SK96494A3 - Piperazine and piperidine derivatives, and their use as antipsychotic - Google Patents

Abstract

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

Description

Technical field

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

BACKGROUND OF THE INVENTION

It is known that dopamine, acting chemical messenger are located in striatal and limbic areas · Such receptors are classified as D ^ and D _2, based on the presence or activity of the receptor and receptor is associated with the brain, and binding studies receptors and the absence of a positive adenylate cyclase linkage. Activation by stimulating adenylate cyclase while the D ₂ receptor mediates dopaminergic effects so that it does not involve a direct enzyme (see Kababian and Calne, Nature 227, 93).

Chem. 30, 1631 (1987)]. although

D ₂ is not clearly separated by D ₂ α receptor antagonism

Seeman, Pharmacol. Rev. 32, 229

Pharmacol. 34

J. Med.

stimulation of this (1979) and Harrold different function is expected to be potent antipsychotic (1981), Seeman 151 (1985), Creese et al., Scien481 (1976) and Leysen in Clinical Pharmacology in Psychiatvyd. Usdin ..., Gram to 52 (1982)).

et al., Dj receptors and correlation between activity (see et al., Biochem. ce 192, ry: Neuroleptic and Antidepressant Research, and Lingjaerde, Macmillan: Basingstoke, p. 35

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

J. Pharm. and Exper. Ther. 224 (2), 658 (1988)]. In particular, it is believed that blocking the central dopamine D ₂ receptors can control the positive symptoms of schizophrenia (e.g. delirious notions and hallucinations), while blocking 5-HT ₂ receptors can help to improve the negative symptoms of schizophrenia (e.g., apathy and social recession). It is also suggested that 5-HT ₂ receptor blocking results in a reduction in extrapyramidal side effects known to occur in the case of neuroleptically maintained therapy by many known antipsychotic agents.

The psychotropic activity described in U.S. Pat. no. No. 0 357 134 piperidines and in European and 0 196 132. piperazines are U.S. Pat. Benzisothiazoles and benzisoxazoles are

968 792

Others described

329 168 and in European patents, antipsychotically effective in DE-A-4,960,149; 25 03 816 0 013 612

SUMMARY OF THE INVENTION

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

The present invention relates to a compound of formula I

Y ----- z ---- N X --- W in / (I) a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, and a physiologically functional derivative thereof.

In the general formula

Y represents a group of formula (a), (b) or (c) (a)

where the single line with a dashed line (- - -) represents a single or double bond,

(C)

where

R ¹ represents one or more ring substituents including a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms, an alkoxy group having 1 to 6 carbon atoms, optionally substituted with at least one halogen atom, hydroxy, N (R ⁴ ) ₂ , nitro, S (O) _n R ⁴ , where n is 0, 1 or 2, C = N, CON (R ⁴ ) 2, COR ⁴ , CO 2 R ⁴ , CO-aryl, azido, benzyloxy, NR ⁴ N (R ⁴ ) 2, -nr ⁴ co ² r ⁴ , -nr ⁴ n = c (r ⁴ ) 2, -NR ⁴ (C = O) CH [N ( R ⁴ ) 2] R ⁴ and -NR ⁴ (C = O) R ⁴ ,

R ² is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -,

-S-, NR ³ -, -N = N- or - (C = O) NR ₄

R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety,

R ⁴ is hydrogen or C 1 -C 6 alkyl, R 5 is -N = C- or -C = N-,

R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , which are the same or different, each represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms, optionally substituted by one or more halogen atoms, an alkoxy group having 1 to 6 carbon atoms, optionally substituted by one or more halogen atoms, hydroxy, a group of formula S (O) _n R ⁴ where n is 0, 1 or 2, a group of formula C = N, CON (R ⁴ ) 2, COR ⁴ , CO2R ⁴ , CO-aryl, azido, benzyloxy, N (R ⁴ ) 2, NR ⁴ N (R ⁴ ) 2,

-NR ⁴ N = C (R ⁴ ) 2, -NR ⁴ (C = O) CH [N (R ⁴ ) 2] R ⁴ , -NR ⁴ (C = O) R ⁴ and -nr ⁴ co ₂ r ⁴ , alkoxycarbonyl having 1 to 6 carbon atoms, alkoxy or a radical of formula PhN = N, or provided pairwise combinations of R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ is a group of formula

V represents an oxygen atom or a sulfur atom,

Z is C 4 -C 8 alkylene optionally interrupted by the formula -S (O) _n , wherein n is 0, 1 or 2, C 4 -C 8 alkenylene or C 4 -C 8 alkynylene,

X represents a nitrogen atom or a carbon atom; and

W represents a group of formula (d)

A is CR ⁴ or N,

B is O, NR ⁴ or S (O) _n , wherein R ^{4 and} h are as defined herein and

R ¹² represents a hydrogen atom or a halogen atom.

The compounds of formula I may form solvates, in particular hydrates or partial hydrates, and all such solvates are also included within the scope of the invention.

As used herein, the term alkyl, in a group or part of a group, may be straight or branched chain and is, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl or

2-methylprop-2-yl. Alkyl groups are most preferably methyl or ethyl.

As used herein, the term alkylene refers to a straight, branched, or cyclic alkylene group of 5 or 6 carbon atoms and is, for example, butylene, pentylene, hexylene, cyclohexylene or - (CH 2) _m ^- cycloalkyl- (CH 2) _m - s The cycloalkyl having 3 to 6 carbon atoms is preferably a cyclopropylene group.

As used herein, the term aryl refers to phenyl, naphthalene, thienyl, pyridyl, furanyl or pyrrolyl optionally substituted by one or more halogen, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, amino , monoalkylamino and dialkylamino or alkanoyl groups.

As used herein, alkenylene refers to a straight, branched or cyclic alkenylene group of 4 to 8 carbon atoms, such as butenylene, pentenylene, hexenylene, and the like.

As used herein, the term alkynylene refers to a straight or branched alkynylene group of 4 to 8 carbon atoms, such as butylene, pentinylene, hexinylene and the like.

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

As used herein, a physiologically functional derivative means any physiologically acceptable ester or salt of such an ester derived from a compound of Formula I or a compound which upon administration to a recipient is capable of providing (directly or indirectly) such a compound or its active metabolite or residue. .

As used herein, the symbol Ac refers to a portion of the formula

- (c = o) ch ₃ .

The term includes all optical isomers of the 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 salts, solvates and derivatives thereof, wherein the nitrogen atom shown in formula I in the position adjacent to the substituent Z is in its oxidized form as an N-oxide.

The present invention includes compounds of formula I in the form of their physiologically acceptable salts. Particularly suitable salts are acid addition salts, including those formed with both organic and inorganic acids. Such salts will generally be physiologically acceptable, although salts that are not physiologically acceptable may be used in the manufacture and purification of the subject compounds. Such preferred salts include salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, trifluoroacetic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and isothionic acid. Salts of the compounds of formula (I) may be prepared by reacting the corresponding free base compound with a suitable acid.

According to a preferred embodiment of the invention, when Y represents a group of formula (a), - - - in each case represents a double bond, R ¹ represents a hydrogen or chlorine atom, more preferably a hydrogen atom, R ² represents a group of the formula -CH 2 -, -CH 2 CH 2 - CH ₂ CH ₂ CH ₂ -, -S-, -N = N-, -NR ³ or - (C = O) NH-, more preferably -N = N-, -CH 2 -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH _2- , most preferably -CH ₂ or -CH ₂ CH ₂ -, R ³ represents a group of the formula -CO ₂ Et or a hydrogen atom, more preferably a hydrogen atom and R ⁴ represents a hydrogen atom or a methyl group, more preferably a hydrogen atom.

In a further preferred embodiment of the invention where Y is a group of formula b), ^R1 is preferably H, chloro, fluoro, methyl, hydroxy, methoxy, nitro, or two chloro, more preferably hydrogen, methyl, fluoro, nitro, or methoxy, most preferably hydrogen or nitro and R ⁵ is preferably of the formula C = N.

According to another preferred embodiment of the invention, when Y is a group of formula (c), R @ 5 is hydrogen or methyl, more preferably hydrogen, R is hydrogen, amino, methylamino, hydroxy, methoxy or acetamido, more preferably amino, methoxy or acetamido methylamino,

Q particularly preferably an amino or methylamino group, R is H, Cl, a group of formula NHCO ₂ t-Bu, Br or amino, preferably hydrogen or bromine, most preferably hydrogen, R ⁹ is hydrogen, methoxy, tri fluoromethyl group, a tert-butyl group, a group of the formula

-N = N-Ph, NHAc, NCO ₂ t -Bu, amino or bromine, more preferably hydrogen or bromine, most preferably bromine, R ¹⁰ represents hydrogen, nitro, bromine or chlorine, hydrogen preferably hydrogen or bromine , most preferably an atom and R ¹¹ represents a hydrogen atom, a methoxy group or a hydroxy group, preferably a methoxy group or a hydroxy group, most preferably a hydroxy group.

According to a further preferred embodiment of the present invention, V represents an oxygen or sulfur atom, preferably an oxygen atom, Z represents an alkylene group having 4 to 6 carbon atoms, preferably an alkylene group having 4 carbon atoms, B represents a sulfur atom, amino or oxygen atom, more preferably sulfur or oxygen, most preferably sulfur, A is CH or N, preferably nitrogen and R ¹² is hydrogen or fluorine, preferably hydrogen.

Preferred compounds of formula I include:

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

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3,4-dihydro-l [2H] -isoquinolinone.

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

6- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-5,7-dione .

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

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

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

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy-6-methoxybenzamide,

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

2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide; and

2-amino-N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino / butyl] benzamide and their physiologically acceptable salts and solvates thereof, in particular hydrates, their physiologically functional derivatives and their N-oxide.

Preferred compounds of formula I include:

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ylic-3-bromo-2-hydroxy-6-methoxybenzamide,

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

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

2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide; and

2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidine / butyl] -benzamide, and their physiologically acceptable salts and solvates thereof, in particular hydrates, their physiologically functional derivatives and their N- oxides.

The most preferred compound of formula I is 2-amino-N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] benzamide hydrochloride and solvates thereof and physiologically functional derivatives thereof.

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

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

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

Certain compounds of Formula I are also potential 5-HT _1A receptor antagonists. This activity is associated with antidepressant and anxiolytic effects as well as a reduction in extrapyramidal side effects. The combination of potent dopamine D ₂ receptor antagonism and 5-HT ₂ receptor antagonism with 5-HT _1A receptor agonism, found in the preferred compounds of formula I, is a particularly advantageous activity profile for antipsychotic agents and especially drugs used to treat schizophrenia.

According to another feature, the invention also provides a method of treating or prophylaxis a mammal in a disease selected from the group consisting of fatigue, muscle cramps, depression, senile dementia aggression, borderline personality disorders, vomiting and psychosis, comprising: administering an effective amount of a compound of Formula I, or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof. In particular, the invention provides a method for the treatment and prophylaxis of psychotic diseases in a mammal comprising administering to the mammal an antipsychotically effective amount of a compound of formula I or a physiologically acceptable salt, solvate, physiologically functional derivative or N-oxide thereof. In particular, the invention provides a method wherein the psychotic disorder is schizophrenia.

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

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

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

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

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

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

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

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

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

Preferred unit dosage formulations are those containing the active ingredient in an amount corresponding to the effective dose as described below, or an appropriate fraction thereof.

It is to be understood that in addition to the ingredients explicitly mentioned above, the compositions of the present invention may also include other substances conventional in the art with respect to the type of formulation concerned.

For example, compositions suitable for oral administration may include flavoring agents.

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

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

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

The present invention also provides processes for the preparation of compounds of Formula I and their physiologically acceptable salts, solvates and N-oxides and their physiologically functional derivatives. In general, the compounds of formula (I) may be prepared by any method known in the art for the production of analogous compounds. In the description below, the groups Y, Z, X, W, V, A, B, R ¹ to R ^{12 have the} meanings ascribed to them under the general formula I, unless otherwise indicated.

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

YH (II) with a compound of formula III ₁ ____ _z ____ _w

V- / (III) in which

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

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

According to the second general process B), compounds of formula I in which Z is 4 or 5 can be prepared by reacting a compound of formula II with a compound of formula IV

A * (IV) in which

A 'is a suitable anion such as derived from a halogen such as bromine or chlorine, sulfonic acid esters such as mesylate or tosylate, and

R ¹³ represents a group of the formula - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, in particular - (CH ₂ ) ₄ -

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

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

Y - Z - L (V) where

L is as defined above, with a compound of formula VI

HN X-W

V_7 (VI)

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

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

NH (VII) with a compound of formula VIII

L - W (VIII) in which:

L is as defined above.

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

According to a fifth general process (E), a compound of formula (I) wherein Y is a), wherein R ² is -CH ₂ - or -N = N- and wherein the single line followed by the dashed line (- - -) represents a double a compound of formula IX

r ~ \

N X --- W wherein O is (IX)

R ¹⁴ is -CH ₂ OH or -NH ₂ .

When R ¹⁴ represents a group of the formula -CH ₂ OH, the general method E) may be carried out as described in Annalen der Chemie 584, 87, (1953), to obtain a compound of the formula I in which R ² represents a methylene group.

When R ¹⁴ is an amino group, the process may be carried out as described in J. Org. Chem. 26, 613 (1961); J. Org. Chem. 27, 1383 (1962) and J. Am. Chem. Soc. 77, 6562 (1955) to obtain compounds of formula I wherein R ² is -N = N-.

According to a sixth general process F) n, the compounds of formula I, wherein Y is a) wherein R is a group of formula _-CH2-, -S-, or -N-N- or Y is a group b) or c), may be prepared by reaction of a compound of formula X

wherein is -CH ₂ - or -N (R ⁴ ) (C = V) - a

R ^ -θ represents R ^ or a group of the formula -C =C-,

- 1 or a compound of formula X

in which

R ¹⁷ is R ⁷ , -SL ² or -CH ₂ -L ² a

L ¹ is, for example, chlorine or bromine, methoxy or hydroxy,

L ² is, for example, chlorine or bromine, OMs or

OTs, with a compound of formula XI '.

R ⁶ x

N /

H

Z --— N X - w

W (XI)

For example, compounds of formula I wherein Y is c) and R ⁷ is -N (R 6) 2 may be prepared by treating a compound of formula X ¹ wherein L is hydroxy, V is oxygen and R is a group of formula -N (R ⁴ ) 2, with a compound of formula XI in the presence of refluxing silica, in a solvent such as anhydrous pyridine (MJ Kornet, J. Heterocyclic Chem. 29, 103 (1992)).

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

i i

Compounds of formula I wherein Z is C 4 -C 8 alkylene can be prepared by reduction of a compound of formula I wherein Z is C 4 -C 8 alkylene or C 4 -C 8 alkynylene. The reduction can be achieved by catalytic hydrogenation with hydrogen in the presence of a suitable catalyst such as palladium, platinum, nickel, rhodium and the like in a suitable solvent such as ethanol, tetrahydrofuran, methanol, ether, ethyl acetate, benzene, toluene, hexane and the like. The reaction may be carried out at atmospheric or elevated pressure and at room or elevated temperature, such as at 20 to 100 C. Partial reduction of the acetylene residue (-C = C-) to an alkylene group (-C = C-) may be carried out by reduction. using a poisoned catalyst as a Lindlar catalyst.

Compounds of formula I wherein Y is a), b) or c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are hydroxy may be prepared from the corresponding methoxy derivatives by known methods [e.g. treatment with a Lewis acid such as boron tribromide or aluminum chloride in a solvent such as dichloromethane at room temperature (JFW Mccomie and DE West, Org. Synth. Coll., Vol. V., 412 (1973), RD Dillard and et al., J. Med Chem 34, 2768-2778 (1991)].

Compounds of formula I wherein Y is a), b) or c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are N (R ⁴ ) 2 or NR ⁴ N (R ⁴ ) 2 may be prepared by hydrolyzing the corresponding alkoxycarbonylamino derivatives by known methods, for example by treating (tert-butoxycarbonyl) amino derivatives with an acid such as trifluoroacetic acid and a tert-butyl cation scavenger such as anisole or thiophenol in a solvent such as is chloroform, at room temperature (BF Lundt, Int. J. Prept. Protein Res. 12, 258 (1978)).

The compounds of formula I, wherein Y is a group of formula a), b) or c) and R ^1, R ^7, R ^8, R ^9, R ° and R ¹¹ is N (R ⁴⁾ _2, can be can also be prepared by reduction of the corresponding nitro derivatives by known methods [for example, by catalytic hydrogenation with hydrogen in the presence of a catalyst such as platinum, palladium or Raney nickel (Org. Synth. 49, 116 (1969), J. Med. Chem. Org Chem 38, 60 (1973)].

Compounds of formula I wherein Y is a), b) or c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are NR ⁴ (C = O) R ⁴ , -NR ⁴ CO ² R ⁴ or -NR ⁴ (C = O) CH [N (R ⁴ ) 2] R ⁴ can be prepared by acetylation of the corresponding amino derivatives by known methods (for example, treatment with an acid chloride such as acetyl chloride or ethyl chloroformate and an organic base such as triethylamines, in a solvent such as dichloromethane).

The compounds of formula I, wherein Y is a group of formula c) and R ⁶ is alkyl of 1 to 6 carbon atoms, can be prepared by alkylation of the corresponding secondary amide by known methods (e.g. by treatment with a base, such as sodium hydride, in a suitable solvent such as dimethylformamide , and then treatment with an alkylating agent such as methyl iodide).

Compounds of formula I wherein Y is a group of formula c) wherein V is sulfur may be prepared by treating a compound of formula I wherein Y is a group of formula c) wherein V is oxygen with a sulfonating agent such as Lawesson's reagent, i.e. 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide, in a solvent such as toluene at elevated temperature (Synthesis, 941 (1979)) Tetrahedron 35, 2433 (1979); Tetrahedron Lett. 21, 404).

Compounds of formula I wherein Y is a) b) or c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are NHN = C (R ⁴ ) ₂ can be produced from the corresponding hydrazine derivatives and the corresponding ketones by known methods.

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

Compounds of formula II in which Y is a group of formula a), wherein R ² is methylene, and where a single line accompanying a is a double bond, the formula II a broken line (- - -) represents phthalimidenes of

(HA) can be produced by reduction of the corresponding phthalimide of formula IIB

(IIB)

Suitable reducing agents include tin with hydrochloric acid in acetic acid at an elevated temperature, for example in the range of from 100 to 130 C. Other suitable reducing agents include zinc in acetic acid (J. Chem. Soc., 2038 (1977)) and a system consisting of CuCr ₂ 0 ₄ , dioxane and hydrogen (Helv. Chim. Acta, 1650 (1977)).

Compounds of formula II in which Y is a group of formula a), wherein R ² is -CH ₂ CH ₂ - and where a single line accompanying a broken line (- - -) represents a double bond, i.e. isoquinolines of formula IIb ¹

NH

(IIC) can be prepared by reacting an arylethylamine of formula XII

(XII) with ethyl chloroformate, for example in the presence of a base such as triethylamine, in a suitable solvent such as dichloromethane, for example at 0 ° C, to give the ethyl carbamate of formula XIII

H (XIII) which is then cyclized with phosphoric acid, increased for example by treatment with polyteplote acid, for example from 140 to 160 C.

Compounds of formula II in which Y is a group of formula a), wherein R ² is -CH ₂ CH ₂ CH ₂ ~, and where a single line accompanying a broken line (- - -) represents a double bond, the IID is of benzazepinone

can be produced by the method described by Gilman in Synth. Commun. 12 (5), 373-380 (1982). This process is included in the reaction scheme below.

According to this reaction scheme, dihydrobenzopyran is converted to dihydrobenzopyranone by treatment with pyridinium chlorochromate in a suitable solvent such as dichloroethane at elevated temperature. Subsequent treatment of dihydrobenzopyranone with sodium cyanide at elevated temperature (e.g., 205 ° C), then with water (e.g., 75 ° C) and finally with hydrochloric acid (at 0 ° C) affords cyanethylbenzoic acid. Subsequent treatment of cyanethylbenzoic acid with thionyl chloride and methanol, both at elevated temperature, affords methyl cyanoethyl benzoate. Reduction of this compound with borane in tetrahydrofuran at 0 ° C affords methylaminopropyl benzoate and treatment with sodium methoxide in methanol at room temperature affords the benzazepinone of formula IID.

Compounds of formula (II) wherein Y is a group of formula (a), wherein R ^z is sulfur and wherein the single line followed by a dotted line (- - -) represents a double bond, i.e., benzisothiazolones of formula IIE

(ΙΙΕ) can be produced by the method of Yevich et al. in J. Med. Chem. 29, 359-369 (1986). This method is included in the scheme below.

According to this reaction scheme, 2,2'-dithiosalicylic acid is treated with thionyl chloride and dimethylformamide at reflux in toluene to give 2,2'-dithiobisbenzoyl chloride. The acid chloride is converted to 1,2-benzisothiazol-3- [2H] -one by cleavage of the disulfide bond with chlorine gas in dichloromethane. Treatment of the resulting dichloride with ammonium hydroxide affords the benzisothiazolone of formula IIE.

The compounds of formula II in which Y is a group of formula a), wherein R ² is a group of formula -NR ³ wherein R ³ is alkoxycarbonyl and where a single line accompanying a broken line (- - -) represents a double bond, i.e. indazoles of of formula IIG

(IIG) can be prepared by reacting the corresponding compound of formula (O) _{x of} formula (IIG) in which R is hydrogen with the corresponding chloroformate of formula (R) Cl.

*

Compounds of formula IIG in which R is hydrogen may be prepared, for example, by reaction of an azide of formula XVI

(XVI) in which

R represents an alkyl group such as methyl, ethyl and the like with hydrazine hydrate in ethanol at elevated temperature (see J. Chem. Soc. Perkin Trans I, 1260 (1974)).

The compounds of formula II in which Y is a group of formula a), wherein R ² is a group of formula - (C = 0) NH- and where a single line accompanying a broken line (- - -) represents a double bond, i.e. phthalazinediones of formula IIJ

0 A * NH 1 Ύ , NH (IIJ) can be produced by reaction or 0 phthalic anhydride of the general formula XIX

(XIX) or a phthalimide of formula XX

(XX) in which

R ¹⁸ represents an alkyl group, for example methyl, ethyl and the like, with hydrazine hydrate (see J. Org. Chem. 32, 1921 (1967)).

The compounds of formula II in which Y is a group of formula a), wherein R ² is a group of formula -N-N- and where a single line accompanying a broken line (- - -) represents a double bond, i.e. benzotriazinóny formula IIK

(UK) i can be synthesized as described in the following documents, which are incorporated by reference.

i) El-Shafei and A.A.G. Ghattas, J. Indian Chem. Soc. 61 (1), 65-67 (1984); (ii) A. Lar, H. C. Gugnani and V. A. Madumere, Pharmazie 35 (8), 466-468 (1980).

Compounds of formula IIK in which R ¹ is hydrogen are commercially available.

Compounds of formula II in which Y is a group of formula b), i.e. compounds of formula IIL

(HL) can be prepared by reaction of the corresponding cyclic anhydride of formula XXI

with urea and acetic acid or with ammonium hydroxide (see

Chem. Reports 16, 574 (1962) and Org. A son. Coll., Vol. 1, 457 (1941).

Compounds of formula (II) wherein Y is a group of formula (c), i.e. compounds of formula (IIM)

R ¹¹ v R ° | s NH J R ^ γ r ⁷ l R ⁴ (IIM) R ⁴ are or known compounds; or can make standard

by techniques known in the art.

Compounds of formula III may be prepared by alkylation of a compound of formula IV with a compound of formula XXII

L - Z - L (XXII) in which:

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

In some cases, for example, if both L are halogen and Z is R ¹³ , especially if it is - (CH ₂ ) ₄ -, the same reaction may lead to a compound of formula IV (J. Med. Chem. 29, 359) 369 (1986)).

Compounds of formula V may be prepared by alkylation of the corresponding compound of formula II with a compound of formula XXII. In another embodiment, a compound of Formula V can be produced by converting a hydroxy group in a compound of Formula XXIII.

Y-Z-OH (XXIII) to a leaving group L as defined above by known methods. Conversely, a compound of formula XXIII can be produced by condensing a compound of formula X or X ¹ with an amino alcohol of formula XXIV

H ₂ N - Z - OH (XXIV), or treating the compound of formula II with a compound of formula

L-Z-OH.

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

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

when X is a nitrogen atom and W is a group of formula (d), wherein A is a nitrogen atom and B is a sulfur atom, see Yevich et al.,

J. Med. Chem. 29, 359-369 (1986) and U.S. Pat. No. 4,590,196 A when X is carbon and W is d) wherein A is nitrogen and B is sulfur, see U.S. Pat. If X is a nitrogen atom and W is a group of formula (d), wherein A is a nitrogen atom and B is an oxygen atom, see J. Med. Chem. 29, 359-369 (1986), when X is a carbon atom and W is a group of formula (d), wherein A is a nitrogen atom and B is an oxygen atom, see J. Med. Chem. 28, 761-769 (1985), when X is a nitrogen atom and W is a group of formula (d), wherein A is a nitrogen atom and B is a sulfonyl, see J. Med. Chem. 34, 3316-3328 (1991), alternatively, these intermediates can be prepared by treating 3-chloroisothiazole-1,1-dioxide (European Patent Application 0 196 096) with piperazine in a solvent such as toluene at elevated temperatures such as from 150 to 160 C, when X is a nitrogen atom and W is a group of formula (d), wherein A is a nitrogen atom and B is a sulfinyl, see J. Med. Chem. 34, 3316-3328 (1991), when X represents a carbon atom and W represents a group of formula (d), wherein A represents a carbon atom and B represents a group of formula NR ⁴ , see U.S. Pat. No. 4,335,127 (issued June 15, 1982) and U.S. Pat. No. 4,710,500 (dated December 1, 1987), when X is a nitrogen atom and W is a group of formula (d), wherein A is a carbon atom and B is a sulfur atom, the intermediates can be prepared according to the reaction scheme shown below by heating substituted aminobenzo [b] thiophenes with piperazine in a solvent such as 1-methyl-2-pyrrolidinone, wherein the desired aminobenzo [b] thiophenes can be prepared by treating the appropriately substituted 2-fluorobenzonitrile with methylthioglycolate anion and then decarbomethoxylating the resulting benzo [b] thiophene

when X is carbon etc and W is d) wherein A is carbon and B is sulfur, see FR patent no. No. 2,253,519 (1975), when X represents a nitrogen atom and W represents a group of formula (d), wherein A represents a nitrogen atom and B represents a group of formula NR ⁴ , see U.S. Pat. No. 4,957,916 (dated September 18, 1990) when X is carbon and W is d) wherein A is carbon and B is sulfonyl, see JP Patent No. 4,957,916. 03 264 583 A2 (of 25 November 1991),

X is C, and W is a group of formula d), wherein A is N and B is NR ^4, the intermediate may be prepared by deprotection of N-protected piperinylindazolov, obtained by reaction of an appropriately substituted 4- (2-fluoroaroyl) piperidine ( J. Med. Chem., 28, 761 (1985)) with hydrazine at the reflux temperature of a solvent such as n-butanol according to the following scheme:

when X is a carbon atom and W is a group of formula (d), wherein A is a carbon atom and B is a sulfonyl, see JP patent no. No. 03 264 583 A2 (dated November 25, 1991), and when X is a carbon atom and W is a group of formula (d), wherein A is a carbon atom and B is a group of formula NR ⁴ , see DE-A-3. No. 3,500,898 (dated July 17, 1986).

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

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

when L is a chlorine atom and W is a group of formula (d), wherein A is a nitrogen atom and B is a sulfur atom, see U.S. Patent No. 4,590,196 A, when L is a chlorine atom and W is a group of formula (d) and B represents an oxygen atom, see J. Med. Chem. 29, 359 (1986) and when L is a chlorine atom and W is a group of formula (d), wherein A is a nitrogen atom and B is a sulfonyl, see European Patent Application no. 0 196,096 A2.

Compounds of formula IX in which R ¹⁴ is -CH ₂ OH and V is O may be prepared as described in Annalen der Chemie 584, 87 (1953), Tetrahedron Lett. 25 (20), 2093 (1984) and Tetrahedron Lett. 27 (20), 2275 (1986). Compounds of formula IX in which R @ ⁴ is amino and V is O may be prepared by reacting isatoic anhydride of formula XXV

ABOUT

R ⁴ (XXV) and

with a compound of formula XI. The reaction may be carried out in a suitable solvent such as ethanol, for example at room temperature.

Phthalimides of formula XA

(XA) phthalic anhydrides of formula XB

(XB) with _{respect to} compounds of formula X

(X ¹⁾ and isatoic anhydrides of formula XE

(XE) are or known compounds or can be prepared by known methods.

For example, isic acid anhydrides of formula XE can be prepared by treating appropriately substituted anthranilic acids with phosgene or a phosgene substitute (e.g., trichloromethyl chloroformate) in a suitable solvent such as benzene or dioxane (J. Het. Chem. 12, 565 (1975), J. Am. Chem. Soc., 72, 4887 (1950), J. Org. Chem., 41, 2070 (1976). Isatoic anhydrides of formula XE in which V is O may be prepared by treating the appropriately substituted phthalic anhydrides of formula XB with azidotrimethylsilane in a suitable solvent such as chloroform. The thioisate anhydrides of the formula XE in which V represents a sulfur atom can be prepared by refluxing xylenes with appropriately substituted isatoic anhydrides with phosphorus pentasulfide.

Compounds of formula XF

(XF) in which, for example

Ί

L is methoxy and n

L < 3 > represents a bromine atom, and may be prepared as described in U.S. Pat. No. 4,289,781, which is incorporated herein by reference in its entirety.

Compounds of formula XI in which R ⁶ is hydrogen may be obtained by cleavage of phthalamides of formula I, i.e. compounds of formula I in which Y represents a group of formula b), wherein R ⁵ represents a group of formula C = C and R ¹ represents a hydrogen atom. The reaction can be carried out with hydrazine hydrate in methanol.

Compounds of formula XI in which R ⁶ is C 1 -C 6 alkyl may be prepared from compounds of formula XIa

R®

N ----- Z ---- N X --- W

P \ ___ / (Xla) in which

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

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

A further embodiment of the invention includes the following compounds:

N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidono / butyl] phthalimide, (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3- yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, (+/-) - trans-2- [4- / 4- (1,2) -benzisothiazol-3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, and

N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidino / butyl] phthalimide and their physiologically acceptable salts, solvates and N-oxides, as well as their physiologically functional derivatives.

Another embodiment of the invention includes:

the use of one of the following compounds and their salts, solvates, N-oxides and derivatives in therapy, ingesting one of the following compounds and their salts, solvates, N-oxides and derivatives for the manufacture of a medicament for the treatment of any of the diseases described hereinabove, the method of treating any of the above administers therapeutically or prophylaxis in a mammal suffering from the described diseases by administering to the mammal an effective amount of one of the following compounds and salts, solvates, N-oxides and derivatives, a pharmaceutical composition comprising one of the compounds and salts thereof, solvates, N-oxides and derivatives and a process for the production of one of the following compounds and their salts, solvates, N-oxides and derivatives, the following compounds being included:

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

3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- [3H] -quinazolinone,

2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1 [2H] phthalazinone,

2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] 1,3 [2H, 4H] -izochinolíndión,

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidino / butyl] phthalimide, (+/-) - cis-2- [4- / 4- (1,2-benzisothiazole) -3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, (+ / -) -trans-2- [4- / 4- ( 1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, and

N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidine / butyl] phthalimide.

Biological data

A. Antipsychotic activity

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

Compounds are administered orally to mice 1 hour before the start of the test. 2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) antagonized apomorphine-induced climbing in the mouse at an _ED50 = 11.0 mg / kg of 2- [4- / 4- (1,2-benzisothiazol-3-yl) piperazinyl / butyl] -1-isoindolinone (example 3) the ED ₅₀ = 6.3 mg / kg po and 6- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-5,7 -dione (example 18) with ED _5Q = 14.4 mg / kg (Costall, Naylor RJ and V. Nohria, Climbing Behavior Induced by Apomorphine in Mice: a Potential Model for the Detection of Neueroleptic Activity, European Journal of Pharmacology 50, 39-50 (1978)].

B. Anti-emetic activity

The anti-emetic activity of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -benzamide was tested for its ability to provide cisplatin-induced irritation after 40 days in ferret (AP Florczyk et al., Cisplatin-Induced Emesis in the Ferret: A New Animal Model, Cancer Treatment Reports 66 (1), 187-189 (1982)).

The test compound is administered orally. Cisplatin (10-15 mg / kg) is then administered intravenously, 30 minutes later via the jugular catheter. After a further 60 minutes, a second dose of the test compound is administered. The onset of emesis and the number of emetic events are recorded over a period of 3 hours. Vehicle-treated animals exhibit 3-5 emesis events, whereas animals receiving 3 mg / kg of the compound of Example 36 exhibit no emesis event.

C. Anxiolytic activity

When 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) is tested for anxiolytic activity using the pigeon conflict procedure ), is observed on the damaged response (ED ₅₀ = 0.17 mg / kg, im) a potential anxiolytic activity. (JE Barrett, J Witskin, RS Mansbach, P. Skolnick and BA Weissman, Behavioral Studies with Anxiolytic Drugs III: Antipunishment Actions of Buspirone in the Pigeon in Not Involve and Benzodiazepine Receptor Mechanism, J. Pharmacol. Experiment. Ther. 238, 1009 1013 (1987)).

D. Antidepressant and anxiolytic activity

2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) was tested as a 5-HT _1A agonist by the _serotinergic inhibition inhibition assay neurons in the core of the dorsal seam. An ID50 value corresponding to 23 μg / kg intravenously is determined. (DS Robinson et al., Serotonergic Anxiolytics and Treatment of Depression, Psychopathology 22, (suppl. 1), 27-36 (1989)).

E. Centrally acting muscle relaxants

2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) causes morphine-induced antagonism (Straub-tail) at the ED ₅₀ level, which corresponds to 2.8 mg / kg po (GD Novack, Studies on the Efficacy and Depressant Potential of Muscle Relaxants in Mice, Drug Dev. Res. 2, 383-386 (1986)).

Examples of pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions in which the active ingredient is a compound of formula I or a physiologically acceptable salt or solvate thereof, for example the compound of Example 36.

A. Tablets

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

* Content shown on the tablet

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

Injections

Injections

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

Formulation II, intravenous injection, active substance sterile phosphate buffer, pH 9.0, pyrogen-free

0.20 g to 10 ml of the salt is dissolved in most of the buffer at 35 to 40 ° C, then made up to and filtered through a sterile microporous filter into which it is sealed

Effective phosphate given volume of sterile vials of 10 ml (type 1), sterile cap and capped with vial cap.

s

C. Capsule composition

Capsule composition

Composition I can be prepared by mixing the ingredients and filling the resulting into two-piece hard gelatin capsules.

active ingredient lactose B. P. starch sodium glycolate magnesium stearate total mg / capsule

250

143

420

Capsule formulation II active ingredient

Macrogel 4000 B.P

mg / capsule

250

350 total

600

Capsules can be made by melting Macrogel 4000 B.P., dispersing the active ingredient in the melt and filling the melt into two-piece hard gelatin capsules.

Capsule formulation III (controlled release capsule) mg / capsule

(a) the active substance 250

(b) microcrystalline cellulose125

(c) lactose B. P.125

(d) ethylcellulose13 total513

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

Syrup active substance sorbitol solution

0,2500 g

1.5000 g glycerol sodium benzoate flavor purified water

1,0000 g

0.0050 g

0.0125 ml as needed to 5.00 ml

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

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

250

1770

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

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

F. Transdermal

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

1) in an optionally buffered aqueous solution,

(2) dissolved in an adhesive substance; or

3) dispersed in the polymer.

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

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples.

Examples

Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without purification. Anhydrous solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, toluene, pyridine and dimethylsulfoxide (DMSO) were obtained from Aldrich Chemical Company in securely sealed containers. The triethylamine is distilled from calcium hydride before use. All reactions using compounds sensitive to air or moisture are carried out under a nitrogen atmosphere. Flash chromatography (WC Still et al., J. Org. Chem. 43, 2923 (1978)) and flush chromatography were performed using EM Science silica gel 60 (with a grain size of 37-64 nm, i.e. 230 g). up to 400 mesh ASTM). Thin-layer chromatography (TLC) is performed on Analtech silica gel FG TLC plates (250 μπι grain size). ¹ H NMR spectra and ¹³ C NMR spectra are determined in a superconducting FT NMR spectrometer at 200, 300 and 500 MHz.

Chemical shifts are expressed as deviation from trimethylsilane in ppm. Significant-1 H NMR values are given in order: multiplicity (s singlet, d doublet, t triplet, q quartet, m multiplet), number of protons and coupling constant, expressed in Hz. Elemental analyzes are performed on either Atlantic Microlab, Inc., Norcross Georgia or Galbraith Laboratories, Inc. Knoxville, Tennessee. Melting points are determined using a capillary temperature determination apparatus (Thomas Hoover) and are uncorrected.

Piperidinebenzisothiazole and piperazinebenzisothiazole intermediates are prepared according to known methods: 3- (4-piperidinyl) -1,2-benzisothiazole See U.S. Pat. No. 4,528,292, July 9, 1985, 3- (1-piperazinyl) -1,2-benzisothiazole and 8- (1,2-benzisothiazol-3-yl) -5,8-diazaspiro [4,5] decanbromide see JP Yevich et al., J. Med. Chem. 29, 359-369 (1986). The piperidine benzisoxazole and piperazine benzisoxazole intermediates are produced or can be prepared according to known methods:

6-fluoro-3- (4-piperidinyl) -1,2-benzisothiazole see J. T. Strupelewski et al., J. Med. Chem. 28, 761-769 (1985) and 1- (1,2-benzisoxazol-3-yl) piperazine see J. P. Yevich et al., J. Med. Chem. 29, 359-369 (1986).

Example 1

a) A method for producing 2- (2-hydroxyethyl) -1-isoindolinone

This compound was prepared according to a modified method described by K. Muro and 50.09 g (0.820 ml) was introduced into a flask (Bull. Chem. Soc. Jpn. 46, 1752 (1973)). Ethanolamine (Aldrich Chemical Company) was added with a round bottom of 300 ml

Dean-Stark cap, reflux condenser, magnetic stir bar and nitrogen inlet. It is then added with stirring

110 g (0.820 mL, 1.0 equivalent) of phthalide (Aldrich Chemical

Company), such as light brown powder. The resulting suspension was placed under a nitrogen atmosphere and heated in an oil bath at 150 ° C for 4 hours. The temperature of the oil bath was raised to 205-210 ° C and the melt was heated for an additional 17 hours. 12 ml of water is collected in a Dean-Stark cap, and the product solidifies upon cooling to give a light brown solid. The crude material was shaken with hot toluene and the solution was filtered hot. The solids thus formed are filtered off after cooling, washed with cold toluene and dried in a vacuum oven. This gives 129.75 g of 2- (2-hydroxyethyl) -1-isoindolinone as a light brown powder, m.p. 117-119 ° C. Yield 88%.

¹ H NMR (CDCl ₃ ): δ 3.28 (br s, 1), 3.69 (m, 2), 3.85 (m,

2), 4.46 (s, 2), 7.40 (m, 3), 7.73 (m, 1) ppm. ¹³ C NMR (CDCl ₃ ): δ 45.84 51.63 61.30, 122.60, 123.44, 127,91 ,, 131.34, 132.44, 141.53, 169.55.

Analysis for ^C 10 ^H II ^{NO 2:} Calculated: 67.78% C, 6.26% H 7.90% N Found: 67.76% C, 6.27% H, 7.89% N.

b) A process for the preparation of 2- (2-chloroethyl) -1-isoindolinone

117.95 g (0.666 ml) of 2- (2-hydroxyethyl) -1-isoindolinone and 400 ml of toluene are introduced into a 1 liter round bottom flask. The solution was cooled in an ice bath and 55.0 mL (89.7 g, 0.754 mol, 1.13 equivalents) of thionyl chloride was added dropwise over 30 minutes. The suspension is allowed to stand at room temperature for 4 hours, with periodic rapid swirling. A condenser was then added and the reaction mixture was heated at 60 ° C for 3 hours. Toluene and excess thionyl chloride were distilled off under reduced pressure. Pour the hot idparate onto 500 ml of petroleum ether and form a brown solid. The crude solid was filtered and shaken with hot toluene. The solution is filtered hot and the toluene solution obtained is poured into 300 ml of petroleum ether with stirring. The resulting solid was filtered off, washed with petroleum ether and dried in a vacuum oven. 103.08 g of a brown solid powder is obtained. A second crop of 15.99 g is then obtained. A total of 119.07 g of 2- (2-chloroethyl) -1-isoindolinone having a melting point of 80-81 ° C is obtained. Yield: 91%.

¹ H NMR (CDCl ₃ ): δ 3.80 (t, 2, J = 5.4), 3.96 (t, 2, J =

5.4), 4.57 (s, 2), 7.50 (m, 3), 7.86 (m, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 7.50, 48.74, 54.98, 128.01, 128.60,

133.08, 136.68, 137.15, 147.11, 172.80.

Analysis for C 10 ^H 10 ^noc1: Calculated: 61.39% C, 5.15% H 7.16% N Found: 61.29% C, 5.18% H, 7.15% N.

c) Method for the preparation of 2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethyl] -2,3-dihydro-1H-isoindol-1-one hydrochloride

6.03 g (30.82 mmol) of 2- (2-chloroethyl) -1-isoindolinone, 6.76 g (30.82 mmol, 1.0 equivalent) of 3- (1-piperazinyl) -1,2-benzisothiazole 5.15 ml (3.74 g, 36.99 mmol, 1.2 equivalents) of triethylamine and 30.0 ml of acetonitrile were added to a 100 ml round bottom flask. The resulting orange mixture was placed under nitrogen and refluxed for 24 hours. The solution was allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate. The dark orange solution is washed with saturated potassium carbonate solution and the organic phase is dried over magnesium sulphate, filtered and evaporated. 13.44 g of an orange oil are obtained. This material was purified by flash chromatography with ethyl acetate / hexanes (5: 1) as eluent. 7.15 g of 2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethyl] -2,3-dihydro-1H-isoindol-1-one are obtained. The free amine was taken up in acetone and 24.5 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The salt was recrystallized twice from 95% ethanol to give 3.05 g of the salt, hydrochloride, as an off-white powder. Yield: 24%. Spectral analytical values indicate the presence of 1 equivalent of hydrogen chloride and 0.5 equivalent of ethanol. The salt had a melting point of 264 DEG-267 DEG C. (decomposition).

¹ H NMR (DMSO-d ₆ ): δ 1.03 (t, 3, J = 6.9), 3.48 (m, 7), 3.70 (broad d, 2, J = 11.0) 4.02 (m, 4), 4.60 (s, 2), 7.55 (m, 6),

8.10 (t, 2, J = 9.2), 11.28 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 8.50, 36.51, 46.17, 49.66, 50.49,

52.88, 55.94, 121.10, 122.84, 123.34, 124.01, 124.55, 126.81,

127.71, 128.05, 131.48, 131.86, 142.24, 152.06, 162.09, 168.00.

Analysis ^{C H} 2 R 22 ^N 4 ^0S · HC1 · 0/5 ^C 2 ^H 6 ^O: Calculated: 60.33% C, 5.98% H, 12.79% N Found: 60.24% C, 6 % H, 12.55;

Example 2

a) Process for the preparation of 2- (3-hydroxypropyl) -1-isoindolinone

This compound was prepared as described in Example 1a). Using 3-amino-1-propanol (Aldrich Chemical Company) as the amino alcohol gave 156.83 g of 2- (3-hydroxypropyl) -1-isoindolinone. Yield: 86%.

σ

NMR (CDCl ₃ ): δ 1/91 (quintet, 2, J = 6.2), 3.55 (broad s, 2), 3.74 (t, 2, J = 6.2), 3.82 (wide s, 1), 4.38 (s, 2),

7.47 (m, 3), 7.80 (m, 1) ppm.

¹³ C NMR (CDCl ₃ ): δ 30.85, 38.81, 50.39, 58.37, 122.73,

123.64, 128.12, 131.45, 132.30, 141.18, 169.67.

Analysis for CHHINE ₃ NO _2: Calculated: 69.09% C, 6.85% H 7.32% N Found: 68.99% C, 6.86% H, 7.28% N.

b) Process for preparing 2- (3-chloropropyl) -1-isoindolinone

This compound was prepared as described in Example 1b). Using 127.53 g of 2- (3-hydroxypropyl) -1-isoindolinone gives 130.94 g of crude chloride. Yield: 94%. A small sample of 5 g was purified by flash chromatography using 4: 1 hexanes / ethyl acetate as eluent. 4.29 g of an analytically pure white solid are obtained, m.p. 56-57.5 ° C.

¹ H NMR (CDCl ₃ ): δ 2.15 (quintet, 2, J = 6.7), 3.58 (t, 2,

J = 6.5), 3.74 (t, 2, J = 6.9), 4.41 (s, 2), 7.46 (m, 3), 7.81 (m, 1) ppm.

