HUT72309A - Piperazine and piperidine derivatives, having antipsychotic activity pharmaceutical compositions containing them and process for their preparation - 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

The compound of formula (I). For example, compounds of formula (II) may be prepared by reacting a compound of formula (II) with a compound of formula (H1) wherein L is a leaving group.

The compounds of the present invention are useful in the treatment and prevention of anxiety, muscle spasms, depression, aggressive behavior associated with senile dementia, personality disorders, vomiting, and psychotic disorders such as schizophrenia.

Representative:

ADVOPATENT Patent Office

PIPERAZINE AND PI PER IDINE DERIVATIVES, PHARMACEUTICAL PREPARATIONS AND METHODS FOR THE MANUFACTURE OF THESE COMPOUNDS

THE WELLCOME FOUNDATION LIMITED, London, England

inventors:

NORMAN Mark Henry, Durham, North Carolina

NAVAS III Frank, Chapel HI11, North Carolina

USA

Date of filing: 11/02/1993

Priority: 12/02/1992 92 029 15.6 Great Britain

International Application Number: PCT / GB93 / 00285

10346 • · · ·

The present invention relates to a group 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.

Chemical messenger dopamine receptors are known to be located in the striatal and limbic regions of the brain; these receptors are classified as type A and D _{2 based} on the presence or absence of a positive relationship between receptor binding assays and the activity of the adenylate cyclase enmirnine. Activation of the receptor is counteracted by the stimulation of adenylate cyclase, whereas the D ₂ receptor mediates dopaminergic effects that do not induce direct stimulation of this enzyme (see Kebabian and Calne, Nat. 227-93, 1979); Harrold et al., J. Med. Chem. Although the role of the A ₂ and D ₂ receptors is not completely clear yet, it is believed that there is a significant correlation between D ₂ receptor antagonism and antipsychotic activity [Seeman, Pharmacol. PEV. 32, 229 (1981); Seeman et al., Biochem. Pharmacol. 151: 1985; Crease et al; Science, 192, 481 (1976); Leysen in Clinical Pharmacology in Psychiatry: Research on Neuroleptics and Anti-Depression Volume 1, published by Gram and Lingjaerde, LIacmillan: Basingstoke 35-52. p. (1982 ().

• · · · • ·

It is a chemical messenger in color. 5-hydroxytryptamine (5-HT) is widely found in the central nervous system; It is known to influence behavioral regulation. Several different 5-HT receptor types and receptor subtypes have been identified. Except for blockade of Dg receptors, it has been hypothesized that antagonism of the 5-HTg receptor is also desirable for an antipsychotic agent [Janssen et al., J. Pharm. and Ezp. Ther. 2, 685 (1988)], in particular, it was hypothesized that blockade of central Dg dopamine receptors may eliminate positive symptoms of schizophrenia (e.g., visions and hallucinations), whereas inhibition of 5-HTg receptors may contribute to the negative effects of schizophrenia, e.g. apathy and social alienation). It is further believed that blockade of 5-HTg receptors reduces the extrapyramidal side effects known to occur during long-term (maintenance) therapy with a number of known antipsychotic agents.

Psychotropic benzisothiazole and benzisazole derivatives are disclosed in United States Patent Nos. 4,988,792 and European Patent Nos. 357,134 and 196,152. Το-

six-pointed piperidine and piperazine

German Patent Nos. 2,505,816; and 329,168;

European Patent Publication No. 013 612.

Piperazine and Piperidine Derivatives New Coverage »7 'v

Dg receptors and / or 5-HTg receptors, and consequently, the present invention relates to compounds of formula I, their physiologically acceptable salts, their physiologically acceptable snolvates and their physiologically functional derivatives. The (I) general-

lan formula

Y is a group of formula (a), (b) or (c) wherein the dashed line following the dashed line (-----) represents a single or double bond; represents one or more ring substituents: hydrogen or halogen; hydroxy; C 1-6 alkyl optionally substituted with one or more halogen atoms; where appropriate a cut; ' C 1 -C 6 alkoxy substituted with multiple halogen atoms; hydroxy, -1T (R ⁴ ) ₂ , nitro, S (O) _Q R ⁴ wherein n is 0, 1 or 2;

nitrile; C 0IT (R ⁴ ) 2, COR ⁴ , CO ² R ⁴ , CO-aryl, azo, benzyloxy, -: ΑΑτ (η ⁴ ) 2, -rr ⁴ co ² r ⁴ , -imhi = c (r ⁴ ) ₂ ,

-1TR ⁴ (C = O) CH (1T (R ⁴ ) ₂ ) R ⁴ ;

group;

B ³

C 1-6 alkyl or C 1-6 alkoxycarbonyl;

Λ

R is hydrogen or (C1-C6) -alkyl;

R1 is -iT = C- or -C = 1T-;

g

R is hydrogen or C 1-6 alkyl

• «·

the same cut ;? they are different and are hydrogen or halogen; nitro; optionally substituted with one or more halogens

C 1-6 alkyl; C 1-6 alkoxy optionally substituted with one or more halo; hydroxy; 3 (0) _Q R6 is a needle group wherein n is 0, 1 or 2; nitrile; COiTCR ug »COR \ ^ Cogr C0-aryl, azido, benzyloxy, 1T (R ^{Z |)} 2, -KR R ⁴ (R ⁴⁾ 2, ⁴ -lH lfeC (R ⁴⁾ 2, -RR ^{Z |} (C = 0), GH (N (R ^Zi) 2) R ^Zi, -RR ⁴ (C = O) ^R4, -íTR ⁴ C0 ₂ R ⁴ group; C 1-6 -alkoxycarboR ⁸ or R ⁸ R ¹¹ together or nylamino or Ph 2 phenyl; or and and R 4, or R 4 and R ¹⁰ , or R ⁰ and ^O , respectively, are represented by the general formula (e) wherein 'Öv' is an alkylene group of 4 to 3 carbon atoms, optionally interrupting a -3 (O) group. ) - a general sulfuric acid group wherein n is 0, 1 or 2; or C 4 -C 8 alkenylene or C 4 -C 3 alkynylene;

h is nitrogen or carbon; and 'J is a group of formula (d); in which ü

A is CR or N, B is O, 11R 'or S (O), 4' 2 where u and R are as defined above and R is hydrogen or halogen.

The compounds of the formula I can form solvates, in particular hydrates or partial hydrates; the invention also relates to all these solvates.

As used herein, alkyl means a group or alkyl portion of a group which may be straight or branched, such as methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, or 2-methylprop-2-yl. Most preferably, the alkyl group is methyl or ethyl.

The alkylene group is straight or branched carbon, or

C 5 -C 6 fatty alkylene groups such as butylene, pentylene, hexylene, cyclohexylene or a - (CH 8) - (3-6 -cycloalkyl) - (0¾) - group in which m is 0 -4; especially wherein C3-6cycloalkyl is cyclopropylene.

The term "group" includes phenyl, naphthalenyl (naphthyl), thienyl, pyridyl, furanyl and pyrrolyl, which may be optionally substituted with one or more halogen, hydrophilic, nitro, cyano, trifluoromethyl, lower alkyl, lower alkylthio, amino, mono- or dialkylamino or alkanoyl.

The alkenylene moiety is a straight, branched or cyclic alkenylene moiety having from 4 to 8 satatyls, such as butenylene, pentenylene, hexenylene.

The alkynylene group refers to a straight-chain branched alkynyl group of 4 to 8 carbon atoms, such as butynylene, pentynylene, hesinylene.

By "halogen" is meant fluorine, chlorine, bromine or iodine.

···· ···· · ·

A physiologically functional derivative is any physiologically acceptable ester of any compound of formula (I), salt of such ester, or (other) compound that provides, directly or indirectly, to the recipient such a compound or an active metabolite or residue thereof. .

The term Ac refers to the group - (C = O) CH 2 -.

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

The present invention further provides compounds of formula (I), and salts, solvates and derivatives thereof, wherein the nitrogen adjacent to Z of formula (I) is in oxidized form, i.e., in the form of E-oxide.

The present invention also encompasses physiologically acceptable salts of the compounds of formula (I). Suitable salts are in particular acid addition salts with organic or inorganic acids. Such acids should generally be physiologically acceptable, although salts formed with physiologically unacceptable acids may be useful in the preparation and purification of the compounds in question. Preferred salts include acidic components such as hydrochloric acid, hydrobromic acid, sulfuric, cioromic, tartaric, phosphorous, milk, pyruvic, trifluoroacetic, vinegar, succinic, oxalic, veneer, maleic,

-8.

oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and isethionic acids. Salts of the compounds of formula (I) may be prepared by reacting the corresponding free base compound with the appropriate acid.

Preferred embodiments of the invention are compounds of formula I wherein the letter symbols are as follows:

Y is a group of formula (a); ----- in each case is a double bond; R ¹ is hydrogen or chlorine, most preferably hydrogen; R is -CH 8 -CH 8 -, -CH 8 -CH 8 -CH 8 -, -S-, -11 = 1'1-, -TR 1 - or - (C = O) R H-; more preferably -JfcH-, -CHg-, -CHgCHg- or -CHgCHgCHg-; most preferably -CHg- or -CHgCHg-; R 4 is -CO 8 ST or hydrogen, most preferably hydrogen; and R is hydrogen or methyl, most preferably hydrogen.

Y is a group of formula (b); R is preferably hydrogen or chloro, fluoro, methyl, hydroxy, methoxy, nitro or di-Cl; more preferably, hydrogen, fluorine, methyl, nitro or methoxy; most preferably hydrogen or nitro; and R 4 is preferably -C = 1 -. group.

Y is a group of formula (c); R ^{6 is} hydrogen or methyl, most preferably hydrogen; R is hydrogen, HHg, 1H, e, hydroxy, methoxy

Or acetylamino; even better! NHg, methoxy, acetylamino or EHEJe; most preferably rUL or NEe; R is hydrogen or chlorine, MiCOg-t-Bu. a group of the formula; Br; or an HHg group; more preferably, hydrogen or bromine; most preferably KHg or JOIe;

Q

R is hydrogen, chlorine or bromine; MHgj NHCOg-t-Bu; more preferably, hydrogen or bromine; most preferably hydrogen; R 4 is hydrogen, methoxy, trifluoromethyl, tert-butyl, -N = N-Ph, nHAc, REDOg-t-Bu, KHg or bromine; more preferably, hydrogen or bromine, most preferably bromine; R ¹⁰ is hydrogen, bromine or chlorine or nitro, more preferably hydrogen or bromine, most preferably hydrogen; and R is hydrogen, methoxy or hydroxy, more preferably methoxy or hydroxy, most preferably hydroxy.

V is O or S, preferably O;

Z represents a C 4 -C 6 alkylene group, preferably a C 4 alkylene group; B is -S-, RH or -O-, more preferably -S- or -O-, most preferably -S-; A is CH or N, preferably N; and R is hydrogen or fluorine, preferably hydrogen.

Preferred compounds of formula I include:

2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl] -1-isoindolinone,

IT- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl} -5,4-dihydro-1 (2H) -isoquinolinone]

2-amino-1'T- {4-L4- (1,2-benzisothiazol-3-yl) -piperidino] butyl] saccharide,

6- {4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] butbutyl-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-5,7-dione .

I'T- [4- [4- (1,2-Benzisodiazol-3-yl) -1-piperazinyl] butyl-2- (methylamino) -benzamide,

B- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -benzamide,

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

N-pl- [4- (1,2-Benzisolazol-p-yl) -1-piperazinyl-3-butyl-3-bromo-2-hydroxy-6-methoxybenzamide,

2-amino-1H-4- [4- (1,2-benzisothiazol-y-yl) -1-piperazinyl] butyl] beazamide,

2-amino-1'- {4- [4-benzo (b) thiophen-3-yl) -1-piperazinyl] butyl] -benzamide,

2-Aniao-ZT- {4 - N - (6-fluoro-1,2-benzisoxazol-5-yl) -1-piperazinyl} -

salts and solvates thereof, in particular their hydrates and physiological

More particularly preferred compounds of formula (i) are:

xrp-4- [4- (1,2-Benzisoliazol-3-yl) -1-piperazinyl] -yl] -3-bromo-2-hydroxy-6-methoxybenzamide,

2-Anino-iT- [4- (4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] -butyl]

· »· <

• · · • · ·

benzamide

2-Amylo-ST - N - [4- (benzo (b) thiophen-p-yl) -1-piperazinyl] buty-

benzamide

2-Amino-1- [4- (4- (1,2-bis-isothiazol-5-yl) -piperidyl] -butyl] -benzamide, as well as the functional derivatives and il-osides of the above compounds from a physiologically acceptable position

The most preferred compound of formula (1) is a

2-IT-f ⁱ r L4- (l, 2-benzisothiazol-3-yl) ^-l-pipe, azinil3 butyl} benzamide hydrochloride .lamint these compounds solvates and physiologically functional derivatives thereof.

The compounds of formula (I) are useful as active compounds. They may also be useful in lipid inhibition of apomorphine-induced clinging [Ogren et al., Pur. J. Pharmacol. 12: 459 (1984); Iversen: Sciense 188,

1034 (1975); and Gudelsky and I.Ioreore, J. ITeural Iransm.

58, 95 (1976)]. The propensity of a compound to induce catalepsy and its ability to induce apomorphic stereo-like behaviors suggest that the compound is expected to induce erythrapyramidal side effects.

applied. This activity profile was supported by the general assay R) and a good correlation between the dose required to induce catalysis in this experiment.

Some of the compounds of formula (I) are also potent agonists of the 5-RR receptor. This effect is based on the existing opinion and the

·· «· ··· <»

15 According to another aspect of the invention; - provides a method for mammals to treat the following diseases:? prevention:

anxiety, muscle cramps, depression, aging! going away with aggressive behavior associated with fury; borderline personality disorders, vomiting, and psychosis. Ξ the method comprises cutting to a mammal a compound of formula (I) or a physiologically acceptable salt thereof;

The invention provides a method for treating or preventing a psychotic disorder in a mammal; this method comprises providing the mammal with a Formula (I). or a physiologically acceptable salt or solvate thereof, or a physiologically acceptable functional derivative or LJ-oxide thereof, in an antipsychotic treatment. In particular, the present invention provides a method where the psychotic disorder is schizophrenia.

In another aspect, the invention provides the therapeutic use of a compound of Formula I, or a physiologically acceptable salt or solvate thereof, or a physiologically acceptable functional derivative or IT-oxide thereof, in particular in the treatment of a psychopath such as schizophrenia;

..... ·. · ·· * ·

The use of compounds of the general formula 9 or their physiologically acceptable salts for the treatment or prevention of psychotic disorders such as schizophrenia.

The compounds of the invention may be administered alone, as a chemical, but are preferably administered in a pharmaceutical form. Thus, the present invention makes it possible to formulate a pharmaceutical composition by admixing a compound of formula (I) or a physiologically acceptable salt thereof, or a solvate thereof or a physiologically functional therapeutically acceptable component thereof. The excipients must be acceptable in the sense of being compatible with the other ingredients of the preparation (pharmaceutical composition) and not deleterious to the

Pharmaceutical formulations are suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, and intravenous), rectal and topical (ophthalmic) formulations, however, the most suitable route of administration may be prepared, e.g.

a step of admixing a compound of the invention or a pharmacologically acceptable salt or solvate thereof (active ingredient) with a carrier, which may include one or more accessory ingredients. Are formulations generally prepared by cutting the active ingredient with liquid carriers? mixed with finely divided solid carriers or both, and if desired, the resulting product is converted to the desired medicament.

The compositions for oral administration of the present invention may be presented as discrete units, such as capsules, lozenges or tablets, each containing a predetermined amount of the active ingredient; or they may be powders or granules; or solutions and suspensions in aqueous or oily aqueous liquid; or liquid oil / water emulsions or liquid water / oil emulsions. The active ingredient may also be formulated as a bolus, paste or lotion.

The tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in free-rolling form such as powder or granules, optionally mixed with a binder, anti-caking agent, inhalable diluent, lubricant, surfactant or dispersant. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable device. Optionally, the tablets may be coated or scored, and may be formulated so that the active component therein is released slowly or at a controlled rate.

Formulations for parenteral administration are aqueous or nonaqueous, sterile injectable solutions containing antiosidants, buffering agents, bacteriostatic agents and isotonic solutions which render the composition isotonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents. The preparations? they may be presented in unit dosage form or in multi-dose containers, such as sealed ampoules or vials; cut;? They may be stored lyophilized by reconstitution with a sterile liquid vehicle such as water for injections immediately before use. Solutions or suspensions for immediate use may be prepared from sterile powders, granules or tablets as described above.

Formulations for transdermal administration (transdermal) can be applied by passive diffusion or electrical

for example, Pharmaceutical Pesearch 313 (1986)], and its general form is an optionally buffered aqueous solution containing the compound of formula (I) or a salt or acid derivative thereof. These formulations preferably contain citrate or bis / tris buffer (pH6) or ethanol-water.

carriers such as cocoa butter or polyethylene glycol

Formulations suitable for topical administration in the mouth, such as the oral or sublingual route, include wafers containing the active ingredient in association with a flavoring agent such as cane sugar and acacia or tragacanth. Further, such are pastilles which contain the active ingredient in the form of gelatine or glycerol or cane sugar and acacia.

Dosage forms containing an effective dosage of the active component or an equivalent proportion thereof are preferred; we will return to this below.

It will be appreciated that the compositions of the invention, other than those specifically mentioned above, may contain other components commonly used in the art, depending upon the type of composition in question; Thus, for example, compositions for oral administration may contain flavoring agents.

The compounds of the present invention are preferably administered orally, parenterally or subcutaneously, for the treatment of psychotic disorders such as schizophrenia.

used. The exact amount of compound that can be administered to a patient is the responsibility of the attending physician, but the dosage used will depend on many factors, such as the age and sex of the patient, the disease to be treated, and its severity! depends on the degree. The route of administration may also depend on the condition and its severity.

The compounds of the present invention may generally be administered orally or by injection at a dose of 0.02 to 50.0 mg / kg / day.

In the case of adult humans, the dosage range will generally be from 1.4 to 5500 mg / day, preferably from 2.3 to 1750 mg / day, more preferably from 7 to 700 mg / day.

The present invention further provides a compound of formula I, physiologically acceptable salts, solvates, iT-oxides thereof and physiologically acceptable functional groups thereof.

The compounds of Formula I may generally be prepared by any of the known processes currently described for the preparation of analogous compounds. In the following description Υ, Ζ, X, W, V, A, B and R '-R ¹² are as defined for formula (I), unless otherwise indicated, a comment is not clearly specified otherwise.

In the first general process (A), compounds of formula (I) may be prepared by reacting a compound of formula (II)

ΥΞ with a compound of formula (III) in which bromine,

L is a leaving group, such as halogen;

- 19 chlorine or iodine, or alkyl or arylsulfonyloxy groups such as methanesulfonyloxy or p-toluenesulfonyloxy groups in the presence of a suitable solvent and base.

This process can be carried out at room temperature or at a higher temperature, for example 60-140 ° C. Suitable solvents include, for example, 1T, ZT-dimethyl 1-formamide (DME for short), acetonitrile, benzene, toluene and xylene. A suitable base may be an organic base such as triethylamine or pyridine; or an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; or an alkali metal hydride such as sodium or potassium hydride.

