steam bath at a maximum of 45 ° C. The active substance was passed through a 200-mm sieve and added to the molten base with stirring using a

Silverson agitator equipped with a cutting head until smooth dispersion is achieved. While maintaining the mixture at 45 ° C, the remainder of Witepsol H15 was added to the slurry, which was stirred to ensure homogeneous mixing. The whole suspension goes through • ·

cumo om stainless steel 250 mm u npu continuous stirring

allowed to cool to 40 ° C. At 38-40 ° C aliquots x 2.02 g of the mixture were filled into plastic molds and allowed to cool at room temperature.

F. Transdermal composition

Formulations suitable for transdermal administration may be in the form of patches adapted for direct contact with the epidermis of the host for an extended period of time. Such patches typically contain the active substance

1) in an optionally buffered aqueous solution, or 2) dissolved in an adhesive, or 3) dispersed in a polymer. A suitable concentration of the active substance is about 1 to 20%, preferably about 3 to 15%. One particular possibility is the delivery of the active substance from the patch by iontophoresis, as described generally in Pharmaceutical Researche, 3 (6), 318 (1986).

The invention is further illustrated by the following examples, which should not be construed as limiting.

Experimental part

Common part

Unless otherwise stated, all substances are commercially available and are used without further purification. Anhydrous solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, toluene, pyridine, and dimethyl sulfoxide (DMSO) are obtained from Aldrich Chemical Company in secure sealed bottles. Triethylamine is distilled off from calcium hydride before use. All reactions with air and moisture sensitive substances are carried out under a nitrogen atmosphere. Flash chromatography [Still, W.C. et al, J.Org.Chem., 43, 2923 (1978)] and chromatography on a jet was carried out with silica gel · · · · · · · · · · · · · · ·

Chemical ppm; relative to internal • · · · • · · • · ·

-sU ··

EM Science 60 (230-400 mesh ASTM). Thin layer chromatography (TLC) was performed with Analgech silica gel plate (250 mm) FG TLC. ^X H NMR and ¹³ C NMR were conducted with a superconducting FT NMR spectrometer at 200, 300 and 500 MHz. displacements are represented in trimethylsilane. Important 1 H NMR data are given in the following order: multiplicity (s - singlet; d - doublet; t - triplet; q - quartet; t - multiplet), number of protons and coupling constant in Hz. Elemental analyzes are performed either by Atlantic Microlab. Inc., Norcross Georgia or by Galbraith Laboratories Inc, Knoxville, Tennessee. Melting points are determined by Thomas Hoover's capillary melting points and are not adjusted. The piperazine-benzisothiazole intermediate 3- (1-piperazinyl) -1,2-benzisothiazole was prepared by known methods [Yevich, JP et al, J.Med.Chem, 29, 359-369 (1986)].

Examples Example 1 (a) Preparation of 2- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) phthalimide hydrochloride 'N- (4-bromobutyl) phthalimide (3.50 g, 0.0124 mol), 3- (1-piperazinyl) -1,2-benzisothiazole (2.72 g, 0.0124 mol, 1.0 equivalents), triethyl amine (2.24 ml, 0.0161 mol, 1.3 equivalents) and acetonitrile (15.0 ml) were placed in a 100-mL round-bottom flask ml. The opaque orange solution was heated under nitrogen and refluxed for 17 hours. The mixture was allowed to cool to room temperature and diluted with dichloromethane. The organic solution was washed with saturated K2CO3 solution, dried over MgSO4, filtered and evaporated to give 5.48 g of a light orange solid. The crude material was recrystallized from acetonitrile and dried in a vacuum oven.

yielding 4.35 g of a light brown powder.

The hydrochloride salt was obtained by the addition of 1 N HCl in ether, recrystallized from 95% ethanol to give 4.53 g (82%) of the title compound as an off-white powder. Mp 258-260 ° C (dec) 1 H NMR (DMSO-d ₆ ): δ 1.72 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.02 (br d, 2, J = 13.7), 7.44 (ddd, 1, J, = 8.1, 7.0, 1.1), 7.57 (ddd, 1, J = 8.1, 7.0,1.1), 7.85 (m, 4), 8.09 (dd, 2 , J = 8.0, 4.5), 11.18 (br s, 1), ¹³ C

NMR (DMSO-dg): 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. Calculated for C23H24N4O2SHCI: C, 60.45; Η 5.51; Ν 12.26.

Found: C, 60.46; Η 5.55; Ν 12.17.

(b) Preparation of 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole

Hydrazine hydrate (Aldrich Chemical Company, 85%) (2.62 g, 1.5 equivalents) was added to a solution of 2- (4- (4- (1,2-benzisothiazol-3yl) -1-piperazinyl) butyl) phthalimide (12.46 g, 0.0296 mol) in methanol (30.0 ml). The reaction mixture was refluxed for 3.5 hours and allowed to cool to room temperature. To the solution was added 1N HCl (59.0 ml) and the resulting white precipitate was filtered and washed with water, the filtrate was basified by the addition of 50% NaOH solution and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and evaporated in a rotary evaporator to give 8.1 g (94%) of the title compound as an orange-brown oil. 1 H NMR (CDCl ₃ ): δ 1.38 (br s, 2), 1.55 (m, 4), 2.45 (t, 2, J = 7.4), 2.68 (t, 4, J = 5.0), 2.74 (t, 2 , J = 6.8), 3.57 (t, 4, J = 5.0), 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, .1 = 8.1), 7.91 (d, 1, J = 8.2). This crude amine was used without further purification.

• · · · · · ·

(c) Preparation of N- (4- (4- (4- (2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3-pyridinecarboxamide hydrochloride

Nicotinoyl chloride hydrochloride (Aldrich Chemical Company) (1.1 g, 6.1 mmol) was added portionwise with stirring to an ice-cooled solution of 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (1.8 g , 6.0 mmol) and triethylamine (2.5 ml, 17.9 mmol, 3.0 equivalents) in dichloromethane (25.0 ml). The resulting suspension was stirred at 0 ° C for 0.5 hours and at room temperature for 2 hours. The cloudy reaction mixture was diluted with dichloromethane (25.0 ml) and washed with saturated NaHCO3 solution (2 x 50 ml). The organic phase was separated, dried over Na 2 SO 4, filtered and evaporated in a rotary evaporator to give an off-white foam. The crude material was dissolved in isopropanol (20.0 ml), cooled with an ice-water bath and treated dropwise with HCl (6.0 ml of 1N solution in ether). The mixture was diluted with ether (40.0 ml) and the resulting off-white solid was filtered off and washed with ether (3 x 10 ml). The salt was recrystallized from 95% ethanol to give 1.47 g (57%) of the title compound as off-white crystals. Melting point: 229-231 ° C. ^X H NMR (DMSO-d 6): δ 1.64 (t, 2), 1.81 (t, 2), 3.27 (t, 4), 3.47 (t, 2), 3.62 (br d, 2, J = 11.5). 4.10 (br d, 2, J = 13.1), 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 (br t, 1, J = 6.2), 9.05 (s, 1), 10.82 (br s, 1); ^r, C. NMR (DMSO-d6): 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, 165.92. Mass spectrum (CI / CH4, 50 mA / sec). m / z: M +1 (396).

Analysis. Calculated for (N, 4SNsOSeHCl: C 58.39; H 6.07; N 16.21; S 7.42; Cl 8.21. Found: C 58.37; H 6.12; N 16.14; S 7.49; Cl 8.14.

