CZ194994A3 - Piperazine and piperidine derivatives, process of their preparation and pharmaceutical compositions containing thereof - 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, particularly in the treatment of psychotic disorders.

BACKGROUND OF THE INVENTION

Dopamine receptors acting via chemical information are known to be located in the corpus striatum and in the limbic region of the brain, and such receptors are classified as α ₂ based on receptor binding studies and the presence or absence of a positive association between receptor and adenylate cyclase activity. . Activation of the D1 receptors is associated with the stimulation of adenylate cyclase, while the D ₂ receptor mediates dopaminergic effects, so that it does not involve direct stimulation of this enzyme (see Kababian and Calne, Nature 227, 93 (1979) and Harrold et al., J. Med.

Chem. 30, 1631 (1987)]. Although the distinct functions of the D ₁ and D ₂ receptors are not clearly separated, a strong correlation is expected between D ₂ receptor antagonism and antipsychotic activity (see Seeman, Pharmacol. Rev. 32, 229 (1981)), Seeman et al., Biochem. Pharmacol. 34 , 151 (1985), Creese et al., Science 192, 481 (1976) and Leysen in Clinical Pharmacology in Psychiatry: Neuroleptic and Antidepressant Research, edited by Usdin ..., Gram and Lingjaerde, Macmillan: Basingstoke, p.

to 52 (1982)).

5-hydroxytryptamine (5-HT, acting via chemical information occurs widely in the central nervous system and is known to be involved in the control of behavior. Have identified a number of different 5-HT receptors and receptor subtypes. Addition to the blockade of receptors D ₂ It is believed that 5-HT ₂ receptor antagonism is also desirable in an antipsychotic agent (see Janssen et al., J. Pharm. and Exper. Ther. 224 (2). 685 (1988)). dopamine receptors D ₂ may control the positive symptoms of schizophrenia (e.g. delusions and hallucinations) whilst blockade of _5-HT2 receptors may assist in improving negative symptoms of schizophrenia (e.g. apathy and social regression). It has also been suggested that blockade of 5-HT ₂ receptor results in a reduction in extrapyramidal side effects that are known to occur in the case of neuroleptically maintained therapy by many known antipsychotic agents.

Psychotropic benzisothiazoles and benzisoxazoles are described in U.S. Patent No. 4,968,792 and European Patent Nos. 0 357 134 and 0 196 132. Other antipsychotically active piperidines and piperazines are disclosed in DE 25 03 816 and European Patent Nos. 0 329 168 and 0 013 612.

SUMMARY OF THE INVENTION

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

The present invention relates to a compound of formula (I) -

-Ν X \ __ y

- a physiologically acceptable salt thereof, a physiologically (I) acceptable solvate thereof, and a physiologically functional derivative thereof.

In formula (I), a group of formula (a), (b) or (c) (a)

where a single line accompanied by a dashed line (- - -) represents a single or double bond,

where

R ¹ represents one or more ring substituents including hydrogen, halogen, C 1 -C 6 alkyl optionally substituted with one or more halogen atoms, C 1 -C 6 alkoxy optionally substituted with at least one halogen atom , hydroxy group, 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 group of formula 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 represents a group of the formula -CH2-, -CH2CH2-, -CH2CH2CH2-, -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-,

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, (C ·-C) alkoxy optionally substituted by one or more halogen, 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, CO 2 R ^4, CO-aryl, azido, benzyloxy, -N (R ⁴⁾ 2, -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 (C = O) R ^4, and -NR ⁴ CO 2 R ^4, alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety, or a group of formula PhN = N, or assuming a paired combination of R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ represents 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 is nitrogen or carbon; and

W represents a group of formula (d) (d)

where

A is CR ⁴ or N,

B represents an oxygen atom, a group of formula NR ⁴ or S (O) _n , wherein R ⁴ and _n are as defined herein and

R ¹² represents a hydrogen atom or a halogen atom.

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

As used herein the term alkyl may have a straight or branched chain in the group or part of a group, 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 ) 1 _{T 1} - C 3 -C 6 cycloalkyl wherein m is 0 to 4. C 3 -C 6 cycloalkyl is especially cyclopropylene.

As used herein, the term aryl refers to phenyl, naphthalenyl, thienyl, pyridyl, furanyl or pyrrolyl, which are optionally substituted with one or more halogen, hydro, 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 C 4 -C 8 alkenylene group 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 butinylene, pentinylene, hexinylene and the like.

As used herein, the term halogen refers to a fluorine, chlorine, bromine and 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. .

When Ac is used herein, it refers to a portion of the formula - (C = O) CH ₃ .

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

The invention further provides compounds of formula I and salts, solvates and derivatives thereof, wherein the nitrogen atom shown in formula I in the position adjacent to 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. Suitable salts are in particular acid addition salts, including those formed with both organic and inorganic acids. Such salts will usually be physiologically acceptable, although salts that are not physiologically acceptable may be used in the manufacture and purification of the subject compounds. Thus 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, acids oxallacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and isethionic 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 present invention, when Y represents a group of formula a) - - - represents in each case a double bond, R ¹ is hydrogen or chlorine, preferably hydrogen, R ² represents a group of formula -CH2-, -CH2CH2-, - 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.

According to another preferred embodiment of the present invention, when Y is a group of formula (b), R ¹ is preferably hydrogen, chlorine, fluorine, methyl, hydroxy, methoxy, nitro or two chlorine atoms, more preferably hydrogen, methyl, fluorine, nitro or methoxy, most preferably hydrogen or nitro and ^R5 is preferably -C = N-.

According to another preferred embodiment of the invention, when Y is a group of formula (c), R ⁶ is hydrogen or methyl, more preferably hydrogen, R ⁷ is hydrogen, amino, methylamino, hydroxy, methoxy or acetamido, more preferably amino, methoxy, acetamido or methylamino, preferably amino or methylamino group, R ⁸ represents a hydrogen atom, a chlorine atom, a group of formula NHCO2t-Bu, Br or amino, preferably hydrogen or bromine, most preferably hydrogen, ^R9 represents hydrogen, methoxy, trifluoromethyl, tert .-butyl group, a group of formula -N = N-Ph, NHAc, NHCO2t-Bu, amino or bromine atom, more preferably hydrogen or bromine, most preferably bromine, R ¹⁰ represents a hydrogen atom, a nitro group, bromine or chlorine atom, preferably is hydrogen or bromine, most preferably hydrogen and R ¹¹ is hydrogen, methoxy or hydroxy, preferably methoxy or hydroxy, most preferably hydroxy.

According to another preferred embodiment of the invention,

V is an oxygen or sulfur atom, preferably an oxygen atom,

Z is C 4 -C 6 alkylene, preferably C 4 alkylene, B is sulfur, amino or oxygen, more preferably sulfur or oxygen, most preferably sulfur, A is CH or N, more preferably nitrogen and R ^X]; represents a hydrogen or fluorine atom, preferably a hydrogen atom.

Preferred compounds of formula I include

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

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

Preferred compounds of formula I include

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

2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidin / butyl] benzamide and their physiologically acceptable salts and their solvates, 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 the formula I show a favorable pharmacological activity profile and are suitable for the treatment of a number of conditions. For example, the compounds exhibit 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 mouse climbing (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 are a measure of behavior that shows the compound's ability to induce extrapyramidal side effects.

The compounds of formula I 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 dose required for the test to that required to induce catalepsy.

Certain compounds of Formula I are also potential 5-HT _1A receptor agonists. 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 for drugs used to treat schizophrenia.

According to another feature, the invention also provides a method of treating or prophylaxis of a mammal in a disease selected from the group consisting of fatigue, muscle cramps, depression, senile dementia aggression, borderline personality disorders, vomiting and psychosis, and 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, physiologically functional derivative or N-oxide thereof for use in therapy, particularly 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. ingredient. The carrier or carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.

Compositions of the invention include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration, although the most preferred route may depend, for example, on the condition and disease 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 this invention, or a pharmacologically acceptable salt thereof, or a 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 the active ingredients, such as powders or granules, as solutions or suspensions in an aqueous or non-aqueous liquid, or as liquid oil-in-water or water-in-oil emulsions. The active ingredient may also be presented in the form of a bite, electuary or paste.

The tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared 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 isotonic state with the blood of the intended recipient, 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 immediately prior to use. for injection. 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., by 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 a salt thereof. 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.

Formulations suitable for topical administration in the mouth, for example, for buccal or sublingual administration, include capsules containing the active ingredient in 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 dosage unit formulations are those containing the active ingredient in an amount corresponding to the effective dose as described below, or a part thereof.

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

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

The compounds of this invention can usually be administered orally or by injection at a dosage ranging from 0.02 to 50.0 mg per kilogram body weight of the recipient per day. The dosage range for an adult human is generally in the range from 1.4 to 3500 mg per day, preferably in the range from 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 and R ¹ to R ^{12 have the} meanings ascribed to them under formula I unless otherwise stated.

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

YH with a compound of formula III / III

LZN X- ^w

W 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 at a temperature of 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, alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, or alkali metal hydrides such as sodium hydride, potassium hydride etc.

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

(Γ7) in which

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

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

- (CH ₂ ) ₄ -.

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

According to a third general process (C), compounds of formula (I) may be prepared by reacting a compound of formula (V) wherein:

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

ΛΑ

ΗΝ Χ '\ _ /

-W (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) wherein X is N may be prepared by reacting a compound of formula (VII)

Γ \

Y-Z-N NH 4 (VII) with a compound of formula VIII

L - W (VIII), in which

L has the meaning given above.

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

According to a fifth general process (E), compounds of formula (I) wherein Y is a) wherein 2

R represents a group of formula -CH ₂ - or -N = N- and where a single line accompanied by a dotted line (- - -) represents a double bond, they can be prepared by cyclization of a compound of formula IX

in which

V represents an oxygen atom and

R ¹⁴ is -CH ₂ OH or -NH ₂ .

When R ¹⁴ represents a group of the formula -CH ₂ OH, the general process 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 represents a methylene group.

When R ¹⁴ is amino, the process can 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 give compounds of formula I wherein R ² is -N = N-.

According to the sixth general process F), the compounds of the general formula I in which Y represents a group a) wherein o

R represents a group of formula _-CH2-, -S- or -N-N- or Y is a group b) or c) can be prepared by reacting compounds of formula X

(X) in which

R ¹⁵ is -CH ₂ - or -N (R ⁴ ) (C = V) - and R ¹⁶ is R ⁵ or -C = C-, or a compound of formula X ¹

in which

I ⁷ is R ⁷ , -SL ² or -CH ₉ -L ² a

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

L 1 is, for example, chlorine or bromine, OMs or OTs, with a compound of formula XI

R ⁶ \

N z

H (xi)

For example, compounds of formula I wherein Y is c) and R ⁷ is -N (R ⁴ ) 2 may be prepared by treating a compound of formula X ¹ in which L ¹ is hydroxy, V is oxygen and R is ¹⁶ represents a group of formula -N (R ⁴ ) 2, 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)).

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

Compounds of formula I wherein Z is C 4 -C 8 alkylene can be prepared by reducing a compound of formula I wherein Z is C 4 -C 8 alkenylene or C 4 -C 8 alkynylene. 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 a temperature of 20 to 100 ° C. partial reduction of the acetylene residue (~ C = C-) to an alkylene group (-C = C-) can be carried out by reduction using a poisoned catalyst such as a Lindlar catalyst.

Compounds of formula (I) in which 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 [ for example by 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 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 hydrolysis of 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)).

Compounds of formula I wherein Y represents a group of formula a), b) or c) and R ^1, R ^7, R ^8, R ^9, R ¹⁰ or R ¹¹ denotes a group of formula N (R ⁴⁾ _2, may also be prepared by reduction of the corresponding nitroderivatives by known methods [e.g. catalytic hydrogenation with hydrogen in the presence of a catalyst such as platinum, palladium or Raney nickel (Org. Synth. 49, 116 (1969), J. Med. Chem. 16, 1043 (1973), J. Org) Chem., 38, 60 (1973)].

Compounds of formula (I) 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 triethylamine, in a solvent such as dichloromethane).

Compounds of formula I wherein Y represents a group of formula c) and R ⁶ represents an alkyl group having 1 to 6 carbon atoms, may 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 a sulfur atom may be prepared by treating a compound of formula (I) wherein Y is a group of formula (c) wherein V is an oxygen atom with a sulfonating agent such as Lawesson's reagent, namely 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-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 represents a group of formula a), b) or c) and R ^1, R ^7, R ^8, R ^9, R ¹⁰ or R ¹¹ denotes a group of formula NHN = C (R ⁴⁾ _2, can be prepared from the corresponding hydrazine derivatives and the corresponding ketones by known methods.

Compounds of formula I in which a nitrogen atom is oxidized to an N-oxide can 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 represents a group of formula a) wherein R ² represents a methylene group, and where a single line accompanying a broken line (- - -) represents a double bond, i.e., formula IIA ftalimideny

may be prepared by reduction of the corresponding phthalimide IIB

Suitable reducing agents include tin with hydrochloric acid in acetic acid at 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 O ₄ , dioxane and hydrogen (Helv. Chim. Acta, 1650 (1977)).

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

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

R ¹ - (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 (XXXI>

which is then cyclized, for example by treatment with polyphosphoric acid, at an elevated temperature, for example from 140 to 160 ° C.

Compounds of formula II in which Y represents a group of formula a) wherein R ² represents a group of the formula -CH2CH2CH2- "and where a single line accompanying a broken line (- - -) represents a double bond, i.e. the recited formula IID

(IID) can be produced as 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 reaction 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. at 205 ° C), then with water (e.g. at 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 cyanethylbenzoate. 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 IID.

Compounds of formula II in which Y represents a group of formula a) wherein R ² represents a sulfur atom, and where a single line accompanying a broken line (- - -) represents a double bond, i.e. benzisothiazolones of formula IIe

can be produced by the method of Yevich et al. v J.

Copper. 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 the 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.

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 6 represents an alkoxycarbonyl group and wherein the single line accompanied by the dotted line (- - -) represents a double bond of formula IIG

(IIG) can be prepared by reacting the corresponding compound of formula IIG in which R ³ is hydrogen with the appropriate chloroformate of formula R ³ Cl.

Compounds of formula IIG, wherein R ³ is hydrogen, can be prepared for example by reacting the azide of formula XVI

R ¹

C ^ R

On (xvi) in which

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

Compounds of formula II in which Y represents a group of formula a) wherein R ² represents a group of formula - (C = O) S.e. where a single line accompanying a broken line (- - -) represents a double bond, i.e. diones of the formula IIJ

(IIJ) can be prepared by reacting either phthalic anhydride of formula XIX (XIX)

or a phthalimide of formula XX

(XX) in which

T Q,

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

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

(IIK) can be synthesized as described in the following prior art documents:

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, wherein R ¹ is hydrogen, are commercially available.

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

(IIL) can be prepared by reacting the general formula XXI of the corresponding cyclic anhydride (m) with urea and acetic acid or with ammonium hydroxide (see Chem. Rumors. 16, 574 (1962) and Org. Syn. Coll., Vol. 1, 457). (1941).

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

NH (IIH) are either known compounds or can be prepared by standard methods known in the art.

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

L is halogen and Z is R ¹³ , especially when it is - (CH ₂ ) ₄ -, the same reaction can 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 prepared by condensing a compound of formula X or X ¹ with an aminoalcohol of formula XXIV

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

L-Z-OH.

Said process can be carried out either at room temperature or at elevated temperature, such as at 60-140 ° 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 either known compounds or can be prepared by known methods, such as:

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

J. Med. Chem. 29, 359-369 (1986) and US Patent No. 4,590,196 A when X is a carbon atom and W is a group of formula (d), wherein

A is nitrogen and B is sulfur, see U.S. Pat.

528,292 A when X is nitrogen and W is d) wherein A is nitrogen and B is oxygen, see J. Med. Chem. 29, 359-369 (1986), when X represents a carbon atom and W represents a group of formula (d), wherein A represents a nitrogen atom and B represents 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-chlorobenzisothiazole-1,1-dioxide (European patent application 0 196 096) with piperazine in a solvent such as toluene at elevated temperatures such as from 150 to 160 C when X is a nitrogen atom and W represents a group of formula (d), wherein A represents a nitrogen atom and B represents 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. Patent 4,335,127 (issued June 15, 1982). and U.S. Pat.

No. 710,500 (dated December 1, 1987), when X represents a nitrogen atom and W represents a group of formula (d) wherein A represents a carbon atom and B represents a sulfur atom, intermediates can be prepared according to the reaction scheme shown below by heating appropriately substituted aminobenzo [b] thiophenes with piperazine in a solvent such as 1-methyl-2-pyrrolidinone, wherein the desired aminobenzophb] thiophenes can be prepared by treating the appropriately substituted 2-fluorobenzonitrile with the methylthioglycolate anion and then decarbomethoxylating

when X represents a carbon atom and W represents a group of formula (d), wherein A represents a carbon atom and B represents a sulfur atom, see FR patent no.

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. Patent No. 4,957,916 (September 18, 1990); denotes a carbon atom and W denotes a group of formula (d), wherein A denotes a carbon atom and B denotes a sulfonyl, see JP patent no.

264 583 A2 (dated November 25, 1991), when X represents a carbon atom and W represents a group of formula (d), wherein A represents a nitrogen atom and B represents a group of formula NR ⁴ , the intermediate may be produced by deprotection of N-protected piperinylindazoles, obtained by appropriately substituted reactions

Of 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 represents a carbon atom and W represents a group of formula (d), wherein A represents a carbon atom and B represents a sulfonyl, see JP patent no.

264 583 A2 (dated November 25, 1991) and 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 DE 3,500,898 A1 (dated 17. July 1986).

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

Compounds of formula VIII are either known compounds or can be prepared by known methods, for example:

when L represents a chlorine atom and W represents a group of formula (d), wherein A represents a nitrogen atom and B represents a sulfur atom, see U.S. Pat.

590 196 A when L is chlorine and W is d) wherein A is nitrogen and B is oxygen, see J. Med. Chem. 29, 359 (1986) and when L is a chlorine atom and W is a group of formula (d), wherein

A represents a nitrogen atom and B represents 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 ¹⁴ is amino and V is oxygen can be prepared by reacting isatoic anhydride of formula XXV

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

Phthalides of formula XA

R ¹ -

(XA) phthalic anhydrides of formula XB

O (XB) compounds of formula X ¹

they are either known compounds or can be prepared by known methods.

For example, isatoic 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. Amer. Chem. Soc., 72, 4887 (1950), J. Org. Chem., 41, 2070 (1976). Isatoic anhydrides of the formula XE in which V represents an oxygen atom may be prepared by treating the appropriately substituted phthalic anhydrides of the 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

L ¹ is methoxy and

L ² represents a bromine atom, and may be prepared as described in U.S. Patent No. 4,289,781, which is incorporated herein by reference in its entirety.

Compounds of formula XI in which R ° is hydrogen may be obtained by cleavage of phthalimides 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

Z · Xla

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

Compounds of formula XIa in which R ⁶ is C 1 -C 6 alkyl may 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) piperidino / butyl] phthalimide, (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3) -yl) -1-piperazinyl / butyl] -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazone, (+/-) - 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 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, the use of one of the following compounds and their salts, solvates, N-oxides and derivatives in the manufacture of a medicament for the treatment of any of the diseases described herein above treating or prophylaxis in a mammal suffering from any of the diseases described herein by administering to the mammal a therapeutically effective amount of one of the following compounds and salts, solvates, N-oxides and derivatives thereof, 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-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] isoquinolinedione,

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) piperidino / 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- (l, 2-benzisothiazol-3-yl) piperazinyl / butylJbenzamid (Example 36) antagonized apomorphine-induced climbing in mice, ED ₅₀ = 11.0 mg / kg after 2- [4- / 4- (l, 2-benzisothiazol-3-yl) piperazinyl / butyl] -l-isoindolinone (example 3) at 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) at ED ₅₀ = 14.4 mg / kg, po (B. Costall, RJ Naylor and V. Nohria, Climbing Behavior Induced by Apomorphine in Mice:

A Potential Model for Detection of Neuroleptic 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 relief. Ferrets (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 episodes, whereas animals receiving 3 mg / kg of the compound of Example 36 exhibit no emesis episode.

C. Anxiolytic activity

When 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) was tested for anxiolytic activity using the pigeon conflict procedure ), observe the damage to the response _(ED50 = 0.17 mg / kg, i.m.) relecting 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

5HT _1a agonist stimulation inhibition assay (firing) serotinergních neurons in the dorsal raphe nucleus. Finds the corresponding ID value _5Q 23 micrograms / kg intravenously. (DS Robinson et al., Serotonergic Anxiolytics and Treatment of Depression, Psychopathology 22 (suppl. 1), 27-36 (1989)).