In a second general process (B), compounds of formula I wherein Z is 4 or 5 membered can be prepared by reacting a compound of formula II with a compound of formula IV wherein A is a suitable anion, such as a halogen ion such as bromine or chlorine or a sulfonic acid ester such as mesylate or tosylate; and R · is - (CH CH) vagy or - (CHg) - -, more particularly - (CHg) - -. The conditions of this reaction may be the same as those of the general procedure (A) above.

In addition, a complexing agent such as 1,4,7,10,15,16-hexa-oxa-cyclooctadecane may be added to the reaction edible.

In a third general process (C), the compounds of formula (I) are formed by forming a compound of formula (V).

Υ ----- Z ---- L, wherein L is as defined above, is a compound of formula VI. compound. The reaction is carried out under the conditions described for general procedure (A).

According to a fourth general CD process, compounds of formula I wherein Z represents a nitrogen atom may be formed by reacting a compound of formula VII with a

L ---- W is reacted with a compound of formula VIII wherein L is as defined above. This reaction may be carried out under the conditions described for general procedure (A).

A fifth compound of formula (I) according to general process (E) wherein Y is a radical of formula (a) wherein R is -CHg- or -H = 1P, wherein the dashed line is a dashed line (- ---) represents a double bond and can be prepared by cyclizing a compound of formula (IZ). The (IZ) where V is oxygen, and R ^ is ^one or -CHgOH HHG group t.

When R 1 is -CH ₂ OH, general procedure (E) may be carried out as described in Annal Deer Ohemie 584, 87, 1955 to give compounds of the formula CO wherein R is -CH2-.

Ί 4

If R · * · is a HHg group, the procedure may be performed according to one of the following statements:

• ·

- 21 J. Org. Chem. 26, 615 (1961);

Telel: 2, 15, 3 (1962); as well as

J. Am. Chem. Soc., 22, 6562 (1955) to give compounds of formula (I) wherein R is -E = üT-.

A sixth process according to General Process (E) is a compound of Formula I wherein R 1 is a group of formula (a) wherein R is -CH 8 -, -S-, or -B = iT; Flaunt? Y is (b) or (c) group of the formula can be prepared hogj ¹ (X) or (X ¹⁾ a compound of formula - wherein R represents -0¾ - or -R (R ^) (C = V ) and R ^ ^w is R ^ or -C = C- wherein R? R 1, -S ² or C ₁₂ -L ² ; L ¹ is, for example, chlorine, bromine, methoxy or hydroxy;

and L is, for example, a chlorine, bromine, methanesulfonyloxy or p-toluenesulfonyloxy group with a compound of general formula (XI).

For example, compounds of formula (I) wherein Y is (c) and R ¹⁷ is -1T (R) 2 can be prepared by reacting a compound of formula (g) wherein L ¹ hydroxy, V is oxygen, and R 1 is N (R 6) 2 is reacted with a compound of formula XI in the presence of silicon tetrachloride at the boiling point of a solvent such as anhydrous pyridine [11. d. Area: J. Heterocyclic Chem. 29,

103 (1992)]

Of formula (I). Compounds of formula (I) may also be prepared from other compounds of formula (I). Examples of such interconversion reactions are given below.

is a C 4 -C 8 alkylene group, may be prepared by reduction of a compound of formula I in which

Z is C 4 -C 8 alkenylene or C 4 -C 3 alkynylene. Ξ reduction by catalytic hydrogenation, i.e., in dosages such as ethanol, tetrahydrofuran (in short: THE), methanol, ether, ethyl acetate, benzene, toluene or hexane. The reaction is atmospheric; at higher pressures, at room temperature or at higher temperatures,

A temperature range of 20-100 ° C can be performed. Reduction of the acetic acid by alkylene bonding is effected in the presence of a poisoned catalyst, such as an all-catalyst.

Compounds of formula (I) wherein Ί represents 17 and 5, hid represents hydroxy may be prepared from methoxy derivatives in a known manner [e.g.

Lewis acid, such as boron tribromide, is treated with aluminum trichloride by treatment with a solvent such as dichloromethane at room temperature (J. E. W. Lycomie et al., Org. Synth. Coll. Vol. V. 412 (1973);

23 S. D. Dillard et al., J. Med. Chem. 34, 2768-2778 (1981).

A compound of formula (I) in which T (a), (b); (c) and R ', R, R ⁸ , ⁹ , ¹⁰ or R ¹¹ are 1T (R ⁴ ) 2 or 1Λ (Β ⁴ ) 2, may be prepared by the appropriate ( alkoxycarbonylamino derivatives are hydrolyzed in a known manner, for example by reacting a (tert-butoxycarbonyl) amino derivative with an acid such as trifluoroacetic acid in the presence of a tert-butyl cation-trapping compound such as anisole or thiophenol. , treated with a solvent such as chloroform at room temperature [BF Lundt, Int. J. Prept. Protein. Gap. 12, 258 (1978)].

Compounds of formula (I) wherein Y is a group of formula (a), (b) or (c) and a ^- , R, PU, a - ', a'' ⁸ or R ¹¹ are 1T (R ^) ₂ group of formula I also can be prepared from the corresponding nitro derivatives in a known manner, for example by reduction of hydrogen and a catalyst such as platinum, palladium or nickel in aaney catalytic hydrogenation inspection [Org. Synth. 49, 116 (1969); and J. Med. Chem. 16, 1043 (1975); and J. Org. Chem., 8, 60 (1973)].

Compounds of formula (I) wherein anol Ί represents a group of formula (a), (b) or (c) and R ', a7, R, ⁹ , P. ¹⁰ or ¹¹ represent 11 R ⁴ (C = O). ) r \ BR ⁴ C02a ⁴ or aa ^ (C = 0) CII [IT (a ^) 2] ^Zi group of the formula can be prepared from the corresponding amino derivatives in a known manner with acetylation (e.g. saykloriddal such as acetyl chloride or ethyl · · · «· • ·

Treated with 24-chloroformate in the presence of an organic base such as triethylamine in a solvent such as dichloromethane).

Compounds of formula (I) wherein Y is (c) and Κθ is (C 1 -C 6) alkyl. alkylation of the corresponding secondary amides in known manner can be accomplished by treatment of the amide in a suitable solvent such as treatment with sodium hydride followed by reaction with thiodide.

(e.g., by reacting a compound of formula (I) in Di.iE with a base, such as an alkylating agent, such as MeOlyan, where Y (c) is a compound of general formula (V) wherein V is a sulfur atom. )

- in which Y is a group of formula (c), wherein

V represents an oxygen atom - with a sulfonating reagent such as Lawesson's reagent (chemically 2,4-bis (4-methosophenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide) in a solvent such as toluene at higher temperatures [Synthesis

941 (1979); Tetrahedron 35: 2435 (1979); Tetrahedron Lett.

21, 404].

Compounds of Formula (I) wherein Y is · η rr q (a), (b); (c) and R ² , PU, R, R 1, R ¹⁰ or R ¹ 4 are hH ¹ T = C (R 1) ₂ may be prepared in a known manner from the corresponding hydrazine derivatives and the corresponding ketones.

Compounds of formula (I) wherein the nitrogen atom is in the 1'-T-oxidized form can be prepared by oxidation of compounds of general formula (I) with a suitable oxidizing reagent such as m-. chloroperoxybenzoic acid in a suitable solvent such as dichloromethane.

Compounds of formula (II) wherein Ϊ is a group of formula (a) wherein R is -CHg- and the dashed line (-----) represents a double bond, that is, a compound of formula (IIA) phthalinidines - can be prepared by reducing a compound of formula (HB). A suitable reducing agent for this purpose is, for example, tin / hydrochloric acid in acetic acid at elevated temperatures, for example in the range of 100 ° C to 100 ° C. A further suitable reducing agent is in the presence of zinc acetic acid [J. Chem. Soc. 2058 (1977) 2 and in the presence of hydrogen in CuCl 2 O 2 in dioxane FHelv. Chim. Acta 1650 3 (1977).

Compounds of formula (11) wherein ϊ is a group of formula (a) wherein R is -CHgCHg and the dashed line (------) accompanying the dotted line represents a double bond, i. The isoquinoline derivatives of formula (III) may be prepared by reacting a methyl aryl ethylamine in formula (III) with ethyl chloroformate, for example, in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane, e.g. Thus, an ethyl carbamate derivative of the formula (III) is obtained which can be further cyclized, for example, by treatment with, for example, polyphosphoric acid at a higher temperature such as 140-160 ° C.

• ·

Compounds of Formula II wherein I is ο (a), wherein R is -CHgCli ^ CE ^ and the dashed line represents a - (-----) double bond, i.e., benzazepinone derivatives of formula IID may be prepared by the method of Gilman [Synth. Commun. 12: 373-380 (1982). This process is carried out according to Scheme 1).

In Scheme 1, a dihydrobenzopyran derivative is reacted with pyridinium (chlorochromate) in a suitable solvent such as dichloromethane to give the corresponding dihydrobenzopyranone derivative. The latter is first treated with sodium cyanide at a higher temperature (e.g. 2 ° C), then with water such as 75 ° C and finally at 0 ° C with hydrochloric acid to give (cyanoethyl) benzoic acid. The latter is treated first with thionyl chloride and then with methanol, both at elevated temperatures, to give (cyanoethyl) benzoic acid methyl ester. The latter compound can be reacted with borane in tetrahydrofuran at 0 ° C (netamino)

-propyl benzoate which is obtained at room temperature for the benzazepinone derivative of mebanol

Compounds of formula (n) wherein Y is a group of formula (a) wherein R is -S- and the dashed line (-----) represents a double bond, that is, a compound of formula (IH) benzizobiazolon

derivatives by the method of Yevich et al. [J.LIed.Chem.29, ····· »· ♦ · · · · ⁴ ·« · ····· * · · · · · ·

27: 359-3θ9 (1986) 3. This procedure is illustrated in Scheme 2. Generally, 2,2'-dithioalicylic acid is treated at the boiling point of toluene with thionyl chloride and DLF,

Acid chloride

2,2'-Dithiobis (benzoyl chloride) is obtained.

cleavage of the disulfide bond with chlorine gas in dichloromethane and reacting the dichloride obtained with ammonium hydroxide to form benzisothiazolone of formula (I-13)

derivatives.

Compounds of formula (11) wherein Y is a group of formula (a) wherein R is -PR ^ - wherein R ^ is alkoxycarbonyl

and the indented indazole derivatives of the dashed line can be prepared by reacting the corresponding compound of formula IIG wherein R 1 is hydrogen with the corresponding general R 1 Cl

-formate.

Compounds of formula IIG wherein R ^{17 is} hydrogen are for example prepared by reacting an azide of formula GCVI wherein R is alkyl, such as methyl or ethyl, with hydrazine hydrate at higher temperatures [J. Chem. Soc. Perkin Trans. I. 1260 (1974) 3.

A compound of formula (II) wherein Y is a group of formula (a) wherein R is - (00) 121- and the dashed line (-----) accompanying the dashed line represents a double bond. that is, the phthalazinedione derivatives of the formula IIJ can be prepared by either cutting a compound of the formula SxY;

wherein S ^{18 is} alkyl, such as methyl, ethyl, may be reacted with hydrazine hydrate [d. Org. Chem., 2, 1921 (1967) 1.

Compounds of formula (II) wherein Y is a group of formula (a) wherein a is -ZT = IT- and the dashed line (------) accompanying the dotted line represents a double bond, i.e. Benzotriazinone derivatives of formula (IIK) may be synthesized as described in the following publications, which are incorporated herein by reference:

i) ΞΙ-Shafei and A.G. Ghaitas: J. Indian Chem. Soc.

61, 65-67 (1984).

(ii) A. Lar et al. Pharmazie 35. 466-468 (1980).

R is available commercially.

It has the general formula (H). compounds wherein Y is a group of formula (b), that is, a compound of formula (III) may be prepared by the preparation of a corresponding compound of formula (ZZ'I). cyclic anhydride may be reacted with acidic amide and acetic acid; may be reacted with ammonium hydroxide [see Chem. 16, 574 (1962); and Org. Synth. Coll Vol 1,

457 (1941)].

··· * · «·

Compounds of formula (II) wherein Y is a group of formula (c), that is, compounds of formula (III) are known or can be prepared by standard methods known in the art.

Compounds of formula (III) may be prepared by reacting a compound of formula (VI) with a compound of formula (mii)

L ----- Z ------ L where L is a leaving group such as halogen such as bromine, chlorine or iodine, alkyl or arylsulfonyloxy such as methanesulfonyl-os cut;? p-toluenesulfonyloxy - alkylated.

In some cases, for example, when both L groups are halogen and Z is R 4, especially - (CH ₂ ) -, the same reaction may lead to a compound of formula IV [J. Chem. 29, 359-369 (19θ6)]. 1 ·

The compounds of formula (V) may be prepared by alkylating a corresponding compound of formula (II) with a compound of formula (mii). Alternatively, compounds of formula (V) may also be formed by reacting a hydroxyl group of a compound of formula (mill)

Y ---- Z ---- OH is converted to the leaving group L as defined above in known manner. The compound of formula (mill) is prepared as follows:

»·« »! * · * «• * · · · ··· · X · V · •» · · «

- 50 can be equipped to (X) or (X ¹⁾ is obtained. compound of the formula CSTV)

The H ₂ N ---- Z ---- OH is condensed with amino alcohol or a compound of formula II is treated with a compound of formula LZ-OH.

This process is carried out at room temperature or at a higher temperature, such as 60-140 ° C. Suitable solvents include DI.IF, acetonitrile, benzene, toluene and xylene; a suitable base is an organic base such as triethylamine or pyridine; obsession; alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; or alkali metal hydrides such as sodium potassium hydride.

The compounds of formula (VI) are known or can be prepared by known methods, for example, in the following literature:

when X is N and 77 is a group of Formula (d), wherein A is N and B is sulfur: Levich et al., J. Led. Chem. 29, 559-369 (1986); and U.S. Patent 4,590,196;

when X represents carbon and 77 (d), wherein A represents niurogen, B represents sulfur: United States Patent 4,528,292;

when X represents a n-hydrogen atom and a group of formula 77 (d), wherein A represents a n-hydrogen atom and B represents an oxygen atom:

I. Led. Chem. 2: 559-369 (1986);

* · * ♦ <··· «« · V · • · · · 9 · «• · · · · · · · · · · · · · · · · · · · · · · · · · · C and W (d), wherein A is -N, B is -Illed. Chem. 28, 761-69 (1985);

when C is n and N is W (d). is a group wherein A is nitrogen and B is SOg: J. LIed. Chem., 3,4, 3316-3328 (1991).

Alternatively, this intermediate can be obtained by reacting 3-chlorobenzisothiazole-1,1-oxide (see European Patent Application 0 196 096) in a solvent such as toluene at elevated temperatures of 150-160 ° C. C is treated with piperazine.

When X is a N and X (d), wherein A is a B, S (O): J. Med. Chem. 1991, 4, 5316-3528;

when X is C, W (d), where A is C, B is US 4 335 127 (June 15, 1982) and 4 710 500 (December 1, 1987);

if X is N and W (d), where A is C, B is S, then the preparation can be carried out according to Scheme 3. An appropriately substituted aminobenzo [b] thiophene derivative is heated with piperazine in a solvent such as 1-methyl-2-pyrrolidinone. The aminobenzo [d] thiophene derivatives required for this can be prepared by treating a suitably substituted 2-fluorobenzonitrile with a methylthioglycolate anion, followed by

32 the carbomethoxy group of the resulting benzoCb] thiophene is removed.

When X is C, W (d) is A, S is B: French Patent No. 2,253,519 (1975);

when X is N, W (d), wherein A is N, B is United States Patent 4,957,916, issued September 18, 1990;

when X is carbon atom, w (d), wherein A is carbon atom, B is SOg: Japanese Patent Application 03264583 A2, November 25, 1991;

when X is C, W (d), where A is N, B is 1TR ²¹ , these compounds can be prepared by the use of an appropriately substituted 4- (2-fluoro-aroyl) -piperidine [J. . Chem. 28. Reaction of 7θ1 (19θ5) 3 hydrazine with a boiling point of a solvent such as n-butanol and deprotection of the resulting IT protecting group piperazinyl indazole. This process is illustrated in Scheme 4.

When X is C, V (d), where A is C, B is SOg: Japanese Patent Application 03264583 A2, November 25, 1991;

• ··· ·· <· ·· · «• · · ·«. * ··· ·····························································································································································································ised (d) represents a group of the general formula wherein A is carbon, B is HR:

German Patent Publication No. 500,898 (July 17, 1986).

Compounds of formula (VII) may be prepared by alkylation of a compound of formula (V) with piperazine.

The compound of formula (VIII) can be prepared by known methods, for example as follows:

when L represents a chlorine atom, a group of the formula 7 (d), wherein A represents a nitrogen atom, B a sulfur atom: United States Patent 4,590,196;

when L represents a chlorine atom, a group of formula 7 (d) wherein A represents a nitrogen atom and B represents an oxygen atom: J. Led. Chem. 2Q, 359 (1986);

when L represents a chlorine atom, a group of formula 7 (d), wherein A represents a nitrogen atom. B represents the SO2 group: 0 196 096 /

Published European Patent Application Publication No. 4,123,123.

Compounds of formula (II) wherein PV 2 is CH 2 OH and V is O may be prepared according to the method described in Annalene dere Chemie 584, 1955 (Tetrahedron Lett. 25, 2095 (1984); and Tetrahedron

Became. 27, 2275 (1986) 2. A compound of formula (H). wherein 3 is V and the oxygen atom can be formed by reacting a compound of formula II.

at room temperature.

- 34 J. Org. Chem., 41, 2070 (1976)]. It is treated with azido-trirethylsilane in chloroform XE. Thioisatinic anhydrides of the general formula (XE) wherein V is sulfur atoms can be formed by reacting in a suitable substituent at the boiling point of the solvent

Compounds of the formula (III) wherein, for example, I-2

It represents the methoxy group, bromine atom h - az. 4,289,781

According to the 3sy Patent Allamok patent:

· · ·

Öv ·· * · • · <

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · means cleavage reaction

- 55 ···· ···· · ························································ (r (pac () (x)) (a) to be carried out in a methanolic solution with hyrazine hydrate:

Compounds of formula (XI) wherein C 1 -C 6 alkyl are available from compounds of formula (Xla) wherein P represents a protecting group such as trifluoroacetate, such that the protecting group is known in the art such as aqueous potassium. with carbonate solution

The reason

H is a compound of formula (Xla) in which

Kapυ obtains there protecting group amine with C 1-6 alkyl halide, for example

Λ J compounds:

N- {4-] 4- (1,2-benzisothiazol-5-yl) -piperidino] -butyl-4-phthalimide, (-) - cis-2- {4- [4- (1H-benzisothiazol-4-yl) -N-] -yl-1-piperazinyl] -butyl-4 -?, 5,6,7,3,3a-hexahydro-1 (2H) -? - thalazinone, (t) -trans-2-4-4- (1,2) benzisothiazol-5-yl) -1-piperazinyl] -butyl-4a, 5,6,7,3,8a-hesahydro-1 (2H) -phthalazinone, as well as 1,1'-zi [4- (6-fluoro) , 2-benzisoxazol-3-yl) -pipe-3-idino-butyl-4-phthalimide, as well as the above-mentioned compounds in physiological eyes.

- salts, solvates and ZT-oxides thereof, and their ziologically functional derivatives, from 36 points.