·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 2 (a) Preparation of piperazinyl) butyl) -4-pyridinecarboxamide hydrochloride

This compound was prepared by the method described in Example 1 (c) using isonicotinoyl chloride hydrochloride (Aldrich Chemical Company) (1.1 g, 6.1 mmol) 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole Example 1 (6) (1.8 g, 6.0 mmol) and triethylamine (2.5 ml,

17.9 mmol, 3.0 equivalents) in dichloromethane (25.0 ml). The crude hydrochloride salt was recrystallized from 95% EtOH to give 1.20 g (46%) of the title compound as off-white crystals. Melting point: 238-240 ° C. 1 H NMR (DMSO-d 6): δ 1.64 (t, 2), 1.80 (t, 2), 3.29 (t, 4), 3.46 (t, 2), 3.61 (br d, 2, J = 10.5). 4.10 (br d, 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 (br t, 1, J = 5.5), 10.80 (br s, 1). ¹³ CNMR (DMSO-d ₆ ): δ 20.76, 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. Mass spectrum (CI / CH4, 50 mA / sec), m / z: M +1 (396).

Analysis. Calculated for C ₂₁ H ₂₅ N ₅ OS · HCl: C 58.39; H, 6.07; N, 16.21; S 7.42; Cl 8.21. Found: C 58.47; H, 6.11; N, 16.12; S, 7.38; Cl 8.15.

Example 3 (a) Preparation of _______ of ________ N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -2-pyridinecarboxamide hydrochloride

Picolinic acid (1.2 g, 9.7 mmol) (Aldrich Chemical Company) and potassium hydroxide (0.56 g, 10.0 mmol) were dissolved in distilled water (25.0 ml). The water was removed by rotary evaporation and the white solid obtained was treated with benzene (25.0 ml). The solution was concentrated and dried under high vacuum. The resulting potassium salt was suspended in benzene (15.0 ml) and cooled in an ice-water bath. Oxalyl chloride (1.0 ml, 11.5 mmol) was added dropwise to this cooled solution. The reaction mixture was allowed to stir. The reaction mixture was allowed to evaporate. · · · · · · · · · · · · · ·

warm to room temperature and gradually warm to moderate boil under reflux. The resulting red-black solution was cooled and added dropwise to a 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (1) (6) (3.0 g, 10.0 mmol) cooling solution (ice-bath). ) and triethylamine (2.5 ml,

17.9 mmol) in dichloromethane (10.0 ml). The reaction mixture was allowed to warm to room temperature and stirred overnight. The dark suspension was concentrated with a rotary evaporator to give a black oil. The residue was dissolved in dichloromethane and washed with saturated ΝηΗΟΟβ. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give 5.01 g of black oil. The crude material was purified by flash chromatography on silica gel with a gradient eluent chloroform (100%) / chloroform-acetone-methanol (28: 2: 1) / chloroformacetone-methanol (14: 2: 1) to give 1.8 g of free amine . The resulting substance was dissolved in dichloromethane, treated with HCl (4.6 ml of 1N solution in ether) and diluted with ethyl acetate. The dark colored precipitate was filtered off and the filtrate was allowed to stand for 3 days. The resultant crystals after filtration were filtered and dried, yielding 1.15 g (27%) of the title compound as off-white crystals. Melting point: 231-234 ° C. NMR (DMSO-dg): δ 1.61 (t, 2), 1.7 (t, 2), 3.18-3.38 (t, 8), 3.57 (t, 2), 4.10 (t, 2), 7.47 (tm, 1 , J, - 7.6), 7.61 (t, 2), 8.02 (t, 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 (br s, 1). ¹³ C NMR (DMSO-d ₆ ): 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 / CH4, 50 mA / sec), m / z: M + 1 / base (396).

Analysis. Calculated for C21H25N5OS.HCI: C 58.39; H, 6.07; N, 16.21; S 7.42; C1 8.21. Found: C, 58.10; H, 6.10; N, 16.04; S 7.39; C1 8.09.

• ··· ··

Examples 4 and 5 (a) Preparation of 3-azaisatoic anhydride and 6-azaisatoic anhydride

A mixture of 2: 1 of 3- and 6-azaisatoic anhydride was obtained from 2,3-pyridinedicarboxylene anhydride (Aldrich Chemical Company) (11.4 g, mmol), azidotrimethylsilane (Aldrich Chemical Company) (11.4 ml, mmol, 1.1 equivalent) and chloroform (50.0 ml) no of the method described by

D. J. Le Court and D.J. Dewsbury, Synthesis, 11, 972 (1982). The precipitate obtained from the reaction mixture was filtered and dried, yielding 6.10 g (48%) of the 2: 1 mixture of the title compounds as a white solid. Melting point: 207-210 ° C (dec). The NMR values for 6-isomers (secondary) are given in rectangular brackets []. NMR (DMSO-d6): δ 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) ], 8.29 (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 (br s, 1 )], 12.53 (br s, 1).

(6) Preparation of 2-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -3-pyridinecarboxamide hydrochloride and 3-amino-N (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -2-pyridinecarboxamide hydrochloride

A mixture of 2: 1 of 3-azaisatoic anhydride and 6-azaisatoic anhydride (1.0 g, 6.1 mmol) was added with stirring to a solution of 3- (4- (4aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (Example 1 (6)) (1.8 g, 6.0 mmol) in tetrahydrofuran (20.0 ml). The reaction mixture was stirred under nitrogen at room temperature for 0.5 h. The solvent was removed with a rotary evaporator and the crude residue obtained was purified by flash chromatography on silica gel with dichloromethane (100%) / dichloromethane-methanol (98.5: 1.5) / dichloromethane-methanol (97: 3) / dichloromethane (97: 3) / dichloromethane (97: 3). 7) to give 1.48 g (91%) of 2-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· Kiridinecarboxamide as foam and 0.54 * (66%) 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) -butyl) -2-pyridinecarboxamide as Yana. The hydrochloride salts of each isomer were independently prepared by dissolving the free amine in dichloromethane (20.0 ml), filtration and treating the filtrate with HCl (1 equivalent of 1N solution in ether). The solutions were diluted with ethyl acetate and stirred at room temperature for 1 hour. The resulting white crystals were filtered and dried 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). Melting point: 220-222 ° C.

NMR (DMSO-d ₆ ): δ 1.59 (t, 2), 1.75 (t, 2), 3.32 (t, 8), 3.57 (t, 2), 4.08 (t, 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 (br t, 1, J = 5.5), 10.55 (br s, 1). 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. Macspectrum (CI / CH4, 50 mA / sec), m / z: M +1 (411).

Analysis. Calculated for Οοι ^ βΝόθ ^ ΗΠ: С 56.43; Η 6.09; N, 18.80; S, 7.17; Cl 7.93. Found: C, 56.36; Η 6.14; N, 18.75; S 7.19; Cl 8.03.

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 (R _f = 0.47). Melting point: 238-240 ° C.

^X H NMR (DMSO-d ₆ ): δ 1.59 (t, 2), 1.74 (t, 2), 3.30 (t, 8), 3.58 (t, 2),

4.08 (t, 2), 6.84 (br s, 2), 7.15 (dd, 1, J = 1.4, 8.4), 7.24 (dd, 1, J = 4.2,

8.4), 7.47 (tm, 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 (br t, 1, J = 6.2), 10.40 (br s, 1). ¹³ C 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 / CH4, 50 mA / sec), m / z: Μ +1 (411).