¹³ C NMR (CDCl ₃ ): δ 31.29, 40.17, 42.22, 50.57, 122.71,

123.63, 128.68, 131.36, 132.68, 141.11, 168.75.

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

This compound was prepared as described in Example 1c) using 2- (3-chloropropyl) -1-isoindolinone. The salt, the hydrochloride is formed and recrystallized from ethanol. This gives 1.58 g of the title compound as a yellow powder, mp 225-226 ° C.

¹ H NMR (DMSO-d 6): δ 2.16 (m, 2), 3.30 (m, 8), 3.60 (m, 4),

4.05 (broad d, 2, J = 12.5), 4.53 (s, 2), 7.55 (m, 6), 8.09 (dd, 2, J = 8.0, 3, 9), 10.70 (broad s, 1.5) ppm.

¹³ C NMR (CDCl ₃ ): δ 23.06, 39.37, 46.58, 50.08, 51.00,

55.09, 120.77, 123.15, 123.22, 123.54, 124.53, 127.26, 128.03,

128.10, 131.76, 131.92, 141.40, 152.95, 161.47, 169.37.

Analysis for ^C 22 ^H 24 ^N 4 ^OS . H, 5.75; N, 12.53. Found: C, 59.06; H, 6.10; N, 12.52.

Example 3

a) Process for the preparation of 2- (4-bromobutyl) -1-isoindolinone

15.6 g (0.056 ml) of N- (4-bromobutyl) phthalamide (Aldrich Chemical Company), 100 ml glacial acetic acid, 15.83 g (0.133 mol,

2.4 eq. Of metallic tin and 20.0 ml of hydrobromic acid are placed in a 250 ml round bottom flask. The resulting pale yellow reaction mixture was placed under a nitrogen atmosphere and refluxed for 6 hours. The solution was filtered and the tin was washed with acetic acid. Most of the acetic acid was evaporated on a rotary evaporator and the resulting cream residue was shaken with dichloromethane and washed with water. The organics were dried over magnesium sulfate, filtered and evaporated. 9.37 g of a light orange oil are obtained. This material was purified by flash chromatography with 3: 1 hexanes / ethyl acetate as eluent. 0.89 g of 2- (4-bromobutyl) -1-isoindolinone is obtained as a colorless oil. Yield 6%.

¹ H NMR (CDCl 3): δ 1.86 (m, 4), 3.47 (t, 2, J = 6.2), 3.66 (t, 2, J = 6.7), 4.39 (S, 2), 7.46 (t, 2, J = 6.4), 7.53 (m, 1),

7.84 (dd, J, 6.8 = 0.38) ppm.

¹³ C NMR (CDCl 3): δ 26.84, 29.64, 33.44, 41.25, 49.80, 122.70, 123.71, 128.08, 131.30, 132.75, 141, 03, 179.05.

Analysis for ^C 12 ^H 14 ^NOBRE: Calculated: 53.75% C, 5.26% H 5.22% N Found: 53.81% C, 5.29% H, 5.21% N.

In the above process, hydrochloric acid may be used instead of hydrobromic acid. Higher yields are thus obtained, but the resulting compound is a mixture of chloride and bromide.

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

3.69 g (15.27 mmol) of a 40:60 mixture of 2- (4-bromobutyl) -1-isoindolinone and 2- (4-chlorobutyl) -1-isoindolinone are placed in a 100 ml round bottom flask. . Then, 2.77 ml (2.01 g, 19.85 mmol, 1.3 equivalents) of triethylamine, 25.0 ml acetonitrile and 3.68 g (16.80 mmol, 1.1 equivalents) were added to the chloride-bromide mixture. The 3- (1-piperazinyl) -1,2-benzisothiazole and the light orange reaction mixture was refluxed for 19 hours under a nitrogen atmosphere. The solution was allowed to cool and transferred to a separatory funnel using ethyl acetate. The organics were washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated. 7.31 g of a dark orange oil is obtained, which solidifies on standing. This crude material was recrystallized from acetonitrile to give 4.38 g of the free amine. The hydrochloride salt was precipitated by the addition of 10.8 mL (1.0 equivalents) of 1 N ethereal hydrogen chloride to a solution of the free amine in ethanol. The salt was recrystallized from 95% ethanol to give 3.47 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1-isoindolinone hydrochloride as an off-white powder. having a melting point of 232-233 ° C. Yield: 51%.

¹ H NMR (DMSO-d 6): δ 1.77 (m, 4), 3.23 (m, 4), 3.57 (m, 6), 4.05 (broad d, 2, J = 13, 8), 4.52 (s, 2), 7.48 (m, 2), 7.60 (d, 3, J = 8.9), 7.69 (d, 1, J = 7.5) , 8.12 (t, 2, J = 7.6), 11.32 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.49, 25.05, 40.96, 46.29, 49.41, 50.43, 55.12, 121.15, 122.65, 123.30 , 123.96, 124.57, 126.92, 127.74, 128.07, 131.17, 132.33, 141.84, 152.06, 162.19, 167.34.

Analysis for ^C 23 ^H 26 ^N 4 ^{OS 'HC1:} Calculated: 62.36% C, 6.14% H, 12.65% N Found: 62.23% C, 6.16% H, 12.62% N.

Example 4

a) A process for the preparation of 6-nitro-1- [3H] -isobenzofuranone

This compound was prepared according to the method of J. Tirouflet (Bull. Soc. Sci. Bretagne, Vol. 26, 7-122 (1951)).

The compound has a melting point of 143-145 ° C (melting point reported in the literature is 143 ° C).

¹ H NMR (CDCl ₃ ): δ 5.44 (m, 2), 7.71 (d, 1, J = 8.4), 8.57 (dd, 1, J = 8.4, 2.0) 8.76 (d, 1 J = 2.0) ppm.

¹³ C NMR (DMSO-d 6): δ 75.57, 125.20, 130.08, 131.76, 134.02, 153.58, 158.44, 174.02.

Analysis for C ₈ H ₅ NO _4:

H, 2.81; N, 7.82. Found: C, 53.70; H, 2.85; N, 7.82.

b) A method for producing 6-amino-1 [3H] isobenzofuranone

This compound was prepared according to the method of J. Tirouflet (Bull. Soc. Sci. Bretagne, Vol. 26, 7-122 (1951)). Mp 181-182 ° C.

¹ H NMR (CDCl ₃ ): δ 3.94 (broad s, 2), 5.21 (s, 2), 6.97 (dd, 1, J = 8.2, 2.3), 7.13 (d, 1, J = 2.3), 7.03 (d, 1, J = 8.2) ppm.

¹³ C NMR (CDCl ₃ ): δ 69.63, 109.79, 121.64, 122.66, 126.95,

136.36, 147.49, 171.47.

Analysis calculated for: CgHC -NNO ^: C, 64.42;

4.73% H,

9.39% N, found:

64.48. % C, 4.73% H,

9.38% N.

c) A method for producing 6-chloro-1 [3H] -isobenzofuranone

2.0 mL of distilled water, 4.0 mL of concentrated hydrochloric acid, and 1.37 g (9.18 mmol) of 6-amino-1 [3H] isobenzofuranone are introduced into a round-bottom flask equipped with a magnetic rod. The resulting white suspension was cooled in an ice bath and a solution of 0.70 g of sodium nitrite in 1.5 ml of distilled water was added dropwise. The reaction mixture was allowed to stir at 0 ° C for 20 minutes and then a solution of 3.13 g (18.36 mmol, 2.0 equivalents) of copper (I) chloride hydrate in 2.0 mL of distilled water was added dropwise. The resulting bright green solution was allowed to stir at 0 ° C for 1 hour. The mixture was heated on a steam bath for 1 hour to give a solid. Ethyl acetate was added to the reaction mixture to dissolve the solid, and the layers were separated. The green aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, filtered and evaporated to give 1.35 g of a brown solid. This crude material was recrystallized from ethanol and dried in a vacuum oven. 0.83 g of 6-chloro-1 [3H] -isobenzofuranone having a melting point of 107-108 ° C is obtained as a pale yellow powder. Yield: 54%.

^{Χ Η} NMR (CDC1 _3): δ 5.29 (s, 2), 7.44 (dd, 1, J = 8.2, 0.68),

7.64 (dd, 1, J = 8.2, 1.8), 7.86 (d, 1, J = 1.8) ppm.

¹³ C NMR (CDCl ₃₎ : δ 69.50, 123.48, 125.69, 127.58, 134.87,

135.39, 144.63, 169.65.

CGH analysis for C ₅ H _2: calculated: 57.00% C, 2.99% H Found: 57.16% C, 3.03% H

d) A process for preparing 6-chloro-2- (2-hydroxyethyl) -1-isoindolinone

9.15 g (0.0543 mol) of 6-chloro-1 [3H] -isobenzofuranone, 3.32 g (1.0 equivalent) of ethanolamine (Aldrich Chemical Company) and 10.0 ml of toluene are introduced into a round-bottomed flask. A 100 ml volume equipped with a magnetic stir bar and a 10 ml Dean-Stark adapter. The solution is heated in an oil bath and toluene, which is collected in a Dean-Stark trap, is recycled to the reaction vessel. The resulting orange melt was heated at 210 ° C for 22 hours. Upon cooling, the material solidified to give 11.75 brown solids. This crude material was used without further purification.

e) Preparation of 6-chloro-2- (2-chloroethyl) -1-isoindolinone The compound was prepared in analogy to Example 1b). 11.75 g of the above title compound is used, m.p.

This written in the ethyl) -1-isoindolinone produced compound named

The yield corresponds to 80% of theory of benzofuranone.

by a method such as 6-chloro-2- (2-hydroxy) to give 10.03 g of a pale yellow powder, to 6-chloro-1 [3H] -iso12-114 ° C.

¹ H NMR (CDCl ₃ ): δ 3.79 (t, 2, J = 5.8), 3.94 (t, 2, J =

5.8), 4.55 (s, 2), 7.38 (d, 1, J = 8.1), 7.50 (dd, 1, J = 8.1,

1.8), 7.80 (d, J, 2.1) ppm.

¹³ C NMR (CDCl ₃ ): δ 42.64, 44.82, 51.22, 123.91, 124.02,

131.76, 134.02, 134.43, 139.51, 167.52.

Analysis for C ₁₀ H ₉ noc1 _2: calculated: 52.20% C, 3.94% H 6.09% N Found: 52.30% C, 3.96% H, 6.03% N.

d) Process for the preparation of 2- [2- / 4- (1,2-benzisothiazol) -3-yl) -1-piperazinyl / ethyl] -6-chloro-1-isoindolinone hydrochloride

This compound was prepared according to the method described in Example 1c). The crude material was purified by flash chromatography with ethyl acetate as eluent. The free amine was treated with 1N ethereal HCl and the resulting salt, hydrochloride, triturated with 95% ethanol. 3.78 g of an off-white powder are obtained, m.p. 272 DEG-275 DEG C. (decomposition).

¹ H NMR (DMSO-d 6): δ 3.24 - 3.62 (m, 6), 3.71 (broad d, 2,

J = 10.8), 4.03 (m, 4), 4.60 (s, 2), 7.44 (dt, 1, J = 8.0, 1.0), 7.58 (dt, 1, J = 7.0, 1.0), 7.69 (m, 3), 8.11 (t, 2, J = 8.9), 11.08 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 36.53, 46.09, 49.39, 50.47, 52.83,

121.07, 122.49, 123.96, 124.51, 125.30, 126.85, 128.02, 131.34,

132.60, 133.90, 140.93, 152.01, 162.01, 166.73.

Analysis for ^C 21 ^H 2 R 4 ^N HC1 ^0SC1: Calculated: 56.13% C, 4.93% H, 12.47% N Found: 56.22% C, 4.95% H, 12.40% N .

Example 5

a) A process for the preparation of 6-chloro-2- (4-chlorobutyl) -1-isoindolinone

This compound was prepared in an analogous manner to that used in Example 1b). The starting compound, 6- (chloro-2- (4-hydroxybutyl)) -1-isoindolinone, was obtained as described in Example 4d). The crude material obtained in this reaction was purified by flash chromatography to give 5.42 g of an orange solid. Yield 39% of theory based on 6-chloro-1 [3H] -isobenzofuranone. The title compound has a melting point of 71-72 ° C.

^Δ NMR (CDCl ₃ ): δ 1.83 (m, 4), 3.59 (t, 2, J = 5.9), 3.65 (t, 2, J = 6.6), 4, 36 (s, 2), 7.37 (d, 1, J = 8.1), 7.49 (dd, 1, J = 8.1, 1.9), 7.79 (d, 1, J = 1.9) ppm.

¹³ C NMR (CDCl ₃ ): δ 25.52, 29.49, 41.53, 44.49, 49.44,

123.84, 123.96, 131.44, 134.36, 134.52, 139.10, 167.28.

I

Analysis for ^C 12 ^H 13 ^Night 2 ^{^:} Calculated: 55.83% C, 5.08% H 5.43% N Found: 55.90% C, 5.12% H, 5.38% N.

b) A process for the manufacture of 2- [4- / 4- (1,2-benzisothiazol) -3-yl) -1-piperazinyl / butyl] -6-chloro-1-isoindolinone hydrochloride hydrate

This compound was prepared in an analogous manner to that described in Example 1c). Starting from 5.02 g (19.4 mmol) of 6-chloro-2- (4-chlorobutyl) -1-isoindolinone, a crude orange solid was obtained which was purified by recrystallization. The salt, hydrochloride, produced by treating the free base with 1N ethereal HCl, is triturated with hot ethanol and dried in a vacuum oven. There was obtained 4.84 g of 2- [4- / 4- (1,2-benzisothiazol) -3-yl) -1-piperazinyl / butyl] -6-chloro-1-isoindolinone hydrochloride hydrate as a brown powder, which had mp 241-242 ° C.

NMR (DMSO-d6): δ 1.71 (broad s, 4), 3.20 (m, 4), 3.35 (m, 6), 4.02 (broad d, 2, J = 13.1) ), 4.50 (s, 2), 7.45 (m, 1), 7.53 (m, 1), 7.65 (m, 3), 8.10 (dd, 2, J = 8, 0.4, 11.14 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.46, 24.93, 41.11, 46.31, 49.22,

50.45, 55.10, 121.14, 122.35, 123.94, 124.56, 125.31, 126.90,

128.06, 131.11, 132.66, 134.33, 140.56, 152.04, 162.16, 166.02.

Analysis for ^C 23 ^H 25 ^N 4 ^OSC · * ·. 0.4 _H2 0: Calculated: 57.00% C, 5.57% H, 11.56% N, 1.49% H _2, Found: 56.62% C, 5.65% H, 11 % N, 1.34% H ₂ O.

Example 6

a) Method for producing 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone

These compounds are prepared as described in Example 3a) above. A mixture of 4.24 g of 2- (5-chloropentyl-1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone (yield = 53% of theory) was obtained by reduction of 10.00 g (0.0338 mol) of N- ( Of 5-bromopentyl) phthalimide (Transworld Chemicals, Inc.) made with 9.62 g (0.081 mol, 2.4 equivalents) of metal tin in 75 mL of acetic acid and 15.0 mL of concentrated hydrochloric acid. individual halides.

b) Process for the preparation of 2- [5- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / pentyl] -1-isoindolinone hydrochloride

This compound was prepared according to the method described in the example

3b). From a mixture of 4.24 g (0.0178 mol) of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone and further 4.30 g (0.0196 mol, 1 (1 equivalent) of 3- (1-piperazinyl) -1,2-benzisothiazole gave 2- [5- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / pentyl] -1-isoindolinone hydrochloride , in the form of an orange powder. The salt, hydrochloride, is obtained as a brown powder with a weight

4.28 g (yield: 53% of theory), after recrystallization from ethanone. The title compound has a melting point of 174-175 ° C.

¹ H NMR (DMSO-d ₆ ): δ 1.34 (m, 2), 1.65 (m, 2), 1.79 (m, 2),

3.20 (m, 4), 3.53 (m, 6), 4.03 (wide d, 2, J = 13.5), 4.47 (s, 2), 7.55 (m, 6) 8.10 (dd, 2, J = 8.0, 5.3), 11.28 (broad S, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 22.58, 23.42, 27.20, 41.16, 46.29,

50.37, 55.28, 121.14, 122.59, 123.28, 123.95, 124.56, 126.91,

127.72, 128.06, 131.10, 132.38, 141.76, 150.05, 162.18, 167.20.

Analysis for ^C 24 ^H 28 ^N 4 ^OSC · * ·. H, 6.40; N, 12.26. Found: C, 63.10; H, 6.39; N, 12.22.

Example 7

a) Method for producing 2- (6-chlorobenzyl) -1-isoindolinone and 2- (6-bromohexyl) -1-isoindolinone

This compound was prepared according to the method described in Example 3a). A 50:50 mixture of 2- (6-chlorobenzyl) -1-isoindolinone and 2- (6-bromohexyl) -1-isonidolinone was obtained by reduction of N- (6-bromohexyl) phthalamide (Transworld Chemicals, Inc.). This material is used as a mixture of halo compounds.

b) Method for producing 2- [6- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / hexyl] -1-isoindolinone hydrochloride

This compound was prepared according to the method described in Example 3b). The crude material was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 4.65 g of a light yellow solid are obtained. The salt, hydrochloride, is formed by treatment with 1N ethereal HCl. 4.18 g of 2- [6- / 4- (1,2-benzisothiazol-3-yl) hydrochloride are obtained.

-1-piperazinyl / hexyl] -1-isoindolinone, in the form of an off-white foam having a melting point of 263-264 ° C. Yield: 61%.

^{Χ Η} NMR _(DMSO-d6): 8 1.35 (m, 4), 1.64 (t, 2, J = 6.9), 1.75 (m, 2), 3.25 (m, 4), 3.50 (m, 2), 3.54 (t, 2, J = 7.0), 4.05 (m, 2), 4.49 (s, 2), 7.48 (m 2), 7.60 (m, 3), 7.67 (broad d, 1, J = 7.5), 8.12 (t, 2, J = 7.2), 10.99 (broad S 1) ppm.

¹³ C NMR (DMSO-d 6): δ 25.78, 27.46, 41.27, 49.23, 122.58,

123.027, 123.95, 124.49, 127.72, 128.01, 131.08, 141.72, 152.02.

Analysis for ^C 25 ^H 30 ^N 4 ^OS * ^HC1: Calculated: 63.74% C, 6.63% H, 11.89% N Found: 63.81% C, 6.65% H, 11.84% N.

Example 8

(a) Method for the preparation of methyl (2-bromomethylbenzoate)

Using the method of W. H. Perkin (J. Chem. Soc. * 121, 2202, (1922)), 2-bromomethylbenzoyl bromide is obtained by bromination of o-toluoyl chloride. 0.184 mol of 2-bromomethylbenzoyl bromide is shaken with 40 ml of dichloromethane and the solution is cooled in an ice bath. To the reaction mixture was added 15 mL of absolute methanol, allowed to warm to room temperature and stirred for 30 minutes. The solution was washed with saturated potassium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated on a rotary evaporator. 42.08 g of a pale yellow oil are obtained. This material was used without further purification.

¹ H NMR (CDCl ₃ ): δ 3.94 (s, 3), 4.96 (s, 2), 7.40 (m, 3),

7.97 (m, 1) ppm.

b) Method for producing 3- [4- / 2- (2-aminoethoxy) ethyl] -1-piperazinyl] -1,2-benzisothiazole

7.45 g (0.017 mol) of N- [2 - [[2- / 4- (1,2-benzothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] phthalimide as prepared in Example 24, Place in a 100 ml round-bottomed flask and contact with 20.0 ml of methanol. To this solution, 1.49 g of a 85% aqueous solution (0.025 mol, 1.5 equivalents) of hydrazine hydrate was added dropwise with stirring, and the mixture was refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture was allowed to cool to room temperature and then 50.0 ml of 1N hydrochloric acid was added. The resulting precipitate was filtered off and washed with distilled water. The filtrate was basified by addition of 50% sodium hydroxide solution and extracted with dichloromethane. The organic phases are dried over magnesium sulphate, filtered and rotary evaporated. 5.31 g of 3- [4- / 2- (2-aminoethoxy) ethyl] -1-piperazinyl] -1,2-benzisothiazole are obtained in the form of a viscous orange oil. This material was used without further purification.

c) Method for producing 2- [2 - [[2- / 4- (1,2-benzothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] -1-isoindolinone

A solution of 5.31 g (0.017 mol) of 3- [4- / 2- (2-aminoethoxy) ethyl] -1-piperazinyl] -1,2-benzisothiazole in 100 ml of toluene was heated in an oil bath at 100-110 ° C. To the amine solution was added dropwise a solution of 3.97 g (0.017 mol, 1 equivalent) of methyl (2-bromomethylbenzoate) and 25 mL of toluene over 15-20 minutes. The reaction mixture was heated under nitrogen for 45 minutes, after which time the addition was complete. The solution was allowed to cool to room temperature and washed with saturated potassium carbonate solution. The organic layers were dried over magnesium sulfate, filtered, and evaporated. ₀ was obtained 6.22 g red-orange oil. This material was purified by flash chromatography with ethyl acetate containing 0.2% triethylamine as eluent and then recrystallized from a solution of ethyl acetate in ethanol. 0.95 g of a brown solid is obtained. The NMR spectrum showed a small amount of ethyl acetate present in the sample. Mp 108-110 ° C.

^T 1 HNMR (CDCl _3): δ 2.69 (m, 6), 3.49 (br t, 4, J = 5.0),

3.66 (t, 2, J = 5.6), 3.74 (dt, 2, J = 1.0, 5.2), 3.82 (broad t, 2, J = 4.7), 4.57 (s, 2), 7.34 (ddd, 1, J = 8.2, 7.0, 1.1), 7.47 (m, 4), 7.82 (m, 3) ppm .

¹³ C NMR (CDCl ₃ ): δ 42.36, 49.80, 51.55, 53.28, 57.82,

68.59, 69.77, 120.53 122.63 123.57, 123.85, 127.50, 127.87,

127.97, 131.23, 132.71, 141.64, 152.73, 163.74, 168.55.

^N , 12.86. Found: 64.74%. ^C 23 ^H 26 ^N 4 ° 2 ^N · ^{15 C} 4 ^H 8 ° 2 'calculated: 6'5.05% C, 6.29% H, 12.86% N. H, 6.33; N, 12.76.

Example 9

a) A process for producing trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone

30.00 g (0.131 mol) methyl (2-bromomethylbenzoate) (Example 8a)), 20.85 g (0.137 mol, 1.05 equivalents) trans-4-aminocyclohexanol hydrochloride (Aldrich Chemical Company), 27.15 g Potassium carbonate (0.196 mol, 1.5 equivalents), toluene (110 ml) and water (20 ml) were placed in a 500 ml round bottom flask equipped with a magnetic stir bar and a Dean-Stark cap. The biphasic mixture was refluxed for 19 hours. The azeotrope of toluene with water is trapped and water is not allowed to return to the reaction vessel. 300 ml of fresh toluene is added to the reaction mixture and the toluene-methanol azeotrope is collected in a Dean-Stark trap. After further heating for 24 hours, the salts are decanted from the solution into a clean round-bottomed flask. The solvent was removed by rotary evaporation to give 25.16 g of a viscous orange oil. This crude material was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 11.88 g of trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone are obtained in the form of a beige solid, m.p. 133-134 ° C. The yield corresponds to 39% of theory.

^X 1 HNMR (CDCl _3): δ 1.56 (m, 4), 1.41 (m, 3), 2.11 (m, 2), 3.66 (m, 1), 4.26 (tt 1, J = 11.5, 3.9), 4.32 (s, 2), 7.47 (m, 3), 7.84 (dd, 1, J = 7.7, 1.6) ppm.

¹³ C NMR (CDCl ₃ ): δ 29.02, 34.46, 46.04, 49.67, 69.90,

122.68, 123.60, 128.01, 131.12, 133.12, 141.12, 165.11.

Analysis for ^C 14 ^H 17 ^{NO 2:} Calculated: 72.70% C, 7.41% H 6.06% N Found: 72.63% C, 7.41% H, 6.04% N.

b) Process for producing trans-4- (1-oxo-2-isoindolinyl) -1-cyclohexylmethanesulfonate

3.94 g (0.017 mol) of trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone are treated with 150 ml of anhydrous dichloromethane and 13.56 ml (2.59 g, 0.025 mol) are added, 1.5 equivalents) of triethylamine. The orange solution was placed under a nitrogen atmosphere and cooled in an ice bath. To this solution was slowly added a mixture of 2.93 g (1.98 mL, 0.025 mol, 1.5 equivalents) of mesyl chloride (Aldrich Chemical Company) in 3.0 mL of anhydrous dichloromethane with stirring. The reaction mixture was allowed to stir at 0-5 ° C for 75 minutes. Another portion of dichloromethane was added and the solution was washed with saturated potassium carbonate solution. The layers were separated and the aqueous phase was extracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. A mixture of 5.40 g of trans-4- (1-oxo-2-isoindolinyl) -1-cyclohexylmethanesulfonate is obtained as an orange solid. This crude material was used without further purification.

c) Method for producing (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1-cyclohexyl] -1-isoindolinone hydrochloride monohydrate

5.27 g (0.017 mL) of trans-4- (1-oxo-2-isoindolyl) -1-cyclohexylmethanesulfonate, 3.92 g (0.079 mol, 1.05 equivalents) of 3- (1-piperazinyl-1,2-) of benzisothiazole, 2.85 mL (2.07 g, 0.020 mol, 1.2 equivalents) of triethylamine and 20 mL of acetonitrile were placed, placed under a nitrogen atmosphere and refluxed for 2.5 days. The organic layers were dried over magnesium sulfate, filtered, and rotary evaporated to give 8.29 g of a viscous orange oil, which was purified by flash chromatography with ethyl acetate as eluent. Purification by further flash chromatography eluting with ethyl acetate / hexane (2: 1) gave 0.224 g of a thick orange oil to give the salt, hydrochloride, this free base, and recrystallized from ethanol and then dried in a vacuum oven. 0.120 g (yield 2% of theory, based on trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone) hydrochloride monohydrate (+/-) - cis-2- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) -1-cyclohexyl] -1-isoindolinone, in the form of peach-colored crystals having a melting point of 231-232 ° C.

¹ H NMR (DMSO-d ₆ ): δ 1.72 (m, 2), 1.95 (m, 2), 2.20 (m, 2),

2.35 (m, 2), 3.33 (m, 2), 3.54 (m, 1), 3.77 (broad d, 2, J =

13.4), 3.85 (broad d, 2, J = 12.2), 4.05 (broad d, 2, J = 13.4), 4.20 (quintet, 1, J = 3.7 ), 4.74 (s, 2), 7.46 (m, 2), 7.58 (m, 3), 7.67 (d, 1, J = 7.3), 8.11 (dd, 2, J = 8.0, 4.7),

10.80 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 23.37, 25.25, 45.96, 47.95, 48.75,

62.03, 121.17, 122.51, 123.15, 123.91, 124.56, 126.93, 127.69,

128.07, 131.13, 132.37, 142.06, 152.09, 162.15, 167.08.

Analysis for ^C 25 ^H 28 ^N 4 ^OS · ^HCl · ^H 2 ^O: calculated: 61.65% C, 6.41% H, 11.50% N, 3.69% H ₂ O, found: 61.65% C, 6.45% H, 11.46% N, 3.97% H ₂ O.

Example 10

a) Process for the preparation of 3- [4- (4-amino-2-butynyl) -1-piperazinyl] -1,2-benzisothiazole

This compound was prepared according to the method described in Example 8b). From 12.54 g (0.630 mol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butynyl] phthalimide (Example 25), 2.66 g of 85% of an aqueous solution of hydrazine hydrate and 30 ml of methanol, 6.23 g (yield: 72.3% of theory) of 3- [4- (4-amino-2-butynyl) -1-piperazinyl] -1,2-benzisothiazole, is obtained in the form of orange oil. This material was used without further purification.

b) Process for the preparation of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butynyl] -1-isoindolinone hydrochloride

6.23 g (0.022 mol) of the crude amine of Example 10 (a) are treated with 50 ml of toluene. A solution of methyl (2-bromomethylbenzoate) (Example 8 a)) was added to the mixture with stirring. The resulting orange solution was refluxed under nitrogen for 18 hours. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel. The solution was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated to an orange oil. This crude material was purified by flash chromatography on a special flash silica with ethyl acetate / hexane (3: 1) as eluent. The salt, pure free base hydrochloride, is prepared by addition of 1N hydrochloric acid. The salt obtained is recrystallized from a mixture of ethanol and ethyl acetate and dried in a vacuum oven. 0.24 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butynyl] -1-isoindolinone hydrochloride is obtained as an off-white powder, m.p. 194-196 ° C. The yield corresponds to 3% of theory.

¹ H NMR (DMSO-d 6): δ 3.40 (m, 3), 3.51 (m, 3), 4.08 (m, 2), 4.22 (broad s, 2), 4.59 (s, 2), 4.61 (s, 2), 7.48 (m, 2), 7.58

(m, 1) 7.63 (m, 2) 7.71 (dt, 1, J = 7.5, 1.0), 8.10 (dt, 1, J = 8.2, 0,9), 8.14 (dt, 1, J = 8.2, 0.9), 12, 00 (s, 1) s them. 13 _c NMR (DMSO-d6): δ 31.32, 44.53, 49 , 05, 49.85, 73.23. 84.95. 121.13 , 122.91, 123 , 54, 123.98, 124, 56, 126.91, 127.96, 128,07, 131.42 , 131.70, 141, 76, 152.03, 162.15 , 163.80. analysis for C 2 3 ^H 22 ^N 4 ^OS: calculated 62 93% C, 5.28 % H, 12.76% N, found: 62 % 79, 5.31 % H, 12.70% N.

Example 11

a) A method for producing 1-isoindolinone

30.0 g (0.204 mol) of phthalimide (Aldrich Chemical Company) is placed in a 500 ml round bottom flask and 150 ml of glacial acetic acid, 75 ml of concentrated hydrochloric acid and 58.07 g (0.489 ml, 2 ml) are added. 4 equivalents) of tin metal (Fisher Scientific). The cream-colored suspension is refluxed in an oil bath. When the solution is heated, the phthalimide dissolves to give a light yellow solution. The reaction mixture was refluxed for 2 hours. The solution is filtered while hot and the tin shavings are washed with fresh acetic acid. The major part of the acetic acid was evaporated on a rotary evaporator to give a light yellow cream solution. This material was shaken with dichloromethane and then washed with distilled water and saturated sodium chloride solution. The organic phases are dried over magnesium sulphate, filtered and evaporated. 17.61 g of a light yellow solid is obtained. This crude material was purified by flash chromatography with ethyl acetate as eluent. 11.93 g of 1-isoindolinone are obtained in the form of a pale yellow powder, m.p. 150-151 ° C. Yield: 47%.

¹ H NMR (CDCl ₃ ): δ 4.48 (s, 2), 7.48 (m, 2), 7.57 (m, 1),

7.76 (broad s, 1), 7.88 (m, 1) ppm.

¹³ C NMR (CDCl ₃ ): δ 45,83 , 123,16, 123.64, 127.95, 131.69, 143.72, 172.35. Analysis for C ₈ H ₇ NO: calculated: 73.16% C, 5,30% H, 10.52% N, found: 72.08% C, 5.35% H, 10.49% N.

b) A method for producing (E) -2- (4-chloro-2-butenyl) -1-isoindolinone

1.54 g of an 80% oil dispersion (1.25 equivalents) of sodium hydride is introduced into a 500 ml round-bottom flask under nitrogen. The sodium hydride was washed twice with hexane and the waste hexane was removed by pipette from the solid. To the washed sodium hydride was added 100 ml of dimethylformamide. A solution of 5.47 g (0.041 mol) of 1-isoindolinone in 50.0 ml of dry dimethylformamide was added to the resulting gray suspension. 13.51 g (0.103 mol, 2.5 equivalents) of trans-1,4-dichloro-2-butene (Aldrich Chemical Company) and 100 ml were added to a separate 500 ml round-bottomed flask previously dried in an oven. of dry dimethylformamide. This solution was cooled in an ice bath and a 1-isoindolinone solution was slowly added through a lance. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The major portion of dimethylformamide was evaporated on a rotary evaporator, the residue was shaken with dichloromethane and washed several times with water. The organic phases are dried over magnesium sulphate, filtered and evaporated. 20.12 g of a dark orange oil are obtained. This crude material was purified by flash chromatography with 1: 1 hexane / ethyl acetate as eluent. There was thus obtained (E) -2- (4-chloro-2-butenyl) -1-isoindolinone (6.48 g) as a pale yellow oil. Yield: 71%.

¹ H and ¹³ C NMR spectra were consistent with the N-alkylated product.

¹³ C NMR (CDCl 3): δ 43.45, 43.99, 49.61 122.78, 123.79,

128.08, 129.26, 129.56, 131.43, 132.54, 141.16, 168.28.

Also, a small amount, weighing 0.80 g, of the bisalkylated product, (E) -2,2 '- (2-butene-1,4-diyl) -bis- (1-isoindolinone), was also obtained as pale yellow crystals having a melting point of 193-196 ° C.

c) Method for producing (E) -2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] -1-isoindolinone hydrochloride

This compound was prepared in an analogous manner to that used in Example 1 (c). A mixture of 3.00 g (0.014 mol) of (E) -2- (4-chloro-2-butenyl) -1-isoindolinone), 2.97 g (0.014 mol, 1.0 equivalent)

3- (1-piperazinyl) -1,2-benzisothiazole and 2.26 ml triethylamine in 20.0 ml acetonitrile were refluxed for 1 hour under a nitrogen atmosphere. The crude product obtained was purified by flash chromatography with ethyl acetate as eluent to give 3.47 of the free base as a pale yellow oil. The salt formed, hydrochloride, is recrystallized from ethanol and dried in a vacuum oven. 2.86 g of (E) -2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butenyl] -1-isoindolinone hydrochloride are obtained as a brown powder. having a melting point of 232-235 ° C. Yield: 48%.

^X H NMR (DMSO-d₆): δ 3.10

4.07 (broad d, 2, J = 13.5), 5.08 (dt, 1, J = 15.4, 6.9), (m, 5), 7.69 (d, 1, J = 7.3), (broad s, 1) ppm.

3.58 (m, 6), 3.82 (broad s, 2),

4.22 (d, 2, J = 5.1), 4.49 (s, 2),

6.04 (dt, 1, J = 15.4, 5.4), 7.55

8.10 (dd, 2, J = 7.5, 5.4), 11.36 ¹³ C NMR (DMSO-d 6): δ 42.95, 46.38, 49.37, 49.92, 56, 33.

120.98, 121.14, 122.77, 123.44, 123.95, 124.56, 126.91, 127.83,

128.07, 131.36, 131.01, 136.08, 141.89, 152.06, 162.13, 167.08.

Analysis for _C2 3 H ₂₄ N ₄ OS. HCl:

H, 5.71; N, 12.70. Found: C, 62.41; H, 5.67; N, 12.60.

Example 12

a) A method for producing (Z) -2- (4-chloro-2-butenyl) -1-isoindolinone

This compound was prepared as described in Example 11

b). Alkylation of 5.75 g (0.043 mol of 1-isoindolinone by treatment with 6.25 g (0.047 mol, 1.1 equivalents) of cis-1,4-dichloro-2-butene (Aldrich Chemical Company) in anhydrous dimethylforamide gives 3.43 g ( yield (36%) of (Z) -2- (4-chloro-2-butenyl) -1-isoindolinone, after purification by flash chromatography.

and ¹³ C and differential. The NMR spectra of the light orange oil are consistent with the N-alkylated product.

¹³ C NMR (CDCl 3): δ 38.42, 38.50, 49.57, 122.77, 123.75,

128.08, 129.01, 129.44, 131.43, 132.44, 141.15, 168.26.

The bis-alkylation by-product, (E) -2,2 '- (2-butene-1,4-diyl) -bis- (1-isoindolinone), weighing 0.88 g, is obtained as a pale yellow solid, having a melting point of 148-150 ° C.

b) A method for producing (Z) -2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] -1-isoindolinone hydrochloride hydrate

This compound was prepared in an analogous manner to that used in Example 1 (c). A mixture of 3.26 g (0.015 mol) of (Z) -2- (4-chloro-2-butenyl) -1-isoindolinone, 3.23 g (0.015 mol, 1.0 equivalents) of 3- (1-piperazinyl) - of 1,2-benzisothiazole, 2.46 ml (1.78 g 0.018 mol, 1.2 equivalents) of triethylamine and 20.0 ml of acetonitrile were refluxed under nitrogen for 3 hours. The crude product obtained after work-up is purified by flash chromatography on silica gel with ethyl acetate as eluent. 4.76 g of a viscous orange oil are obtained. The salt, hydrochloride, is prepared by recrystallization twice from 95% ethanol. 2.16 g of (Z) -2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butenyl] -1-isoindolinone hydrochloride hydrate are obtained as a brown powder. having a melting point of 234-236 ° C. Yield: 33%.

¹ H NMR (DMSO-d ₆ ): 83, 34 (m, 4), 3/55 (M, 3), , 4 10 (m, 4) 4.33 (d, 2, J = 5.9), 4.49 (with, 2), 7.95 (M, 2), 7 52 (m, 5) 7.68 (dd, 1, J = 7.3, 1.0), 8.12 (t, 2, J = 8 , 0), 11 65 (br S, 1) ppm. ¹³ C NMR (DMSO-d ₆ ): δ 38.86 , 46,40, 49 26 50 , 04 , 51,79,

121.15, 121.50, 121.71, 123.40, 123.95, 124.58, 126.94, 127.81,

128.08, 131.34, 131.99, 133.93, 141.86, 152.07, 162.13, 167.06.

Analysis for ^C 23 ^H 24 ^N 4 ^OS . HCl. 0.5 _H2O: Calculated: 61.39% C, 5.82% H, 12.45% N, 2.00% H ₂ H Found: 61.05% C, 5.79% H, 12, % N, 2.28% H ₂ O.

Example 13

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

350 g (0.0124 mol) of N- (4-bromobutyl) phthalimide (Aldrich Chemical Company), 2.72 g (0.0124 mol, 1.0 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole (JP Yewich et al., 29, 359-369 (1986)), 2.24 ml (0.0161 mol, 1.3 equivalents) of triethylamine and 15.0 ml of acetonitrile are introduced into a 100 ml round bottom flask. . The cloudy orange solution was refluxed under nitrogen for 7 hours. The mixture was allowed to cool to room temperature and shaken with dichloromethane. The organic solution was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated. 5.48 g of a light orange oil are obtained. This crude material was recrystallized from acetonitrile and dried in a vacuum oven. 4.35 g of a brown powder are thus obtained. The salt, hydrochloride, was prepared by addition of 1N ethereal HCl and recrystallized from 95% ethanol. 4.53 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] phthalimide hydrochloride are obtained in the form of an off-white powder, m.p. dec). Yield: 82%.

^X H NMR (DMSO-d₆): 1.72 (m, 4), 3.20 (m, 4), 3.54 (m, 6),

4.02 (broad d, 2, J = 13.7), 7.44 (ddd, 1, J = 8.1, 7.0, 1.0), 7.57 (ddd, 1, J = 8) 1, 7.0, 1.0), 7.85 (m, 4), 8.09 (dd, 2, J =

8.0, 4.5), 11.18 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.52, 25.25, 36.82, 46.30, 50.44,

54.98, 121.13, 122.98, 123.94, 124.56, 126.90, 128.06, 131.58,

134.33, 152.04, 162.16, 167.93.

Analysis for ^C 23 ^H 24 ^N 4 ° 2 ^S. HC1:

H, 5.51; N, 12.26. Found: C, 60.46; H, 5.55; N, 12.17.

I

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

To a solution of 12.46 g (0.0296 mol) of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] phthalimide in 30.0 ml of methanol was added 2.62 g (1.5 equivalents) of 85% hydrazine hydrate. The reaction mixture was refluxed for 3.5 hours and allowed to cool to room temperature. To the solution was added 59.0 mL of 1N hydrochloric acid, the resulting white precipitate was filtered off and washed with water. The filtrate was basified with 50% sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. 8.1 g of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole are obtained in the form of an orange-brown oil. Yield: 94%.

¹ H NMR (CDCl 3): δ 1.38 (broad 2, J = 7.4), 2.68 (t, 4.4, J = 5.0), 7.35 (ddd,

J = 1.1, 7.0, 8.1), 7.81 s, 2),

J = 5.0) 2.74 (t,

1, J = 1.1, 7.0, (d, 1, J = 8.1),

2.45

3.57 (ddd,

J = 8.2 (t, (t,

1 ppm.

This crude amine was used without further purification.

c) Process for preparing 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-methylphthalimide hydrochloride

2.70 g (9.3 mol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole and 27.0 ml of pyridine are introduced into a 300 ml round bottom flask. To this solution was added 1.66 g (10.2 mmol, 1.1 equivalents) of acid anhydride with stirring

4-methylphthalic. The reaction mixture was placed under a nitrogen atmosphere and refluxed for 5 hours. The solution was evaporated and the residue was shaken with dichloromethane and washed with saturated potassium carbonate solution. The organic phase is dried over magnesium sulphate, filtered and evaporated. The crude material was purified by flash chromatography (hexane / ethyl acetate 3: 1). 3.82 g of white crystals are obtained. This free amine was shaken with ethyl acetate and added

8.7 ml of 1N (8.7 mmol, 1.0 equivalent) ethereal hydrogen chloride solution. The resulting salt, hydrochloride, is recrystallized from 95% ethanol and dried in a vacuum oven. 2.70 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-methylphthalimide hydrochloride are obtained in the form of a white powder, m.p. 255.5. up to 258 ° C. Yield: 67%.

NMR _(DMSO-d6): δ 1.74 (m, 4), 2.46 (s, 3), 3.25 (m, 4), 3.53 (m, 6), 4.02 (br d, 2, J = 13.6), 7.44 (ddd, 1, J =

8.1, 7.1, 0.9), 7.62 (m, 4), 8.10 (dd, 2, J = 8.0, 4.7), 11.18 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.54, 21.29, 25.28, 36.75, 46.31,

50.45. 55. 00, 121.12, 122.90, 123.42, 123.94, 124.56, 126.90. 128.06. 128 , 96, 131.94, 134.63, 145.24, 152.05, 162.15, 167.90. 168.00. analysis for ^C 24 ^H 26 ^N 4 ^OS · ^HCl: calculated: % C, 61.20;% H, 5.78;% 11.89. N, found: % C, 60.91;% H, 5.78;% 11.75 N.

Examples 14 to 22

The compounds of Examples 14 to 20 and 22 were prepared from the corresponding substituted phthalic anhydride precursors as described in Example 13 (c). The phthalic anhydrides used are obtained from commercial suppliers or made by methods known from the literature cited. The analytical values for these phthalimides are given below.

Example 14

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

Starting compound: 3-fluorophthalic anhydride (Lancaster Synthesis, Inc.). Yield 1.22 g (16% of theory). The title compound has a melting point of 258-260 ° C.

¹ H NMR _(DMSO-d6): δ 1 67 (m, 2) 1.80 (m, 2) 3.22 (m, 2) 3.55 (m, 6), 4.05 (broad d. 2, J = 13.5) , 7.47 (Ddd, 1, J 8.1. 7.0, 1.1), 7.46 (ddd, 1 J = 8.1, 7.0 , i, D, 7.74 (dt, 1 J = 7.3, 0.7), 7.90 (ddd, 1 J = 8.4, 7.3 , 4,6), 8.11 (tm, 1 J = 7.5), 11.12 (broad s, D ppm.

¹³ C NMR (DMSO-d 6): δ 20.48, 25.09, 36.98, 46.30, 50.46,

55.00. 117.28. 117.53. 119.49, 119.55, 121.12, 122.19, 122.58. 123.94. 124.56, 126.90. 128.06, 133.98, 134.01, 137.27, 137.43. 152.05. 153.94. 159.13. 162.14, 164.79, 166.87, 166.93. analysis for C ₂₃ ^H 23 ^N 4 ° 2 ^SF . HC1:

H, 5.09; N, 11.79. Found: C, 57.93; H, 5.15; N, 11.71.

Example 15

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

Starting compound: 3-hydroxyphthalic anhydride (Aldrich Chemical Company). Yield 0.94 g (24% of theory). The title compound has a melting point of 247-248 ° C.

1 H NMR (DMSO-d 6): δ 1.65 (m, 2), 1.77 (m, 2), 3.23 (m, 4), 3.54 (m, 6), 4.05 ( wide d, 2, J = 13.6), 7.27 (dd, 1, J = 3.5, 0.8), 7.29 (dd, 1, J = 4.8, 0.8), 7.47 (ddd, 1, J = 8.2, 7.0, 1.1), 7.60 ((m, 2), 8.02 (tt, 2, J = 7.7, 1.1) 11.02 (broad s, 1), 11.19 (s, 1) ppm.

¹³ C NMR (DMSO-d 2): δ 20.57, 22.30, 36.44, 38.21, 40.71,

46.32, 50.48, 55.05, 113.82,

124.56, 126.90, 128.06, 133.47,

166.63, 166.74.