Beware of using their derivatives or their salts, solvates, IT-oxides or any

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 (211) -phthalazinone,

2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,3 (2H _z 4H) -isoquinolindione, [4- (1,2-Benzisothiazol-3) -il) -pip® £ idihi] -butylj-f thalimide, • · ·

- 37 (R) -cis-2- [4- (4- (1,2-Benzisothiazol-3-yl) -1-piperazilyl] butyl] -4-a, 5,6,7,8, Sa- Hesahydrol (2H) -phthalazone, η 1 -trans-2- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -4a, 5 6,7,8,8a-hesahydro-1 (2H) -phalazinone and

N-p1- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino] butyl] phthalimide.

Results of biological tests

A. Examination of the antipsychotic effect

The inhibition of mouse triggering by apomorphine (5 mg / kg subcutaneously) also reflects the expected anti-psychotic effect of dopamine in the mesolimbic brain area.

compounds were administered orally 1 hour before emergence. In Example 35, 2-amino-η 4 - [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl-butyl] -benzamide, mice exhibited apomorphine-induced adhesion at 11.0 mg / kg oral ED. Antagonized with a _Q value; the oral value of the 2- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl] -1-isoindol-olinone of Example 3 · 6.3 mg / kg, 6- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl-6,7-dihydro-5H-pyrrolo [33-b] pyridine ^from Example 18 The oral value of -5,6-dione was 14.4 ng / kg.

Ξ studies were performed by the method of B. Costall et al. (Apomori'in-Induced Gripping Behavior in Mice: A Potential Model for Detecting Neuroleptic Effect, 1978, Europeen Journal of Pharmacology 50, 39-pO).

• · · • · · · · · · · · · · · · · · · · · · · · ·

B. Examination of the antiemetic effect

The antiemetic activity of F-2-amino-N-p1- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butybutyl-benzamide was evaluated by its ability to suppress cisplatin-induced emesis in the warts [A . P. Elorczyk et al; "Cisplatin-Induced Vomiting in Weasels as a New Model of Animal Testing", Cancer Treatment Reports, 66. 1, 187-189 (1982) 1.

Then the onset of vomiting and vomiting! the number of episodes was monitored for 3 hours. The vehicle treated animals during this period

They vomited 3-5 times; whereas vomiting was not observed in animals treated with 3 g / kg of the compound of Example 3θ.

C. Anxiolytic (anxiolytic) effect

The anxiolytic effect of Example 36 2-amino-1- [4- [4- (1,2, benzisothiazol-3-yl) -1-piperazinyl] butbutyl] amide was investigated in a pigeon conflict model; we observed that 0.17 mg / kg of the punished response after increased ris administration resulted in an i □ tramadol, suggesting an expected anxiolytic effect.

In our study, J.E.

It was conducted

With anxiolytic agents according to the method of Witskin et al

III. The antipathetic effects of buspirone observed in the pigeon are not mediated by the benzodiazepine receptor mechanism '. J. Pharmacol. Experiment. Ther. 238: 1009-1013 (1987)].

D.

Antidepressant-anxiolytic effect ···· ······································ ·

- 39 As in Example 36

Inhibitory effect of 2-amino-IT- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -benzamide on 5-HT1-4 agonist on excitatory state of myelinergic neurons. It was observed that the ID50 value after intravenous administration was 23 µg / kg.

This study was conducted by D. S. Robinson et al., 1989, "Serotonergic Anxiety Disorders and Treatment of Depression," Psychopathology 22 (suppl. 1) 27-36 (1989).

Ξ. Central muscle relaxant effect

2-Amino-1T- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} benzamide exemplified by 3θ · showed an anagonist activity in the morphine-induced Straub tail test;

after oral administration, ΕΕ ^ θ was 2.8 mg / kg.

This study was conducted by the method of G. D. ZTovack [Study of the Effectiveness and Depressiveness of Muscle Relaxants in Mice]: Drug Dev. Gap. 2: 383-336 (1986)].

Example for the preparation of pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions containing an active compound of formula (I) or a physiologically acceptable salt or solvate thereof, such as that described in Example 35 below.

···· «··· · · · · · · · · · · · · · · · · · · · · ···

- 40 A. Preparation of Tablets

The components are mg / ha of phthalate

Lactose

200

The granules of granules are granulated with lactose and starch and an aqueous solution of polyvinylpyrrolidone.

The granules thus obtained are dried, mixed with magnesium stearate and compressed into tablets.

Preparation of injection

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

II. intravenous injection

0.20 g

Sterile, pyrogen-free phosphate buffer (pH 9.0) required per ml

The salt form of the active ingredient is dissolved in the majority of the phosphate buffer at 35-40 ° C, then filled to the volume indicated, filtered through a sterile microporous filter into 10 ml sterile glass ampoules (type 1) and the ampoules sterile. · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

- 41 C. Preparation of Capsule

I. Tomb of the Zula

Capsule Form I can be prepared by mixing the components and filling the resulting mixture into two-piece hard gelatin capsules.

components mg / capsule (a) Active substance 250 (b) Lactose (according to British Pharmacopoeia) quality) 143 (c) ITiumium (starch glycolate) 25 (d) Lagnesium Stearate 2 420 II. capsule mg / kauszula (a) Active substance 250 (b) Macrogel 4000 (British Pharmacopoeia quality) ? 50 600

The encapsulated composition can be prepared by melting the LIacrogel 4000 material, dispersing the active ingredient in the melt, and filling the resulting mixture into two-piece hard gelatin capsules.

III. capsule (controlled release capsule

components mg / kaoszula (a) Active substance 250 (b) Microcrystalline cellulose 125 (c) Lactose 125 (d) Ethyl cellulose . .11 513

· · ♦ l l l l l l l l l l l l l l l l «« «« «« «

The sustained release capsule formulation may be prepared by extruding a mixture of components (a) to (c), then spheronizing (forming spherical granules) and drying. The dried pellets are coated with ethylcellulose (d), a controlled release membrane, and the resulting product is filled into double hard gelatin capsules.

Syrup production components .σ ' agent .2500 Szorbittoldat 1,5000 Glycerol 1.0000 Hátrium benzoate 0.0050 flavoring 0.0125 ml Purified water as needed 5.0 nl

Sodium benzoate is dissolved in a portion of the purified water and the sorbic acid addition is added and the a. and dissolve. The resulting solution is mixed with glycerol and made up to volume with purified water.

E. Preparation of Suppository mg / cup

Active ingredient (65 / Um) * 250

Hard Fat (Quality 3 Gy.) (Witepsol H15, product of Dynamit Köbei) 1770

2020 φ The active ingredient is formulated as a powder with at least 90% of the particles having a diameter of 63 µm or less.

«· *» · · · * * * * * * * * * * * * * *

- 43 One fifth of Witepsol 315 is melted in a steam jacket at a temperature of not more than 45 ° C. The active ingredient is passed through a 200 µm mesh sieve and mixed with the molten feedstock while stirring, using a Silverson blender fitted with a cutting head, until a uniform dispersion is obtained.

While maintaining the temperature of the mixture at 45 ° C, the remaining Uitepsol 315 is added to the suspension, which is then stirred until homogeneous. The whole suspension was then passed through a 250 µm stainless steel screen and allowed to cool to 40 ° C with constant stirring. At 38-40 ° C, 2.02 g aliquots of the mixture are filled into suitable plastic molds and the suppository is allowed to cool to room temperature.

F. Preparation of a transdermal formulation

Formulations for transdermal administration may be presented as discrete patches that will be capable of maintaining intimate contact with the patient's skin over extended periods of time. Such patches are preferably the active ingredient

1) optionally buffered, dissolved in an aqueous solution, or 2) cut in adhesive, and 3) dispersed in a polymer.

A preferred concentration of the active ingredient is about 1-20%, preferably about 5-15%. As a special possibility, the active ingredient is delivered from the patch by iontophoresis (see General Pharmaceutical Research Ji, 518 (1986)).

· «·· ff 9 ·«

Chemical examples

General remarks to the examples

Unless otherwise noted, all ingredients'

- It was obtained from 44 commercial suppliers and used without further purification. Anhydrous solvents such as dimethylformamide (DI.IF), tetrahydrofuran (THE), methylene chloride (DELI), toluene, pyridine and dimethylsulfoside (DI.1SO) are available from Aldrich.

It was purchased from Chemical Company in securely sealed containers.

Rrietylamine was distilled from calcium hydride before use. all the reactions you air-cut? neaves □ in an androgen atmosphere, hair flash chromatography [W. C. Still et al., J. Org. Chem. 43, 2923 (1978) 2 and flush-chromatographed using 31.1 Science silica gel 60 (particle size, 230-400 mesh ASTi.1). Thin layer chromatography (VEK) was performed on Analtech silica gel RG TLC plates (layer thickness 250 µm). The ¹H-EI.I.R and CC-HLIR spectra were determined on superconducting ET KIIR spectrometers (200, 300 and 500 LHz). Chemical shifts are expressed in ppm downstream of the trimethylsilane internal standard. Significant Τΐ-'ϊίΠ data are given in the following order: multiplicity (s = singlet; d = doublet; t the triplet;

q = quartet; m = mullet), number of protons and coupling constants in Hz. Elemental analyzes were performed by Atlantic I'icrolab. Inc. (iTorcross Georgia) or Galbraith Laboratories, Inc. (Knoxville Tennessee).

· «« · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 45 Melting points were determined using a Tüionas Hoover capillary melting point apparatus and are uncorrected. The piperidine and piperazine benzisothiazole intermediates were prepared by known methods, which were:

3- (4-piperidinyl) -1,2-benzisothiazole (U.S. Patent 4,528,292, July 9, 1985); 3- (1-piperazinyl) -1,2-benzisothiazole and 8- (1,2-benzisothiazol-3-yl) -5,8-diazaspiro [4,5] <3-decane bromide [Yevich et al., J Med.

Chem. 29, 359-569 (1986). The piperidine and piperazine benzisoxazole intermediates were prepared by known methods or can be prepared as follows: 6-fluoro-3- (piperidinyl) -1,2- ^{ze2Siso ;} '° l ^of [3trupelevzski JT et al., J. Med. Chem 28 (1985) 761-769]; and 1- (1,2-benzisoxazol-3-yl) piperazine (JP Yevich et al., 1986, J. Med. Chem. 29, 359-369).

In the general abbreviations above,

in sync data - the following notations are also used br wide quintet = quintet dd double doublet ddd = the doublet of the double doublet dt double triplet tt triple triplet tm = triple threesome dm = double multiplet dq double quartet

···· ···················································································································ing · · · · · · · · · · · · · · ·

Example 1 (a) Preparation of 2- (2-Hydroxyethyl) -1-isolaldoline

This compound was prepared by K. Lurata, Bull. Chem. Soc. Jpn. 46, 1752 (1975)].

Ethanolamine (50.09 g, 0.820 ml) (Aldrich Chemical Oompany) was charged into a 300 ml round bottom flask equipped with a Dean-Stark plug fitted with a reflux condenser, a magnetic stirrer and a nitrogen inlet. Phthalide (110.0 g, 1.0 eq, 0.820 mol) was added as a light beige powder with stirring.

The resulting slurry was heated at 150 ° C in an oil bath under N 2 for 4 hours, then the oil bath temperature was raised to 205-210 ° C and the molten was heated for 17 hours.

The Dean-Stark attachment collects 12 ml of water. Upon cooling, the reaction product solidifies into a light brown solid. 3 crude products were taken up in hot toluene and filtered hot.

On cooling, the solid product was filtered off, washed with cold toluene and dried in a vacuum oven to give 129.75 g (88%) of the desired product as a pale beige powder, m.p. 117-119 ° C.

Si NMR (CDCl3,?): 3.28 (br s, 1), 3.69 (n, 2), 3.85 (n, 2), 4.46 (s, 2), 7.40 ( m, 3), 7.73 (η, 1).

¹³ C NMR (00012, ((): 45.84, 51.63, 61.30, 122.60, 123.44, 127.91,

131.34, 132.44, 141.53, 169.55.

Analysis of the formula:

Calculated: C, 67.78; H, 6.26; ΙΪ 7.90) 6;

Found: C, 67.76; H, 6.27; 7.89%.

- 47 Co) Preparation of 2- (2-chloroethyl) -1-isoindolinone in a 1 liter round bottom flask 117.95 g (0.666 mol)

2- (2-Hydroxyethyl) -1-isoindolinone and 400 ml of toluene are added and 55.0 ml (89.7 g, 0.754 mol, 1.13 eq.) Of thionyl chloride are added dropwise over 50 minutes under ice-cooling. . The suspension was allowed to stand at room temperature for 4 hours, stirring occasionally.

The reaction mixture was cooled and the reaction mixture was heated at 60 ° C for 3 hours. The toluene and the excess thionyl chloride were removed under vacuum with a water pump and the hot residue was poured into 500 ml of light petroleum. A brown solid precipitates which is filtered and taken up in hot toluene. The solution is filtered hot and the hot toluene solution is poured into 300 ml of light petroleum with stirring. The precipitated solid precipitate was filtered off, washed with petroleum ether and dried in a vacuum oven to give 103.08 g of beige powder. Together with another 15.99 g of the second generation, the overall yield was 119.07 g (91%) of the title compound, m.p. 80-81 ° C.

NMR (CDCl _3? ) _: 3.80 (t, 2, J - 5.4), 3.96 (t, 2, J - 5.4), 4.57 (s,

2), 7.50 (n, 3), 7.86 (η, 1). 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 ^ qH ^ qITOCI:

Calculated: C, 61.39; H, 5.15; H, 7.16%;

Found: C, 61.29; Ξ 5.18; IT 7.15%.

(c) Preparation of 2- {2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] ethyl} -2,3-dihydro-5-isoindol-1-one hydrochloride

In a 100 mL round bottom flask, 6.03 g (30.82 mmol) of 2- (2-chloroethyl) -1-isoindolinone, 6.75 g (30.82 mmol, 1.0 equiv.) Of 3- (1- piperazinyl) -1,2-benzisothiazole, 5.15 mL (3.74 g, 36.99 mmol)

A mixture (1.2 eq.) Of triethylamine and 30.0 ml of acetonitrile (orange mixture) was heated under reflux for 24 hours, allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate. The dark orange solution was washed with a saturated potassium carbonate solution and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated to give 13.44 g of an orange oil. This crude product was purified by flash chromatography (5: 1 ethyl acetate: hexane) to give 7.15 g of 2-} 2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl]. ethyl ethyl -2,3-dihydro-1H-isoindol-1-one is obtained. This free amine was taken up in acetone and 24.5 mL (1.0 eq) of a 1N solution of hydrogen chloride in ether was added. The resulting salt was recrystallized twice from 95% ethanol to give 3.05 g (24%) of the title hydrochloride as an off-white powder. The spectacle! and analytical data indicate that the salt contained 1 equivalent of HCl and 0.5 equivalent of ethanol in γ-glaze, m.p. 264-267 (dec.).

- 49 Si NMR (DMSO-d6, δ) _: 1.03 (t, 3, J = 6.9), 3.48 (a, 7), 3.70 (br d, 2, J - 11.0), 4, O 2 (a, 4), 4.60 (s, 2), 7.55 (a, 6), 8.10 (t, 2, J - 9.2), 11.28 (br s, 1). ¹³ c

NMR (DMSO-d6, t6) 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 of the ^G ^ 02 ^ 22¾ ^03,1101,0 2 ^H 6 ° calcd: C, 60.35; Η 5.9θ; 3, 12.79%;

Found: C, 60.24; Ξ 6.08; M 12.55% ·

Example 2 (a) Preparation of 2- (3-Hydroxypropyl) -1-isoindolinone

Compound ítjuk was prepared by the method described in Example 1, step (a). Using 3-amino-1-propanol as the amino alcohol, 156.83 g (86%) of the title compound are obtained.

Si NMR (CDCl3,?): 1.91 (quincet, 2, J = 6.2), 3.55 (br s, 2), 3.74 (t, 2, J = 6.2), 3, 82 (br s, 1), 4.38 (s, 2), 7.47 (a, 3), 7.80 (a, 1). ¹³ C NMR

123.64, 128.12,

H, 7.52%;

Π 7.28%.

\ wuuxj5 ö J * Jv _z öj, <jo _r ol, ou.jy,

131.45, 132.30, 141.18, 169.67.

calcd

Analysis calculated for O-q H-?

069.09; Ξ 6.85;

found

C, 68.99; 3, 6.86;

(b) Preparation of 2- (3-Chloropropyl) -1-isoindolinone

This compound was prepared according to the procedure described in Example 1 (b). Starting from 127.55 g of 2- (3-hydroxypropyl) -1-isoindolinone, 130.94 g (94%) of the crude chlorine are obtained. This one

Purify 50 samples (5 g) of crude chroma by chromatography, eluting with 4: 1 hexane: ethyl acetate, to give 4.29 g of analytically pure white solid, m.p. 56-57.5 ° C.

NMR (CDCl ₃ ,?): 2.15 (quintet, 2, J = 6.7), 3.58 (t, 2, J = 6.5).

3.74 (ε, 2, J = 6.9), 4.41 (s, 2), 7.46 (a, 3), 7.81 (a, 1). ¹³ C

NMR (CDCl 3,?): 31.29, 40.17, 42.22, 50.57, 122.71, 123.63,

128.68, 131.36, 132.68, 141.11, 168.75.

(c) Preparation of 2-) 3- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] propyl} -1-isoindolinone hydrochloride

Compound ítjuk was prepared according to the procedure described in Example 1 (c) using 2- (3-chloropropyl) -1-isoindolinone as starting material. Recrystallization of the hydrochloride from ethanol gave 1.58 g of a yellow powdery cin compound, m.p. 225-226 ° C.

NMR (DMSO-d6, δ: 2.16 (a, 2), 3.30 (a, 8),

3.60 (a, 4), 4.05 (br d, 2, J - 12.5), 4.53 (s, 2), 7.55 (a, 6), 8.09 (dd, 2) , J = 8.0, 3.9), 10.70 (br s, 1.5). ¹³ C NMR (CDCl ₃ , δ): 23.06, 39.37, 46.58, 50.08, 51.00, 55.09, 120.77, 123.15,

123.22, 123.54, 124.53, 127.26, 128.03, 128.10, 131.76, 131.92,

141.40, 152.95, 161.47, 169.37.

Analysis for C ₂₂ H 2 _{Z 3} N _· 0S. For 1.5 HCl:

Calculated: C, 59.09; Ξ 5.75; N, 12.53%;

Found: C, 59.06; E, 6.10; il 12.52%.

Example 5 (a) Preparation of 2- (4-Bromobutyl) -1-isoindolinone

A mixture of 15.6 g (0.05.6 ml) of N- (4-bromobutyl) phthalimide, 100 ml of glacial acetic acid, 15.83 g (0.133 mol, 2.4 eq.) Of metal and 20.0 ml of hydrobromic acid is added. (pale yellow) Place in a 250 ml round-bottomed flask under nitrogen and reflux for one hour. The solution was then filtered and the tin washed with acetic acid. Most of the acetic acid was removed on a rotary evaporator and the resulting creamy residue was washed with water in DKLI. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. This gave 9.37 g of a pale orange oil which was purified by flash chromatography.

Elution with 3: 1 hexane: ethyl acetate gave 0.89 g (6%) of the title compound as a colorless oil.

(CDCl3, 86 (m, 4), 3.47 (t, 2,

6.7), 4.39 (s, 2), 7.46 (ε, 2, J 1, J -6.8, 0.38). ¹³ C NMR (CDCl 3, J): 26.84.