Analysis. Calcd for C 24 H 23 OS 4 HCl: C 56.43; H, 6.09; N, 18.80; S

7.17; Cl 7.93. Found: C, 56.36; H, 6.12; N, 18.70; S 7.12; Cl 7.85.

Examples b 7 (a) Preparation of 4-azaisatoic anhydride and 5-azaisatoic anhydride

Anhydrous chloroform (50.0 ml), 3,4-pyridinedicarboxyl anhydride (11.5 g, 77.1 mmol) and azidotrimethylsilane (10.1 g, 88.0 mmol,

1.14 equivalents) are placed in a 250 ml round bottom flask under nitrogen.

The resulting creamy suspension was warmed gently to initiate the reaction. The reaction is exothermic and nitrogen gas is released. After 10 minutes, the gas evolution ceased and the solution was heated at reflux for 0.75 hours. In the course of the reaction the solids dissolve to give a clear pale yellow solution. The reaction mixture was allowed to cool to room temperature and ethanol (4.5 ml, 77.1 mmol. 1.0 equivalent) was added in one go. Solids are immediately precipitated by the addition of the solution. The mixture was allowed to stir at room temperature for 15 minutes, after which the solids were filtered, washed with chloroform and dried in a vacuum oven at room temperature to give 12.6 g of a light yellow powder. This substance was stirred with acetonitrile (100 ml) and the insoluble solids filtered. The filtrate was heated at reflux for 0.5 hours. The solution was allowed to cool to room temperature, then cooled in an ice bath, the solids obtained were filtered off and the filtrate was evaporated in a rotary evaporator to give 1.8 g of a yellow powder. An additional amount of the substance is obtained by suspending the undissolved solids in intestinal acetonitrile (100 ml) for

1.5 hours. The mixture was filtered hot and the filtrate was evaporated to give 3.35 g (41% total) of the title compound as a yellow solid. The crude substance is a 1: 1 mixture of 4- and 5-azaisatoic anhydride as determined by integrating the corresponding signals into 41 NMR. 41 NMR (DMSOd ₆ , 300 MHz): 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 (br s, 2). This substance is used without further purification.

(b) Preparation of 3-aminoH-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -4-pyridinecarboxamide dihydrochloride hydrate and 4aMHOH-N- (4- (4- ( 1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3-pyridinecarboxamide dihydrochloride

A mixture of 1: 1 of 4-azaisatoic anhydride and 5-azaisatoic anhydride (4.71 g, 28.7 mmol) was added with stirring to a solution of 3- (4 (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (example 1 (6)) (8.33 g, 28.7 mmol, 1.0 equivalents) in anhydrous tetrahydrofuran (40.0 ml). The reaction mixture was stirred under nitrogen at room temperature for 1 hour. The solvent was removed with a rotary evaporator and the crude residue obtained was purified by flash chromatography (2 x) on silica gel: once with eluent 5:95 methanol: dichloromethane and 0.1% triethylamine and once with eluent 3:97 methanol: dichloromethane and 0.1% triethylamine to give 3.11 g (26%) of 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -4-pyridine-carboxamide as a light brown powder (TLC: silica gel, methanol / dichloromethane 95: 5, Rf = 0.44) and 2.99 g (24%) of 4-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -

1-pyrrolidinyl) butyl) -3-pyridinecarboxamide as an orange solid (TLC: silica gel, methanol / dichloromethane 95: 5, Rf = 0.32). The hydrochloride salts of each isomer are independently prepared

Salt. ··· ···· ···. · · · · ·· ·· ··· _a · · ·· ·· ·· ··· · ··· ···· · · -4 ^ ……….

on the other by treatment with 1N ether HCl.

recrystallized from either ethanol / ether / EtOAc or 95% ethanol and dried in a vacuum oven.

Example 6: 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) - N-nun erasinyl) butyl) -4-pyridinecarboxamide dihydrochloride hydrate. Melting point: 229-231 ° C. Ή 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 (br d, 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, 1, J = 8.1), 8.31 (s, 1), 9.24 (br t, 1, J = 4.4). 11.45 (br s, 1). 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. Calculated for C ₂ H ₂₆ N ₆ OS.2HC1.0.5 H ₂ O: C 51.22; H, 5.94; N, 17.07; Cl 14.40; H ₂ O 1.82. Found: C, 51.02; H, 6.05; N, 16.98; Cl 14.09; H ₂ O 1.54.

Example 7: 4-Amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3-pyridinecarboxamide dihydrochloride. Melting point: 122130 ° C (appreciation). 1 H NMR (DMSO-d ₆ , 200 MHz): δ 1.64 (t, 2), 1.79 (t, 2), 3.07 (t, 2), 3.30 (t, 8), 3.74 (br s, 2). 6.93 (d, 1 J = 6.6), 7.48 (t, 1, J, = 7.5), 7.61 (t, 1, J = 8.7, 0.8), 8.12 (m, 1), 8.44 (br d, 2). 8.74 (s, 1), 8.97 (br t, 1, J = 5.6), 12.40 (br s, 1). 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. Calculated for C ₂ H ₂₆ N ₆ OS ₂ HCl: C 52.17; Η 5.84; Ν 17.38. Found: C, 52.25; Η 6.17; Ν 17.31.

Example 8:

(a) Preparation of 3-aminoH-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -2-thiophenecarboxamide hydrochloride

3- (4- (4-Aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (Example 1 (6)) (2.83 g, 9.75 mmol) and anhydrous chloroform (50.0 ml) were poured into a 250 ml round bottom flask and are mixed under N ₂ . Trimethylaluminum (9.8 ml, 19.6 mmol, 2.01 equivalents) was added dropwise (Aldrich)

Chemical Company, 2.0 M in toluene) and the reaction mixture was stirred for 0.5 h. A solution of methyl-3-amino-2-thiophenecarboxylate (1.66 g, 0.56 mmol, 1.08 equivalents) (in anhydrous chloroform (25 ml) was added and the orange solution heated at 45-50 ° C for 5 hours .

The reaction mixture was slowly added to 1N hydrochloric acid (100 ml).

The pH of the mixture was adjusted to pH = 10 with saturated K2CO3 solution and the mixture was transferred to a separatory funnel. Chloroform is added to the funnel and the phases are separated. The organic phase was washed with water (2 x 200 ml). The aqueous phases were combined and extracted with chloroform. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give 6.53 g of a crude substance as a dilute dark brown oil. The free base was purified by flash chromatography eluting with dichloromethane and then with dichloromethane / methanol (95: 5) to give 1.32 g of a light brown solid. The free base (1.23 g, 3.06 mmol) was dissolved in dichloromethane and 1N ethereal HCl (3.06 ml, 1.0 equivalent) was added. The hydrochloride salt was recrystallized from ethanol / water to give 0.93 g (21%) of the title compound as a light brown solid. Melting point: 230-232 ° C. ^X H NMR (DMSO-d ₆ ): δ 1.54 (t, 2), 1.75 (t, 2), 3.26 (t, 6), 3.48 (t, 2), 3.61 (br d, 2, J = 11.1) , 4.10 (br d, 2, J = 12.5), 6.42 (br s, 1),

6.60 (d, 1, J = 5.3), 7.40 (d, 1, J, = 5.3), 7.55 (m, 2), 8.15 (br t, 2, J = 6.9), 10.51 (br s, 1). 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. Calculated for C2oH25N50S ₂ «HC1: C 53.14; Η 5.80; Ν 15.49.