E. Centrally acting muscle relaxant

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

Examples of pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions wherein the active ingredient is a compound of Formula I or a physiologically acceptable salt or solvate thereof, such as the compound of Example 36.

A. Tablets

active substance 150 mg lactose 200 mg cornstarch 50 mg polyvinylpyrrolidone 4 mg magnesium stearate 4 mg

showing content on a 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.

Injection

Injection I

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

Formulation II comprising intravenous injection active substance 0.20 g sterile phosphate buffer pH 9.0, pyrogen-free to 10 ml

The active ingredient in salt form is dissolved in most of the phosphate buffer at 35 to 40 ° C, then made up to volume and filtered through a sterile microporous filter into sterile 10 ml (type 1) vials, sealed with a sterile cap and capped. bottle cap.

C. Capsule composition

Capsule composition

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

mg / capsule active ingredient 250 lactose B. P. 143 starch sodium glycolate 25 magnesium stearate 2 total 420

Capsule formulation II mg / capsule active ingredient 250

Macrogel 4000 B. P. 350 total 600

Capsules can be prepared 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 capsules) mg / capsule

(a) the active substance

250

(b) microcrystalline cellulose 125 C) lactose B. P. « 125 (d) ethylcellulose 13 total 513

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

Syrup active substance sorbitol solution glycerol sodium benzoate flavor purified water

0.2500 g 1.5000 g 1.0000 g 0.0050 g 0.0125 ml up to 5.00 ml as needed

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

Suppository form mg / suppository active substance (63 μη) * 250 hard fat, B. P. (Witepsol H15 - Dynamite 1770

Total

2020

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

One fifth of Witepsol H15 melts in a steam-ladle pan at a maximum temperature of 45 ° C. The active substance is sieved through a 200 μm sieve and added to the molten base with stirring, using a Silverson cutter-mounted stirrer, stirring is continued until a smooth dispersion is obtained. The mixture was maintained at 45 ° C, the remaining Witepsol H15 was added to the suspension and mixed to ensure a homogeneous mixture. All suspension is passed through a 250 μπι stainless steel sieve and allowed to cool to 40 ° C with continuous stirring. At 38-40 ° C, 2.02 g portions of the mixture were filled into suitable plastic molds and the suppositories were allowed to cool to room temperature.

F. Transdermal composition

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 the active ingredient is about 1 to 20%, preferably about 3 to 15%. A particular 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. Triethylamine is distilled from calcium hydride before use. All reactions using air-sensitive or moisture-sensitive compounds are carried out under a nitrogen atmosphere. Flash chromatography (WC Still et al., J. Org. Chem. 43, 2923 (1978)) and flush chromatography are performed using EM Science silica gel 60 (grain size 37-64 nm, i.e. 230-400 mesh ASTM). Thin-layer chromatography (TLC) was performed on Analtech silica gel FG TLC plates (250 µη grain size). ¹ H NMR spectra and ¹³ C NMR spectra were determined in a FT NMR spectrometer under superconducting state, at 200, 300, and 500 MHz. Chemical ponons are expressed as a deviation from trimethylsilane in ppm. Significant HH NHR values are listed in order: multiplicity (siglet, 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 melting point apparatus (Thomas Hoover) and are uncorrected.

Piperidinebenzisothiazole and piperazinobenzisothiazole intermediates are prepared according to known methods: 3- (4-piperidinyl) -1,2-benzisothiazole see U.S. Pat.

528,292, of 9 July 1985, 3- (1-piperazinyl) -1,2-benzisothiazole and 8- (1,2-benzisothiazol-3-yl) -5,8-diazaspiro [4,5] decanebromide see JP Yevich et al., J. Med. Chem. 29,

359-369 (1986). Piperidinebenzisoxazole and piperazinebenzisoxazole 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) Process for the preparation of 2- (2-hydroxyethyl) -1-isoindolinone

This compound was prepared according to a modified method of K. Murata (Bull. Chem. Soc. Jpn. 46, 1752 (1973)). 50.09 g (0.820 mL) of ethanolamine (Aldrich Chemical Company) was charged to a 300 mL round bottom flask equipped with a Dean-Stark trap, reflux condenser, magnetic stir bar and nitrogen inlet. 110 g (0.820 mol, 1.0 equivalent) of phthalide (Aldrich Chemical Company), as a light brown powder, are then added with stirring. 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 was collected in the Dean-Stark adapter. Upon cooling, the product solidified to give a light brown solid. The crude material was taken up in 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 having a melting point of 117-119 ° C. Yield 88%.

^{Χ Η} NMR (CDC1 _3): δ 3.28 (br s, 1H), 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 Calculated for ^C io ^H LL ^{N0 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 mol) of 2- (2-hydroxyethyl) -1-isoindolinone and 400 ml of toluene are placed in 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, periodically creating a rapid swirl. The condenser was then connected and the reaction mixture was heated to 60 ° C for 3 hours. Toluene and excess thionyl chloride were distilled off under reduced pressure. The hot residue was poured onto 500 mL of petroleum ether to give a brown solid. The crude solid was filtered off and taken up in hot toluene. The solution is hot filtered and the resulting hot toluene solution 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. This gives 103.08 g of a brown solid powder. A second crop of compound (15.99 g) was then obtained. This gave a total of 119.07 g of 2- (2-chloroethyl) -1-isoindolinone, m.p. 80-81 ° C. 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) Process 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 was 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 pale orange solution was washed with saturated potassium carbonate solution and the organic phase was dried over magnesium sulfate, filtered and evaporated. 13.44 g of an orange oil are obtained. This material was purified by flash chromatography with 5: 1 ethyl acetate: hexanes as eluent. 7.15 g of 2- (2- / 4- (1,3-benzisothiazol-3-yl) -1-piperazinyl / ethyl] -2,3-dihydro-1H-isoindol-1-one are obtained. The mixture is taken up in acetone and treated with 24.5 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride.The salt is recrystallized twice from 95% ethanol to give 3.05 g of the hydrochloride salt as an off-white powder (24% yield). analytical data indicated the presence of 1 equivalent of hydrogen chloride and 0.5 equivalent of ethanol, m.p. 264 DEG-267 DEG C. (decomposition).

^{Τ Η} NMR (DMSO-d _6): 1.03 (t, 3, J = 6.9), 3.48 (m, 7H), 3.70 (br 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 for ^C 21 ^H 22 ^N 4 ^OS · HCl. 0.5 C ₂ H ₆ O:

H, 5.93; N, 12.79. Found: C, 60.24; H, 6.08; N, 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 gives 156.83 g of 2- (3-hydroxypropyl) -1-isoindolinone. Yield 86%.

1 H 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 (broad 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 ^C 11 ^H 13 ^{NO 2:} Calculated: 69.09% C 6.85% H 7.32% N Found: 68.99% C, 6.86% H, 7.28% N.

b) A process for the preparation of 2- (3-chloropropyl) -1-isoindolinone

This compound was prepared as described in Example 1b). Using 127.53 g of 2- (3-hydroxypropyl) -1-isoindolinone gave 130.94 g of crude chloride. Yield: 94%. A small sample of 5 g was purified by flash chromatography with 4: 1 hexanes / ethyl acetate as eluent. 4.29 g of an analytically pure white solid are obtained, having a melting point of 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) Method 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 produced and recrystallized from ethanol. 1.58 g of the title compound is obtained as a yellow powder, m.p. 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 _C22 H24 ^{N4 OS} · ^{lf5 HC1 Calculated:} 59.09% C, 5.75% H, 12.53% Found: 59.06% C, 6.10% H, 12.52%

N,

N.

Example 3

and)

Method of production

Of 2- (4-bromobutyl) -1-isoindolinone

15.6 g (0.056 ml) of N- (4-bromobutyl) phthalimide (Aldrich Chemical Company), 100 ml of glacial acetic acid, 15.83 g (0.133 mol, 2.4 equivalents) of metallic tin and 20.0 ml of hydrobromic acid Place in a 250 ml round-bottomed flask. The resulting light yellow reaction mixture was placed under nitrogen 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 taken up in 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 (3: 1 hexanes / ethyl acetate). 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 ^NOBRE Cl2 ^{H 14:} 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 can be used in place of hydrobromic acid. This yields higher yields, but the resulting material is a mixture of chloride and bromide.

b) Process for preparing 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 added to a 100 ml round bottom flask. . Then, 2.77 g (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 were refluxed for 19 hours under a nitrogen atmosphere. The solution was allowed to cool and transferred to a separatory funnel with 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 salt, hydrochloride, was precipitated by adding 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 which mp 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 ₂ N ₄ OS. HC1:

H, 6.14; N, 12.65. Found: C, 62.23; H, 6.16; N, 12.62.

Example 4

a) A method for producing 6-nitro-1 [3H] isobenzofuranone

This compound was prepared as described in 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 (s, 2), 7.71 (d, 1, J = 8.4), 8.57 (dd, 1, J = 8.4, 2.0) 8.76 (d, 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 ₆ 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 as described by J. Tirouflet (Bull. Soc. Sci. Bretagne, Vol. 26, 7-122, (1951)). Mp 181-182 ° C.

^{Τ Η} NMR (CDC1 _3): δ 3.94 (br s, 2H), 5.21 (s, 2H), 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 for C ₇ H ₇ NO ₂ :

calculated: 64.42% C, 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 placed in a round-bottom flask equipped with a magnetic stir bar. 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 cuprous 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 cause solids to dissolve, and the layers were separated.

The green aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over 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 is obtained as a pale yellow powder, m.p. 107-108 ° C. Yield: 54%.

¹ H NMR (CDCl 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.

Analysis for C ₈ H ₅ O ₂ C1:

calculated: 57.00% C, 2.99% H, found: 57.16% C, 3.03% H.

d) A process for the preparation of 6-chloro-2- (2-hydroxyethyl) -1-isoindolinone

9.15 g (0.0543 mol) of 6-chloro-1 [3H] -isobenzofuranone,

3.32 g (1.0 equivalents) of ethanolamine (Aldrich Chemical Company) and 10.0 ml of toluene are placed in a 100 ml round bottom flask equipped with a magnetic stir bar and a 10 ml Dean-Stark cap. The solution was heated in an oil bath and the toluene collected in the Dean-Stark trap was returned to the reaction vessel. The resulting orange melt is heated to 210 ° C for 22 hours. Upon cooling, the solidified to give 11.75 g of a brown solid. This crude material was used without further purification

e) A process for the preparation of 6-chloro-2- (2-chloroethyl) -1-isoindolinone

This compound was prepared in an analogous manner to that described in Example 1 b). Use 11.75 g of 6-chloro-2- (2-hydroxyethyl) -1-isoindolinone produced above to give 10.03 g of the title compound as a pale yellow powder. The yield was 80% of theory

6-chloro-1 [3H] -isobenzofuranone. Mp 112-114 ° C.

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, 1, 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 NOCl ₂ :

H, 3.94; N, 6.09. Found: C, 52.30; H, 3.96; N, 6.03.

f) 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 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 21 ^N 4 ^OSCl . HC1: calculated: 56.13 % C, 4.93 % H, found: 56.22 % C, 4.95 % H.

N, 12.47. N, 12.40.

Example 5

and)

Method of production

6-chloro-2- (4-chlorobutyl) -1-isoindolinone

This compound was prepared in an analogous manner to that used in Example 1 b). The starting compound, 6- (chloro-2- (4-hydroxybutyl)) - 1-isoindolinone, was obtained as described in Example 4 d). 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.

¹ H 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.

H, 5.08; H, 5.08. Found: C, 55.90; H, 5.12;

N, 5.43. N, 5.38.

b) Process for the preparation 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 1 (c). From 5.02 g (19.4 mmol) of 6-chloro-2- (4-chlorobutyl) -1-isoindolinone gave a crude orange solid which was purified by recrystallization. The salt, the hydrochloride produced by treating the free base with 1 N ethereal hydrogen chloride, was triturated with hot ethanol and dried in a vacuum oven. 4.84 g of 2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -6-chloro-1-isoindolinone hydrochloride hydrate are obtained as a brown powder having a temperature of mp 241-242 ° C.

¹ H NMR (DMSO-d 6): 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, 4.5), 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 H ₂ 0:

calculated: 57.00% C, 5.57% H, 11.56% N, 1.49% H ₂ O, found: C 56.62, H 5.65, N 11.31, 34% H ₂ O.

Example 6

a) Method for the preparation of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone

These compounds were prepared as described in Example 3 a). A mixture of 4.24 g of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone (yield: 53% of theory) gives a reduction of 10.00 g (0.0338 mol) of N- (5-bromopentyl) phthalimide (Transworld Chemicals, Inc) performed

9.62 g (0.081 mol, 2.4 equivalents) of tin metal in 75 mL of acetic acid and 15.0 mL of concentrated hydrochloric acid. The mixture obtained is used directly, without separation into 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 Example 3b). From a mixture of 4.24 g (0.0178 mol) of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone, followed by 4.30 g (0.0196 mol, 1.1 equivalent of 3- (1-piperazinyl) -1,2-benzisothiazole, 2- [5- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / pentyl] -1-isoindolinone hydrochloride is obtained in the form of orange powder. The salt, hydrochloride, was obtained as a brown powder weighing 4.28 g (53% yield) after recrystallization from ethanol. The title compound has a temperature 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 (broad 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 1. HC1:

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-isoindolinone was obtained by reduction of N- (6-bromohexyl) phthalimide (Transworld Chemicals, Inc). This material is used as a mixture of halogenated compounds.

b) Process for the preparation of 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 pale yellow solid are obtained. The salt, hydrochloride, is formed by treatment with 1N ethereal hydrogen chloride solution. It is obtained

4.18 g of 2- [6- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / hexyl] -1-isoindolinone hydrochloride as an off-white powder, m.p. 263-264 ° C. Yield: 61%.

¹ H NMR (DMSO-d ₆ ): δ 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 72, 128.01, 131.08, 141.72, 152.02.

Analysis for ^C 25 ^H 30 ^N 4 ^OS · ^HCl: 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 described by 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 taken up in 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 phases were dried over magnesium sulfate, 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-benzisothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] phthalimide as prepared in Example 24 are added. into a 100 ml round-bottomed flask and brought into contact with 20.0 ml of methanol. To this stirred solution was added dropwise 1.49 g of an 85% aqueous solution (0.025 mol,

1.5 equivalents) of hydrazine hydrate and the mixture was refluxed under nitrogen 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 were dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. 5.31 g of 3- [4- [2- (2-aminoethoxy) ethyl] -1-piperazinyl] -1,2-benzisothiazole was obtained as a viscous orange oil. This material was used without further purification.

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

A solution of 5.31 g (0.017 mol) of 3- [4- [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 mL, 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, at which time addition was complete. The solution was allowed to cool to room temperature and washed with saturated potassium carbonate solution. The organic phases were dried over magnesium sulfate, filtered and evaporated. 6.22 g of a red-orange oil are obtained. 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 1} H NMR spectrum shows a small amount of ethyl acetate present in the sample. Mp 108-110 ° C.

¹ H NMR (CDCl ₃ ): δ 2.69 (m, 6), 3.49 (broad 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.

Analysis for ^C 23 ^H 26 ^N 4 ^S 2 ° '°' ^{15 C} 4 ^H 8 ° ^2: calculated: 65.05% C 6.29% H 12.86% N Found: 64.74% C, H, 6.33; N, 12.76.

Example 9

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

30.00 g (0.131 mol) of methyl (2-bromomethylbenzoate) (Example 8a)), 20.85 g (0.137 mol, 1.05 equivalents) of trans-4-aminocyclohexanol hydrochloride (Aldrich Chemical Company), 27.15 g (0.196 mol, 1.5 equivalents) of potassium carbonate, 110 mL of toluene and 20 mL of water were added to a 500 mL round bottom flask equipped with a magnetic stir bar and a Dean-Stark trap. 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 was added to the reaction mixture and the toluene-methanol azeotrope was collected on a Dean-Stark trap. After further heating for 24 hours, the salts were 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. There was thus obtained trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone (11.88 g) as an off-white solid, m.p. 133-134 ° C. Yield 39%.

¹ H NMR (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 :

H, 7.41; N, 6.06. Found: C, 72.63; H, 7.41; N, 6.04.

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

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, 1 ml) are added. , 5 equivalents) of triethylamine. The orange solution was placed under a nitrogen atmosphere and cooled in an ice bath. To this stirred 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. 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. 5.40 g of trans-4- (1-oxo-2-isoindolyl) -1-cyclohexyl methanesulfonate are 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- (oxo-2-isoindolyl) -1-cyclohexyl methanesulfonate, 3.92 g (0.079 mol, 1.05 equivalents)

3- (1-piperazinyl) -1,2-benzisothiazole, 2.85 ml (2.07 g,

Triethylamine (0.020 mol, 1.2 equivalents) and acetonitrile (20 mL) were combined, placed under a nitrogen atmosphere, and refluxed for 2.5 days. The mixture was allowed to cool to room temperature and washed with saturated potassium carbonate solution. The organic layers were dried over magnesium sulfate, filtered and rotary evaporated. 8.29 g of a viscous orange oil are obtained. This crude material was purified by flash chromatography with ethyl acetate as eluent. The isolated material was purified by further flash chromatography using a 2: 1 mixture of ethyl acetate and hexanes as eluent. 0.224 g of a thick orange oil is obtained. The salt, hydrochloride, of this free base is formed 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)), (+/-) - cis-2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / 1-cyclohexyl] -1-isoindolinone as 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), 3.45 (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 'HC1 H} 2 ^0: 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) Production method of 3- [4- (4-amino-2-butynyl) -1-piperazinyl] 68

-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 were prepared to give 6.23 g (72.3% yield) of 3- [4- (4-amino-2-butynyl) -1-piperazinyl] -1,2-benzisothiazole as a crude orange oils. 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) above were contacted with 50 ml of toluene. To the stirred mixture was added a solution of methyl (2-bromomethylbenzoate) (Example 8 a)). 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. The crude material was purified by flash chromatography on a special flash silica with ethyl acetate / hexanes (3: 1) as eluent. The salt, pure free base hydrochloride, is prepared by adding 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. 196 ° C. Yield 3%.

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) ppm.

¹³ C NMR (DMSO-d 6): 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,

166.80.

Analysis for ^C 23 ^H 22 ^N 4 ^OS: Calculated: 62.93% C 5.28% H 12.76% N Found: 62.79% C, 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 150.0 ml of glacial acetic acid, 75.0 ml of concentrated hydrochloric acid and 58.07 g ( 0,489 ml,

2.4 equivalents) of tin metal (Fisher Scientific). The cream-colored suspension is refluxed in an oil bath. As the solution warms, the phthalimide dissolves to give a light yellow solution. The reaction mixture was refluxed for 2 hours. The solution is hot filtered and the tin shavings are washed with fresh acetic acid. The bulk of the acetic acid was evaporated on a rotary evaporator to give a light yellow cream solution. This material was taken up in dichloromethane and then washed with distilled water and saturated sodium chloride solution. The organic phases were dried over magnesium sulfate, 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 as a pale yellow powder having a melting point of 150-151 ° C. Yield 47%.

- 70 ^{Χ Η} NMR (CDC1 _3): δ 4.48 (s, 2H), 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 ΟθΗ ₇ ΝΟ:

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 was placed in a 500 ml round bottom flask under nitrogen. The sodium hydride is washed twice with hexanes and the waste hexanes are drawn off with a solid pipette. 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. In a separate 500 ml round-bottomed flask, previously dried in the oven, 13.51 g (0.103 mol, 2.5 equivalents) of trans-1,4-dichloro-2-butene (Aldrich Chemical Company) and 100, 0 ml 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 taken up in dichloromethane and washed several times with water. The organic phases were dried over magnesium sulfate, filtered and evaporated. 20.12 g of a dark orange oil are obtained. The crude material was purified by flash chromatography (1: 1 hexanes / ethyl acetate). There was thus obtained (E) -2- (4-chloro-2-butenyl) -1-isoindolinone (6.48 g) as a pale yellow oil. Yield: 71%.

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 bis-alkylated product, (E) -2,2 '- (2-butene-1,4-diyl) -bis (1-isoindolinone), was 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) of 3- (1-piperazinyl) - 1,2-benzisothiazole and 2.26 ml of triethylamine in 20.0 ml of acetonitrile were refluxed for 1 hour under a nitrogen atmosphere. The crude product obtained was purified by flash chromatography using ethyl acetate as eluent to give 3.47 g 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 mp 232-235 ° C. Yield 48%.

@ 1 H NMR (DMSO-d6): .delta.3.10-3.58 (m, 6), 3.82 (broad s, 2), 4.07 (broad d, 2, J = 13.5), 4.22 (d, 2, J = 5.1), 4.49 (s, 2), 5.08 (dt, 1, J = 15.4, 6.9), 6.04 (dt, 1) , J = 15.4,

5.4), 7.55 (m, 5), 7.69 (d, 1, J = 7.3), 8.10 (dd, 2, J =

7.5, 5.4), 11.36 (broad s, 1) ppm.