41.25, 49.80, 122.70, 123.71, 128.08, 131.30,

J = 6.2), 3.66 (t, 2,

6.4), 7.53 (m, 1), 7.84 29.64, 132.75,

NMR

J (dd,

33.44, 141.03.

l, 5.26;

N, 5.22%;

found:

C, 53.31;

5.29;

N, 5.21%.

In the above process, hydrochloric acid can be used instead of hydrobromic acid, which gives a higher yield, but the resulting product is a mixture of chlorine and bromine.

(B) Preparation of 2- [4- (4-L4- (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-isoindoline in 100 mL placed in a round-bottomed flask, 2.77 ml (2.01 g,

19.35 mmol, 1.3 (sq) triethylamine, 25.0 mL of acetonitrile and 3.68 g (16.80 mmol, 1.1 eq) of 3- (1-piperazinyl) -1,2- benzisothiazole was added and the slightly orange reaction mixture was refluxed for 19 hours under nitrogen. At this time, the solution was allowed to cool and transferred to a separatory funnel with ethyl acetate. The organic solution was dried over saturated water, filtered and evaporated. This gives 7.31 g of a dark orange oil which solidifies on standing.

The crude solid was recrystallized from acetonitrile

4.38 g of the free amine are obtained. The hydrochloride was prepared by adding 10.8 ml of a 1N solution of hydrogen chloride in ether (1.0 equiv) to a solution of the free amine in ethanol. The salt was recrystallized from 95% ethanol to give 3.47 S (51%) of the hydrochloride as an off-white powder, m.p. 232-233 °. 1?

NMR (DMSO-d6) 1.77 (m, 4), 3.23 (m, 4), 3.57 (m, 6), 4.05 (br 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 (br s, 1). ¹³ C

NMR (DMSO-d6, 4): 20.49, 25.05, 40.96, 46.29, 49.41, 50.43, 55.12,

127 ^ 74, 128.07,

12.55%;

12.62%.

Example 4 (a) Preparation of 6-Nitro-1 (3R) -isobenzofuranone

- 53 The title compound was prepared according to the procedure of J. Tirouflet (Bull. Soc. Sci. Bretaae 1951, Spec. No. 26, 7-122), m.p. 143-145 ° C. C).

NMR (CDCl ₃ ,?): 5.44 (s, 2),

7.71 (d, 1, J - 8.4), 8.57 (dd, 1, J - 8.4, 2.0), 8.76 (d, 1, J - 2.0). ¹³ C NMR (DMSO-d6, δ) · 75.57, 125.20, 130.08, 131.76,

134.02, 153.58, 158.44, 174.02.

Analysis for CgH ^ ITO ^:

calcd: C, 55.64; Ξ 2.81; r, 7.32%;

Found: C, 53.70; 2 2.85; N, 7.82%.

(b) Preparation of 6-Amino-1 (3H) -isobenzofuranone

The title compound was prepared by the method of J. Tirouflet (Bull. Soc. Sci. Bretagne 1951, Spec. No. 26, 7-122), m.p. 181-182 ° C.

NMR (CDCl ₃ , δ) δ 3.94 (br s, 2), 5.21 (s, 2), 6.97 (dd, 1, J = 8.2, 2.3), 7.13 ( d, 1, J = 2.3), 7.03 (d, 1, J 8.2). ¹³ C NMR (CDCl ₃ , δ); 69.63, 109.79, 121.64, 122.66. 126.95,

136.36, 147.49, 171.47.

Analysis for CgH ^ NC ^:

Calculated: C, 64.42; II, 4.73; N 9 → 39%;

Found: G, 64.48; H, 4.73; N, 9.38%.

(c) Preparation of 6-chloro-1 (3H) -isobenzofuranone

A mixture of 2.0 ml of distilled water, 4.0 ml of concentrated hydrochloric acid and 1.37 3 (9.13 mmol) of 6-amino-1 (3H) -isobenzofuranone was stirred under ice-cooling in a round-bottomed flask equipped with a magnetic stirrer and the resulting white suspension 0.70 g Sodium Nitrite • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «« «

A solution of 1.5 ml of distilled water was added dropwise.

The reaction mixture was stirred at 0 ° C for 20 minutes and then

A solution of copper (II) chloride hydrochloride (5.15 g, 18.56 mmol, 2.0 eq) in distilled water (2.0 mL) was added dropwise, and the resulting gray-green solution was stirred at 0 ° C for 1 h, then heat on a steam bath for 10 minutes; a solid precipitates. Ethyl acetate was added to dissolve the solid product and the layers were separated.

The green aqueous phase was extracted with ethyl acetate. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.55 g of a tan solid which was recrystallized from ethanol and dried in a vacuum oven. Thus 0.8J g (54%) of the pale yellow powder-like end; ⁷ meeting, mp .: 107-108 ° C.

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). ¹³ C NMR (CDCl ₃ ?): 69.50, 123.48, 125 _; 69, 127.58, 134.87,

135.39, 144.63, 169.65.

Analysis for CgH ^ OgCl calculated:

calcd

57.00; Ξ 2.99%;

found:

C, 57.16; Preparation of 5.05% (d) 6-Chloro-2- (2-hydroxy-esyl) -1-isoindolinone

9.15 g (0.0545 mmol) in a 100 mL round bottom flask fitted with a magnetic stirrer and 10 mL Dean-Stark flask.

6-chloro-1 (5H) -isobenzofuranone, 5.52 g (1.0 eq) of etazolamine, and • ·

- Heat in a 10.0 mL solution of toluene in an oil bath. The toluene collected on the Dean-Stark cartridge is not returned to the reaction vessel. The orange melt thus obtained was heated at 210 ° C for 22 hours. After cooling, the reaction product solidifies to give 11.75 g of a brown solid title compound which is used without further purification.

(e) Preparation of 6-chloro-2- (2-chloroethyl) -1-isoindolinone

The title compound was prepared in a similar manner to that described in Example 1 (b). Starting from 11.75 g of 6-chloro-2- (2-hydroxyethyl) -1-isoindolinone (material from the previous step d), 10.03 g of a yellow powdery product are obtained (80% yield of 6 m.p. 112-114 ° C for chloro-1 (3H) -isobenzofuranone). i.

1 H NMR (CDCl 3), δ): 3.79 (t, 2, J - 5.8), 3.94 (t, 2, J - 5.8), 4.55 (s,

2), 7.38 (d, 1, J = 8.1), 7.50 (dd, 1, J = 8.1, 1.8). 7.80 (d, 1,

51.22, 123.91,

II, 6.09%;

K, 6.03%.

(f) Preparation of 2- {2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] ethyl} -6-chloro-1-isoindolinone hydrochloride

• V · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. The free amine was treated with 1 L of ethereal hydrogen chloride and the hydrochloride thus obtained was thoroughly worked up with 95% ethanol. 3.7 g of tetrachloride are obtained in the form of an off-white powder, m.p. 272-275 ° C (with decomposition).

1 H NMR (DMSO-d 6, 4 ') δ 3.24-3.62 (m, 6), 3.71 (br 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 (n , 3), 8.11 (t, 2, J = 8.9), 11.08 (br s, 1). ¹³ C NMR (DMSO-d 6,? Q: 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 E ^ OSCl.HC1:

calcd: C, 56.13; H, 4.93; H, 12.47%; Found: C, 56.22; H, 4.95; H, 12.40%.

Example 5 (a) Preparation of 6-Elho-2- (4-chlorobutyl) -1-isoindolinone

The title compound was prepared in a similar manner to that described in Example 1, step (b). The starting material was 6-chloro-2- (4-hydroxybutyl) -isoindolinone obtained according to the procedure described in Example 4 (d). The crude product obtained in this reaction was subjected to flash chromatography

5.42 g (59% of 6-chloro) were obtained as an orange solid

m.p. 71-72 ° C (calculated for -1 (3H) -isobenzofuranone).

· «« · ·· »·

NMR (CDCl ₃ ,?): 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). 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.

• · · ···

- 57 Analysis of the formula:

calcd: C 5 H 83; Ξ 5.08; iT 5.43%;

c, 55.90; Ξ 5.12; IT 5.38%.

('O) Preparation of 2- [4- (4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -6-chloro-1-isoindolinone hydrochloride

The title compound was prepared according to the procedure described in Example 1 (c). Starting from 6-chloro-2- (4-chlorobutyl) -1-isoquinolinone (5.02 g, 19.4 mmol), an orange crude product is obtained which is recrystallized. The free base was treated with a 1M aqueous solution of hydrochloric acid, which was thoroughly triturated with hot ethanol and dried in a vacuum oven to give 4.84 g (51%) of the title compound as a tan powder, m.p. 241-242 ° C. .

NMR (DMSO-d 6, 6): 1.71 (br s, 4), 3 _r 20 ( _B , 4), 3.35 (n, 6), 4.02 (br d, 2, J = 13). 1), 4.50 (s, 2), 7.45 (m, 1), 7.53 (m, 1), 7.65 (n, 3). 8.10 (dd, 2, J = 8.0, 4.5), 11.14 (br s, 1).

C NMR (DMSO-d6, S): 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 ₂ ^ E ₂ ^ iT ^ 0SCl: C.4 H2O:

Calculated: C, 57.00; E, 5.57; M il, 56; Hg0, 1.49%; Found: C, 56.82; Ξ 5.65; IT 11.51; Η2θ, 1.34%.

···· «*« -t · • · <»· 9 · • ···« «I» · ·· · ν · 9 ·· «V · · 9» 9 · · 3 * 4

Example 6 (a) Preparation of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone

The title compounds were prepared according to the procedure described in Example 3 (a). N- (5-Bromopentyl) phthalimide (10.00 g, 0.0338 mol) was reduced with a metal ion (9.62 g, 0.081 mol, 2.4 eq) in acetic acid (75 ml) and concentrated hydrochloric acid (15.0 ml).

A mixture of 4.24 g (55%) of 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone is obtained. This mixture is used directly without separation of the halogen compounds.

(b) Preparation of 2- / 5- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -pentyl} -1-isoindolinone hydrochloride

The title compound was prepared according to the procedure described in Example 3 (b). A mixture of 4.24 g (0.0178 moles), 2- (5-chloropentyl) -1-isoindolinone and 2- (5-bromopentyl) -1-isoindolinone and 4.30 g (0.0196 moles) (1.1 eq.) Of 3- (1-piperazinyl) -1,2-benzisothiazole gives the title hydrochloride as an orange powder. The latter was recrystallized from ethanol to give 4.28 g (53%) of a tan powder, m.p. 174-175 ° C after recrystallization from ethanol.

NMR (DMSO-d6, µ): 1.34 (a, 2), 1.65 (a, 2), 1.79 (a, 2), 3.20 (a, 4), 3.53 (a) , 6), 4.03 (br d, 2, J - 13.5), 4.47 (s, 2), 7.55 (a, 6), 8.10 (dd, 2, J - 8, 0, 5.3), 11.28 (br s, 1). ¹³ C NMR (DMSO-d _&, ü): 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.

- 59 Analysis for C ^ HggifyOS.HCl:

calcd: C, 63.07; H, 6.40; IT 12.26%;

Found: C, 63.10; H, 6.39; N, 12.22%.

Example 7 (a) Preparation of 2- (6-chlorobenzyl) -1-isoinaolinone and 2- (6-bromohexyl) -1-isoindolinone

The title compounds were prepared according to the procedure described in Example 3 (a). A 50:50 mixture of 2- (6-chlorobenzyl) -1-isoindolinone and 2- (6-bromohexyl) -1-isolide olinone was prepared with l- (6-bromohexyl) phthalimide (available from Transworld Chem., Inc.). This product is used as a mixture of halides.

(b) Preparation of 2- (6- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] hexyl] -1-isoindolinone hydrochloride

The title compound was prepared according to the procedure described in Example 3 (b). The crude product was purified by flash chromatography eluting with 0.1% triethylamine in ethyl acetate to give 4.65 g of a pale yellow solid. The product was treated with 1 K ethereal HCl in vacuo to give 4.18 g (61%) of the title hydrochloride as an off-white powder, mp 263-264 ° C.

overgrowth

NMR (DMSO-d6-, 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 (br d, 1, J = 7.5), 8.12 (t, 2, J - 7.2), 10.99 (br s, 1). ¹³ C NMR (DMSO-d 6, δ S): 25.78,

27.46, 41.27, 49.23, 122.58, 123,027. 123.95, 124.49, 127.72,

128.01, 131.08, 141.72, 152.02.

- 60 Analysis for ^ 25 ^ 30¾ ^OS * ^HC1 :

Calculated: C, 63.74; H, 6.63; R, 11.89%;

Found: C, 63.81; H, 6.65; N, 11.84%.

Example 8 (a) Preparation of 2- (Bromomethyl) benzoic acid methyl ester

U. Davies and W. Ξ. Percutaneous procedure [J. CBEM. Soc., 121, 2202 (1922)] by bromination of 2-methylbenzoyl chloride to give 2- (bromomethyl) benzoyl bromide. A mass of this bromide (0.184 mol) was dissolved in 40 ml of DE.I and the solution was cooled in ice-water with 15 ml of abs. methanol was added and the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was washed with saturated potassium carbonate solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator to give 42.08 g of a pale yellow oil which was used without further purification. 1,

1 H NMR (CDCl ₃ , δ): 3.94 (s, 3), - 4.96 (s, 2). 7.40 (a, 3), 7.97 (m, 1).

(b) Preparation of 3- {4- (2-Amino-ethoxy) -ethyl] -1-piperazinyl} -1,2-benzisothiazole

In a 100 mL round bottom flask, 7.5 g (0.017 mol) of 17- [2- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethoxy] ethyl] prepared in Example 24 were added. phthalimide is taken up in 20.0 ml of methanol and, while stirring, 1.49 g of 85% aqueous hydrazine hydrate solution (0.025 mol, 1.1 eq.) are added dropwise and the reaction mixture is refluxed for 2 hours. ·

After boiling under 61, allow to cool to room temperature and add 50.0 mL of 1 L hydrochloric acid. The precipitate was filtered off, washed with distilled water, the filtrate basified with 50% sodium hydroxide solution and extracted with DKM. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated on a rotary evaporator to give the title compound as a viscous, pale yellow oil (5.51 g) which was used crude without further purification.

(c) Preparation of 2- {2- [2- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl-3-ethoxy] ethyl} -1-isoindolinone

A solution of 5.51 (0.017 mole) of 5- [4- [2- (aminoethoxy) ethyl] -1-piperazinyl} -1,2-benzisothiazole and 100 ml of toluene was heated in an oil bath at 100-110 ° C. A solution of 2- (bromomethyl) benzoic acid methyl ester (0.017 µl, 1.0 eq) in toluene (25 mL) was added dropwise over 15-20 min and the reaction mixture was heated under nitrogen for 45 min after completion of the addition. After cooling, the solution was washed with saturated potassium carbonate solution, the combined organic extracts dried over magnesium sulfate and evaporated. 6.22 g of an orange-red oil are obtained. This crude product was purified by flash chromatography eluting with 0.2% triethylamine in ethyl acetate and recrystallized from ethyl acetate / ethanol. The title compound is thus obtained in a yield of 0.95 S as a tan solid.

The spectrum indicates the presence of a small amount of ethyl acetate in the product. mp 108-110 ° C.

NMR (CDCl ₃ , δ): 2.69 (m, 6), 3.49 (br t, 4, J = 5.0), 3.66 (t,

2, J = 5.6), 3.74 (dt, 2, J = 1.0, 5.2), 3 _Z 82 (br 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 (n, 3). 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 a

calcd

Calculated: C, 65.05; E, 6.29; E, 12.86%;

064.74; Ξ 6.33; IT 12.76%.

Example 9 (a) Preparation of trans-2- (4-Hydroxy-1-cyclohexyl) -1-isoindolinone

In a 500 mL round bottom flask equipped with a magnetic stirrer and a Dean-Stark plug, 30.00 g (0.151 mol) of methyl 2- (bromomethyl) benzoate, prepared according to Step 8 (a), 20.85 g. 0.157 mole (1.05 eq.) Of trans-4-aminocyclohexanol hydrochloride, a mixture of 27.15 g (0.196 mole, 1.5 eq.), 110 ml toluene and 20 ml water (biphasic system) was refluxed for 19 hours. while boiling the aqueous toluene azeotrope on the pad and preventing the water from returning to the reaction vessel. Fresh toluene (300 mL) was then added and the toluene methanol azeotropically removed with Dean-Stark half. After heating for another 24 hours, decant the solution from the salts into a clean round-bottomed flask. The solvent was evaporated in a rotary evaporator to give 25.16 g of a viscous orange oil. This crude product was purified by flash chromatography eluting with 0.1% triethylamine.

ethyl acetate to give 11.38 g (39%) of a grayish white title compound, mp 153-134 ° C.

1 H NMR (CDCl ₃ ) * 156 (n, 4), 1.41 ( _m , 3), 2.11 (n, 2), 3.66 (m, 1), 4.26 (εε, 1, J - 11.5, 3.9), 4.32 (s, 2), 7.47 (m, 3), 7.84 (dd, 1, J - 7.7,

1.6). ¹³ C NMR (CDCl ₃ , A): 29.02, 34.46, 46.04, 49.67, 69.90.

165.11.

IT 6.06%;

Found: C, 72.63; Ξ 7.41; IT 6.04%.

(b) [trans-4- (1-Oxo-2-isoisoindinyl) -1-cyclohexyl] -

-methanesulfonate

To a solution of 3.94 g (0.017 mol) of 2- (4-hydroxy-1-cyclohexyl) -1-isoindolinone in 150 ml of anhydrous DEI

Triethylamine (13.56 mL, 2.59 g, 0.025 mol, 1.5 eq) was added and the orange solution was cooled in an ice-water bath under nitrogen. To this solution, while stirring, a solution of 1.98 ml (2.95 S, 0.025 mol, 1.5 eq.) Of mesyl chloride and 3.0 ml of anhydrous DKH are added slowly. The reaction mixture was stirred at 0-5 ° C for 1 min, at which time additional DIQ.I was added.

After this time, the aqueous phase was extracted with Di.

the organic phase is dried over magnesium sulfate, filtered and concentrated by rotary evaporation. Obtained as an orange solid crude product (5.40 g) which was used without further purification in crude form.

• ·

(c) Preparation of (-) - cis -2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1-cyclohexyl] -1-isoindolinone hydrochloride monohydrane

Trans-4- (1-oxo-2-isoindolinyl) -1-cyclohexyl methanesulfonate (5.27 g, 0.017 mL), 3.92 g (0.079 mol, 1.05 eq.)

A mixture of 3- (i-piperazinyl) -1,2-benzisothiazole, 2.85 mL (2.07 g, 0.020 mol, 1.2 quart) of triethylamine and 20 mL of acetonitrile was refluxed under nitrogen for 2.5 days. boil. The mixture was then allowed to cool to room temperature and washed with saturated potassium carbonate solution. The combined organic extracts were dried over magnesium sulfate, filtered, and rotovaped to give an 8.29 S viscous orange oil which was purified by flash chromatography. Elution was carried out with ethyl acetate and the isolated product was further purified by flash chromatography. Elution now with ethyl acetate / hexane (2: 1) gave 0.224 g of a sticky orange oil. This free base was converted to its hydrochloride, recrystallized from ethanol, dried in a vacuum oven to give 120 g of [trans-2- (4-hydroxy-1-cyclohexyl) -1-isoindol-olinone 2%] as light, peach-colored crystals. 251-232 ° C. overgrowth

NMR (DMSO-d6, <$>. 1.72 (a, 2), 1.95 (a, 2). 2.20 (a, 2), 2.35 (a,

2), 3.33 (a, 2), 3.45 (a, 1), 3.77 (br d, 2, J = 13.4). 3.85 (br d, 2, J - 12.2), 4.05 (br d, 2, J - 13.4), 4.20 (quintec, 1, J 3.7), 4.74 ( s, 2), 7.46 (a, 2), 7.58 (a, 3), 7.67 (d, 1, J 7.3), 8.11 (dd, 2, J -8.0) , 4.7), 10.80 (br s, 1). ¹³ C NMR (DMSO-d ^, £> 23.37, 25.25, 45.96, 47.95, 48.75, 62 _y 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 ^ H ^ IT ^ OS.HCl.HgO:

calcd: C, 61.65; H, 6.41; 1T 11.50%;

Found: C, 61.65; H, 6.45; II, 11.46; H ₂ O, 5.97%.