Found: C, 53.23; Η 5.86; Ν 15.36.

• methyl-4 - ((tert-butoxycarbonyl) amino) -3 ·· ·· • · · · · · · * · · · · · · · · · · · · · · · · · · 44

Example 9 (a) Preparation of thiophenecarboxylate

Methyl-4-aminothiophene-3-carboxylate hydrochloride (6.57 g, 33.9

4-dioxane (25 ml) and 5% in a round-bottom flask of 500 ml and mmol) (Maybridge Chemical Company), 1,

A solution of Na2CC> 3 (25 ml) was added

the mixture is cooled in an ice water bath. A solution of di-tert-butyldicarbonate (18.6 g, 85.2 mmol, 2.51 equivalents) (Aldrich Chemical Company) in 1,4-dioxane (25 ml) was added slowly to the reaction mixture. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and left for 18 hours. Additional di-tert-butyl dicarbonate (3.86 g, 17.7 mmol, 0.52 equivalents) in 1,4-dioxane (10 ml) was added and the reaction mixture was stirred at room temperature for 26 hours. The reaction mixture was transferred to a separatory funnel. Water and ethyl acetate were added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed twice with water, dried over MgSO ₄ , filtered and concentrated to give a red-brown liquid. The crude material was partially purified by flash chromatography with gradient eluent hexane (100-95%): ethyl acetate (0.5%) to give a colorless liquid. The title compound precipitated after standing, yielding 2.09 g (24%) of the desired substance. Melting point: 100-102 ° C. 41 NMR (DMSO-d ₆ ): δ 1.48 (s, 9), 3.84 (s, 3), 7.53 (d, 1, J = 3.5), 8.32 (d, 1, .T, = 3.5), 9.01 ( br s, 1). ¹³ C NMR (CDCl 3): δ 28.69, 52.27, 80.94, 107.74, 121.74, 132.96, 137.74, 153.49, 164.78.

Analysis. Calculated for C11H15N4O4S: C 51.35; Η 5.88; Ν 5.44. Found: C, 51.28; Η 5.90; N5.48.

·· ····

4 - ((kfet-butoxycarbonyl) amino) -3I

(b) Preparation of thiophenecarboxylic acid

Methyl-4 - ((tert-butoxycarbonyl) amino) -3-thiophenecarboxylate (2.08 g, 8.08 mmol), 95% ethanol (40 ml) and 50% sodium hydroxide (10 ml) were poured into a 500 ml round bottom flask and heated for 1 hour at

45 ° C. The reaction mixture was allowed to cool and the pH was adjusted to pH = 2 using 1N hydrochloric acid. The reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over MgSO4, filtered and evaporated to give a white solid. The substance was dried a second time as described above and then dried in a vacuum oven to give 1.83 g (93%) of the title compound as a white solid. Melting point: 167-168 ° C (foaming).

^X H NMR (DMSO-d6): δ 1.50 (s, 9), 7.54 (br d, 1, J = 3.3), 8.32 (d, 1, J, = 3.5), 9.31 (br s, 1). ¹³ C NMR (DMSQ-d6): δ 28.85, 81.07, 108.30, 122.83,

134.94, 137.35, 152.89, 166.20.

Analysis. Calculated for C1QH13NO4S: C, 49.37; H, 5.39; N, 5.76. Found:

C, 49.30; H, 5.44; N, 5.72.

(c) Preparation of tert-butyl-N- (4- (N- (4- (4- (4- (1,2-benzisothiazol-3yl) -1-piperazinyl) butyl) carbamoyl) -3-thienyl) carbamate

4 - ((tert-butoxycarbonyl) amino) -3-thiophenecarboxylic acid (1.49 g, 6.12 mmol), 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (2.02 g, 7.20 mmol 1.18 equivalents) ) (Example 1 (b)) and anhydrous N, N-dimethylformamide (20 ml) were placed in a 500 ml round bottom flask. A solution of 1,3-dicyclohexylcarbodiimide (1.60 g, 7.75 mmol, 1.27 equivalents) (Aldrich Chemical Company) in anhydrous Ν, dimethylformamide (5 ml) was added dropwise to the reaction mixture and the solution was stirred under N2 in ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · · ·· ···· ·· ·· ·· ··· o'clock. To the solution was added 1 0.25 hydroxybenzotriazole hydrate (1.0 g, 7.40 mmol, 1.21 equivalents) (Aldrich Chemical Company) and the reaction mixture was stirred under N 2 at room temperature for 2.75 days. The suspension was filtered and the filtrate was concentrated to give an orange oil. The crude free base was dissolved in dichloromethane and the solution was transferred to a separatory funnel. The organic phase was washed with saturated NaHCO3 solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated to give an orange oil. The free base was partially purified by flash chromatography with eluent dichloromethane and then with dichloromethane: methanol (96: 4) to give a cloudy orange oil. The oil was dissolved in dichloromethane, filtered and concentrated to give a less cloudy orange oil. The crude free base was dissolved in ethyl acetate, filtered and concentrated to give 2.73 g (86%) of the free base as a clear orange oil. A portion of the free base was isolated as the hydrochloride salt upon recrystallization from ethanol. Melting point: 116-119 ° C.

^L II NMR (DMSO-d6): δ 1.44 (s, 9), 1.60 (t, 2), 1.78 (t, 2), 3.29 (t, 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 (br s, 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 (br t 1, J = 5.6), 10.17 (s, 1 ), 10.63 (br s, 1). ¹³ C NMR (DMSO-d6): 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. Calculated for 1з3 ^50з8? * HCl »H ?O: C 52.66; H, 6.36; N, 12.28; H ₂ O 3.16. Found: C, 52.76; H, 6.36; N, 12.38; H ₂ O 2.90.

• ·

Example 10:

(a) Preparation of 4-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1 piperazinyl) butyl) -3-thiophenecarboxamide hydrochloride

Tpem-6yl-N- (4- (N- (4- (4- (1,2-benzisothiazol-3-yl) -1-nuilepazinyl) butyl) carbamoyl) -3-thienyl) carbamate (3.13 g, 6.07 mmol ) (Example 9 (c)), trifluoroacetic acid (24 ml) (EM Science), anhydrous anisole (6.4 ml) (Aldrich Chemical Company) and anhydrous chloroform (50 ml) were mixed in a 250 ml round bottom flask and stirred under N ₂ at room temperature for 20 minutes. Thin layer chromatography shows that the reaction is complete. The reaction mixture was concentrated to give an orange liquid. The crude material was dissolved in dichloromethane and transferred to a separatory funnel. The organic phase was washed with saturated NaHCO3 solution and separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over MgSO4, filtered and concentrated to give an orange liquid. The crude free base was purified by flash chromatography eluting with dichloromethane then dichloromethane: methanol (96: 4) to give 1.57 g of free base as a pale orange oil. The free base 140 g (3.37 mmol) was dissolved in ethyl acetate and 3.4 ml of 1N ether HCl (1.0 equivalent) were added. The hydrochloride salt was filtered off and dried, yielding 1.01 g (37%) of the title compound as an off-white solid. Melting point: 204-206 ° C.