¹³ C NMR (DMSO-d ₆ ): δ 42.95, 46.38, 49.37, 49.92, 56.33,

120.98, 127.83, 162.13,

121,14,

128.07,

167.08.

122,77,

131,36,

123.44, 132.01,

123,95,

136,08,

124,56,

141,89,

126,91,

152,06,

Analysis for ^C 23 ^H 24 ^N 4 ^OS · Calculated: 62.64% C 5.71% H Found: 62.41% C, 5.67% H,

N, 12.70. 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 the Example

b). Alkylation of 5.75 g (0.043 mol) of 1-isoindolinone by treatment

6.25 g (0.047 mol, 1.1 equivalents) of cis-1,4-dichloro-2-butene (Aldrich Chemical Company) in anhydrous dimethylformamide gave 3.43 g (yield = 36% of theory) of (Z) -2- (4-chloro-2-butenyl) -1-isoindolinone, after purification by flash chromatography.

1 H, ¹³ C and differential. The NMR spectra of the light orange oil were 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 by-product of bis-alkylation, (Z) -2,2 '- (2-butene-1,4-diyl) -bis (1-isoindolinone) weighing 0.88 g, is obtained as a pale yellow solid having mp 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 equivalent) of 3- (1-piperazinyl) - 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 material 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, was 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 which is: mp 234-236 ° C. Yield: 33%.

¹ H NMR (DMSO-d 6): δ 3.34 (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 7.68 (dd J = 7.3 , ι, ο), 8, 12 (t, 2) J = 8.0) ii , 65 (wide 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 H ₂ 0:

calculated: 61.39% C, 5.82% H, 12.45% N, 2.00% H ₂ O, found: 61.05% C, 5.79% H, 12.19% N, 2, 28% H ₂ O.

Example 13

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

3.50 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 Yevich et al., J. Med. Chem. 29, 359) -369 (1986)), 2.24 mL (0.0161 mol, 1.3 equivalents) of triethylamine and 15.0 mL of acetonitrile were added to a 100 mL round bottom flask. The cloudy orange solution was refluxed under a nitrogen atmosphere for 17 hours. The mixture was allowed to cool to room temperature and taken up in 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. That's how it gets

4.35 g of brown powder. 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 as an off-white powder, m.p. 258 DEG-260 DEG C. (decomposition). . Yield: 82%.

¹ H NMR (DMSO-d 6): δ 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 ^S · ° 2 ^{HC1 Calculated:} 60.45% C, 5.51% H, 12.26% N Found: 60.46% C, 5.55% H, 12 17% N.

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

To a solution of 12.46 g (0.0296 mol) of 2- [4- / 4- (1,2-benziso75-thiazol-3-yl) -1-piperazinyl / butyl] phthalimide in 30.0 ml of methanol is added 2.times. 62 g (1.5 equivalents) of 85% hydrazine hydrate. The reaction mixture is 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 phases were dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. 8.1 g of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole were obtained as an orange-brown oil. Yield: 94%.

¹ H NMR (CDCl ₃ ): δ 1.38 (broad s, 2), 1.55 (m, 4), 2.45 (t,

2, J = 7.4), 2.68 (t, 4, J = 5.0), 2.74 (t, 2, J = 6.8),

3.57 (t, 4, J = 5.0), 7.35 (ddd, 1, J = 1.1, 7.0, 8.1), 7.46 (ddd, 1, J = 1, 1, 7.0, 8.1), 7.81 (d, 1, J = 8.1), 7.91 (d,

1, J = 8.2 ppm.

This crude amine was used without further purification.

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

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

4-methylphthalic acid. The reaction mixture was placed under nitrogen and refluxed for 5 hours. The solution was evaporated and the residue taken up in dichloromethane and washed with saturated potassium carbonate solution. The organic phases were dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (3: 1 hexanes / ethyl acetate). 3.82 g of white crystals are obtained. This free amine is taken up

- 76 ethyl acetate and 8.7 ml of 1N (8.7 mmol, 1.0 equivalent) ethereal hydrogen chloride solution is added. 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 as a white powder, m.p. 255.5-258. Deň: 32 ° C. Yield: 67%.

1 H NMR (DMSO-d ₆ ): δ 1.74 (m, 4), 2.46 (s, 3), 3.25 (m, 4), 3.53 (m, 6), 4, 02 (broad 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. HC1:

H, 5.78; N, 11.89. Found: C, 60.91; H, 5.78; N, 11.75.

Examples 14 to 22

The compounds of Examples 14-20 and 22 were prepared from the corresponding substituted phthalic anhydride precursors as described in Example 13c). The phthalic anhydrides used are obtained from commercial suppliers or are prepared by methods known in the literature as indicated. 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.

³ H NMR (DMSO-d ₆ ): 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, 1.1), 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, 1) ppm. ¹³ C NMR (DMSO-dg): 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: calculated: 58.16% C, 5.09% H, 11.79% N, 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 ( broad 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 6): δ 20.57, 22.30, 36.44, 38.21, 40.71,

46.32, 50.48, 55.05, 113.82, 114.57, 121.12, 123.19, 123.94, 124.56, 126.90, 128.06, 133.47, 135, 77, 152.05, 155.19,

162.14, 166.63, 167.74.

Analysis for ^C 22 ^H 23 ^N 5 ° 2 ^S · HCl:

H, 5.34; N, 11.86. Found: C, 58.48; H, 5.35; N, 11.90.

Example 16

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

¹ H NMR (DMSO-d 6): δ 1.71 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.03 (broad d, 2, J = 13, 4), 7.45 (ddd, 1, J = 8.1, 6.9, 1.0), 7.58 (ddd, 1, J = 8.1, 6.9, 1.0), 7 89 (dd, J, J =

4.8, 1.1), 8.10 (dd, 1, J = 8.0, 4.2), 9.09 (d, 1, J = 4.9),

9.12 (d, 1, J = 0.8), 10.86 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): 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, 2), 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 (6, 1, J = 7.2), 8.08 (d, 1, J = 4.5), 8.11 (s,

1), 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 (broad 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 3 H ₂₃ N ₂ O ₄ S _5. HCl:

H, 4.82; N, 13.95. Found: C, 55.06; H, 4.85; N, 13.96.

Example 18

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

Starting compound: 3,4-pyridinedicarboxylic 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, 50.43, 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 22 ^H 23 ^N 5 ° 2 ^S * ^HCl · Calculated: C 55.51, H 5.51, Found: C 55.75, H 5.52, ^H 2 °:

14.71% N, 3.78% H ₂ O, 14.71% N, 3.92% H ₂ O.

Example 19

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

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, 36.64, 46.36, 50.52, 55.06, 120.61, 121.13, 123.94, 124.55, 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 26 ^N 4 ^S ° 2 ^{'HC1 H} 2 ^0: Calculated: 58.95% C 5.98% H 11.46% N Found: 59.07% C, 5.99% H, 11.32.

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 £ 23 2 ¹ ^^^ ^ ½ ^HC1 · ^{1 H} 2 ^0: Calculated: 50.79% C 4.63% H 10.30% N Found: 50.63% C, 4.67% H, 10.23% N.

The second portion of crystals obtained is 0.44 g of hydrochloride dihydrate, m.p. 262-265 ° C.

Analysis for ^C 23 ^H 22 ^N 2 4 ° ^SC1 2 · ^{HC1 «H} 2 ^{0 2:} calculated: 49.16% C 4.84% H 9.97% N Found: 49.21% C 4, 83% H, 9.93% N.

Example 21

a) Process for the preparation of 4-chlorophthalimide

10.0 g (0.0661 mol) of 4-aminophthalimide (Kodak) dissolved in 14.0 ml of distilled water and 27.0 ml of concentrated hydrochloric acid are placed in a 500 ml round-bottom flask. The resulting pale yellow solution was cooled in an ice bath and a solution of 4.57 g (0.0669 mol, 1.1 equivalents) of sodium nitrite (Malinckrodt) in 100 mL of distilled water was added dropwise. After this addition, the reaction mixture turns yellow in gold. The solution was allowed to stir at 0 ° C for 20 minutes and then a solution of 21.0 g (0.123 mol, 2.0 equiv.) Of copper (II) 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 gave 9.61 g of the title compound as a brown solid. This material was used without further purification.

b) Preparation of N- (4-chlorobutyl) -4 -chlorftalimidu ¹ and N- (4-bromobutyl) -4 -chlorftalimidu ¹

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) Method 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 13a). From 2.50 g (0.0029 mol) of a mixture of N- (4-chlorobutyl) -4-chlorophenylsulfonamido ¹ phthalimide and N- (4-bromobutyl) -4 ¹ -chlorftalimidu 80:20 and 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 produced, 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%.

^{Χ Η} NMR (DMSO-d₆) δ 1.69 (m, 4H), 3.23 (m, 4H), 3.53 (m, 6), 4.03 (br 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 2 4 ° ^{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- (1,3-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): 3.94 (s, 3), 4.03 8.5), 7.60 (tm, 1, 2, J = 7.9, 4.6), δ 1, 70 (m, 4), 3.25 (m, (broad d, 2, J = 13.4), J = 5.0), 7.79 (tm, 1, 11.19 (broad s, 1)) ppm.

4), 3.54 7.48 (d,

J = 7.3), (m, 6),

2, J = 8.10 (dd, 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 O 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-neck, round-bottom, oven-dried, flask equipped with a pressure equalizing 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 was complete, the ice bath was removed and the solution was allowed to stir at room temperature for 10 minutes. A solution of 25.0 g (0.134 mol) of trans-diethyl 1,2-cyclopropanedicarbonate (Aldrich Chemical Company) was added dropwise to the resulting suspension. The reaction mixture was 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. (+/-) - trans-1,2-cyclopropanedimethanol was obtained as a colorless oil.

¹ H NMR (CDCl 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 (CDCl 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, 0 ml of anhydrous dichloromethane is added to a 500 ml three-necked round-bottomed flask which has been dried in an oven. The reaction mixture was 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 were added. The solution was allowed to stir at room temperature for an additional 6 days. Then, 5.43 mL (3.95 g, 0.039 mol, 1.0 equivalent) of triethylamine was added and the solution was allowed to stir for an additional 24 hours. The reaction is still incomplete, so the mixture is refluxed for 90 minutes and the solvent is removed by rotary evaporation. A sticky brown-colored solid is obtained. The crude material was purified by flash chromatography with 1: 1 hexanes / ethyl acetate followed by 19: 1 ethyl acetate / methanol. 1.85 g of (+/-) - trans-2- (chloromethyl) -1-cyclopropanethanol were obtained. A portion of the starting diol weighing 0.87 g was recovered 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 is 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 phases were dried over magnesium sulfate, filtered and evaporated. 3.55 g of a dark orange oil are obtained. The crude material was purified by flash chromatography (5: 1 hexanes / ethyl acetate). 1.12 g of (+/-) - trans - N - [[2- (hydroxymethyl) cyclopropyl / methyl] phthalimide is obtained as a white powder having a melting point of 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 mmol) 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 were added to a 50 mL round bottom flask. The solution was placed under nitrogen and cooled in an ice bath. To this cold 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 becomes a clear pale orange solution which is 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 off-white solid is obtained. This material was purified by flash chromatography on silica gel with 1: 1 hexanes / ethyl acetate as eluent. It will

1.29 g of (+/-) - trans- [2- (phthalimidomethyl) -1-cyclopropyl] methylmethylsulfonate as a white powder having a melting point of 118-121 ° 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] methyl methanesulfonate, 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 were added to a 100 mL round bottom flask. The cloudy suspension is overlaid with a nitrogen atmosphere and refluxed for 3.5 hours.

An additional 0.083 g (0.10 equivalents) of piperazinobenzisothiazole 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 phases are 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 with 2: 1 hexanes / ethyl acetate as eluent. 1.30 g of the free base is obtained. The salt, the hydrochloride is formed and recrystallized from aqueous ethanol. 1.11 g of (+/-) - trans-N - [[2 - [[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclopropylmethyl] hydrochloride are obtained. talimide as an off-white powder, after drying in a vacuum oven. This compound has a melting point of 246-248 ° C. Yield: 61%.

1 H-NMR (DMSO-d 6): δ 0.74 (m, 2), 1.29 (m, 2), 3.12 (broad 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-d6) ): δ 9,64, 12.01, 17.07, 46,24, 49 , 87, 50.22, 58.47, 12 and, 16 123 02, 124.01, 12 4.61, 126, 93, 128.11, 131.67, 13 4.37, 15 2.08, 162.16, 168.02. Analysis calculated for C ₂₄ H 24 n ₄ o ₂ sec. HCl. 0.5 H ₂ O: calculated: 60.30 % C, 5.48 % H, 11.72% N, 1.88 % h ₂ °, found: 60.37 % C, 5.51 % H, 11.72% N, 1.85 % h ₂ °.

Example 24

a) Process for the preparation of N- [2- (2-chloroethoxy) ethyl] phthalimide

15.0 g (0.081 mol) of potassium phthalimide (Aldrich Chemical Company) as a fluffy powder and 28.5 ml (34.74 g, 0.243 mol, 3.0 equivalents) of 2-chloroethyl ether (Aldrich Chemical Company) as a colorless oil are added. into a 250 ml round-bottomed flask. The reaction mixture was heated to 170 ° C under an atmosphere of nitrogen in an oil bath for 19 hours. As the mixture warms, the solution changes to a more fluid and brown color. The mixture was removed from the oil bath and distilled water was 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. The crude material was purified by flash chromatography with 3: 1 hexanes / ethyl acetate as eluent. 13.53 g of a light orange oil are obtained, corresponding to a yield of 67% of theory. This oil solidifies rapidly on standing. An analytically pure white powder is obtained by recrystallization from ethyl acetate and has 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 = 5.8, 0.9), 3.89 (dt, 2, J =

5.4, 1.2), 7.71 (m, 2), 7.83 (m, 2) ppm.

¹³ C NMR (CDCl 3): δ 37.14, 42.70, 67.92, 70.61, 123.27, 132.97, 168.27.

Analysis for ^{C H} i2 i2 ^NO 3 ^Cl: 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-benzhisothiazole, 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. There were obtained 0.87 g of N- [2- [2- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / ethoxy] ethyl] phthalimide hydrochloride as off-white crystals, m.p. 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 = 5.4)

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: 58.50% C, 5.36% H, 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 phthalimide (Aldrich Chemical Company) and 25.9 (0.212 mol, 3.0 equivalents) of 1,4-dichloro-2. -Butin (Aldrich Chemical Company) 10.64 g of pale yellow solid was obtained after elution chromatography with hexanes / ethyl acetate (4: 1). Yield: 65%. Analytically pure, diamond-like colorless crystals were crystallized from a solution of hexanes 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 12 ^H 8 ^NO 2 ^{C1 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 13 a). 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. pale yellow flakes, after recrystallization from a mixture of ethanol and ether. The title compound has a melting point of 231-233 ° C.

¹ H NMR (DMSO-d ₆ ): δ 3.49 (m, 6), 4.09 (m, 2), 4.23 (broad s, 2), 4.54 (s, 2), 7, 47 (ddd, 1, J = 8.1, 7.0, 1.0), 7.60 (ddd, 1, J = 8.0, 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 ₂ ^H 3 ^N 4 20 ° 2 ^S · ^HC1: Calculated: 60.99% C 4.67% H 12.37% N Found: 60.82% C, 4.72% H, 12 , 27% N.

Example 26

a) Process for the preparation of (E) -N- (4-bromo-2-butenyl) phthalimides

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 were 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 / ethyl acetate (4: 1) as eluent. It will

3.25 g of (E) -N- (4-bromo-2-butenyl) phthalimide. Yield: 26%. An analytically pure sample was obtained by crystallization from ether. The product consisted of white crystals having a melting point of 97-99 ° C.

¹ H NMR (CDCl ₃ ): δ 3.89 (d, 2, J = 6.4), 4.29 (d, 2, J =

5.1), 5.87 (m, 2), 7.72 (m, 2), 7.84 (m, 2) ppm.

¹³ C NMR (CDCl ₃ ): δ 31.27, 38.62, 123.40, 128.36, 129.96, 132.04, 143.09, 167.77.

Analysis for C ₁₂ ^H io ^N0 2 ^Br: Calculated: 51.58% C 3.61% H 5.01% N Found: 51.53% C, 3.60% H, 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 mol, 1.0 equivalent) of 3- (1-piperazinyl) of 1,2-benzisothiazole gave 14.31 g of a dark orange solid. The crude material was purified by column chromatography eluting with hexanes / ethyl acetate (1: 1). 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 as a brown powder, m.p. up to 244 ° C.

¹ H NMR (DMSO-d 6): δ 3.20 (m, 2), 3.45 (m, 4), 3.80 (broad s, 2), 4.04 (broad d, 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), 7.56 (t, 1, J = 7.3), 7.85 (m, 4), 8.08 ( dd, 2,

J = 7.4, 6.4), 11.72 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 38.50, 46.29, 49.80, 56.06, 120.96, 121.09, 123.12, 123.96, 124.53, 126.88, 128.03, 131.50,

134.45, 152.03, 162.12, 167.39.

Analysis for C23H2 ₀ N ₄ O ₂ S. HCl:

H, 5.10; N, 12.31. Found: C, 60.62; H, 5.15; N, 12.25.

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- of dichloro-2-butene. The crude material was purified by column chromatography eluting with hexanes / ethyl acetate (4: 1). 12.87 g of (Z) -N- (4-chloro-2-butenyl) phthalimide are obtained as a pale yellow solid. Yield: 78%. The material was found to be a 90:10 mixture of (Z) and (E) isomers as determined by ¹³ C NMR spectral analysis. The title compound has a melting point of 63-66 ° C.

^{Χ Η} NMR (CDC1 _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.

The following ¹³ 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 process for the preparation of (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 90:10 mixture of (Z) and (E) -N- (4-chloro-2-butenyl) phthalimide and 9.17 g (0.0418 mol, 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 column chromatography eluting with hexanes / ethyl acetate (1: 1). It will

14.35 g of an orange oil which solidifies on standing. Yield: 82%. A portion of this material (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, was 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 are obtained (m.p. 100% theory of the Z-isomer) as 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, J, 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 O ₂ S. HCl. 0,25 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, O, 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 (J.

Yevich, P. et al., J. Med. Chem. 29, 359-369 (1986)) and 50.0 ml of dichloromethane are added to a 150 ml flask. Chlorine gas is bubbled through the resulting cloudy solution with stirring. This gives a rust-colored mixture. A solution of 7.12 g (0.112 mol, 2.1 equivalents) of ethanolamine was added to a separatory funnel,

16.3 mL (11.8 g, 0.117 mol, 2.1 equivalents) of triethylamine and 50.0 mL of dichloromethane. The mixture was cooled in an ice bath and the bis-chloride solution was slowly added to the cold 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. It is obtained

22.74 g of crude orange oil. The 1 H NMR spectrum of this material was consistent with 2- (2-hydroxyethyl) -1,2-benzisothioazol-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 contacted with toluene (100 ml). The solution was cooled in an ice bath and 15.68 g (0.132 mol, 1.13 equivalents) of thionyl chloride was added dropwise over a period of 15 minutes. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours.

Toluene and excess thionyl chloride were distilled off under reduced pressure, using an invert Hopkins capacitor. The red-orange residue was purified by flash chromatography with 1: 1 hexanes / ethyl acetate as eluent. 10.24 g (yield = 41% of theory, based on 2,2'-dithiobisbenzoyl chloride) of 2- (2-chloroethyl) -1,2-benzisothiazol-3 [2H] one is obtained 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 ppm.

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 (0.0182 mol, 1.1 equivalents) of 3- (1 (piperazinyl) -1,2-benzisothiazole is obtained

6.94 g of crude material. This material was purified by flash chromatography with 1: 1 hexanes / ethyl acetate as eluent. 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 as a white crystalline solid. mp 250-252 ° C. Yield: 25%.

NMR (DMSO-d6): 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 ₂₀ H ₂₀ N ₄ OS ₂ . HC1:

H, 4.89; N, 12.94. Found: C, 55.53; H, 4.92; N, 12.89.

Example 29

a) Method for producing 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) 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-benzhisothiazole 4.40 g of the corresponding compound is obtained 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 as an off-white powder which is mp 185-187 ° C. Yield: 32%.

^{Χ Η} NMR (DMSO-d _6): δ 2.19 (m, 2), 3.28 (m, 4H), 3.55 (m, 4H), 4.00 (m, 4H), 7.44 (tt, 2, J = 7.5, 1.0), 7.57 (ddd, 1, J =

8.3, 6.8, 1.0), 7.69 (ddd, 1, J = 8.5, 7.3, 1.2), 7.87 (dq,

1, J = 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 2 · 1.5 HCl:

calculated: 54.21% C, 5.09% H, 12.04% N, found: 54.48% C, 5.46% H, 11.93% N.