Example 10 (a) Preparation of 5- [4- (4-Amino-2-butynyl) -1-piperazinyl] -1,2-benzisothiazole

The title compound was prepared according to the procedure described in Example 8, Step Cb). 12.54 g (0.630 mol) of N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl-2-butynyl} phthalimide, prepared according to Example 25, (2.66 g, 85%). starting from an aqueous hydrazine hydrate solution and 30 ml of methanol to give 6.23 S (72.3%) of the cinic compound as a crude orange oil; this product was used without further purification.

(b) 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 from Example 10, step a) above are taken up in 50 mL of toluene · To this mixture is stirred 2-bromomethylbenzoic acid prepared according to Example 8, step a) methyl ester solution. The resulting orange solution was refluxed under nitrogen for 18 hours, then 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 concentrated. This gives an orange oil which is purified by flash chromatography on silica gel. Elution was carried out with a 3: 1 mixture of ethyl acetate and hexane. The pure free base hydrochloride is prepared by adding 1 N hydrochloric acid. The salt was crystallized from a mixture of ethanol and ethyl acetate and dried in a vacuum oven to give 0.24 g (3%) of 2- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2- m.p. 194-196 DEG C. butinyl 1-isoindolinone hydrochloride is obtained in the form of an off-white powder.

1 H NMR (DMSO-d 6, δ); 3.40 (a, 3), 3.51 (a, 3),

4.08 (a, 2), 4.22 (br s, 2), 4.59 (s, 2), 4.61 (s, 2), 7.48 (a,

2), 7.58 (a, 1), 7.63 (a, 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). Ί D

1 H 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 a ANCESTOR according to the formula: date: C 62.93; H, 5.28; N, 12.76; found: C 62.79; H, 5.31; N, 12.70 Example 11

(a) Preparation of 1-isoindolinone

30.0 g (0.204 mol) of phthalimide in 150.0 ml of glacial acetic acid. A mixture of 75.0 ml of concentrated hydrochloric acid and 53.08 g (0.485 ml, 2.4 eq.) Of a creamy suspension was heated in a 500 ml round-bottomed flask.

During this process, the phthalimide dissolves and forms a pale yellow solution

Who

The reaction mixture was allowed to reflux for 2 hours, then the solution was filtered hot and the tin slices washed with fresh acetic acid.

The majority of the acetic acid is evaporated in a rotavapor to give a pale yellow cream product.

The latter is taken up in DKLI and washed first with distilled water and then with brine. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated by filtration. 17.61 g of a pale yellow solid are obtained. The crude product was purified by flash chromatography eluting with ethyl acetate to give 11.91 g (47%) of 1-isoindolinone as a pale yellow powder, m.p. 150-151 ° C.

1 H NMR (CDCl ₃ , δ): 4.48 (s, 2),

7.48 (a, 2), 7.57 (m, 1), 7.76 (br s, 1), 7.88 (n, 1). ¹³ C NMR (CDCl ₃ ,?): 45.83, 123.16, 123.64, 127.95, 131.69, 143.72, 172.35.

Analysis a

For CgH ^ BO:

Calc'd: C, 75.16; H, 5.50;

10.52%;

Found: 072.03; 35.55; 310.49%.

(b) Preparation of (E) -2- (4-Chloro-2-butenyl) -1-isoindole

Sodium hydride (1.54 g, 1.25 eq.) In 80% oil dispersion (1.25 eq.) Was placed in a 500 ml round-bottomed flask dried in a vacuum oven, and the waste hexane was purged from the solid product. To the washed sodium hydride was added 100 ml of anhydrous DEEE. To the gray slurry was added a solution of 5.47 g (0.041 mol) of 1-isoindolinone in 50.0 ml of dry DL6F.

oven-dried 500 mL round bottom flask was charged with 15.51 g (0.105 mol, 2.5 eq) of trans-1,4-dichloro-2-butene and 100.0 mL of dry DLH. The solution was placed in an ice-water bath and a solution of 1-isoindolinone was slowly added via cannula. Dosing head ································································ ··· · · ·

After stirring, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Most of the DI> was removed on rotavap and the residue was taken up in DMF and washed several times with water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 20.12 g of a dark orange oil. The crude product 3 was purified by flash chromatography eluting with hexane / ethyl acetate 1: 1 to give the title compound as a yellow oil (6.48 g, 71%). This product and its spectrum matched

IT-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.

0.80 g of a dialkylated product, (E) -2,2 '- (2-butene-1,4-diyl) -bis (1-isoindolinone), is also obtained in the form of pale yellow crystals, m.p. 193-196 ° C.

(c) Preparation of (E) -2- [4-E4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl] -1-isoindolinone hydrochloride

The title compound was prepared in a similar manner to that used in Example 1 (c). 3.00 g (0.014 mol) of (3) -2- (4-chloro-2-butenyl) -1-isoindolinone, 2.97 g (0.014 mol, 1.0 eq.) Of 3- (1-piperazinyl) A mixture of -1,2-benzisothiazole and 2.26 ml of triethylamine in 20.0 ml of acetonitrile was heated under reflux for 1 hour under a stream of nurogen. The crude product thus obtained is purified by thin-layer chromatography, eluting with ···· ···· • 4 • 4

3.47 g of the free base are obtained. This is converted to the hydrochloride,

Recrystallize from 69 ethanol and dry under vacuum.

Yield: 2.86 g (48%) of the title compound as a tan powder, m.p. 232-235 ° C.

NMR (DMSO-d 6,?): 3.10-3.58 (m, 6), 3.82 (br s).

2), 4.07 (br 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 (n, 5), 7.69 (d, 1, J = 7.3), 8.10 (dd, 2, J = 7.5, 5.4), 11.36 (br s, 1). ¹³ C NMR (DMSO-d 6) δ 42.95, 46.38,49.37, 49.92,

56.33, 120.98, 121.14, 122.77, 123.44, 123.95, 124.56, 126.91.

127.83, 128.07, 131.36, 132.01, 136.08, 141.89, 152.06, 162.13,

167.08.

Analysis for C ₂ ^ ^H 24 ³ 4 ^0S · ΞΟ1:

Calculated: C, 62.64; H, 5.71; 12.70%.

found; C, 62.41; Ξ 5.67; N, 12.60%.

Example 12 (a) Preparation of (Z) -2- (4-Chloro-2-butenyl) -1-isoindolinone

The title compound was prepared using the method described in Example 11 (b). 5.75 g (0.043 mol)

Alkylation of 1-isoindolinone with 6.25 g (0.047 mol, 1.1 eq.) Of cis-1,4-dichloro-2-butene in anhydrous DI.IF gives 3.43 g (5θ%) of the cin-title compound by flash chromatography. after. The pale orange oil has a Ü, ^ 0 differential n.O.e. EI.ÍR.

its spectra were consistent with those of the product.

«« * · · · ««

- 70 ¹³ C NMR (CDCl ₃ , s): 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 the bis-alkylation, 0.88 g of (Z) -2,2 '- (2-butene-1,4-diyl) bis (1-isoindolinone), is also obtained in the form of a pale yellow solid, m.p. 148 -150 ° C.

(b) Preparation of (Z) -2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl} -1-isoindolinone hydrochloride

The cin compound was prepared in a similar manner to that described in Example 1, step c). 5.26 g (0.015 mol) of (Z) -2- (4-chloro-2-butenyl) -1-isoindolinone, 3.23 g (0.015 mol, 1.0 eq.) Of 3- (1-piperazinyl) - A mixture of 1,2-benzisothiazole, 2.46 mL (1.78 g, 0.018 mol, 1.2 equiv.) of triethylamine and 20.0 mL of acetonitrile was heated under reflux for 3 hours under nitrogen. The crude product obtained after work-up is purified by silica gel column chromatography eluting with ethyl acetate to give 4.76 g of a viscous orange oil. This was converted to the hydrochloride and recrystallized twice from 95% ethanol. This gave 2.16 g (33%) of the cin hydrochloride as a tan powder, m.p. 234-236 ° C.

NMR (DMSO-d6, S):

3.34 (m, 4), 3.55 (m, 3), 4.10 (n, 4), 4.33 (d, 2, J = 5.9), 4.49 (s, 2), 7 , 95 (n, 2), 7.52 (m, 5), 7.68 (dd, 1, J = 7.3, 1.0),

8.12 (t, 2, J = 8.0), 11.65 (br s, 1). ¹³ C NMR (DMSO-d 6, S):

38.68, 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.

• · · ·

- 71 Analysis of Cg ^ b ^ l ^ OS.HGl. 0.5 for H2O:

Calculated: C, 61.39; H, 5.82; N 12.45? HgO, 2.00%;

Found: C, 61.05; Ξ 5.79; E, 12.19; H ₂ O, 2.28%.

Example 13 (a) 2- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -

Preparation of butyl-phthalimide hydrochloride

In a 100 mL round bottom beaker, 3 x 50 g (0.0124 mole) of iT- (4-bromobutyl) phthalimide, 2.72 g (0.0124 mole, 1.0 eq.) Of 3- (1-piperazinyl) -1,2-benzisothiazole [Yevich et al., J.I.Ied. Chem. 2Q, 359-369 (1986)], protected by a mixture of 2.24 ml (0.0161 mol, 1.3 eq.) Of triethylamine and 15.0 ml of acetonioril (orange cloudy solution) under reflux for 17 hours. boil, allow to cool to room temperature, and

We'll record it in DKLI. The organic layer was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated. 3.48 g of a slightly orange solid are obtained, which is recrystallized from acetonitrile. The resulting product was dried in a vacuum oven to give 4.35 g of a tan powder. The hydrochloride is prepared by adding 1 ΪΤ of ethereal hydrogen chloride solution; The product was recrystallized from 95% ethanol to give 4.53 5 (82%) of the title hydrogel chloride as an off-white powder, m.p. 258-260 ° (dec). H® _(MSO-d6, f) 1.72, (4).

3.20 (n, 4), 3.54 (m, 6), 4.02 (br d, 2, J = 13.7), 7.44 (ddd, 1, J = 8.1, 7, 0, 1.1), 7.57 (ddd, 1, J - 8.1, 7.0, 1.0), 7.85 (m,

4), 8.09 (dd, 2, J -8.0, 4.5), 11.18 (br s, 1). ¹³ C NMR (DMSO-d 6): 20.52, 25.25.36,82,466.30, 50.444.98, 121.13,

122.98, 123.94, 124.56, 126.90, 128.06, 131.58, 134.33, 152.04,

162 _f 16, 167.93.

• ·· 9 ·· «* * ·« 4 • · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 72 Analysis a

calcd

Calculated: C, 60.45; H, 5.51; N, 12.26%;

Found: 0, 60.46; H, 5.55; N, 12.17%.

(b) Preparation of 3- [4- (4-Amio-butyl) -1-piperazilyl] -1,2-beazisothiazole

To a solution of 12.46 g (0.0296 mol) of 2- {4- [4- (1,2-bis-1-isisothiazol-3-yl) -1-piperazilyl] butyl] phthalimide in 30.0 ml of methanol is 2.62 85% hydrazine hydrate (1.5 eq.) was added and the reaction mixture was refluxed for 3.5 hours and then allowed to cool to room temperature. At this time, 59.0 ml of 11 Hydrochloric acid were added, the white precipitate was filtered off, washed with water and the filtrate was basified with 50% sodium hydroxide solution and extracted with DKLI. The organic extract presented is dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The title compound was obtained as a tan oil (3.1 g, 94%).

1 H NMR (CDCl ₃ , δ) Γ 1.38 (br s,

2), 1.55 (m, 4), 2.45 (t, 2, J - 7.4), 2.68 (t, 4, J - 5.0), 2.74 (t, 2, J - 6.8), 3.57 (t, 4, J - 5.0), 7.35 (ddd, 1, J - 1.1, 7.0, 8.1), 7.46 (ddd, 1, J - 1.1, 7.0) , 8.1), 7.81 (d, 1, J 8.1), 7.91 (d, 1, J - 8.2).

The crude amine compound thus obtained was used without further purification.

(c) Preparation of 2- {4 - [- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -butyl} -4-methylphthalimide hydrochloride

2.70 g (9.3 vnol) of 3- [4- (aminobutyl) -1-piperazinyl] -1,2-

For a solution of benzisothiazole and 27.0 ml of pyridine in a 50U ml sphere, V · V

- In a mixture of 73 bits, 4-methylphthalic anhydride (1.66 g, 10.2 mmol, 1.1 eq.) Was added. The reaction mixture was purged with nitrogen gas and refluxed for 5 hours. At this time, the solution was evaporated and the residue was taken up in DCM and washed with saturated potassium carbonate solution. The combined organic extracts were dried over magnesium sulfate, filtered, evaporated to give the crude product. This product was purified by flash chromatography (3: 1 hexane: ethyl acetate) to give the title compound as a white crystalline solid (5.82 g). This free amine was taken up in ethyl acetate and 8.7 mL of a 1N solution of Hiarogen chloride (8.7 mmol, 1.0 equiv) was added. The hydrochloride thus obtained was recrystallized from 95% ethanol and dried in a vacuum oven. Yield: 2.70 g (67%) of the title hydrochloride as a white powder, m.p. 255.5-258 ° C.

1 H NMR (DMSO-d ₆ , _δ ): 1.74 (n, 4), 2.46 (s, 3), 3.25 (n, 4), 3.53 (m,

6), 4.02 (br d, 2, J = 13.6), 7.44 (ddd, 1, J = 8.1, 7.1, 0.9),

7.62 (n, 4), 8.10 (dd, 2, J - 8.0, 4.7), 11.18 (br s, 1). 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 Cg ^ I ^ glT ^ OS.HCl:

Calculated: C, 61.20; Ξ 5.78; IT 11.89%; Found: 0, 60.91; H, 5.78; IT 11.75%.

···· «« · «

34th-22nd examples

14-20. Examples 1 to 6 and the compounds of Example 22 were prepared from their corresponding substituted phthalic anhydride precursors by the procedure described in Example 15, step (c).

Phthalic anhydrides were purchased from commercial suppliers or prepared according to known literature methods as already pointed out. Analytical data for phthalimides are shown below.

Example 14 Preparation of 1 - {4 - [- (1,2-Benzisothiazol-5-yl (-1-piperazinyl) -butyl] -3-fluorophthalimide hydrochloride

The starting material was 3-fluorophthalic anhydride, yield 1.22 g (16%), m.p. 253-260 ° C.

Si NMR (DMSO-d6, S): 1.67 (m, 2), 1.80 (m, 2), 3.22 (m, 2), 3.55 (n, 6), 4.005 ( br d, 2, J -

13.5), 7.47 (ddd, 1, J - 8.1, _{r is} 0 7, 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 _r ll (tm, 1, J - 7.5), 11.12 (br. S, 1). ¹³ C NMR (DMSO-d _g, £): 20.48,

25.09, 36.98, 46.30, 50.46, 55.00, 117 _r 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 ^J 4 ° 2 ^S 2 calcd date: C, 53.16; H, 5.09; 11 11.79%; found: 57.93; Ξ 5.15; % 11.71%.

Example 15 Preparation of 1- [4- (4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1-yl] -3-hydroxyphthalimide hydrochloride

Starting material: 3-Hydroxyphthalic anhydride. Yield 0.94 g (24%), m.p. 247-248 ° C.

75 Si NMR (DMSO-d6);

I, 65 (a, 2), 1.77 (a, 2), 3.23 (a, 4). 3.54 (a, 6). 4.05 (br. 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 (a, 2). 8.02 (tt, 2, J - 7.7, 1.1),

II, 02 (br s, 1), 11.19 (s, 1). ¹³ C NMR _(DMSO-fi £): 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 822 ^ 25¾¾ ³ :

Calculated: C, 58.44; H, 5.34; IT 11.86%;

Found: C, 58.48; H, 5.55; IT 11.90%.

Example 16

2- {4- [1- (1,2-Bis-isothiazol-5-yl) -1-piperazilyl] butyl] -2,5-dihydro-1H-pyrrolo [5,4-c] pyridine-1,5-d preparation of ion hydrochloride

Starting material: 2,5-Pyridine dicarboxylic acid anhydride (available from Aldrich Chemical Company). Yield: 5.05 g (76%), m.p. 258-259 ° C.

Si NMR (DMSO-d, r) i _r 71 (?, 4), 3.20 (a, 4), 3.54 (a, 6). 4 _T 03 (br 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, 1, 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 (br s, 1). ¹³ C NMR (DMSO-d _g, £): 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 .HCl:

Calculated: C, 57.75; H, 5.29; IT 15.52%;

57.60; H, 5.50; IT 15.33%.

found:

Example 17

Preparation of N - [(1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl-4-nitrophthalimide hydrochloride

The starting material is 4-nitrophthalic anhydride (available from Aldrich). Yield: 3.50 g (73%) of the title compound, m.p. 258.5-259 ° C. .

Π1 NMR (DMSO-d6, δ):

1.69 (b, 4), 3.20 (n, 2), 3.50 (m, 2), 3.66 (i, 2), 4.04 (br 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 (br s, 1). ¹³ C NMR (DMSO-d _g, S): 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.

calcd

Calc'd: C, 55.05; h, 4.82; IT 15.95%;

C, 55.06; H, 4.85; IT 13.96%.

Example 18

6- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine-5,7- Preparation of <3 ion hydrochloride monohydrate

Starting material: 33-pyridine dicarboxylic acid anhydride (Alorich). Yield 1.52 g (54%), m.p. 253-254 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, $): 1.70 (n. 4). 3.27 (n, 6), 3.52 (m, 2), 3.65 (t, 2, J 6.3), 4.05 (br 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 (br s, 1). ¹³ C NMR (DMSO-d 6, S): 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.

calculation formula:

calcd: 0 55.51; --5.51; 14.71 »^ 2θ» 5.73%;

Found: 0 55.75, H 5.52; IT 14.72; H ₂ O, 5.92%.

Example 19

IT-PI [4- (l, 2-Bei3zizotiazol-5-yl) -l-pip93? ^the 2-yl! -butyl-3-yl methyl phthalimide hydrochloride monohydrate

The starting material; 3-Nethyl phthalic anhydride (available from Kodak Laboratory Chemicals). The cin compound has a mosaic of 3.54 g (75%), m.p. 272-274 C. nmr (DMSO-dg,?):

1.68 (m, 4), 2.62 (s, 3), 3.17 (m, 4), 3.53 (o, 6), 4.03 (br d, 2, J 12.4). , 7.45 (m, 1), 7.63 (m, 4), 8.10 (dd, 2, J - 7.9, 4.4), 10.98 (br s, 1). 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 calculated for C24 H26 N2 O2: C, 53.95; Ξ 5.98; IT 11.46%;

Found: C, 59.07; H, 5.99; H, 11.32%.