'll NMR (DMSO-d _6): δ 1.58 (m, 2), 1.79 (m, 2), 3.00-3.80 (m, 10), 4.04 (m, 2), 5.80 (br s, 2), 6.10 (d, 1, J = 3.3), 7.49 (ddd, 1, J = 1.0, 7.0, 8.1), 7.62 (ddd, 1, J = 1.0, 7.0, 8.1), 8.03 (d, 1, J = 3.5) , 8.15 (br t, 2, J = 6.8), 8.40 (br t, 1, J = 5.5). ¹³ C NMR (DMSO-dJ: δ 21.70, 27.29, 38.70, 47.46, 51.51, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Analysis. Calculated for (C10H10N5Cl3) HCl: C 53.14; H 5.80; N 15.49.

Found: C, 53.20; H, 5.84; N, 15.34.

Example 11 (a) Preparation of methyl-3-aminobenzo [b] thiophene-2-carboxylate

This compound was prepared by the method of J.R. Beck [J. Oorg.

Chem; 37, 3224 (1972)] using 2-nitrobenzonitrile (50.0 g,

0.338 mol) (Aldrich Chemical Company), methylthioglycolate (33.2 ml,

36.4 g, 0.344 mmol, 1.11 equivalents) (Aldrich Chemical Company), N, N-dimethylformamide (400 ml) and aqueous KOH (37.4 g / 187 ml water) to give 36.1 g (52%) of the title compound as pale beige solid. hl NMR (CDCl3): δ 3.90 (s, 3), 5.92 (br s, 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, 1, J = 0.8, 1.5, 8.0), 7.74 (ddd, 1, J = 0.8, 1.2, 8.0).

(6) Preparation of 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) benzo [b] thiophene-2-carboxamide hydrochloride 3- (4- (4 -aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (2.6 g,

8.96 mmol) (Example 1 (b)) and anhydrous chloroform (20 ml) were placed in a 100 ml round bottom flask and stirred under N3. A solution of trimethylaluminum (4.6 ml, 9.2 mmol, 1.03 equivalents) (Aldrich Chemical Company, 2.0 M in toluene) was slowly added to the reaction mixture and the pale yellow solution was stirred under N3 for 20 minutes. Another portion of trimethylaluminum (4.6 ml, 9.2 mmol, 1.03 equivalents) was added to the reaction mixture. A solution of methyl 3-aminobenzo [b] thiophene-2-carboxylate (1.86 g, 8.98 mmol, 1.0 equivalents) in anhydrous chloroform (10 ml) was added to the reaction mixture and stirred at N3 at room temperature for 0.5 hours. The golden yellow solution was heated at 40 ° C for 4 days. The oil bath was removed and the dark orange solution was allowed to cool. To the weak • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The warm reaction mixture was slowly added to IN HCl (50 ml). The acidic reaction mixture was heated at 40 ° C for 0.5 h.

The reaction mixture was allowed to cool and a saturated solution of K2CO3 was added. The reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated to give the crude substance as an orange liquid. The free base was purified by flash chromatography with dichloromethane gradient eluent (100-95%): methanol (0-5%). 1.4 g (27%) of the free base are obtained as an orange oil. The free base 1.05 g (2.25 mmol) was dissolved in ethyl acetate and 2.25 ml of IN HCl (1.0 equivalents) were added. The hydrochloride salt was recrystallized from ethanol to give 0.82 g (18%) of the title compound as a beige solid. Melting point: 242-244 ° C. Ή NMR (DMSO-d ₆ ): δ 1.58 (m, 2), 1.76 (m, 2), 3.103.50 (m, 8), 3.59 (br d, 2 J = 11.2), 4.08 (br d, 2) , J = 13.4), 7.07 (br s, 2), 7.38 (ddd, 1, J = 11, 7.1, 8.1), 7.47 (tm, 2, J = 7.6), 7.60 (ddd, 1, J = 1.1. 7.1, 8.2), 7.68 (br t, 1, J = 5.6), 7.83 (d, 1, J = 7.7), 8.03 (d, 1, J = 7.9), 8.12 (t, 2, J = 8.3). 10.39 (br s, 1). 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. Calculated for C24H27N5OS2 »HCl: C 57.41; Η 5.62; Ν 13.95.

Found: C, 57.42; Η 5.68; Ν 13.94.

Example 12 (a) Preparation of 2-cyano-X- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) acetamide

3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (2.23 g, 7.69 mmol) (Example 1 (b)) and cyanoacetic acid (0.76 g, 8.93 mmol, 1.16 equivalents) (Aldrich Chemical Company) and dimethylformamide (20 ml) are placed in a 250 ml round bottom flask and are

confuse foot N2. A solution of 1,3-dicyclohexylcarbodiimide (1.86 g, 9.01 mmol, 1.17 equivalents) (Aldrich Chemical Company) in N, N-dimethylformamide (5 ml) was added dropwise to the reaction. 1-Hydroxybenzotriazole hydrate (1.24 g, 9.18 mmol, 1.19 equivalents) (Aldrich Chemical Company) was added and the reaction mixture was stirred.

I was left to stir for 23 hours at room temperature and below N2. The suspension was filtered and the solid was washed with N, N-dimethylformamide. The filtrate was concentrated to give an orange oil. The crude free base was dissolved in ethyl acetate and filtered. The filtrate was fed directly onto a silica gel column and partially purified by flash chromatography with gradient eluent ethyl acetate (90-80%): methanol (10-20%). 2.92 g of the crude material are obtained as an orange oil. The crude free base was dissolved in dichloromethane and washed with saturated K2CO3 solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over MgSO4, filtered and concentrated to give 1.93 g (70%) of the title compound as a pale beige solid. NMR (CDCl3): δ 1.63 (br t, 4, J = 3.3), 2.47 (br t, 2, J = 6.7), 2.69 (br t, 4, J = 4.9), 3.36 (m, 2), 3.37 (s, 2), 3.57 (br t, 4, J = 4.9), 6.66 (br s, 1), 7.36 (ddd, 1, J = 1.2, 7.0, 8.1), 7.47 (ddd, 1.1 = 1.2 , 6.9, 8.2), 7.82 (dt, 1, J = 7.8, 1.1), 7.91 (dm, 1, J = 8.0).

(6) Preparation of 2-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -3-thiophenecarboxamide

2-cyano-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) acetamide (1.83 g, 5.12 mmol), 1,4-dithian-2,5-diol (1.79 g, 11.8 mmol, 2.30 equivalents) (Aldrich Chemical Company), triethylamine (1.70 ml, 1.23 g, 12.2 mmol, 2.38 equivalents) and ethanol (30 ml) were placed in a 500 ml round bottom flask and heated at 60- 65 ° C under a nitrogen atmosphere for 3 hours. The oil bath was removed and the reaction was allowed to cool. Water and dichloromethane were added and the reaction mixture was transferred to a separatory funnel. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over MgSO ₄ , filtered and evaporated to give a reddish-brown solid. The free base was partially purified by flash chromatography with gradient eluent ethyl acetate (100-98%): methanol (0-2%). A partially solidified orange oil is obtained. The free base was dissolved in ethyl acetate and filtered. The filtrate was partially concentrated to give a suspension. The pale light brown solid was filtered off and dried. 0.239 g (11%) of the title compound are obtained. Melting point: 155-159 ° C. ^X H NMR (CDCl ₃ ): δ 1.668 (br s, 4), 2.48 (br s, 2), 2.68 (br s, 4), 3.42 (m, 2), 3.58 (br s, 4), 5.84 ( br s, 1), 6.07 (br s, 2), 6.23 (d, 1, J = 5.8), 6.71 (br d, 1, J = 5.8), 7.35 (ddd, 1, J = 11, 7.0, 8.1 ). 7.46 (ddd. 1, J = 11, 7.0, 8.1), 7.81 (d. 1,

J = 8.2), 7.90 (d, 1, J = 8.2). 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, 124.18, 124.22, 124.43, 127.40, 127.89, 152.06, 161.05, 163.52, 165.45.