Example 30

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 gave 14.16 g of a dark orange oil. The crude material was purified by flash chromatography, eluting with ethyl acetate: dichloromethane (4: 1), followed by recrystallization of the free amine from 95% ethanol. 3.68 g of off-white powder are obtained. 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 as an off-white powder which is mp 215-216 ° C. Yield: 22%.

¹ H NMR (DMSO-d 6): 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, 2), 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 24 ^N 4 ^OS 2 · ^HCl: 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 hexanes 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) was added to the resulting gray suspension.

1 [2H] phthalazinone in 50.0 ml of anhydrous dimethylformamide and the resulting solution was allowed to stir at room temperature for 30 minutes. The anion solution thus prepared is introduced into a 500 ml round-bottomed 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. As the reaction proceeds, the mixture becomes 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. The organic phases were dried over magnesium sulfate, filtered and evaporated. 16.49 g of crude product 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. NMR spectral analysis showed the product to be a 80:20 mixture of 2- (4-chlorobutyl) -1 [2H] phthalazinone and its corresponding bromide as determined by integrating triplets at 3.56 and 3.43 ppm. Diferen. n. O. e. experiments show N-alkylated products versus O-alkylated products. The chloride-bromide mixture was used without further purification.

b) 2- [4- / 4- (1,2-Benzisothiazole) hydrochloride

100 ALIGN!

-3-yl) -1-piperazinyl / butyl] -1 (2H) -phthalazinone

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) of 3- (1-piperazinyl) -1,2-benzisothiazole and 4.00 g (0.163 mol) of a mixture of 2- (4-chlorobutyl) -1 [2H ] of phthalazinone and 2- (4-bromobutyl) -1 [2H] phthalazinone in a ratio of 80:20 yielded 7.75 g of crude material which was purified by flash chromatography using a 3: 1 mixture of ethyl acetate and hexanes 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) hydrochloride. butyl] -1 [2H] phthalazinone as a white crystalline solid having a melting point of 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, 1, 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,

55.11, 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 °. HCl:

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

101

75.0 g (0.46 mol) of 2-acetylbenzoic acid is added to 800.0 ml of 95% ethanol and a solution of 33.0 ml (0.57 mol) is added.

85% hydrazine hydrate in 50.0 ml 95% ethanol. The solution was refluxed for 1 hour. As the reaction proceeds, a white solid forms. 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. It will

68.19 g of 4-methyl-1 [2H] phthalazinone as a white solid having a melting point of 222-224 ° C (melting point 222-223 ° C according to literature), A. Hisrch, DG Orphanos, J. Het. Chem., 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 ₉ H ₉ N ₂ O:

H, 5.03; N, 17.49. Found: C, 67.62; H, 5.08; N, 17.50.

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 having a melting point of 166-172 ° C. Yield 34%.

1 H NMR (DMSO-d ₆ ): 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) A process for the manufacture of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-methyl-1 [2H] phthalazinone hydrochloride hydrate

102

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 - (1-piperazinyl) -1,2-benzisothiazole, was purified by recrystallization from acetonitrile. 2.89 g of the free base is obtained as 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 having 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 (m, 4), 4.04 (broad d, 2, J = 13.3), 4.14 (m, 2),

7.45 (t, 1, J = 7.5), 7.59 (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 OS. HCl. 0.25 H ₂ 0:

H, 6.05; N, 14.76. Found: C, 60.73; H, 6.11; N, 14.73.

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, 1.0 equivalent)

103

3- (4-piperidinyl) -1,2-benzisothiazole, 0.57 ml (0.412 g,

4.07 mmol (1.2 equiv.) Of triethylamine and 5.0 ml of acetonitrile are placed in a round-bottomed flask. The resulting mixture was covered with nitrogen atmosphere and refluxed overnight. The pale orange solution was allowed to cool to room temperature and transferred to a separatory funnel with dichloromethane. The reaction mixture was washed with saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. This gave 1.65 g of a dark orange oil. This oil was purified by flash chromatography with ethyl acetate as eluent. 1.30 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] phthalimide was obtained as a pale orange oil which solidified on standing to a pale yellow solid. The free base was taken up in ethyl acetate and treated with 2.7 mL of 1N (1 equivalent) of ethereal HCl. The salt was recrystallized from aqueous ethanol to give 0.810 g of hydrochloride. This salt is a white solid. Yield: 53%. The spectral and analytical values indicate the presence of 1 equivalent of hydrogen chloride and 0.5 equivalent 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 ^S. HCl. 0.5 H ₂ O:

calculated: 61.99 % C, 5.85 .% H, 9.04 % N, found: 61.80 % C, 5.89 % H, 9.05 % N.

Example 34

104

a) Method for the production of 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 bottom flask. capacity 1 liter, equipped with 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 was stirred for 30 minutes and then 150 mL of ether was 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 sodium chloride solution, 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 as a pale orange oil. The yield corresponds to 5.1% of theory based on phenethylamine.

¹ H NMR (CDCl 3): δ 3.01 (t, 2, J = 6.6), 3.58 (dt, 2, J =

105

2.9, 6.6), 7.36 (ddd, 7.5, 9.0),

6.20 (broad s, 1), 7.22 (dd, 1, J = 0.7, 7.4 L, J = 1.3, 7.6, 8.3), 7.46 (ddd, 1, J = 1.6, 8.07 (dd, 1, J = 1.1, 7.7) ppm.

c) Process for preparing 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 charged to a 1 liter round bottom flask equipped with a magnetic stir bar and nitrogen inlet using a flask that had been dried before use. flame. The sodium hydride is washed three times with hexanes and the waste hexanes are drawn off with a solid pipette.

To the washed sodium hydride was added 20.0 mL of anhydrous N, N-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 och, Ν-dimethylformamide was added dropwise to the cold 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) was added dropwise.

1.1 equivalents) of 1-bromo-4-chlorobutane. 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 over magnesium sulfate, filtered, and evaporated. 5.16 g of an orange oil are obtained. The crude material was purified by flash chromatography (3: 2 hexanes / ethyl acetate). 1.90 g of 2- (4-chlorobutyl) -3,4-dihydro-1 [2H] isoquinolinone are obtained as a colorless oil. Yield: 63%.

d) Method for the preparation of N- [4- / 4- (1,2-benzisothiazol-3-yl) 1-piperazinyl / butyl] -3,4-dihydro-1 [2H] isoquinolino-10-yne 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 a magnetic stirrer, 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 therefore an additional portion of 0.350 g (1.60 mmol, 0.2 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole and 0.670 mL (0.486 g) is added. , 4.81 mmol, 0.6 equiv) of 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 a saturated potassium carbonate solution. The organic portion was dried over magnesium sulfate, 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 eluent. 2.26 g of an orange oil are obtained. The free base was taken up in ethyl acetate and 5.37 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution 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%.

^{Χ Η} NMR (DMSO-d₆) δ 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.

@ ¹ H NMR (DMSO-d6): .delta. = 20.46, 24.37, 27.36, 45.36, 45.69,

107

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.

Analysis for ^C 24 ^H 28 ^N 4 ^OS · ^HCl: calculated: 63.07% C, 6.40% H, 12.26% N, found: 63.04% C, 6.43% H, 12.23% N.

Example 35

a) A process 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 6.0 g (43.8 mmol) of anthranilic acid (Aldrich Chemical Company) with 15.5 mL (13.9 g, 116.8 mmol, 2.67 equivalents) of Ν, Ν-dimethylformamide dimethyl acetal (Aldrich Chemical Company) renders

6.2 g (69% of theory) of methyl [2- (N, N-dimethyl-N ' -formamidinyl] benzoate] as a purple liquid.

b) Method for producing 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 equivalent) of methyl [2- (N, N-dimethyl-N ' -formamidinyl) benzoate] are placed in a round-bottomed flask 250 ml, equipped with a magnetic stir bar, condenser and nitrogen inlet, using a flask which was flame dried before use. 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 over magnesium sulfate, 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 equiv.) Ethereal HCl. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 0.810 g of 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4 [3H] quinazolinone hydrochloride as a white solid mp 238 DEG-240 DEG C. (decomposition). Yield: 59%.

¹ H NMR (DMSO-d 6): δ 1.80 (broad s, 4), 3.28 (m, 4), 3.47 (broad t, 2, J = 12.6), 3.58 (wide d, 2, J = 12.0), 4.05 (broad s, 3), 4.08 (m, 1), 7.47 (ddd, 1, J = 1.1, 6.9,

8.1), 7.58 (qm, 2, J = 8.4), 8.12 (t, 3, J = 8.0), 8.18 (ddd, 3, J = 0.6, 1) 6, 8.0), 8.46 (s, 1), 10.86 (broad s, 1) ppm. ¹ H NMR (DMSO-d 6): δ 20.24, 25.78, 45.25, 46.31, 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: Calculated: 60.58% C, 5.75% H, 15.36% N Found: 60.68% C, 5.75% H, 15.41% N.

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) isatinic anhydride (Aldrich Chemical Company) 15.0 mL ethanol and 1.59 g (5.48 mmol)

109 mmol, 1.0 equivalents) of 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisothiazole (Example 13b)) was placed in a round bottom 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. The crude material was purified by flash chromatography using a 19: 1 mixture of dichloromethane and methanol as eluent. 1.28 g of an orange oil was obtained, which on standing turned to a pale yellow solid. 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. The resulting salt, hydrochloride, was 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 white 227 DEG-228 DEG. Yield: 60%.

¹ H NMR (DMSO-d 6): δ 1.58 (m, 2), 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.

¹ H 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

110

a) Method for producing 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 are added to a round-bottom 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 was 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 was extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. 0.900 g of an orange oil is obtained.

The crude material was purified by flash chromatography with ethyl acetate / hexanes (2: 1) as eluent. 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, was 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, m.p. 242-243.5 ° C. Yield: 46%.

^{Σ Η} NMR (DMSO-d₆) δ 1.89 (m, 4), 3, E4 (m, 4H), 3.43 (br t, 2, J = 11.9), 3.59 (br t , 2, J = 11.1), 4.07 (broad d,

2, J = 11.4), 4.46 (t, 2, J = 6.5), 7.47 (tm, 1, J = 7.5), 7.60 (tm, 1, J = 7) , 5), 7.96 (ddd, 1, J = 1.3, 7.2, 7.9),

8.12 (m, 3), 8.24 (dd, 1, J = 0.7, 8.1), 8.29 (ddd, 1, J =

111

0.5, 1.4, 7.9), 10.5 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.36, 25.52, 46.33, 48.50, 50.49,

55.02, 119.24, 121.15, 123.96, 124.54, 124.57, 126.91,

127.94, 128.08, 132.89, 135.35, 143.66, 152.06, 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) Process 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 by 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)] was placed in a 300 ml round bottom flask which was dried in an oven. The solution was covered with nitrogen and 4.13 mL (0.0476 mol, 2.7 equivalents) of thionyl chloride was added. The light yellow solution was heated to 75 DEG C. and 0.25 ml of anhydrous dimethylformamide was added. The reaction mixture is heated at 65-75 ° C for 75 minutes and the solvent is removed by rotary evaporation. The resulting orange residue was taken up in anhydrous chloroform (50 mL) and placed under a nitrogen atmosphere. To this crude acid chloride was added 5.63 g (0.0194 mol, 1.1 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)) in 20 ml of chloroform and then added

2.94 ml (0.021 mol, 1.2 equivalents) of anhydrous triethylamine. The resulting clear orange mixture was allowed to stir at temperature

112 rooms for 45 minutes. The solvent was removed on a rotary evaporator and the viscous orange oil was taken up in dichloromethane and washed with saturated potassium carbonate solution. The organic portion was dried over magnesium sulfate, filtered, and evaporated.

10.03 g of a viscous orange oil are obtained. This crude material was purified by flash chromatography using ethyl acetate as the eluent and then ethyl acetate containing 0.1% triethylamine as the next eluent. It is obtained

4.78 g of the free base in the form of a pale yellow oil. Dissolve the free base in ethanol and add 9.24 mL of 1N ethereal HCl. The solution is warmed and filtered while hot. Ether was added to the ethanol solution and the mixture was allowed to cool. The solids formed upon cooling are filtered off, washed with ether and dried in a vacuum oven. 2.96 g of the title compound is obtained as a light brown solid having a melting point

198.5 to 200 ’C. Yield 30%.

¹ H NMR (DMSO-d 6): δ 1.16 (3, J = 7.5), 1.60 (m, 2), 1.83 (broad 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, 1, J = 5, 3), 10.66 (broad 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 t 150.88, 152.48, 153.96, 162 , 56, 164.26. Analysis for ^C 26 ^H 33 ^N 4 ° 3 ^SC1 ' HC1: calculated: C 56.41, 6.19 % H, 10, 12 % N, found: 56.31% C, 6.18 % H, 10, 08 / % N.

Example 39

a) A method for producing ethyl- [2,3-dihydro-3-oxo-1H-indazole-1113]

-carboxylate /

Starting materials: 3-indazolinone (Aldrich Chemical Company) and ethyl chloroformate (Aldrich Chemical Company).

This compound was prepared by the method of S. D. Wyrick et al., 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, 3, J = 7.1), 4.41 (q, 2, J = 7.1), 7.34 (ddd, 1, J = 0.8, 7.1, 8.0), 7.61 (ddd, 1, J =

1.2, 7.2, 8.4), 7.75 (dt, 1, J = 7.8, 1.0), 8.04 (d, 1, J = 8.4), 12.13 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 14.14, 62.84, 114.09, 117.16, 120.43, 123.36, 130.00, 140.28, 150.04, 158.50.

Analysis ^ ^ιο Η ιο Ν 2 ° ^3: calculated: 58.25% C 4.89% H 13.59% N Found: 58.30% C, 4.93% H, 13.61% N .

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-1H-indazole-1-carboxylate /

1.51 g (50.3 mmol, 1.2 equivalents) of sodium hydride as an 80% oil dispersion was added to a 250 mL three-necked round bottom flask equipped with a magnetic stir bar, reflux condenser and nitrogen inlet using a flask which has been flame-dried before use. The sodium hydride was washed three times with hexanes. To the washed sodium hydride was added 50.0 ml of anhydrous N, N-dimethylformamide and the resulting gray suspension was cooled in an ice bath. To the cold reaction mixture was slowly added a spatula of 8.65 g (41.9 mmol) of ethyl [2,3-dihydro-3-oxo-1H-indazole-1-carboxylate] with a spatula.

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)

114

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 partitioned between ethyl acetate and distilled water. The organic portion was dried over magnesium sulfate, filtered, and evaporated. 12.2 g of an orange oil are obtained. ¹ H 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 with 3: 1 hexanes / ethyl acetate as eluent. 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. dihydro-3-oxo-1H-indazole-1-carboxylate] as a 60:40 mixture of chloride and bromide. The chloride to bromide ratio 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) 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]

Mixtures 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 ratio, 3.84 g (17.5 mmol, 1.8 equivalents) of 3- (1-piperazinyl) -1 Of 2-benzisothiazole, 2.44 ml (1.77 g, 17.5 mmol, 1.8 equivalents) of triethylamine and 30.0 ml of acetonitrile are placed in a 50 ml round-bottom flask equipped with a magnetic stir bar, condenser and nitrogen supply. The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature

The reaction mixture was partitioned between ethyl acetate and saturated potassium carbonate solution. The organic portion was dried over magnesium sulfate, filtered, and evaporated. 7.18 g of an oily brown colored solid are obtained. The crude material was purified by flash chromatography with ethyl acetate / hexanes (2: 1) and then with ethyl acetate as the next eluent. 2.97 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 6.2 mL of 1N (1.0 equivalent) of ethereal HCl. The resulting salt, hydrochloride, was recrystallized from ethanol to give 0.52 g of ethyl [2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3 hydrochloride. of dihydro-3-oxo-1H-indazole-1-carboxylate] as a beige solid having a melting point of 189-190 ° C. Yield 8%.

¹ H NMR (DMSO-d 6): δ 1.41 (t, 2, J = 7.1), 1.66 (broad s,

3), 3.23 (m, 6), 3.42 (broad 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 (broad) s, l) 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 25 ^H 29 ^N 5 ^S ° 3 ^{'· HCl:} Calculated: 58.19% C 5.86% H 13.57% N Found: 58.06% C, 5.89% H, 13 51% N.

Example 40

a) Method for producing 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,2-dihydro-3H-indazole hydrochloride hydrate

116

-3-one

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 placed in 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 over magnesium sulfate, filtered, and evaporated. 1.37 g of crude material are obtained as an orange oil. The crude material was purified by flash chromatography using a 92: 8 mixture of dichloromethane and methanol 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 a 1N (1.0 equivalent) 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] -1,1-hydrochloride hydrate, 2-dihydro-3H-indazol-3-one as a white solid having a melting point of 80-90 ° C (softening, shrinkage) and 125-145 ° C (effervescence). Yield 20%.

³ Η NMR (DMSO-d ₆ ): δ 1.77 (m, 4), 3.25 (m, 4), 3.44 (m, 2),

3.56 (broad d, 2, J = 11.4), 3.87 (t, 2, J = 6.0), 4.06 (broad d, 2, J = 13.3), 7.11 (ddd, 1, J = 0.8, 7.1, 8.0),

7.28 (dt, 1, 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.

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

117

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. HCl. 0.75 H ₂ 0:

calculated: 57.76% C, 6.06% H, 15.31% N, 2.95% H ₂ O, 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 acid anhydride

5-chloroisatin (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, was 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 as a white solid, m.p. 173-176 ⁰ C. Yield 65%.

¹ H NMR (DMSO-d 6): δ 1.57 (m, 2), 1.78 (m, 2), 3.10 - 3.68 (m, 12), 4.08 (broad 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.

118

Analysis for ^C 22 ^H 26 ^N 5 ^OSC ^ · * HC1: calculated: 55.00 % C, 5.66 % H, 14.58 % N, found: 54.91 % C, 5.69 % H, 14.51 % N.

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 as described in Example 36 using 1.08 g (5.17 mmol) of acid anhydride

5-nitroisatin (Trans World Chemicals) 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 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 as a yellow solid, m.p. Mp 224-230 ° C (dec.). Yield: 43%.

¹ H NMR (DMSO-d 6): 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:

H, 5.54; N, 17.12. Found: C, 53.95; H, 5.57; N, 17.05.

Example 43

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

This compound was prepared as in Example 36 using 0.92 g (5.17 mmol) of acid anhydride

5-methylisatin (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 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 light beige solid, m.p. 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), 633 (d, 1, J = 8) 3), 7.29 (t, 1, J = 7.7), 7.48 (t,

1, J = 7.5), 7.57 (d, 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,

H, 6.60; N, 15.13.

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

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, 42.34, 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 mixing rod, partition

121 and a reflux condenser using a flask that has been flame dried. The reaction mixture was cooled in an ice bath containing sodium chloride. To the cooled reaction mixture was slowly added 69.0 mL (69.0 mmol, 1 equivalent) of borane in tetrahydrofuran (Aldrich Chemical Company) via syringe over 25 minutes. The stirred solution was allowed to warm to room temperature overnight. The reaction mixture was cooled in an ice bath, and 55.0 ml of distilled water and 17.0 g of potassium carbonate were added. The aqueous and organic phases are separated. The aqueous phase was 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 with 2: 1 hexanes / ethyl acetate. 6.47 g of (+/-) - cis-methyl- [2- (hydroxymethyl) -1-cyclohexanecarboxylate] are obtained as a colorless oil. Yield: 59%.

1 H NMR (CDCl ₃ ): δ 1.30 - 1.75 (m, 7), 1.89 (m, 1), 1.97 (t,

1, J = 6.0), 2.02 (m, 1), 2.76 (m, 1), 3.63 (m, 2), 3.68 (s,

3) ppm.

¹³ C NMR (CDCl ₃ ): δ 23.55, 26.22, 26.34, 40.65, 42.32, 51.44,

64.27, 175.75.

Analysis for C _g H 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 is placed in a 1 L 3-neck round bottom flask equipped with

122 using a magnetic stir bar, thermometer and nitrogen inlet using a flask that 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) was added in three portions over three minutes. The reaction mixture was allowed to stir for 90 minutes. Then 200.0 ml of distilled water are added and the aqueous and organic phases are 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 over magnesium sulfate, filtered, and evaporated. 7.45 g of a pale yellow oil are 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 as 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-1 [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 an 85% aqueous solution were 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 distilled water (100 ml) and ethyl acetate (300 ml). 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 of production of (+/-) - cis-2- (4-chlorobutyl) -4A, 5,6,7,8,8A123

-hexahydro-1 [2H] phthalazinone and (+/-) - trans-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [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 septum and / or plug using a flask which has been flame dried. The sodium hydride was washed three times with hexanes and 30.0 ml of anhydrous Ν, Ν-dimethylformamide was added. Cool the suspension in an ice bath and slowly add 7.79 g (51.2 mmol) of (+/-) - cis-4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone, and (+/-) - trans-4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone in 40.0 ml of anhydrous Ν, Ν-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 the 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 (6: 1 hexanes / ethyl acetate). 3.02 g of (+/-) - cis-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone are obtained (Rf = 0.13) as colorless. oil and 3.78 g of (+/-) - trans-2- (4-chlorobutyl) 4a, 5,6,7,8,8a-hexahydro-l [2H] -phthalazinone _(Rf = 0.20) as 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 ₁₂ H ₁₉ N ₂ OCl:

H, 7.89; N, 11.54. Found: C, 59.28; H, 7.91; N, 11.48.

trans-isomer: 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.