Example 20

Preparation of N- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -3,6-dichlorophthalimide hydrochloride monohydrate Starting material: 3,6-dichlorophthalic anhydride. available from Eluka Chemicals AG). Yield: 2.25 g (49%), m.p. 265-267 ° C.

NMR (DMSO-d ^) n _y 73 (a, 4), 3.20 (in, 4), 3.57 (a, 6), 4.03 (br d, 2, J - 13.5) , 7.45 (c, 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 _z 05 (br s, 1). ¹³ C NMR (DMS0-d _fi £): 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.

calculated found;

C, 50.63; Ξ 4.67; ü 10.23%

The second generation of crystalline product was 0.44 g of hydrochloride dihydrate, m.p. 262-265 ° C.

_Q ^ 2 ^ 2522-4 Theory: C

Example 21 (a) Preparation of 4-chlorophthalimide

In a 500 mL round bottom flask was added 14.0 mL of distilled water and 27.0 mL of concentrated hydrochloric acid to 10.0 g (0.0671 mole) of 4-aminoxtalimide (Kodak). The resulting pale yellow solution was cooled in an ice-water bath and treated with 4.57 S (0.0679 mol, 1.1 eq.) Of sodium nitrate.

- A solution of 79 r in 100 ml of distilled water is added dropwise. The color of the reaction mixture turns golden yellow during addition. The solution was allowed to stir at 0 ° C for 20 min and a solution of copper (II) chloride dihydrate (21.0 g, 0.123 mol, 2.0 eq) in 140 mL of distilled water was added dropwise.

The resulting green solution was stirred at 0 ° C for 1 hour and then heated on a steam bath for 15 minutes. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and evaporated. 9.51 g of the title compound are obtained in the form of a yellowish brown solid which is used without further purification.

(b) ZT- (4-Chlorobutyl) -4'-chlorophthalimide and ZT- (4-bromo

-butyl) -4'-chlorophthalimide

The title compounds were prepared in a similar manner to that described in Example II (b). 9.61 g (0.0529 mol),

From 4-chlorophthalimide and 9.98 g (0.0582 mole) of l-bromo-4-chlorophthalimide, 15.91 g of product is obtained after purification by flash chromatography (eluting with 8: 1 hexane: ethyl acetate). used) gives a mixture of 15.91 S which contains the corresponding chlorine compound in a ratio of 80:20 to the bromine compound. The product as a mixture of balogens was used without further purification (c) Preparation of Z7- [4- (4- (1,2-Benzisothiazol-5-yl) -19piperazinyl] butyl] -4-chlorophthalimide hydrochloride

The title compound was prepared by ly. Prepared according to the procedure described in step (a) of Example 1B. 2.57 (0.029 mol), Z7 - (- bromobutyl) -4'-chlorophthalimide and

17- (4-Bromobutyl) -4'-chlorophthalate from a mixture containing 80:20 imide in 80:20 ratio and 3- (1-piperazinyl) -1,2-benzisothiazole (1.95 g, 0.0089 mol), 30 g of the title compound are obtained in the form of the free base. This was converted to its hydrochloride, recrystallized from 95% ethanol and dried. dried in a hot oven. 1.79 g (41%) of the title compound are obtained in the form of pale yellow crystals, m.p. 255-255 ° C.

NMR (DMSO-d6, S): 1.69 (a, 4), 3.23 (a, 4),

3, .53 (a, 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 (br s, 1). ¹³ C NMR (DMSO-d., S):

She

20.46, 25.14, 37.06, 46.29, 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 ^Ii 24 ' ⁱ 4 ^ 2 ^SC! Combine ' ¹ ' to 2:

calcd: C, 56.21; H, 4.92;

H, 11.40%;

iá u down:

C, 56.18; H, 4.95; N, 11.54%.

Example 22

N- {4- [4- (1,3-Benzisothiazol-3-yl) -1-piperazinyl] butyl

Preparation of -3-methoxyphthalimide hydrochloride hydrate

The starting material is 3-methoxyphthalic anhydride (Alfred Bader

Library). Yield: 2.17 g (47%), m.p.

232-234 C. Irish NMR (DMSO-d6, s) 1.70 (a, 4),

3.25 (a, 4), 3.54 (a, 6), 3.94 (s, 3), 4.03 (br d, 2, J = 13 _; 4), 7.48 (d, 2) , J - 8.5), 7.60 (tan, 1, J - 5.0), 7.79 (un, 1, J - 7.3), 8.10 (dd, 2, J - 7, 9, 4.6), 11.19 (br s, 1). 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.

• ·

- 81 Analysis for ^ 24 ^ 26¾ ⁰ ^ * ^ 25 H ₂ °:

Calculated: C, 57.58; H, 5.57; 11.19; H ₂ 0, 0.39%;

found; C, 57.65; H, 5.87; 1110.92; H ₂ O, 1.17%.

Example 23 · Preparation of (a) (-) - trans-1,2-cyclopropanemimethanol

To a 500 mL three-neck, round-bottomed flask with a pressure equalizing addition funnel, weigh 7.60 g (0.201 mol, 1.5 eq.) Of lithium tetrahydroaluminate, purge with hydrogen over hydrogen, and cool with ice-water (200.0 mL). anhydrous THE is added. After the addition was complete, the cooling bath was removed and the solution was stirred at room temperature for 10 minutes and then 25.0 g (0.154 mol) of trans-1,2-cyclopropanedioic acid diethyl ester was added dropwise to the gray suspension. The reaction mixture was then refluxed for 6 hours and stirred at room temperature for a further 20 hours. At this time, the solution was placed in an ice-water bath and 45 ml of saturated ammonium chloride solution was added slowly. Ethyl acetate (50.0 mL) was added, and the solid precipitate was filtered and washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and evaporated. 8.00 g of a cloudy oily residue is obtained, which is purified by flash chromatography. The title compound is eluted with 19: 1 ethyl acetate: methanol as a colorless oil.

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 (br s, 2). ¹³ C

NMR (CDCl ₃ , S): 7.16, 19.98, 66.08.

(B) (-) - trans-2- (Chloromethyl) -1-cyclopropanemethanol · ····· production

In a 500 ml round-bottomed flask, which was previously dried in Remene, 4.0 g (0.059 mol) of trans-1,2-cyclopropanedimethanol, 8.96 g (0.047 mol, 1.2 equiv.) Tosyl chloride, 5.30 g dimethylaminopyridine and 75.0 mL of DKM were weighed. The reaction mixture was covered with nitrogen gas and stirred at room temperature for 24 hours. Further details of the above reagent, 2.24 g tosyl chloride, 1.0 g aimethylaminopyridine and 1.0 ml DKLI were added, which was then stirred at room temperature for 6 days. At this time, 5.43 µl (5.95 g, 0.039 mol, 1.0 eq) of triethylamine were added and the solution was stirred for 24 hours: the reaction was not complete. Therefore, the mixture is refluxed for 90 minutes, then the solvent is evaporated off on a rotary evaporator to give a sticky, tan solid which is purified by flash chromatography.

first with hexane and

acetate (1: 1) followed by ethyl acetate: methanol (19: 1) to give the title compound (1.85 g). In addition, the starting nuts (0.87 g) are unchanged.

(c) (trans) -H- [2- (Hydroxy-methyl) -cyclopropylmethyl] -

Preparation of phthalimide

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

A mixture of (1.7 eq) (n) -trans-2- (chloromethyl) -1-c-cyclopropanomethanol and 50.0 ml of anhydrous dimethylformamide was refluxed in a 100 ml round-bottomed flask for 20 hours and then at room temperature.

Allow to cool to 33 ° C and remove most of the DLIF under vacuum in a rotary evaporator. The residue is taken up in DKlI and washed twice with water. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give 5.55 g of a dark orange oil. The crude product was purified by flash chromatography (5: 1 hexane: ethyl acetate) to give 1.12 g (64%) of the title compound as a white powder, m.p. 117-118 ° C.

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 (br s, 1), 3.45 (ni, 2), 3.59 (dd, 2, J = 7.0, 2.2), 7.70 (m, 2), 7.84 (m, 2). ¹³ C NMR (CDCl ₃ 3): 8.99, 16.17, 20.68, 41.57, 66.09, 123.43, 132.12,

133.95, 168.48.

Analysis of the formula:

Calculated: C, 67.52; Ξ 5.67; H, 6.06%;

Found: 0, 67.45; Ξ 5.71; I'T 5.99%.

(d) Preparation of (l) -trans- [2- (Phthalidine o -methyl) -1-cyclopropyl] -methyl methanesulfonate (1.04 g, 4.50 mmol) (-) - trans-E- in a 1 ml round bottom flask. N - [2- (hydroxymethyl) -cyclopropyl] -methyl] -phthalinide, freshly distilled triethylanine from calcium hydride (0.94 mL, 0.68 g, 6.75 mmol, 1.5 eq) and To 0 ml of anhydrous DE.I mixture under ice-water cooling with 0.52 ml (0.77 g>

6.75 mmol, 1.5 eq.) Of mesyl chloride and 2.0 ml of DKIT were added.

After stirring at room temperature, the reaction mixture was filtered, evaporated to give 1.40 g of an off-white solid. obtained by flash chromatography on silica üiszalkalmazzuk to give a white powder of the title is obtained (1.29 g, 93%), m.p .: 118-121 ⁰

NMR (CDCl ₃ , δ): 0.65 J - 8.4, 5.4), 1.33 (m, 2),

7.2), 3.65 (dd, 1, J - 14.2,

J = 10.8, 7.0)

C.

(dt, 1, J = 8.6, 5.4),

2.94 (s, 3), 3.58 (dd,

6.9), 3.99 (dd, 1, J 7.74 (m, 2), 7.86

C NMR (CDCl ₃ , S) 19.97, 16.90, 17.26, 37.79, 40.86, 73.22,

0.83 (dt, 1,

1. J = 14.2,

10.8, 7.5), 4.09 (dd, 1,

2). ¹³

123.29, 132.09, 134.02, 168.29.

(e) Preparation of (-) - trans-3 - {[2- [1,4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] methyl] cyclopropylmethyl} phthalimide hydrochloride (m.

1.17 g (3.78 mmol) of (I) -trans- [2- (phthalimid o-methyl) -1-cyclopropyl] methyl methanesulfonate in a 1 ml round-bottomed flask,

0.912 g (4.16 mmol, 1.1 equiv.) Of 3- (1-piperazinyl) -1,2-benzisothiazole, 0.633 mL (0.459 g, 4.54 mmol, 1.2 equiv.) Of triethylamine and 10 , 0 ml of a mixture of acetonitrile (cloudy solution) nitrogen gas is added

The oily crude product was purified by flash chromatography to give 1.50 g of the free base. The latter is converted to the hydrochloride and recrystallized from aqueous ethanol. 1.11 g (61%) of an off-white powdery title hydrochloride are obtained (in vacuo, after drying), m.p. 246-248 ° C. .

1 H NMR (DMSO-d 6): 0.74 (n, 2). 1.29 (m, 2),

3.12 (br s. 2), 3.20-3.67 (m, 8). 4.05 (n. 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 (br s, 1). ¹³ C NMR _(DMSO-fi £): 9.64, 12.01, 17.07, 46.24,

49.87, 50.22, 58.47, 121.16, 123.02, 124.01, 124 _; 61, 126.93,

128.11, 131.67, 134.37, 152.08, 162.16, 168.02.

Analysis for C ^ H ^ l ^ OgS.HCl.O ^ HgO:

calcd: C, 60.30,? '5.48; il 11.72 ;; H ₂ O, 1.88%; Found: 0, 60.37; H, 5.51; N, 11.72; ΙΪ ₂₀ 0, 1.85%.

Example 24 (a) Preparation of 1 - [2- (2-Chloroethoxy) ethyl] phthalinide

15.0 g (0.081 mol) of fluffy powdered phthalimide potassium and 28.5 -1 (54.74 g 0.243 mol, 3.0 equiv.) Are colorless, oily.

250 ml

The oil bath was heated under hydrogen at 170 ° C for 19 hours

···· ·· «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

washed, dried over anhydrous magnesium sulfate, filtered and evaporated to give 56.1 g of a dark orange brown oil. This crude product was purified by flash chromatography using 3: 1 hexane: ethyl acetate as eluant to afford 13.55 g (67%) of a light orange oil which solidified rapidly on standing.

Analytically triturate with ethyl acetate with crystalline water, m.p. 67-70 ° C.

¹ H NMR (CDCl ₃ , δ): 3.54 (dt, 2, J 0 _z 6), 3.75 (dt, 2, J = 5.8,

7.71 (n, 2), 7.83 (m, 2).

67 _z 92, 70.61. 123.27, 132.06,

6 _y 2, 0.8), 3.72 (dt, 2, J = 5.9,

0.9), 3.89 (dt, 2, J = 5.4, 1 _; 2), ¹³ C NMR (CDCl ₃ , δ: 37.14, 42.70,

133.97, 168.27.

Analysis 0 _Ί glycolic, £ 270 ^ 01: Calcd: C, 56.31; Ξ 4.77; N, 5.52%; Found: C, 56.38; Ξ 4.79; H, 5.49%.

(b) IT- {2- [2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl]

-ethoxy] -ethyl} -phthalimide hydrochloride

The title compound was prepared in a similar manner to that described in Example 13, step (a). 1.33 g (5.2 mmol) of 77- [2- (2-chloroethoxy) ethyl] phthalimide, 1.15 g of 3- (1-piperazinyl) -1,2-benzisothiazole, 0.94 g 1.17 g of the free base from ml (0.0685 g, 6.8 mmol, 1.3 equiv) of triethylamine and 6.0 ml of acetonitrile

we get, op .: 199-200 ··· «··« · «« «·

- 87. 1 H NMR (DMSO-d 6,?) 3.26-3.56 (a, 8), 3.70 (t, 2, J - 5.4), 3.82 (t, 2, J -) 5 _? 4),

3.88 (b, 4), 7.48 (ddd, 1, J = 8.1, 7.0, 1.1). 7.60 (ddd, 1, J 8.1, 7.0, 1.1), 7.80 (o, 2), 7.85 (a, 2), 8.06 (dt, 1, J - 8.2, 0.9), 8.11 (dt, 1, J = 8.1, 0.9), 11.12 (br s, 1). ¹³ C NMR (DMSO-d6 _? ): 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 ^ H ^ ZT ^ O ^ S.HCl:

Calculated: C, 58.40; H, 5.33; N, 11.84%;

Found: C, 58.50; 5 5.36; N, 11.81%.

Example 25 · Preparation of (a) ΪΤ- (4-Chloro-2-butyl) phthalimide

The cinic compound was prepared according to the procedure described in Example 24, Step f). 15.0 g (0.0702 moles) of phthalic potassium and 25.9 g (0.212 mol, 3.0 equiv.) Of 1,4-dichloro-2-butine. The product was purified by flash chromatography (4: 1 hexane: ethyl acetate) to give 10.64 g (65%) of the title compound as a pale yellow solid. For analysis, a sample is recrystallized from hexane / ethyl acetate to give a colorless,

like crystals, m.p. 112-115 ° C.

1 H NMR (CDCl ₃ , δ D: 4.09 (t, 2, J - 2.1), 4.49 (t, 2, J - 2.1), 7.73 (a, 2), 7 87 (a, 2). ¹³ C NMR (CDCl 3,?): 27.22, 30.10, 77.86, 79.91, 123.58,

131.94. 134.24, 166.95.

Analysis for C- ^ HgNOgCl:

Calculated: 0 61.69; Ξ 3.45; X 5.99%;

Found: 0, 61.74; Ξ 3.48; I; 5.95%.

• ••••• «4 · · · · • ♦ · · · • • ♦ ♦« · * ·· • · · · · (b) ϊΓ- ^ 4- [4- (l, 2-Beazizothiazole). -3-yl) -1-piperazinyl] -2-butynyl] phthalimide hydrochloride

The title compound was prepared according to the procedure described in Example 13, step (a). 10.64 g (0.0455 mol) of N- (4-chloro-2-butynyl) phthalimide and 9.98 g (0.0455 mol, 1.0 eq.)

5- (1-Piperazinyl) -1,2-benzisothiazole gives 14.14 g (74%) of the free amine base. This product is converted to the hydrochloride:

4.49 g free

3.17 g of cin hydrochloride are obtained in the form of slightly yellow plates (after recrystallization from ethanol / ether), m.p. 231-233 ° C.

NMR (DMSO-d 6, S): 3.49 (a, 6), 4.09 (m, 2), 4.23 (br s, 2), 4.54 (s, 2), 7.47. (ddd, 1, J = 8.1, 7.0, 1.0, .0), 7.60 (ddd, 1, J - 8.0, 7.0, 0.9), 7.90 (a, 4), 8.12 (dd, 2, J = 11.1, 8.1), 11.82 (br s, 1). ¹³ C NMR (DMSO-d 6, $): 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 Cg ^ HgQIIl ^ OgS.HCl:

Calculated: C, 60.99; H, 4.67; 1T 12.37%;

Found: 0, 60.82; Ξ 4.72; 1! 12.27%.

Example 26

(.a) Preparation of (E) -IT- (4-Bromo-2-butenyl) phthalimide

The title compound was prepared in a similar manner to that described in Example 24, Step (a). 8.35 g (0.0451 mole) of phthalimide potassium, 24.1 g (0.1127 mole, 2.5 equiv.) Of trans-1,4-dibromo-2-butene (available from Aldrich Chenical Company) and 400.0 mL of D1IF mixture at 125 ° C under nitrogen

Heat for 3.5 hours, then remove Di.IF on a rotary evaporator ···································································· The crude product was flash chromatographed with ethyl acetate. 3.25 g (26%). A compound of analytical purity is obtained by recrystallization of this product from batch; white crystals, m.p. 97-99 ° C.

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). ¹³ C

NMR (CDCl ₃ , δ): 31.27, 38.62, 123.40, 128.36, 129.96, 132.04,

134.09, 167.77.

Analysis for C-j ^ H ^ QrTOgBr:

calcd: C, 5.58; Ξ 5.61; 1, 5.01%;

Found: C, 51.55; Ξ 5.60; IT 5.02%.

(b) Preparation of (e) -yl- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -2-butenyl} phthalamide hydrochloride

The title compound was prepared according to the procedure described in Example 13, step (a). 8.45 g (0.0502 mol) of (E) -N- (4-bromo-2-butenyl) phthalimic and 6.61 g (0.0502 mol, 1.0 eq)

3- (1-piperazinyl) -1,2-benzisothiazole gave 14.31 g of a dark orange solid. The crude product was purified by flash chromatography eluting with hexane: ethyl acetate (1: 1) to give 7.48 g of the free amine base. After preparation of the hydrochloride salt, recrystallization from ethanol 955 gave 1.99 g of the title compound as a tan powder, m.p. 243-244 ° C.

• ·:

NMR (DMSO-d _g , S): 3.20 (m, 2), 3.45 (m, 4), 3.80 (br s, 2), 4.04 (br d, 2, J , 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 (br s, 1). C NMR (DMS0-d _g, o): 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.

- 90 Analysis for ^G 23 ^H 20 → 4 ° 2 ^S calculated: C, 60.72; Η 5.10; ΪΤ 12.31%;

Found: C, 60.62; H, 5.15; m, 12.25%.