Analysis. Calculated for C20H2sN50S2 * 3/20 C4HsO2 * 0. 3 TH: C 56.98; II 6.22; N, 16.13. Found: C, 56.70; H, 6.15; N, 16.26.

Example 13 (a) Preparation of ________ of N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -8-quinolinecarboxamide hydrochloride

Anhydrous N, N-dimethylformamide (20 ml), 8-quinolinecarboxylic acid (1.04 g, 6.01 mmol), (Aldrich Chemical Company), 1hydroxybenzotriazole hydrate (0.898 g, 6.65 mmol, 1.11 equivalents) (3- ( 4- (4-Aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (1.75 g, 6.03 mmol, 1.0 equivalents) (Example 1 (6)) was mixed in a 250 ml round bottom flask. The reaction mixture was cooled under N2. To the reaction mixture was added 1,3-dicyclohexylcarbodiimide (1.37 g,

··· ··· · · · · ··· · «in an ice water bath and a solution is added dropwise.

6.64 mmol., 1.10 equivalents) (Aldrich Chemical Company) in anhydrous

N, N-dimethylformamide (12 ml). The diluted water bath was removed and the reaction mixture was stirred for 20 hours at room temperature. The suspension was concentrated in vacuo and the crude material was partitioned between ethyl acetate and saturated NaHCO 3 solution.

The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over MgSO ₄ , filtered and concentrated to give a mixture of finely dispersed solid in orange oil. Ethyl acetate was added to the mixture and the suspension filtered. The filtrate was concentrated to give 2.98 g of the crude as an orange oil. The crude material was purified by flash chromatography eluting with dichloromethane, dichloromethane methanol (99: 1) and dichloromethane: methanol (97: 3). The necessary fractions were combined, concentrated, redissolved in dichloromethane, filtered and concentrated to give 1.46 g of the crude base as a yellow oil. The free base was dissolved in dichloromethane and 1N HCl (3.28 ml, 1.0 equivalents) was added to the solution. The solvent was removed in vacuo.

The resulting hydrochloride salt was dissolved in methanol and the solution filtered directly through a folded filter into ethyl acetate, which was stirred rapidly. The suspension was filtered to give 0.265 g of the title compound as a pale yellow solid, the filtrate was concentrated and recrystallized from methanol to give an additional amount (0.447 g). The total yield was 0.712 g (25%). Melting point: 187-189 ° C.

NMR (DMSO-d ₆ ): δ 1.68 (t, 2), 1.91 (t, 2), 3.10-3.42 (t, 4), 3.56 (t, 6), 4.03 (dr d, 2, J = 11.8), 7.43 (t, 1, J = 7.5), 7.56 (t, 1. J = 7.6), 7.65 (dd, 1, • · • ·· ·· • · · • ·.

· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

J = 4.3, 8.3), 7.72 (t, 1, J = 7.7.), 8.09 (t, 2, 1 = 7.7.), 8.17 (d, 1 4 = 8.1), 8.54

1). ¹³ C NMR (DMSO-d 6): δ 21.24, 26.95, 38.85, 46.72, 50.82, 55.59, 121.52,

Example 14 (a) Preparation of 1,2,3,4-tetrahydro-8-quinolinecarboxylic acid

The compound was prepared by the method described by Coppola, GM (J. Heterocyclic Chem., 1978, 15, 645) using 8 quinolinecarboxylic acid (1.73 g, 9.99 mmol) (Aldrich Chemical Company), platinum oxide hydrate (0.182 g) ( EM Science) and ethanol (30 ml). The mixture was hydrogenated in a Parr hydrogenator at 50 psi (feet per square inch) for 2 hours. The reaction mixture was filtered through a celite cartridge and the filtrate concentrated to give 1.76 g (99%) of the title compound as a pale yellow solid. Melting point: 158160 ° C [liter. t, t. 165-167C]. '11 NMR (DMSO-d ₆ ): δ 1.77 (quin. 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). 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. Calculated for C ₁₈ H 13 NO ₂ : C 67.78; H, 6.26; N, 7.90. Found: C, 67.56; H, 6.32; N, 7.85.

(b) Preparation of _______ of ________ N- (4- (4- (1,2-benzisothiazol-3-yl) -1piperazinyl) butyl) -1,2,3,4-tetrahydro-8-quinolinecarboxamide The compound was prepared by the method described in example 13 (a) using 1,2,3,4-tetrahydro-8-quinolinecarboxylic acid (1.06 g, 5.98 mmol), 1-hydroxybenzotriazole hydrate (0.90 g, 6.66 mmol, 1.1 equivalents) (Aldrich Chemical Company), 1 , 3 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Dicyclohexylcarbodiimide (1.47 g, 7.12 mmol, 1.2 equivalents) (Aldrich Chemical Company), 3- (4- (4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (1.82 g, 6.27 mmol, 1.05 eq. of anhydrous) (Example 1 (6)) and anhydrous N, N-dimethylformamide. The reaction mixture was allowed to stir at room temperature for 18 hours, concentrated in vacuo and the crude was partitioned between dichloromethane and saturated NaHCCH. the fine dispersed solid was filtered off and the filtrate concentrated to give the crude free base. This substance was purified by flash chromatography as described in Example 13 (a).

The purified free base (2.28 g, 5.07 mmol) was dissolved in dichloromethane and 1N HCl (5.07 ml, 1.0 equivalent) was added to the solution. The solvent was removed in vacuo and the resulting hydrochloride salt was dissolved in MeOH. The solution was filtered through a folded filter directly into vigorously stirred ethyl acetate. The suspension was filtered to give 0.28 g (9%) of the title compound as an orange-beige solid. Melting point: 138-142 ° C. NMR (DMSO-d6): δ 1.55 (m, 2), 1.77 (m, 4), 2.69 (t, 2, J = 6.0), 3.21 (m, 8), 3.47 (t, 2, J = 12.9 ), 3.56 (d, 2, J = 11.6), 4.05 (d, 2, J = 13.4), 4.46 (br s, 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, 1 = 8.2), 8.32 ( br t, 1, J = 5.3), 10.9 (br s, 1). ⁱ³ 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, 129.29, 132.84, 146.19, 153.26,

163.35, 170.20.

Analysis. Calculated for C25H3iNsOS · !. 5 HCl * 0.35 TH: C 58.81; H, 6.55;

N, 13.72; Cl 10.41; H ₂ O 1.23. Found: C, 58.47; H, 6.62; N, 13.43; CI 10.18; H ₂ O 0.85.

• · • · • · ·· <

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 15 (a) Preparation of 2- (2,3-dihydro-1H-indol-1-yl) glyoxyloyl chloride

This compound was prepared by the method described by Welstead, W.J. tt al., (J. Med. Chem., 1979, 22, 1074) c modifications. Oxalyl chloride (102.1 g, 0.804 mol) (Aldrich Chemical Company) and anhydrous dichloromethane (400 ml) were placed in a 2 L round bottom flask.