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 ^{OC 1:} 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-1 [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 were charged to 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 did 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 mmol) were added. (0.2 equivalents) of triethylamine and the resulting reaction 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 over magnesium sulfate, filtered, and evaporated. 2.54 g of an orange oil are obtained. This crude material was purified by flash chromatography with mixture

125 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 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).

¹ H NMR (DMSO-d 6): 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 (broad d, 3, J = 14.7), 3.70 (m, 2), 4.06 (broad 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 (W,

1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.18, 22.76, 23.22, 23.54, 24.34, 24.87, 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 21 ^N 5 ^OS . HCI:

H, 6.98; N, 15.16. Found: C, 59.82; H, 7.02; N, 15.08.

Example 45

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

126 g (10.3 mmol) of (+/-) - trans-2- (4-chlorobutyl) -4A, 5,6,7,8,8A-hexahydro-1 [2H] phthalazinone (Example 44 e)) into a round-bottomed flask equipped with a magnetic stir bar, reflux condenser and 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-piperazinyl) -1,2-benzisothiazole and 0.72 mL ( 0,52 g,

5.14 mmol, 0.5 equiv) of triethylamine, and the reaction mixture was refluxed for an additional 24 hours. The reaction mixture was allowed to cool to room temperature and ethyl acetate was added. The organic portion was washed with a saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated. 6.2 g of an orange oil are obtained. This crude material 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 equiv.) 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) δ 1.21 (m, 4H), 1.61 (br q, 2, J =

6.6), 1.71 (ra, 4), 1.97 (m, 2), 2.19 (ra, 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 (broad 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,

127

168.07.

Analysis for C ₂₃ H ₃₁ N ₅ OS. HC1:

calculated: 59.79% C, 6.98% H, 15.16% N, found: 59.85% C, 6.97% H, 15.12% N.

Example 46

a) Method for preparing 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) mmol, 1 equivalent) of 4-amino-1-butanol (Aldrich Chemical Company) was charged to a three-necked 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 was slowly warmed to 170 ° C and held at this temperature for 45 minutes. The hot reaction mixture was poured onto 150 g of crushed ice. The viscous organic material was separated from the 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] isoquinolinone as a pale yellow solid, m.p. 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, 1, 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.

128

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) Process for the preparation of 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) - Of 1,2-benzisothiazole, 5.52 mL (4.0 g, 39.6 mmol, 1.2 equivalents) of triethylamine and 50.0 mL of acetonitrile were charged to a round bottom flask equipped with a magnetic stir bar, condenser and nitrogen inlet. . The reaction mixture was refluxed for 3.5 hours. The crude mixture was absorbed on silica gel and purified by flash chromatography with ethyl acetate / hexanes (2: 1) then ethyl acetate as eluents. 11.9 g 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 1 N (1.0 equiv.) Ethereal HCl. The resulting salt, hydrochloride, is recrystallized from aqueous ethanol. 6.57 g of 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,3 [2H, 4H] isoquinolinedione hydrochloride hydrate are obtained as an orange solid, temperature mp 190-195 ° C. Yield 40%.

¹ H NMR (DMSO-d 6): δ 1.64 (m, 2), 1.75 (m, 2), 3.10-3.60 (m,

4), 3.91 (q, 2, J = 6.8), 4.05 (broad d, 2, J = 13.0), 7.55 (m, 4), 8.12 (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.

129

Analysis for C ₂₄ H ₂₆ N ₄ O ₂ S. HCl. 0.5 H ₂ O:

calculated: 60.05% C, 5.88% H, 11.67% N, 1.87 H ₂ O Found: 60.30% C, 5.85% H, 11.74% N, 1.79 H ₂ 0.

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) was charged to a three-necked round bottom flask equipped with a magnetic stir bar, reflux condenser and nitrogen inlet using a previously dried flask flame. The sodium hydride was washed three times with hexanes and then 10.0 ml of anhydrous Ν, Ν-dimethylformamide was added. Cool the suspension in an ice bath, add 0.549 g (3.39 mmol) phthalhydrazide and 1.2 g (3.39 mmol, 1.0 equivalent) 8- (1,2-benzisothiazol-3-yl) - Of 5,8-diazaspiro [4.5] decan-5-onium bromide and the reaction mixture was refluxed overnight.

The reaction mixture was then cooled in an ice bath and 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. 0.63 g of crude material is obtained, which is combined with a further 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 was obtained. The crude material (1.70 g total weight) was purified by flash chromatography with dichloromethane / methanol (94: 6) as eluent. 0.64 g of the free base is obtained, which is a white solid. To the free base solution

130 in chloroform was added 1.47 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. 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 having a temperature of mp 242-245 ° C (dec.). Yield 13%.

¹ H NMR (DMSO-d 6): δ 1.81 (broad S, 4), 3.26 (m, 4), 3.45 (broad t, 2, J = 12.0), 3.57 (broad) 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 ^S ° 2 * ^HC1: 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

These compounds were prepared according to a modified method of F. Bonadies and R. Di Fabio (J. Org.

Chem. 49, 1647 (1984)]. 32.8 ml (35.0 g, 0.261 mol)

3,4-dihydro-1H-2-benzopyran (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 placed in a 1 liter three-necked round-bottomed flask equipped with a condenser, magnetic stirrer.

131 with a rod and 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-1H-2-benzopyran-1-one is obtained as 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 = 1.0, 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 H ₉ O ₂ :

calculated: 72.96% C, 5.44% H, found: 72.88% C, 5.42% H.

b) 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-ene by as described by NW Gilman in Synthetic Commun. 12, 373 (1982) 0.393 ml (0.586 g, 3.42 mmol, 1.2 equivalents) with 1-bromo-4-chlorobutane (Aldrich Chemical Company) affords 0.40 g of 2- (4-chlorobutyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as an orange oil. Yield 56

132% of theory.

c) Process for preparing 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-1- onu

This compound was prepared as described in the Example

d). Alkylation 0.40 g (1.59 mmol) of 2- (4-chlorobutyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 0.52 g (2.39 mmol, 1, 5 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole affords 0.45 g of the free base which is purified by flash chromatography with ethyl acetate / hexanes (2: 1) containing 0.1% triethylamine as eluent. agent. 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- 215 DEG-217 DEG C. (decomposition), corresponding to a yield of 30% of theory.

¹ H NMR (DMSO-d ₆ ): δ 1.67 (m, 2), 1.81 (m, 2), 1.99 (quintet, 2, J = 6.7), 2.73 (t, 2, J = 7.0), 3.18 (t, 2, J = 6.4),

3.27 (m, 4), 3.53 (m, 6), 4.08 (broad d, 2, J = 13.0), 7.25 (dd, 1, J = 1.2, 7, 5), 7.33 (td, 1, J = 7.5, 1.4), 7.42 (td, 1, J = 7.4, 1.6), 7.48 (ddd, 1, J) = 1.1, 7.0, 8.1), 7.51 (dd,

1, J = 1.6, 7.4), 7.60 (ddd, 1, J = 1.1, 7.0, 8.1), 8.13 (t,

2, J = 9.1), 10.92 (broad s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.61, 25.55, 29.30, 29.58, 45.59,

45.69, 46.35, 50.46, 55.23, 121.15, 123.95, 124.57, 126.59, 126.91, 127.94, 128.07, 128.24, 130, 51, 136.25, 137.09, 152.06, 162.16, 169.78.

Analysis for C ₂₅ H ₃₀ N ₄ OS. HC1:

H, 6.63; N, 11.89. Found: C, 63.76; H, 6.67; N, 11.87.

133

Example 49

a) Method for producing 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) were placed in a three-necked round bottom flask. 250 ml capacity, equipped with a magnetic stir bar, dropping funnel, nitrogen inlet and reflux condenser. The reaction mixture was heated to reflux and 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 the 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 as an orange oil. Yield: 91%.

^{Χ Η} NMR (CDC1 _3): 5 1.57 (m, 7H), 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 hydrochloride

This compound was prepared as described in the Example

36. Alkylation of 0.68 g (4.15 mmol) of isatinic anhydride;

134 (Aldrich Chemical Company) 1.2 g (4.15 mmol, 1.0 equivalent) of 3- [1- (4-aminobutyl) -4-piperidinyl] -1,2-benzisothiazole gives 1.38 g of the free base, Purification by flash chromatography with ethyl acetate / hexanes (2: 1) containing 0.1% triethylamine as eluent. The salt, the hydrochloride, is made and recrystallized from aqueous ethanol. 1.09 g of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] benzamide hydrochloride 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, J, 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 28 ^N 4 ^OS · ^HC1: Calculated: 62.08% C 6.57% H 12.59% N Found: 62.11% C, 6.61% H.

Example 50

a) Process for the preparation of [[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 placed in a 200-ml three-necked round-bottomed flask,

135 equipped with a magnetic stir bar, a dropping funnel and a nitrogen inlet using a flask that had 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 20 mL of dichloromethane was added dropwise. The reaction mixture was allowed to cool to room temperature and stirred for 15 minutes. The reaction mixture was then washed with cold saturated potassium carbonate solution. The organic portion was dried over magnesium sulfate, 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 with dichloromethane / methanol (95: 5) as eluent. 2.93 g of product are obtained as 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] carbamoylphenylacetate and N- [4 - / (1,2-benzisothiazole) The 3-yl) -1-piperazinyl / butyl] -2-hydroxybenzamide was charged to a 300 mL round bottom flask equipped with a magnetic stir bar, dropping funnel and nitrogen inlet. A solution was added dropwise to the reaction mixture

38.5 mg (7.12 mmol, 1.1 equivalents) of sodium methoxide (Aldrich Chemical Company) in 60 mL of methanol. 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 was 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, 7.2, 8.8), 7.47 (ddd, 1, J = 1.1, 6.9, 8.1), 7.60 (ddd, 1, 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 .

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 225 ^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 the preparation of 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) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b) 0.6 ml (0.727 g) (5.17 mmol) of benzoyl chloride over 1 hour afforded 1.49 g of the free base which 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) of ethereal hydrogen chloride. The salt, hydrochloride, is recrystallized from ethanol. 1.04 g of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride are obtained as a pale light.

137 beige solid having a melting point of 200 to 201.5 C. Yield 47%.

¹ H NMR (DMSO-d ₆ ): δ 1.61 (m, 2), 1.80 (m, 2), 3.27 (m, 6),

3.47 (broad t, 2, J = 12.6), 3.59 (broad d, 2, J = 11.7), 4.08 (broad d, 2, J = 13.4), 7, 50 (m, 4), 7.60 (t, 1 J)

7.6), 7.87 (m, 2), 8.13 (t, 2, J = 8.4), 8.58 (broad t, 1,

J = 5.5), 10.72 (broad s, 1) ppm.

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.

Analysis for ^C 22 ^H 26 ^N 4 ^{OS '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 process for the preparation of N- (4-chlorobutyl) -N-methylbenzamide

This compound was prepared as described in Example 34 (c). 3 g (22.2 mmol) of N-methylbenzamide (Aldrich Chemical Company) with alkyl was 2.81 ml (4.19 g, 24.4 mmol, 1.1 equivalents) 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 as 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 the Example

d). 1.50 g (6.65 mmol) of N-methyl-N- (4-chlorobutyl) benzamide

138 and 1.60 g (7.3 mmol, 1.1 equivalents) of 3- (1-piperazinyl) -1,2-benzisothiazole were heated at reflux 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 eluent. 1.40 g of the free base is obtained as 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. 151-154. 'C. Yield: 26%.

^{Τ Η} NMR (DMSO-d₆) δ 1.57 to 1.83 (m, 4H), 2.98 (m, 4H), 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) ppm.

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. HCl:

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 equivalents) of triethylamine and 10.0 mL of dichloromethane were added to a 100 mL three-necked round bottom flask equipped with a magnetic stir bar, nitrogen inlet and dropping funnel using

139 flask which was flame dried. 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 to a separatory funnel with ethyl acetate. The organic portion was washed with a saturated potassium carbonate solution, dried over magnesium sulfate, 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 as a white solid. The free base was dissolved in a mixture of ethyl acetate and dichloromethane and added

2.31 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. 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 as a white solid, m.p. 209 DEG-210 DEG. C (decomposition). Yield 56%.

¹ H NMR (DMSO-d 6): δ 1.60 (m, 2), 1.79 (m, 2), 3.15-3.37 (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) ppm.

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 ^OSC1 '^ · ^Hc calculated: 55.69% C 5.74% H Found: 55.58% C, 5.69% H,

0.5 H ₂ O: N 11.81, N 11.71,

1.90 H ₂ 0, 2.02 H ₂ 0th

Example 54

140

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 equivalents) of triethylamine and 0.723 g (3.45 mmol, 1.0 equivalents) of 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 as a white solid. The salt, 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 as a beige solid, m.p. 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 = 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) ppm.

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 ^OSC1 2 ^{'HC1 Calculated:} 52.86% C 5.04% H 11.21% N Found: 52.94% C, 5.09% H, 11.16 % N.

Example 55

141

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 equivalents) of triethylamine and 0.589 g (3.45 mmol, 1.0 equivalents) of 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 as 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 (s, 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 =

1.0, 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) ppm.

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 'HC1 Calculated:} 59.92% C, 6.34% H, 12.15% N Found: 60.00% C, 6.39% H, 12.19% N.

Example 56

a) A method for producing N- [4- / 4- (1,2-benzisothiazole-3142) hydrochloride

-yl) -1-piperazinyl / butyl] -4- (trifluoromethyl) benzamide

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 equivalents) 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 using a 1: 1 mixture of ethyl acetate and 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, the hydrochloride, is produced and 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 m.p. 207 ° C (dec.). Yield 15%.

¹ H NMR (DMSO-d 6): δ 1.62 (m, 2), 1.83 (m, 2), 3.15-3.40 (m,

6), 3.50 (broad 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) ppm.

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. HC1:

H, 5.25; N, 11.23. Found: C, 55.46; H, 5.26; N, 11.18.

Example 57

143

a) Method 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, 1.0 equivalent) 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 recrystallized from the free base 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. 220.5. mp 222 ° C (dec.). 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) ppm.

¹³ C NMR (DMSO-d 6): 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 · ^HCl: calculated: 64.11% C, 7.24% H, 11.50% N, found: 64.00% C, 7.25% H, 11.43% N.

Example 58

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

This compound was prepared as described in the Example

144

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 was purified by flash chromatography with ethyl acetate / hexanes (3: 1) containing 0.1% triethylamine, then ethyl acetate containing 0.1% triethylamine and then ethyl acetate containing 0.2% triethylamine as eluents. 1.42 g of compound is obtained in the form of 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 made 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. 225-227. Deň: 32 ° 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) ppm. 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, 127.95, 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 Found: 62.91% C, 5.85% H,

N, 15.71; N, 15.63.

Example 59

145

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 equipped with a magnetic stir bar, nitrogen inlet, thermometer and a rubber septum, using a flask which has been previously flame dried. 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 was filtered, dried over magnesium sulfate, filtered again and evaporated. 1.70 g of a yellow oil are obtained. The crude product 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 as 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 hydrogen chloride solution. 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 as a pale cream solid having a melting point greater than 250 DEG. C. Yield: 23%.

¹ H NMR (DMSO-d ₆ ): δ 1.59 (m, 2), 2.07 (s, 3), 3.25 (m, 6),

146

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 = 7.6), 7.66 (d, 2, J = 8.7), 7.82 (d, 2, 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) ppm.

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 · ^HCl: Calculated: 59.06% C, 6.20% H, 14.35% N Found: 58.99% C, 6.20% H, 14 43% N.

Example 60

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% sodium carbonate solution and 40.0 ml of 1,4-dioxane are placed in a 500 ml round-bottomed flask equipped with magnetic stir bar and dropping funnel. The solution is cooled in an ice bath and a solution of 23.8 g (109 mmol) is added dropwise to the cooled solution.

1.5 equivalents) of di-tert-butyl dicarbonate (Fluka) in 4.0 mL of 1,4-dioxane. 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 white solid. The pH is adjusted to approximately 2 by addition of 1N hydrochloric acid and organic

The 147 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%.

^{Τ Η} NMR (CDC1 _3): δ 1.50 (s, 9H), 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 as described in the 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 equivalent) of isobutyl chloroformate (Aldrich Chemical Company) and 2.51 g (8.65 mmol, 1.0 equivalent) of 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 as a white solid. The impure fractions were combined and purified by flash chromatography with dichloromethane / methanol 9: 1 as eluent. 0.40 g of the free base is obtained in the form of a white solid. The free bases obtained from each column were 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) of ethereal HCl. 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 which is: mp 205-208 ° C (foaming). Yield: 14%.

³ 148 Η NMR (DMSO-d₆): δ 1.49 (s, 9H), 1.60 (m, 2), 1.80 (m, 2),

3.10-3.54 (m, 8), 3.59 (m, 2), 4.08 (broad 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. ¹³ 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.

Analysis for ^C 27 ^H 35 ^N 5 ^S 3 ° * ^HC1: Calculated: 59.38% C 6.64% H 12.82% N Found: 59.43% C, 6.65% H, 12 92% N.

Example 61

a) A process for the preparation of 3 - [(tert-butoxycarbonyl) amino] benzoic acid

This compound was prepared as described in the Example

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 was treated with 7.48 g of 3 - [(tert-butoxycarbonyl) amino] benzoic acid as a white solid. Yield 86%.

¹ H 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) 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 the Example

149

59, using 2.45 g (10.3 mmol) of 3 - [(tert-butoxycarbonyl) amino] benzoic acid, 1.72 mL (1.25 g, 12.4 mmol, 1.2 equivalents) of triethylamine, 1.34 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 a saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated to 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 is obtained as a 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, hydrochloride, was 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 as a white solid. m.p. 139-144 ° C (foaming). Yield: 23%.

1 H NMR (DMSO-d ₆ ): 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 ° 3 ^S. 0,75 HCl:

calculated: 57.95% C, 6.75% H, 12.51% N, 2.41% H ₂ O, found: 57.86% C, 6.74% H, 12.61% N, 2, 44% H ₂ O

150

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 60) (b)), 1.5 ml of anisole (Aldrich Chemical Company), 15.0 ml of anhydrous chloroform and 15.0 ml of trifluoroacetic acid (EM Scientific) are placed in a 500 ml round-bottom flask equipped with a magnetic stir bar and inlet. nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil. 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 a 1N (1.0 equivalent) ethereal HCl solution. 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 hydrochloride are obtained as a brown solid, m.p. 213.5-214.5. 'C. Yield: 29%.

¹ H NMR (DMSO-d ₆ ):? & 1.56 (m, 2), 1.77 (m, 2), J = 12.5), 3.59 (broad d, 3.27 (m, = 11 6), , 9) 3.45 (wide t, 2, 2, J 4.08 (wide 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)? 6 Ϊ ^: δ 20.65, 26.52, 38.11, 46, 37, 50 , 44,

151

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 22 ^H 27 ^N 5 ^OS · ^HCl: calculated: 59.25% C, 6.33% H, 15.70% N, found: 59.03% C, 6.32% H, 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 (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 as 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 rusty orange solid, m.p. up to 130 ^e C (foaming). Yield 20%.

¹ H NMR (DMSO-d 6): δ 1.59 (m, 2), 1.80 (m, 2), 3.05-3.75 (m, 10), 4.08 (broad 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,

152

126.98, 128.14, 128.72, 135.61, 146.36, 152.13, 162.22,

166.77.

Analysis for C ₂ ^H 27 ^N 5 ^OS · HCl. 0.5 H ₂ O:

calculated: 58.07% C, 6.42% H, 15.39% N, 1.98 H ₂ O, found: 58.17% C, 6.41% H, 12.25% N, 2.35 H ₂ O.

Example 64

a) Method 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 placed in a 100 ml three-necked round-bottom flask equipped with a magnetic stir bar, nitrogen inlet, dropping funnel and thermometer using a flask that has been flame-dried beforehand. To the reaction mixture was added dropwise 1.12 mL (1.83 g, 15.4 mmol, 2.7 equivalents) of thionyl chloride at room temperature. Replace the dropping funnel with a reflux condenser and heat the reaction mixture to 65 ° C. 0.03 ml of dimethylformamide was added to the reaction mixture 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 a saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated. 3.24 g of orange are obtained

153 oil. 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 as 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, m.p. Mp 220-221 ° C (dec.). Yield: 27%.