Example 27 (a) Preparation of (Z) -I- (4-Chloro-2-butenyl) phthalimide

The title compound was prepared according to the procedure described in Example 24, Step (a), from 13.0 g (0.0702 mol) of phthalimide potassium and 26.5 6 (0.211 mol, 3.0 eq) of cis-1- ^ dichloro-2-butene. The crude product was purified by flash chromatography eluting with 4: 1 hexane: ethyl acetate to give the title compound (12.87 g, 78%) as a pale yellow solid. This product was found to be a 90:10 mixture of isomers (Z) and (E), m.p. 65-66 ° C.

NMR (CDCl ₃ ,?); 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). The signals observed on the trans isomer can be seen in parentheses. ¹⁵ C ”3. (0301 ^, ^): 34.05, 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) (Z) -iT- {4 - [, 4- (1,2-Benzisoliazol-5-yl) -1-piperazinyl] -2-butenyl] -? Preparation of thallium hydrochloride hydrate

Compound ítjuk was prepared according to the procedure described in Example 15, step (a). A mixture of 9.36 g (0.0418 moles), 90 and 10 (z) and (E) -IT- (4-chloro-2-butenyl) phthalimide and 9.17 g (0.0418 moles) Reaction of 5- (1-piperazepinazinyl) -1,2-benzisothiazole (1.0 eq.) Gave 18.95 g of a dark orange viscous oil. The crude product was purified by flash chromatography (1: 1 hexane: ethyl acetate) to give 14.55 g (82%) of an orange oil which crystallized on standing. The product (8.44 g) was recrystallized from ethyl acetate to give 4.92 g of pale yellow crystals. This recrystallization ratio of isomers in the (E) to the (Z) -isomer of approximately 90: 10 to 97: 5 ^ ^to increase. The hydrochloride was prepared from product Ξ and crystallized twice from ethanol 9575. 1.54 g (7%) of (Z) -M- {4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl-2-butenyl} · -phthalimide hydrochloride hydrate are obtained, m.p. It is a pale yellow crystalline material and is composed entirely of the (Z) -isomer, m.p.

247-249 ° ^c -η

1 H NMR (DMSO-d _g , S): 3.52 (m, 4), 4.13 (m, 4), 4.39 (d, 2, J = 5.6), 5.87 (m, 2), 7.49 (ddd, 1, J - 8.1, 7.0, 1.0), 7.61 (ddd, 1, J - 8.1, 7.0, 1.0),

7 _? 88 (a, 4), 8.14 (dd, 2, J = 11.1, 8.1). ¹³ C NMR (DMSO-d ⁶ ,?):

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 of the calculated; C, 60.12; II found:

59.73; H, 5.17; % 12.11; H ₂ O, 0.51%.

···· V *:

Example 92 (a) Preparation of 2- (2-Hydroxy-ethyl) -1,2-benzisothiazol-3 (2H) -one

Into a 150 µL beaker was added 20.0 g (0.0583 mol) of 2,2'-dithiobis (benzoyl chloride). [J.P. Yevich et al. (1986) J. Med. Chem. 29, 559-569], 50.0 ml of DIHI were added and chlorine gas was bubbled through the cloudy solution. The color of the reaction mixture turns rust red. Into another flask. A solution of 7.12 g (0.112 mol, 2.1 eq.) Of ethanol amide, 16.5 ml (11.3 g, 0.117 mol, 2.1 eq.) Of triethylamine and 50.0 ml of DEM is added and cool with ice water baths. The bis chloride solution is added slowly to the cooled solution of the amino alcohol with stirring. The resulting orange mixture was washed with water, the organic layers were separated, combined, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. 22.74 g of an orange oily crude product are obtained. This material has ^ Ή-ΓΪΙΊΒ. · Its spectrum is consistent with the structure of the title compound and is used without further purification.

Bending

Benzisothiazol-3 (2H) -one is dissolved in 100.0 ml of toluene, ice-water is removed and the reaction mixture is stirred at room temperature for 2 hours ···························································· ·· · • · · · · · ·

999 99 99 999 to get him out. The toluene and excess thionyl chloride were removed by distillation under reduced vacuum on a Hopkins condenser.

The orange-red residue was purified by thin-layer chromatography. Elution with hexane / ethyl acetate (1: 1) gave the title compound (10.24 g, 41% relative to 2,2'-dithiobis-Coenzoyl chloride) as an orange oil which solidified on standing, m.p. 73-78 ° C. ¹³ C NMR (CDCl 3, S)? 42.11, 45.90, 120.31, 125, 68, 126.80,

132.18, 140.65, 165.67., (C) 2- {2- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] ethyl] -1,2-benzisothiazol-3 ( Preparation of 2H) -one hydrochloride

This compound was prepared by ly. Prepared in a similar manner to that described in step (a). 3.54 g (0.0165 mole) of 2- (2-chloroethyl) -1,2-benzisothiazol-3 (2H) -one and 4.00 g (0.0182 mole).

6.94 g of crude 3- (1H-piperazinyl) -1,2-benzisothiazole (1.1 eq.) Which is purified by thin-layer chromatography.

ethyl acetate (1: 1) gave 4.00 g of the free anin base. This base is hiaroklo-

-i - Belt

M.p. 250-252 ° C (25%).

NMR (DMSO-d 6, A ') 3.46 (m, 6), 3.76 (br d, 2, J = 10.2), 4.10 (br d, 2, J 12.3), δ , 36 (br 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 (n, 3), 11.34 (br s, 1). ¹³ C NMR (DMSO-d 6, δ) 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.

··· * ··· «* ·· ··· · ···················································· ·

• · »··

- 94 Analysis for ^C 2CT20 * ^ ^0S 2:

Found: C, 55.48; Ξ a, 89; N, 12.94%:

Found: G, 55.53; H, 4.92; 1T 12.8 °%.

Example 29 (a) 2- [4- (1,2-Bis-isol-thiazol-5-yl) -1-piperazinyl] -propyl] -1,2-beazzo-thiazol-3 (2-one) -O Preparation of n hyd r0 chlorine

This compound was prepared according to the procedure described in Example 28, steps (a) to (c). 5.29 g (0.0252 mole) of 2- (3-chloropropyl) -1,2-benzisothiazol-3 (2H) -one and 5.09 g (0.0252 mole, 1.0 equiv.) Of 5- Reaction of (1-piperazinyl) -1,2-benzisothiazole gave 4.40 g of the desired product after flash chromatography, eluting with ethyl acetate. This was converted to the hydrochloride, which was recrystallized from 95% ethanol to give 3.41 g (52%) of the title hydrochloride as an off-white powder, m.p. 185-187 ° C.

Ski NMR (DMSO-d <s) :. 2.19 (a, 2), 3 _y 28 (a, 4), 3.55 (a, 4), 4.00 (in, 4), 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 (a, 2). ¹³ C NMR (DMSO-d 6, δ): 23.55, 40.48, 46.28, 50.49, 52.93, 121.08, 121.94,

123.90, 123.90, 124.51, 125.45, 125.52, 126.85. 128.02, 131.79,

140.51, 152.01, 162.07, 164.48.

Analysis for 0 _2Ί Η ₂₂ Η ^ 03 ₂ .1,5 HCl:

calcd: tt: 0, 54.21; H, 5.09; Π 12.04%; Found: C, 54.48: Ξ 5.46; ΣΤ 11.93 ^ ·

Example 50

Preparation of 2- {4- [4- (1,3-Benzisothiazol-3-yl) -1-piperazinyl] -butyl-1,2-benzisothiazol-3 (2H) -one hydrochloride This compound was prepared according to Example 28 (a) - ( c). 6.61 g (0.0275 mole) of 2- (4-chlorobutyl) -1,2-benzisothiazol-5 (2E) -oa and 6.78 g (0.0509 mole, 1.15 eq.) Reaction of (1-piperazinyl) -1,2-benzisothiazole gave 14.16 g of a dark orange oily product which was purified by thin-layer chromatography. Elution was carried out with a 4: 1 mixture of ethyl acetate and DKH and the resulting free amine base was recrystallized from 95% ethanol. 5.68 g of an off-white powder are obtained.

This was used to prepare the hydrochloride, which was recrystallized from 95% ethanol and dried in a vacuum oven. Yield: 2.81 g (22%) of the title hydrochloride as an off-white powder, m.p. 215-216 ° C.

Ή NMR (DMSO-d _g "<£): 1.75 (br s, 4H), 3.19 (m,

4), 3.49 (m, 4), 3.87 (m, 2), 4.02 (br 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 (de, 1, J - 8.1,

0.9), 8.09 (n, 2), 11.15 (br s, 1). ¹³ C NMR (DMSO-d _g): 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 of ^ 22 ^ ⁰⁵ 24¾ ^ 2 * ^c - calcd: C, 57.51; Ξ 5.46; E, 12.15%; Found: C, 57.21; Ξ 5.51; % 12.66%.

Example 31 (a) Preparation of 2- (4-Chlorobutyl) -1 (2H) -phthalazinone

Sodium hydride (2.56 g, 0.0855 mol, 80% dispersion, 1.25 eq.) Was covered with nitrogen gas in a 250 mL round bottom flask and the sodium hydride was washed twice with hexane. to the hydride 100.0 ml anhydrous

DllI is given.

10.0 g (0.0684 mol) of 1 (2H) -phthalazinone dissolved in 50.0 ml of anhydrous DEE are added to the suspension, and the resulting solution is stirred at room temperature for 50 minutes. The anionic solution thus prepared was treated with 8.67 ml (12.91 g, 0.0753 mol, 1.1 eq.) Of 1-bromo-4-chlorobutane over one spoon.

100.0 ml anhydrous DI.2? Add to a solution of 500 ml in a round-bottomed flask and stir at room temperature for 1 hour. As the reaction proceeds, the mixture becomes a light orange color. Thereafter, 10.0 ml of distilled water was added and most of the solvent was removed on a rotary evaporator. The residue is taken up in DEM and washed twice with 50 ml of water. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated; 16.49 g of crude product are obtained, which is purified by flash chromatography. Elution with 2: 1 hexane / ethyl acetate gave 13.11 g of a pale orange oil. According to the 1 H-1EZZR pattern, this product is 2- (4-chlorobutyl) -1 (2H)

80:20 mixture of phthalazinone and the corresponding bromine number (determined by the integration of triplets at ρρη 3.56 and 3.45), difference n.O.e. " tests against O-alkylated products refer to IT-97 alkylated products. The chloride-bromide mixture was used without further purification.

(b) 2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -

- butyl] · - (2H) -phthalazinone hydrochloride

This compound was prepared in a similar manner to that described in Example 13 (a). 3 * 93 S (0.0179 mol, 1.1 eq.)

3- (1-pierazinyl) -1,2-benzisothiazole and 4.00 g (0.163 mol) of 2- (4-chlorobutyl) -1 (2H) phthalazinone and 2- (4-bromobutyl) -. l (2H) phthalazinone 80:20

7.75% of crude product is obtained which is purified by thin layer chromatography. Elution with 3: 1 ethyl acetate: hexane gave the product (base) as a hydrochloride, recrystallized from aqueous ethanol, dried in a vacuum oven to give 4.09 g (55%) of the title compound as white crystalline hydrochloride, m.p. 252-255 ° C.

1 H NMR (DMSO-d 6, δ): 1.83 (n, 4), 3.22 (m, 4), 3.61 (br 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 (br s, 1). ¹³ C NMR _(DMSO-fi, o): 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, 1-16.

Analysis for C ₂ yl ₂ ^ L ^ O.HCl:

Calc'd: C, 60.58; H, 5.75; K, 15.56%; Found: 0, 60.47; H, 5.78; IT 15.29%.

Example 32 (a) Preparation of 4-ethyl-1 (2H) -phalazinone

75.0 g (0.46 mol) of 2-acetylbenzoic acid are dissolved in 800.0 ml of 95% ethanol to give 33.0 ml (0.57 mol) of 85% hydrazine hydrate and 50.0 of ethanol (95 ml) was added and the solution was refluxed for one hour.

half of the original volume of the solution in a moon, rotary evaporator. The solid product is filtered off, dried in a vacuum oven to give 68.19 S (93%) of the title compound as a white solid, m.p. 222-224 ° C. A. Hirsch and D.G. Orphanos:

J. Week. Chem. 53 (1963) 2H NMR (DMSO-d6, 6): 2.50 (s, 3), 7.81-8.26 (o,

4), 12.40 (br s, 1).

Analysis for CqHqI ^ O:

Calculated: C, 67.49; H, 5.03; Π 17.49%;

found:

(b) Preparation of 2- (4-3-bromobutyl) -4-methyl-1 (2H) -phthalazinone

Compound Ξ was prepared in a similar manner to that described in Example 31, step a. Reaction of 50.0 g (0.31 mole) of 4-methyl-1 (2H) phthalazinone with 80.33 g (0.37 mole) of 1,4-dibromobutane gave 51.05 g (3%) of the title compound. m.p. 166-172 ° C.

99.99 NMR (DMSO-d6,?) $

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 (?, 2), 8.29 (dm) , 1, J = 8.7).

(c) Preparation of 2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -4-methyl-1 (2H) -phthalazinone hydrochloride

This end is prepared according to the procedure described in Example 13 (a). 2- (4-Bronobutyl) -4-methyl-1 (2H) -phthalazinone (2.48 g, 8.4 mmol) and 1.95 S (8.80 mmol, 1.05 eq.) 3- (i) The crude product from the reaction of piperazinyl) -1,2-benzisothiazole is recrystallized from acetonitrile to give 2.89 g of a pale orange solid free base. This was converted to the hydrochloride, recrystallized from 95% ethanol, and dried in vacuo. 2.71 g (68%) of the title hydrochloride hydrate is an off-white powder, m.p. 228-230 ° C.

NMR (DMSO-dg, S) n _R 80 (br s, 4H), 2.56 (s, 3), 3.20 (m, 4), 3.52 (m, 4), 4.04 (br 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 (η, 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 (br s, 1). ¹³ C NMR (DMSO-d 6, S): 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 Ο ^ Ο ^ Ε-ΟΕ.ΖΞΟΙ.0.25 HgO: Calculated: C, 60.75; H, 6.05; Ϊ7 14.76%; results; 0 60.75; E, 6.11; 17 14.75 ^.

- 100 -

Example 33

0.956 g (3.59 omol) of (4-bromobutyl) phthalimide,

0.740 g (3.59 nmol, 1.0 eq.) Of 3- (4-piperidinyl) -1,2-benzisothiazole, 0.57 ni (0.412 g,

of amine and 5.0 ml of acetonitrile was refluxed overnight in a round-bottomed flask, protected by nitrogen gas.

The reaction mixture was quenched with saturated potassium carbomate solution, evaporated to give 1.65 g of IT-4- [4- (1,2-benzisothiazole-3 il) -pipenidinoylbutyl] phthalimide is obtained which is converted into a fish product. The free base was taken up in ethyl acetate and 2.7 µl of a 1T ethereal hydrogen chloride solution (1.0 eq) was added. The resulting salt was recrystallized from aqueous ethanol by image analysis and • · * • ·

- 101 ^Σ Η NMR (DMSO-d6): 1.73 (o, 4), 2.21 (b, 4), 3.12 (br s, 4), 3.62 (b, 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 ( a, 4), 8.21 (d, 1, J = 8.1), 8.28 (d, 1, J 8.1), 10.13 (br s, 1). ¹³ C NMR (DMS0-d _fi, S) t 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 _z 33, 151.89, 167.49, 167.94.

Analysis: Calculated for C 8 H 12 N 3 O 4 S · H 2 O · H 2 O 2: C, 61.99; H, 5.35; I 9.04%;

Found: C, 61.80; H, 5.89; H, 9.05%.

Example 54 (a) Preparation of 1T- (2-Ethenethyl) -carbamic acid ethyl ester

51.1 mL (50.0 g, 0.248 mol) of phenethylamine (available from Aldrich Chemical Company), 54.6 mL (25.1 g, 0.248 mol),

A mixture of 1.0 eq. Of triethylamine and 300.0 ml of anhydrous DKm was cooled in a 1 liter, 3-neck, round-bottomed flask equipped with a magnetic stirring funnel and nitrogen inlet, and 23.7 µl (26.9 g, 0.248 mol) (1.0 eq.) Of ethyl chloroformate and 25 ml of DELI are added dropwise. The reaction mixture was stirred for CC minutes and then 150 ml of ether was added.

The resulting suspension is filtered, the filtrate is evaporated and the crude product is used without further purification.

- 102 (b) Preparation of 2,4-Dihydro-1 (2H) -isoquinolinone

A mixture of 46.0 g (0.258 mol) of ethyl 11- (2-phenethyl) -carbamic acid and 475.0 g of polyphosphoric acid in a 1 liter round-bottom flask equipped with a magnetic stirrer and reflux was heated at 140-160 ° C for 2 hours. the mixture was allowed to cool to room temperature and the product extracted with ethyl acetate (2.4 L) was washed with brine, dried over magnesium sulfate and, after filtration, concentrated to give the title compound as a light orange oil.

H

NMR (CDCl ₃ , δ): 3.01 (t, 2, J-6.6), 3.58 (dt, 2, J-2.9, 6.6),

6.20 (br s, 1), 7.22 (dd, 1, J - 0.7, 7.4), 7.36 (ddd, 1, J 1.3, 7.6, 8-, 3 ), 7.46 (ddd, 1, J = 1.6, 7.5, 9.0), 8.07 (dd, 1, J ', 1.1, 7.7).

The reaction mixture was poured into a 100 ml round-bottomed flask with nitrogen inlet and the sodium hydride was washed three times with hexane. To the washed sodium hydride, 20.0 ml anhydrous

Give DI.ZF • · · «··· ·· · * ···

To the cooled reaction mixture was added dropwise 3,4-dihydro-1 (2K) -isoquinolinone (1.85 g, 12.6 mmol, 1.0 equiv) in DLIF (20.0 mL). The reaction mixture was stirred for 15 minutes under cooling, then allowed to warm to room temperature,

(1 x 9 mL, 1p, 3 mmol, 1.1 eq.) 1-Bron-4-chlorobutane was added dropwise.

allow to warm to ambient temperature and stir for 30 minutes.

The reaction mixture was quenched with 10 mL of distilled water, the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. 5.16 g of an orange oil are obtained, which is purified by flash chromatography. Elution with 3: 2 hexane: ethyl acetate gave 1.90 g (63%) of a colorless oil.

(d) 1T-? 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -

Preparation of butyl] -3,4-dihydro-1 (2E) -isoquinolinone hydrochloride

2- (4-Chlorobutyl) -3,4-dihydro-1 (2H) -isoquinolinone, 1.90 g (7.99 mmol), 2.10 g (9.59 mmol, 1.2 eq) 3 - A mixture of (1-piperazinyl) -1,2-benzisothiazole, 1.56 mL (1.15 g, 11.2 mmol, 1.4 eq.) Of triethylamine and 25.0 mL of acetonitrile with magnetic stirrer, with radiator and nitrogen inlet

10C ml round bottom flask protected with nitrogen for 50 hours ································································•

Reflux under 104 reflux. At this point, the TLC analysis showed that the reaction was not complete, so 0.350 g (1.60 mmol, 0.2 equiv) of 3- (1-piperazinyl) -1,2-benzisothiazole and 0.670 mL (0.486 g, 4.81 triethylamine (0.6 eq., mmol) was added and the reaction mixture was refluxed for a further 24 hours, then allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate.