The flask is equipped with a mechanical stirrer, a funnel for additives and an inlet for N ₂ . A solution of indoline (48.0 g, 0.403 mol) in anhydrous dichloromethane (350 ml) was added dropwise over a period of 2 hours to the stirring mixture. The reaction mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. The resulting reddish-brown solution was concentrated and diethyl ether was added to the residue. The suspension was filtered and the filtrate concentrated to give 56.75 g (68%) of the acid chloride as a yellow-green solid. The crude acid chloride was used without further purification. ^! TT NMR (DMSOd ₆ ): δ 3.19 (t, 2, J = 8.3), 4.17 (t, 2, 1 = 8.3), 7.1.2 (t, 1, J = 6.9), 7.24 (t, 1, J = 7.1), 7.33 (d, 1, J = 7.0), 8.01 (d, 1, J = 7.6).

(6) Preparation of 4,5-dihydropyrrolo [3.2.1-chi] indoline-1,2-dione

Aluminum chloride (12.7 g, 95.2 mmol, 5.0 equivalents) (Aldrich Chemical Company) and 2- (2,3-dihydro-1H-indol-1-yl) glyoxyloyl chloride (4.00 g, 19.1 mmol) were placed in a round-bottom flask of 300 ml equipped with magnetic stirrer and inlet for N ₂ . The mixture was heated rapidly to 100-120 ° C and allowed to stir for 20 minutes. The oil bath was removed to cool the reaction mixture to room temperature. The resulting solid was crushed with a spatula and added to ice water (600 ml). The aqueous mixture was stirred for 1 hour and extracted with chloroform. The organic phase was dried over MgSOg, filtered and concentrated to give an oily red residue. The residue was suspended in acetone and sat

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· filtered to give 0.71 g (22%) of the title compound as a solid red. Melting point: 203-207 ° C. [literature (Welstead, WJ, et al., J. Med. Chem., 1979, 22, 1074) Melting point: 206-208 ° C.] 41 NMR (DMSO-d ₆ ): δ 3.36 (t, 2 , J = 7.9), 4.06 (t, 2, J = 7.9), 6.95 (t, 1, 1 = 7.5), 7.24 (d, 1, J = 7.6), 7.46 (d, 1, J = 7 1) . 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, 184.71.

Analysis. Calculated for C10H7NO2: C 69.36; H, 4.07; N, 8.09. Found: C 69.09: H 4.10; N, 8.00.

(c) Preparation of indoline 7-carboxylic acid

A solution of sodium hydroxide (1.82 g in 20.2 ml of water) and 4.5dihydropyrrolo [3.2.1-chi] indoline-1,2-dione (1.0 g, 5.8 mmol) were combined in a 100 ml round bottom flask and stirred at room temperature. temperature for 30 minutes. Hydrogen chloride was added dropwise to the reaction mixture. the reaction mixture was oupic · 'in a separatory funnel and washed with benzene'. The water was adjusted to 6-7 by diavance of a 1N solution.

L82 ml of H2O2 body in 18.2 ml of H2O) for hours. 1 'and ·.> ·> Ι; ί> and the mixture <.- with the iipt phase is separated, the pH is in HC! and the solution was extracted with chloroform The pH of the aqueous phase was adjusted to 4-5 by the addition of 1N HCl υ was extracted with an additional amount of chloroform. The organic phases were dried over MgSO4. Filter π concentrate to give a bony ^ golden brown solid.

The crude material was suspended in benzenoazooctane (3: 1). yielding 0.54 g ι> 7 ^) of

compound as a light brown solid. Melting point: 164-166 ° C. 1 References (Welstead. WJ. Et ai .. .1. Med. Chem. 1979, 22, 1074) Melting point: 164-168 ° C.] ¹ H NMR (DMSOd ₆ ): 6 2.93 (t, 2 , 1 = 8.6), 3.55 it, 2, 1 = 8.6). 6.44 (t, 1. 1 = 7.0). 7.13 (d, 1. .1 = 6.7.36 (d, .1, 1-7.5). IJ C NMR (DMSO-df;): δ 28 19. Legal Entity Yu7ll5 "

· · · · · · ·

Μγ · · · · · · ·

Analysis. Calculated for C9H9NO2: C 66.25; H, 5.56; N, 8.58. Found: C

65.98; H, 5.51; N, 8.48.

(d) Getting ________ on ^! _______ N- (4- (4- (1,2-benzisothiazol-3-yl) -1- »piperazinyl) butyl) -2,3-dihydro-1H-indole-7-carboxamis |

This compound was prepared by the method described in Example 13 (a) using indoline-7-carboxylic acid (0.86 g, 5.27 mmol), 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2 -benzisothiazole (1.60 g, 5.51 mmol, 1.05 equivalents) (Example 1 (6)), 1-hydroxybenzotriazole hydrate (0.78 g, 5.77 mmol, 1.10 equivalents) (Aldrich Chemical Company), 1,3-dicyclohexylcarbodiimide (1.35 g, 6.54 mmol 1.24 equivalents) (Aldrich (.-Hemical Company) and anhydrous NN dimethylformamide. The reaction mixture was allowed to stir at room temperature for 24 hours and the solvent removed in vacuo. Ethyl acetate was added to the residue and the mixture filtered - ρ with is ν / .parties undissolved ·.;, mothers ·.>. The shimmer rt, ie.;. ·. · with a saturated solution of NaiiCO · ^. The organic phase is dried over MgSO ₄ , filtered and cc was concentrated to give 3.12 g of a crude substance as an orange oil. The crude substance was purified by flash chromatography with eluent ethyl acetate: meth: s (99: 1) followed by e.ethyl acetate: methanol <97: 3) . The necessary fractions were combined, concentrated, dissolved in dichloromethane, filtered to give 6.96 g (42%) of oil. 1 H NMR (DMSO-d ₆ ):

.1 = 4.5). 2.89 π. ί ... 1 = 8.6k h ../ 7 concentrate and, with bone, the title compound as a plow. *

1.51 (t, 4), 2.36 (r, 2, 1 = 6.4), 2.54 (K hr i. 2. 4 = 6 (n. 3.4 · (br L 4. 1-4.5 ». 3.5

ON

1,1 ~ H ή k * · <ι ι j—> a, ι ·· • · · • · · ·

Example 16 ΐ (a) Preparation of 1H-indole-7-carboxylic acid

This compound was prepared by the method described by Ikan R and Rapaport, E (Tetrahedron, 1967, 23, 3823) using indoline-7carboxylic acid (3.0 g, 18.4 mmol) (Example 15 (B)), 10% Pd on charcoal (0.75 g) (Aldrich Chemical Company) and xylene (150 ml). The reaction mixture was heated for 4 hours. The hot solution was filtered through a celite cartridge and the filtrate was concentrated to give i g (52%) of the title compound as a red-beige solid. Melting point: 202-294 ° C. [Literal data 202 ° C]. ¹ H NMR (DMSO-d *): δ 6.52 (dd, 1, J = 2.0, 3.0), 7.01 (µ 1.

1 = 7.7., 7.35 (ι, ι, 1 = 2.8), /./4 (dd, i, j = 1.2, 7.5), 7.81 (cl lj = 7.9), H.05 (s, 1). 12.98 (br s, 1). 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.