^{Χ Η} NMR (DMSO-d₆) δ 1.56 (m, 2), 1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4H), 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. Analysis for ^C 24 ^H 29 ^N 4 ° 3 ^SBr · ^HCl; calculated: % C, 50.58;% H, 5.31; 9.83 % N, found: % C, 50.69;% H, 5.32. 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 the 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),

154

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 equivalents) of acetyl chloride. The reaction mixture was stirred in 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 g 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 1N (1.0 equivalent) of ethereal HCl. 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 as a beige solid, m.p.

189.5-190.5 ° 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, 1, J = 8.2), 8.84 (broad t, 1, J = 5.2),

10.86 (broad s, 1), 11.24 (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, 126.92, 128.09, 131.68, 138.78, 152.06, 162.17, 168.08, 161.18.

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

155

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 3a)), 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 with stirring rod 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 1N (1.0 equivalent) 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) piperidino / butyl] -1-isoindolinone hydrochloride is obtained as a light beige solid, m.p. 211 DEG-214 DEG C. ( decomposition). Yield: 45%.

¹ H NMR (DMSO-d 6): δ 1.74 (m, 4), 2.22 (m, 4), 3.13 (m, 4),

3.59 (t, 4, J = 6.1), 3.65 (m, 1), 4.52 (s, 2), 7.51 (m, 1), 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 (broad s, 1) ppm.

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. HC1:

H, 6.38; N, 9.51. Found: C, 65.31; H, 6.41; N, 9.51.

156

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) piperazinyl / butyl] -3-bromo-2,6-dimethoxybenzamide (Example 64 a)) and Place 75.0 ml of anhydrous dichloromethane in a 250 ml round-bottomed 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 1 N (9.25 mmol, 0.99 equivalents) ethereal hydrogen chloride solution, and then 9.35 mL of 1 N (9.35 mmol, 1.0 equivalents) bromide was added dropwise. boron (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 was added. Dissolve the solids with dichloromethane and water. The phases were separated and the aqueous phase was washed with dichloromethane. The organics were combined, washed with water, dried (MgSO4), 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 as an oil (R1 = 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 minor isomers, N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-bromo-6-hydroxy-2-methoxybenzamide (R _{f), was obtained.} = 0.34) as a brown solid. The salts, hydrochlorides of each of the isomers, are produced independently of one another

157 by dissolving the free amine in ethyl acetate and treating the solution with 1N (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 hydrochloride hydroxy-6-methoxybenzamide as a light pink solid, m.p. 191-192.5 ° C. Yield: 32%.

¹ H NMR (DMSO-d 6): δ 1.54-1.90 (m, 4), 3.05-3.70 (m, 10),

3.94 (s, 3), 4.07 (broad 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 (broad s, 1), 14.87 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): 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, 168.79.

Analysis for ^c 23 ^H 27 ^N 4 ° 3 ^SBr · HCl:

H, 5.08; N, 10.08. Found: C, 49.79; H, 5.11; N, 9.98.

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 as a white solid having a temperature of mp 185-187 ° C. Yield: 2%.

158 ¹ H NMR (DMSO-d ₆ ): δ 1.60 (m, 2), 1.83 (m, 2), 3.10-3.70 (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, 1, 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 OF 154.34, 156.85, 162.24, 165.15. Analysis for C ₂₃ H ₂₇ N ₄ O ₃ SBr. HCl: calculated: 49.69% C, 5.08 % H, 10,08 % N, Found: C 49.79, 5.11 % H, 10.00 % N.

Example 69

a) Process for the preparation of N- [4- / 4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino / butyl] phthalimide 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)

N- (4-bromobutyl) phthalimide (Aldrich Chemical Company), 1.56 mL (1.13 g, 11.2 mmol, 1.5 equivalents) of triethylamine and 30 mL of acetonitrile were charged to a 100 mL round bottom flask. , equipped with a magnetic stirring bar. A reflux condenser and nitrogen inlet were added to the flask, and the reaction mixture was refluxed for 15 hours. The oil bath was removed and the reaction mixture was allowed 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 from solution. The suspension is placed in the freezer for 1 hour and the solid is filtered off. The filtrate was evaporated to give the crude material as an orange-mustard-colored oil-solid mixture (4.19 g). This crude material was adsorbed onto silica gel and dried. Purification by flash chromatography eluting with dichloromethane: methanol (95: 5). 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 a yellow solid. To a solution of the free base in a mixture of ethyl acetate and dichloromethane was added 4.5 mL of 1N (1.0 equiv.) Ethereal HCl. 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-d 6): 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, 1, 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, 43, 162.40, 163.45, 163.64, 165.69, 168.32.

Analysis for C ₂₄ H ₂₄ N ₃ O ₃ F. HCl:

H, 5.50; N, 9.18. Found: C, 63.05; H, 5.52; N, 9.14.

Example 70

a) Method 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.

160 ml, equipped with a magnetic stir bar, thermometer, dropping funnel and nitrogen inlet, using a flask that was previously flame dried.

The solution was cooled in an ice bath, and then a solution of 4.40 mL (6.53 g, 31.1 mmol, 1.5 equivalents) of trifluoroacetic anhydride in 20 mL of dichloromethane was added dropwise over 30 minutes. The reaction mixture was allowed to stir for 2 hours. To the cold reaction mixture was slowly added 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 was dried over magnesium sulfate, filtered and evaporated. 6.87 g of the title compound is obtained as an orange oil. Yield 86%. The crude material was used without further purification.

NMR (CDC1 _3): S 1.71 (broad s, 4), 2.51 (wide 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) Method for producing 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 added to a 250 mL three neck round bottom flask equipped with a rubber septum, magnetic stir bar, dropping funnel and nitrogen inlet using a previously dried flask. flame. The sodium hydride is washed three times with hexanes and 30.0 ml of tetrahydrofuran are added to the washed substance. The suspension was 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] was slowly added over 35 minutes. butyl] -2,2,2-trifluoroacetamide in 30.0 mL of anhydrous tetrahydrofuran over a period of 35 minutes. Remove the ice bath and add 1.1 mL (2.53 mL) dropwise to the reaction mixture

161 g (17.8 mmol) of methyl iodide in 20 mL of anhydrous tetrahydrofuran. 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 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 organics were combined, dried (MgSO4), filtered and evaporated. The crude material was obtained as an orange oil. The crude free base was purified by flash chromatography with ethyl acetate as eluent. This gave 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 solution of potassium carbonate 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 was evaporated under reduced pressure and the organic portion was 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

162

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 isatin (Aldrich Chemical Company) and 25.0 ml of ethanol are placed in a 100 ml round bottom flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was 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 was purified by 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 a 1N (1.0 equivalent) ethereal HCl solution. The solvent was evaporated under reduced pressure and the solid was recrystallized from a mixture of ethanol and ether. 0.625 g of the title compound is obtained as a brown solid, m.p. 188-189 ° C. Yield 30%.

¹ H NMR (DMSO-d 6): δ 1.61 (broad s, 4), 2.93 (s, 3), 2.95-3.72 (m, 10), 4.07 (broad d, 2) J = 12.0), 5.13 (broad s, 2), 6.58 (td, 1, J = 7.4, 1.1), 6.73 (dd, 1, J = 0.8) , 8.1), 7.02 (dd, 1, J = 1.4, 7.7), 7.09 (ddd, 1, J = 1.7, 7.3, 8.0),

7.48 (ddd, 1, J = 1.0, 7.1, 7.9), 7.60 (ddd, 1, J = 1.0,

6.9, 8.0), 8.13 (t, 2, J = 8.2), 10.85 (broad s, 1) ppm.

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 ^OS . HCl: calculated: 60.05% C, 6.57% H, found: 59.98% C, 6.60% H,

N, 15.22; N, 15.13.

163

Example 71

a) Process for the preparation of 3-hydroxy-1,2-benzisoxazole

This compound was prepared as described by R. Friary and BR Sunday in J. Heterocyclic. Chem. 16, 1277/1979 /, using 47.2 grams (0.308 mole) salicylhydroxamic acid (Aldrich Chemical Company) (100.0 g, 0.617 mol, 2.0 equivalents) of 1,1 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.

15.7 g of the title compound is obtained as an off-white solid. The second crop obtained additionally has a weight of 9.4 g and thus the total yield is 25.1 g, corresponding to 60% of theory.

^{Χ Η} NMR (DMSO-d₆) 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, 1) ppm.

b) A process for the preparation of 3-chloro-1,2-benzisoxazole

24.8 g (0.184 mol) of 3-hydroxy-1,2-benzisoxazole and 25.6 ml (18.6 g, 0.184 mol, 1.0 equivalent) of dry triethylamine are placed in a 300 ml round-bottom flask, equipped with a magnetic stir bar using a flame-dried flask. The flask was equipped with a dropping 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. Remove the ice bath and reflux the flask. Heat the reaction mixture in an oil bath at 150 ° C overnight. Remove the oil bath and allow the dark brown-orange liquid to cool to room temperature. The reaction mixture was poured slowly into 500 mL of stirred ice / water solution. After warming to room temperature, the reaction mixture was transferred to a separatory funnel with 250 mL of dichloromethane. The organic portion was separated and the aqueous phase was separated

164 was washed with 250 ml of dichloromethane. The organics were combined, dried (MgSO4), filtered and evaporated. 28.3 g of crude material are obtained 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 placed in a 500-ml round-bottom flask. ml. The flask was equipped with a reflux condenser and nitrogen inlet, and the mixture was heated in an oil bath at 155 ° C for 18 hours. Pour the hot, dark orange reaction mixture into 600 mL of ice water. The organic portion was extracted with a heterogeneous mixture of water and dichloromethane. The organic portion was dried over magnesium sulfate, filtered, and evaporated. 22.8 g of a dark orange liquid is obtained. 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, 1, 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 placed in a round bottom flask equipped with a magnetic stir bar. The flask is equipped with a reflux condenser and nitrogen inlet. The reaction mixture was allowed to stir at reflux for 3 hours. The oil bath was removed and 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 over magnesium sulfate, filtered and evaporated to give the crude free 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 are dissolved in a mixture of ethyl acetate and dichloromethane and 14.6 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride solution are added. The solvent was evaporated under reduced pressure and the resulting salt, hydrochloride, was recrystallized from aqueous ethanol. 0.71 g of the title compound of melting point 257 DEG-259 DEG C. (decomposition) is obtained as an off-white solid. Yield 8.2%.

^{Τ Η} NMR (DMSO-d _6): δ 1.71 (m, 4H), 3.21 (m, 4H), 3.55 (m, 6),

4.14 (broad 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 = 8.0), 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 * ^HC1: Calculated: 62.65% C 5.71% H 12.71% N Found: 62.51% C, 5.68% H, 12.65 % N.

166

Example 72

a) Method for producing 3- (4- (4-aminobutyl) -1-piperazinyl) -1,2-benzisoxazole

This compound was prepared as described in Example 13b) 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 precipitate. An additional 0.87 g (1.5 equivalents) of hydrazine was added to the reaction mixture and the reaction mixture was refluxed for an additional hour. After work-up, 2.1 g of crude product is obtained, which is obtained as an oil which solidifies on standing. Yield: 77%.

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] benzamide hydrochloride

This compound was prepared according to the procedure 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 using a 19: 1 mixture of ethyl acetate and methanol as eluent. 1.37 was obtained as a viscous yellow oil

167 g of free base. 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 pale yellow solid, m.p. 249-252 ° C. Yield: 60%.

¹ H NMR (DMSO-d ₆ ): δ 1.58 (m, 2), 1.79 (m, 2), 3.29 (m, 6),

3.56 (m, 4), 4.14 (m, 2), 6.45 (broad 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, 1), 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 (broad s,

1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.70, 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:} Calculated: 61.46% C 6.56% H 16.29% N Found: 61.57% C, 6.54% H, 16.34 % N.

Example 73

a) Process for the preparation of ethyl [N- [2 - [[[4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl) amino] carbonyl] 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 are placed in a 50 ml round-bottom flask which has been flame-dried. 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) was added dropwise.

168 in 10 ml of anhydrous chloroform. 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 equivalent) and 0.35 mL (0.4 g, 3.66 mmol, 1.0 equivalent) was added to the reaction mixture. ) of ethyl chloroformate. The solution was allowed to stir at room temperature for 4 days. The reaction mixture was transferred to a separatory funnel, dichloromethane was added, and the solution was washed with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO4), filtered and evaporated. 1.74 g of crude material are obtained as an orange oil. The free base was purified by flash chromatography with 2: 1 ethyl acetate: hexanes containing 0.1% triethylamine and then ethyl acetate containing 0.1% triethylamine as eluents. 0.49 g of the free base is obtained in the form of an oil. To a solution of 0.46 g (0.96 mmol) of the free base in a mixture of dichloromethane and ethyl acetate was added 0.96 mL of 1N (1.0 equiv.) Ethereal HCl. The salt, hydrochloride, is filtered off and dried in a vacuum oven. 0.385 g of the title compound is obtained as a white solid, m.p. 195-195.5 ° C. Yield 20%.

¹ H NMR (DMSO-d 6): δ 1.24 (t, 3, J = 7.2), 1.62 (m, 2), 1.83 (m, 2), 3.26 (m, 6) ), 3.47 (m, 2), 3.61 (m, 2), 4.07 (m, 2),

4.14 (q, 2, J = 7.2), 7.10 (tm, 1, J = 7.7), 7.49 (m, 2),

7.60 (ddd, 1, J = 1.1, 7.0, 8.1), 7.79 (dd, 1, J = 1.5,

7.9), 8.12 (tm, 2, J = 8.4), 8.20 (dd, 1, J = 0.9, 8.3), 8.89 (broad t, 1, J = 5.5), 10.85 (broad s, 1), 10.97 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): δ 14.41, 20.68, 26.01, 38.47, 46.44,

50.53, 55.16, 60.61, 118.62, 119.59, 121.25, 121.70, 124.04,

124.67, 127.00, 128.18, 128.24, 132.18, 139.30, 152.16,

169

159.91, 162.24, 168.36.

Analysis for ^C 25 ^H 31 ^N 5 ^S ° 3 ^{'HC1 Calculated:} 57.96% C 6.23% H 13.52% N Found: 58.07% C, 6.28% H, 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 Ν, Ν-dimethylformamide, 15 mL anhydrous toluene and 1.2 g (5.15 mmol) acid

3-bromo-2,6-dihydroxybenzoic acid [produced by bromination of dihydroxybenzoic acid (Aldrich Chemical Company) with bromine according to the method of F.P.Doyle et al. in J. Chem. Soc. 497-506 (1963)] was placed in a 100 ml three-necked round-bottomed flask, which was flame dried. The solution was placed under a nitrogen atmosphere and heated to 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. A solution of 1.5 g (5.15 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13) was added to the resulting suspension.

b)) in 15 ml of anhydrous dichloromethane and the reaction 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 with saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried (MgSO4), filtered and evaporated. 2.94 g of crude material are obtained as a brown-beige solid. The free base was purified twice by flash chromatography using a 93: 7 mixture of dichloromethane and methanol as eluent.

170 reagent. 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 (1.0 equiv.) Ethereal hydrogen chloride solution was added. The salt, hydrochloride, is filtered off, washed with ether and dried in a vacuum oven. 0.454 g of the title compound is obtained as an off-white solid, m.p. 228 DEG-230 DEG C. (decomposition). 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 ° 3 ^s . HCl:

H, 4.84; N, 10.34. Found: C, 48.67; H, 4.86; N, 10.25.

Example 75

a) A process for the preparation of 6-fluoroisatin 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 250 ml round-bottomed flask equipped with a magnetic stir bar. The solution is placed under a nitrogen atmosphere and refluxed for 6 hours. The reaction mixture was allowed to cool to room temperature and evaporated. That's how it gets

171

3.8 g of a crude substance which is an off-white solid. This material was used without further purification.

¹ H NMR (DMSO-d 6): 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 <? (8.28 mmol) of 6-fluoro-isatinic anhydride and 40 ml of anhydrous tetrahydrofuran are placed in a 300 ml round-bottom flask which has been flame-dried. Reaction. The mixture was placed under a nitrogen atmosphere and a solution of 2.4 g (8.28 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole was added (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 using a 19: 1 mixture of dichloromethane and methanol as eluent. 2.79 g of the free base are obtained in the form of a yellow oil. Dissolve the free base in ethyl acetate and add 6.53 mL of 1 N (1.0 equiv.) Ethereal HCl. The salt, hydrochloride, is recrystallized from aqueous ethanol. 2.0 g of the title compound is obtained as a beige solid, m.p. 218-220 ° C. Yield: 52%.

¹ H NMR (DMSO-d 6): δ 1.57 (m 2), 1.80 (m, 2), 3.10-3.75 (m, 10), 4.10 (broad 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.

^{X 3} 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,

172

121.49, 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 · ^HC1: Calculated: 56.95% C 5.86% H 15.09% N Found: 57.06% C, 5.95% H, 14.94% N.

Example 76

a) Process for the preparation of 3-fluoroisatinic anhydride and 6-fluoroisatinic anhydride ml of anhydrous chloroform, 10.0 g (60.2 mmol) of 3-fluorophthalic anhydride (Fluorochem Limited) and 8.0 ml (60.2 mmol, 1 (0 equivalent) azidotrimethylsilane (Aldrich Chemical Company) was introduced under a nitrogen atmosphere into a 250 ml three-necked round-bottom flask which was flame dried. The reaction mixture was gently heated with a heat gun until gas evolution was 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. Yield: 7.78 g of the title compound as off-white solids. Integration of ¹ H NMR indicated 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.

@ 1 H NMR signals observed for acid anhydride

The 6-fluoroisatin are identical to the signals found in Example 75 a). This mixture was used without further purification.

173

b) Method 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) 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-fluoroisatinic anhydride Place 40:60 in a 100 ml three neck round bottom flask. 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 ethyl acetate / hexanes (2: 1) and 100% ethyl acetate as eluents. This gave 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. The salt, hydrochloride, was recrystallized twice from ethanol. 0.36 g (yield: 15% of theory, based on 3-fluoroisatin anhydride) of the title compound is obtained as brown crystals, m.p. 175 DEG-176 DEG.

1 H-NMR (DMSO-d 6, 200 MHz): δ 1.59 (m, 2), 1.80 (m, 2), 3.18-3.66 (m, 10), 4.09 (broad) 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.

174

Analysis for C ₂₂ H ₂₆ FNOS 'HCl:

H, 5.87; N, 15.09. Found: C, 56.93; H, 5.95; N, 15.03.

Example 77

(a) Method of preparation of 2 - [(tert-butoxycarbonyl) amino] benzoic acid (0.182 mol) of 2-aminobenzoic acid and 100 ml of 1,4-dioxane is placed in a 2 L round-bottomed flask and cooled to ice bath. To the mixture was added 125 mL of a 5% aqueous sodium carbonate solution, then slowly added a solution of 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 was adjusted to 2 by the 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 was separated, washed with water, dried over magnesium sulfate, 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%.

³ H NMR (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) Method for the preparation of 2 - [(tert-butoxycarbonyl) amino] -N- (4-hydroxybutyl) benzamide

175

37.94 g (0.160 mol) of 2 - [(tert-butoxycarbonyl) amino] benzoic acid, 26.8 ml (19.46 g, 0.19 2 mol, 1.2 equivalents) of anhydrous triethylamine and 125 ml of anhydrous tetrahydrofuran The flask was contacted in a 1 liter three-necked round-bottomed flask equipped with a magnetic stir bar, thermometer, dropping funnel and nitrogen inlet using a flask that had been flame-dried beforehand. The orange solution 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 from -15 to -30 ° C during the addition of isobutyl chloroformate. After the addition of isobutyl chloroformate is complete, the resulting thick suspension is vortexed for 5 minutes. A solution of 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 was slowly added to the reaction mixture and the reaction mixture was allowed to stir at temperature. from -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 (MgSO4), 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 afforded 41.34 g of the title compound as a pale yellow oil. Yield 84%.

¹ H NMR (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.

176

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 placed in 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, 2.0 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. The reaction mixture was evaporated to give an orange oil. The oil was transferred to a separatory funnel with 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. 18.19 g of crude material are obtained in the form of an orange oil. The mesylate was purified by column chromatography eluting with ethyl acetate / hexanes (1: 1). This gives 11.46 g of the title compound as a pale orange oil. Yield: 65%.

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)

Place 177 and 9 ml of toluene in a 500 ml three-necked round-bottomed flask. The reaction mixture was placed under a nitrogen atmosphere and heated to 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 with water (3 x 400 ml), dried (MgSO 4), filtered and evaporated. 7.24 g of the title compound is obtained as a brown solid. Yield 34%.