Analysis for ^C 22 ^H 23 ^N 5 ° 2 ^S · ^HCl: calculated: 58.44% C, 5.34% H, found: 58.48% C, 5.35% H,

114.57, 121.12, 123.19, 123.94,

135.77, 152.05, 155.19, 162.14,

11.86% N,

11.90% N.

Example 16

2- [4- / 4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3- dione

Starting compound: 2,3-pyridinedicarboxylic anhydride (Aldrich Chemical Company). Yield 3.03 g (76% of theory). The title compound has a melting point of 258-259 ° C.

^X H NMR (DMSO-d): δ 1.7 1 (m, 4), 3.20 (m, r 4), 3.54 (m, 6) 4.03 (Širc • when d, 2, J = 13 , 4) 7.45 (ddd, J) 8.1, 6.9 , i, o) 7.58 (Ddd, 1, J = 8.1, , 6 9. 1.0), 7.89 (dd, 1 J = 4.8 , i, D, 8.10 (Dd, 1, J = 8.0, 4. 2), 9.09 (d, J, J = 4. 9), 9.12 (d, 1, J = ( ), 8), 10.86 (wide with, D ppm. 13 _c NMR _(DMSO-d6): δ 20.49, 25.01, 37, , 13 , 46,32, 50.49;

55.01, 116.78, 121.13, 123.93, 124.56, 125.87, 126.90, 128.07,

139.34, 143.79, 152.06, 155.74, 162.13, 166.89, 167.29.

Analysis for ^C 22 ^H 23 ^N 5 ^S 2 · ° ^HC1: Calculated: 57.75% C, 5.29% H, 15.32% N Found: 57.60% C, 5.30% H, 15, 33% N.

Example 17

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

Starting compound: 4-nitrophthalic anhydride (Aldrich Chemical Company). Yield 3.30 g (73% of theory). The title compound has a melting point of 258.5-259 ° C.

¹ H NMR (DMSO-d 6): δ 1.69 (m, 4), 3.20 (m, 4), 3.50 (m, 2),

3.66 (m, 2), 4.04 (broad d, 2, J = 13.3), 7.45 (t, 1, J = 7.4), 7.58 (s, 1, J = 7.2), 8.08 (dd, 1, J = 4.5), 8.14 (d, 1, J = 3.3), 8.49 (d, 1, J = 1.8), 8.62 (dd, 1, J = 8.2, 2.0), 10.88 (br s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.50, 25.02, 37.40, 46.32, 50.48,

54.98, 117.70, 121.14, 123.93, 124.44, 124.57, 126.89, 128.07,

129.51, 133.09, 136.36, 151.31, 152.05, 162.13, 166.09, 166.35.

Analysis for ^C 22 ^H 23 ^N 4 ° 5 ^S · ^HC1: Calculated: 55.03% C, 4.82% H, 13.95% N Found: 55.06% C, 4.85% H, 13, 96% N.

Example 18

Process for the preparation of 6- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6,7-dihydro-5H-pyrrolo [3,4-b] hydrochloride monohydrate pyridine-5,7-dione

Starting compound: 3,4-pyridinedicarboxylic acid anhydride (Aldrich Chemical Company). Yield 1.52 g (34% of theory). The title compound has a melting point of 253-254 ° C.

¹ H NMR (DMSO-d 6): δ 1.70 (m, 4), 3.27 (m, 6), 3.52 (m, 2), 3.65 (t, 2, J = 6.3) ), 4.05 (broad d, 2, J = 12.7), 7.45 (t, 1, J = 8.0), 7.58 (t, 1, J = 7.6), 7, 78 (dd, 1, J = 7.6, 5.1), 8.09 (d, 1, J = 8.0), 8.12 (d, 1, J = 8.0), 8.30 (dd, 1, J = 7.6, 1.4), 8.97 (dd, 1, J = 5.1, 1.4), 10.52 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.46, 25.13, 36.94, 46.29, 50.53,

54.99, 121.12, 123.94, 124.56, 126.90, 127.24, 127.73, 128.06,

131.14, 151.49, 152.05, 154.66, 162.15, 166.28, 166.37.

Analysis for C ₂ ^H 23 ^N 5 ° 2 ^S · ^HCl * ^H 2 ^0: calculated: found:

C 55.51, H 5.51, N 14.71,

% C, 55.75;% H, 5.52;% N, 14.71.

Example 19

A process for the production of hydrochloride monohydrate

3.78% H ₂ O

3.92% H ₂ O.

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

Starting compound: 3-methylphthalic anhydride (Kodak Laboratory Chemicals). Yield 3.34 g (73% of theory). The title compound has a melting point of 272-274 ° C.

¹ H NMR (DMSO-d 6): δ 1.68 (m, 4), 2.62 (s, 3), 3.17 (m, 4),

3.53 (m, 6), 4.03 (broad d, 2, J = 12.4), 7.45 (m, 1), 7.63 (m,

4), 8.10 (dd, 2, J = 7.9, 4.4), 10.98 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 16.98, 20.59, 25.26, 34.64, 46.36, 50.52, 55.06, 120.61, 121.13, 123.94, 126.90, 128.06, 128.20, 131.95, 133.83, 136.41, 137.04, 152.05, 162.17, 167.80, 168.62.

Analysis for C ₂₄ H ₂ N ₄ O ₂ S. HCl. _H2O: Calculated: 58.95% C, 5.98% H, 11.46% N Found: 59.07% C, 5.99% H, 11.32% N.

Example 20

Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3,6-dichlorophthalimide hydrochloride monohydrate

Starting compound: 3,6-dichlorophthalic anhydride (Fluka Chemie AG). Yield 2.23 g (49% of theory). The title compound has a melting point of 265-267 ° C.

¹ H NMR (DMSO-d 6): δ 1.73 (m, 4), 3.20 (m, 4), 3.57 (m, 6), 4.03 (broad d, 2, J = 13, 5), 7.45 (t, 1, J = 8.0), 7.58 (t, 1, J = 8.0), 7.83 (s, 2), 8.09 (d, 1, J = 8.0), 8.11 (d, 1, J = 8.0), 11.05 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.48, 24.93, 37.24, 46.31, 50.47, 55.01, 121.13, 123.93, 124.56, 126.89, 128.06, 128.16, 129.28, 136.72, 152.05, 162.14, 164.35.

Analysis for ^C 23 ^H 22 N ₄ O ₂ SC _{1 2} . HC1 . H ₂ O: calculated: 50,79 % C, 4.63% H, 10,30 % N, found: 50,63 % C, 4.67% H, 10.23 % N.

The second part of the crystals obtained is 0.44 g of hydrochloride dihydrate, their melting point is 262-265 ° C.

Analysis for ^C 23 ^H 22 ^N 4 ° 2 ^SC 12 ^HC · - · * ^'2H 2 ^0: Calculated: 49.16% C, 4.84% H 9.97% N Found: 49.21% C H, 4.83; N, 9.93.

Example 21

a) A method for producing 4-chlorophthalimide

10.0 g (0.0671 mol) of 4-aminophthalimide (Kodak) dissolved in 14.0 ml of distilled water and 27.0 ml of concentrated hydrochloric acid are introduced into a 500 ml round-bottom flask. The resulting pale yellow solution was cooled in an ice bath

A solution of 4.57 g (0.0669 mol, 1.1 equivalents) of sodium nitrite (Malincrodt) in 100 ml of distilled water is added dropwise. After this addition, the color of the reaction mixture turns yellow to gold. The solution was allowed to stir at 0 ° C for 20 minutes and then a solution of 21.0 g (0.123 mol, 2 equivalents) of copper (I) chloride dihydrate in 140 mL of distilled water was added dropwise. The resulting green solution was allowed to stir at 0 ° C for 1 hour and then heated on a steam bath for 15 minutes. The mixture was extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. This gives 9.61 g of the title compound as a brown solid. This material was used without further purification.

b) Process for the preparation of N- (4-chlorobutyl) -4'-chlorophthalimide and N- (4-bromobutyl) -4'-chlorophthalimide

The title compounds were prepared in a manner analogous to Example 11b). From 9.61 g (0.0529 mol) of 4-chlorophthalimide and 9.98 g (0.0582 mol) of 1-bromo-4-chlorophthalimide (Aldrich Chemical Company), 15.91 g of a mixture of the corresponding chloride and bromide are obtained in a ratio of: 80: 20, after flash chromatography with 8: 1 hexanes / ethyl acetate as eluent. This material was used as a mixture of halides without further purification.

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

This compound was prepared according to the method described in Example 13 a). From 2.50 g (0.0029 mol) of a mixture of N- (4-chlorobutyl) -4'-chlorophthalimide and N- (4-bromobutyl) -4'-chlorophthalimide in a ratio of 80:20 to 1.95 g (0, 3- (1-piperazinyl) -1,2-benzisothiazole gave 2.30 g of the target compound as the free base. The salt, hydrochloride, is recrystallized from 95% ethanol and dried in a vacuum oven. This gives 1.79 g of the title compound as pale yellow crystals having a melting point of 253-255 ° C. Yield: 41%.

1 H NMR (DMSO-d ₆ ): δ 1.69 (m, 4), 3.23 (m, 4), 3.53 (m, 6),

4.03 (broad d, 2, J = 13.1), 7.44 (t, 1, J = 7.7), 7.57 (t, 1, J = 6.9), 7.88 ( d, 2, J = 1.1), 7.94 (d, 1, J = 1.1), 8.09 (dd,

2, J = 4.3, 8.0), 11.18 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.46, 25.14, 37.06, 46.26, 50.42,

54.96, 121.13, 123.10, 123.93, 124.55, 124.71, 126.89, 128.05,

130.20, 133.67, 134.04, 139.08, 152.04, 162.14, 166.69, 167.05.

Analysis for C ₂₃ H ₂₄ N ₄ O ₂ SC1 _2: calculated: 56.21% C, 4.92% H, 11.40% N Found: 56.18% C, 4.95% H, 11.34 % N.

Example 22

Process for preparing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-methoxyphthalimide hydrochloride hydrate

Starting compound: 3-methoxyphthalic anhydride (Alfred Bader Library). Yield 2.17 g (47% of theory). The title compound has a melting point of 232-234 ° C.

¹ H NMR (DMSO-d ₆ ): δ 1.70 (m, 4), 3.25 (m, 4), 3.54 (m, 6),

3.94 (s, 3), 4.03 (broad d, 2, J = 13.4), 7.48 (d, 1 , J = 8.5), 7.60 (tm, 1, J = 5.0), 7.79 (tm, 1, J = 7.3) 8.10 (Dd, 2, J = 7.9. 4.6), 11.19 (broad s, 1) ppm. ¹³ C NMR (DMSO-d 6): δ 20.52, 25.26, 36, 59, 46 , 29, 50.42.

54.99, 56.16, 114.88, 116.42, 118.52, 121.13, 123.94, 124.56,

126.90, 128.06, 133.56, 136.57, 152.05, 156.13, 162.16, 166.16,

167,54.

Analysis for ^C 24 ^H 26 ^N 4 ° 3 ^S. 1.25 HCl. 0.25 H ₂ 0:

calculated: 57.58% C, 5.57% H, 11.19% N, 0.89% H ₂ O, found: 57.65% C, 5.87% H, 10.92% N, 1, 17% H ₂ O.

Example 23

a) Method for producing (+/-) - trans-1,2-cyclopropanedimethanol

7.60 g (0.201 mol, 1.5 equivalents) of lithium aluminum hydride (LAH) are placed in a 500 ml three-necked round-bottomed flask, dried in an oven equipped with a pressure dropping funnel. The lithium aluminum hydride was placed under a nitrogen atmosphere, cooled in an ice bath, and 200.0 ml of anhydrous tetrahydrofuran was added. After the addition is complete, buy ice skating! was removed and the solution was allowed to stir at room temperature for 10 minutes. A solution of 25.0 g (0.0134 mol) of trans-diethyl 1,2-cyclopropanedicarbonate (Aldrich Chemical Company) was added dropwise to the suspension. The reaction mixture is refluxed for 6 hours and then allowed to stir at room temperature for 20 hours. The solution was cooled in an ice bath and 45 mL of ammonium chloride was slowly added. 50.0 ml of ethyl acetate are then added and the solids are filtered off and washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and evaporated to give 8.00 g of a cloudy oil. The crude material was purified by flash chromatography using a 19: 1 mixture of ethyl acetate and methanol as eluent. There was obtained (+/-) - trans-1,2-cyclopropanedimethanol as a colorless oil.

¹ H NMR (CDC1 _3): δ 0.41 (t, 2, J = 6.8), 1.00 (m, 2), 3.00 (dd, 2, J = 11.3, 8.8), 3.83 (dd, 2, J = 11.3, 4.4), 4.22 (broad s, 2) ppm. ¹³ C NMR (CDC1 _3): δ 7.16. 19.98. 66.08.

b) Method for producing (+/-) - trans-2- (chloromethyl) -1-cyclopropanethanol

4.0 g (0.039 mol) of (+/-) - trans-1,2-cyclopropanedimethanol, 8.96 g (0.047 mol, 1.2 equivalents) of tosyl chloride (TsCl), 5.30 g of dimethylaminopyridine (DMAP), and 75 g. 1.0 ml of anhydrous dichloromethane is placed in a 500 ml three-necked round-bottomed flask which is dried in an oven. The reaction mixture is placed under a nitrogen atmosphere and allowed to stir at room temperature for 24 hours. Additional portions of reagents, 2.24 g of tosyl chloride, 1.0 g of dimethylaminopyridine and 1.0 ml of dichloromethane are then added. The solution is allowed to stir at room temperature for a further 6 days. Then 5.43 ml (3.95 g, 0.039 mol, 1.0 equivalent) of triethylamine are added and the solution is allowed to stir for an additional 24 hours. The reaction is still incomplete and therefore the mixture is refluxed for 90 minutes and the solvent is removed by rotary evaporation. A sticky brown solid is obtained. The crude material was purified by flash chromatography with hexane / ethyl acetate (1: 1) and then with ethyl acetate / methanol (19: 1) as eluent. 1.85 g of (+/-) - trans-2- (chloromethyl) -1-cyclopropanethanol are obtained. A 0.87 g portion of the starting diol was obtained unchanged.

(c) Method for producing (+/-) - trans-N - [[2- (hydroxymethyl) cyclopropyl / methyl] phthalimide

1.44 g (7.62 mmol) of potassium phthalimide, 1.59 g (13.20 mmol,

1.7 equivalents) of (+/-) - trans-2- (chloromethyl) -1-cyclopropanethanol and 50.0 ml of anhydrous dimethylformamide are placed in a 100 ml round bottom flask. The resulting cloudy suspension was refluxed for 20 hours. The reaction mixture was allowed to cool to room temperature and most of the dimethylformamide was evaporated under reduced pressure on a rotary evaporator. The residue is taken up in dichloromethane and washed with two portions of water. The organic phase is dried over magnesium sulphate, filtered and evaporated. 3.55 g of a dark orange oil are obtained. The crude material was purified by flash chromatography (5: 1 hexane: ethyl acetate). 1.12 g of (+/-) - trans - N - [[2- (hydroxymethyl) cyclopropyl / methyl] phthalimide is obtained in the form of a white powder, m.p. 117-118 ° C. Yield: 64.

¹ H NMR (CDCl ₃ ): δ 0.48 (ddd, 1, J = 13.6, 10.3, 5.2), 0.65 (ddd, 1, J = 13.6, 10.3, 5.0), 1.17 (m, 2), 1.52 (broad s, 1),

3.45 (m, 2), 3.59 (dd, 2, J = 7.0, 2.2), 7.70 (m, 2), 7.84 (m, 2) ppm.

¹³ C NMR (CDCl ₃ ): δ 8.99, 16.17, 20.68, 41.57, 66.09, 123.43, 132.12, 133.95, 168.48.

Analysis for C ₁₃ H ₁₃ NO _3: Calculated: 67.52% C, 5.67% H 6.06% N Found: 67.45% C, 5.71% H, 5.99% N.

d) Method for producing (+/-) - trans- [2- (phthalimidomethyl) -1-cyclopropyl] methylmethylsulfonate

1.04 g (4.50 mol) of (+/-) - trans - N - [[2- (hydroxymethyl) cyclopropyl / methyl] phthalimide, freshly distilled over calcium hydride, 0.94 ml (0.68 g, 6, 75 mmol (1.5 equivalents) of triethylamine and 14.0 ml of anhydrous dichloromethane are introduced into a 50 ml round bottom flask. The solution was placed under a nitrogen atmosphere and cooled in an ice bath. To this cooled mixture was added a solution of 0.52 mL (0.77 g, 6.75 mmol, 1.5 equivalents) of mesyl chloride in 2.0 mL of dichloromethane. After this addition, the white suspension turned into a clear pale orange solution, which was allowed to stir at 0 ° C for 1 hour. The reaction mixture was allowed to warm to room temperature and washed with saturated potassium carbonate solution. The organics were dried over magnesium sulfate, filtered and evaporated. 1.40 g of an off-white solid are obtained. This material was purified by flash chromatography on silica gel with hexane / ethyl acetate (1: 1) as eluent. 1.29 g of (+/-) - trans- [2- (phthalimidomethyl) -1-cyclopropyl] methylmethylsulfonate are obtained in the form of a white powder, m.p.

to 121 ° C. Yield: 93%. ¹ H NMR (CDCl ₃ ) : δ 0.65 (Dt, 1, J = 8.6. 5.4). 0.83 (dt, 1, J = 8.4, 5.4), 1.33 (m, 2) 2.94 (s, 3), 3.58 (Dd, 1, J = 14.2, 7.2), 3.65 (dd, 1, J = 14.2, 6,9) , 3.99 (Dd, 1, J = 10.8, 7.5),

4.09 (dd, 1, J = 10.8, 7.0), 7.74 (m, 2), 7.86 (m, 2) ppm.

¹³ C NMR (CDCl ₃ ): δ 9.97, 16.90, 17.26, 37.79, 40.86, 73.22,

123.29, 132.09, 134.02, 168.29.

e) Method for producing (+/-) - trans-N - [[2 - [[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / methyl] cyclopropyl] methyl] phthalimide hydrochloride hydrate

1.17 g (3.78 mmol) of (+/-) - trans- [2- (phthalimidomethyl) -1-cyclopropyl / methylmethylsulfonate, 0.912 g (4.16 mmol, 1.1 equivalents) of 3- (1 -piperazinyl) -1,2-benzisothiazole, 0.633 mL (0.459 g, 4.54 mmol, 1.2 equivalents) of triethylamine and 10.0 mL of acetonitrile are introduced into a 100 mL round bottom flask. The cloudy suspension is overlaid with nitrogen and refluxed for 3.5 hours. An additional 0.083 g (0.10 equivalents) of piperazine-benzisothiazole was added to the reaction mixture and heating was continued for a total of 20 hours. The solution was allowed to cool to room temperature and dichloromethane was added. The solution is washed with saturated potassium carbonate solution, the organic phase is dried over magnesium sulphate, filtered and evaporated. 1.92 g of a viscous orange oil are obtained. The crude material was purified by flash chromatography (2: 1 hexane: ethyl acetate). 1.30 g of the free base is obtained. The salt, hydrochloride is prepared and recrystallized from aqueous ethanol. 1.11 g of (+/-) - trans - N - [[2 - [[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / methyl] cyclopropyl] methyl] phthalimide hydrochloride is obtained. , in the form of an off-white powder, after drying in a vacuum oven. Mp 246-248 ° C. Yield: 61%.

^X H NMR (DMSO-d): 8 0.74 (m, 2), 1.29 (m, 1), 3.12 (br

S, 2), 3.20 - 3.67 (m, 8), 4.05 (m, 2), 7.45 (t, 1, J = 7.5), 7.58 (t, 1, J = 7.5), 7.18 (m, 4), 8.09 (d, 2, J = 8.2), 11.12 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 9.64, 12.01, 17.07, 46.24, 49.87,

50.22, 58.47, 121.16, 123.02, 124.01, 124.61, 126.93, 128.11, 131.67, 134.37, 152.08, 162.16, 168, 02.

Example 24

a) A method for producing N- [2- (2-chloroethoxy) ethyl] phthalimide

15.0 g (0.081 mol) of potassium phthalimide (Aldrich Chemical Company), as a powder and 28.5 ml (34.74 g, 0.234 mol, 3.0 equivalents) of 2-chloroethyl ether (Aldrich Chemical Company), as a colorless The oil is added to a round bottom mined flask

250 ml. The reaction mixture is heated in an oil bath at 170 ° C and the solution turns brown. The mixture was removed from the oil under a nitrogen atmosphere for 19 hours. After heating, the liquid is more liquid and colored in the bath and distilled water is added. The solution was allowed to cool to room temperature and extracted with dichloromethane. The organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated. 36.1 g of a dark orange brown oil are obtained. This crude material was purified by elution with 3: 1 hexanes / ethyl acetate. 13.53 g of a light orange oil are obtained, which corresponds to a yield of 67% of theory. This oil solidifies rapidly on standing.

An analytically pure white powder was obtained by recrystallization from ethyl acetate and had a melting point of 67-70 ° C.

¹ H NMR (CDCl 3): δ 3.54 (dt, 2, J = 6.2, 0.8), 3.72 (dt, 2)

J = 5.9, 0.6), 3.75 (dt, 2, J 1.2), 7.71 (m, 2), 7.83 (m, 2) ¹³ C NMR (CDC1 _3): δ 37 132.97, 168.27 _and

5.8, 0.9), 3.89 (dt, 2, J = 5.4, ppm).

14, 42.70, 67.92, 70.61, 123.27,

Analysis for ^C 12 ^H I 2 ^C ^ ^{NO 3:} Calculated: 56.81% C, 4.77% H 5.52% N Found: 56.88% C, 4.79% H, 5.49% N .

b) Process for the preparation of N- [2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] phthalimide hydrochloride

This compound was prepared in an analogous manner to that used in Example 13 (a). From 1.33 g (5.2 mmol) of N- [2- (2-chloroethoxy) ethyl] -phthalimide, 1.15 g (5.2 mmol), 1.0 equivalent) of 3- (1-piperazinyl) -1, Of 2-benzisothiazole, 0.94 mL (0.0685 g, 6.8 mmol, 1.3 equivalents) of triethylamine and 6.0 mL of acetonitrile gave 1.17 g of the free base. The salt, the hydrochloride is formed and recrystallized from ethanol. 0.87 g of N- [2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] phthalimide hydrochloride is obtained as off-white crystals, m.p. to 200 ° C. Yield: 35%.

¹ H NMR (DMSO-d 6): δ 3.26 - 3.56 (m, 8), 3.70 (t, 2, J = 5.4), 3.82 (t, 2, J = 5, 4), 3.88 (m, 4), 7.48 (ddd, 1, J = 8.1, 7.0, 1.1), 7.60 (ddd, 1, (J = 8.1, 7.0, 1.1), 7.80 (m, 2), 7.85 (m, 2), 8.06 (dt, 1, J = 8.2, 0.9), 8.11 ( dt, 1, J = 8.1, 0.9), 11.12 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 36.93, 46.21, 51.06, 54.86, 64.35,

67.25. 121.14, 122 , 96, 123.88, 124.57, 126.85, 128.06, 131.46, 134.35. 152.04. 162 , 05, 167.82.

Analysis for ^C 23 ^H 24 ^N 4 ^S ° 3 ^'HC1: Calculated: 58.40% C, 5.33% H, 11.84% N Found:

% C, 58.50;% H, 5.36.

11.81% N.

Example 25

a) A process for the preparation of N- (4-chloro-2-butynyl) phthalimide

This compound was prepared according to the method described in Example 24 a) from 13.0 g (0.0702 mol) of potassium phthalamide (Aldrich Chemical Company) and 25.9 g (0.212 mol, 3.0 equivalents).

1,4-dichloro-2-butyne (Aldrich Chemical Company). Elution with hexane / ethyl acetate (4: 1) as eluent gave 10.64 g of a pale yellow solid. Yield: 65%. Analytically pure, diamond-like colorless crystals are formed by crystallization from a solution of hexane in ethyl acetate. The title compound has a melting point of 112-115 ° C.

¹ H NMR (CDCl ₃ ): δ 4.09 (t, 2, J = 2.1), 4.49 (t, 2, J =

2.1), 7.73 (m, 2), 7.87 (m, 2) ppm.

¹³ C NMR (CDCl ₃ ): δ 27.22, 30.10, 77.86, 79.91, 123.58,

131.94, 134.24, 166.95.

Analysis for ^C 8 ^H 12 ^NO 2 ^{C 1:} calculated: 61.69% C, 3.45% H 5.99% N Found: 61.74% C, 3.48% H, 5.95% N.

b) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butynyl] phthalimide hydrochloride

This compound was prepared as described in Example 13a). From 10.64 g (0.0455 mmol) of N- (4-chloro-2-butynyl) phthalimide and 9.98 g (0.0455 mmol, 1.0 equivalent) of 3- (1-piperazinyl) -1.2 -benzisothiazole gave 14.14 g of the free amine. Yield: 74%. The salt, hydrochloride, was prepared from 4.49 g of the amine to give 3.17 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butynyl] phthalimide hydrochloride. , in the form of yellow flakes, after recrystallization from a mixture of ethanol and ether. The title compound has a melting point of 231-233 ° C.

^T H NMR (DMSO-d₆): δ 3.49 (m, 6), 4.09 (m, 2), 4.23 (br s, 2), 4.54 (s, 2), 7.47 (ddd, 1, J = 8.1, 7.0, 1.0), 7.60 (ddd, 1, J = 8.01, 7.0, 0.9), 7.90 (m, 4 ), 8.12 (dd, 2, J = 11.1,

8.1), 11.82 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 26.90, 44.37, 46.32, 49.84, 72.01,

84.25, 121.10, 123.34, 123.97, 124.55, 126.88, 128.06, 131.33,

134.72, 152.04, 162.09, 166.65.

Analysis for C 3 H ₂₀ N ₂ 0 ₄ S _2. HCl:

H, 4.67; N, 12.37. Found: C, 60.82; H, 4.72; N, 12.27.

Example 26

a) A method for producing (E) -N- (4-bromo-2-butenyl) phthalimide

This compound was prepared in an analogous manner to that described in Example 24 (a). 8.35 g (0.0451 mol) of potassium phthalimide (Aldrich Chemical Company), 24.1 g (0.1127 mol, 2.5 equivalents) of trans-1,4-dibromo-2-butene (Aldrich Chemical Company) and 400.0 ml of dimethylformamide was heated under a nitrogen atmosphere at 125 ° C for 3.5 hours. The dimethylformamide was evaporated on a rotary evaporator and the crude material was purified by flash chromatography with hexanes. Yield: 26% and ethyl acetate (4: 1).

3.25 g of (E) -N- (4-bromo-2-butenyl) phthalimide. Yield of theory. An analytically pure sample was obtained by crystallization from ether. The product consists of white crystals having a melting point of 97-99 ° C.

5.1) ¹ H NMR (CDCl ₃ ): δ

5.87 (m, 2), 7.72

3.89 (d, 2, J = 6.4), 4.29 (m, 2), 7.84 (m, 2) ppm.

(d, 2, J = ¹³ C NMR (CDCl 3): δ 31.27, 132.04, 143.09, 167.77.

38.62, 123.40, 128.36, 129.96,

Analysis for C ₁₂ H ₁₀ NO ₂ Br: calculated: 51.58% C, 3.61% H, found: 51.53% C, 3.60% H,

5.01% N,

5.02% N.

b) Method for producing (E) -N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] phthalimide hydrochloride

This compound was prepared according to the method described in Example 13 a). From 8.45 g (0.0302 mmol) of (E) -N- (4-bromo-2-butenyl) phthalimide and 6.61 g (0.0302 mmol, 1.0 equivalent) of 3- (1-piperazinyl) -1.2

of benzisothiazole gave 14.31 g of a dark orange solid. The crude material was purified by elution with 1: 1 hexanes: ethyl acetate as eluent. 7.48 g of free amine is obtained. The salt, hydrochloride, was prepared and recrystallized from 95% ethanol. 1.99 g of (E) -N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] -phthalimide hydrochloride are obtained in the form of a brown powder, which has: mp 243-244 ° C.

s, ^τ Η NMR (DMSO-d6):

2), 4.04 (wide d, δ 3.20 (m, 2), 3.45 (m, 4), 3.80 (wide

2, J = 12.6), 4.24 (d, 2, J = 4.8), 5.83 (dt, 1, J = 15.6, 6.8),

6.04 (dt,

1, J = 15.6, 5.1), 7.42 (t, 1,

J = 7.8),

7.4, 6.4)

7.56 (t, 1, J, 11.72 (broad = 7.3), 7.85 (m, 4), 8.08 (dd, s, 1) ppm.

2, J

13 _c

121.09.

152,03,

NMR _(DMSO-d6):

123.12, 123.96,

162.12, 167.39.

δ 38.50

124.53.

46.29, 49.80, 56.06,

128.03, 131.50, /

126.88.

120.96.

134.45, for

Analysis calculated found:

HC1

N,

N.

Example 27

a) A method for producing (Z) -N- (4-chloro-2-butenyl) phthalimide

This compound was prepared according to the method described in Example 24 a) from 13.0 g (0.0702 mol) of potassium phthalimide (Aldrich Chemical Company) and 26.3 g (0.211 mol, 3.0 equivalents) of cis-1,4- dichloro-2-butene. The crude material was purified by elution with 4: 1 hexanes / ethyl acetate. 12.87 g of (Z) -N- (4-chloro-2-butenyl) phthalimide are obtained as a light yellow solid. Yield: 78%. ⁰ It was found that the substance forms a zmnes (Z) and (R) isomers = 90: 10, as determined by ¹³ C NMR spectral analyzes. The title compound has a melting point of 63-66 ° C.

¹ H NMR (CDCl ₃ ): δ 4.32 (dd, 2, J = 7.7, 0.9), 4.35 (dd, 2, J = 7.4, 1.2), 5.70 (dm, 1, J = 10.6), 5.84 (dm, 1, J = 10.6), 7.72 (m, 2), 7.84 (m, 2) ppm.

* Ί “7

The following C signals observed for the trans-isomer are enclosed in parentheses.

¹³ C NMR (CDCl ₃ ): δ 34.03, 38.60 (43.48), (58.30), (119.62), 123.34 (123.52), (127.09), 127 , 15, 132.05, 134.06, (134.20), (135.27), 167.73.

b) A method for producing (Z) -N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / -2-butenyl] phthalimide hydrochloride hydrate

This compound was prepared as described in Example 13 (a). From 9.86 g (0.0418 mmol) of a mixture of (Z) - and (E) -N- (4-chloro-2-butenyl) phthalimide in a ratio of 90:10 and 9.17 g (0.0418 mmol, 1). (0 equivalent) of 3- (1-piperazinyl) -1,2-benzisothiazole gave 18.93 g of a dark orange viscous oil. The crude material was purified by elution with 1: 1 hexanes / ethyl acetate. 14.35 g of an orange oil are obtained, which solidifies on standing. Yield: 82%. A portion of this material, weighing 8.44 g, was recrystallized from ethyl acetate. 4.92 g of pale yellow crystals are obtained. Recrystallization increases the ratio of the (Z) to (E) isomer from approximately 90: 10 to 97: 3. The salt, hydrochloride, is recrystallized twice from 95% ethanol. 1.34 g (yield = 7% of theory) of (Z) -N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] phthalimide hydrochloride (yield) are obtained. 100% of theory of the Z-isomer), in the form of pale yellow crystals having a melting point of 247-249 ° C.

¹ H NMR (DMSO-d ₆ ): δ 3.52 (m, 4), 4.13 (m, 4), 4.39 (d, 2, J = 5.6), 5.87 (m, 2), 7.49 (ddd, 1, J = 8.1, 7.0, 1.0), 7.61 (ddd, 1, J = 8.1, 7.0, 1.0), 7 88 (m, 4), 8.14 (dd, 2, J = 11.1)

8.1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 34.59, 46.38, 50.03, 51.87, 121.16,

121.29, 123.06, 123.95, 124.59, 126.92, 128.08, 131.60, 132.85,

134.42, 152.07, 162.10, 167.46.

Analysis for ^C 23 ^H 22 ^N 4 ° 2 ^S · ^HCl · · ° / ²⁵ H ₂ O: calculated: 60.12% C, 5.15% H, 12.19% N, 0.98% H ₂ O, found: 59.73% C, 5.17% H, 12.11% N, 0.61% H ₂ O.

Example 28

a) Method for producing 2- (2-hydroxyethyl) -1,2-benzisothiazol-3 [2H] -one

20.0 g (0.0583 mol) of 2,2'-dithiobisbenzoyl chloride (JP Yevich et al., J. Med. Chem. 29, 359-369 (1986)) and 50.0 ml of dichloromethane are introduced into a round-bottomed flask. 150 ml. Chlorine gas is bubbled through the cloudy solution obtained with stirring. A rust-colored mixture is thus obtained. A solution of 7.12 g (0.112 mol, 2.1 equivalents) of ethanolamine, 16.3 ml (11.8 g, 0.117 mol, 2.1 equivalents) of triethylamine and 50.0 ml of dichloromethane was added to a separatory funnel. The mixture was cooled in an ice bath, and the bis-chloride solution was slowly added to the cooled amino-alcohol solution with stirring. The resulting orange mixture was washed with distilled water, and the organic phases were dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. 22.74 g of a crude orange oil are obtained. The NMR spectrum of this material was consistent with 2- (2-hydroxyethyl) -1,2-benzisothiazol-3 [2H] -one and was used without further purification.

b) Method for producing 2- (2-chloroethyl) -1,2-benzisothiazol-3 [2H] -one

Crude 2- (2-hydroxyethyl-1,2-benzisothiazol-3 [2H] -one) (22.74 g, 0.116 mol) was treated with toluene (100 mL) and cooled in an ice bath. 68 g (0.132 mol, 1.13 equivalents) of thionyl chloride for 15 minutes, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours. The orange residue was purified by flash chromatography (hexane / ethyl acetate 1: 1) to give 10.24 g (41% yield based on 2,2'-dithiobisbenzoyl chloride) of 2- (2-chloroethyl). -1,2-benzisothiazol-3 [2H] -one, as an orange oil which solidifies on standing. The title compound has a melting point of 73-78 ° C.

¹³ C NMR (CDCl ₃ ): δ 42.11, 45.90, 120.31, 125.68, 126.80, 132.18, 140.65, 165.67.

c) Method for producing 2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethyl] -1,2-benzisothiazol-3 [2H] -one hydrochloride

This compound was prepared in an analogous manner to that described in Example 13 (a). From 3.54 g (0.0165 mol) of 2- (2-chloroethyl) -1,2-benzisothiazol-3 [2H] -one and 4.00 g (0.0128 mol, 1.1 equivalents) of 3- ( 1-piperazinyl) -1,2-benzisothiazole gave 6.95 g of crude material. This material was purified by flash chromatography (hexane / ethyl acetate 1: 1). 4.00 g of free amine is obtained. The salt, hydrochloride, is recrystallized from 95% ethanol. 1.76 g of 2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethyl] -1,2-benzisothiazol-3 [2H] -one hydrochloride are obtained in the form of a white solid. crystalline substance having a melting point of 250-252 ° C. Yield: 25%.

¹ H NMR (DMSO-d 6): δ 3.46 (m, 6), 3.76 (broad d, 2, J = 10.2), 4.10 (broad d, 2, J = 12.3) 4.36 (broad t, 2, J = 5.9), 7.47 (tt, 2, J = 7.1, 1.1), 7.59 (t, 1, J = 7.2) 7.72 (dt, 1, J = 8.3, 1.2), 7.91 (dd, 1, J = 7.9, 0.5), 8.11 (m, 3), 11, 34 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 37.78, 46.28, 50.82, 53.73, 121.07, 122.09, 123.59, 123.96, 124.51, 125.53, 125.59, 126.85, 128.02, 132.00, 140.96, 152.02, 162.02, 164.90.

Analysis for C ₂ 0 ^H 20 ^N 4 ^OS 2 ^'HC1: Calculated: 55.48% C, 4.89% H, 12.94% N Found: 55.53% C, 4.92% H, 12, 89% N.

Example 29

a) Process for the preparation of 2- [3- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / propyl] -1,2-benzisothiazol-3 [2H] -one hydrochloride

This compound was prepared according to the method described in Example 28 a) to c). From 5.29 g (0.0232 mol, 1.0 equivalents) of 2- (3-chloropropyl) -1,2-benzisothiazol-3 [2H] -one and 5.09 g (0.0232 mol, 1 (0 equivalent) of 3- (1-piperazinyl) -1,2-benzisothiazole gave 4.40 g of the title compound after flash chromatography with ethyl acetate as eluent. The salt, hydrochloride, is recrystallized from 95% ethanol. 3.45 g of 2- [3- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / propyl] -1,2-benzisothiazol-3 [2H] one hydrochloride are obtained in the form of: an off-white powder having a melting point of 185-187 ° C. Yield: 32%.

¹ H NMR (DMSO-d 6):

4.00 (m, 4), 7.44 (tt,

2.19 (m, 2), 3.28 (m,

2, J = 7.5, 1.0), 7.57

4), 3.55 (m, 4), (ddd, 1, J = 8.3,

6.8, 1.0),

7.69 (ddd, J, J)

8.5, 7.3, 1.2), 7.87

7.2, 0.8), 8.01 (dt, 1, J = 8.3, 0.8),

8.09 (m,

2) ppm.

¹³ C NMR (DMSO-d 6): δ 23.55, 40.48, 46.28, 50.49, 52.93, 121.08, 121.94, 123.90, 124.51, 125.45, 125.52, 126.85, 128.02,

131.79, 140.51, 152.01, 162.07, 164.48.

Analysis for ^C 21 ^H 22 ^N 4 ^OS · ¹ 2 ^* - ^{5 HC1:} Calculated: 54.21% C, 5.09% H, 12.04% N Found: 54.48% C, 5.46% H , 11.93% N.

Example 30

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

This compound was prepared according to the method described in Example 28 a) to c). From 6.61 g (0.0273 mol) 2- (4-chlorobutyl-1,2-benzisothiazol-3 [2H] -one) and 6.78 g (0.0309 mol, 1.13 equivalents) 3- (1

(piperazinyl) -1,2-benzisothiazole oil. This crude material was chromatographed with ethyl acetate as eluent and 95% ethanol.

then

3.68 g of off-white are obtained, 14.16 g of dark orane are obtained, purified by flash chromatography of dichloromethane (4: 1) by recrystallization of the free amine powder. The salt, hydrochloride, is recrystallized from 95% ethanol and dried in a vacuum oven. 2.81 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2-benzisothiazol-3 [2H] -one hydrochloride are obtained in the form of an off-white powder, m.p. 215 DEG-216 DEG C. The yield corresponds to 22% of theory.

NMR (DMSO-d6): δ 1.75 (broad s, 4), 3.19 (m, 4), 3.49 (m, 4), 3.87 (m, 2), 4.02 (broad) d, 2), 7.44 (dddd, 2, J = 1.1, 2.8, 7.0, 8.2), 7.57 (ddd, 1, J = 1.1, 7.0, 8.0), 7.68 (ddd, 1, J = 1.3, 7.1, 8.4), 7.86 (dq, 1, J = 7.8, 0.7), 8.00 (dt, 1, J = 8.1, 0.9), 8.09 (m, 2H), 11.15 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.26, 26.27, 42.34, 46.29, 50.45, 54.93, 121.12, 121.91, 123.94, 124.05 , 124.55, 125.47, 125.54, 126.90, 128.06, 131.75, 140.38, 152.04, 162.16, 164.34.

Analysis for ^C 22 ^H 2 H 2 ^OS · ^HC1: Calculated: 57.31% C, 5.46% H, 12.15% N Found: 57.21% C, 5.51% H, 12.06% N .

Example 31

a) Method for producing 2- (4-chlorobutyl) - [2H] phthalazinone

2.56 g (0.0855 mol, 1.25 equivalents) of an 80% sodium hydride dispersion were placed under a nitrogen atmosphere in a 250 mL round bottom flask. The sodium hydride was washed twice with hexane and the waste hexanes discarded. To the washed sodium hydride was added 100.0 ml of dimethylformamide. A solution of 10.0 g (0.0684 mol) of 1 [2H] phthalazinone in 50.0 ml of anhydrous dimethylformamide was added to the resulting gray suspension and the resulting solution was allowed to stir at room temperature for 30 minutes. The anion solution thus prepared is introduced via a lead tube into a 500 ml round bottom flask containing 8.67 ml (12.91 g, 0.0753 mol, 1.1 equivalents) of 1-bromo-4-chlorobutane in 100 ml, 0 ml of anhydrous dimethylformamide. The reaction mixture was allowed to stir at room temperature for 4 hours. During the reaction, the mixture turned to a clear orange solution. Distilled water (10.0 ml) was added to the reaction mixture and most of the solvent was removed by rotary evaporation. The residue is taken up in dichloromethane and washed twice with 50 ml of water each time. 16.49 g of crude material are obtained, which is purified by flash chromatography with 2: 1 hexanes / ethyl acetate as eluent. 13.11 g of a light orange oil are obtained. ¹ H NMR spectral analysis showed the product to be a mixture

2- (4-chlorobutyl) -1 [2H] phthalazinone and its corresponding bromide in an 80:20 ratio, as determined by integration of triplets at 3.56 and 3.43 ppm. Differential. n.O.e. experiments show N-alkylated products versus O-alkylated products. The chloride mixture was used without further purification.

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

This compound was prepared in an analogous manner to that described in Example 13 (a). From 3.93 g (0.0179 mol, 1.1 equivalents)

3- (1-piperazinyl) -1,2-benzisothiazole and 4.00 g (0.163 mol) of a mixture of 2- (4-chlorobutyl) -1 [2H] phthalazinone and 2- (4-bromobutyl) -1 [2H] phthalazinone at 80:20, 7.75 g of crude material was obtained, which was purified by flash chromatography with a 3: 1 mixture of ethyl acetate and hexane as eluent. The salt, the hydrochloride, was recrystallized from aqueous ethanol, dried in a vacuum oven to give 4.09 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl]. 1-l [2H] -phthalazinone, as a white crystalline solid, m.p. 252-253 ° C. Yield: 55%.

¹ H NMR (DMSO-d 6): δ 1.83 (m, 4), 3.22 (m, 4), 3.61 (broad q, 4, J = 10.5), 4.25 (d, 2, J = 13.2), 4.20 (t, 1, J = 5.9), 7.47 (ddd, 2, J = 8.1, 7.0, 1.1), 7.59 (ddd, 1, J = 8.1, 7.0, 1.1), 7.89 (m, 1), 7.96 (m, 2), 8.12 (tt, 2, J = 7, 6, 1.4), 8.28 (dm, 1, J = 7.8), 8.48 (d, 1, J = 0.7), 11.16 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.35, 25.29, 46.32, 49.43, 50.46,

54.11, 121.12, 123.94, 124.55, 125.71, 126.78, 126.91, 126.99,

128.06 129.28 132.00 133.45, 138.01, 152.05, 158.36. Analysis for ^C 23 ^H 25 ^N 5 ° . HC1 calculated: 60.58% C, 5.75 % H, 15.36 % N, found: 60.47% C, 5.78 % H, 15.29 % N.

Example 32

a) A method for producing 4-methyl-1 [2H] phthalazinone

75.0 g (0.46 mol) of 2-acetylbenzoic acid are added to 800.0 ml of 95% ethanol and a solution of 33.0 ml (0.57 mol) of 85% hydrazine hydrate in 50.0 ml of 95% ethanol is added. The solution is refluxed for 1 hour. A white solid forms during the reaction. The solution is evaporated to half its original volume under reduced pressure on a rotary evaporator. The solid is filtered off and dried in a vacuum oven. 68.19 g are obtained

4-methyl-1 [2H] phthalazinone, as a white solid, m.p. 222-224 ° C (melting point 222-223 ° C according to literature), A. Hirsch, DG Orphanos, J. Het. 3, 38 (1966)). Yield: 93%.

¹ H NMR (DMSO-d 6): δ 2.50 (s, 3), 7.81-8.26 (m, 4), 12.40 (broad s, 1) ppm.

Analysis for C _g HGN ₂ O: Calculated: 67.49% C, 5.03% H, 17.49% N Found: 67.62% C, 5.08% H, 17.50% N.

b) Process for preparing 2- (4-bromobutyl) -4-methyl-1 [2H] phthalazinone

This compound was prepared in an analogous manner to that described in Example 31 (a). From 50.0 g (0.31 mol) of 4-methyl-1 [2H] phthalazinone and 80.33 g (0.37 mol) of 1,4-dibromobutane gave 31.05 g of 2- (4-bromobutyl) - 4-methyl-1 [2H] phthalazinone, as orange crystals, m.p. 166-172 ° C. Yield: 34%.