N- (4- (4- (l, 2-6eH3 · piperazinyl 4 a * - ^v ) ~ 1H-ind: i -. - r - <ϊ rboxamide

This compound was obtained by the method described using 1H-indole-7-carboxylic acid mmol, 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (2.47 g. 801 mmol, 1.04 equivalents) (Example 1 (6)), 1-xg hydrate (1.20 y. 8.88 mmol, 1.08 equivalents) Company), 1,3-ucyclohexylcarbodiimide (1.87 scioents)>. 1 σ eoimethylformno. Reaction ·· '· »!” # Eu leaves o nri room w> ν ». r> k- et I p vi · ι f · · <

.kCh.-ix 4. J j. t.i rKkZllh ·. ·· '-. ·' I 'C * X.L 4.4..iS'bM residue was added with a thinner and a slurry> h · * filtration.

the filtrate cc washes separated. Organ.

t-concentrate '.';

rt. wt. in a saturated solution of Na! 1 ιί> the eye phase is eliminated above Mt8 <. <

'·' Which produces the raw, o. The crude free base was purified by flash

I chromatography on eluent ethyl acetate, ethyl acetate: methanol (99: 1) and ethyl acetate: methanol (97: 3). Obtained <x 3.27 g (92%) of the title compound as a yellow oil. 1 H NMR (DMSO-dJ: δ 1.57 (t, 4), 2.39 (t, 2, J = 6.9), 2.57 (br t, 4, J = 4.5), 3.35 (m, 2), 3.42 (br t , 4,, T = 4.5), 6.46 (t, 1, J = 2.9), 7.04 (t, 1.1 = 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).

Claims (14)

Patent Claims A compound of formula I V Ri (I) where Y represents a heteroaryl group optionally substituted by one or more halogen atoms, nitro, C 1 -C 4 -alkyl, C 1 -C 5 alkoxy, aryloxy, aryl-C 1 -C 6 alkyleneoxy, hydroxy, S (O) _n R ₂ or S (O) n (R 2) 2 , where n is 0, 1 or 2, CN, CON (R ₂ ) ₂ , COR ₂ , CO ₂ R ₂ , (X) -aryl, azido. -N (R ₂ ) ₂ , NR ₂ N (R _2a ) ₂ , -NR jN = C (R _2a ) ₂ : -NR ₂ (C = O) CH (N (R _2a ) ₂ ) R2b, -NR ₂ (C = O) R _2a , NR ₂ CO ₂ R _2a , C _r C ₆ alkoxycarbonylamino or PhN = N, provided that Y does not include benzisothiazolyls or benzisoxazolyls; V represents O or S; Ζ represents Cj.g-alkylene, optionally interrupted is -O- or -S (O) _n -, wherein n is 0, 1 or 2, C ^ -alkenylene or C ₂ _8 alkynylene; X represents N. CR; or COR ₂ ; A represents CR4 or Ν; P> represents oxygen, NR5 or S (O) _n , where n is 0, 1 or 2; and R | represents hydrogen or one or more halogen atoms, hydroxy, nitro, CN, N (R ₍ , h, C 1-6 alkoxy, aryloxy, aryl-C 1-4 alkyleneoxy, or COR 2, R, R ₂ , R _2a , R ₂ b> R 3 »R-1- R? and R < 3 > independently represent hydrogen or C1-C6 alkyl; Or a salt, solvate, N-okcug or physiologically active derivative thereof. A compound, salt, solvate, N-oxide or derivative according to claim 1, wherein the heteroaryl group is selected from the group comprising: pyrazolinolin tetrahydroquinolinyl, indolinyl, quinoxalinyl, triazolyl or thiadiazolyl. A compound, salt, solvate, N-oxide or derivative according to claims 1 and 2, wherein the heteroaryl group is substituted with N (R ₂ ) ₂ . A compound, salt, solvate, N-oxcug or derivative according to any one of claims 1 to 3 ', the hetero anal group is pyridine, thiophene or benzthiophene optionally substituted with N14 ?, NHMe or NHAc and R is H or Me. A compound, salt, solvate, N-oxide or derivative according to any one of claims 1 to 4, wherein R is H and the heteroaryl group is pyridine or thiophene substituted with ΝΗρ. 6. Compounds: No. (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -2-pyridinecarboxamide; N- (4- (4- (1,2-benzisosiazol-3-yl) -1-tracerazin-1-yl) 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) butyl) carbamophen) -3-thienyl) carbamate; • · · · 2-Hmuho-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-tterazinyl) 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) -3iophenecarboxamide; N (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -8-quinolinecarboxamide; N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -1,2,3,4tetrahydro-8-quinolinecarboxamide; N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -2,3-dihydro-1H-indole-7-carboxamide; N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -1H-indole-7carboxamide; and their physiologically acceptable salts, solvates, physiologically active derivatives and N-okcugu. 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) -2piperidine; N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -2-pyridine carboxamide; N- [4- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) biphenyl) -3-pyridinecarboxamide; and their physiologically acceptable salts, solvates, physiologically active derivatives and N-okcugu. 8. 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -2-pyridinecarboxylamide; and its physiologically acceptable salts, solvates, physiologically active derivatives and N-okcugu. 9. A process for the preparation of a compound of formula (I): (I) wherein Υ, V, Z, X, A, B, R, Rj, R, R ₂ , R _2a , R _3> R 4, R 5 and R ₍ , are defined in any one of claims 1 to 9; or a salt, N-oxide solvate or physiologically active derivative thereof, wherein a compound of formula (II) is reacted with a compound of formula (III) (II) · (III) wherein L is a leaving group; or a compound of formula (II) is reacted with a compound of formula (IV) (IV) wherein W is a suitable anion and R 2 is - (N-N- or - (N-N '-; or a compound of formula (V) V (V) where L is a leaving group is reacted with a compound of formula (VI) 9 9 (VI) or a compound of formula (VII) A N · I R (VII) is reacted with a compound of formula (VIII) Ri (VIII) where L has the meaning given above; or compounds of formula (IX) or (1Xa) wherein C is halogen, OMe or OH, (IX) V (IXa) u where Y, V and R2 have the meanings given above and are reacted with a compound of formula (X) R1 (X) or a compound of formula (Xa) V R1 (Xa) is treated with 1,4-dithian-2,5-diol; or a compound of formula (I), wherein Z is C ₂ _8 ~ alkenylene or Sz_8alkinilen is reduced; or the corresponding alkoxycarbonylamine derivative of a compound of formula (I), which is optionally substituted by one or more N (R ₂ ) ₂ or NRN (R ₂ ) ₂ , is hydrolyzed. • · · · · A compound of formula (I) as defined in claim 1, or a physiologically acceptable salt, solvate, N-oxide or physiologically active derivative thereof for therapeutic use. 11. The therapeutic administration of any of the following compounds or of their physiologically acceptable salts, solvates, N-okcugu or physiologically active 3-amino-N- (4- (4- (1,2-benzisothiazol-3-yl) derivatives) -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; N- (4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl) -3-pyridinecarboxamide; and their physiologically acceptable salts, solvates, physiologically active derivatives, and N-oxide ¹ '. The use of a compound of formula J) as defined in claim 1, or a physiologically acceptable salt, solvate, oxide or physiologically active derivative thereof, for the manufacture of a medicament for the treatment or prevention of a mental illness. The use of claim 12, wherein the mental illness is schizophrenia. A pharmaceutical composition comprising a compound of formula (1) as defined in claim (I), or a physiologically acceptable salt, solvate, N-oxide or physiologically active derivative thereof.