¹ H NMR (CDCl ₃ ): δ 1.74 (broad 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.

e) Production method of N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [(tert-butoxycarbonyl) amino] benzamide-S, S- of 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)

2 - [(tert-butoxycarbonyl) amino] -N- [4 - [(methylsulfonyl) oxy] butyl] benzamide, 2.2 mL (1.60 g, 1.58 mmol, 1.25 equivalents) triethylamine and 75 mL anhydrous of acetonitrile is placed in a 500 ml round-bottom flask which has been flame-dried 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 over magnesium sulfate, filtered and evaporated. 6.09 g of a yellow-beige glass-like substance is obtained. The crude material was purified by flash chromatography with a mixture of ethyl acetate and methanol

178 ratio 19: 1. This gave 4.58 g of the title compound similar to pale beige glass. Yield 62%.

1 H NMR (CDCl ₃ ): δ 1.52 (s, 9), 1.64 (m, 4) 2.47 (broad t,

2, J = 6.5), 2.63 (broad 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 minutes. The reaction mixture was evaporated and the resulting orange liquid was dissolved 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 (MgSO4), filtered and evaporated. The crude material is obtained as an orange liquid. This material was purified by column chromatography with 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 added

4.64 ml of 1N (1.05 equivalent) ethereal hydrogen chloride solution. The salt, hydrochloride, was recrystallized twice from aqueous ethanol. 0.83 g of the title compound is obtained as a light beige solid having a temperature

179 mp 259-261 ° C (dec.). 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 (m, 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 · ^HCl: Calculated: 55.33% C 5.91% H 14.67% N Found: 55.08% C, 6.00% H, 14 58% N.

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 phosphorus pentasulfide (Aldrich Chemical Company) and 100 mL of xylenes are combined A 500 ml round bottom flask which was flame dried and placed under a nitrogen atmosphere. The reaction mixture was 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

180 fabric. Yield: 63%.

^{Τ Η} NMR (DMSO-d₆) 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, J, 8.2) ppm.

f) Method for preparing 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] thiobenzamide hydrochloride with anhydrous tetrahydrofuran and 2.9 g (13.7 mmol)

The 1,4-dihydro-2H-3,1-benzothiazine-2,4-dithione was contacted in a 1 L 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 tetrahydrofuran. The reaction mixture was allowed to stir at room temperature for 30 minutes. An additional portion of 1.0 g (3.45 mmol, 0.25 equivalents) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b) in 10 mL was then added. of anhydrous tetrahydrofuran and the reaction mixture was allowed to stir for 15 minutes. The suspension is filtered and the filtrate is evaporated. 7.6 g of a red-orange oily residue are obtained. This residue was combined with an additional 0.65 g of the crude obtained in the previous experiment. The combined material was partially purified by flash chromatography, eluting with dichloromethane: methanol (97: 3). Further purification was carried out on Harrison's research chromatotron using a gradient elution using 100% dichloromethane, dichloromethane / methanol 99: 1 and dichloromethane / methanol 97: 3.

0.718 g of the free base is 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 equiv.) Ethereal HCl was added. The solids were filtered off, washed with ethyl acetate and ether and recrystallized from ethanol. 0.229 g of the title compound is obtained as a yellow solid

181 m.p. 198 DEG-201 DEG. Yield 2.7%.

¹ H NMR (DMSO-d 6): δ 1.78 (m, 4), 3.05-3.80 (m, 10), 4.10 (broad 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,

128.49, 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 ^{'HC1 Calculated:} 57.19% C 6.11% H 15.16% N Found: 56.95% C, 6.17% H, 14.98 % N.

Example 79

e) 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 bottom flask and placed 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. Layers

182 was 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. 1.9 g of the title compound is obtained as a beige glass-like substance. 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 (broad s, 1), 6.97 (ddd, 1, J = 1.1, 7.3, 7.8),

7.41 (d, 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 preparing 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-butoxycarbonyl) amino] benzamide -S-oxide, 5.0 ml of anhydrous anisole (Aldrich Chemical Company), 68 ml of dichloromethane and 17.0 ml of trifluoroacetic acid are placed in 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. Then, saturated sodium bicarbonate solution was 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 (MgSO4), filtered and evaporated. The crude material was partially purified by flash chromatography with a mixture of dichloromethane and methanol

183 (97: 3) and dichloromethane / methanol (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 as a white glass-like substance. This free base was dissolved in dichloromethane and 1.34 mL of 1 N ethereal HCl (1.0 equivalent) was added. The salt, hydrochloride, was filtered off and dried. 0.47 g of the title compound is obtained as a hygroscopic off-white solid, m.p. 208 DEG-213 DEG C. (decomposition). Yield: 27%.

^{Τ Η} NMR (DMSO-d _6): δ 1.58 (m, 2), 1.79 (m, 2), 3.17 (m, 2),

3.28 (m, 2), 3.45 (m, 2), 3.58 (wide s, 2), 3.73 (wide s, 2), 4.67 (wide S, 2), 6, 54 (t, 1, J = 7.5), 6.71 (d, 1,

J = 8.1), 7.15 (ddd, 1, J = 1.5, 7.1, 8.4), 7.51 (d, 1, J = 8.1), 7.75 (m 2), 8.09 (m, 1), 8.22 (m, 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 Calculated: 55.05% C 6.30% H Found: 55.28% C, 6.21% H, h ° _^2:

14.59% N, 3.75% H ₂ 0, 14.58% N, 4.07% H ₂ 0th

Example 80

a) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [[N- (9H-fluoren-9-ylmethoxy) carbonyl] -L184

-valyl] aminobenzamide

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 sodium carbonate solution is added to a 300 ml round-bottomed flask. To the biphasic reaction mixture was added 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 and Chem., 51, 3734 (1986), using N - [(9H-fluoren-9-ylmethoxy) carbonyl] -L-valine (BACHEM California)) in 60 mL of chloroform. The biphasic 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. 6.48 g of a pale yellow oil is obtained. The crude material was purified by flash chromatography using a 95: 5 mixture of ethyl acetate and methanol as eluent. 4.5 g of the title compound is obtained as a white glass-like substance. Yield: 95%.

¹ H NMR (CDCl 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 (broad t, 4, J = 4.8), 4.37 (m, 4), 5.55 (d, 1, J = 8.6), 6.83 (broad s, 1), 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 (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] -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)] 1-L-valyl] aminobenzamide, 110 mL chloroform and 50 mL

4- (Aminomethyl) piperidine (Aldrich Chemical Company) was added to 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. The organic layer was washed three times with 250 ml of water each time, separated, dried over magnesium sulfate, filtered and evaporated. 5.67 g of crude material are obtained 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 g 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 additional 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. Appropriate fractions were combined, evaporated, dissolved in aqueous methanol and lyophilized. This afforded 0.87 g of the title compound as a white powder. Yield 48%.

^{Χ Η} NMR (DMSO-d₆) δ 1.01 (t, 6, J = 6.5Hz), 1.60 (m, 2), 1.77

(m, 2), 2.18 (m, 1), 3.30 (m, 8), 5.61 (m, 2) 3.95 (m, 1), 4.10 (m, 2) 7.25 (t, J) = 7.7), 7.48 (tm, 1, , J = 7.5), 7.58 (m, 2) 7.76 (d, J, J) = 7.8), 8.13 (t, 2, J = 9.0), 8.24 (d, 1, J = 8.4), 8.40 (wide s, 1 ), 8.89 (wide t, 1,

J = 4.8), 10.33 (broad s, 1), 11.48 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): 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 C ₂₇ H ₃ gNgO ₂ S. 2.35 CF ₃ CO ₂ H. 0.75 H ₂ 0:

H, 5.08; N, 10.64; F, 16.95.

1.71% H ₂ O,

186 found: C 48.18, H 5.10, N 10.78, F 16.90,

1.79% H ₂ O.

Example 81

a) Method for producing N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -2 - [[N- (9H-fluoren-9-ylmethoxy) carbonyl] -D] -valyl] aminobenzamide

This compound was prepared in an analogous manner to that 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 / butylbenzamide (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 sodium carbonate solution. (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%.

¹ H NMR (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 (t m, 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 the Example

b), using 3.47 g (4.75 mmol) of N- [4- / 4- (1,2-benziso187)

,. ·.; · ’. ' thiazol-3-yl) -1-piperazinyl / butyl] -2 - [N - (9H-fluoren-9-ylmethoxy) carbonyl] -D-valyl] aminobenzamide, 100 mL chloroform and 50 mL 4- (aminomethyl) piperidine . The crude material was purified by column chromatography with a 85:15 mixture of ethyl acetate and methanol. 1.99 g of a viscous oil free base is obtained. 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%.

¹ H NMR (DMSO-d 6): 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 (wide S, 3), 7.24 (t,

1, J = 7.7), 7.48 (t, 1, J = 7.7), 7.58 (m, 2), 7.77 (d, 1,

J = 7.5), 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 ^S 2 °. 2.35 CF ₃ CO ₂ H. 0.75 H ₂ 0:

calculated: 48.19% C, 5.08% H, 10.64% N, 16.95% F,

1.71% H ₂ O Found: 48.03% C, 5.06% H, 10.62% N, 16.63% F,

1.68% H ₂ O.

Example 82

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

188

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 1, 4-dioxane and 10 ml of a 5% aqueous sodium carbonate solution are combined in a 250 ml round-bottom flask. The flask is equipped 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 and the reaction mixture was allowed to stir at room temperature for for 45 hours. Then, an additional 1.76 g (8.06 mmol, 1.0 equivalent) 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 (MgSO4), filtered and evaporated. It will

6.56 g of crude material as 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 which is a yellow oil. Yield: 83%.

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 producing 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) of 50-60% m-chloroperoxybenzoic acid (Aldrich Chemical Company) in 50 mL of dichloromethane was added to a solution of 3.32 g. (6.51 mmol) N- [4- / 4- (1,2-benzisothiazol-3-yl) 189

-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 (MgSO4), filtered and evaporated. 4.6 g of a yellow glass crude material are obtained. The crude material was purified by flash chromatography using a 4: 1 mixture of dichloromethane and methanol as eluent. This gave 2.28 g of the title compound as a pale yellow solid. Yield: 59%.

¹ H NMR (CDCl ₃ ): δ 1.50 (s, 9), 1.84 (ra, 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) Method 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 of anhydrous anisole (Aldrich Chemical Company) 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. Chloroform and cold saturated sodium bicarbonate solution were added slowly to the reaction mixture. The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous phase was extracted with chloroform. The organic layers were combined, dried

190 magnesium sulfate, filtered and evaporated. The material was purified by flash chromatography with dichloromethane / methanol (4: 1) as eluent. 0.686 g of the free base is obtained in the form of a pale yellow glass-like substance. 0.686 g (1.55 mmol) of the free base was dissolved in a mixture of dichloromethane and methanol and treated with

1.55 ml of 1N (1.0 equivalent) of ethereal hydrogen chloride. 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%.

¹ H NMR (DMSO-d 6): 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, 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).

Analysis for θ22 ^Η 27 ^Ν 5 ° 4 ^δ * ^HCl: calculated: 53.49% C, 5.71% H, 14.18% N, 7.18% Cl, found: 53.57% C, 5.75 % H, 14.14% N, 7.23% Cl.

Example 83

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

3.28 g (8.01 mmol) of 2-amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] benzamide (Example 36) and 75 mL of anhydrous Dichloromethane was combined 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. 2.30 g (6.7 to 8.0 mmol, 0.8 to 1.0 equivalents) of 50 to 60% m-chloroperoxybenzoic acid (Aldrich Chemical Company) are added to the pear-shaped flask. The m-chloroperoxybenzoic acid was covered with nitrogen, 25 mL of anhydrous dichloromethane was added and the solution was cooled to -40 ° C with a dry ice (carbon dioxide) bath in acetone. At this temperature part of m-chloroperoxybenzoic acid is insoluble. The supernatant was transferred to a cold benzamide solution through a feed tube and the remaining peroxyacid was dissolved in 10 mL of anhydrous dichloromethane and cooled in an ice bath. 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 (MgSO4), 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 using a 17: 3 mixture of dichloromethane and methanol as eluent. A beige-colored 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. 0.991 g of free base is obtained as a 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. This gave 0.470 g of the title compound as a brown solid

192, m.p. 177.5-178.5 ° C (dec.). Yield 13%.

¹ H NMR (DMSO-d 6): δ 1.61 (ra, 2), 1.91 (m, 2), 3.29 (broad t 2, J = 6.8), 3.66 (m, 2) ), 3.90 (m, 6), 4.10 (broad d, 2,

J = 13.7), 6.53 (ddd, 1, J = 1.0, 7.1, 7.6), 6.71 (dd, 1,

J = 1.0, 8.4), 7.15 (ddd, 1, J = 1.5, 7.1, 8.4), 7.50 (m,

1), 7.52 (dm, 1, J = 7.6), 7.63 (tm, 1, J = 7.6), 8.14 (d,

1, J = 8.0), 8.20 (d, 1, J = 8.0), 8.34 (broad 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 ° 2 ^S. HCl:

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-bottomed flask. and cooled in an ice bath. The flask was equipped with a dropping funnel and a solution of 9.6 g (44.0 mmol, 1.1 equivalents) of di-tert-butyl dicarbonate (Aldrich Chemical Company) in 20 mL 1,4-dioxane was slowly added dropwise. The ice bath was removed and 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

193 was dissolved in 10 mL of 1,4 dioxane and 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 trituted with hexanes and dried in a vacuum oven. 9.13 g of the title compound is obtained as a brown-beige solid. Yield: 91%.

¹ H NMR (DMSO-d 6): 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 in a 100 ml round bottom flask which was 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) is slowly added

2.97 g (10.2 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (Example 13b)) in 30 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to stir under stirring

194 temperatures from -15 to -30 ° C for 45 minutes. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature 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 over magnesium sulfate, filtered and evaporated. 5.89 g of an orange oil are obtained. The crude material was purified by column chromatography using a 19: 1 mixture of dichloromethane and methanol as eluent. 3.01 g of the title compound is obtained 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), 7.01 (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, 8.76 (broad s, 1) ppm.

c) Process for the preparation of 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] -2- [2- (tert-butoxycarbonyl) hydrazino] of benzamide, 5.0 ml of anhydrous anisole (Aldrich Chemical Company) and 75 ml of anhydrous chloroform were combined in a 500 ml round bottom flask. To the stirred light yellow solution was added 25 mL of trifluoroacetic acid (EM Science). 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. The organic layers were combined, washed with sat

195% sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to an orange liquid. The crude material was purified by column chromatography eluting with a mixture of 97 to 95% dichloromethane and 3 to 5% methanol in a gradient. 1.54 g of the free base is obtained as a partially solidifying yellow oil. 1.41 g (3.32 mmol) of the free base was dissolved in dichloromethane and 6.8 ml of 1N (2.05 equivalents) of ethereal hydrogen chloride was added. The resulting salt, dihydrochloride, is recrystallized from a mixture of aqueous ethanol and ether. 1.1 g of the title compound are obtained as a gold yellow solid, m.p. 222 DEG-226 DEG C. Yield: 40% of theory.

1 H NMR (DMSO-d 6): δ 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);

8.0), 7.46 (m, 2), 7.58 (t, 1, J = 7.6), 7.73 (dd, 1, J =

1.3, 7.5), 8.06 (W, 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 NGO. 2 HCl. 0.5 H ₂ O: calculated: 52.17% C, 6.17 1.78% H ₂ O, % H, 16.59 % N, 14.00 % Cl found: C 52.23, 6.34 % H, 16.30 % N, 14.04 % Cl

2.05% H ₂ O.

Example 85

196

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. 32, 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 a solution of potassium hydroxide in 187 ml of water to give 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 (wide s, 2), 7.37 (ddd, 1, J = 1.3, 7.0, 8.2) 7.48 (ddd, 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 process for the preparation of 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 L round bottom flask and placed under a nitrogen atmosphere. The light orange solution was heated to 180-185 ° C for 3.5 hours. The reaction mixture was evaporated and the residue was partially purified by eluting with dichloromethane. 24.7 g of an orange liquid are obtained. Further purification by column chromatography with dichloromethane as eluent gave 20.1 g of the title compound as an orange liquid. Yield 87%.

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.

197

c) A process for the preparation of 1- (benzo [b] thiophen-3-yl) piperazine

15.86 g (0.106 mol) benzo [b] thiophen-3-amine, 21.07 g (0.245 mol, 2.3 equivalents) piperazine (Aldrich Chemical Company) and 100 ml 1-methyl-2-pyrrolidinone (Aldrich Chemical Was placed in a 500 ml round bottom flask and placed under a nitrogen atmosphere. The reaction mixture was 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 eluting with 100% dichloromethane and dichloromethane: methanol (85:15). 14.41 g of the title compound is obtained as a yellow solid. Yield 62%.

¹ H NMR (DMSO-d 6): 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 are 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 saturated sodium chloride solution, separated, dried over magnesium sulfate, filtered and evaporated. 13.26 g of crude material are obtained in the form of an orange

198 oil. This material was purified by eluting with 1: 1 ethyl acetate: hexanes. 8.5 g of the free base, consisting of a yellow solid, is obtained.

Dissolve 1.55 g (3.69 mmol) of the free base in ethyl acetate and add 3.70 mL of a 1N (1.0 equivalent) ethereal HCl solution. The salt, hydrochloride, is recrystallized from aqueous ethanol. 1.30 g of the title compound is obtained as a white solid, m.p. &gt; 250 DEG C. Yield: 65%.

^{Τ Η} NMR (DMSO-d₆) δ 3.52 (br s, 4), 3.20 (m, 6), 3.61 (m, 6), 7.11 (s, 1H), 7.42 (ra, 2), 7.88 (m, 4), 7.89 (d, 2,

J = 2.7), 10.56 (broad s, 1) ppm.

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

d) Method for producing 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 55% of a 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 was allowed to cool to room temperature and then 25 mL of water was added. The reaction mixture was acidified to pH 2 by addition of 1 N aqueous

199 hydrochloric acid. The resulting solid was filtered and washed with water. The pH of the filtrate was adjusted to 12 by addition of 1N sodium hydroxide solution, the reaction mixture was transferred to a separatory funnel and extracted with dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, decolourised with charcoal, filtered again and evaporated. This afforded 2.00 g of the title compound as a pale yellow oil which solidified on standing to a beige solid. Yield: 82%.

¹ H NMR (CDCl ₃ ): δ 1.22 (broad 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) Process for the preparation of 2-amino-N- [4- / 4- (benzo [b] thiophen-3-yl) -1-piperazinyl / butyl] benzamide hydrochloride

1.79 g (6.18 mmol) of 4- [4- (benzo [b] thiophen-3-yl) -1-piperazinyl] butylamine, 1.21 g (7.42 mmol, 1.2 equivalents) of acid anhydride isatin (Aldrich Chemical Company) and 25 ml 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 saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic layers were combined, dried (MgSO4), filtered and evaporated. 3.41 g of crude material are obtained in the form of an orange oil. The free base was purified by flash chromatography with ethyl acetate as eluent. 2.37 g of a colorless oil are obtained. Free base of mass

2.21 g (5.41 mmol) was dissolved in ethyl acetate and added

5.41 ml of 1N (1.0 equivalent) ethereal hydrogen chloride solution. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 1.38 g of the title compound.

200 as an off-white solid having a melting point of 210-212 ° C. Yield 50%.

¹ H NMR (DMSO-d 6): δ 1.61 (m, 2), 1.82 (m, 2), 3.06 - 3.46 (m, 8), 3.61 (broad d, 4, J = 10.7), 6.43 (broad s, 2), 6.54 (t, 1, J = 7.4), 6.71 (d, 1, J = 8.0), 7.12 (s, 1), 7.16 (t, 1, J = 8.2), 7.43 (m, 2), 7.53 (d, 1, J = 7.8), 7.83 (m , 1),

7.97 (m, 1), 8.33 (broad t, 1, J = 5.3), 10.72 (broad s,

1) ppm.

¹³ C NMR (DMSO-d 6): δ 20.86, 26.54, 38.25, 48.78, 51.13,

55.38, 109.10, 114.86, 115.12, 116.63, 122.11, 123.77,

124.24, 125.08, 128.42, 131.88, 134.02, 138.96, 145.09, 149.90, 169.29.

Analysis for ^C 23 ^H 28 ^N 4 ^OS * ^HC1: Calculated: 62.08% C 6.57% H 12.59% N Found: 61.83% C, 6.65% H, 12.50% N.