^X H NMR (DMSO-d₆): δ 1.85 (m, 4), 2.56 (s, 3), 3.58 (t, 2, J = 6.2), 4.13 (t, 2 J = 6.6), 7.88 (m, 1), 7.95 (m, 2), 8.29 (dm, 1, J = 8.7) ppm.

c) Process for the preparation of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-methyl-1 [2H] -phthalazinone hydrochloride hydrate

This compound was prepared as outlined in Example 13 (a). Crude obtained from the reaction of 2.48 g (8.4 mmol) of 2- (4-bromobutyl) -4-methyl-1 [2H] phthalazinone and 1.93 g (8.80 mmol, 1.05 equivalents) of 3 Of (1-piperazinyl) -1,2-benzisothiazole, is purified by recrystallization from acetonitrile. 2.89 g of the free base is obtained in the form of a pale orange solid. The salt, hydrochloride, was recrystallized from 95% ethanol and dried in a vacuum oven. 2.71 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-methyl-1 [2H] -phthalazinone hydrochloride hydrate are obtained as an off-white solid. mp 228-230 ° C. Yield: 68%.

¹ H NMR (DMSO-d 6): δ 1.80 (broad s, 4), 2.56 (s, 3), 3.20 (m,

4), 3.52 µm, 4), 4.04 (broad d, 2, J = 13.3), 4.14 (m, 2), 7.45 (t, 1, J = 7.5) 7.57 (t, 1, J = 7.5), 7.87 (m, 1), 7.98 (d, 2, J = 3.7), 8.11 (dd, 2, J = 7.8, 4.9), 8.29 (d, 1, J = 7.7), 11.08 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 18.55, 20.37, 25.31, 46.36, 49.14, 50.51, 55.13, 121.15, 123.95, 124.57 , 125.61, 126.14, 126.90, 128.08, 129.15 131.75, 133.31, 143.46, 152.06, 158.19, 162.15.

Analysis for C ₂₄ H ₂₇ N ₅ O ₅ S. HC1 .0.25 H ₂ O: Calculated: 60.75% C, 6.05% H, 14.76% N Found: 60.73% C, 6.11% H, 14.73% N.

Example 33

a) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] phthalimide hydrochloride hydrate

0.956 g (3.39 mmol) of N- (4-bromobutyl) phthalimide (Aldrich Chemical Company), 0.740 g (3.39 mmol, ridinyl) -1,2-benzisothiazole, 0.57 ml equivalent) flask with an orange solution Allow to cool to room temperature and

1.0 equivalents) 3- (4-pipe (0.412 g, 4.07 mmol, 1.2 ecacetonitrile) was added to the mixture and covered with nitrogen overnight. Dark triethylamine and 5.0 mL round bottom. Resulting and refluxing The reaction mixture was washed with saturated potassium carbonate solution and the organic phase was dried (MgSO 4), filtered and evaporated to give 1.65 g of a dark orange oil which was purified by flash chromatography with ethyl acetate as the eluent. 1.30 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino] -4-butyl] phthalimide is obtained as a pale orange oil which solidifies on standing to a pale yellow solid. The free base is shaken with ethyl acetate and treated with 2.7 ml of 1N (1 equivalent) ethereal hydrogen chloride, and the salt is recrystallized from aqueous ethanol to give 0.810 g of the hydrochloride, which is a white solid. % te ry. The spectral and analytical data indicated one equivalent of HCl, and 0.5 equivalents of water. The hydrochloride obtained has a melting point of 220-222 ° C.

¹ H NMR (DMSO-d ₆ ): δ 1.73 (m, 4), 2.21 (m, 4), 3.12 (broad s,

4), 3.62 (m, 5), 7.54 (ddd, 1, J = 1.1, 7.0, 8.1), 7.63 (ddd, 1, J = 1.2, 6) , 9, 8.1), 7.88 (m, 4), 8.21 (d, 1, J = 8.1), 8.28 (d, 1, J = 8.1), 10.13 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.55, 25.30, 27.63, 35.50, 36.80,

51.44. 55.48, 120.66, 122.98. 123.50, 124.86, 127.97, 131.59, 133.28. 134.33, 151.89, 167.49. 167.94. analysis for ^C 24 ^H 25 ^N 3 ° 2 ^N . HCl. 0.5 H ₂ 0:

H, 5.85; N, 9.04. Found: C, 61.80; H, 5.89; N, 9.05.

Example 34

a) Method for producing ethyl N- (2-phenethyl) carbamate

31.1 ml (30.0 g, 0.248 mol) of phenethylamine, 34.6 ml (25.1 g, 0.248 mol, 1.0 equivalent) of triethylamine and 300.0 ml of anhydrous dichloromethane are placed in a three-necked round-bottomed flask. volume of 1 liter, equipped with a magnetic stir bar, dropping funnel and nitrogen inlet. The solution was cooled in an ice bath and then a solution of 23.7 mL (26.9 g, 0.248 mol, 1.0 equivalent) of ethyl chloroformate (ALdrich Chemical Company) in 25 mL of dichloromethane was added dropwise. The reaction mixture is stirred for 30 minutes and then 150 ml of ether are added. The resulting suspension was filtered and the filtrate was evaporated. 46 g of an oil are obtained, which solidifies on standing to a white solid. Yield 96%. The crude material was used without further purification.

b) A process for the preparation of 3,4-dihydro-1 [2H] isoquinolinone

46.0 g (0.238 mol) of ethyl (N- (2-phenethyl) carbamate) and 475.0 g of polyphosphoric acid are introduced into a 1 liter round bottom flask equipped with a magnetic stir bar and a reflux condenser. Heat the mixture in an oil bath at 140-160 ° C for 2 hours. The reaction mixture was allowed to cool to room temperature and poured into 2.4 L of distilled water. The organic portion was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, filtered and evaporated. 4.36 g of an orange oil are obtained. The crude material was purified by flash chromatography with ethyl acetate as eluent. 1.85 g of 3,4-dihydro-1 [2H] isoquinolinone are obtained in the form of a pale orange oil. The yield corresponds to 5.1% of theory based on phenethylamine.

^{Σ Η} NMR (CDC1 _3): δ 3.01 (t, 2, J = 6.6), 3.58 (dt, 2, J

2.9, 6.6), 6.20 (broad S, 1), 7.22 (dd, 2, J = 0.7, 7.4), 7.36 (ddd, 1, J = 1, 3, 7.6, 8.3), 7.46 (ddd, 1, J = 1.6, 7.5, 9.0), 8.07 (dd, 1, J = 1.1, 7, 7) ppm.

c) Method for producing 2- (4-chlorobutyl) -3,4-dihydro-1 [2H] isoquinolinone

0.945 g (31.5 mmol, 2.5 equivalents) of an 80% oil dispersion of sodium hydride was introduced into a 1 liter round bottom flask equipped with a magnetic stir bar and nitrogen inlet using a flask that had been previously flame dried. The sodium hydride was washed three times with hexanes and the waste hexanes were removed by pipette from the solid. To the washed sodium hydride was added 20.0 mL of anhydrous Ν, Ν-dimethylformamide and the resulting suspension was cooled in an ice bath. A solution of 1.85 g (12.6 mmol, 1.0 equivalent) of 3,4-dihydro-1 [2H] isoquinolinone in 20.0 mL of anhydrous Ν, Ν-dimethylformamide was added dropwise to the cooled reaction mixture. The cold reaction mixture was allowed to stir for 15 minutes and then allowed to warm to room temperature. After 5 minutes, the reaction mixture was cooled in an ice bath and 1.59 mL (2.37 g, 13.8 mmol, 1.1 equivalents) of 1-bromo-4-chlorobutane was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Excess sodium hydride was removed by treatment with 10 ml of distilled water, the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic portion was dried (MgSO 4), filtered and evaporated. 5.16 g of an orange oil are obtained. The crude material was purified by flash chromatography with hexane / ethyl acetate 3: 2 as eluent. There was obtained 1.90 g of 2- (4-chlorobutyl) -3,4-dihydro-1 [2H] isoquinolinone as a colorless oil. Yield: 63%.

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

1.90 g (7.99 mmol) of 2- (4-chlorobutyl) -3,4-dihydro-1 [2H] -isoquinolinone, 2.10 g (9.59 mmol, 1.2 equivalents) of 3- (1 -piperazinyl) -1,2-benzisothiazole, 1.56 ml (1.13 g, 11.2 mmol, 1.4 equivalents) of triethylamine and 25.0 ml of acetonitrile are placed in a 100 ml round bottom flask equipped with magnetic stir bar, cooler and nitrogen inlet. The reaction mixture was refluxed under nitrogen for 30 minutes. The reaction is not complete as shown by thin layer chromatography, and an additional 0.350 g (1.60 mmol, 0.2 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole and 0.670 ml (0.486) is added. g, 4.81 mmol, 0.6 equiv) triethylamine. The reaction mixture was further refluxed for an additional 24 hours. The solution was allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate. The solution was then washed with saturated potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 5.2 g of an orange oil are obtained, which is purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as the eluent. 2.26 g of an orange oil are obtained. The free base was shaken with ethyl acetate and 5.37 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The resulting mixture was recrystallized from ethanol to give 2.0 g of a light orange solid, mp 229-231 ° C. Yield: 55%.

^X H NMR (DMSO-d): 8 1.66 (m, 2), 1.78 (m, 2), 3.00 (t, 2,

J = 6.6), 3.27 (m, 4), 3.52 (m, 8), 4.07 (broad d, 2, J = 13.0), 7.31 (d, 1, J) = 8.0), 7.37 (dd, 1, J = 1.5, 7.4), 7.48 (dt, 2, J = 1.2, 7.5), 7.60 (dt, 1, J = 0.8, 7.5), 7.88 (dd, 1,

J = 1.1, 7.5), 8.12 (t, 2, J = 7.9), 10.68 (broad S, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.46, 24.37, 27.36, 45.36, 45.69,

46.31, 50.44, 55.22, 121.14, 123.95, 124.56, 126.60, 126.91,

127.17, 127.26, 128.06, 129.15, 131.45, 138.60, 152.05, 162.17,

163.17.

100

Analysis for C ₂₄ H ₂₈ N ₄ OS. HC1:

H, 6.40; N, 12.26. Found: C, 63.04; H, 6.43; N, 12.23.

Example 35

a) Method for the preparation of methyl [2- (N, N-dimethyl-N'-formamidinyl) benzoate]

This compound was prepared according to the method of J. T. Gupton et al. (Tetrahedron 43, 1747 (1987)). Treatment of 0.6 g (43.8 mmol) of anthranilic acid (Aldrich Chemical Company) with 15.5 mL (13.9 g, 116.8 mmol, 2.67 equivalents)

N, N-dimethylformamide (Aldrich Chemical Company) methyl 2- (N, N-dimethyl-N ' -formamidinyl) benzoate] dimethyl acetal gave 6.2 g as a purple liquid. Yield: 69%.

b) Process for the preparation of 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4 [3H] quinazolinone hydrochloride

0.960 g (3.31 mmol, 1.1 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13 (b)), 0.1 g of p-toluenesulfonic acid, 45 ml of anhydrous 1,4-dioxane and 0.621 g (3.01 mmol, 1.0 equivalents) of methyl [2- (N, N-dimethyl-N ' -formamidinyl) benzoate] are placed in a round-bottomed flask of volume 250 ml, equipped with a magnetic stir bar, a condenser and a nitrogen inlet using a mined, flame-dried mine. The reaction mixture was refluxed for 1 hour, allowed to cool to room temperature and evaporated to give an orange oil. This oil was dissolved in a solution of ethyl acetate and dichloromethane, and the organic portion was washed with saturated potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 1.41 g of a brown solid are obtained. The crude material was purified by flash chromatography with dichloromethane / methanol (24: 1) as eluent. 1.02 g of a white solid is obtained. To a solution of the free base in ethyl acetate was added 2.43 mL of 1N (1.0 equivalent) of ethereal HCl. Salt, hydrochloride, sa

101 was recrystallized from aqueous ethanol to give 0.810 g of 3- [4- / 4- (1,2-benzothiazol-3-yl) -1-piperazinyl / butyl] -4 [3H] quinazolinone hydrochloride as a white solid having a melting point

238 DEG-240 DEG C. (decomposition).

^X H NMR _(DMSO-d6): δ (br t, 2, J = 12.6), with years, 3), 4.08 (m, 1) (qm, 2, J = 8.4), 8.12 1.6, 8.0), 8.46 (s, 1),

The yield corresponds to 5

1.80 (broad s, · 4)

3.58 (broad d, 2

7.47 (ddd, 1, J = t, 3, J = 8.0), .delta

0.86 (broad s, 1)% of theory.

3.28 (m, 4), 3.47

J = 12.0), 4.05 (š—

1.1, 6.9, 8.1), 7.58 18 (ddd, 3, J = 0.6, ppm).

¹³ C NMR (DMSO-d 6): δ 20.24, 25.78, 45.25, 43.31, 50.42, 54.89, 121.12, 121.48, 123.94, 124.56, 125.97, 126.90, 126.97,

127.11, 128.06, 134.22, 147.87, 147.96, 152.05, 160.17, 162.16.

Analysis for ^C 23 ^H 25 ^N 5 ^OS . HC1:

H, 5.75; N, 15.36. Found: C, 60.68; H, 5.75; N, 15.41.

Example 36

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

0.894 g (5.48 mmol) of isatinic anhydride (Aldrich Chemical Company), 15.0 mL of ethanol and 1.59 g (5.48 mmol, 1.0 equivalents) of 3- [4- (4-aminobutyl) -1] -piperazinyl / -1,2-benzisothiazole (Example 13b)) was introduced into a round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was allowed to stir at room temperature for 22 hours. The solvent was evaporated under reduced pressure to give 2.35 g of a brown oil. This crude material was purified by flash chromatography, eluting with dichloromethane: methanol (19: 1). 1.28 g of an orange oil is obtained, which is switched to a light yellow solid by standing. To a solution of 0.35 g (0.855 mmol) of the free base in a mixture of ethyl acetate and ethanol was added 0.855 mL of 1N (1.0 equivalent) of ethereal hydrogen chloride solution. Resulting salt,

102 hydrochloride is recrystallized from 95% ethanol to give 0.230 g of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride as a white solid. m.p. 227-228 ° C. Yield: 60%.

1 H NMR (DMSO-d 6): δ 1.58 (m, 4), 1.79 (m, 2), 3.27 (m, 6), 3.47 (broad t, 2, J = 12, 8), 3.59 (broad d, 2, J = 12.4), 4.09 (broad d, 2, J = 13.2), 6.41 (broad s, 2), 6.51 (ddd) J = 1.1, 7.0, 8.1), 6.69 (dd, 1, J = 1.1, 8.2), 7.13 (ddd, 1, J = 1.5, 7) 0, 8.4), 7.48 (m, 2), 7.60 (ddd, 1, J = 1.1, 7.0, 8.0), 8.13 (t, 2, J = 8.4), 8.29 (t, 1, J = 5.5), 10.68 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.64, 26.28, 37.98, 46.35, 50.42,

55.14, 114.49, 114.75, 116.26, 121.14, 123.95, 124.57, 126.10,

126.91, 128.01, 128.07, 131.51, 149.47, 152.06, 162.16, 168.85.

Analysis for ^C 22 ^H 27 ^N 5 ^OS · ^HCl: calculated: 59.25% C, 6.33% H, 15.70% N, found: 59.18% C, 6.35% H, 15.68% N.

Example 37

a) Process for the preparation of 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2,3-benzotriazin-4 [3H] one hydrochloride

0.960 g (2.34 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36 a)), 11.0 ml of distilled water and 1.06 ml of concentrated hydrochloric acid is introduced into a round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet and dropping funnel. The reaction mixture was cooled in an ice bath and a solution of 0.186 g (2.70 mmol, 1.15 equivalents) of sodium nitrite in 2.58 mL of distilled water was added dropwise. The reaction mixture is stirred for 2 hours and then treated with 1.2 ml of 10N sodium hydroxide solution. After 1 hour, the pH is adjusted to 6-7 by addition of acetic acid and then to pH 10 by addition of 10 N sodium hydroxide solution. The organic portion is extracted with ethyl acetate,

The residue was dried over magnesium sulfate, filtered and evaporated. 0.900 g of an orange oil is obtained. The crude material was purified by flash chromatography (2: 1 ethyl acetate: hexane). 0.630 g of a white solid is obtained. The obtained free base was dissolved in ethyl acetate and 1.5 ml of 1N ethereal HCl (1.0 equivalent) was added. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol to give 0.490 g of 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2,3-benzotriazine hydrochloride. 4- [3H] -one, as a white solid, mp 242-243.5 ° C. Yield: 46%.

¹ H NMR (DMSO-d 6): Δ 1.89 (m, 4), 3.24 (m, 4), 3.43 (wide,

2), J = 11.9), 3.59 (broad t, 2, J = 11.1), 4.07 (broad d, 2,

J = 11.4), 4.46 (t, 2,

1, J = 7.5), 7.96 (ddd, (dd, 1, J = 0.7, 8.1) (broad s, 1) ppm.

(R,

8.24

10.5

55.02.

128.08, ¹³ C NMR (DMSO-d6)

119.24, 121.15,

132.89, 135.35,

20.36.

123.96, 124.54

143.66, 152.06,

25.52, 46.33, 48.50, 50.49,, 124.57, 126.91, 127.94,

154.78, 162.16.

Analysis for ^C 22 ^H 24 ^N 6 ^OS · ^HCl: calculated: 57.82% C, 5.51% H, 18.39% N, found: 57.92% C, 5.53% H, 18.45% N.

Example 38

a) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2,6-dimethoxybenzamide hydrochloride

100.0 ml of anhydrous toluene and 4.32 g (0.0176 mol) of 3-chloro-5-ethyl-2,6-dimethoxybenzoic acid [obtained in a three-step process from 2,4-dimethylacetophenone (Aldrich Chemical Company) as described above de Paulis et al. in J. Med. Chem. 28 (9), 1263-1269 (1985) and in J. Med. Chem. 29 (1), 61-69 (1986)]

104 into a round-bottom flask in an oven. The solution was 4.13 ml (0.0476 mol, the yellow solution was heated to anhydrous dimethylformamide: 65-75 ° C during evaporation. The resulting orange chloroform was added under acid chloride and 3- / 4- (4-aminobutyl) was added. (1-piperazinyl) -1,2-benzisothiazole (Example 13 (b)) in 20 ml of chloroform, and then 2.94 equivalents) are added, and the mixture is allowed to stir at room temperature. overlay with nitrogen and add Light

2.7 equiv) 75 The reaction mixture was 75 minutes and thionyl chloride solvent.

The mixture was heated to 50 ° C and heated and evaporated to a rotary evaporator with 50 ml of anhydrous nitrogen atmosphere. To this crude, 5.63 g (0.0194 mol, 1.1 equivalents)

0.25 ml of the evaporator temperature was washed

The mixture was concentrated in vacuo to give the material (ml (0.021 mol, 1.2 clear orange mixture over 45 minutes), viscous orange magnesium sulfate solution, orange chromatography with ethyl acetate, eluting with a yellow solid.

The resulting temperature a

10.08 g of a viscous viscous product are dried over high speed as eluent, followed by 0.1% triethylamine, as an additional g of the free base, in the form of light ethanol and to the triethylamine obtained. of the laboratory on a rotary shaker with dichloromethane and potassium. The organic filtered and evaporated to an oil. This was crude with ethyl acetate containing the reagent. 4.78 oil are obtained. Dissolve the free base and add 9.24 mL of 1 N ethereal chlorine solution, heat and filter while hot. Ether was added to ethanol and the mixture was allowed to cool. The solids were filtered, washed with ether and dried to give 2.96 g of the title compound. The solution was added with ether and formed after cooling in a vacuum oven.

The title compound is a pale brown solid having a melting point of 198.5-200 ° C. The yield corresponds to 30% of theory.

¹ H NMR (DMSO-d ₆ ): δ 1.16 (3, J = 7.5), 1.60 years s, 2), 2.58 (q, 2, J = 7.5), 3, 20- 3.63 3), 3.78 (s, 3), 4.10 (broad d, 2, J = 12.1), (t, 1, J = 7.5), 7.62 (t 1, J = 7.5), 8.14 8.50 (t, 1, J = 5.3), 10.66 (broad s, 1) ppm.

(m, 2), 1.83 (w (m, 10), 3.74 (s, 7.38 (s, 1)), 7.49 (t, 2, J = 7.0),

105 ¹³ C NMR (DMSO-d ₆ ): δ 14.76, 20.73, 21.80, 26.46, 46.57,

50.67, 55.39, 61.89, 62.27, 121,49, 121.76. 124.30, 124.95 127.28, 128.45, 129.16, 130.17, 134,64, 150.88. 152.48. 153.96 162.56, 164.26. Analysis for C ₂₆ H ₃₃ N ₄ O ₃ SC1. HC1: calculated: C 56.41, H 6.19, 10,12% N, found: C 56.31, H 6.18, 10.08% N.

Example 39

a) Process for the preparation of ethyl (2,3-dihydro-3-oxo-1H-indazole-1-carboxylate)

Starting materials: 3-indazoline (Aldrich Chemical Company) and ethyl chloroformate (Aldrich Chemical Company). This compound is prepared according to the method of S. D. Wyrick et al. in J. Med. Chem. 27, 768 (1984). The title compound has a melting point of 193-195 ° C.

¹ H NMR (DMSO-d 6): δ 1.37 (t,

7.1), 7.34 (ddd, 1, J = 0.8, 7.1,

7.2, 8.4), 7.75 (dt, 1, J = 7.8, 12.13 (broad s, 1) ppm).

3, J = 7.1), 4.41 (q, 2, J =

8.0), 7.61 (ddd, 1, J = 1.2, 1.0), 8.04 (d, 1, J = 8.4), ¹³ C NMR (DMSO-d6): δ 14 , 14, 62.84,

114.09, 117.16, 120.43,

123.36, 130.00, 140.28, 150.04, 158.50.

Analysis for C _lo ^H IO 2 ^N ° ^3: Calculated: 58.25% C, 4.89% H, 13.59% N,

found: % C, 58.30;% H, 4.93;% N, 13.61.

b) A process for the preparation of ethyl [2- (4-chlorobutyl) -2,3-dihydro-3-oxo-1H-indazole-1-carboxylate] and ethyl [2- (4-bromobutyl) -2,3-dihydro] 3-oxo-lH-indazole-l-carboxylate /

1.51 g (50.3 mmol, 1.2 equivalents) of sodium hydride as an 80% oil dispersion was introduced into a three-necked round bottom flask.

106 with a volume of 250 ml, equipped with a magnetic stir bar, reflux condenser and nitrogen inlet, using a flask that was flame dried before use. The sodium hydride was washed three times with hexane. To the washed sodium hydride was added 50.0 mL of anhydrous Ν, Ν-dimethylformamide and the resulting gray suspension was cooled in an ice bath. To the cooled reaction mixture was slowly added with a spatula 8.65 g (41.9 mmol) of ethyl [2,3-dihydro-3-oxo-1H-indazole-1-carboxylate]. To the cooled reaction mixture was added 5.31 mL (7.91 g, 46.1 mmol, 1.1 equivalents) of 1-bromo-4-chlorobutane (Aldrich Chemical Company). The reaction mixture was allowed to warm to 65 ° C and stirred at this temperature overnight. The reaction mixture was allowed to cool and the excess sodium hydride was quenched with 2 mL of distilled water. The bulk of the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and distilled water. The organic portion was dried (MgSO 4), filtered and evaporated. 12.2 g of an orange oil are obtained.

NMR spectral analysis of this crude material indicated that both N-alkylated and O-alkylated products were formed. In addition, these alkylated products were obtained as a mixture of their corresponding chlorides and bromides. The crude oil was purified by flash chromatography (3: 1 hexanes / ethyl acetate). 2.00 g of ethyl [2- (4-chlorobutyl) -2,3-dihydro-3-oxo-1H-indazole-1-carboxylate] and ethyl [2- (4-bromobutyl) -2,3] are obtained. of dihydro-3-oxo-1H-indazole-1-carboxylate] as a 60:40 mixture of chloride and bromide. The ratio of chloride to bromide is determined by integrating their corresponding methylene triplets at 3.39 and 3.52 ppm. This material was used as a mixture without further isolation of each halide.

c) A process for the preparation of ethyl [2- (4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-3-oxo-1H-indazole-1 carboxylate]

A mixture of 3.13 g (9.68 mmol) of ethyl [2- (4-chlorobutyl) -2,3-dihydro-3-oxo-1H-indazole-1-carboxylate] and ethyl [2- (4-bromobutyl)]. -2,3-dihydro-3-oxo-1H-indazole-1-carboxylate / 60:40, 3.84 g (17.5 mmol, 1.8 equivalents of 3- (1-piperazinyl) -1), 2-benzisothiazole

107

2.44 ml (1.77 g, 17.5 mmol, 1.8 equivalents) of triethylamine and 30.0 ml of acetonitrile were introduced into a 50 ml round bottom flask equipped with a magnetic stir bar, condenser and nitrogen inlet. The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and partitioned between ethyl acetate and saturated potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 7.18 g of an oily brown colored solid are obtained. This crude material was purified by flash chromatography (ethyl acetate / hexanes 2: 1) then ethyl acetate as the next eluent. 2.97 g of the free base are obtained in the form of a yellow oil. To a solution of the free base in ethyl acetate was added 6.2 mL of 1N (1.0 equivalent) of ethereal HCl. The resulting salt, hydrochloride, is recrystallized from ethanol to give 0.52 g of ethyl [2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3 hydrochloride. dihydro-3-oxo-1H-indazole-1-carboxylate], in the form of a beige solid, m.p. 189-190 ° C. The yield corresponds to 8% of theory.

^X H NMR _(DMSO-d6): δ 1.41 (t, 2, J = 7.1), 1.66 (br s, 3), 3.23 (m, 6), 3.42 (br t, 2, J = 12.1), 3.53 (broad d,

2, J = 12.0), 4.05 (broad d, 2, J = 13.2), 4.15 (m, 2), 4.44 (q, 2, J = 7.1), 7.46 (m, 2), 7.60 (ddd 1, J = 0.9, 7.1, 8.0), 7.78 (ddd, 1 , J = 1.3, 7.2, 8.5), 7, 84 (ddd, 1, J = 0.8, 1.3, 7.7), 7.94 (d 1, J = 8.4), 8.12 (t, 2, J = 6.9), 10, 53 (wide, 1) ppm. 13 C NMR (DMSO-d _6): δ 14, 05. 20.36, 24.51 , 45.78, 46.27, 50.41. 54.90, 64.10, 115.39, 117 , 86, 121.14, 123.37, 123.95, 124.57. 124.90, 126.91, 128.07, 133 , 88, 142.68, 150.63, 152.05, 162.15. 163.75. analysis for C ₂ H ₂₉ N 4 O ₃ S * HCl: calc %: 58.19% C, 5.86% H, 13 57% N, found % H, 5.89;% C, 58.06; 13 51% N.

108

Example 40

a) Process for the preparation of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2-dihydro-3H-indazol-3-one hydrochloride hydrate

1.88 g (3.92 mmol) of ethyl [2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3-dihydro-3-oxo 1 H-indazole-1-carboxylate] (Example 39 (c)) and 23.7 ml of a 0.67 molar solution of potassium hydroxide in ethanol are introduced into a 300 ml round bottom flask equipped with a magnetic stir bar, nitrogen inlet and condenser. . The reaction mixture was refluxed for 2 hours under a nitrogen atmosphere. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 1.37 g of crude material are obtained in the form of an orange oil. The crude material was purified by flash chromatography with dichloromethane / methanol (92: 8) as eluent. 1.03 g of the free base is obtained in the form of a pale yellow solid. To a solution of the free base in a mixture of ethyl acetate and dichloromethane was added 2.53 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride solution. The resulting salt, hydrochloride, is recrystallized from ethanol / ether to give 0.36 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1 hydrochloride hydrate, 2-dihydro-3H-indazol-3-one, as a white solid having a melting point of 80-90 ° C (softening, shrinking) and 125-145 ° C (effervescence). Yield: 20%.

¹ H NMR (DMSO-d 6): δ 1.77 (m, 4), 3.25 (m, 4),

3.56 (broad d, 2, J = 11.4), 3.87 (t, 2, J = 6.0),

3.44 (m, 2),

4.06 (broad d, 2, J = 13.3), 7.11 (ddd, 1, J = 0.8,

J = 8.3, 0.8), 7.47 (ddd, 1, J = 1.1, 6.4, 8.2), 7.52 (ddd, 1,

J = 1.2, 6.5, 8.3), 7.60 (ddd, 1, J = 1.1, 7.0, 8.2), 7.65 (dt,

1, J = 7.9, 1.1), 8.12 (t, 2, J = 7.8), 10.4 (broad S, 1), 10.7 (broad s, 1) ppm.

109 ¹³ C NMR (DMSO-d 6): δ 20.31, 25.04, 42.41, 46.33, 50.49,

54.94, 112.12, 117.20, 120.80, 121.15, 122.87, 123.96, 124.58,

126.91, 128.08, 131.20, 145.91, 152.06, 160.58, 162.16.

Analysis for ^C 22 ^H 25 ^N 5 ^OS · ^HC ^ '°' ^{75 H2 0:} Calculated: 57.76% C, 6.06% H, 15.31% N, 2.95% _H2O Found: 57 , 71% C, 6.10% H, 15.20% N, 2.73% H ₂ O.

Example 41

a) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-chlorobenzamide hydrochloride

This compound was prepared as described in Example 36 using 1.02 g (5.17 mmol) of 5-chloroisatinic anhydride (Aldrich Chemical Company) and 1.5 g (5.17 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)). The free base was purified by flash chromatography with ethyl acetate / hexanes (1: 1) as eluent. The salt, hydrochloride, is recrystallized from aqueous ethanol. 1.61 g of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-chlorobenzamide hydrochloride are obtained in the form of a white solid which has: mp 173-176 ° C. Yield: 65%.

^X H NMR (DMSO-d₆): δ 1.57 (m, 2), 1.78 (m, 2), 3.10 to 3.68 (m, 12H), 4.08 (br d, 2, J = 13.1), 6.74 (d, 1, J = 8.9), 7.18 (dd, 1, J = 2.4, 8.8), 7.48 (tm, 1, J = 7.2), 7.57 (d, 1, J =

2.4), 7.60 (tm, 1, J = 7.2), 8.13 (t, 2, J = 8.6), 8.45 (t, 1,

J = 5.3), 10.70 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ, 20.64, 26.19, 38.20, 46.35, 50.44,

55.16, 116.75, 118.78, 119.04, 121.18, 124.00, 124.61, 126.95,

127.44, 128.12, 131.37, 146.88, 152.11, 162.21, 167.41.

110

Analysis for ^C 22 ^H 26 ^N 5 ^0SC · · * 1 * ^HC; H, 5.66; N, 14.58. Found: C, 54.91; H, 5.69; N, 14.51.

Example 42

a) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-nitrobenzamide hydrochloride

This compound was prepared according to the procedure in Example 36 using 1.08 g (5.17 mmol) of 5-nitroisatinic anhydride (Trans World Chemicals) and 1.5 g (5.17 mmol, 1 equivalent) of 3- / 4. - (4-aminobutyl) -1-piperazinyl / -1,2-benzisothiazole (Example

b)). The free base was purified by flash chromatography with ethyl acetate as eluent. The salt, hydrochloride, is recrystallized from aqueous ethanol and dried in a vacuum oven. 1.10 g of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-nitrobenzamide hydrochloride are obtained in the form of a yellow solid, which has: mp 224-230 ° C (dec.). Yield: 43%.

^X H NMR (DMSO-d₆): δ 1.61 (m, 2), 1.80 (m, 2), 3.28 (m, 4),

3.46 (broad t, 4, J = 12.1), 3.59 (broad d, 2, J = 10.2), 4.08 (broad d, 2, J = 12.8), 6, 82 (d, 1, J = 9.3), 7.48 (t, 1, J =

7.6), 7.60 (t, 1, J = 7.2), 7.80 (broad s, 2), 8.03 (dd, 1, J = 2.5, 9.1), 8 13 (t, 2, J = 8.3), 8.52 (d, 1, J = 2.5), 8.80 (t, 1, J = 5.3), 10.72 (broad s 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.72, 26.17, 38.34, 46.38, 50.48,

55.20, 112.87, 115.85, 121.18, 123.99, 124.61, 125.71, 126.95,

127.35, 128.11, 134.86, 152.11, 155.31, 162.21, 167.21.

Analysis for ^C 22 ^H 26 ^N 6 ° 3 ^S · ^HCl: calculated: 53.82% C, 5.54% H, 17.12% N, found: 53.95% C, 5.57% H, 17. 05% N.

111

Example 43

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

This compound was prepared according to the procedure in Example 36 using 0.92 g (5.17 mmol) of 5-methylisatinic anhydride (Aldrich Chemical Company) and 1.5 g (5.17 mmol, 1 equivalent) of 3- / 4. - (4-aminobutyl) -1-piperazinyl / -1,2-benzisothiazole (Example 13b)). The free base was purified by flash chromatography with ethyl acetate as eluent. The salt, hydrochloride, was recrystallized from ethanol / ether and dried in a vacuum oven. 1.22 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2- (methylamino) benzamide hydrochloride are obtained as a beige solid having a temperature of mp 169-173 ° C. Yield: 51%.

¹ H NMR (DMSO-d ₆ ): δ 1.58 (m, 2), 1.81 (m, 2), 2.77 (s, 3),

3.30 (m, 4), 3.48 (broad d, 3, J = 13.8), 3.58 (broad d, 3,

J = 12.9), 4.07 (Broad d, 2, J = 14.8), 6.56 (t, 1, J = 7.4),

6.63 (d, 1, J = 8.3), 7.29 (t, 1, J = 7.7), 7.48 (t, 1, J =

7.56), 7.5760 (dt, 1, J = 7.2), 7.61 (d, 1, J = 7.4), 7.64 (broad S, 1), 8.13 (t , 2, J = 8.3), 8.41 (Broad t, 1, J = 5.4),

11.00 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.66, 26.28, 29.33, 38.08, 46.36,

50.44, 55.18, 110.55, 114.03, 115.24, 121.17, 123.99, 124.61,

126.96, 128.11, 128.20, 132.26, 149.91, 152.12, 162.20, 169.12.

Analysis for ^C 23 ^H 29 ^N 5 ^OS · ^HCl: Calculated: 60.05% C, 6.57% H, 15.22% N Found: 60.09% C, 6.60% H, 15.13% N.

112

Example 44

(a) Method for producing (+/-) - cis-2- (methoxycarbonyl) -1-cyclohexanecarboxylic acid

10.0 g (64.9 mmol) of cis-1,2-cyclohexanedicarboxylic acid anhydride (Aldrich Chemical Company) and 2.76 ml (2.18 g, 68.1 mmol, 1.05 equivalents) of methanol are added to a flask with round bottom, equipped with a magnetic stirring bar and a reflux condenser. Heat the reaction mixture in an oil bath at 100 ° C for 1 hour. The reaction mixture was allowed to cool to 0 ° C

room temperature and excess methanol was evaporated under reduced pressure. 12.0 g of (+/-) - cis-2- (methoxycarbonyl) -1-cyclohexanecarboxylic acid are obtained in the form of an oil, which on standing is converted to a white solid, m.p. 63-66 ° C. Yield 100%. theory.

¹ H NMR (CDCl ₃ ): δ 1.35-1.65 (m, 4), 1.80 (m, 2), 2.03 (m,

2), 2.86 (m, 2), 3.68 (s, 3) ppm.

¹³ C NMR (CDCl ₃ ): δ 23.63, 23.75, 25.96, 26.26, 42.48,

51.71, 174.04, 179.71.

Analysis for C ₉ H ₁₄ O ₄ : calculated: 58.05% C, 7.58% H, found: 57.97% C, 7.61% H.

b) Method for producing (+/-) - cis-methyl- [2- (hydroxymethyl) -1-cyclohexanecarboxylate]

11.7 g (63.0 mmol) of (+/-) - cis-2- (methoxycarbonyl) -1-cyclohexanecarboxylic acid and 35.0 ml of anhydrous tetrahydrofuran are placed in a 250 ml three-necked round-bottomed flask equipped with a magnetic with a stir bar, baffle and reflux condenser, using a flask that has been dried over a flame. The reaction mixture was cooled in an ice bath containing sodium chloride. The cooled reaction mixture was injected

113 syringe slowly add 69.0 mL (69.0 mmol, 1 equivalent) of borane in tetrahydrofuran (Aldrich Chemical Company) over 25 minutes. The solution was allowed to warm to room temperature overnight with stirring. The reaction mixture is cooled in an ice bath and 55.0 ml of distilled water and 17.0 g of potassium carbonate are added. The aqueous and organic phases are separated. The aqueous phase is extracted with ethyl acetate and then with ether. The organics were combined and washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. 10.9 g of an oil are obtained. The crude material was purified by flash chromatography (2: 1 hexanes / ethyl acetate). 6.47 g of (+/-) - cis -methyl- (2- (hydroxymethyl) -1-cyclohexanecarboxylate) are obtained in the form of a colorless oil. Yield: 59%.

NMR (CDCl ₃ ): δ 1.30 - 1.75 (m, 7), 1.89 (m, 1), 1 .97 (t, 1, J = 6,0), 2.02 (m, D, 2.76 (m, 1), 3.63 (m, 2), 3.68 (S, 3) ppm. 13 C NMR (cdci ₃ ) : δ 23.55, 26.22, 26.34, 40.65, 42.32. 51.44. 64.27. 175.75.

Analysis of the CGH ₁₆ O _3: Calculated: 62.77% C, 9.36% H Found: 62.69% C, 9.35% H

c) A method for producing methyl 2-formylbenzoate

7.20 g (41.8 mmol) of (+/-) - cis -methyl- (2- (hydroxymethyl) -1-cyclohexanecarboxylate), 42.0 ml of anhydrous dimethylsulfoxide,

200.0 ml of anhydrous dichloromethane and 29.1 ml (21.2 g, 209 mmol, 5 equivalents) of triethylamine are introduced into a 1 liter three-necked round-bottomed flask equipped with a magnetic stir bar, thermometer and nitrogen inlet. a flask which has been dried over a flame. The reaction mixture was cooled in an ice bath and 26.6 g (167 mmol, 4.0 equivalents) of sulfur trioxide pyridine complex (Aldrich Chemical Company) were added in three portions over 5 min. re

The 114 action mixture was allowed to stir for 90 minutes. Then 200.0 ml of distilled water are added and the aqueous organic phase is separated. The aqueous phase was washed with dichloromethane, the organics were combined and evaporated to give a light orange liquid. The product was partitioned between distilled water and ether. The organic portion was dried (MgSO 4), filtered and evaporated. 7.45 g of a pale yellow oil is obtained. The crude product was purified by flash chromatography with hexanes / ethyl acetate (12: 1) as eluent. 4.98 g of methyl 2-formylbenzoate are obtained in the form of a colorless liquid. Yield: 70%.

d) Method for producing (+/-) - cis-4A, 5,6,7,8,8A-hexahydro-1 [2H] -phthalazinone and (+/-) - trans-4A, 5,6,7,8 8A-hexahydro-l [2H] -phthalazinone

11.9 g (69.8 mmol) of (+/-) - cis-methyl-2-formylbenzoate, 120 mL of 95% ethanol and 9.0 g (154 mmol, 2.2 equivalents) of hydrazine hydrate (Fisher Scientific) as 85 The aqueous solution was added to a round-bottom flask equipped with a magnetic stir bar, reflux condenser and nitrogen inlet. The reaction mixture was refluxed for 30 minutes, cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between 100.0 mL of distilled water and 300.0 mL of ethyl acetate. The organics were dried over magnesium sulfate, filtered and evaporated. 7.79 g of a pale yellow oil are obtained. Yield: 74%. The crude material was used without further purification.

e) Method for producing (+/-) - cis-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] -phthalazinone and (+/-) - trans-2 - (4-chlorobutyl) -4A, 5,6-7,8,8A-hexahydro-l [2H] -phthalazinone

3.07 g of an 80% oil dispersion (103 mmol, 2 equivalents) of sodium hydride (Aldrich Chemical Company) is placed in a 500 ml three-necked round bottom flask equipped with a magnetic stir bar, thermometer and septum and / or cap using flame-dried flask. The sodium hydride was washed three times with hexanes and 30.0 mL was added

115 of anhydrous Ν, Ν-dimethylformamide. The suspension was cooled in an ice bath and 7.79 g (51.2 mmol) of (+/-) - cis-4A, 5,6,7,8,8A-hexahydro-1 [2H] -phthalazinone was slowly added. and (+/-) - trans-4A, 5-6,7,8,8A-hexahydro-1 [2H] -phthalazinone in 40.0 ml of anhydrous N, N-dimethylformamide. After the addition of phthalazinone was complete, 6.47 mL (9.65 g, 56.3 mmol, 1.1 equivalents) of 1-bromo-4-chlorobutane was added dropwise. After 15 minutes, excess sodium hydride was removed by treatment with 30 mL of distilled water and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and the organics were washed with water. The organics were dried over magnesium sulfate, filtered and evaporated. 14.0 g of an orange oil are obtained. The crude material was purified by flash chromatography (hexanes / ethyl acetate 6: 1). 3.02 g of (+/-) - cis-2- (4-chlorobutyl) -4-A, 5,6,7,8,8A-hexahydro-1 [2H] -phthalazinone are obtained, (Rf = 0.13). ), in the form of a colorless oil and 3,78 g (+/-) - trans-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] -phthalazinone (Rf = 0.20), as a colorless oil.

cis-isomer:

¹ H NMR (CDCl ₃ ): δ 1.25-1.71 (m, 8), 1.77 (quintet, 4, J = 3.2), 2.48 (q, 1, J = 6.4) ), 2.67 (m, 1), 3.55 (m, 2), 3.78 (m, 2), 7.03 (dd, 1, J = 1.0, 2.6) ppm.

¹³ C NMR (CDCl ₃ ): δ 22.71, 23.25, 23.51, 24.29, 24.98,

29.15, 34.04, 37.06, 44.95, 46.10, 149.21, 167.53.

Analysis for ^C 19 ^H I 2 ^N 2 ^0C - ^{1 ·:} calculated: 59.38% C, 7.89% H, 11.54% N Found: 59.28% C, 7.91% H, 11.48 % N.

trans-isomer:

¹ H NMR (CDCl ₃ ): δ 1.28 (m, 4), 1.79 (m, 7), 2.10 (m, 2),

2.34 (m, 1), 3.56 (m, 2), 3.73 (m, 1), 3.84 (m, 1), 7.02 (s, 1) ppm.

116 ¹³ C NMR (CDCl ₃ ): δ 25.03, 25.21, 25.54, 25.66, 28.42,

29.67, 37.52, 39.92, 44.61, 47.14, 150.58, 168.66.

Analysis for ^C 12 ^H 19 ^N 2 ^0C1: Calculated: 59.38% C, 7.89% H, 11.54% N Found: 59.20% C, 7.85% H, 11.43% N.

f) Method for producing (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl) -4A, 5,6,7,8, 8A-hexahydro-l- [2H] phthalazinone

1.05 g (4.33 mmol) of (+/-) - cis-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, 1.04 g (4.76 mmol, 1.1 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole, 0.725 mL (0.526 g,

5.20 mmol (1.2 equivalents) of triethylamine and 10 ml of acetonitrile are introduced into a round bottom flask equipped with a magnetic stir bar, reflux condenser and nitrogen inlet. The reaction mixture was refluxed for 6 hours. Thin layer chromatography was not complete and therefore 0.19 g (0.2 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole and 0.12 mL (87 mg, 0.86) were added. mmol (0.2 equiv.) triethylamine and the resulting mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue is taken up in dichloromethane and washed with saturated potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 2.54 g of an orange oil are obtained. This crude material was purified by flash chromatography with ethyl acetate / hexanes (2: 1) and then with ethyl acetate as eluents. 1.05 g of the free base is obtained in the form of a yellow oil. To a solution of the free base in ethyl acetate was added 2.47 mL of a 1N (1.0 equivalent) ethereal hydrogen chloride solution. The salt, hydrochloride, was recrystallized from ethanol to give 0.58 g of the title compound as a white solid. Yield: 29%. The salt, hydrochloride, contains 10% of the isomer. The substance has a melting point of 191-193 ° C (decomposition).

117 ¹ H NMR (CDCl ₃ ): δ 1.32 (m, 1), 1.46 (m, 3), 1.58 (m, 5),

1.73 (M, 3), 2.73 (m, 1), 3.25 (m, 4), 3.46 (broad d, 2, J = 12.4) , 3 , 55 (wide, 3, J = 14.7), 3.70 (m, 2), 4.06 (wide d, 2, J = 14.2), 7.16 (d 1, J = 1.1), 7.20 (d, 1, J = 2.6), 7.48 (Ddd, 1 J = 1.1, 7.0 , 8.1), 7.60 (ddd, 1, J = 1.1, 7.0, 8.1), 8.12 (T, 2, J = 8.1), 10.83 (br s, 1) ppm. 13 _c NMR (CDC1 ₃₎ : δ 20.18, 22.76, 23.22, 23 , 54, 24.34, 24.87 9 34.03, 37.13, 46.28 (2 carbons), 50.41, 55, 12, 121.14,

123.95, 124.56, 126.91, 128.07, 149.42, 152.06, 162.16, 167.65.

Analysis for ^C 23 ^H 31 ^N 5 ^OS · ^HCl: calculated: 59.79% C, 6.98% H, 15.16% N, found: 59.82% C, 7.02% H, 15.08% N.

Example 45

f) Method for producing (+/-) - trans-2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8, 8A-hexahydro-l- [2H] phthalazinone

2.92 g (13.3 mmol, 1.3 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole, 2.16 mL (1.57 g, 15.5 mmol, 1.5 equivalents) of triethylamine , 20.0 mL of acetonitrile and 2.49 g (10.3 mmol) of (+/-) - trans-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] of phthalazinone, (Example 44 e)) is introduced into a round bottom flask equipped with a magnetic stir bar, a reflux condenser and a nitrogen inlet. The reaction mixture was refluxed for 24 hours. Thin layer chromatography was not complete and therefore additional portions of reagents, 0.450 g (2.05 mmol, 0.2 equivalents) of 3- (1-piprazinyl) -1,2-benzisothiazole and 0.72 ml were added. (0.52 g, 5.14 mmol, 0.5 equivalent) of triethylamine and the reaction mixture was refluxed for an additional 25 hours. The reaction mixture was allowed to cool to room temperature and ethyl acetate was added. The organic portion was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered ‘and evaporated. 6.2 g of an orange oil are obtained. This su

The 118 was purified by flash chromatography with ethyl acetate as eluent. 2.72 g of the free base are obtained in the form of a pale yellow solid. To a solution of the free base in ethyl acetate was added 6.41 mL of 1N (1.0 equivalent) of ethereal HCl. The resulting salt, hydrochloride, is recrystallized from ethanol. 2.25 g of (+/-) - trans-2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl) -4A, 5,6,7, 8,8A-hexahydro-1 [2H] phthalazinone, as an off-white solid, m.p. 186-188 ° C. Yield: 47%.

^{Τ Η} NMR _(DMSO-d6): 8 1.21 (m, 4), 1.61 (br q, 2, J

6.6), 1.71 (m, 4), 1.97 (m, 2), 2.19 (m, 2), 3.24 (m, 4), 3.47 (broad t, 2, J = 13.0), 3.54 (broad d, 2, J = 11.1), 3.69 (td,

2, J = 2.5, 6.5), 4.06 (W, d, 2, J = 13.7), 7.16 (d, 1, J =

1.1), 7.48 (ddd, 1, J = 1.1, 7.0, 8.1), 7.60 (ddd, 1, J = 1.1,

7.0, 8.0), 8.12 (t, 2, J = 7.9), 10.8 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.14, 24.45, 24.65, 24.87, 25.35,

27.59, 36.68, 38.82, 46.25, 46.30, 50.41, 55.15, 121.13, 123.95,

124.56, 126.91, 128.06, 151.05, 152.06, 162.15, 168.07.

Analysis for ^C 23 ^H 31 ^N 5 ^OS . H, 6.98; N, 15.16. Found: C, 59.85; H, 6.97; N, 15.12.

Example 46

a) Production method of 2- (4-bromobutyl) -1,3- [2H, 4H] isoquinolinedione g (92.5 mmol) homophthalic anhydride (Aldrich. Chemical Company) and 8.54 ml (8.26 g, 92 (5 mmol, 1 equivalent) of 4-amino-1-butanol (Aldrich Chemical Company) was introduced into a 3-neck round bottom flask equipped with a reflux condenser and an addition funnel. Heat the reaction mixture in an oil bath at 150 ° C for 2 hours. The green solution was cooled to room temperature and 6.0 mL (17.1 g, 63 mmol) of phosphorus tribromide was added dropwise. The reaction mixture is slowly warmed to

119 ° C and poured into 150 g of crushed ice at this temperature. The viscous organic material was separated from ice and ethanol was added. Upon addition of ethanol, the material turned to a white solid. The solvent was evaporated under reduced pressure to give a yellow solid. This solid was recrystallized from ethanol to give 17.1 g of 2- (4-bromobutyl) -1,3- [2H, 4H] isoquinolinedione, as a light yellow solid, mp 87-89 ° C. Yield: 62%.

¹ H NMR (CDCl ₃ ): δ 1.88 (m, 4), 3.43 (t, 2, J = 6.5), 4.02 (t, 4, J = 7.0), 4, Δ (s, 2), 7.26 (d, 1, J = 7.2), 7.43 (t, 1, J = 7.5), 7.58 (td, 1, J = 7.4) 1.4, 8.20 (d, J, 7.8) ppm.

¹³ C NMR (CDCl ₃ ): δ 26.26, 29.64, 32.55, 35.88, 38.66,

124.77, 126.63, 127.26, 128.66, 133.17, 133.54, 164.32, 169.44.

Analysis for C ₁₃ H ₁₄ NO ₂ Br: Calculated: 52.72% C, 4.76% H 4.73% N Found: 52.79% C, 4.80% H, 4.74% N.

b) A method for producing 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,3 [2H, 4H] -isoquinolinedione hydrochloride hydrate

9.74 g (33 mmol) of 2- (4-bromobutyl) -1,3- [2H, 4H] isoquinoline-dione, 7.96 g (36.3 mmol, 1.1 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole, 5.52 ml (4.0 g, 39.6 mmol, 1.2 equivalents) of triethylamine and 50.0 ml of acetonitrile are placed in a round-bottom flask equipped with a magnetic stir bar, condenser and supply of nitrogen. The reaction mixture was refluxed for 3.5 hours. The crude mixture was absorbed on silica gel and purified by flash chromatography with 2: 1 ethyl acetate: hexanes then ethyl acetate as eluents. 11.9% of the free base is obtained in the form of an orange oil. To a solution of the free base in ethyl acetate was added 27.4 mL of 1N (1.0 equivalent) of ethereal hydrogen chloride. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol. 6.57 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-hydrochloride hydrate are obtained.

120

-piperazinyl / butyl] -1,3 [2H, 4H] -isoquinolinedione, as an orange solid, mp 190-195 ° C. Yield: 40%.

^{Χ Η} NMR (DMSO-d₆): δ 1.64 (m, 2), 1.75 (m, 2), 3.10 to 3.60 (m, 4), 3.91 (q, 2, J = 6.8), 4.05 (broad d, 2, J = 13.0), 7.55 (m, 4), 10.60 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.57, 24.66, 36.02, 38.53, 46.32,

50.44, 55.12, 121.13, 123.94, 124.57, 124.84, 126.90, 127.20,

127.48, 127.93, 128.06, 133.46, 135.41, 152.06, 162.15, 164.53,

170.08.

Analysis for ^C 24 ^H 26 ^N 4 ° 2 ^S. HCl. 0.5 _H2 0: Calculated: 60.05% C, 5.88% H, 11.67% N, 1.87% H ₂ 0, Found: 60.30% C, 5.85% H, 11 , 74% N, 1.79% H ₂ O.

Example 47

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

0.102 g of an 80% oil dispersion (3.39 mmol, 1 equivalent) of sodium hydride (Aldrich Chemical Company) is introduced into a three-necked round reflux condenser, which is prewashed with hexanes, a bottom equipped with a magnetic stir bar, and nitrogen inlet. use a flask, dried by flame. Sodium hydride was added three times and then 10.0 ml of anhydrous was added

Ν, Ν-dimethylformamide. Cool the suspension in an ice bath, add 0.549 g (3.39 mmol) of phthalhydrazide and 1.2 g (3.39 mmol, 1.0 equivalent) of 8- (1,2-benzisothiazol-3-yl) - The 5,8-diaza spiro [4.5] decane-5-onium bromide was added and the reaction mixture was refluxed overnight. The reaction mixture was then cooled in an ice bath and the excess sodium hydride was removed by treatment with 5.0 ml of distilled water. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate, filtered and evaporated. It will be obtained

121

0.63 g of crude material which was combined with another 1.3 g of crude material obtained in the previous experiment. The aqueous phases from both experiments were also combined and washed with dichloromethane. The dichloromethane phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. An additional 0.34 g of crude material is obtained. The crude material (total weight 1.70 g) was purified by flash chromatography with dichloromethane / methanol (94: 6) as eluent. 0.64 g of white base is obtained. To a solution of the free base in chloroform was added 1.47 mL of 1N (1.0 equivalent) of ethereal HCl. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol. 0.429 g of 2- [4- / 4- (1,3-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,4 [2H, 3H] phthalazinedione hydrochloride is obtained as a white solid, m.p. Mp 242-245 ° C (dec.). Yield: 13%.

^X H NMR (DMSO-d): 8 1.81 (br s, 4), 3.26 (m, 4), 3.45 (br t, 2, J = 12.0), 3.57 (br d, 2, J = 11.5), 4.06 (m, 4), 7.47 (ddd, 1, J = 0.8, 7.2, 8.1), 7.60 (ddd, 1) , J = 1.0,

7.1, 8.1), 7.90 (m, 2), 7.98 (m, 1), 8.12 (t, 2, J = 7.2), 8.25 (m, 1) , 10.69 (broad s, 1), 11.70 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 20.37, 25.14, 46.33, 48.32, 50.45,

55.12, 121.13, 123.93, 124.07, 124.55, 126.41, 126.90, 128.06,

128.71, 132.22, 133.03, 150.23, 152.05, 157.15, 162.15.

Analysis for ^C 23 ^H 25 ^N 5 ° 2 ^S · ^HCl: calculated: 58.53% C, 5.55% H, 14.84% N, found: 58.38% C, 5.60% H, 14. 76% N.

Example 48

a) A process for the preparation of 3,4-dihydro-1H-2-benzopyran-1-one

This compound was prepared according to a modified method described by F. Bonadies and R. Di Fabio (J. Org. Chem. 49, 1647 (1984)). 32.8 mL (35.0 g, 0.261 mol) of 3,4-dihydro-1H-2-benzopyran

122 (Aldrich Chemical Company), 56.3 g (0.261 mol, 1 equivalent) of pyridinium chlorochromate (Aldrich Chemical Company) and 100.0 ml of anhydrous dichloromethane are charged into a 1 liter three-necked round bottom flask equipped with a condenser, magnetic stir bar and a nitrogen inlet using a flame-dried flask. Heat the reaction mixture in an oil bath at 60-70 ° C. After 2 and 4 hours, additional equivalents of pyridinium chlorochromate are added in each case and the reaction mixture is refluxed overnight. The reaction mixture was allowed to cool to room temperature, the solvent was decanted from a dark orange-brown residue, and the residue was washed with dichloromethane. The organics were combined and evaporated. 37 g of an orange oil are obtained. The crude material was purified by flash chromatography with 3: 1 hexanes / ethyl acetate. 20.2 g of 3,4-dihydro-ΙΗ-2-benzopyran-1-one are obtained in the form of a colorless oil. Yield: 52%.

¹ H NMR (CDCl ₃ ): δ 3.07 (t, 2, J = 6.0), 4.54 (t, 2, J = 6.0), 7.27 (d, 1, J = 7) 5), 7.40 (tm, 1, J = 7.6), 7.54 (td, 1, J = 7.5, 1.3), 8.10 (dd, 1, J = 1, (7.8) ppm.

¹³ C NMR (CDCl ₃ ): δ 27.82, 67.31 125.30, 127.24, 127.68,

130.38, 133.67, 139.55, 165.13.

Analysis for C ₉ HqO _2: calculated: 72.96% C, 5.44% H Found: 72.88% C, 5.42% H

a) Method for producing 2- (4-chlorobutyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-1-one

This compound was prepared as described in Example 34

c). Alkylation of 0.46 g (2.85 mmol) of 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (made from 3,4-dihydro-1H-2-benzopyran-1-one by method, which was described by NW Gilman in Synthetic Commun. 12, 373 (1982)), 0.393 ml (0.586 g, 3.42 mmol, 1.2 equivalents) of 1-bromo-4-chlorobutane (Aldrich Chemical Company) yields 0.40 g. 2- (4

123

(chlorobutyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as an orange oil. Yield: 56%.

c) 2- [4- / 4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-1- one

This compound was prepared as described in Example 34d). Alkylation of 0.40 g (1.59 mmol) of 2- (4-chlorobutyl) -2,3,4,5-tetrahydro-ΙΗ-2-benzazepin-1-one with 0.52 g (2.39 mmol, 1 (5 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole gave 0.45 g of the free base which was purified by flash chromatography (ethyl acetate / hexanes 2: 1, 0.1%). triethylamine as eluent. The salt, hydrochloride, is recrystallized from ethanol and dried in a vacuum oven. 227 mg of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-1 hydrochloride is obtained. -one, in the form of a beige solid having a melting point of 215-217 ° C (decomposition). The yield corresponds to 30% of theory.

^{Χ Η} NMR (DMSO-d?) 2, J = 6.7), 2.73 (t 4), 3.53 (m, 6),

1.2, 7.5), 7.33

1.6), 7.48 (ddd, 7.4), 7.60 (ddd,

10.92 (broad s,: δ 1.61 (m, 2, 2, J = 7.0), 4.08 (broad d, 2 (td, 1, J = 7.5,

1, J = 1.1, 7.0, 1, J = 1.1, 7.0,

1) ppm.

2), 1.99 (quintet, J = 6.4), 3.27 (m,

7.25 (dd, 1, J = (td, 1, J = 7.4, (dd, 1, J = 1.6, (t, 2, J = 9.1)),

45.69.

126.91.

162.16, ¹³ C NMR (DMSO-d ₆ ): δ 20.61, 46.35, 50.46, 55.23,

127.94, 128.07, 128.24,

169.78.

25.55

121,15,

130.51, 29.30, 29.58, 45.59,

123.95, 124.57, 126.59,

136.25, 137.09, 152.06, for C ₂₅ H ₃₀ N ₄ OS% C

Analysis: Calculated: C, 63.76; HC1:

6.63% H,

6.67% H,

11,89%

11,87%

N,

N.

124

Example 49

a) Method for the preparation of 3- [1- (4-aminobutyl) -4-piperidinyl] -1,2-benzisothiazole

40.0 ml of methanol and 6.77 g (16.1 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] phthalimide (Example 33) are introduced into a three-necked flask with 250 ml round bottom equipped with magnetic stir bar, dropping funnel, nitrogen inlet and reflux condenser. The reaction mixture was refluxed and then 1.41 g of a 55% aqueous solution (24.2 mmol, 1.5 equivalents) of hydrazine hydrate (Aldrich Chemical Company) was added dropwise. The solution was refluxed for 3 hours after the addition of hydrazine hydrate was complete. The reaction mixture was allowed to cool to room temperature and then acidified to pH 2 with 1N hydrochloric acid. The suspension was filtered and the filtrate was cooled in an ice bath. The cooled filtrate is adjusted to pH 10 by addition of 50% sodium hydroxide solution. The organic portion was extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated. 4.22 g of 3- [1- (4-aminobutyl) -4-piperidinyl] -1,2-benzisothiazole are obtained,

in the form of an orange oil. Yield: 91%. ^X H NMR (CDC1 _3): δ 1.57 (.7), 2.10 (m, 6), 2.42 (t, 2, J = 7.4), 2.74 (t, 2, J = 6.6), 3.10 (dd, 2, J = 2.0. 7.0), 7.41 (ddd, 1, J = 7.0, 8 , 1), 7.50 (ddd, 1, J = 1.1, 7.0. 8,0), 7.92

(dt, 1, J = 8.1, 1.0), 8.00 (dt, 1, J = 8.1, 1.0) ppm.

b) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] benzamide hydrochloride

This compound was prepared as described in Example 36. Alkylation of 0.68 g (4.15 mmol) isatinic anhydride (Aldrich Chemical Company), 1.2 g (4.15 mmol, 1.0 equivalent) 3- / 1- (4-aminobutyl) -4-piperidinyl] -1,2-benzisothiazole gives 1.38 g of the free base which is purified by flash chromatography with ethyl acetate / hexanes (2: 1) containing 0.1%

125 triethylamine as eluent. The salt, the hydrochloride is formed and recrystallized from aqueous ethanol. 1.09 g of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] benzamide is obtained as a beige solid, m.p. 239-240 ° C. . Yield: 59%.

¹ H NMR (DMSO-d 6): δ 1.58 (m, 2), 1.78 (m, 2), 2.33 (m, 4),

3.14 (m, 4), 3.27 (q, 2, J = 6.3), 3.65 (m, 3), 6.40 (broad s, 2), 6.51 (ddd, 1) J = 1.3, 7.0, 8.4), 6.69 (dd, 1, J = 0.9, 8.2), 7.13 (ddd, 1, J = 1.6, 7) 1, 8.7), 7.52 (m, 2), 7.63 (ddd,

1, J = 1.0, 7.0, 8.0), 8.22 (d, 1, J = 8.1), 8.27 (d, 1, J =

8.1), 8.29 (m, 1), 10.0 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.73, 26.37, 27.71, 35.57, 37.98,

51.45, 55.67, 113.33, 114.51, 114.79, 116.28, 120.72, 123.53,

124.92, 128.06, 131.55, 133.32, 149.56, 151.95, 167.52, 168.91.

Analysis for ^C 23 ^H 2S ^N 4 ^OS · ^HC1: Calculated: 62.08% C, 6.57% H, 12.59% N Found: 62.11% C, 6.61% H

Example 50

a) Method for producing [[4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] phenylacetate

3.0 g (10.4 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 1.74 mL (1.26 g, 12.5 mmol (1.2 equivalents) of triethylamine and 50.0 ml of dichloromethane are introduced into a 200 ml three-necked round-bottomed flask equipped with a magnetic stir bar, dropping funnel and nitrogen inlet using a flask that has been flame-dried beforehand. The reaction mixture was cooled in an ice bath and a solution of 2.06 g (10.4 mmol, 1.0 equivalent) of acetylsalicyloyl chloride (Aldrich Chemical Company) in 200 mL of dichloromethane was added dropwise. The reaction mixture was allowed to cool to room temperature and stirred for 15 minutes. The reaction mixture is then washed with cold saturated

126 with potassium carbonate solution. The organic portion was dried (MgSO 4), filtered and evaporated. 5.8 g of crude material are obtained in the form of an orange oil. The crude reaction mixture was purified by flash chromatography using a 95: 5 mixture of dichloromethane and methanol as eluent. 2.93 g of product are obtained in the form of a mixture of [[4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] phenylacetate and N- [4 - / (1,2) benzisothiazole-3-yl) -1-piperazinyl / butyl] -2-hydroxybenzamide.

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

30.0 ml of methanol and 2.93 g of a mixture of N- [4 - [(1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] phenylacetate and N- [4 - / (1,2-benzisothiazole- 3-yl) -1-piperazinyl / butyl] -2-hydroxybenzamide was added to a 300 mL round bottom flask equipped with a magnetic stir bar, dropping funnel and nitrogen inlet. A solution of 38.5 mg (7.12 mmol, 1.1 equivalents) of sodium methoxide (Aldrich Chemical Company) in 60 mL of methanol was added dropwise to the reaction mixture. The reaction mixture was allowed to stir for 90 minutes, neutralized with Dowex resin, filtered and evaporated. 2.68 g of free base are obtained in the form of a viscous pale orange oil. To a solution of the free base in ethyl acetate was added 6.53 mL of 1N (1.0 equiv.) Ethereal HCl. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol. 2.32 g of N- [4 - [(1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-hydroxybenzamide hydrochloride are obtained as an off-white solid. The yield corresponds to 50% of theory based on acetylsalicyloyl chloride.

¹ H NMR (DMSO-d 6): δ 1.63 (m, 2), 1.80 (m, 2), 3.27 (m, 6),

3.47 (broad t, 2, J = 12.7), 3.59 (broad d, 2, J = 11.3), 4.07 (broad d, 2, J = 13.5), 6, 89 (m, 2), 7.40 (ddd, 1, J = 1.7, 7.0, 8.8), 7.47 (ddd, 1, J = 1.1, 6.9, 8, 1), 7.60 (ddd, J, J =

1.1, 7.0, 8.1), 7.90 (dd, 1, J = 1.4, 7.9), 8.12 (t, 2, J = 8.4), 8.98 (broad t, 1, J = 5.5), 10.80 (broad s, 1), 12.68 (s, 1) ppm.

127 ¹³ C NMR (DMSO-d 6): δ 20.60, 25.99, 38.38, 46.35, 50.44,

55.06, 115.07, 117.31, 118.43, 121.14, 123.95, 124.57, 126.90,

127.69, 128.07, 133.59, 152.05, 160.09, 162.16, 169.03.

Analysis for ^C 22 ^H 26 ^N 4 ^S ° 2 ^'HC1: Calculated: 59.11% C, 6.09% H, 12.53% N Found: 59.00% C, 6.10% H, 12, 47% N.

Example 51

a) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride

The free base of this compound was prepared as described in Example 50 a). Acylation 1.5 g (5.17 mmol, 1.0 equivalent)

3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.6 ml (0.727 g, 5.17 mmol) benzoyl chloride over 1 hour gave 1.49 g The free base was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. To a solution of the free base in ethyl acetate was added 3.8 mL of 1N (1 equivalent) ethereal hydrogen chloride. The salt, the hydrochloride, is recrystallized from ethanol. 1.04 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride is obtained as a pale beige solid having a melting point of 200 to 201.5. C. Yield: 47%.

¹ H NMR (DMSO-d 6): δ 1.61

3.47 (broad t, 2, J = 12.6), (broad d, 2, J = 13.4), 7.60 (m, 2), 8.13 (t, 2, J = 8, 4), (broad s, 1).

(m, 2), 1.80 (m, 2), 3.27 (m, 6),

3.59 (broad d, 2, J = 11.7), 4.08 (m, 4), 7.60 (t, 1, J = 7.6), 7.87

8.58 (broad t, 1, J = 5.5), 10.72 ¹³ C NMR (DMSO-d 6): δ 20.59, 26.25, 38.36,

46.32, 50.41,

55.09.

121.14, 123.95,

124.56, 126.90,

127.12, 128.07, 128.16,

131.01,

134.47.

152.05.

162.16.

166.15.

128

Analysis for ^C 22 ^H 26 ^N 4 ^{0S 'HC1:} Calculated: 61.31% C, 6.31% H, 13.00% N Found: 61.27% C, 6.34% H, 12.98% N.

Example 52

a) A method for producing N- (4-chlorobutyl) -N-methylbenzamide

This compound was prepared as described in Example 34c). 3 g (22.2 mmol) of N-methylbenzamide (Aldrich Chemical Company) is alkylated with 2.81 mL (4.19 g, 24.4 mmol, 1> 1 equivalent) of 1-bromo-4-chlorobutane (Aldrich Chemical Company) ). The crude reaction mixture was extracted with dichloromethane and purified by flash chromatography with 2: 1 ethyl acetate: hexanes. 3.02 g of N- (4-chlorobutyl) -N-methylbenzamide are obtained in the form of a pale yellow oil. Yield: 60%.

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

This compound was prepared as described in Example 34 d). 1.50 g (6.65 mmol) of N-methyl-N- (4-chlorobutyl) benzamide and 1.60 g (7.3 mmol, 1.1 equivalents) of 3- (1-piperazinyl) -1,2- of benzisothiazole, was refluxed overnight to give 3.64 g of crude free base. The crude material was purified by flash chromatography (2: 1 ethyl acetate / hexanes) containing 0.1% triethylamine as the eluent. 1.40 g of the free base is obtained in the form of a yellow oil. The salt, the hydrochloride, is formed and recrystallized from a mixture of ethanol and ether. 0.76 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl-N-methyl] benzamide hydrochloride is obtained as a white solid, m.p. to 154 ° C. Yield: 26%.

¹ H NMR (DMSO-d ₆ ): δ 1.57-1.83 (m, 4), 2.98 (m, 4), 3.26 (m, 4), 3.55 (m, 5) 4.07 (broad d, 2, J = 12.6), 7.44 (m, 6), 7.60 (t, 1, J = 7.3), 8.13 (t, 2, J = 8.1), 11.07 (broad S, 1).

129 ¹³ C NMR (DMSO-d ₆ ): δ 20.29, 23.68, 36.91, 45.74, 46.27,

50.40, 55.22, 121.14, 123.95, 124.56, 129.15, 136.70, 152.06,

162.17, 170.15.

Analysis for ^C 23 ^H 28 ^N 4 ^OS . H, 6.57; N, 12.59. Found: C, 62.01; H, 6.56; N, 12.53.

Example 53

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

1.0 g (3.45 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.721 mL (0.524 g, 5.18 mmol,

1.5 eq) and 10.0 ml of dichloromethane is introduced into a three-necked round-bottomed flask of 100 ml objmeme, magnetic stir bar, nitrogen inlet and addition funnel using a parison, which was dried ⁰ flame. The reaction mixture was cooled in an ice bath and a solution of 0.61 g (3.45 mmol, 1.0 equivalent) of 4-chlorobenzoyl chloride (Aldrich Chemical Company) in 10.0 mL of dichloromethane was added dropwise. The reaction mixture was allowed to stir for 30 minutes and then transferred with ethyl acetate to a separatory funnel. The organic portion was washed with saturated potassium carbonate solution, dried (MgSO 4), filtered and evaporated. 1.4 g of a pale yellow oil are obtained. The crude reaction mixture was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 0.99 g of the free base is obtained in the form of a white solid. The free base was dissolved in a mixture of ethyl acetate and dichloromethane and 2.31 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The solvent was evaporated under reduced pressure and the salt, hydrochloride, was recrystallized from aqueous ethanol. 0.915 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-chlorobenzamide hydrochloride hydrate is obtained in the form of a white solid, m.p. 209-210. ° C (dec.). Yield: 56%.

130

NMR (DMSO-d ₆ ): δ 1.60 (m, 2), 1.79 (m, 2), 3.15-3.3? (m, 5), 3.45 (broad t, 3, J = 12.7), 3.59 (broad d, 2, J = 12.0), 4.08 (broad d, 2, J = 12) 9), 7.48 (ddd, 1, J = 1.0, 7.1,

8.1), 7.55 (dm, 2, J = 8.6), 7.60 (ddd, 1, J = 1.2, 7.0, 8.2), 7.90 (dm, 2 J = 8.7), 8.13 (t, 2, J = 8.2), 8.68 (broad t, 1, J = 5.5), 10.59 (broad s, 1).

¹³ C NMR (DMSO-d 6): δ 20.58, 26.17, 38.44, 46.32, 50.41,

55.08, 121.13, 123.95, 124.56, 126.91, 128.07, 128.25, 129.10,

133.18, 135.84, 152.05, 162.16, 165.09.

Analysis for ^C 22 ^H 25 ^N 4 ^OSC 1 ^'HC ^ -' ^{0.5 H2 0:} Calculated: 55.69% C, 5.74% H, 11.81% N, 1.90% H ₂ O, Found: C 55.58, H 5.69, N 11.71, H ₂ O 2.02.

Example 54

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

This compound was prepared as described in Example 53 using 1.0 g (3.45 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.721 ml (0.524 g,

5.18 mmol, 1.5 equiv) triethylamine and 0.723 g (3.45 mmol, 1.0 equiv) 3,4-dichlorobenzoyl chloride (Aldrich Chemical Company). The crude reaction mixture was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 1.52 g of the free base is obtained in the form of a white solid. The salt, the hydrochloride, is recrystallized from aqueous ethanol and dried in a vacuum oven. 0.88 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3,4-dichlorobenzamide hydrochloride is obtained in the form of a beige solid, m.p. Mp 208-210 ° C (dec.). Yield: 51%.

¹ H NMR (DMSO-d 6): δ 1.61 (m, 2), 1.82 (m, 2), 3.27 (m, 6),

3.52 (m, 4), 4.07 (broad d, 2, J = 13.4), 7.47 (t, 1, J = 7.6), 7.60 (t, 1, J = 7.5), 7.76 (d, 1, J = 8.5), 7.88 (dd, 1, J =

131

2.0, 8.4), 8.12 (t, 2, J = 8.2), 8.14 (d, 1, J = 2.0), 8.86 (t,

1, J = 5.5), 11.10 (broad s, 1).

¹³ C NMR (DMSO-d 6): δ 20.58, 26.07, 38.62, 46.33, 50.44,

55.08, 121.14, 123.95, 124.57, 126.91, 127.52, 128.07, 129.13,

130.59, 131.16, 133.85, 134.75, 152.07, 162.17, 163.88.

Analysis for ^C 22 ^H 24 ^N 4 ^0SC1 2 · ^HC1: Calculated: 52.86% C, 5.04% H, 11.21% N Found: 52.94% C, 5.09% H, 11.16 % N.

Example 55

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

This compound was prepared as described in Example 53 using 1.0 g (3.45 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.721 ml (0.524 g,

5.18 mmol (1.5 equiv) triethylamine and 0.589 g (3.45 mmol, 1.0 equiv) p-anisolyl chloride (Aldrich Chemical Company). The crude reaction mixture was purified by flash chromatography using a 93: 7 mixture of dichloromethane and methanol as eluent. 0.73 g of the free base is obtained in the form of a light beige solid. The salt, hydrochloride, is recrystallized from ethanol and dried in a vacuum oven. 0.287 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] 4-methoxybenzamide hydrochloride is obtained as a brown solid, m.p. 171-173 ° C. (decomposition). Yield: 18%.

¹ H NMR (DMSO-d 6): δ 1.59 (m, 2), 1.78 (m, 2), 3.26 (m, 6),

3.49 (broad d, 2, J = 12.1), 3.58 (broad d, 2, J = 13.8), 3.81 (m, 3), 4.07 (broad d, 2, J = 13.4), 7.00 (dm, 2, J = 8.9),

7.48 (ddd, 1, J = 1.2, 7.0, 8.1), 7.60 (ddd, 1, J = 1.1, 7.0,

8.1), 7.86 (dm, 2, J = 8.9), 8.13 (t, 2, J = 8.3), 8.45 (t, 1, J = 5.6), 10.81 (broad s, 1).

132 ¹³ C NMR (DMSO-d ₆ ): δ 20.63, 26.35, 38.29, 46.35, 50.43,

55.13, 55.27, 113.35, 121.15, 123.96, 124.58, 126.69, 126.92,

128.08, 128.94, 152.07, 161.39, 162.17, 165.64.

Analysis for ^C 23 ^H 28 ^N 4 ^OS . H, 6.34; N, 12.15. Found: C, 60.00; H, 6.39; N, 12.19.

Example 56

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

This compound was prepared as described in Example 53 using 1.0 g (3.45 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.721 ml (0.524 g,

5.18 mmol, 1.5 equivalents) of triethylamine and 0.513 mL (0.720 g,

3.45 mmol, 1.0 equivalent) of benzoyl chloride (Aldrich Chemical Company). After addition of 4- (trifluoromethyl) benzoyl chloride, the ice bath was removed and the reaction mixture was stirred for 90 minutes. The crude reaction mixture was purified by flash chromatography (1: 1 ethyl acetate / hexanes) containing 0.1% triethylamine and then ethyl acetate mixed with 0.1% triethylamine as eluents. 0.57 g of the free base is obtained as a solid. The salt, hydrochloride, is recrystallized from ethanol. 0.26 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- (trifluoromethyl) benzamide hydrochloride is obtained as a brown solid, m.p. 205 DEG-207 DEG C. (decomposition). Yield: 15%.

^X H NMR (DMSO-d₆): δ 1.62 (m, 2), 1.83 (m, 2), 3.15 -3.40 (m, 6), 3.50 (br t, 2, J = 13.0), 3.59 (broad d, 2, J =

11.6), 4.08 (broad d, 2, J = 13.3), 7.48 (ddd, 1, J = 1,0,7,1,

8.1), 7.60 (ddd, 1, J = 1.0, 6.9, 8.1), 8.08 (d, 2, J = 8.8),

8.11 (m, 4), 8.87 (broad t, 1, J = 5.5), 10.95 (broad s, 1).

133 ¹³ C NMR (DMSO-d 6): δ 20.63, 26.15, 38.50, 46.37, 50.47,

55.12, 121.18, 122.13, 123.99, 124.61, 125.23, 126.95, 128.11,

130.79, 138.25, 152.10, 162.20, 165.04.

Analysis for ^C 23 ^H 25 ^N 4 ^OSF 3 · ^HCl: calculated: 55.36% C, 5.25% H, 11.23% N, found: 55.46% C, 5.26% H, 11.18 % N.

Example 57

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

This compound was prepared as described in Example 56 using 1.0 g (3.45 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.721 ml (0.524 g,

5.18 mmol, 1.5 equivalents) of triethylamine and 0.674 mL (0.679 g,

3.45 mmol, 1.0 equivalent) of tert-butylbenzoyl chloride (Aldrich Chemical Company). 0.560 g of the salt, hydrochloride, is produced from the free base and recrystallized from ethanol. 0.251 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-tert-butylbenzamide hydrochloride is obtained as a brown solid, m.p. 222 'C (decomposition). Yield: 15%.

¹ H NMR (DMSO-d 6): δ 1.31 (s, 9), 1.60 (m, 2), 1.82 (m, 2),

3.25 (m, 6), 3.55 (m, 4), 4.08 (broad d, 2, J = 13.3), 7.49 (m, 3), 7.62 (t, 1, J = 7.4), 7.83 (d, 2, J = 8.4), 8.14 (m, 2), 8.55 (t, 1, J = 5.7), 11.06 (broad s, 1). 13 _c NMR _(DMSO-d6): δ 20.82, 26.55, 31.15, 34.77, 34.77, 38.53. 46.63, 50.71, 55.39, 121.51, 124.32, 124.93, 125.28, 127.28. 127.35, 128.45, 132.11, 152.45, 154.15, 162.57, 166.47. analysis for C ₂₆ H ₃₄ N ₄ OS. HC1: calculated: 64.11% C, 7.24% H, 11.50% N, found: H, 7.25; N, 11.43.

134

Example 58

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

This compound was prepared according to the procedure in Example 53 using 1.24 g (4.27 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)), 0.893 ml (0.648 g,

6.41 mmol (1.5 equiv) triethylamine and 1.05 g (4.27 mmol, 1.0 equiv) p-phenylazobenzoyl chloride (Kodak). The reaction mixture was allowed to stir for 1 hour and then p-phenylazobenzoyl chloride was added. The free base is purified by flash chromatography with ethyl acetate / hexanes (3: 1) containing 0.1% triethylamine, then ethyl acetate containing 0.1% triethylamine and finally ethyl acetate containing 0.2% triethylamine, as eluents. 1.42 g of compound is obtained as an orange solid. The free base was recrystallized from ethyl acetate to give 0.781 g of pure compound as an orange solid. The salt, the hydrochloride is formed and recrystallized from aqueous ethanol. 0.589 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- (phenylazo) benzamide hydrochloride is obtained as an orange solid, m.p. 227 ° C. Yield: 26%.

¹ H NMR (DMSO-d ₆ ): δ 1.67 (m, 2), 1.82 (m, 2), 3.36 (m, 8),

3.63 (broad d, 2, J = 10.4), 4.11 (broad d, 2, J = 11.9), 7.49 (tm, 1, J = 7.6), 7.64 (m, 4), 7.98 (m, 4), 8.14 (m, 4), 8.82 (broad t, 1, J = 5.6), 10.50 (broad s, 1).

¹³ C NMR (DMSO-d ₆ ): δ 20.65, 26.22, 38.56, 46.36, 50.45,

55.12. 119.43, 119.91, 121.16, 122.30. 122.68. 123.97. 124.58, 126.91. 127.45, 128.09, 128.50, 128.84. 129.52. 131.98. 132,61, 136.64. 151.82, 152.07, 153.15, 153,46, 155, 71, 162.17. 165.18. 165.39. analysis for C ₂₈ H ₃₀ N ₆ OS. HC1: calculated: 62.85% C, 5.84% H, 15,71% N, found % C, 62.91;% H, 5.85; 15,63% N.

135

Example 59

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

0.742 g (4.14 mmol) of 4-acetamidobenzoic acid, 0.693 ml (0.503 g, 4.97 mmol, 1.2 equivalents) of triethylamine and 20.0 ml of anhydrous tetrahydrofuran are placed in a 100 ml three-necked round bottom flask, provided with a magnetic stir bar, nitrogen inlet, thermometer and rubber septum, using a miner which has been flame dried beforehand. The reaction mixture was cooled to -15 ° C with a dry ice (carbon dioxide) bath and isopropanol. 0.537 mL (0.565 g, 4.14 mmol, 1.0 equivalent) of isobutyl chloroformate was added to the reaction mixture. After 5 minutes, a solution of 1.20 g (4.14 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b) in 10 mL was added dropwise. 1.0 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -15 ° C for 1 hour and then allowed to warm to room temperature. After 18 hours, the reaction mixture was transferred to a separatory funnel with dichloromethane and washed with saturated potassium carbonate solution. The organic portion is filtered, dried over magnesium sulfate, filtered again and evaporated. 1.70 g of a yellow oil are obtained. The crude material obtained from the reaction mixture was purified by flash chromatography using a 9: 1 mixture of dichloromethane and methanol as eluent. 0.74 g of the free base is obtained in the form of a white foam. To a solution of the free base in a mixture of ethyl acetate and dichloromethane was added 1.57 ml of 1N (1.0 equivalent) ethereal HCl. The solvent was evaporated under reduced pressure and the salt was recrystallized from aqueous ethanol. 0.474 g of 4-acetamido-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -benzamide hydrochloride is obtained in the form of a light cream solid having a melting point higher than as 250 ° C. Yield: 23%.

^T H NMR (DMSO-d₆): δ 1.59 (m, 2), 2.07 (s, 3), 3.25 (m, 6),

3.46 (broad t, 2, J = 12.9), 3.59 (broad d, 2, J = 11.4), 4.08 (broad d, 2, J = 13.4), 7 48 (t, 1, J = 7.5); 7.60 (t, 1, J =

136

7.6), 7.66 (d, 2, J = 8.7), 7.82 (d, J = 8.6), 8.13 (t, 2, J = 8.3), 8.46 (broad t, 1, J = 5.2), 10.23 (s, 1), 10.68 (broad s, 1).

¹³ C NMR (DMSO-d 6): δ 20.67, 24.09, 26.37, 38.34, 46.40,

50.49; 55.18, 118.01, 121.19. 124.00, 124.61, 126.95, 127.98, 128.12, 128.75, 141.84, 152.11. 162.20. 165.73, 168.66. analysis for ^C 24 ^H 29 ^N 5 ° 2 ^N . HC1:

H, 6.20; N, 14.35. Found: C, 58.99; H, 6.20; N, 14.43.

Example 60

a) A process for the preparation of 4 - [(tert-butoxycarbonyl) amino] benzoic acid

10.0 g (72.9 mmol) of 4-aminobenzoic acid (Aldrich Chemical Company), 50 ml of 5% potassium carbonate solution and

40.0 ml of 1,4-dioxane is introduced into a 500 ml round-bottom flask equipped with a magnetic stir bar and an addition funnel. The solution was cooled in an ice bath and a solution of 23.8 g (109 mmol, 1.5 equivalents) of di-tert-butyl dicarbonate (Fluka) in 40.0 mL of 1,4-dioxane was added dropwise. Remove the ice bath and allow the reaction mixture to warm to room temperature and stir for 24 hours. The reaction mixture was cooled in an ice bath and another portion (1.0 equivalent) of di-tert-butyl dicarbonate in 20.0 mL of 1,4-dioxane was added dropwise. The ice bath was removed again and the reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure and 150.0 mL of water was added to the resulting solid. The pH was adjusted to approximately 2 by addition of 1N hydrochloric acid and the organic portion was extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to a white solid. The solid was triturated with hexanes and dried. 14.80 g of product are obtained as a white solid. Yield: 86%.

^{137; H} NMR (DMSO-d): 8 1.50 (s, 9), 7.58 (d, 2, J = 8.8), 7.86 (d, 2, J = 8.8), 9.76 (broad s, 1), 12.67 (broad s, 1) ppm.

b) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4 - [(tert-butoxycarbonyl) amino] benzamide hydrochloride

This compound was prepared according to the procedure in Example 59, using 2.05 g (8.65 mmol) of 4 - [(tert-butoxycarbonyl) amino] benzoic acid, 1.45 mL (1.05 g, 10.4 mmol). , 1.2 equivalents) of triethylamine, 1.12 mL (1.18 g, 8.65 mmol, 1.0 equivalents) of isobutyl chloroformate (Aldrich Chemical Company) and 2.51 g (8.65 mmol, 1.0 equivalents) 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)). The crude reaction mixture was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 0.78 g of the free base is obtained in the form of a white solid. The fractions were combined and purified by flash chromatography using a 9: 1 mixture of dichloromethane and methanol as eluent. 40 g of the free base is obtained in the form of a white solid. The free bases obtained from each column are combined and dissolved in a mixture of ethanol and chloroform. To the free base solution was added 2.41 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. The solvent was evaporated and the salt, hydrochloride, was recrystallized from ethanol. 0.644 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4 - [(tert-butoxycarbonyl) amino] benzamide hydrochloride is obtained as a beige solid having a temperature of mp 205-208 ° C (foaming), yield 14% of theory.

^X H NMR (DMSO-d₆): δ 1.49 (s, 9), 1.60 (m, 2), 1.80 (m, 2),

3.10-3.54 (m, 8) 3.59 (m, 2), 4.08 (wide d, 2, J = 12.5), 7.55 (m, 4), 7.80 ( d, 2, J = 8.8), 8.14 (m, 2), 8.45 (broad t, 1, J = 5.4), 9.64 (s, 1), 10.80 (broad) s, 1) ppm.

^{X 3} C NMR (DMSO-d 6): δ 20.64, 26.34, 28.01, 38.28, 46.36,

50.33, 55.12, 79.39, 117.00, 121.15, 123.96, 124.58, 126.92,

127.79, 127.96, 128.08, 142.11, 152.06, 152.54, 162.17, 165.70.

138

Analysis for C ₂₇ H ₃₅ N ₅ O ₃ S. H, 6.64; N, 12.82. Found: C, 59.43; H, 6.65; N, 12.92.

Example 61

a) A process for the preparation of 3 - [(tert-butoxycarbonyl) amino] -benzoic acid

This compound was prepared as described in Example 60

a), using 5.0 g (36.5 mmol) of 3-aminobenzoic acid (Aldrich Chemical Company), 25 ml of 5% sodium carbonate solution and 19.9 g (91.1 mmol, 2.5 equivalents) of di- tert-butyl dicarbonate (Fluka). After 65 hours, the reaction mixture is worked up to 7.48 g of 3 - [(tert-butoxycarbonyl) amino] benzoic acid, which is obtained as a white solid. Yield: 86%.

NMR (CDCl ₃ ): δ 1.49 (s, 9), 7.37 (t, 1, J = 7.9), 7.54 (dd, 1, J = 1.2, 6.5), 7.63 (dd, 1, J = 0.9, 7.9), 8.15 (s, 1), 9.56 (broad s, 1), 12.92 (broad s, 1) ppm.

b) A process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3 - [(tert-butoxycarbonyl) amino] benzamide hydrochloride hydrate

This compound was prepared as described in Example 59 using 3.45 g (10.3 mmol) of 3 - [(tert-butoxycarbonyl) amino] benzoic acid, 1.72 mL (1.41 g, 10, 3 mmol, 1.0 equivalent) of isobutyl chloroformate (Aldrich Chemical Company) and 3.0 g (10.3 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2- benzisothiazole (Example 13b)). After 20 hours the reaction mixture was transferred to a separatory funnel with dichloromethane. The organic portion was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated to give the crude free base. The crude material was purified by flash chromatography using a 95: 5 mixture of dichloromethane and methanol as eluent. 2.82 g of the free base are obtained as

139 white solid. To a solution of 1.0 g (1.96 mmol) of the free base in chloroform was added 1.96 mL of 1N (1.0 equivalent) of ethereal HCl. The salt, the hydrochloride, is recrystallized from a mixture of ethanol and ether. 0.46 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3 - [(tert-butoxycarbonyl) amino] benzamide hydrochloride hydrate is obtained in the form of: white solid, m.p. 139-144 ° C (foaming). Yield: 23%.

^X H NMR (DMSO-d₆): δ 1.48 (s, 9), 1.59 (m, 2), 1.80 (m, 2),

3.16-3.54 (m, 8) 3.59 (broad d, 2, J = 11.8), 4.08 (broad d, 2, J = 13.1), 7.32 (t, 1, J = 7.9), 7.48 (m, 3), 7.60 (ddd, 1, J = 1.1, 6.9, 8.1), 8.00 (s, 1), 8.13 (t, 2, J = 8.1), 8.50 (broad t, 1, J = 5.6), 9.49 (s, 1), 10.72 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.84, 26.48, 29.29, 38.66, 46.62,

50.71, 55.41, 79.43, 117.68, 120.82, 121.04, 121.50, 124.31, 124.93, 127.27, 128.44, 128.72, 135, 72, 139.92, 152.45, 153.12, 162.56, 166.82.

Analysis for ^C 27 ^H 35 ^N 5 ^S 3 °. 0.75 HCl:

calculated: 57.95% C, 6.75% H, 12.51% N, 2.41% H, found: 57.86% C, 6.74% H, 12.61% N, 2.44% H O.

Example 62

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

800 mg (1.57 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- [(tert-butoxycarbonyl) amino] benzamide (Example 60b) 1.5 ml of anisole (Aldrich Chemical Company), 15.0 ml of anhydrous chloroform and 15.0 ml of trifluoroacetic acid (EM Scientific) are introduced into a 500 ml round-bottom flask equipped with a magnetic stir bar and nitrogen inlet. . The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil.