Example 87

a) Process 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)) was placed in a 300 ml round bottom flask which was 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. Then the solution is heated to 65-75 ° C for 75 minutes. The solvent was removed by rotary evaporation to give the acid chloride in the form

201 orange residue. This crude acid chloride was dissolved in 50 mL of anhydrous chloroform and placed under a nitrogen atmosphere. To the acid chloride solution 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 was allowed to stir at room temperature for 45 minutes and then the solvent was 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, dried over magnesium sulphate, filtered and evaporated. 10.03 g of 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. This gave 4.78 g of a pale yellow oil. The salt, hydrochloride, was prepared by adding 9.24 g of a 1N (1.0 equivalent) ethereal HCl 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. Yield 30%.

¹ H NMR (DMSO-d 6): δ 1.16 (t, 3, J = 7.5), 1.60 (m, 2), 1.83 (broad 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, 1, 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 ° 3 ^{SC 1} · ^HCl;

H, 6.19; N, 10.12. Found: C, 56.31; H, 6.18; N, 10.08.

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 (4.0 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. Both resulting isomers were partially purified by flash chromatography on silica gel with ethyl acetate / hexanes (2: 1) as eluent. Further purification on Harrison's research chromatotron with a 1: 1 and 2: 1 mixture of ethyl acetate and hexanes as eluents afforded a total of 1.07 g of the major isomer,

N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -3-chloro-5-ethyl-6-hydroxy-2-methoxybenzamide _(Rf = 0.18, with a 2: 1 mixture of ethyl acetate and hexanes as eluent) 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, 2: 1 ethyl acetate: hexanes) as light orange oils. Salts, hydrochlorides of each isomer are prepared independently 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

203 of ethanol / 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 as a hydrochloride salt. an off-white powder having a melting point of 179-181 ° C. Yield 35%.

¹ H NMR (DMSO-d ₆ ): 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 (broad 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 (broad t, 1, J = 5.1), 11.25 (broad s, 1), 13.60 (s, 1) ppm.

¹³ C NMR (DMSO-d 6): 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 O ₃ SC1. HCl:

H, 5.98; N, 10.38. Found: C, 55.56; H, 5.99; N, 10.29.

Example 89

The salt, the minor isomer hydrochloride, is recrystallized from 95% ethanol and dried in a vacuum oven. There was obtained 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 as fluffy. off-white crystals having a melting point of 171-173 ° C. Yield: 7%.

¹ 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.

204 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 ^SC1 HCl . and, 25 h ₂ ° ^: calculated: C 53.43, 6.19 % H, 9.97 % N, 4.00 h ₂ o, found ^- : C 53.46, 6.14 % H, 9.99 % N, 4.02 h ₂ 0.

Example 90

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

This compound was prepared as described in Example 75 b). From 3.35 g (0.017 mol) 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 mol, 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 ethanol (10 ml) and added

4.4 ml of 1N (1.0 equivalent) ethereal hydrogen chloride. The salt, hydrochloride, is recrystallized from a mixture of ethanol and isopropanol. This gives 1.93 g of the title compound as off-white crystals having a melting point of 136-138 ° C. Yield: 65%.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.59 (m, 2), 1.80 (m, 2), 3.12-3.60 (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,

205

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,

163.18, 169.79.

Mass spectrum (MS) (CI / CH ₄ , 50 mA / s): M + 1, base (440).

Analysis for ^C 23 ^H 29 ^N 5 ° 2 ^S · ^HCl: calculated: 59.03% C, 6.35% H, 14.71% N, 6.74% S,

Cl, 7.45%. Found: C, 57.94; H, 6.42; N, 14.57; S, 6.71.

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 according to the procedure 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 Company). 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, was recrystallized from ethanol / ether and dried in a vacuum oven. 0.66 g of the title compound is obtained as an off-white powder, m.p. 214-215 ° C. Yield: 41%.

¹ H NMR (DMSO-d 6, 200 MHz): δ 1.61 (m, 2), 1.85 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4 , 09 (broad d, 2, J = 13.5), 7.48 (dd,

1, J = 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.

206 ¹³ C NMR (DMSO-d 6, 75.43 MHz): δ 21.44, 26.95, 39.32, 47.30,

51.39, 56.06, 122.18, 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 22 ^H 25 ^N 5 ° 3 ^S · ^HCl: calculated: 55.51% C, 5.50% H, 14.71% N, found: 55.56% C, 5.55% H, 14. 72% N.

Example 92

a) A process for the preparation of 2-amino-α, α, α-trifluoro-p-toluylic 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 activated carbon. The vessel was placed in a Parr hydrogenator and the solution was placed under a hydrogen atmosphere at 20 psi. The reaction mixture was shaken at room temperature until no more hydrogen was consumed (for 2 hours). The solution was filtered through an AP filter and the filtrate was evaporated on a rotary evaporator. 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) 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-toluylic acid and 2.00 g (6.5 mmol, 1.0 equivalent) of 3- [4- (4-aminobutyl) -1] -piperazinyl / -1,2-benzisothiazole (Example 13 (b)) was added to a round bottom flask

207 of 100 ml. Place the solution under a nitrogen atmosphere, slowly 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 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 with ethyl acetate (3.times.200 ml). The organic layers were combined, dried (MgSO4), 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 gradient elution. There was thus obtained 1.45 g of the free amine. This material was dissolved in ethanol and 3.04 mL of 1 N ethereal hydrogen chloride was added. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 0.512 g of the title compound as white crystals, m.p. 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 , 09 (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,

208

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.

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, 5.38% H, 13.57% N, 6.32% S,

6.92% Cl.

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 prepared by known methods as indicated. 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.

^{Τ Η} NMR (DMSO-d₆, 300 MHz): 1.58 (m, 2), 1.78 (m, 2), 2.08 (s, 3H), 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,

209

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, 170.34.

Mass spectrum (CI / CH ₄ , 50 mA / s): M + 1, base (424).

Analysis for ^C 23 ^H 29 ^N 5 ^OS · ^HCl: calculated: 60.05% C, 6.57% H, 15.22% N, 6.97% S,

7.71% Cl, found: 60.08% C, 6.61% H, 15.12% N, 7.06% S,

7.76% Cl.

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.

^{Χ Η} NMR (DMSO-d₆, 200 MHz): δ 1.59 (m, 2), 1.82 (m, 2), 3.15 - 3.61 (m, 10), 4.08 (br 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, 2,

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.

Mass spectrum (CI / CH ₄ , 50 mA / s): M + 1, base (444).

210

Analysis for C ₂₂ H ₂₆ n. ₅ soci. HCl: calculated: 55.00 % C, 5.66 % H, 14.58 % N, 6.67% S, 14.76 % Cl, found: 55.09 % C, 5.66 % H, 14.55 % N, 6.74% S, 14.66 % Cl.

Example 95

Process for the preparation of 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.

^{Τ Η} NMR (DMSO-d₆, 300 MHz): d 1.58 (m, 2), 1.80 (m, 2), 3.29 (m, 6), 3.45 (m, 2), 3 59 (broad d, 2, J = 10.9), 4.08 (broad d, 2, J = 12.6), 6.30 (broad s, 2), 6.71 (dd, i,

J = 8.9, 5.1), 7.05 (dt, 1, J = 2.7, 9.9), 7.37 (dd, 1, J =

2.7, 10.3), 7.47 (t, 1, J = 7.5), 7.60 (t, 1, J = 7.5), 8.12 (t, 2, J = 8) 3), 8.37 (broad t, 1, J = 5.3), 10.65 (broad s, 1) ppm. .

¹³ C NMR (DMSO-d 6, 75.43 MHz): d 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.

Mass spectrum (CI / CH ₄ , 50 mA / s)

M + 1 base (428).

Analysis for C ₂₂ H _{2 5} g of N FOS. HCl:

H, 5.87; N, 15.09.

Cl, 7.64. Found: C, 56.84; H, 5.84; N, 15.01.

7.73% Cl.

6.91% N,

7,01% S,

211

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-d 6, 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.

Weight spectrum (CI / CH ₄ , 50%) mA / s): M + 1 base (424) Analysis for ' ^C 23 ^H 29 ^N 5 ^SO · ^HCl: calculated: % C, 60.05;% H, 6.57; 15.22 % N, 6.97 % S, 7.71% Cl, found: % C, 59.99;% H, 6.58; 15.17 % N, 7.08 % S,

7.64% Cl.

Example 97

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

Starting material: 3-amino-2-naphthoic acid (Aldrich

Chemical Company). Yield: 0.284 g (9% of theory). Compound

212, the title compound having a melting point of 216-218 ° C.

¹ H NMR (DMSO-d 6, 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, 50.29 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 + 1 base (460).

Analysis for ^C 26 ^H 29 ^N 5 ^{SO 'HC1 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

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 (decomposition).

³ 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 88 (m, 2), 6.67 (d, 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),

213

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 ° 2 ^S · ^HCl: calculated: 58.03% C, 6.35% H, 14.71% N, 6.74% S,

Cl, 7.45%. Found: C 58.09; H, 6.34; N, 14.62; S, 6.82.

7.39% Cl.

Example 99

a) A process for the preparation of 4-fluoroisatin 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).

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.

214

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, m.p. 234-236 ° C. Yield: 43%.

¹ H NMR (DMSO-d 6, 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 (broad t, 1, J = 5.3), 10.90 (broad 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 ^{0FS 'HC1 Calculated:} 56.95% C, 5.86% H, 15.09% N, 6.91% S,

% C, 7.64; Found: C, 56.89; H, 5.83; N, 15.10.

7.61% Cl.

Example 100

a) Method for the preparation of 3- [1- (4-aminobutyl) -4-piperidinyl] -6-fluoro-1,2-benzisosazole

215

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 are added to a 100 mL round bottom flask. The reaction mixture was refluxed for 2 hours. The oil bath was removed and 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 (MgSO4), filtered and evaporated. This afforded 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,

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 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 on standing. 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 added

216 was dissolved in ethyl acetate and 1.68 mL of 1N (1.0 equiv.) Ethereal hydrogen chloride was added. The salt, hydrochloride, was recrystallized from aqueous ethanol to give 0.51 g of the title compound as an off-white solid, m.p. 242.5-245 ° C (dec.). Yield: 57%.

¹ H NMR (DMSO-d ₆ ): 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 (broad d, 2,

J = 12.0), 6.93 (broad S, 2), 6.51 (tm, 1, J = 7.4), 6.69 (dd, 1, J = 0.9, 8.1) 7.13 (tm, 1, J = 7.6), 7.35 (td, 1,

J = 9.1, 2.1), 7.49 (dd, 1, J = 1.2, 7.9), 7.74 (dd, 1, J = 2.1, 9.1), 8 17 (m, 1), 8.29 (m, 1), 10.3 (broad s, 1) ppm. 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, 153.35, 165.03, 168.98.

Analysis for ^C 23 ^H 27 ^N 4 ^F · ° 2 ^{HC1 Calculated:} 61.81% C 6.31% H 12.54% N Found: 61.86% C, 6.33% H, 12 53% N.

o- 217 JUDr. Ivan KORSČEK

Law and patent office

160 00 Prague 6, Na baště sv. Jiří 9

Claims (27)

PATENTOVÉ 1. A compound of formula (I): Y Xw-2- _N \ _ / wherein is a group of formula a), b) or c) (a) where a single line accompanying a broken line (- - -). Represents a single or double bond, wherein 218 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, formula C-N, CON ^(R4) 2, COR ^4, CO 2 R ^4, CO-aryl, azido, benzyloxy, -NR ⁴ group of formula 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, an alkyl group having 1 to 6 carbon atoms optionally substituted by one or a plurality of halogen atoms and an alkoxy group having 1 to 6 carbon atoms optionally substituted by at least one halogen atom, R ² represents a group of the formula -CH2-, -CH2CH2-, -CH2CH2CH2-, -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-, R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁷ , R ⁸ , R 6, R ¹⁸ and R ¹¹ , which are the same or different, each represent a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a group of the formula 219 S (O) _n R ⁴ wherein n represents O, 1 or 2, a group of formula C = N, CON ^(R4) 2, COR ^4, CO 2 R ^4, CO-aryl, azido, benzyloxy, -N (R ⁴ ) 2, -NR ⁴ N (R ⁴ ) 2, -NR ⁴ N = C (R ⁴ ) ₂ , ^-NR4 (C = O) CH [N (R ⁴⁾ 2] R ⁴ and -NR ⁴ (C = O) R ^4, -NR ⁴ CO 2 R ^4, alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy group, of formula PhN = N, an alkyl group having 1 to 6 carbon atoms optionally substituted by one or more halogen atoms or an alkoxy group having 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, or assuming a paired combination of R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ represents a group of formula represents an oxygen atom or a sulfur atom represents an alkylene group of 4 to 8 carbon atoms, optionally interrupted by the group -S (O) _n , wherein n represents 0, 1 or 2, a (C 4 -C 8) alkenylene group or a (C 4 -C 8) alkynylene group, represents a nitrogen atom or a carbon atom and represents a group of formula (d) 220 d R ' ² 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 is hydrogen or halogen, or a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, or a physiologically functional derivative thereof . The compound, salt, solvate or derivative according to claim 1, wherein the nitrogen atom of formula I, which is adjacent to the substituent Ž 2 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) a R ¹ is hydrogen or chlorine, R ² is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -S-, -NR ³ , - (C = O) NH-, or -N = N- and - - - in each case represents a double bond, 221 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. The compound, salt, solvate or derivative of claim 3, where Ί R is hydrogen, R ² is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ or -N = N- and R ³ and R ⁴ are hydrogen. The compound, salt, solvate or derivative of claim 4, where R ² 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) a R ¹ is hydrogen, chlorine, fluorine, methyl, hydroxyl, methoxy, nitro or two chlorine atoms and / R is -C = N-. A compound, salt, solvate or derivative according to claim 6, where R represents a hydrogen atom, a methyl group, a fluorine atom, a nitro group or a methoxy group. A compound, salt, solvate or derivative according to claim 222 7, where R ¹ is hydrogen or nitro. A compound, salt, solvate or derivative according to any one of claims 1 and 2, wherein Y is a group of formula (c) a 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, Q R is chloro, NHCO ₂ t-Bu, bromo or amino, Q R is hydrogen, methoxy, trifluoromethyl, tert-butyl, -N = N-Ph, NHAc, NHCO ₂ -Bu, bromo or amino, 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. A compound, salt, solvate or derivative according to claim 9 wherein r6 is hydrogen, R is amino, methoxy, acetamido or methylamino, Q R is hydrogen or bromine, 223 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. A compound, salt, solvate or derivative according to claim 10, where R ⁸ R ⁹ _R io R ¹¹ and R ¹⁰ are hydrogen, are hydroxy and are amino or methylamino, or are methoxy, are hydrogen, are bromine, are hydrogen and are hydroxy. A compound, salt, solvate or derivative according to any one of claims 1 to 11, wherein Z represents a C 4 -C 6 alkylene group. A compound, salt, solvate or derivative according to any one of claims 1 to 12, wherein W represents a group of formula (d) a B is S or O; and R ¹² represents a hydrogen atom or a fluorine atom. A compound, salt, solvate or derivative according to claim 13, where B represents a sulfur atom and 224 R ¹² represents a hydrogen atom. 15. Compounds 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-1 [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- dion, N- [4- / 4- (1,2-benzisothiazol-3-yl) piperidino / butyl] phthalimide, 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, (+ / -) - 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 / 225 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. 17. 2-Amino-N- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperidinyl] 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) piperidino / butyl] phthalimide. A compound of formula I either according to claim 1 or 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, for use in therapy. 20. Any of the following compounds, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, for use in therapy: N- [4- / 4- (i _f 2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4-nitrophthalimide. 226 3- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -4 [3H] quinazolinone, 2- [4- / 4- (1,2-benzisothizzol-3-yl) -1-piperazinyl / butyl] -1 [2H] phthalazinone, 2- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl / butyl] -1,3 [2H, 4H] isoquinolinedione, 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) piperidino / butyl] phthalimide. 21. 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 according to either of Claims 1 or 2 of the formula I or a physiologically acceptable salt, solvate or N-oxide thereof or a physiologically functional derivative thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease selected from fatigue, muscle spasm, depression, aggression associated with senile dementia, borderline personality diseases, vomiting and psychosis. Use according to claim 23, a compound of formula I either according to claim 1 or 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, wherein the disease is psychotic 227 diseases. Use according to claim 24, a compound of formula I either according to claim 1 or 2, or a physiologically acceptable salt, solvate or N-oxide thereof, or a physiologically functional derivative thereof, wherein the disease is schizophrenia. Use of any of the compounds of claim 20, or a salt, solvate or N-oxide or derivative thereof, in the manufacture of a medicament for use in the treatment of any of the diseases described in claim 23. A process for the preparation of a compound of formula I (1) in which it represents a group of formula (a), (b) or (c) (a) wherein the single line accompanied by the dotted line (- - -) represents a single or double bond; 228 (b) (c) wherein R ¹ represents one or more ring substituents selected from the group consisting of hydrogen, halogen, C 1-6 alkyl optionally substituted by one or more halogen atoms, C 1-6 alkoxy optionally substituted by at least one halogen, 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, 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 represents a group of the formula -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR ³ -, -N = N- or - (C = O) NR 4, 229 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-, 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, (C 1 -C 6) alkoxy optionally substituted by one or more halogen atoms, hydroxy groups, 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, -NHN = C (R ⁴ ) 2, -NR ⁴ (C = O) CH [N (R ⁴ ) 2] R ⁴ , -NR ⁴ (C = O) R ⁴ , -NR ⁴ N (R ⁴ ) 2 and -NR ⁴ CO ₂ R ⁴ , an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, or a group of formula PhN = N, or provided a paired combination of R ⁷ and R ⁸ or R ⁸ and R ⁹ or R ⁹ and R ¹⁰ or R ¹⁰ and R ¹¹ represents a group of the formula 230 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 , wherein 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 is nitrogen or carbon; and W represents a group of formula (d) wherein, A represents a group of formula CR ⁴ or a nitrogen atom, * B represents an oxygen atom, a group of formula NR ⁴ or S (O) _n wherein n represents 0, 1 or 2 and R represents a hydrogen atom or a halogen atom, characterized in that it is reacted 231 compound of formula II YH (II), with a compound of formula III -Ν X-W (III) in which it is a leaving group, or reacts a compound of formula II with a compound of formula IV A * (IV) in which A 'is a suitable anion and R ¹³ is - (CH ₂ ) ₄ - or is reacted with a compound of formula V Y - Z - L in which ( ^ch 2) ₅ -, or (V), L is a leaving group, 232 (VI) with a compound of formula VI HN X · Or reacting a compound of formula (VII): Y - Z --N NH 4 / (VII) with a compound of formula VIII L - W (VIII), in which L is as defined above, or when Y is a) wherein R ² is CH ₂ - or -N = N-, a single line accompanied by a dotted line (- - -) represents a double bond and V is an oxygen atom, cyclizes a compound of formula IX (ix) wherein: R ¹⁴ represents a group of formula -CH ₂ OH or -NH ₂ , or reacted with a compound of formula X 233 in which R ¹⁵ is -CH ₂ - or -N (R ⁴ ) (C = V) - and R ¹⁶ is R ⁵ or -C = C-, or a compound of formula X ¹ wherein: R ¹⁷ represents R ^7, a group of formula -SL ² or -CH ₂ ^- and L ² L ¹ represents a chlorine atom or a bromine atom, a methoxy group or a hydroxy group, L ² represents a chlorine atom or a bromine atom, OMs or OTs, with a compound of formula XI (XI) 234 or when Y is c) and R ⁷ is -N (R ⁴ ) 2, treats a compound of formula X ¹ wherein L ² is hydroxy, V is oxygen and R ¹⁶ is -N (R 2) ⁴ ) 2, with a compound of formula XI, or when Y is a), b) or c) and R ^x , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are hydroxy, treat the corresponding methoxy derivatives, or when Y represents a group of formula a), b) or c) and R ^1, R ^7, R ^8, R ^9, R ¹⁰ or R ¹¹ denotes a group of formula N (R ⁴⁾ 2, or NR ⁴ N (R ⁴⁾ 2z hydrolyzed the corresponding alkoxycarbonylamino derivatives, or when Y represents a group of formula (a), (b) or (c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ represent a group of formula N (R ⁴ ) ₂ ; when Y represents a group of formula (c) and R ⁶ represents an alkyl group having 1 to 6 carbon atoms, alkylates the corresponding secondary amides, or when Y represents a group of formula a), b) or c) and R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ represent a group of the formula -NR ⁴ N = C (R ⁴ ), reacting the corresponding hydrazine derivatives with the corresponding ketones, and optionally reducing a compound of formula I wherein Z is C 4 -C 8 alkenylene or C 4 -C 8 alkynylene to give another compound of formula I wherein Z is C 4 -C 8 alkylene, optionally treating a compound of formula I wherein: Y represents a group of formula (c) and V represents an oxygen atom, s 235 with a sulfonating agent to form another compound of formula I wherein Y is a group of formula c) wherein V is sulfur, and optionally oxidizes a compound of formula I to form another compound of formula I wherein the nitrogen atom is oxidized to N -oxide.