140

The crude oil was dissolved in ethyl acetate, washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated to a yellow solid. The crude amine was purified by flash chromatography with ethyl acetate containing 0.2% triethylamine as eluent. 0.37 g of amine is obtained in the form of an oil. To a solution of the amine in a mixture of ethyl acetate and dichloromethane was added 0.90 mL of 1N (1.0 equivalent) of ethereal HCl. The solvent was evaporated under reduced pressure and the salt, hydrochloride, was recrystallized from aqueous ethanol. 200 mg of 4-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide is obtained as a brown solid, m.p. 213.5-214.5 °. C. Yield: 29%.

^X H NMR (DMSO-d₆): δ 1.56 (m, 2), 1.77 (m, 2), 3.27 (m, 6),

3.45 (broad t, 2, J = 12.5), 3.59 (broad d, 2, J = 11.9), 4.08 (broad d, 2, J = 13.2), 5, 61 (broad s, 2), 6.54 (d, 2, J =

8.6), 7.48 (ddd, 1, J = 1.1, 7.1, 8.1), 7.60 (m, 3), 8.12 (m,

3), 10.65 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.65, 26.52, 38.11, 46.37, 50.44,

55.15, 112.43, 121.16, 123.96, 124.58, 126.91, 128.08, 128.62, 151.44, 152.06, 162.18, 166.20. Analysis for C ₂ H ₂₇ N ₅ OS. HCl: calculated: 59.25% C, 6.33% H, 15,70% N, Found: C 59.03, H 6.32, 15,62% N.

Example 63

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

This compound was prepared as described in Example 62 using 1.77 g (3.47 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3 - [(tert-butoxycarbonyl) amino] -benzamide (Example 61b), 3.0 ml of anisole (Aldrich Chemical Company),

30.0 ml of anhydrous chloroform and 30.0 ml of trifluoroacetic acid

141 (EM Scientific). The crude amine was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine and then with ethyl acetate containing 0.2% triethylamine. 1.16 g of the free base is obtained in the form of an orange oil. The salt, the hydrochloride is formed and recrystallized from a mixture of ethanol and ether. 0.31 g of 3-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -benzamide hydrochloride hydrate is obtained as a rust-orange solid, m.p. 122-130. 'C (foaming). Yield: 20%.

^{Τ Η} NMR (DMSO-d₆): δ 1.59 (m, 2), 1.80 (m, 2), 3.05 to 3.75 (m, 10), 4.08 (br d, 2, J = 13.0), 6.10 (broad s, 2), 6.79 (d, 1, J = 7.4), 7.13 (m, 3), 7.48 (ddd, 1, J) = 1.0, 6.9, 8.1), 7.60 (ddd, 1, J = 1.1, 6.9, 8.1), 8.13 (t, 2, J = 8.4 8.38 (broad t, 1, J = 5.5), 10.77 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.66, 26.35, 38.36, 46.40, 50.49,

55.20, 114.21, 115.93, 117.63, 121.21, 124.05, 124.64, 126.98,

128.14, 128.72, 135.61, 146.36, 152.13, 162.22, 166.77.

Analysis for C ₂₂ ^H 27 ^N 5 ^OS · ^{HC1 '0.5 H2 0:} Calculated: 58.07% C, 6.42% H, 15.39% N, 1.98% H _2, Found: 58 , 17% C, 6.41% H, 12.25% N, 2.35% H ₂ O.

Example 64

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2,6-dimethoxybenzamide hydrochloride

1.48 g (5.69 mmol) of 3-bromo-2,6-dimethoxybenzoic acid [obtained by bromination of 2,6-dimethoxybenzoic acid (Aldrich Chemical Company) as described by F. P. Doyle et al. in J. Chem. Soc. 497 (1963)] and 50 ml of anhydrous toluene are introduced into a 100 L three-necked round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet, dropping funnel and thermometer using a flask that has been previously flame dried. 1.12 ml is added dropwise to the reaction mixture

142 (1.83 g, 15.4 mmol, 2.7 equivalents) thionyl chloride at room temperature. Replace the sas dropping funnel with a reflux condenser and heat the reaction mixture at 65 ° C. To the reaction mixture was added 0.03 mL of dimethylformamide and the temperature was maintained at 65 ° C for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in 20 ml of chloroform. To this solution was added 1.5 g (5.17 mmol, 0.9 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b), 12, 0 mL of chloroform and 1.08 mL (0.785 g, 7.76 mmol, 1.4 equivalents) of triethylamine. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the orange solution was dissolved in ethyl acetate. The organic portion was washed with saturated potassium carbonate solution, dried (MgSO 4), filtered and evaporated. 3.24 g of an orange oil are obtained. This crude material was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine and then with ethyl acetate containing 0.2% triethylamine as eluents. 1.45 g of the free base is obtained in the form of a yellow oil. To a solution of the free base in ethyl acetate was added 2.72 mL of a 1N (1.0 equivalent) ethereal hydrogen chloride solution. The solvent was evaporated under reduced pressure and the salt, hydrochloride, was recrystallized from ethanol. 0.867 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2,6-dimethoxybenzamide hydrochloride is obtained as a white solid having a temperature of mp 220-221 ° C (dec.). Yield: 27%.

¹ H NMR (DMSO-d 6): δ 1.56 (m, 2), 1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4), 3.78 ( s, 6), 4.08 (broad d, 2, J = 13.4), 6.85 (d, 1, J = 9.0), 7.48 (t, 1, J = 7.5) 7.59 (d, 1, J = 8.9), 7.60 (tm, 1, J = 8.1), 8.13 (t, 2, J = 8.9), 8.38 ( broad t, 1, J =

5.6), 10.92 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.36, 36.23, 38.01, 46.29, 50.39, 55.07, 56.12, 61.72, 106.87, 109.21, 121.16, 123.97, 124.01, 124.59, 126.92, 128.09, 132.97, 152.06, 153.45, 156.20, 162.17,

163,33.

143

Analysis for ^C 24 ^H 29 ₁ N ₄ O ₃ SBr. HC1: calculated: 50.58 % C, 5.31 % H, N 9.83% found: 50.69 % C, 5.32 % H, 9.80% N.

Example 65

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

This compound was prepared as described in Example 53 using 1.3 g (3.17 mmol) of 2-amino-N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl]. butyl] benzamide (Example 36), 0.66 mL (0.48 g, 4.78 mmol, 1.5 equivalents) of triethylamine and 0.226 mL (0.25 g, 3.17 mmol, 1.0 equivalent) of acetyl chloride. The reaction mixture was stirred on an ice bath for 1 hour and then allowed to warm to room temperature. The reaction mixture was worked up after 18 hours. The free base was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 1.09 of the free base is obtained in the form of an oil. To a solution of 1.04 g (2.30 mmol) of the free base in ethyl acetate was added

2.30 ml of a 1N (1.0 equivalent) ethereal HCl solution. The solvent was evaporated under reduced pressure and the salt, hydrochloride, was recrystallized from ethanol. 0.859 g of 2-acetamido-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -benzamide hydrochloride is obtained in the form of a beige solid, m.p. 190.5 ° C. Yield: 56%.

¹ H NMR (DMSO-d 6): δ 1.67 (m, 2), 1.84 (m, 2), 2.10 (s, 3), 3.10-3.75 (m, 10), 4.09 (broad d, 2, J = 12.9), 7.16 (tm, 1, J = 7.7), 7.49 (t, 2, J = 7.8), 7.62 ( t, 1, J = 7.4), 7.78 (dm,

1, J = 7.8), 8.13 (d, 1, J = 7.6), 8.16 (d, 1, J = 7.8), 8.36 (d,

I, J = 8.2), 8.84 (broad t, 1, J = 5.2), 10.86 (broad S, 1),

II, 24 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.61, 24.78, 25.99, 38.40, 46.33,

50.41, 55.08, 120.46, 121.07, 121.16, 122.49, 123.96, 124.58,

144

126.92, 128.09, 131.68, 138.78, 152.06, 162.17, 168.08, 161.18,

163,33.

Analysis for ^C 24 ^H 29 ^N 5 ^S 2 ° ^'HC1: Calculated: 59.06% C, 6.20% H, 14.35% N Found: 59.13% C, 6.25% H, 14, 41% N.

Example 66

a) Method for producing 2- [4- / 4- (1,2-benzisothiazol-3-yl) -piperidino / butyl] -1 [3H] -isoindolinone hydrochloride

1.25 g (5.73 mmol) of 3- (4-piperidinyl) -1,2-benzisothiazole, 1.54 g (6.88 mmol, 1.2 equivalents) of 2- (4-chlorobutyl) -1-isoindolinone (Example 3 (a)), 2.0 mL (1.45 g, 14.33 mmol, 2.5 equivalents) of triethylamine and 25.0 mL of acetonitrile were charged to a 100 mL round bottom flask equipped with a reflux condenser, magnetic stir bar and nitrogen inlet. The reaction mixture was refluxed for 2 days. The solvent was evaporated under reduced pressure and the crude reaction mixture was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine and then with ethyl acetate containing 0.2% triethylamine as eluent. 1.55 g of the free base is obtained. To the free base solution was added 1 N (1.0 equivalent) of ethereal hydrogen chloride solution. The solvent was evaporated under reduced pressure and the salt, hydrochloride, was recrystallized from ethanol. 1.15 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidino / butyl] -1- [3H] -isoindolinone hydrochloride are obtained in the form of a light beige solid, which is mp 211-214 ° C (dec.). Yield: 45%.

¹ H NMR (DMSO-d ₆ ): δ 1.74 (m, 4) , 2.22 (m, 4) , 13 (M, 4), 3.59 (t, 4, J = 6.1), 3.65 (m, D, 4.52 (S, 2), 7, 51 (M, D, 7.54 (ddd, 1, J = 1.1, 7.0, 8.1) , 7, 63 (m, 3), 7.70 (dt , 1, J = 7.4 1.0), 8.21 (d, 1, J = 8.1), 8.28 (d, 1 , J = 8.1), 10 , 25 (are you- years s, 1) ppm.

145 ¹³ C NMR (DMSO-d ₆ ): δ 20.51, 25.04, 27.63, 35.50, 40.88,

49.36, 51.42, 55.61, 120.66, 122.64, 123.30, 123.49, 124.86,

127.73, 127.93, 131.16, 132.31, 133.27, 141.83, 151.89, 167.33,

167.49.

Analysis for C 24 H 27 N 3 OS. HCl: calculated: 65.21% C, 6.38% H,

9.51% N, found:

65.31% C,

6.41% H,

9.51% N.

Examples 67 and 68

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy-6-methoxybenzamide hydrochloride and N- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -3-bromo-6-hydroxy-2-methoxybenzamide

4.99 g (9.35 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2,6-dimethoxybenzamide (Example 64 a and 75.0 ml of anhydrous dichloromethane are introduced into a 250 ml round-bottom flask equipped with a magnetic stir bar, nitrogen inlet and pressure equalizing dropping funnel using a flame-dried flask. To this solution was added 9.25 mL of 1N (9.25 mmol, 0.99 equivalents) ethereal hydrogen chloride solution, and then 9.35 mL of 1N solution (9.35 mmol, 1 equivalent) of boron tribromide (9.35 mmol, 1 equivalent) was added dropwise. Aldrich Chemical Company) in dichloromethane. The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and 50 ml of 1N ammonium hydroxide solution were added. Dissolve the solids with dichloromethane and water. The phases are separated and the aqueous phase is washed with dichloromethane. The organics were combined, washed with water, dried (MgSO 4), filtered and evaporated. 3.61 g of crude material are obtained as a sticky yellow residue. The crude free base was purified by flash chromatography using a 97: 3 mixture of dichloromethane and methanol as eluent. 2.06 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy-6-methoxybenzamide are obtained, in the form of:

146 oil _(Rf = 0.10) and 1.32 g of a mixture of isomers. This mixture was purified by flash chromatography with ethyl acetate as eluent. 0.18 g of the minor isomer of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-6-hydroxy-2-methoxybenzamide (Rf = 0.34) is obtained. ), in the form of a brown solid. The salts, hydrochlorides of each of the isomers, are prepared independently of each other by dissolving the free amine in ethyl acetate and treating the solution with 1-normal (1 equivalent) ethereal hydrogen chloride.

Example 67

The salt, major isomer hydrochloride is recrystallized from aqueous ethanol to give 1.67 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy hydrochloride -6-methoxybenzamide as a light pink solid having a melting point of 191-192.5 ° C. Yield: 32%.

¼ NMR (DMSO-d ₆ ): δ 1.54-1.90 (m, 4), 3.05-3.70 (m, 10), 3.94 (s, 3), 4.07 ( Wide d, 2, J = 12.8), 6.60 (d, 1, J = 9.2), 7.47 (m, 1), 7.60 (m, 1), 7.66 ( d, 1, J = 9.0), 8.11 (d,

1, J = 7.6), 8.14 (d, 1, J = 7 9), 8.93 (t, 1, J) = 6 , 2) , 10.75 (wide s, 1), 14.87 ( s, 1) ppm. ¹³ C NMR (DMSO-d6) ): δ 10, 62, 25.95, 38.58, 46 35 50.44. 55.04, 56.69, 102.30, 103.14, 104.76, 121.17, 123 99 124.60. 126.95, 128.10, 136.07 , 152,10, 158.08, 159.27, 162, 21 16 8.79. Analysis for ^C 23 ^H 27 ^N 4 ° 3 SBr. HC1: calculated: 49.69% C, 5.08% H, 10.08% N, found: C 49.79, 5.11% H, 9.98% N. Example 68

The minor isomer hydrochloride salt is filtered off and dried under high vacuum in an Abderholden apparatus. 76 mg of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-6-hydroxy-2-methoxybenzamide hydrochloride are obtained in the form of a white solid.

147 a substance having a melting point of 185-187 ° C. Yield: 2%.

^X H NMR (DMSO-d₆): δ 1.60 (m, 2), 1.83 (m, 2), 3.10 to 3.70 (m, 10), 3.79 (s, 3), 4.09 (m, 2), 6.70 (d, 1, J = 8.8), 7.49 (m, 2), 7.62 (t, 1, J = 7.5), 8, 15 (t, 2, J = 7.8), 8.47 (broad t,

I, J = 5.2), 10.65 (broad s, 1), 10.99 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.50, 26.17, 38.14, 46.44, 50.55,

55.27, 61.66, 104.70, 114.00, 119.20, 121.19, 124.04, 124.63,

126.99, 128.13, 133.81, 152.13, 154.34, 156.85, 162.24, 165.15.

Analysis for ^C 23 ^H 27 ^N 4 ° 3 ^SBr · ^HC1: Calculated: 49.69% C, 5.08% H, 10.08% N Found: 49.79% C, 5.11% H, 10, 00% N.

Example 69

a) Process for the preparation of N- [4- / 4- (6-fluoro-1,2-benzisothiazol-3-yl) piperidino / butyl] phthalamide hydrochloride

1.64 g (7.45 mmol) of 6-fluoro-4- (4-piperidinyl) -1,2-benzisoxazole, 2.63 g (9.31 mmol, 1.25 equivalents) of N- (4-bromobutyl) -phthalimide (Aldrich Chemical Company), 1.56 ml (1.33 g,

(2 mmol, 1.5 equivalents) of triethylamine and 30 ml of acetonitrile are introduced into a 100 ml round bottom flask equipped with a magnetic stir bar. A reflux condenser and nitrogen inlet were connected to the flask, and the reaction mixture was refluxed for 15 hours. Remove the oil bath and allow the reaction mixture to cool to room temperature. The reaction mixture was transferred to a separatory funnel with ethyl acetate. The organic portion was washed with saturated potassium carbonate solution and the two phases were separated. The aqueous phase was extracted with ethyl acetate and the organics were combined and a white solid precipitated out of solution. The suspension was placed in the freezer for 1 hour and the solid was filtered off. The filtrate was evaporated to give a crude material, such as an orange mustard-colored oil / solid mass

148

4.19 g. This crude material was adsorbed onto silica gel and purified by flash chromatography with dichloromethane / methanol (95: 5) as eluent. The free base is obtained as a yellow solid. The free base was dissolved in dichloromethane, filtered and evaporated to an oil (1.9 g) which solidified rapidly to give a yellow solid. To a solution of the free base in a mixture of ethyl acetate and dichloromethane was added 4.5 mL of a 1N (1.0 equivalent) ethereal hydrogen chloride solution. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol. This gives 1.39 g of the title compound as a light beige solid, m.p. 227-229 ° C. Yield: 41%.

¹ H NMR _(DMSO-d6): δ 1.68 (m, 2), 1.78 (m, 2), 2.27 (m, 4) 3.10 (m, 4) 3.47 (m, 1), 3.62 (m, 4), 7.34 (dt, i, J = 2,0, 8,9) , 7.73 (dd, 1, J = 9.1, 1.8), 7.88 (m, 4), 8.20 (m, 1)

10.55 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.97, 25.71, 27.16, 31.52, 37.21, 51.60, 55.78, 97.67, 98.03, 112.90, 113.24, 117.00, 123.36,

124.15, 124.30, 131.99, 134.71, 160.42, 162.40, 163.45, 163.64, 165.69, 168.32.

Analysis for ^C 24 ^H 24 ^N 3 ° 3 ^F * ^HCl: calculated: 62.95% C, 5.50% H,

N 9.18%, found:

63.05% C,

5.52% H,

9.14% N.

Example 70

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

6.0 g (20.7 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13 (b)) and 50 ml of anhydrous dichloromethane are placed in a three-necked round-bottomed flask. A 250 ml volume equipped with a magnetic stir bar, a thermometer, a dropping funnel and a nitrogen inlet using a flask that has been previously flame dried. The solution is cooled on ice

A solution of 4.40 mL (6.53 g, 31.1 mmol, 1.5 equivalents) of trifluoroacetic anhydride in 20 mL of anhydrous dichloromethane was added dropwise over 30 minutes. The reaction mixture was allowed to stir for 2 hours. To the cooled reaction mixture was added slowly 50 mL of saturated potassium carbonate solution. The reaction mixture was transferred to a separatory funnel and the organic portion was extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. This gives 6.87 g of the title compound as an orange oil. Yield: 86%. The crude material was used without further purification.

1 H NMR (CDCl 3): δ 1.71 (broad s, 4), 2.51 (broad t, 2, J = 6.2), 2.71 (t, 4, J = 4.8), 3 .41 (m, 2), 3.59 (t, 4, J = 4.9), 7.36 (t, 1, J = 7.9), 7.49 (t, 1, J = 7, 9), 7.83 (d, 1, J = 8.0), 7.90 (d, 1, J = 7.9) ppm.

b) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -N-methyl-2,2,2-trifluoroacetamide

0.587 g (19.6 mmol) of an 80% sodium hydride dispersion in oil was introduced into a 250 mL three-necked round-bottomed flask fitted with a rubber septum, magnetic stir bar, dropping funnel and nitrogen inlet using a pre-dried flask. flame. The sodium hydride was washed three times with hexanes and 30.0 mL of tetrahydrofuran was added to the washed material. The suspension is cooled in an ice bath and a solution of 6.87 g (17.8 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] is slowly added over 35 minutes. -2,2,2-Trifluoroacetamide in 30.0 ml of anhydrous terahydrofuran over a period of 35 minutes. Ice bath! The reaction mixture was removed and a solution of 1.1 mL (2.53 g, 17.8 mmol) of methyl iodide in 20 mL of anhydrous terahydrofuran was added dropwise. The yellow-orange solution was allowed to warm to room temperature and stirred for 4 days. Excess sodium hydride was quenched with 15 mL of water and then the tetrahydrofuran was evaporated under reduced pressure. The residue was partitioned between water and dichloromethane. The two phases were separated and the aqueous phase was washed twice more with dichloromethane. The organic fractions are combined, you

Dry with magnesium sulfate, filter and evaporate. The crude material was obtained as an orange oil. The crude free base was purified by flash chromatography with ethyl acetate as eluent. There was obtained 4.55 g of the title compound as a white solid. Yield: 64%.

¹ H NMR (CDCl ₃ ): δ 1.59 (m, 2), 1.71 (m, 2), 2.47 (t, 2, J = 7.0), 2.68 (m, 4) , 3.04 and 3.14 (2 singlets, 3, NCH ₃ tautomers), 3.45 (m, 2), 3.58 (m, 4), 7.36 (t, 1, J = 7.2 7.48 (t, 1, J = 7.5), 7.82 (d, 1, J = 7.7), 7.91 (d, 1, J = 8.0) ppm.

c) Method for producing 3- [4- / 4- (methylamino) butyl] -1-piperazinyl] -1,2-benzisothiazole

2.0 g (5.0 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -N-methyl-2,2,2-trifluoroacetamide, 50 ml of methanol and 20.0 ml of a 7% aqueous potassium carbonate solution are introduced into a 250 ml round-bottom flask equipped with a magnetic stir bar. The reaction mixture was allowed to stir at room temperature for 6 hours. Methanol is evaporated under reduced pressure and the organic portion is extracted from the aqueous phase with dichloromethane. The organics were dried over magnesium sulfate, filtered and evaporated. The crude product was obtained as a yellow oil which was used without further purification.

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

1.4 g (4.6 mmol) of 3- [4- / 4- (methylamino) butyl] -1-piperazinyl] -1,2-benzisothiazole, 0.750 g (4.6 mmol, 1.0 equivalent) of acid anhydride of isatin (Aldrich Chemical Company) and 25.0 ml of ethanol are added to a round bottom flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture is placed under a nitrogen atmosphere and allowed to stir at room temperature for 20 hours and then allowed to stand without stirring for 6 hours. The reaction mixture was evaporated under reduced pressure to give the crude material as a brown-orange liquid. The free base is purified

151 flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 1.06 g of the free base is obtained. To a solution of 1.06 g (2.50 mmol) of the free base in ethyl acetate was added

2.5 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. The solvent was evaporated under reduced pressure and the solid was recrystallized from a mixture of ethanol and ether. This gives 0.625 g of the title compound as a brown solid, m.p. 188-189 ° C. The yield corresponds to 30% of theory.

^X H NMR (DMSO-d₆): δ 1.61

10), 4.07 (broad (td, 1, J = 7.4, 1.1), 6.73 (dd, 1, J)

J = 1.4, 7.7), 7.09 (ddd, 1, J = 1)

J = 1.0, 7.1, 7.9), 7.60 (ddd, 1, J)

2, J = 8.2), 10.85 (broad s, 1) ppm.

- 3.72 (m,

2), 6.58 (dd, 1, (ddd, 1, 8.13 (t, (broad d, 2, J))

3), 2.95 (broad s, 8.1), 7.02 8.0), 7.48 6.9, 8.0), ¹³ C NMR (DMSO-d 6): δ 20.36, 24 , 20, 46.34, 50.40, 55.13,

115.50, 120.26, 121.16, 123.97, 124.58, 126.92, 127.36, 128.09,

129.69, 145.35, 152.06, 162.18, 169.86,

Analysis for ^C 23 ^H 29 ^N 5 ^S · ° ^HC1: Calculated: 60.05% C, 6.57% H, 15.22% N Found: 59.98% C, 6.60% H, 15.13 % N.

Example 71

a) Process for the preparation of 3-hydroxy-1,2-benzisoxazole

This compound was prepared as described by R. Friary and B. R. Sunday in J. Heterocyclic. Chem. 16, 1277 (1979), using 47.2 g (0.308 mmol) of salicylhydroxamic acid (Aldrich Chemical Company), 100.0 g (0.617 mol, 2.0 equivalents) of 1,1'-carbonyldiimidazole and 1750 ml of anhydrous tetrahydrofuran. After work-up, the crude material precipitated as a beige solid, which was recrystallized from ethyl acetate. This gives 15.7 g of the title compound as an off-white solid. Second share

The 152 obtained additionally has a mass of 9.4 g and thus the total yield is 25.1 g, corresponding to 60% of theory.

¹ H NMR (DMSO-d ₆ ): δ 7.34 (ddd, 1, J = 1.6, 6.3, 8.0), 7.61 (m, 2), 7.78 (d, 1) J = 7.7), 12.39 (broad s, 1H) ppm.

ABOUT

b) A process for the preparation of 3-chloro-1,2-benzisoxazole

24.8 g (0.184 mol) of 3-hydroxy-1,2-isoxazole and 25.6 ml (18.6 g, 0.184 mol, 1.0 equivalent) of dry triethylamine are introduced into a 300 ml round-bottomed flask, provided with a magnetic stir bar using a flame-dried flask. The flask was additionally equipped with an addition funnel and nitrogen inlet and the solution was cooled in an ice bath. To the reaction mixture was added dropwise 37.8 ml (62.1 g, 0.405 mol, 2.2 equivalents) of phosphorus oxychloride. The ice bath was removed and the flask was fitted with a reflux condenser. Heat the reaction mixture in an oil bath at 150 ° C overnight. The oil bath was removed and the dark brown-orange liquid was allowed to cool to room temperature. The reaction mixture was poured slowly into 500 ml of ice and water with stirring. After warming to room temperature, the reaction mixture was transferred to a separatory funnel with 250 mL of dichloromethane. The organic phase is separated and the aqueous phase is washed with 200 ml of dichloromethane. The organics were combined, dried (MgSO 4), filtered and evaporated. This gives 28.3 g of the crude title compound as a dark orange liquid. Yield 100%. The crude material was used without further purification.

¹ H NMR (DMSO-d 6): δ 7.56 (tm, 1, J = 7.2), 7.85 (m, 3) ppm.

c) A process for the preparation of 1- (1,2-benzisoxazol-3-yl) piperazine

28.3 g (0.184 mol) of 3-chloro-1,2-benzisoxazole, 95.1 g (1.10 mol, 6.0 equivalents) of piperazine and 10.0 ml of toluene are introduced into a 500 ml round bottom flask. ml. The flask is additionally equipped with a reflux condenser and nitrogen inlet and the mixture

153 was heated in an oil bath at 155 ° C for 18 hours. The hot, dark orange reaction mixture was poured into 600 mL of ice water. The organic portion was extracted with a heterogeneous mixture of water and dichloromethane. The organic portion was dried (MgSO 4), filtered and evaporated. 22.8 g of product are obtained in the form of a dark orange liquid. To the crude material was added 6.0 mL of ethyl acetate, and the resulting solution was placed in a refrigerator. The dark orange thus formed is filtered off, crushed with a spatula, washed with ethyl acetate and ether and air-dried. 10.1 g of a mustard-colored solid are obtained. The crude material was used without further purification.

¹ H NMR (DMSO-d 6): δ 2.91 (m, 4), 3.42 (m, 4), 7.31 (m, 1), 7.59 (d, 2, J = 3, 5.), 7.99 (d, J, 8.0) ppm.

d) Process for the preparation of N- [4- / 4- (1,2-benzisoxazol-3-yl) -1-piperazinyl / butyl] phthalimide hydrochloride

4.0 g (19.7 mmol) of 1- (1,2-benzisoxazol-3-yl) piperazine, 6.66 g (23.6 mmol, 1.2 equivalents) of N- (4-bromobutyl) phthalimide (Aldrich) Chemical Company), 4.12 mL (2.99 g, 29.6 mmol, 1.5 equivalents) of triethylamine and 30 mL of acetonitrile are introduced into a round bottom flask equipped with a magnetic stir bar. The flask is additionally equipped with a reflux condenser and nitrogen inlet. The reaction mixture was allowed to stir at reflux for 3 hours. Oil purchase! The dark brown solution was allowed to cool to room temperature. The reaction mixture was transferred to a separatory funnel and partitioned between saturated potassium carbonate solution and 200 mL of ethyl acetate. The two phases are separated and the aqueous phase is extracted with 100 ml of ethyl acetate. The organics were combined and the solid precipitated out of solution. Dissolve the solid with a mixture of methanol and dichloromethane. The organic portion was dried (MgSO 4), filtered and evaporated to give the crude base. The free base was purified by flash chromatography with ethyl acetate as eluent to give the pure compound as a viscous yellow oil. 5.89 g (14.6 mmol) of the free base was dissolved in a mixture of ethyl acetate and dichloromethane and added to the solution.

154

14.6 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. The solvent was evaporated under reduced pressure and the resulting salt, hydrochloride, was recrystallized from aqueous ethanol. The title compound was obtained as an off-white solid (0.71 g), m.p. 257 DEG-259 DEG C. (dec.). Yield 8.2%.

^X H NMR _(DMSO-d6): δ 1.71 (m, 4), 3.21 (m, 4), 3.55 (m, 6), 4.14 (br d, 2, J = 13 2), 7.38 (m, 1), 7.65 (d, 2, J = 3.7), 7.90 (m, 4), 8.06 (broad d, 1, J = 8, 10.62 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.50, 26.24, 37.84, 45.61, 50.91, 56.00, 111.17, 116.05, 123.64, 123.94, 124.01, 131.30, 132.62, 135.36, 161.01, 164.27, 168.95,

Analysis for ^C 23 ^H 24 ^N 4 ° 3 * ^HCl: Calculated: C, 62.65; H, 5.71;

12.71% N, found:

62.51% C,

5.68% H,

12.65% N.

Example 72

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

This compound was prepared as described in Example 13 b) using 4.04 g (9.99 mmol) of N- [4- / 4- (1,2-benzisoxazol-3-yl) -1-piperazinyl (butyl) phthalimide (Example 71 d)), 0.87 g of a 55% solution (14.99 mmol, 1.5 equivalents) of hydrazine hydrate and 30 mL of methanol. The reaction mixture was refluxed for 2.5 hours. After cooling, the by-product (phthalhydrazide) cannot be precipitated. An additional 0.87 g (1.5 equivalents) of hydrazine hydrate was added to the reaction mixture, and the reaction mixture was refluxed for one more hour. After work-up, 2.1 g of crude material are obtained, which is obtained as an oil which solidifies on standing. Yield: 77%.

155 ¹ H NMR (CDCl ₃ ): δ 1.55 (m, 4), 1.72 (m, 2), 2.44 (t, 2, J = 7.1), 2.65 (t, 4) J = 4.9), 2.75 (t, 2, J = 6.5), 3.60 (t, 4, J = 5.0), 7.22 (m, 1), 7.46 (m, 2), 7.70 (d, 1, J = 8.0) ppm.

This material was used without further purification.

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

This compound was prepared as described in Example 36 using 1.0 g (3.65 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisoxazole, 0.656 g ( 4.02 mmol (1.1 equivalents) of isatinic anhydride and 10 mL of ethanol. After 24 hours, the solvent was evaporated under reduced pressure and the crude material was purified by flash chromatography with ethyl acetate / methanol (19: 1) as eluent. 1.37 g of the free base are obtained in the form of a viscous oil. The salt, hydrochloride, is recrystallized from aqueous ethanol and then dried in a vacuum oven. This gives 1.08 g of the title compound as a light yellow solid, m.p. 249-252 ° C. Yield: 60%.

NMR (DMSO-d6): δ 1.58 (m, 2), 1 79 (m 2) , 3 , 29 (M, 6), 3.56 (m, 4), 4.14 (m, 2), 6.45 (br S, 2), 6 , 53 (T, 1 J = 7.6), 6, 71 (d, 1, J = 8.0), 7.15 (t, 1 , J = 7.7) , 7 , 37 (M, D 7.52 (d, 1, J = 7.2), 7.65 (d, 2, J; = 3.7) ,, 8 , 06 (D, 1 J = 8.2), 8, 30 (broad t, 1 , J = 5.4) , 10.79 (wide p , D ppm • 13 _c NMR (DMSO-d6) : δ 20.7 0, 26, 34, 38.07, 44 , 75, 49 , 97, 55.23. 110.26 114.58 114.82. 115.13. 116.35. 122. 73. 123 , 02,

128.10, 130.38, 131.61, 149.57, 160.11, 163.35, 168.95.

Analysis for ^C 22 ^H 27 ^N 5 ° 2 · HCl:

H, 6.56; N, 16.29. Found: C, 61.57; H, 6.54; N, 16.34.

156

Example 73

a) Process for the preparation of ethyl [N- [2 - [[[4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] amino] carnonyl] phenyl] carbamate hydrochloride]

1.5 g (3.66 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -

-1-piperazinyl / butyl] benzamide (Example 36), 0.638 mL (0.463 g, 4.58 mmol, 1.25 equivalents) of triethylamine and 10 mL of anhydrous chloroform were placed in a 50 mL round bottom flask which was dried flame. The reaction mixture was placed under a nitrogen atmosphere, cooled with an ice bath, and a solution of 0.385 mL (0.437 g, 4.03 mmol, 1.1 equivalents) of ethyl chloroformate (Aldrich Chemical Company) in 10 mL of anhydrous chloroform was added dropwise. After the addition of ethyl chloroformate was complete, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. An additional portion of triethylamine (0.51 mL, 0.37 g, 3.66 mmol, 1.0 equiv) and 0.35 mL (0.4 g, 3.66 mmol) was added to the reaction mixture. the mixture is transferred to a solution and washed. The layers are separated

The organic layers are combined,

The free base is obtained with a mixture of ethyl acetate and triethylamine and then 0.1% triethylamine, and dichloromethane and sodium are added.

, 1.0 equivalent) of ethyl chloroformate.

at room temperature for 4 days. The diluting funnel, saturated bicarbonate solution and the aqueous layer were dried over magnesium sulfate, and the crude was extracted with dichloromethane.

filtered and evaporated to an orange oil by chromatography containing 0.1% containing 0.1% triethylamine as 0.49 g of the free base as an oil by adding 0.96 mL of 0.46 g (0.96 mmol) in the mixture 1-Normal (1.0 hydrogen chloride. The salt, hydrochloride) was filtered off and dried in a vacuum oven to give 0.285 g of the title compound as a very rapid 2: 1 hexanes with ethyl acetate as eluents. To the solution of the free base with dichloromethane and ethyl acetate, an equivalent of an ether solution is obtained as a white solid, m.p.

195.5 C. Yield: 20%.

157 ¹ H NMR (DMSO-d ₆ ): δ 1.24 (t,

3.47 (m, (t m, 1,

7.79 (dd, J = 0.9, 10.97 (m, 2)), 3.26 (m, (q, 2, J = 7.2),

1, J = 1,1,7,0

J = 8.4), 5.5),

6).

7.10

8.1),

8.20 (dd, 1,

10.85 (broad s, 1),

3, J = 7.2), 1.62 (m, 2),

2), 3.61 (m, 2), 4.07 (m, 2), J = 7.7), 7.49 (m, 2), 7.60

1, J = 1.5, 7.9), 8.12 (tm,

8.3), 8.89 (broad t, 1.1 J (s, 1) ppm).

1.83

4.14 (ddd, 2, ¹³ C NMR (DMSO-d₆): δ 14.41, 20.68, 26.01, 38.47, 46.44,

50.53. 124.67. 162.24. 55.16, 60.61, 118.62, 127.00, 128.18, 128.24, 168.36. 119.59. 132.18. 121.25. 139.30. 121.70. 152.16. 124.04 159.91 analysis for C ₂₅ H ₃₁ N ₅ O ₃ S. HC1: calculated: 57.96% C, 6.23% H, 13,52% N, found: % C, 58.07;% H, 6.28. 13,47% N.

Example 74

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2,6-dihydroxybenzamide hydrochloride

1.46 mL (2.4 g, 20 mmol, 3.8 equivalents) thionyl chloride, 0.05 mL anhydrous N, N-dimethylformamide, 15 mL anhydrous toluene and 1.2 g (5.15 mmol) 3-bromo-2 acid 6-dihydroxybenzoic acid [produced by bromination of dihydroxybenzoic acid (Aldrich Chemical Company) with bromine according to the method of FP Doyle et al., In J. Chem. Soc. 497-506 (1963)] is introduced into a 100 ml three-necked round-bottomed flask which has been flame-dried. The solution was placed under a nitrogen atmosphere and heated at 60-85 ^° C for 1 hour. The solvent was evaporated under reduced pressure and a mixture of 15 mL of anhydrous dichloromethane and 1.08 mL (0.782 g, 7.73 mmol) of triethylamine was added to the solid residue. To the resulting suspension was added a solution of 1.5 g (5.15 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b) in 15 ml of anhydrous dichloromethane and the reaction the mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was transferred to a separatory funnel, dichloromethane was added and the solution was washed

158 with saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic extracts were combined, dried (MgSO4), filtered and evaporated. 2.94 g of crude material are obtained in the form of a brown-beige solid. The free base was purified twice by flash chromatography, eluting with dichloromethane: methanol (93: 7). 0.703 g of the free base is obtained in the form of a yellow solid. 0.703 g (1.39 mmol) of the free base was dissolved in a mixture of dichloromethane and ethyl acetate and 1.39 ml of 1N (1 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, is filtered off, washed with ether and dried in a vacuum oven. There was obtained 0.454 g of the title compound as an off-white solid, m.p. 228-230 ° C (dec.). Yield 16%.

¹ H NMR (DMSO-d 6): δ 1.62 (m, 2), 1.77 (m, 2), 3.00-3.70 (m, 10), 4.05 (m, 2), 6.49 (d, 1, J = 8.8), 7.48 (tm, 1, J = 7.2), 7.48 (d, 1, J = 8.8), 7.60 (t 1, J = 7.6), 8.13 (t, 2, J = 8.8), 9.09 (broad s, 1), 10.50 (broad s, 1), 11.85 (broad s, 1), 14.81 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.71, 26.05, 38.32, 46.47, 50.58,

55.16, 99.68, 103.61, 107.57, 121.25, 124.05, 124.68, 127.00,

128.18, 135.99, 152.15, 157.05, 159.25, 162.26, 169.57.

Analysis for ^C 22 ^H 25 ^BrN 4 ^S ° 3 ^'HC1: Calculated: 48.76% C, 4.84% H, 10.34% N Found: 48.67% C, 4.86% H, 10, 25% N.

Example 75

a) A process for the preparation of 6-fluoroisatinic anhydride

3.0 g (19.3 mmol) of 2-amino-6-fluorobenzoic acid (Maybridge Chemical Company), 15.0 g (75.8 mmol, 3.9 equivalents) of trichloromethyl chloroformate (Johnson-Matthey Chemical Company) and Place 60 ml of anhydrous 1,4-dioxane in a round-bottomed flask

159, 250 ml, equipped with a magnetic stir bar. The solution was placed under nitrogen and refluxed for 6 hours. The reaction mixture was allowed to cool to room temperature and evaporated. There was thus obtained 3.8 g of a crude material which was an off-white solid. This material was used without further purification.

^X H NMR (DMSO-d₆): δ 6.97 (d, 1, J = 8.2), 7.06 (dd, 1, J =

8.4, 10.7), 7.73 (m, 1), 11.90 (broad s, 1) ppm.

b) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6-fluorobenzamide hydrochloride

1.5 g (8.28 mmol) of 6-fluoroisatinic anhydride and 40 ml of anhydrous tetrahydrofuran are placed in a 300 ml round-bottom flask, which has been flame-dried. The reaction mixture was placed under nitrogen and a solution of 2.4 g (8.28 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole ( Example 13 (b)) in 25 ml of anhydrous tetrahydrofuran. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated and the crude free material was purified by column chromatography eluting with dichloromethane: methanol (19: 1). 2.79 g of the free base is obtained in the form of a yellow oil. The free base was dissolved in ethyl acetate and 6.53 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The salt, hydrochloride, is recrystallized from aqueous ethanol. This gives 2.0 g of the title compound as a beige solid, m.p. 218-220 ° C. Yield: 52%.

^X H NMR (DMSO-d₆): δ 1.57 (m, 2), 1.80 (m, 2), 3.10 to 3.75 (m, 10), 4.10 (br d, 2, J = 13.1), 5.89 (broad s, 2), 6.34 (dd, 1, J = 8.0, 10.5), 6.53 (d, 1, J = 8.2) , 7.09 (ddd, 1, J = 6.8, 8.0, 8.2), 7.49 (t, 1, J = 7.6), 7.62 (t, 1, J = 7) 5), 8.15 (t, 2, J = 7.2), 8.28 (m, 1), 10.55 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.75, 26.38, 38.39, 46.57, 50.66,

55.38, 101.81, 102.27, 107.65, 108.01, 111.63, 111.68, 121.49,

160

124.32, 124.93, 127.29, 128.44, 131.20, 131.42, 149.90, 150.03,

152.46, 158.21, 162.58, 163.05, 164.66.

Analysis for ^C 22 ^H 26 ^FN 5 ^OS · ^HCl: calculated: C 56.95%, H 5.86%, N 15.09%, found: C 57.06%, H 5.95%, 14.94% N.

Example 76

(a) Method for the preparation of 3-fluoroatric anhydride and 6-fluoroisatinic anhydride ml of anhydrous chloroform, 10.0 g (60.2 mmol). 3-fluorophthalic anhydride (Fluorchem Limited) and 8.0 mL (60.2 mmol, 1.0 equivalents) of azidotrimethylsilane (Aldrich Chemical Company) were introduced under a nitrogen atmosphere into a 250 mL three-necked round-bottomed flask which was dried flame. The reaction mixture is gently heated with a heat gun until gas evolution is observed and then refluxed for 3.5 hours. The solution was allowed to cool to room temperature and then 10 mL of 95% ethanol was added. The milky solution was cooled with an ice bath and the resulting precipitate was filtered off and dried in a vacuum oven. This gives 7.78 g of the title compound as an off-white solid. 1H NMR showed a 60:40 mixture of 3-fluoro- and 6-fluoro-isomers.

3-Fluoroisatinic anhydride:

¹ H NMR (DMSO-d 6, 300 MHz): δ 7.24 (dt, 1, J = 4.7, 8.1),

7.68 (ddd, 1, J = 1.3, 8.2, 10.7), 7.76 (dt, 1, J = 7.9, 0.9) ppm.

^{The 1} H NMR signals observed for 6-fluoroisatinic anhydride were identical to those found in Example 75 a). This mixture was used without further purification.

161

b) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-fluorobenzamide hydrochloride in tetrahydrofuran, 2.55 g (8.80) mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole and 1.59 g (8.80 mmol, 1.0 equivalent) of a mixture of 3-fluoroisatinic anhydride and 6- of fluorisatin in a 40:60 ratio is introduced into a three-necked round-bottomed flask of 100 ml. The reaction mixture was allowed to stir at room temperature for 10 minutes and the solvent was removed by rotary evaporation. The resulting viscous oil was purified four times by flash chromatography on silica gel with 2: 1 ethyl acetate: hexanes and 100% ethyl acetate as eluents. This gives 0.88 g of the title compound as its free base. This material was dissolved in ethyl acetate and 1.89 mL of 1N (1.0 equiv.) Ethereal HCl was added to the solution. The salt, hydrochloride, is recrystallized twice from ethanol. 0.36 g (15% of theory, based on 3-fluoroisatinic anhydride) of the title compound is obtained as brown crystals, m.p. 175 DEG-176 DEG C. ^{@ 1} H NMR (DMSO-d6, 200 MHz). ): δ 1.59 (m, 2), 1.80 (m, 2), 3.18 - 3.66 (m, 10), 4.09 (wide d, 2, J = 13.3), 4.30 (broad s, 2), 6.56 (ddd, 1, J = 5.1, 8.0, 8.0), 7.14 (dd, 1, J = 1.4,

8.0), 7.20 (dd, 1, J = 1.2, 8.0), 7.41 (d, 1, J = 8.0), 7.49 (tm, 1, J = 7) 7), 7.62 (tm, 1, J = 7.4), 8.14 (t, 2, J = 6.9), 8.48 (broad t, 1, J = 5.6), 10.72 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 20.68, 26.26, 38.17, 46.41, 50.49, 55.18, 113.99, 114.09, 116.63 , 116.87, 117.32, 117.38,

121.24, 123.72, 123.75, 124.05, 124.67, 127.00, 128.17, 137.77,

137.95, 149.63, 152.16, 152.78, 162.27, 168.00, 168.04.

Analysis for ^C 22 ^H 26 ^{FNOS 'HC1:} Calculated: 56.95% C, 5.87% H, 15.09% N Found: 56.93% C, 5.95% H, 15.03% N.

162

Example 77

a) Method for the preparation of 2 - [(tert-butoxycarbonyl) amino] -benzoic acid g (0.182 mol) of 2-aminobenzoic acid and 100 ml of 1,4-dioxane are introduced into a 2-liter round-bottom flask and cooled on an ice bath. To the mixture was added 125 mL of 5% aqueous sodium carbonate, and then slowly added

99.5 g (0.456 mol, 2.5 equivalents) of di-tert-butyl dicarbonate (Aldrich Chemical Company) in 120 mL of 1,4-dioxane. When the addition was complete, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 67 hours. The reaction mixture was evaporated to a viscous orange-brown solution. This solution was diluted with 140 mL of water and cooled in an ice bath. The pH of the solution is adjusted to 2 by addition of 1N hydrochloric acid. The reaction mixture was transferred to a separatory funnel and the product was extracted with ethyl acetate. The organic phase is separated, washed with water, dried over magnesium sulphate, filtered and evaporated. An off-white solid is obtained. This solid was triturated with hexanes, filtered and dried. This gives 38.16 g of the title compound. Yield 88%.

^X 1 HNMR (CDCl _3): δ 1.55 (s, 9), 7.05 (tm, 1, J 7.7), 7.58 (tm, 1, J = 7.9), 8, 11 (dd, 1, J = 1.6, 8.0), 8.48 (d, 1, J = 8.6), 10.03 (s, 1), 10.84 (broad s, 1) ppm

b) Process for the preparation of 2 - [(tert-butoxycarbonyl) amino] -N- (4-hydroxybutyl) benzamide

37.94 g (0.160 mol) no / benzoic acid, 26.8 ml (19.46 g, anhydrous triethylamine and 125 ml)

2 - [(tert-butoxycarbonyl) amino (0.192 mol, 1.2 equivalents) of anhydrous terahydrofuran is contacted in a 1 liter three-necked round bottom flask equipped with a magnetic stir bar, thermometer, dropping funnel and nitrogen inlet, a flask which has been previously flame dried is used. The orange solution was added

163 was cooled to -25 ° C with a dry ice (carbon dioxide) bath in acetone and 20.8 mL (21.90 g, 0.160 mol, 1.0 equivalent) of isobutyl chloroformate (Aldrich Chemical Company) was added dropwise. The temperature is maintained at -15 to -30 ° C during the addition of isobutyl chloroformate. After the addition of isobutyl chloroformate is complete, the resulting thick suspension is swirled for 5 minutes. A solution was slowly added to the reaction mixture

14.8 mL (14.3 g, 0.161 mol, 1.0 equivalent) of 4-amino-1-butanol (Aldrich Chemical Company) in 50 mL of anhydrous tetrahydrofuran and allowed to stir at -15 to -30 ° C for 50 minutes. Remove the cooling bath and allow the solution to stir at room temperature for 18 hours. The reaction mixture was then transferred to a separatory funnel, ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 62.1 g of crude material are obtained in the form of an orange liquid. The crude material was purified by flash chromatography with ethyl acetate as eluent. This gives 41.34 g of the title compound as a pale yellow oil. Yield: 84%.

^X 1 HNMR (CDCl _3): δ 1.52 (s, 9), 1.72 (m, 4), 3.48 (q, 2, J

6.2), 3.75 (m, 2), 6.59 (broad s, 1), 6.97 (tm, 1, J = 7.5), 7.42 (m, 2), 8, 36 (dd, 1, J = 0.9, 8.9), 10.22 (broad s, 1) ppm.

c) Process for the preparation of 2 - [(tert-butoxycarbonyl) amino] -N- [4- (methylsulfonyl) oxy] butyl] benzamide

14.0 g (45.3 mmol) of 2 - [(tert-butoxycarbonyl) amino] -N- (4-hydroxybutyl) benzamide and 100 ml of anhydrous pyridine are introduced into a 500 ml round-bottomed flask previously charged flame dried and placed under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and 7.0 mL (10.38 g, 90.6 mmol, 2 equivalents) of methanesulfonyl chloride (Aldrich Chemical Company) was added dropwise. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours.

164

The reaction mixture was evaporated to give an orange oil. The oil was transferred to a separatory funnel using ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered and evaporated. It will be obtained

18.19 g of crude material as an orange oil. The mesylate was purified by 1: 1 column chromatography, eluting with the title compound, corresponding to 65% of theory.

with a mixture of ethyl acetate and hexanes in a tanning agent. 11.46 g of compound are obtained in the form of a pale orange oil. Yield ¹ H NMR (CDCl ₃ ): δ 1.52 (s, 9), 1.81 (m, 4), 3.03 (s, 3),

3.49 (q, 2, J = 6.3), 4.30 (t, 2, J = 6.0), 6.27 (broad S, 1), 6.99 (tm, 1, J = 8.2), 7.42 (d, 1, J = 7.9), 7.44 (m, 1), 8.36 (dm, 1, J = 8.4), 10.13 (broad s 1) ppm.

d) Method for producing 3- (1-piperazinyl) -1,2-benzisothiazole-1,1-dioxide

16.93 g (84 mmol) of 3-chlorobenzisothiazole-1,1-dioxide (European Patent Application No. 0 196 096), 43.5 g (0.505 mol, 6.0 equivalents) of piperazine (Aldrich Chemical Company) and 9 ml of toluene was added to a 500 ml three-necked round bottom flask. The reaction mixture was placed under a nitrogen atmosphere and heated at 160-170 ° C for 22 hours. The reaction mixture solidified upon cooling to room temperature. The crude material was partitioned between chloroform and water. The organic layer was separated, washed three times with 400 ml of water each time, dried over magnesium sulfate, filtered and evaporated. There was obtained 7.24 g of the title compound as a brown solid. Yield: 34%.

^X 1 HNMR (CDCl _3): δ 1.74 (br s, 1), 3.08 (t, 4, J = 5.1), 4.03 (t, 4, J = 5.0), 7 68 (m, 2), 7.84 (dd, 1, J = 1, 2, 6.9), 7.97 (dd, 1, J = 1.8, 6.9) ppm.

This material was used without further purification.

165

e) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide-S, S-dioxide

3.2 g (12.7 mmol) of 3- (1-piperazinyl) -1,2-benzisothiazole-1,1-dioxide, 5.0 g (12.9 mmol, 1.02 equivalents) t-butoxycarbonyl) amino] -N- [4 - [(methylsulfonyl) oxy] butyl] benzamide, 2.2 mL (1.60 g, 1.58 mmol, 1.25 equivalents) of triethylamine and 75 mL of anhydrous acetonitrile are added. into a 500 ml round-bottom flask which has been vopored by flame-drying and placed under a nitrogen atmosphere. The reaction mixture was refluxed for 22 hours. The orange solution was transferred to a separatory funnel with ethyl acetate and the solution was washed with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 6.09 g of a yellow-beige glass-like substance is obtained. The crude material was purified by flash chromatography with ethyl acetate / methanol (19: 1) to give 4.58 g of the title compound as a light beige glass. Yield: 62%.

^X 1 HNMR (CDCl _3): δ 1.52 (s, 9), 1.64 (m, 4), 2.47 (br t, 2, J = 6.5), 2.63 (br t, 4, J = 5.0), 3.48 (broad q, 2, J = 6.2), 4.03 (broad t, 4, J = 4.9), 6.50 (broad s, 1) 6.98 (t, 1, J = 7.6), 7.41 (d, 1, J = 7.7), 7.43 (m, 1), 7.69 (m, 2), 7 , 81 (d, 1, J = 7.7), 7.96 (d, 1, J = 7.2), 8.36 (d, 1, J = 8.6), 10.14 (broad s 1) ppm.

f) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide-S, S-dioxide hydrochloride ml of trifluoroacetic acid (Aldrich Chemical Company) , 100 mL of chloroform, 8 mL of anhydrous anisole (Aldrich Chemical Company) and 4.58 g (7.98 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) 1-piperazinyl / butyl] The 2- (tert-butoxycarbonyl) amino / benzamide-S, S-dioxide was contacted in a 500 ml round bottom flask and stirred at room temperature for 30 hours. The reaction mixture was evaporated and the resulting orange liquid dissolved

166 in dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. The crude material was obtained as an orange liquid. This material was purified by column chromatography using a 97: 3 mixture of ethyl acetate and methanol and a 96: 4 mixture of ethyl acetate and methanol as eluents. 3.06 g of the free base is obtained. 1.95 g (4.42 mmol) of this free base was dissolved in dichloromethane and 4.64 ml of 1N (1.05 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, was recrystallized twice from aqueous ethanol. There was obtained 0.83 g of the title compound as a light beige solid, m.p. 259 DEG-261 DEG C. (decomposition). Yield: 34%.

¹ H NMR (DMSO-d 6): δ 1.58 (m, 2), 1.78 (m, 2), 3.00-3.80 (m, 8), 3.95 (broad s, 2) 4.68 (broad s, 2), 6.54 (t, 1, J = 7.4), 6.71 (d, 1, J = 8.1), 7.15 (tm, 1, J) = 7.6), 7.51 (dm, 1, J = 7.4), 7.87 (s, 2), 8.09 (m, 1), 8.30 (m, 2) ppm.

¹³ C NMR (DMSO-d 6): δ 20.87, 26.48, 38.22, 44.64, 50.07, 55.31, 114.94, 115.19, 116.66, 122.34, 127.14, 127.30, 128.39, 131.88, 133.55, 133.77, 144.16, 149.75, 160.56, 169.25.

IR (KBr): 1297, 1163 cm ^{@ -1} .

MS ion spray m / z (relative intensity): 442 (MH ⁺ , 100).

Analysis for ^C 22 ^H 27 ^N 5 ^S 3 °. H, 5.91; N, 14.67. Found: C, 55.08; H, 6.00; N, 14.58.

Example 78

a) A process for the preparation of 1,4-dihydro-2H-3,1-benzothiazine-2,4-dithione

3.0 g (18.39 mmol) of isatinic anhydride (Aldrich Chemical Company), 18.0 g (40.49 mmol, 2.2 equivalents) of sulfide

167 of phosphorus (Aldrich Chemical Company) and 100 ml of xylene were contacted in a 500 ml round bottom flask, which was flame dried, and placed under a nitrogen atmosphere. The reaction mixture is refluxed for 19 hours, then allowed to cool to room temperature and filtered. The filtered solid was washed with tetrahydrofuran and the combined filtrates were evaporated. The crude material is obtained as a red-brown solid. This material was purified by flash chromatography with 3: 1 hexanes / ethyl acetate as eluent. 2.44 g of the title compound are obtained as a purple solid. Yield: 63%.

¹ H NMR (DMSO-d 6): δ 7.43 (t, 1, J = 7.4), 7.56 (d, 1, J =

8.2), 7.90 (t, 1, J = 7.7), 8.33 (d, 1, J = 8.2) ppm.

f) 2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] thiobenzamide hydrochloride »ml of anhydrous tetrahydrofuran and 2.9 g (13.7 mmol) The 1,4-dihydro-2H-3,1-benzothiazine-2,4-dithione is contacted in a 1 liter round bottom flask and placed under a nitrogen atmosphere. Then a solution of 4.2 g (14.4 mmol, 1.05 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b) in 35 mL was slowly added. of anhydrous terahydrofuran. The reaction mixture was allowed to stir at room temperature for 30 minutes. Then an additional portion of 1.0 g (3.45 mmol, 0.25 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13 b)) in 10 mL was added. of anhydrous terahydrofuran and the reaction mixture is allowed to stir at room temperature for 15 minutes. The suspension is filtered and the filtrate is evaporated. 7.6 g of a red-orange oil residue are obtained. This residue was combined with an additional 0.65 g of the crude material obtained in the previous experiment. The combined material was partially purified by flash chromatography twice at high speed using a 97: 3 mixture of dichloromethane and methanol as eluent. Further purification is performed on Harrison's research chromatotron by gradual elution, using 100% dichloromethane, dichloromethane: methanol 99: 1.

168 and a 97: 3 mixture of dichloromethane and methanol. 0.718 g of the free base was obtained as a yellow oil. 0.718 g (1.69 mmol) of this free base was dissolved in ethyl acetate and 1.69 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The solids were filtered off, washed with ethyl acetate and ether and recrystallized from ethanol. The title compound was obtained as a yellow solid (0.229 g), m.p. 198 DEG-201 DEG. Yield: 2.7%.

^X H NMR (DMSO-d₆): δ 1.78 (m, 4), 3.05 to 3.80 (m, 10), 4.10 (br d, 2, J = 12.7), 5, 74 (broad s, 2), 6.59 (t, 1, J = 7.5), 6.74 (d, 1, J = 8.0), 7.08 (m, 2), 7.50 (t, 1, J = 7.7), 7.63 (t, 1, J = 7.6), 8.15 (t, 2, J = 7.2), 10.30 (m, 1) , 10.83 (m, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 21.74, 25.35, 45.37, 47.32, 51.43,

56.10, 118.56, 118.78, 122.18, 124.98, 125.59, 127.93, 128.39,

128.49, 129.11, 129.37, 130.98, 143.37, 153.08, 163.20, 197.17.

Chemical ionization (CI) MS m / z (relative intensity): 426 (MH ⁺ , 100).

Analysis for ^C 22 ^H 27 ^N 5 ^S 2 · ^HCl: calculated: 57.19% C, 6.11% H, 15.16% N, found: C 56.95%, H 6.17, 14.98 % N.

Example 79

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] -benzamide-S-oxide

1.48 g (6.29 mmol) of 3- (1-piperazinyl) -1,2-benzisothiazole-1-oxide (J. Med. Chem. 34, 3316 (1991)), 2.52 g (6.52) mmol, 1.04 equivalents) 2 - [(tert-butoxycarbonyl) amino] -N- [4 - [(methylsulfonyl) oxy] butyl] benzamide (Example 77 c)), 1.05 mL (0.762 g,

7.53 mmol, 1.2 equivalents) of triethylamine and 50 ml of acetonitrile are placed in a 250 ml round-bottomed flask and placed

169 under a nitrogen atmosphere. The reaction mixture was refluxed for 24 hours. The orange suspension was transferred to a separatory funnel, ethyl acetate was added, and the solution was washed with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated. 3.08 g of an orange-yellow residue are obtained. The crude material was purified by flash chromatography using a 97: 3 mixture of dichloromethane and methanol and a 95: 5 mixture of dichloromethane and methanol as eluents. This gives 1.9 g of the title compound as a beige glass. Yield: 57%.

¹ H NMR (CDCl ₃ ): δ 1.51 (s, 9), 1.69 (m, 4), 2.46 (t, 2, J = 6.8), 2.61 (t, 4, J = 5.0), 3.47 (q, 2, J = 6.2), 4.00 (m, 4), 6.56 (W, S), 6.97 (ddd, 1, J) = 1.1, 7.3, 7.8), 7.41 (d, 1, J = 7.6), 7.42 (m, 1), 7.60 (m, 2), 7.83 (dm, 1, J =

6.3), 7.99 (dm, 1, J = 6.1), 8.36 (d, 1, J = 8.0), 10.11 (broad s, 1) ppm.

b) A process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide-S-oxide hydrochloride hydrate

1.9 g (3.6 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxacarbinol) amino] benzamide- S-oxide, 5.0 ml of anhydrous anisole (Aldrich Chemical Company), 68 ml of dichloromethane and 17 ml of trifluoroacetic acid are introduced into a 300 ml round bottom flask. The flask was equipped with a magnetic stir bar and nitrogen inlet and the solution was allowed to stir at room temperature for 30 minutes. The reaction mixture was evaporated and the crude material was dissolved in dichloromethane. Saturated sodium bicarbonate solution was then added and the mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. The crude material was partially purified by flash chromatography using a 97: 3 mixture of dichloromethane and methanol and dichloromethane / MeOH.

170 toluene in a ratio of 95: 5 as eluents. 2.41 g of an orange-brown oil are obtained. This material was further purified by flash chromatography using a gradient elution using a mixture of dichloromethane and methanol containing 98-95% dichloromethane and 2-5% methanol. 0.57 g of the free base is obtained in the form of a white glass-like substance. This free base was dissolved in dichloromethane and 1.34 mL of 1N (1.0 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, is filtered off and dried. There was obtained 0.47 g of the title compound as a hygroscopic off-white solid, m.p. 208 DEG-213 DEG C. (decomposition). Yield: 27%.

^X H NMR (DMSO-d₆): δ 1.5

3.28 (m, 2); 3.45 (m, 2);

2), 4.67 (broad S, 2), 6.54

2), 3.17 (m, 2),

3.73 (wide s,

6.71 (d, J, J =

8.1), 7.15 (ddd, J)

7.75 (m, 2), 8.09 (m, = 1.5, 7.1,

1), 8.22 (m,

8.4), 7.51 (d,

1, J = 8.1)

1), 8.32 (broad t, 1, J =

5.3), 11.25 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.65, 26.28, 38.10, 44.31, 50.17,

55.15, 116.45, 116.54, 117.52, 125.45, 126.57, 128.23, 129.84,

131.69, 131.93, 147.10, 156.75, 164.53, 168.56.

IR (KBr): 1069 cm ^-1 .

MS ion spray m / z (relative intensity): 426 (MH ⁺ , 100).

Analysis for ^C 22 ^H 27 ^N 5 ^S 2 · ° ^{HC1 H} 2 ^0: Calculated: 55.05% C, 6.30% H, 14.59% N, 3.75% H _2, Found: 55, 28% C, 6.21% H, 14.58% N, 4.07% H ₂ O.

Example 80

a) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [[N- (9H-fluoren-9-ylmethoxy) carbonyl] -L] valyl] aminobenzamide

171

2.39 g (5.84 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36), 60 mL of anhydrous chloroform and 60 ml of a 5% aqueous solution of sodium carbonate is introduced into a 300 ml round bottom flask. A solution of 3.3 g (9.22 mmol, 1.58 equivalents) of N - [(9H-fluoren-9-ylmethoxy) carbonyl] -L-valyl chloride (made according to the method described by LA Carpino) was added to the biphasic reaction mixture. et al., J. Org. Chem., 51, 3734 (1986), using N - [(9H-fluoren-9-ylmethoxy) carbonyl] -L-valine (BACHEM California) in 60 mL of chloroform. The reaction mixture was allowed to stir at room temperature for 10 minutes and then transferred to a separatory funnel, chloroform was added and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated to give 6.48 g of a pale yellow oil crude. Purification by flash chromatography eluting with ethyl acetate / methanol (95: 5) gave 4.5 g of the title compound as a white glass charkter solid.

answer á 95 % of theory. ^X H NMR (CD Cl ₃ ): δ 1.00 (d, 3, J = 6,9), 1.07 (d, 3, J = 6.8), 1.64 (M, 4), 2.36 (m, 3), 2.62 (M, 4), 3.38 (m, 2), 3.53 (wide t, 4 , J = 4.8), 4.37 (m, 4), 5 55 (D, i, J = 8.6), 6.83 (wide with, D, 7.10 (t, 1, J = 7.6). 7 30 (m, 4), 7.48 (t, 4, J = 7.1), 7 , 66 (t, 2, J = 8.1) 7.82 (m , 4), 8.61 (d, 1, J = 8.3), 11.59 (br s, 1) ppm.

b) A process for the preparation of N- [2- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] phenyl] -L-valinamide trifluoroacetate hydrate

3.57 g (4.88 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [[N- (9H-fluorene-9- ylmethoxy) carbonyl / -L-valyl] -aminobenzamide, 110 ml of chloroform and 50 ml of 4- (aminomethyl) piperidine (Aldrich Chemical Company) are placed in a 500 ml round bottom flask. The reaction mixture was stirred under nitrogen at room temperature for 30 minutes. The reaction mixture was transferred to a separatory funnel and 150 mL of chloroform was added.

172

The organic layer was washed three times with 250 ml of water each time, separated, dried over magnesium sulfate, filtered and evaporated to give 5.67 g of the crude product as a yellow oil. The free base was purified by column chromatography on silica gel with ethyl acetate / methanol (85:15) as eluent. 2.13 of the free base is obtained in the form of a viscous oil. A portion of the free base weighing 1.17 g was purified by further semi-preparative high pressure liquid chromatography (Vydac C-18 column) with a mixture of 0.1% aqueous trifluoroacetic acid and 0.1% trifluoroacetic acid in acetonitrile, at a gradient of 9: 1 to 1: 9. The appropriate fractions are combined, evaporated, dissolved in aqueous methanol and lyophilized. This gives 0.87 g of the title compound as a white powder. Yield: 48%.

¹ H NMR (DMSO-d 6): δ 1.01 (t, 6, J = 6.5), 1.60 (m, 2), 1.77 (m, 2), 2.18 (m, 1) ), 3.30 (m, 8), 3.61 (m, 2), 3.95 (m, 1), 4.10 (m, 2), 7.25 (t, 1, J = 7, 7), 7.48 (tm, 1, J = 7.5), 7.58 (m,

2), 7.76 (d, 1, J = 7.8), 8.13 (t, 2, J = 9.0), 8.24 (d, 1, J = 8.4), 8.40 (broad s, 1), 8.89 (br t, 1, J = 4.8) , 10.33 (wide p 1), 11.48 (s, 1) ppm. 13 _c NMR (DMSO-d6): δ 17.96, 18.05. 20.90, 25.92, 29.88.

46.63, 50.67, 55.31, 58.78, 121.26, 121.58, 123.01, 123.95,

124.02, 124.69, 126.97, 128.21, 128.25, 131.83, 137.09, 152.16,

157.69, 158.11, 158.54, 158.96, 162.17, 166.70, 168.00.

Analysis for .delta. 2.35 CF3CO2H. H, 5.08; N, 10.64; F, 16.95; I, 1.71%. Found: C, 48.18; , 10% H, 10.78% N, 16.90% F, 1.79% H ₂ O.

Example 81

a) Method for the preparation of N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -2 - [[N- (9H-fluoren-9-ylmethoxy) carbonyl]] - D-valyl] amino-benzamide

This compound is prepared in an analogous manner to that described above

173 described in Example 80 a), using 2.33 g (5.7 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36), 3.22 g (9.0 mmol, 1.58 equivalents) of N - [(9H-fluoren-9-ylmethoxy) carbonyl] -D-valyl chloride 120 mL of anhydrous chloroform and 60 mL of 5% aqueous solution sodium carbonate. (N - [(9H-fluoren-9-ylmethoxy) carbonyl] -D-valine is available from BACHEM California). The crude material was purified to give 3.42 g of the title compound as a white solid. Yield: 82%.

^X 1 HNMR (CDCl _3): δ 1.01 (d, 3, J = 6.8), 1.07 (d, 3, J = 6.8), 1.64 (m, 4), 2, 36 (m, 3), 2.62 (broad t, 4, J = 4.5), 3.42 (m, 2), 3.53 (broad t, 4, J = 4.8), 4, 37 (m, 4), 5.55 (d,

1, J = 8.6), 6.80 (broad S, 1), 7.10 (t, 1, J = 7.2), 7.36 (tm, 4, J = 4.4), 7 48 (tm, 4, J = 7.6), 7.67 (t, 2, J = 8.2), 7.80 (m, 4), 8.62 (dm, 1, J = 8, 9), 11.58 (broad s, 1) ppm.

b) A process for the preparation of N- [2- [N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] carbamoyl] phenyl] -D-valinamide trifluoroacetate hydrate

This compound was prepared as described in Example 80 b) using 3.47 g (4.75 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [[N- (9H-fluoren-9-ylmethoxy) carbonyl] -dvalyl] aminobenzamide, 100 mL of chloroform and 50 mL of 4- (aminomethyl) piperidine. The crude material was purified by column chromatography with ethyl acetate / methanol (85:15) to give 1.99 g of a free base consisting of a viscous oil. A portion of the free base weighing 0.61 g was applied to a semi-preparative column to give 0.54 g of the title compound as a white powder. Yield: 57%.

^X H NMR (DMSO-d₆): δ 1.01 (t, 6, J = 6.5), 1.60 (m, 2), 1.78 (m, 2), 2.18 (m, 1 ), 3.32 (m, 8), 3.62 (m, 2), 3.95 (m, 1), 4.10 (broad d, 2, J = 10.5), 4.56 (broad) s, 3), 7.24 (t, 1, J = 7.7), 7.48 (tm, 1, J = 7.7), 7.58 (m, 2), 7.77 (d, 1, J = 7.5)

174

8.13 (m, 2), 8.23 (d, 1, J = 8.1), 8.34 (broad s, 3), 8.90 (broad t, 1, J = 5.3), 10.54 (broad s, 1), 11.49 (s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 18.91, 18.97, 21.78, 26.86, 30.80,

47.52, 51.55, 56.21, 59.69, 122.18, 122.51, 123.98, 124.87,

124.95, 125.61, 127.90, 129.12, 129.20, 132.72, 138.00, 153.09,

158.68, 159.11, 159.54, 159.98, 163.12, 167.62, 168.91.

Analysis for C ₂₇ H ₃₆ N ₆ O ₂ S. 2.35 CF ₃ CO ₂ H. 0.75 _H2O: Calculated: 48.19% C, 5.08% H, 10.64% N, 16.95% F, 1.71% H ₂ 0, Found: 48.03% C, - 5.06% H, 10.62% N, 16.63% F, 1.68% H ₂ 0th

Example 82

a) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide

3.3 g (8.06 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36), 10 mL of 1,4- Dioxane and 10 ml of a 5% aqueous solution of sodium carbonate are combined in a 250 ml round bottom flask. The flask is additionally provided with a magnetic stirring bar and a dropping funnel. A solution of 4.41 g (20.2 mmol, 2.5 equivalents) of di-tert-butyl dicarbonate (Aldrich Chemical Company) in 10 mL of 1,4-dioxane was added dropwise to the reaction mixture, and the reaction mixture was allowed to stir at room temperature for 45 hours. An additional 1.76 g (8.96 mmol, 1.0 equivalents) of di-tert-butyl dicarbonate in 10 mL of 1,4-dioxane was added to the reaction mixture and the suspension was allowed to stir for 5 days. The reaction mixture was filtered and the filtrate was transferred to a separatory funnel. Ethyl acetate and water were then added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 6.56 g of crude material are obtained in the form of an orange liquid. The crude carbamate was purified by flash chromatography with ethyl acetate as eluent. This gives 3.39 g of the title compound as a yellow oil. Yield: 83%.

175 ¹ H NMR (CDCl ₃ ): δ 1.52 (s, 9), 1.71 (m, 4), 2.50 (broad t, 2, J = 6.4), 2.67 (broad t 4, J = 4.9) 3.48 (m, 2), 3.55 (broad t, 4, J = 4.9), 6.74 (m, 1), 6.98 (tm, 1) J = 7.6), 7.42 (m, 4), 7.82 (d, 1, J = 8.0), 7.90 (d, 1, J = 8.1), 8.36 (dd, 1, J = 1.0, 9.0), 10.18 (broad s, 1) ppm.

b) Method for preparing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide-N1, S, S trioxide

A solution of 4.49 g (13.0-15.6 mmol, 2.0-2.4 equivalents), 50-60% m-chloroperoxybenzoic acid (Aldrich Chemical Company) in 50 mL dichloromethane was added to a solution of 3.32 g. (6.51 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide in 50 mL of dichloromethane. The reaction mixture was allowed to stir at room temperature for 1.5 minutes. The solution was transferred to a separatory funnel and dichloromethane and saturated sodium bicarbonate solution were added. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 4.6 g of a yellow glass crude product are obtained. The crude material was purified by flash chromatography with dichloromethane / methanol (4: 1) as eluent. This afforded 2.28 g of the title compound as a light yellow solid. Yield: 59%.

¹ H NMR (CDCl ₃ ): δ 1.50 (s, 9), 1.84 (m, 2), 2.08 (m, 2),

3.33 (m, 6), 3.50 (m, 2), 4.48 (m, 4), 6.95 (t, 1, J = 7.7),

7.40 (tm, 1, J = 8.0), 7.71 (m, 4), 7.94 (d, 1, J = 6.7), 8.20 (broad s, 1), 8 32 (d, 1, J = 8.8), 10.40 (s, 1) ppm.

c) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide-N1, S, S-trioxide hydrochloride

2.28 g (3.87 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide- N1, -S, S-trioxide, 4.0 mL anhydrous anisole (Aldrich Chemical

176

And 50 ml of anhydrous chloroform were combined in a 500 ml round bottom flask and then 5.0 ml of trifluoroacetic acid (EM Science) was added. The reaction mixture was allowed to stir under nitrogen at room temperature for 30 minutes. To the reaction mixture was added 15 mL of trifluoroacetic acid, and the resulting solution was allowed to stir for 30 minutes. To the reaction mixture was slowly added chloroform and cold saturated sodium bicarbonate solution. The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous phase is extracted with chloroform. Combine the organic layers, dry over magnesium sulfate, filter, and wash. The material was purified by flash chromatography (dichloromethane / methanol 4: 1). 0.686 g of the free base is obtained in the form of a light yellow glass-like substance. 0.686 g (1.55 mmol) of the free base was dissolved in a mixture of dichloromethane and methanol, and 1.55 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, is recrystallized from aqueous ethanol. 0.51 g of the title compound is obtained as a beige solid, m.p. 226-228 ° C. Yield: 26%.

^X H NMR (DMSO-d₆): δ 1.61 (M, 2), 1.91 (m, 2), 3.32 (m, 2), 3.96 (m, 8), 4.75 (broad s) , 2), 6.53 (ddd, 1 J = 1.1, 7.1, 8.1), 6.70 (dd, 1, J = 1.1, 8,4) , 7.15 (ddd, 1 J = 1.4, 7.1, 8.4), 7.52 (dm, 1, J = 8.1), 7.87 (m, 2) 8.10 (M, 1), 8.31 (dm, 2, J = 6.2 ppm. ¹³ C NMR (DMSO-d 6): δ 19.73 26.77 39 00. 42.84, 61.74,

68.28, 115.50, 115.67, 117.27, 123.10, 127.85, 127.88, 129.03,

129.03, 132.56, 134.23, 134.51, 144.80, 150.54, 161.17, 169.90.

IR (KBr): 1311, 1162, 587 cm ^{@ -1} .

MS ion spray m / z (relative intensity): 458 (MH ⁺ , 80), 480 ((M + Na) ⁺ , 100).

177

Analysis for ^C 22 ^H 27 ^N 5 ° 4 ^S · ^HCl 1 ^: calculated: 53.49% C, 5.71% H,

N, 14.18; Cl, 7.18.

% C, 53.57;% H, 5.75;

N, 14.14. Cl, 7.23.

Example 83

a)

Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide-N1-oxide hydrochloride

3.28 g (8.01 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -

of 1-piperazinyl / butyl] benzamide (Example 36) and 75 mL of anhydrous dichloromethane were contacted in a 250 mL round bottom flask. The reaction mixture was allowed to stir under a nitrogen atmosphere and cooled to -78 ° C with a dry ice (carbon dioxide) bath in acetone. (6.7 to 8.0 mmol, 0.8 m-chloroperoxybenzoate m-chloroperoxybenzoate was covered with 25 mL

2.30 g to 1.0 equivalents (Aldrich

-40 ° C of anhydrous dichloromethane and a dry temperature bath is part

The supernatant was tube and acid added. The solution was cooled to ice (carbon dioxide) in acetone. With m-chloroperoxybenzoic acid, the remaining peroxyacid is not dissolved in the cold benzamide solution and is dissolved in an ice bath.

Chemical Nitrogen up to 60% Company).

atmosphere, this desolate is cooled. in 10 ml of anhydrous dichloromethane and cooled

The cold m-chloroperoxybenzoic acid solution was transferred to the benzamide solution and the reaction mixture was stirred at -78 ° C for 30 minutes. The reaction mixture was diluted with dichloromethane, transferred to a separatory funnel, and washed with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 3.57 g of crude material is obtained, which is a beige solid. The crude free base was purified by flash chromatography with dichloromethane: methanol (17: 3) as eluent. A beige solid is obtained. This solid was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, dried (MgSO 4), filtered and evaporated. It will be obtained

178

0.991 g of the free base, in the form of a light beige solid. 0.986 g (2.32 mmol) of the free base was dissolved in a mixture of dichloromethane and methanol, and 2.32 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, is recrystallized from aqueous ethanol. 0.470 g of the title compound is obtained as a brown solid, m.p. 177.5-178.5 ° C (dec.). Yield: 13%.

^X H NMR (DMSO-d₆): δ 1.61 (m, 2, J = 6.8), 3.66 (m, 2), 3.90

13.7), 6.53 (ddd, 1, J = 1.0, 8.4), 7.15 (ddd, 1, J = 1.5,

1, J = 7.6, 7.63 (tm, 1, J (d, 1, J = 8.0), 8.34 (broad)

2), 1.91 (m, 2), 3.29 (broad t, (m, 6), 4.10 (broad d, 2, J =

7.1, 7.6), 6.71 (dd, 1, J = 1.1,

7.1, 8.4), 7.50 (m, 1), 7.52 (dm, = 7.6), 8.14 (d, 1, J = 8.0), 8.20 t, 1, J = 5.6 ppm.

¹³ C NMR (DMSO-d 6): δ 18.87, 26.02, 38.28, 43.90, 61.34, 67.36, 114.88, 115.07, 116.65, 121.54, 124.32, 124.96, 127.17, 128.39, 128.47, 131.91, 149.89, 152.55, 162.12, 169.30.

MS ion spray m / z (relative intensity): 426 (MH ⁺ , 100).

Analysis for ^C 22 ^H 27 ^N 5 ^S 2 · ° ^HC1: Calculated: 57.19% C, 6.11% H, 15.16% N Found: 57.29% C, 6.13% H, 15, 10% N.

Example 84

a) Process for the preparation of 2- / 2- (tert-butoxycarbonyl) hydrazino / benzoic acid

7.5 g (40.0 mmol) of 2-hydrazinobenzoic acid hydrochloride (Aldrich Chemical Company), 40 ml of 1,4-dioxane and 75 ml of a 5% aqueous solution of sodium carbonate are combined in a 500 ml round bottom flask. and cool the ice bath. The flask was additionally equipped with an addition funnel and slowly added dropwise a solution of 9.6 g (44.0 mmol, 1.1 equivalents) of di-tert-butyl dicarbonate.

179 (Aldrich Chemical Company) in 20 ml 1,4-dioxane. Ice bath! The reaction mixture was allowed to stir at room temperature for 6 hours. Another portion of 0.99 g (4.54 mmol, 0.11 equivalents) of di-tert-butyl dicarbonate was dissolved in 10 mL of 1,4-dioxane and the resulting solution was slowly added to the reaction mixture. The reaction mixture was allowed to stir for an additional 26 hours and evaporated to give a red-orange residue. Water (200 ml) was added to the residue and the mixture was cooled in an ice bath. The pH was adjusted to 1 by addition of a 1N aqueous hydrochloric acid solution and the resulting solution was extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to give a solid. The solid was triturated with hexanes and dried in a vacuum oven. 9.13 g of the title compound is obtained as a brown-beige solid. Yield: 91%.

NMR (DMSO-d6): δ 1.43 (s, 9), 6.77 (t, 1, J = 7.5), 6.88 (d, 1, J = 8.2), 7.45 (tm, 1, J = 7.7), 7.83 (dd, 1, J = 1.5, 7.9), 8.89 (s, 1), 9.07 (broad s, 1), 12.98 (broad s, 1) ppm.

b) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2- [2- (tert-butoxycarbonyl) hydrazino] benzamide

2.57 g (10.2 mmol) of 2- / 2- (tert-butoxycarbonyl) hydrazino / benzoic acid, 30 mL of anhydrous tetrahydrofuran and 1.70 mL (1.23 g, 12.2 mmol, 1.2 equivalents) of anhydrous triethylamine is contacted in a 100 ml round bottom flask which has been flame - dried. The orange solution was stirred under a nitrogen atmosphere and cooled to -20 to -35 ° C in a dry ice (carbon dioxide) and isopropanol bath. To the reaction mixture was added 1.32 mL (1.39 g, 1.0 equivalents) of isobutyl chloroformate (Aldrich Chemical Company) and the resulting mixture was allowed to stir for 5 minutes. To the cold solution (20-35 ° C) was added slowly 2.97 g (10.2 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2- benzisothiazole (Example 13 b)) in 30 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to stir at -15 to -30 ° C for 45 minutes. Cooling bath! The reaction mixture was allowed to stir at room temperature

180 for 90 minutes. The reaction mixture was then transferred to a separatory funnel, dichloromethane was added and the solution was washed with saturated sodium carbonate solution. The layers were separated and the aqueous phase was extracted with dichloromethane. The organic layers were combined, dried (MgSO 4), filtered and evaporated. 5.89 g of an orange oil are obtained. The crude material was purified by column chromatography eluting with dichloromethane: methanol (19: 1). This gives 3.01 g of the title compound as a light beige colored glass. Yield: 56%.

¹ H NMR (CDCl ₃ ): δ 1.45 (s, 9), 1.68 (broad t, 4, J = 3.0),

2.49 (broad t, 2, J = 6.8), 2.67 (broad t, 4, J = 4.8), 3.45 (broad q, 2, J = 6.0), 3, 55 (broad t, 4, J = 4.8), 6.32 (broad s, 1), 6.61 (m, 1), 6.78 (tm, 1, J = 7.5), 7, Δ (d, 1, J = 8.2), 7.35 (m, 3), 7.47 (tm, 1, J = 7.5), 7.81 (d, 1, J = 8.0) 7.90 (d, 1, J = 8.0), 8.76 (broad s, 1) ppm.

c) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2-hydrazinobenzamide dihydrochloride hydrate

2.85 g (5.43 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2H-2- (tert-butoxycarbonyl) of hydrazino-benzamide, 5.0 ml of anhydrous anisole (Aldrich Chemical Company) and 75 ml of anhydrous chloroform are combined in a 500 ml round bottom flask. To the light yellow solution was added 25 mL of trifluoroacetic acid (EM Science) with stirring. The reaction mixture was allowed to stir under a nitrogen atmosphere for 10 minutes and then the solution was evaporated under reduced pressure. The residue was transferred to a separatory funnel with chloroform and washed with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with chloroform. Combine the organic layers, wash with saturated sodium bicarbonate, dry over magnesium sulfate, filter, and concentrate to an orange liquid. The crude material was purified by column chromatography by gradient elution with a mixture of 97-95% dichloromethane and 3-5% methanol. 1.54 g of the free base is obtained as a partially solidifying yellow oil. 1,41 g

181 (3.32 mmol) of the free base was dissolved in dichloromethane and added

6.8 ml of 1N (2.05 equivalent) ethereal hydrogen chloride. The resulting salt, dihydrochloride, is recrystallized from a mixture of aqueous ethanol and ether. This gives 1.1 g of the title compound as a yellow solid, m.p. 222-226 ° C. Yield: 40%.

^X H NMR (DMSO-d): 8 1.62 (m, 2), 1.83 (m, 2), 3.17 (m, 2),

3.29 (q, 2, J = 5.8, 6.6), 3.37 (m, 2), 3.54 (broad s, 4), 4.05 (broad s, 2), 6, 99 (t, 1, J = 7.5), 7.12 (d, 1, J = 8.0), 7.46 (m, 2), 7.58 (t, 1, J = 7.6) ), 7.73 (dd, 1, J = 1.3, 7.5), 8.06 (Wide S, 1), 8.09 (d, 1, J = 8.2), 8.13 ( d, 1, J = 8.2), 8.78 (t, 1, J = 5.6), 9.18 (s, 1), 10.27 (broad s, 3), 11.18 (broad) s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.62, 26.15, 38.25, 46.40, 50.51,

55.15, 114.43, 118.83, 120.41, 121.24, 124.07, 124.68, 127.01, 128.17, 128.36, 132.07, 145.66, 152, 14, 162.30, 167.93.

Chemical ionization (CI) MS m / z (relative intensity): 425 (MH ⁺ , 10), 291 (100).

Analysis for ^C 22 ^H 28 ^N 6 ^OS · ² · calculated: 52.17% C, 6.17% H,

0.5 H ₂ 0:

16.59% N, 14.00% Cl,

1.78% H ₂ O, found:

% C, 52.23;% H, 6.34;

16.30% N,

14.04% Cl,

2.05% H ₂ O.

Example 85

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

This compound was prepared as described by J. R. Beck in J. Org. Chem. 37, 3224 (1972), using 50.0 g (0.338 mol) of 2-nitrobenzonitrile (Aldrich Chemical Company), 33.2 ml (36.4 g, 0.343 mmol, 1.11 equivalents) of methylthioglycolate (Aldrich Chemical Company) , 400 ml of Ν, Ν-dimethylformamide and 37.4 g of hydroxide solution

182 mg of potassium in 187 ml of water gives 36.1 g of the title compound as a light beige solid. Yield: 52%.

¹ H NMR (CDCl ₃ ): δ 3.90 (s, 3), 5.92 (broad s, 2), 7.37 (ddd, 1, J = 1.3, 7.0, 8.2) 7.48 (ddd, 4, 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) ppm.

b) A method for producing benzo [b] thiophen-3-amine

32.09 g (0.155 mol) of methyl (3-aminobenzo [b] thiophene-2-carboxylate), 150.0 ml of 1-methyl-2-pyrrolidinone (Aldrich Chemical Company) and 43.0 ml (38.83 g) (0.388 mol, 2.50 equivalents) of 1-methylpiperazine (Aldrich Chemical Company) was contacted in a 1 liter round bottom flask and placed under a nitrogen atmosphere. The light orange solution was heated at 180-185 ° C for 3.5 hours. The reaction mixture was evaporated and the residue was partially purified by column chromatography eluting with an orange liquid. Yield: 87%.

činifdlom.

is obtained

24.7 g of chromatography are obtained with 20.1 g of the compound dichloromethane as an orange liquid. Additional dichloromethane as the eluent of the title, ¹ H NMR (CDCl ₃ ): δ 3.84 (broad s, 2), 6.34 (s, 1), 7.38 (m, 2), 7.61 ( m, 1), 7.80 (m, 1) ppm.

c) A process for the preparation of 1- (benzo [b] thiophen-3-yl) piperazine

15.86 g (0.106 mol) of benzo [b] thiophen-3-amine, 21.07 g (0.245 mol, 2.3 equivalents) of piperazine (Aldrich Chemical Company) and 100 ml of 1-methyl-2-pyrrolidone (Aldrich Chemical Company) is placed in a 500 ml round bottom flask and placed under a nitrogen atmosphere. The reaction mixture is heated at 185-190 ° C for 5.5 hours and then allowed to stand at room temperature overnight. The reaction mixture was evaporated and the residue was purified by elution chromatography with 100% dichloromethane and brine

183 as dichloromethane / methanol 85: 15 as eluents. Obtained 14.41 g of the title compound as a yellow solid. Yield: 62%.

^X 1 HNMR (CDCl _3): δ 2.95 (m, 8), 6.89 (s, 1), 7.38 (m, 2), 7.75 (m, 1), 7.92 (m 1) ppm.

d) Process for the preparation of N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] phthalimide hydrochloride

5.23 g (24.0 mmol) of 1-benzo [b] thiophen-3-yl] piperazine, 8.18 g (29.0 mmol, 1.21 equivalents) of N- (4-bromobutyl) phthalimide (Aldrich Chemical Company) 5.0 mL (3.63 g, 35.9 mmol, 1.5 equivalents) of triethylamine and 100 mL of acetonitrile were combined in a 250 mL round bottom flask and placed under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours. The reaction mixture was then transferred to a separatory funnel, dichloromethane was added and the solution was washed with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, separated, dried (MgSO 4), filtered and evaporated. 13.26 g of crude material are obtained in the form of an orange oil. This material was purified by elution with 1: 1 ethyl acetate: hexanes. 8.5 g of a yellow base are obtained. The free base (1.55 g, 3.69 mmol) was dissolved in ethyl acetate and ethereal HCl (3.70 mL, 1.0 eq.) Was added. The salt, hydrochloride, is recrystallized from aqueous ethanol. This gives 1.30 g of the title compound as a white solid, m.p. > 250 ° C. Yield: 65%.

^X H NMR (DMSO-d₆): δ 3.52 (br s, 4), 3.20 (m, 6), 3.61 (m, 6), 7.11 (s, 1), 7.42 (m, 2), 7.88 (m, 4), 7.89 (d, 2, J = 2.7), 10.56 (broad s, 1) ppm.

184 ¹³ C NMR (DMSO-d 6): δ 20.62, 25.38, 36.94, 48.57, 50.98,

55.03, 108.83, 121.82, 123.08, 123.49, 123.95, 124.80, 131.69,

133.73, 134.43, 138.66, 144.78, 168.02.

Analysis for ^C 24 ^H 25 ^N 3 ^S · 2 ° ^HC1: Calculated: 63.22% C, 5.75% H 9.21% N Found: 63.19% C, 5.78% H, 9, 13% N.

Example 86

a) Method for the preparation of 4- / 4- (benzo [b] thiophen-3-yl-) -1-piperazinyl / butylamine

3.52 g (8.39 mmol) of N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] phthalimide (Example 85 d)), 0.75 g of a 55% solution ( 12.87 mmol, 1.53 equivalents) of hydrazine hydrate (Aldrich Chemical Company) and 25 mL of methanol were combined in a 100 mL round bottom flask and placed under a nitrogen atmosphere. The reaction mixture was refluxed for 105 minutes. The suspension is allowed to cool to room temperature and then 25 ml of water are added. The reaction mixture was acidified to pH 2 by addition of 1N aqueous hydrochloric acid. The resulting solid was filtered off and washed with water. The pH of the filtrate was adjusted to 12 by the addition of 1N sodium hydroxide solution, the reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, decolourised with charcoal, filtered again and evaporated. This afforded 2.00 g of the title compound as a yellow oil which solidified on standing to a tan beige solid. Yield: 82%.

^X 1 HNMR (CDCl _3): δ 1.22 (br s, 2), 1.56 (m, 4), 2.46 (t, 2, J = 7.4), 2.73 (m, 6 ), 3.18 (broad t, 4, J = 4.6), 6.62 (s, 1), 7.34 (m, 2), 7.77 (m, 2) ppm.

b) A process for the preparation of 2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride

185

1.79 g (6.18 mmol) of 4- [4- (benzo [b] thiophen-3-yl) piperazinyl] butylamine, 1.21 g (7.42 mmol, 1.2 equivalents) of isatinic anhydride (Aldrich) Chemical Company) and 25.0 mL of ethanol were contacted in a 100 mL round bottom flask. The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 90 minutes. The solution was diluted with dichloromethane and washed with sodium. The organic phase is separated with a saturated bicarbonate solution and the aqueous phase is extracted with dichloromethane. The organic layers are magnesium, filtered and evaporated to an orange oil. Combined freely, dried with sulfate to give 3.41 g of crude material. The base was purified by flash chromatography with ethyl acetate as eluent.

2.37 g of a colorless oil. The free base (5.41 mmol) was dissolved in ethyl acetate and reagent. 5.41 ml was added to obtain a weight of 2.21 g

1-normal (1.0 equivalent) ethereal hydrogen chloride solution.

The salt, the hydrochloride, is recrystallized from aqueous ethanol and recovered

1.38 g of the title compound as an off-white solid, m.p. 210-212 ° C. The yield corresponds to 50% of theory.

¹ H NMR (DMSO-d 6): (m, 8), 3.61 (broad d (t, 1, J = 7.4), 6.71

J = 8.2), 7.43 (m, 2), (m, 1), 8.33 (broad t, δ 1.61 (m, 2), 4, J = 10.7) (d, 1, J = 8.0)

7.53 (d, J, J)

2, J = 523.7),

1.82

6.43

7.12 = 7.8), /, q j \ w,

10.7256 (wide s,

55.38.

125.08, ¹³ C NMR (DMSO-d6)

109.10, 114.86,

128.42, 131.88, (m, 2), (wide i (s, 1),

7.83 (m δ 20.86, 26.54, 38.25, 48.78, 51.13,

115.12, 116.63, 122.11, 123.77, 124.24,

134.02, 138.96, 145.09, 149.90, 169.29.

Analysis for C ₂₃ H ₂₈ N ₄ OS. HC1:

H, 6.57; N, 12.59. Found: C, 61.83; H, 6.65; N, 12.50.

186

Example 87

a) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2,6-dimethoxybenzamide hydrochloride

100 ml of toluene and 4.32 g (17.6 mmol) of 3-chloro-5-ethyl-2,6-dimethylbenzoic acid (produced by the method of de Paulis et al. In J. Med. Chem. 69 (1986)) is introduced into a 300 ml round bottom flask which has been dried in an oven. The solution was placed under a nitrogen atmosphere and 4.13 mL (5.67 g, 47.6 mmol, 2.7 equivalents) of thionyl chloride (Aldrich Chemical Company) was added. The light yellow reaction mixture was heated to 75 ° C and 0.25 mL of anhydrous dimethylformamide was added. The solution is then heated at 65-75 ° C for 75 minutes. The solvent was removed by rotary evaporation to give the acid chloride as an orange residue. This crude acid chloride was dissolved in 50 ml of anhydrous chloroform and placed under a nitrogen atmosphere. To a solution of the acid chloride was added a solution of 5.63 g (19.4 mmol, 1.1 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)) in 20 ml of anhydrous chloroform, and then 2.94 ml (2.14 g, 2.10 mmol, 1.2 equivalents) of dry triethylamine are added. The reaction mixture is allowed to stir at room temperature for 45 minutes and then the solvent is removed by rotary evaporation. The resulting orange residue was dissolved in dichloromethane and washed with a saturated aqueous potassium carbonate solution.

The organic phase is dried over magnesium sulphate, filtered and evaporated. 10.03 g of an orange viscous oil are obtained. The crude material was adsorbed onto silica gel and purified by flash chromatography on silica gel with ethyl acetate containing 0.1% triethylamine as eluent. 4.78 g of a pale yellow oil are obtained. The salt, hydrochloride, was prepared by adding 9.24 g of a 1N (1.0 equivalent) ethereal hydrogen chloride solution to a solution of the free base in ethanol. The salt was recrystallized from aqueous ethanol and dried in a vacuum oven to give

2.96 g of the title compound as a light brown powder, mp 198.5-200 ° C. The yield corresponds to 30% of theory.

187 ^{Τ Η} NMR (DMSO-d₆): δ 1.16 (t, 3, J = 7.5), 1.60 (m, 2), 1.83 (br s, 2), 2.58 (q , 2, J = 7.5), 3.20 - 3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (broad d, 2, J = 12.1), 7.38 (s, 1),

7.49 (t, 1, J = 7.5), 7.62 (t, 1, J = 7.5), 8.14 (t, 2, J = 7.0), 8.50 (t .Delta., J = 5.3), 10.66 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 14.76, 20.73, 21.80, 26.46, 46.57,

50.67. 55.39, 61.89, 62.27, 121,49, 121.76. 124.30, 124.95 127.28. 128.45, 129.16, 130.17, 134,64, 150.88. 152.48. 153.96 162.56. 164.26. analysis for C ₂₆ H ₃₃ N ₄ O ₃ SC1. HC1: calculated: C 56.41, H 6.19, 10,12% N, found: C 56.31, H 6.18, 10.08% N.

Examples 88 and 89

a) Process for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-6-hydroxy-2-methoxybenzamide hydrochloride and hydrochloride hydrate N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2-hydroxy-6-methoxybenzamide

2.07 g (4.00 mmol) of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2,6-dimethoxybenzamide (Example 87 (a)) was monodemethylated as described in Examples 67 and 68. The two resulting isomers were partially purified by flash chromatography on silica gel with ethyl acetate / hexanes (2: 1) as eluent. Further purifications on Harrison Research Chromatotron with 1: 1 and 2: 1 ethyl acetate: hexanes as eluents gave a total of 1.07 g of the major isomer, N- [4- / 4- (1,2-benzisothiazole-3- yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-6-hydroxy-2-methoxybenzamide _(Rf = 0.18, with ethyl acetate: hexanes 2: 1 as eluant) and 0 , 27 g of the minor isomer, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2-hydroxy-6-methoxybenzamide (Rf) = 0.11, with a mixture of ethyl acetate and hexanes in the ratio

188

2: 1 as eluent) in the form of pale orange oils. The salts, the hydrochlorides of each isomer, are prepared independently of each other by dissolving the free amine in ether and adding 1N (1 equivalent) of ethereal hydrogen chloride.

Example 88

The salt, the major isomer hydrochloride, is recrystallized from a mixture of ethanol and ether and dried in a vacuum oven. 0.76 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-6-hydroxy-2-methoxybenzamide hydrochloride is obtained, in the form of an off-white powder having a melting point of 179-181 ° C. The yield corresponds to 35% of theory.

fs NMR (DMSO-d6): δ 1.12 (t, 3, J = 7.3), 1 64 (m, 2), 1.81 (m, 2) 2.52 (m, 3), 3.20 3.60 (m, 9), 3.82 (s, 3), 4.06 (br d, 2, J = 12.3), 7.38 (S, 1), 7.47 (m, 1) 7.60 (t, 1, J) = 7.5), 8.12 (t, 2, J = 6.6). 8.83 (t, J, 5.1) , 11.25 (broad s, D, 13.60 (s, 1) ppm. 13th C NMR (DMSO-d6): δ 13.69, 20.65, 22.00, 26.04, 38.33, 46.39. 50.46, 55.15, 61,64 , 110.73, 115.79, 121.24, 124.05, 124.66. 127.00, 128.16 129. 76, 132.33, 152.03, 152.16, 157.96, 162.27. 167.77. analysis for ^C 25 ^H 31 ^N 4 ° 3 ^SC1 . HC1: calculated: 55.65% C, 5 , 98% H, 10.38% N, found %: 55.56% C, 5 , 99% H, 10.29% N.

Example 89

The salt, the minor isomer hydrochloride, is recrystallized from 95% ethanol and dried in a vacuum oven. 0.156 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-2-hydroxy-6-methoxybenzamide hydrochloride hydrate is obtained as our

189 sickly off-white crystals having a melting point of 171 to 171

173 ° C. Yield: 7%.

³ H NMR (DMSO-d 6): δ 1.15 (t, 3, J = 7.6), 1.62 (m, 2), 1.81 (m, 2), 2.52 (q, 2) , J = 7.6), 3.20 - 3.62 (m, 10), 3.72 (s, 3), 4.08 (broad d, 2, J = 12.7), 7.40 ( s, 1), 7.47 (t, 1, J = 7.6), 7.60 (t, 1, J = 7.5), 8.12 (t, 2, J = 8.3), 8.78 (broad t, 1, J = 5.6), 10.63 (broad s, 1), 12.64 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 15.77, 21.54, 22.13, 26.99, 39.34, 47.32, 51.40, 56.09, 63.26, 114.02, 117.53, 122.16, 124.97, 125.58, 127.93, 129.09 129.13, 133.19, 153.08, 154.66, 155.93, 163.20, 168.18 .

Analysis for ^C 25 ^H 31 ^N 4 ° 3 ^SC 1 · calculated: 53.43% C, 6.19 found: 53.46% C, 6.14

HCl. 1.25 H ₂ 0:

% H, 9.97% N, 4.00 _H2 O,% H, 9.99% N, 4.02 H ₂ O.

Example 90

a) A method for producing hydrochloride

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

This compound was prepared as described in Example 75 b). From 3.35 g (0.017 mmol) of 3-methoxyisatinic anhydride (obtained from 2-amino-3-methoxybenzoic acid (Aldrich Chemical Company) as described in Example 99) and 5.33 g (0.017 mmol, 1.0 equivalent) 3- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole afforded 5.41 g of the title compound as the free base. A portion of this material (1.94 g) was dissolved in 10 ml of ethanol and 4.4 ml of 1N (1.0 equivalent) ethereal hydrogen chloride was added. The salt, the hydrochloride, is recrystallized from a mixture of ethanol and isopropanol. This gives 1.93 g of the title compound as off-white crystals, m.p. 136-138 ° C. Yield: 65%.

190 ^{Χ Η} NMR (DMSO-d₆, 200 MHz): δ 1.59 (m, 2), 1.80 (m, 2), 3.12 to 3.60 (m, 6), 3.81 (s 3), 4.09 (broad d, 2, J = 12.9), 6.13 (broad s, 1), 6.54 (t, 1, J = 8.0), 6.91 (d 1, J = 7.6), 7.20 (d, 1, J = 7.8), 7.49 (t, 1, J = 7.4), 7.62 (t, 1, J = 7.5), 8.14 (t, 2, J = 6.8), 8.33 (broad t, 1, J = 5.4), 10.89 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.68, 27.29, 39.04, 47.38, 51.48, 56.20, 56.54, 112.83, 114.92 , 115.40, 120.73, 122.18,

124.98, 125 , 59, 127.93, 129.11, 140 50. 147.88. , 153, , 09, 1 63.18 169.79. wEIGHT MS (CI / CH4 ₎ , , 50 mA / s): M + 1 a base (440) • Analysis for ^ 23 ^R 29 ^R 5®2 ¹³ * HCl: calculated: % C, 59.03;% H, 6.35; 14 71% N, 6.74 % WITH, 7.45 % Cl, found: % C, 57.94;% H, 6.42; 14 57% N, 6.71 % WITH, 7.55 % Cl.

Example 91

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

This compound was prepared as described in Example 53 using 0.99 g (3.4 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)). 0.72 mL (0.52 g, 5.1 mmol,

1.5 equivalents) of triethylamine and 0.70 g (3.4 mmol, 1.0 equivalents) of 2-nitrobenzoyl chloride (Aldrich Chemical Comany). The crude reaction mixture was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 0.94 g of the free base is obtained in the form of a yellow solid. The salt, hydrochloride, is recrystallized from ethanol / ether and dried in a vacuum oven. This gives 0.66 g of the title compound as an off-white powder, m.p. 214-215 ° C. Yield: 41%.

^X H NMR (DMSO-d₆, 200 MHz): δ 1.61 (m, 2), 1.85 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4 .Lambda., 09 (broad d, 2, J = 13.5), 7.48 (dd, 1, J)

191 = 7.2, 7.8), 7.72 (m, 4), 8.06 (d, 1, J = 8.0), 8.15 (t, 2, J = 7.0), 8.83 (broad t, 1, J = 5.5), 11.29 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ , 75.43 MHz): δ 21.44, 26.95, 39.32, 47.30,

51,39, 56.06 122.28 124.86. 124,99, 125.99, 127.94, 129.09, 130.07. 131.63, 133.57, 134.55. 148.01. 153.09, 163.20, 166.42. analysis for C ₂ ^H 25 ^N 5 ° 3 ^N . HC1:

H, 5.50; N, 14.71. Found: C, 55.56; H, 5.55; N, 14.72.

Example 92

a) A process for the preparation of 2-amino-α, α, α-trifluoro-p-toluic acid

A solution of 5.00 g (21.3 mmol) of 2-amino-α, α, α-trifluoro-p-toluylic acid (Aldrich Chemical Company) in 100 mL of absolute ethanol is placed in a Parr hydrogenator vessel containing 50 mL of ethanol and 100 mg of 5% palladium on charcoal. The vessel is placed in a Parr hydrogenator and the solution is placed under a hydrogen atmosphere at a pressure of 240 kPa. The reaction mixture was shaken at room temperature until hydrogen consumption ceased (within 2 hours). The solution was filtered through a millipore AP filter and the filtrate was rotovapped. The residue was dried under reduced pressure to give 4.22 g of the title compound as a pale yellow solid. Yield: 97%. This material was used without further purification.

b) Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- (trifluoromethyl) benzamide hydrochloride ml of anhydrous pyridine, 1.33 g (6.5 mmol) of 2-amino-α, α, α-trifluoro-p-toluic acid and 2.00 g (6.5 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1] -piperazinyl / -1,2-benzisothiazole (Example 13b)) is introduced into a 100 ml round bottom flask. Place the solution under a nitrogen atmosphere, slowly

192 add 1.48 mL (2.19 g, 13.0 mmol, 2 equivalents) of silica chloride (Aldrich Chemical Company) and heat the solution at 145 ° C for 18 hours. The reaction mixture was allowed to cool to room temperature, poured onto crushed ice and evaporated under reduced pressure. Distilled water (200 ml) was added and the solution was evaporated to dryness. Toluene (200 ml) was added to the resulting brown solid and the solvent was removed by rotary evaporation. This procedure was repeated with two additional portions of 200 ml of toluene each. Distilled water (200 ml) was added to the residue and the solution was basified to pH 11 by addition of 1N sodium carbonate solution. The aqueous solution was extracted three times with 200 ml of ethyl acetate each time. The organic layers were combined, dried (MgSO 4), filtered and evaporated. Toluene (200 ml) was added and the solvent was removed on a rotary evaporator. This procedure was repeated with two additional portions of 200 ml toluene each. The crude material was left under high vacuum overnight and purified by flash chromatography on silica gel eluting with 100% ethyl acetate, 1:99 methanol / ethyl acetate and 2: 98 methanol / ethyl acetate to give 1.45 g. of free amine. This material was dissolved in ethanol and 3.04 mL of 1N ethereal HCl was added. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 0.512 g of the title compound as white crystals, mp 205-207 ° C. Yield: 15%.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.60 (m, 2), 1.80 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4 10 (d, 2, J = 13.8), 6.74 (s, 2), 6.81 (d, 1, J = 8.3), 7.07 (s, 1), 7.49 (t, 1, J = 7.5), 7.62 (t, 1, J = 7.5), 7.71 (d, 1, J = 8.3), 8.14 (m, 2) 8.57 (broad t, 1, J = 5.4), 10.94 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 20.75, 26.22, 38.21, 46.45, 50.55, 55.22, 110.09, 110.13, 110.18 , 110.23, 112.29, 112.35, 112.40, 112.45, 117.88, 121.24, 122.23, 124.04, 124.66, 125.84, 127.00, 128 , 17, 129.34, 131.38, 131.79, 149.66, 152.16, 162.24, 167.88.

193

Mass spectrum (MS) (CI / CH ₄ , 50 mA / s): M + 1, base (478).

Analysis for ^C 23 ^H 26 ^N 5 ^OSF 3 · ^HCl: calculated: 53.74% C, 5.29% H, 13.62% N, 6.24% S, 6.90% Cl, found: 54.04 % C, H 5.38, N 13.57, S 6.32, Cl 6.92.

Examples 93 to 98

The compounds of Examples 93 to 98 were prepared from the corresponding substituted anthranilic acid precursors as described in Example 92 (b). The anthranilic acids used are obtained from commercial sources or are prepared by known methods as indicated. The analytical values for these 2-aminobenzamides are given below.

Example 93

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

Starting material: 2-amino-3-methylbenzoic acid (Aldrich Chemical Company). Yield: 0.806 g (54% of theory). The title compound has a melting point of 208-210 ° C.

^X H NMR (DMSO-d, 300 MHz): δ 1.58 (m, 2), 1.78 (m, 2), 2.08 (s, 3), 3.31 (m, 8), 3 59 (m, 2), 4.08 (broad d, 2, J = 12.1), 6.21 (broad S, 2), 6.48 (t, 1, J = 7.6), 7 .07 (d, 1, J = 7.1), 7.39 (d, 1, J = 7.8), 7.47 (t, 1, J = 7.5), 7.60 (t, 1, J = 7.5), 8.12 (t, 2, J = 8.3), 8.30 (broad t, 1, J = 5.2), 10.58 (broad s, 1) ppm .

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 18.57, 21.73, 27.27, 39.08, 47.44, 51.52, 56.24, 115.39, 115.75 , 122.16, 123.95, 124.97,

125.61, 126.88, 127.92, 129.11, 133.36, 148.47, 153.08, 163.18

163.18, 170.34.

Mass spectrum (CI / CH ₄ , 50 mA / s): M + 1, base (424).

194

Analysis for calculated: ^C 23 ^H 29 ^N 5 ^0S . HCl: 6.57% H, 15.22 % N, 6.97% N, 7.71% C1 60,05 % C, found: 60,08 % C, 6.61% H, 15,12 % N, 7.06% N, 7.76% C1

Example 94

Process for preparing 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chlorobenzamide hydrochloride

Starting material: 2-amino-3-chlorobenzoic acid (Lancaster Synthesis Inc.). Yield: 0.75 g (24% of theory). The title compound has a melting point of 211-213 ° C.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.59 (m, 2), 1.82 (m, 2), 3.15-3.61 (m, 10), 4.08 (broad d) 2, J = 13.5), 5.23 (broad s, 2), 6.61 (d, 1, J = 7.8), 6.66 (d, 1, J = 8.2), 7.05 (t, 1, J = 8.0), 7.49 (t, 1, J = 7.5), 7.62 (t, 1, J = 7.5), 8.14 (t 2, J = 7.2), 8.47 (broad t, 1, J = 5.3), 10.70 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.70, 27.06, 39.18, 47.40, 51.48, 56.21, 114.59, 117.02, 122.16 , 122.66, 124.98, 125.61, 127.93, 129.11, 130.98, 131.18, 148.13, 153.08, 163.18, 166.48.

weight spectrum (ci / ch ₄ , 50 mA / s): M +, base (444). Analysis for ^C 22 ^H 26 ^N 5 ; SOC1. HCl: calculated: 55,14% C, 5.66 % H, 14.58 % N, 6.67 % S, 14.76 % Cl, found: 55,21% C, 5.66 % H, 14.55 % N, 6.74 % S, 14.66 % Cl.

Example 95

Process for preparing 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-fluorobenzamide hydrochloride

Starting material: 2-amino-5-fluorobenzoic acid (Riedel). Yield: 0.65 g (22% of theory). The title compound has a melting point of 219-221 ° C.

^{195; H} NMR (DMSO-d, 300 MHz): δ 3.45 (m, 2), 3.59 (br d, 12.6), 6.30 (br s, 2),

J = 2.7, 9.9), 7.37 (dd, 7.60 (t, 1, J = 7.5),

J = 5.3), 10.65 (wide (m, 6),

2, J

7.05 (dt, 1,

1, J = 7.5), (wide t, 1,

1.58 (m, 2);

2, J = 10.9)

6.71 (dd, 1,

1, J = 2.7,

8.12 (t, 2)

S, 1) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.72, 27.17, 39.12, 47.42, 51.51, 56.21, 114.36, 114.67, 115.39 , 115.46, 118.45, 118.54, 119.82, 120.12, 122.16, 124.97, 125.61, 127.92, 129.11, 147.27, 152.10, 153 , 07, 155.15, 163.18, 168.80, 168.84.

base (428).

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

Analysis for ^c ₂₂ ^H 26 ^N 5 ^FOS ' ^HCl: calculated: % C, 56.95;% H, 5.87; 15,09 % N, 6,91% with, 7.64 % ci, found: C 56.84, H 5.84, 15,01 % N, 7,01% with, 7.73 % Cl.

Example 96

Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6-methylbenzamide hydrochloride

Starting material: 2-amino-6-methylbenzoic acid (Aldrich Chemical Company). Yield: 1.10 g (21% of theory). The title compound has a melting point of 194-196 ° C.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.59 (m, 2), 1.80 (m, 2), 2.21 (s, 3), 3.32 (m, 6), 3 55 (m, 4), 4.10 (m, 2), 4.93 (broad s, 1), 6.44 (d, 1, J = 7.4), 6.55 (d, 1, J = 8.0), 6.96 (t, 1, J = 7.7), 7.50 (t, 1, J = 7.5), 7.67 (t, 1, J = 7.5) 8.15 (t, 2, J = 7.1), 8.30 (broad t, 1, J = 5.3), 10.80 (broad s, 1) ppm.

¹³ C NMR (DMSO-d6, 75.43 MHz): δ 20.68, 21.73, 27.27, 39.02, 47.37, 51.44, 56.17, 113.70, 118.82 , 122.18, 124.18, 124.99, 125.61, 127.93, 129.11, 129.76, 133.30, 146.32, 153.08, 163.20,

169.29.

196 base (424).

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

Analysis for ^C 23 ^H 29 n ₅ Sat . HCI: calculated: 60,05 % C, 6.57% H, 15.22 % N, 6.97% with, 7.71% Cl found: 59.99 % C, 6.58% H, 15.17 % N, 7.08% with, 7.64% Cl

Example 97

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

Starting material: 2-amino-3-naphthoic acid (Aldrich Chemical Company). Yield: 0.284 g (9% of theory). The title compound has a melting point of 216-218 ° C.

^X H NMR (DMSO-d₆, 200 MHz): δ 1.62 (m, 2), 1.84 (m, 2), 3.33 (m, 8), 3.59 (m, 2), 4 12 (broad d, 2, J = 12.7), 6.11 (broad S, 2), 6.98 (S, 1), 7.15 (t, 1, J = 7.4), 7 36 (t, 1, J = 7.4), 7.54 (m, 3), 7.72 (d, 1, J = 8.2), 8.06 (s, 1), 8.14 (t, 2, J = 7.0), 8.68 (broad t, 1, J = 5.2), 10.69 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ , 75.43 MHz): δ 20.94, 26.43, 38.47, 46.65, 50.75, 55.47, 108.56, 121.41, 121, 51, 121.93, 124.32, 124.95, 125.08, 125.42, 127.28, 127.80, 128.45, 128.70, 128.90, 135.90, 146.02, 152.48, 162.58, 169.11.

Mass spectrum (CI / CH ₄ , 50 mA / s): M +, a base (460). Analysis for ^C 26 ^H 29 ^N 5 ^SO . HCI: calculated: 62.95% C, 6.10% H, 14.12 % N, 6.46 % S, 7.15 % Cl found: 62.88% C, 6.14% H, 14.03 % N, 6.53 % S, 7.21 % Cl

Example 98

Process for the preparation of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -5-methoxybenzamide hydrochloride

197

-JA

Starting material: 2-amino-5-methoxybenzoic acid [obtained by reduction of 2-nitro-5-methoxybenzoic acid (Apin Chemicals Ltd.) as described in Example 92 a)]. Yield: 0.313 g (10% of theory). The title compound has a melting point of 150 ° C (dec.).

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.60 (m, 2), 1.79 (m, 2), 3.37 (m, 12), 3.71 (s, 3), 3 Δ 88 (m, 2), 6.67 (d, 1, J = 8.8), 6.86 (dd, 1, J = 2.7, 8.8), 7.10 (d, 1, J = 2.7), 7.48 (t, 1, J = 7.5), 7.62 (t, 1, J = 7.5), 8.12 (d, 1, J = 7.5) 8.15 (d, 1, J = 7.5), 8.37 (broad t, 1, J = 4.7) ppm.

¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.84, 27.33, 39.08, 47.54, 51.60, 56.29, 56.60, 113.18, 116.18 , 118.66, 120.20, 122.16, 124.97, 125.59, 127.94, 129.09, 144.58, 150.34, 153.08, 163.22, 169.58.

Mass spectrum (CI / CH ₄ , 50 mA / s): M + 1, base (440).

Analysis for ^C 23 ^H 29 ^N 5 ^S 2 ° ^'HC1: Calculated: 58.03% C, 6.35% H, 14.71% N, 6.74% S, 7.45% Cl found: 58, H, 6.34; N, 14.62; S, 6.82; Cl, 7.39.

Example 99

a) A method for producing 4-fluoroisatinic anhydride

0.97 g (6.25 mmol) of 2-amino-4-fluorobenzoic acid (obtained by reduction of 4-fluoro-2-nitrobenzoic acid (The Sigma-Aldrich Library of Rare Chemicals) as described in Example 92 a)) 20 ml of anhydrous 1,4-dioxane and 5.0 g (25.2 mmol, 4.0 equivalents) of trichloromethyl chloroformate (Johnson-Matthey Chemicals Company) were placed in a 100 ml round bottom flask. The reaction mixture was refluxed for 11 hours. The reaction mixture was allowed to cool and stirred at room temperature overnight. Evaporate the solvent on a rotary evaporator to give 1.18 g of the title compound as an off-white solid. The yield corresponds to more than 100% of theory (crude material).

198 ¹ H NMR (DMSO-d ₆ , 200 MHz): δ 6.90 (dd, 1, J = 2.3, 9.6), 7.13 (dt, 1, J = 2.3, 7, 6), 8.02 (dd, 1, J = 6.0, 8.8), 11.90 (broad s, 1) ppm.

This compound was used without further purification.

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

This compound was prepared as described in Example 75 b). From 1.18 g (6.51 mmol) of 4-fluoroisatinic anhydride and 2.0 g (6.51 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1, 2-Benzisothiazole gave 1.31 g of the title compound as a light yellow solid, mp 234-236 ° C. Yield: 43%.

^X H NMR (DMSO-d, 300 MHz): δ 1.53 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.53 (m, 4), 4 .07 (d, 2, J = 13.4), 6.31 (dt, 1, J = 2.5, 8.5), 6.45 (d, 1, J = 2.5, 7.2) 6.75 (broad S, 2), 7.47

(t, 1, J = 7.5), 7.60 (m, 2), 8.12 (t, 2, J = 8.3), 8.32 (br t, 1, J = 5.3), 10.90 (wide s, 1) ppm. ¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.66, 27.25, 39.02. 47,37, 51.47, 56.17, 102.14, 102.33, 102 45, 102.63, 112 , 35, 112.37.

122.18, 124.97, 125.59, 127.93, 129.11, 131.51, 131.66, 152.97,

153.09, 153.13, 163.17, 163.66, 166.92, 169.10.

Mass spectrum (CI / CH ₄ , 50 mA / s): M + 1 base (428).

Analysis for ^C 22 ^H 26 ^N 5 ^OFS * ^HCl: calculated: 56.95% C, 5.86% H, 15.09% N, 6.91% S, 7.64% C1, found: 56.89% C, 5.83; N, 15.10; S, 6.90; Cl, 7.61.

Example 100

a) Process for the preparation of 3- [1- (4-aminobutyl) -4-piperidinyl] -6-fluoro-1,2-benzisoxazole

199

1.04 g (2.47 mmol) of N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) -piperidino / butyl] phthalimide (Example 69), 0.24 g ( 4.24 mmol, 1.67 equivalents) of hydrazine hydrate (Aldrich Chemical Company), as a 55% aqueous solution and 15 mL of methanol, were added to a 100 mL round bottom flask. The reaction mixture was refluxed for 2 hours. Oil purchase! The reaction mixture was allowed to cool. Distilled water (50 ml) was added to the cooled reaction mixture and the pH was adjusted to 1 by addition of 1N hydrochloric acid. Filter the suspension and wash the solid with water. The pH is adjusted to 12 by addition of saturated potassium carbonate solution. The basic filtrate was transferred to a separatory funnel and extracted three times with 100 ml of dichloromethane each. The organic layers were combined, dried (MgSO 4), filtered and evaporated. This gives 0.58 g of the title compound as a pale yellow oil. Yield: 81%.

¹ H NMR (CDCl ₃ ): δ 1.54 (m, 4), 1.80 (broad s, 2), 2.10 (m, 6), 2.41 (broad t, 2, J = 7, 2), 2.74 (broad t, 2, J = 6.4), 3.08 (m, 3), 7.05 (dt, 1, J = 2.1, 8.9), 7.23 (dd, 1, J = 5.1, 8.7) ppm.

b) Process for the preparation of 2-amino-N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino / butyl] benzamide hydrochloride

0.58 g (1.99 mmol) of 3- [1- (4-aminobutyl) -4-piperidinyl] -6-fluoro-1,2-benzisoxazole, 0.325 g (1.99 mmol, 1.0 equivalent) of anhydride of isatinic acid (Aldrich Chemical Company) and 12 ml of ethanol are placed in a 25 ml round bottom flask and stirred under a nitrogen atmosphere for 3 hours. The reaction mixture was evaporated to give a brown-orange oil, which solidified. The crude free base was purified by flash chromatography with ethyl acetate containing 0.1% triethylamine as eluent. 0.69 g of the free base is obtained in the form of an oil. 0.69 g (1.68 mmol) of the free base was dissolved in ethyl acetate and 1.68 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride was added. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 0.51 g

200 of the title compound as an off-white solid, m.p. 242.5-245 ° C (dec.). Yield: 57%.

¹ H NMR (DMSO-d6): δ 1.57 (m, 2), 1, 78 (m, 2), 2.25 (m, 4) 3 12 (m, 4) 3.27 (m, 2), 3.47 (m, 1), 3.62 (wide d, 2, J 12 , 0) , 6.93 (broad s, 2), 6.51 (tm, 1, J = 7.4). 6.69 (dd, 1H) J = 0.9, 8, 1), 7.13 (tm, 1, J = 7.6), 7.35 (Dt, 1, J = 9.1 2 D, 7.49 (dd, 1, J = 1,2,7,9), 7.74 (Dd, 1, J = 2.1, 9.1) θ, 17 (m, 1) 8.29 (m, 1), 10.3 (broad s, D PP m.

¹³ C NMR (DMSO-d 6): δ 20.81, 26.44, 26.91, 31.26, 38.07,

51.27. 55.65. 97.72, 112.70, 112.95. 114.59. 114.85. 115.35. 115.75. 123.88. 124.00, 128.13, 131.63. 149,63, 160.17. 162,55, 163.21. 163.35. 165.03, 168.98. analysis for C ₂₃ ^H 27 ^N 4 ° 2 ^F · ^HC:

H, 6.31; N, 12.54. Found: C, 61.86; H, 6.33; N, 12.53.

Claims (27)

PATENT CLAIMS 1. A compound of formula (I): Y ----- Z ---- N X --- W (I) in which Y represents a group of formula (a), (b) or (c) wherein the single line accompanied by a dashed line (- - -) represents a single or double bond, (b) (c) 202 where R ¹ represents one or more ring substituents including hydrogen, halogen, hydroxy, N (R ⁴ ) ₂ , nitro, S (O) _n R ⁴ , where n is 0, 1 or 2, of formula C-N, CON ^(R4) 2, COR ^4, CO 2 R ^4, CO-aryl, azido, benzyloxy, a group of formula NR ⁴ N (R ⁴⁾ 2, NR ⁴ N = C (R ⁴⁾ 2, - ^NR4 (C = O) CH [N (R ⁴⁾ 2] R ^4, -NR ⁴ CO 2 R ^4, and -NR ⁴ (C = O) R ⁴ , C 1 -C 6 alkyl optionally substituted by one or more halogen atoms and C 1 -C 6 alkoxy optionally substituted by at least one halogen atom, R ² is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -S-, NR ³ -, -N = N- or - (C = O) NR 4 R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁵ is -N = C- or -C = N-, R6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , which are the same or different, each represent hydrogen, halogen, nitro, hydroxy, S (O) _n R ⁴ , where n is 0, 1 or 2 203 is of the formula C-N, CON ^(R4) 2, COR ^4, CO 2 R ^4, CO-aryl, azido, benzyloxy, a group of formula N (R ⁴⁾ 2, NR ⁴ N (R ⁴⁾ 2, -NR ⁴ n = c (r ⁴ ) 2, -NR ⁴ (C = O) CH [N (R ⁴ ) 2] R ⁴ , -NR ⁴ (C = O) R ⁴ and -NR ⁴ CO ₂ R ⁴ , an alkoxycarbonyl group with (C 1 -C 6) alkoxy or PhN = N, (C 1 -C 6) alkyl optionally substituted by one or more halogen atoms or (C 1 -C 6) alkoxy optionally substituted by one or more halogen atoms, or provided pairs of combinations R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ represent a group of the formula V represents an oxygen atom or a sulfur atom, Z is C 4 -C 8 alkylene optionally interrupted by the formula -S (O) _n , wherein n is 0, 1 or 2, C 4 -C 8 alkenylene or C 4 -C 8 alkynylene, X represents a nitrogen atom or a carbon atom; and W represents a group of formula (d) (d) R2 ' 204 where A is CR ⁴ or N, B is O, NR ⁴ or S (O) _n , wherein n is 0, 1 or 2 and R ¹² represents a hydrogen atom or a halogen atom. or a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, or a physiologically acceptable functional derivative thereof. A compound, salt, solvate or derivative according to claim 1, wherein the nitrogen atom of formula I, which is adjacent to the substituent Z, and which is part of a monocyclic six membered ring, is in its oxidized form as an N-oxide. A compound, salt, solvate or derivative according to any one of claims 1 and 2, wherein Y is a group of formula a) and R ¹ is H or Cl, R ² is a group of formula -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, NR ^{3 4} -, - (C = O) NR 4, or N = N and - - - represents in each case a double bond, R ³ represents a group of the formula -CO ₂ Et or a hydrogen atom and R ⁴ represents a hydrogen atom or a methyl group. A compound, salt, solvate or derivative according to claim 3, wherein it is hydrogen, 205 R ² represents a group of the formula -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ 'or -N = N- and R ³ and R ⁴ represent a hydrogen atom. The compound, salt, solvate or derivative of claim 4, wherein n _x R is -CH ₂ -, -CH ₂ CH ₂ - or -N = N-. A compound, salt, solvate or derivative according to any one of claims 1 and 2, wherein Y is a group of formula (b) and R ¹ is hydrogen, chloro, fluoro, methyl, hydroxy, methoxy, nitro, or two chlorine atoms, and R ⁵ is -C = N-. The compound, salt, solvate or derivative of claim 6, wherein R ¹ represents a hydrogen atom, a methyl group, a fluorine atom, a nitro group or a methoxy group. The compound, salt, solvate or derivative of claim 7, wherein R ¹ represents a hydrogen atom or a nitro group. A compound, salt, solvate or derivative according to any one of claims 1 or 2, wherein Y is a group of formula (c) and R ⁶ represents a hydrogen atom or a methyl group, R ⁷ represents a hydrogen atom, an amino group, a methylamino group, a hydroxy group, a methoxy group or an acetamido group, R ⁸ represents a chlorine atom, a group of the formula NHCO ₂ t -Bu, a bromine atom or an amino group, 206 R ⁹ represents a hydrogen atom, a methoxy group, a trifluoromethyl group, a tert-butyl group, a group of the formula -N = N-Ph, NHAc, NHCO ₂ -Bu, a bromine atom or an amino group, R ¹⁰ represents a hydrogen atom, a nitro group, a bromine atom or a chlorine atom and R ¹¹ represents a hydrogen atom, a methoxy group, or a hydroxy group. The compound, salt, solvate or derivative of claim 9, wherein R ⁶ represents a hydrogen atom, R ⁷ is amino, methoxy, acetamido or methylamino, R ⁸ represents a hydrogen atom or a bromine atom, R ⁹ represents a hydrogen atom or a bromine atom, R ¹⁰ represents a hydrogen atom or a bromine atom and R ¹¹ is methoxy or hydroxy. The compound, salt, solvate or derivative of claim 10, wherein R ⁸ , R ⁹ and R ¹⁰ are hydrogen, R ¹¹ is hydroxy, and R ⁷ is amino or methylamino; R ⁷ is methoxy, R ⁸ represents a hydrogen atom, R ⁹ represents a bromine atom, R ¹⁰ represents a hydrogen atom and R ¹¹ is hydroxy. q 207 A compound, salt, solvate or derivative according to any one of claims 1 to 11, wherein Z represents an alkylene group of 4 to 5. 6 carbon atoms. A compound, salt, solvate or derivative according to any one of claims 1 to 12, wherein W represents a group of formula (d) and B is sulfur or oxygen; and R ¹² represents a hydrogen atom or a fluorine atom. A compound, salt, solvate or derivative according to claim 13, wherein B represents a sulfur atom and R ¹² represents a hydrogen atom. 15. Compounds 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ylic-1-isoindolinone, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3,4-dihydro-l [2H] -isoquinolinone. 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] benzamide, 6- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-5,7-dione . N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidine / butyl] phthalimide, N- [4- / 4- (1,2-benzisothiazol-3-yl) piperazinyl / butyl] -2- (methylamino) benzamide, 208 N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide, 2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide, (+/-) - cis-2- [4- / 4- (1) 2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy-6-methoxybenzamide, 2-amino-N- [4- / 4- (1,2-benzisoxazol-3-yl) -1-piperazinyl / butyl] benzamide; and 2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide, and their physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides. 16. N- [4- / 4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo- -2-hydroxy-6-methoxybenzamide, 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide, 2-amino-N- [4- / 4- (1,2-benzisoxazol-3-yl) -1-piperazinyl / butyl] benzamide, 2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide; and N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-2-hydroxy-6-methoxybenzamide, and their physiologically acceptable salts, solvates, N-oxides and physiologically functional derivatives. 209 17. 2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride. 18. Compounds: N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] phthalimide, (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3- yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, (+/-) - trans-2- [4- / 4- (1,2) -benzisothiazol-3-yl) -1-piperazinyl-butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, and N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidine / butyl] phthalimide. A compound of formula I or claim 1 or claim 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, for use in therapy. Use of any of the following compounds or a physiologically acceptable salt, solvate or N-oxide thereof or a physiologically functional derivative thereof in therapy: N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-nitrophthalimide. 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4- [3H] -quinazolinone, 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1 [2H] -phthalazinone. 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,3 [2H, 4H] izochinolíndión, 210 N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidino / butyl] phthalimide, (+/-) - cis-2- [4- / 4- (1,2-benzisothiazole) -3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, (+/-) - trans-2- [4- / 4- ( 1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone; and N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino / butyl] phthalimide. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof. 22. A pharmaceutical composition comprising any of the compounds of claim 20, or a salt, solvate or N-oxide thereof, or a derivative thereof. Use of a compound of formula I as defined in claim 1 or claim 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disease selected from fatigue , muscle cramps, depression, senile dementia aggression, borderline personality diseases, vomiting and psychosis. The use, according to claim 23, of a compound of formula I as defined in claim 1 or claim 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, wherein the disease is a psychotic disorder. Use of a compound of formula I as defined in claim 1 or claim 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or 211 is a physiologically functional derivative thereof, wherein the disease is schizophrenia. The use of any of the compounds of claim 20, or a salt, solvate or N-oxide or derivative thereof, for the manufacture of a medicament for the treatment of any of the diseases described in claim 23. A process for the preparation of a compound of formula (I) wherein: Y represents a group of formula (a), (b) or (c) (a) wherein the single line accompanied by a dashed line (- - - j represents a single or double bond, (b) 212 (C) R ¹¹ IN II t— r ’° JL JL A I R® R ⁷ R® y R® where R ¹ is one or larger number of substituents circle, comprising an atom hydrogen atom halogen, alkyl group having 1 to 6 atoms carbon, optionally substituted one or a plurality of halogen atoms and an alkoxy group having 1 to 6 carbon atoms, optionally substituted with at least one halogen atom, a hydroxy group, a group of formula N (R ⁴ ) ₂ , a nitro group, a group of formula S (O) _n R ⁴ where n is 0, 1 or 2, a group of formula C-N, CON ^(R4) 2, COR ^4, CO 2 R ^4, CO-aryl, azido, benzyloxy, a group of formula NR ⁴ N (R ⁴⁾ _2, NR ⁴ N = C (R ⁴ ) 2, -NR ⁴ (C = O) CH [N (R ⁴ ) 2] R ⁴ , -nr ⁴ co ₂ r ⁴ and -NR ⁴ (C = O) R ⁴ , R ² is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -S-, NR ³ -, -N = N- or - (C = O) NR ₄ R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, R ⁴ represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 6 carbon atoms, R ⁵ is -N = C- or -C = N-, R ⁶ represents a hydrogen atom or an alkyl group having from 1 to ⁵ carbon atoms; 6 carbon atoms 213 R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ , which are the same or different, each represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms, optionally substituted by one or more halogen atoms, (C 1 -C 6) alkoxy optionally substituted by one or more halogen atoms, hydroxy, S (O) _n R ⁴ , where n is 0, 1 or 2, C = N, CON (R ⁴ ) 2 , COR ⁴ , CO2R ⁴ , CO-aryl, azido, benzyloxy, N (R ⁴ ) 2 / nr ⁴ n (r ⁴ ) 2, -nr ⁴ n = c (r ⁴ ) 2, -nr ⁴ (c = o) ch [n (r ⁴ ) ² ] r ⁴ , -NR ⁴ (C = O) R ⁴ and -NR ⁴ CO ₂ R ⁴ , a (C 1 -C 6) alkoxycarbonyl group or a group of formula PhN = N, or provided pairs of combinations R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ³ · ⁸ or R 3 · ⁹ and R ^3-1 represent a group of the formula V represents an oxygen atom or a sulfur atom, Z represents an alkylene group having 1 to 8 carbon atoms, optionally interrupted by the group -S (O) _n where n is 0, 1 or 2, an alkenylene group having 4 to 8 carbon atoms or an alkynylene group having 4 to 8 carbon atoms, X represents a nitrogen atom or a carbon atom; and W represents a group of formula (d) 214 d R ¹² where A is CR ⁴ or N, B is O, NR ⁴ or S (O) _n , where n is 0, 1 or 2 and R ¹² represents a hydrogen atom or a halogen atom, characterized in that a compound of formula II is reacted YH (II) with a compound of formula III (III) In- / in which L represents a leaving group, or reacts a compound of formula II with a compound of formula IV 215 (IV) in which A ^- is a suitable anion and R ¹³ represents a group of formula - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, or a compound of formula V (V) in which: L is a leaving group, with a compound of the formula VI; HN X - W \ y (VI) or reacting a compound of formula (VII) with a compound of formula (VIII) 216 (VIII) in which L is a leaving group, or when Y is a) where R ² is -CH ₂ - or -N = N- and wherein the single line followed by a dotted line (- - -) represents a double bond and V is an oxygen atom, cyclizing the compound of formula (IX): N X - W (IX) in which R ¹⁴ represents a group of formula -CH ₂ OH or -NH ₂ , or a compound of formula X (X) wherein: R ¹⁵ is -CH ₂ - or -N (R ⁴ ) (CV) - a R ¹⁶ represents R ⁵ or a group of the formula -C = C 17 or a compound of formula X ¹ (X ¹ ) wherein R ^{17 is} R ⁷ , -SL ² or -CH ₂ -L ² a L ¹ represents a chlorine atom or a bromine atom, a methoxy or a hydroxy group, L ² is chlorine or bromine, OMs or OTs, with a compound of formula XI (XI) or, when Z is c) and R ⁷ is a group of formula - (R ⁴ ) 2, a compound of formula X ¹ is processed in which L ² is hydroxy, V is oxygen and R ¹⁶ is -N (R ⁴ ) 2, with a compound of formula XI, or ii when Y is a, b or c and R ¹ , R ⁷ , R ⁸ , R ⁹ , R or R are hydroxy, the corresponding methoxy derivatives are treated or, when Y is a group of formula (a), (b) or (c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ³⁹ or R 8 ³ represents a group of formula N (R ⁴ ) ₂ or 218 NR ⁴ N (R ⁴ ) ₂ , the corresponding alkoxycarbonylamino derivatives are hydrolyzed, or when Y is a group of formula (a), (b) or (c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ is N (R ⁴ ) ₂ , the corresponding nitro derivatives are reduced, or when Y is a group of formula (c) R ⁶ is a C 1 -C 6 alkyl group, the corresponding secondary amides are alkylated, or when Y is a group of formula (a), (b) or (c) ) and R 1, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are -NR ⁴ N = C (R ⁴ ), reacting the corresponding hydrazine derivatives with the corresponding ketones, and optionally reducing the compound of formula I in which Z is a C 4 -C 8 alkenyl or C 4 -C 8 alkynylene group to give another compound of the formula I in which Z is a C 4 -C 8 alkylene group, optionally treating a compound of the general formula I of formula I wherein Y is a group of formula (c) and V is an oxygen atom with a sulfonating agent to give another compound of formula (I) wherein Y is a group of formula (c) wherein V is a sulfur atom and optionally oxidizes a compound of formula (I) to form another compound of formula of formula I wherein the nitrogen atom is oxidized to the N-oxide.