The solution was washed with saturated potassium carbonate solution, and the organic layer was dried over magnesium sulfate, filtered and evaporated. so

5.2 g of an orange oil are obtained. This crude product was purified by flash chromatography eluting with 0.1% triethylamine in ethyl acetate to give 2.26 g of an orange oily free base. The latter was taken up in ethyl acetate, 5.57 µl of 1 µl ethereal hydrogen chloride solution (1.0 eq.) And the resulting salt was recrystallized from ethanol. Thus, the title hydrochloride is obtained as a pale orange solid. Yield: 2.0 g (55%), m.p. 229-231 ° C.

Si NMR (DMSO-d ₆ → 5): δ _T 66. (n, 2), 1.78 (m, 2), 3.00 (ε, 2, J -6.6), 3.27 (n 4), 3.52 (m, 8), 4.07 (br 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 (br s, 1). ¹³ C NMR (DMSO-d 6, δ) S 20.46, 24.37,

27.36, 45.36, 45.69, 46.31, 50.44, 55.22, 121.14, 123 ^ 95, 124.56, 126.60, 126.91, 127.17, 127, 26, 128.06, 129.15, 131.45, 138.60,

152.05, 162.17, 163.17.

····· «·· ·· * ·« · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 105 Analysis for Cg ^ HggíT ^ OS.ECl:

Calculated: C, 65.07; H, 6.40; H, 12.26%;

found; 065.04; H6,43; 1, 12.23%.

Example 35 (a) Preparation of 2- (11,10-IT-Bimethyl-H-formamidinyl) -benzoic acid methyl ester

This compound is described in JT Gupton et al., Tetrahedron 43 _; 1747 (1987) 3. 6.0 g (45.3 mmol) of anthranilic acid treated with 15.5 mL (13.9 g, 116.3 mmol, 2.67 eq.) Of 11,11 - 3-methylformamide (dimethyl acetate), 2 g (69%) of the title compound are obtained as a bib-liquid.

(h) Preparation of 3- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl (3H) -quinazolinone hydrochloride

0.960 g (5.51 mmol, 1.1 eq.) Of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 15, step b), , 1 g of p-toluenesulfonic acid in 45 ml of anhydrous 1,4-dioxane and 0.621 g of '(3.01 mmol, 1.0 equiv.) In 2- (11,17-dimethyl-1'-formamidinyl) in The mixture of methyl ester of zoic acid was refluxed for 1 hour in a 250 ml round-bottomed flask equipped with a flame-dried magnetic stirrer, a reflux condenser and a nitrogen inlet, then allowed to cool to room temperature and evaporated. The oily orange residue was ethyl acetate and ethyl acetate

This organic solution was dissolved in DIG.I and the saturated potassium organic layer was dried over magnesium sulfate, filtered and evaporated to give 1.41 g of a tan solid. Ξ crude product flash chromatography ········· *

Purify with 106 using a 24: 1 mixture of DEM and methanol to give 1.02 g of solid free base. The free base was dissolved in ethyl acetate, 2.43 mL of 1 N HCl (1.0 eq) was added and the resulting hydrochloride was recrystallized from aqueous ethanol to give 0.810 g (59%) of the title compound. white solid hydrochloride, m.p. 258-240 ° C (with decomposition).

1 H NMR (DMSO-d 6, S): 1.80 (brs, 4), 3.28 (m, 4), 3.47 (br t, 2, J - 12.6), 3.58 (br d) , 2, J - 12.0), 4.05 (br 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 (br s, 1). ¹³ C NMR (DMS0-d _fi, E): 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 a

_O C _was -űi -Here-0S.HCl

2p 25 5:

Found: C, 60.58; H, 5.75; N, 15.56%;

found; 060.68; H5,75; 17 15.41%.

Example 36 (a) Preparation of 2-Amino-iT-4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butybenzamide hydrochloride

In a round-bottomed flask equipped with a magnetic stirrer and a nicrogen inlet flask, 0.394 g (5.43 mmol) of isatinic anhydride (available from Aldrich Chemical Company), 15.0 Al ethanol and

1.59 δ (5.48 mmol, 1.0 equiv.) 3- [4- (4-Amino-butyl) -1-piperazinyl] • 9 • * · ♦ · · * «··· ·· ·· · ·

- 107

The mixture of -1,2-benzisothiazole (see Example 15, step b) was stirred at room temperature for 22 hours and the solvent removed in vacuo to give 2.31 g of a brown oil. This crude product was purified by flash chromatography eluting with a 19: 1 mixture of DI3: methanol to give 1.28 g of an orange oil which solidified on standing to a pale yellow product. To a solution of the free base (0.35 g, 0.355 mmol) in ethyl acetate was added ethanol followed by 0.855 mL of a solution of 1ogén ethereal hydrogen chloride (1.0 equiv). Recrystallization from the hydroethanol thus obtained gave 0.250 g (60%) of the title compound as a white solid, m.p. 227-228 ° C.

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

3.27 (n, 6), 3.47 (br t, 2, J - 12.8), 3.59 (br d, 2, J - 12.4),

4.09 (br d, 2, J = 13.2), 6.41 (br 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 (n, 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 (br s, 1). ¹³ C NMR (DMSO-d _g , g): 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 calculated for C22 H25 N2 O2% 588% O: Calculated: 0 59.25; H6,33; 17 15.70%;

Found: C, 59.13; H, 6.55; % 15.68%.

Example 57 (a) 3- (4- [4- (1,2-Benzisoliazol-3-yl) -1-piperazinyl] butyl] -1,2,5-benzo-triazine-4- (5H) ) -one hydrochloride

0.930 g (2.54 mmol) of 2-anino-7 '- [4-14- (1,2-benzisothiazole) ·

- 108 -5-yl) -1-piperazinyl] butybutylbenzamide (see Example 36 (a)), a mixture of 11.0 ml of distilled water and 1.06 ml of concentrated hydrochloric acid in a round-bottomed flask fitted with a nitrogen inlet and a funnel. cooled in an ice-water bath and a solution of 0.136 g (2.70 mmol, 1.15 eq) of sodium nitrite in 2.58 distilled water was added dropwise with stirring. The reaction mixture was stirred for 2 hours and treated with 1.2 mL of 10 N sodium hydroxide solution. After 1 hour, the pH was adjusted to 6-7 by addition of acetic acid and the pH was raised to 10 with 10 H sodium hydroxide solution. The organic material was extracted with ethyl acetate, and the organic extract was dried over magnesium sulfate, filtered, and concentrated to give 0.900 g of an orange oil. This crude product was purified by thin layer chromatography using ethyl acetate / hexane (2: 1) as eluent to afford 0.650 g of a white solid, titled base. The free base was dissolved in ethyl acetate and to this solution was added 1.5 µl of 1ΪΤ ethereal hydrogen chloride solution (1.0 eq.). The hydrochloride thus obtained was recrystallized from aqueous ethanol to give 0.490 g (46%) of the title compound as a white solid hydrochloride, m.p. 242-243.5 ° C.

NMR (DMSO-d6, δ): 1.89 (m, 4), 3.24 (a, 4), 3.43 (br t, 2, J = 11.9), 3.59 (br t, 2, J - 11.1), 4.07 (br d, 2, J 11 _; 4), 4.46 (t, 2, J - 6.5), 7.47 (tn, 1, J - 7) , 5), 7.60 (on, 1, J - 7.5), 7.96 (ddd, 1, J - 1.3, 7.2, 7.9), 8.12 (m, 3), 8 , 24 ^(<Íd ' ^X ' 13 ~ ^0/7 '^8/1>' ^{8/29 <ddd} ' ^X ' ^J "° ^{/ 5, 1/4} ' ^7j9) '^{10> 5 (br} s, 1). C NMR (DMS0-d _fi, 5): 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.

• ν · * ···· · a

Analysis for C ^ Hg ^ NgOS.HCl:

Calculated: C, 57.82; H, 5.51; IT 18.39%;

Found: 057.92; H, 5.55; 1118.45%.

109 Example 38 (a) Preparation of [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl} -3-chloro-5-ethyl-2,6-dimethoxybenzamide hydrochloride

300 ml,

100 ml of anhydrous toluene and 4.52 g (0.0176 mol) in a round-bottomed flask under nitrogen

3-Chloro-5-ethyl-2,6-dimethoxybenzoic acid (from 2,4-dimethylacetophenone (Aldrich Chemical Company) by the method of Paulis et al., J. I. Ed. Chem. 28, 1263-1269 (1985) and

J. LIed. Chem., 29, 61-69 (1986)]

Thionyl chloride (4.15 mL, 0.0476 mol, 2.7 eq.) Was added. The pale yellow solution was heated to 75 ° C and 0.25 mL of anhydrous DLIF was added. The reaction mixture was heated at 65-75 ° C for 85 minutes, and then the solvent was removed on an evaporator. The orange residue was taken up in 50 ml of anhydrous chloroform and a nitrogen gas was passed through. 3- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzoisothiazole (5.63 g, 0.0194 mol, 1.1 eq.) Was added to the acid chloride. followed by addition of anhydrous triethylamine (2.94 mL, 0.021 mol, 1.2 eq.).

pure orange

-we wash it.

The organic phase is dried over magnesium sulfate • ·· ·····································

Stir, filter, evaporate to give 10.05 g of a viscous orange oil which is purified by flash chromatography as a crude product.

Elution with ethyl acetate followed by ethyl acetate containing 0.1% triethylamine gave 4.78 g of the free base as a pale yellow oil. This free base was dissolved in ethanol and 9.24 mL of 1 IT hydrogen chloride olate was added. The solution is heated, filtered hot, ether is added to the ethanol solution and the mixture is allowed to cool. The solid which precipitated on cooling was filtered, washed with ether and dried in vacuo. Yield: 2.96 g (50%) of a tan powdered hydrochloride m.p. 198.5-200 ° C.

-¼ NMR _(DMSO-d6, £): 1.16 (6, 3, J - 7.5), 1.60 (m, 2), 1.83 (br s, 2), 2.58 ( q, 2, J = 7.5), 3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br 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 (br s, 1). ¹³ C NMR (DMSO-d _g, S) jl4,76, 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 02 ^ 9 ^ 9 ^ 801.1101:

Calc'd: 056.41; % 6.19; N, 10.12%;

Found: C, 56.31; H, 6.18; IT 10.08%.

Example 39 (a) Preparation of 2,3-Dihydro-3-O-o-indazole-1-carboxylic acid ethyl ester

Starting materials are 3-indazolinone (Aldrich Chemical ti. S. 3. Uyrick et al.

111 before [J. Lied. Chem. 2E, 768 (1984)], m.p. 193-195 ° C.

NMR (BMSO-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 (br s, 1). ¹³ C NMR (DMSO-d ₆ , $) _: 14.14, 62.84, 114.09, 117.16, 120.43,

123.36, 130.00, 140.28, 150.04, 158.50.

Analysis for C ^ qILj:

calcd: C, 58.25; H, 4.89; IT 13.59%;

Found: C, 58.50; H, 4.95; H, 13.61%.

(b) 2- (4-Chloro-b-ethyl) -2,3-dihydro-5-oxo-1 H -indazole-1-carboxylic acid ethyl ester and 2- (4-bromobutyl) -2 Preparation of 3-Dihydro-3-oxo-1H-ind ol-1-carbono ss av-e tyl and z ter

In a 25C mL flame-dried three-necked round bottom flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen inlet, was washed with 1.51 g (? 0.3 mmol, 1.2 equiv.) Of hexane and then

DI.E. was added and 3.65 g (41.9 ol) of 2,3-indidro-5-oxo-1 H -indazole carboxylic acid was added. 5.31 (7.91 g, 46.1 mmol, 1.1 equiv.) Of l-bromo-4-chlorobutane are then added to the cooled reaction mixture, or the reaction mixture is · 9 ···· «··· · ν 99 · • · · · »·· • ··· 99,999 · · · · · & · · · 999 99 99 ···

Evaporate in 112 villages, partition the residue between ethyl acetate and distilled water. The organic layer was dried over magnesium sulfate, filtered to yield 12.2 g of an orange oil. The% 3-BLIR spectrum of this crude product indicates that both IT-alkylated and O-alkylated products were formed. Furthermore, these alkylated derivatives were prepared as mixtures of the corresponding chlorine compounds and bromine compounds. The crude products were purified by thin-layer chromatography using hexane (3: 1) to give ethyl 2- (4-chlorobutyl) -2,3-dihydro-3-oxo-1H-indazole-1-carboxylic acid ethyl ester. and 2- (4-bromobutyl) -2,3-dihydro-3

2.00 g of a mixture of ethyl oxo-1H-indazole-1-carboxylic acid are obtained. The mixture is a 60:40 mixture of chloride and bromide. The ratio of chloride to bromide was determined by integrating their methylene triplets at 3.39 and 3.52 ppm, respectively. This product was used as a mixture without further purification or isolation of the halides.

(c) 2- {4-L4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -butyl} -2,3-dihydro-3-oxo-1 H -indole Preparation of av ethyl ester hydrochloride

2- (4-Chlorobutyl) -2,3-dihydro-3-oxo-1H-indazole-1-carboxylic acid ethyl ester and 2- (4-bromobutyl) -2,3-dihydro-3- of a 60:40 mixture of oxo-1H-indazole-1-carboxylic acid ethyl ester, 3.13 g (9.63 mmol), 3.34 g (17.3 mmol, 1.3 eq) of y- ( 1-piperazinyl) -1,2-benzisothiazole and 2.44 mL (1.77 g,

17.5 mmol, 1.3 eq.) Of triethylamine in 30.0 ml of acetonitrile

···· * ··· • · · " • · ·· • ··· ·· • • tr • • · • • · • l • ·· • • 4 ·· ·· · · ·

A solution of 115 was refluxed under nitrogen for 50 days in a 50 mL round bottom flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen inlet, and then the reaction mixture was allowed to cool to room temperature with ethyl acetate and saturated potassium carbonate.

The organic extract was dried over magnesium sulfate, filtered and evaporated to give 7.18 g of an oily yellowish residue. This crude product was purified by flash chromatography eluting with 2: 1 ethyl acetate: hexane followed by ethyl acetate to give 2.97 g of the free base as a yellow oil. To a solution of the free base in ethyl acetate

6.2 ml of a 1: 3 hydrogen chloride solution (1.0 eq) were added and the hydrochloride thus obtained was partitioned between ethanol.

The title hydrochloride was obtained as a beige solid (0.52 g, 8%), m.p. 189-190 ° C.

NMR (DMSO-d6, $) _: 1.41 (t, 2, J = 7.1), 1.66 (br s, 3), 3.23 (m, 6), 3.42 (br t, 2, J - 12.1), 3.53 (br d, 2, J - 12.0), 4.05 (br 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 (br s, 1). ¹³ C NMR (DMSO-d 6, §):

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 Ο ^ Ξ ^ Ε ^ Ο ^ ', ΉΟΙ: Calculated; C, 58.19; H, 5.86; 3, 15.57%;

Found: C, 58.06; H, 5.89; 3 15.51%.

• * ·

- 114 -

Example 40 (a) Preparation of 2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-dihydro-3H-indazol-3-one hydrochloride In a JOO ml round-bottomed flask equipped with a magnetic stirrer, a niurogen inlet flask and a reflux condenser, 1.83 g (3.92 mmol) of 2- {4- [4- (1,2-benzisothiazol-3-yl) -piperazinyl] -butyl}. A mixture of -2,3-dihydro-3-oso-1H-indazole-1-carboxylic acid ethyl ester (see Example 39 (c)) and 23.7 mL of a 0.67 M solution of potassium hydroxide in ethanol under reflux for 2 hours. After cooling, the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated potassium carbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated; 1.37 g of an orange-red oil-like crude product are obtained. This crude product was purified by thin layer chromatography eluting with DK1I and methanol

A 92: 8 mixture was used to give 1.03 g of a pale yellow solid free base. This base was dissolved in a mixture of ethyl acetate and DELI, 2.53 mL of 1 L hydrochloric acid (1.0 eq.) Was added and the resulting hydrochloric acid was stirred in ethanol and

m.p. 30-90 ° C · (softens and aggregates, decomposes with bubbling at 125-145 ° C).

- 115 NMR (DMSO-d6, S); 1.77 (m, 4), 3.25 (m, 4), 3.44 (m, 2), 3.56 (br d,

- 6.0), 4.06 (br d, 2, J 8.0), 7.28 (dt, 1, J - 8.3, 8.2), 7.52 (ddd, 1, J - 1.2,

7.0, 8.2), 7.65 (dt, 1, J 2, J - 11 _r

7.11 (ddd,

7.47 (ddd,

8.3), 7.60

1 / .1), 8.12

2, J

7.1

6.4

1.1

11.4), 3.87 (t,

1, J = 0.8,

1. J = 1.1, <-dd, 1, J (t, 2, J = 7.8), 10.4 (br s, 1), 10.7 (br s, 1). NMR (DMSO-d6, S): 20.31, 25.04, 42.41, 46.33, 50.49.

112.12, 117.20, 120., 80, 121.15, 122 _f 87, 123.96, 124.58,

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

13.3)

0.8)

6.5

7.9, ¹³ C

54.94.

126.91,

Analysis for C ^ l ^ E ^ OS.HCl.0,75 H ₂ 0: Calcd calculated: G 57.76; Ξ 6.06; LT 15.51; H ₂ O, 2.95%. Found: C, 57.71; H, 6.10; V, 15.20; H ₂ 0, 2.75% ·

Example 41 (a) Preparation of 2-Amylo-r- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -5-chlorobenzarine hydrochloride

This compound was prepared according to the procedure of Example 36 from 1.02 g (5.17 mmol) of 5-chloro-isatinic anhydride (Aldrich Chemical Company) and 1.5 g (5.17 mmol, 1.0 eq) of 3- [ 4- (aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b). The free base was purified by flash chromatography eluting with ethyl acetate: hexane (1: 1).

Prepare the hydrochloride salt by recrystallization from aqueous eq. To give 1.61 g (655) of the title compound as a white solid hydrochloride, m.p. 175-176 °.

NMR (DMSO-d6,?): 1.57 (n, 2), 1.78 (n, 2), 3.10-3.68 (n, 12), 4.08 (br d, 2, J 13.1), 6.74 (d, 1, J - 8.9), 7.18 (dd, 1, J - 2.4, 8.8), 7.48 (ta, 1, J - 7.2), 7.57 (d, 1, J = 2.4), 7.60 (tn, 1, J = 7.2),

8.13 (t, 2, J = 8.6), 8.45 (t, 1, J = 5.3), 10.70 (br s, 1). ¹³ C

NMR (DMSO-d6, 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.

Analysis

Cg 2¾ ^ h ^ O.öCl · HCl sum image down tre:

calcd there: C> 5.00; H, 5.6c; 1Ϊ 14.58%; Found: C, 54.91; Ξ5, e9; 1. 14.51%.

Example 42 (a) Preparation of 2-Anino-iT-4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl-5-nitrobenzamide hydrochloride.

Example. Of 1.08 g (5.17 mmol) of 5-nitroisatinic anhydride (available from Trans Borid Chemicals) and 1.5 g (5.17 mmol, 1.0 eq) of 5- [4- (4-Amyloxy) butyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 15, step b), purified by flash chromatography, eluting with ethyl acetate. After the hydrochloride was prepared, it was crystallized from water-containing ethanol and then dried under high temperature to give 1.10 g (45%) of a cin, yellow solid hydrochloride, m.p. 224-250 ° C. C (during decomposition).

1 H NMR (DMSO-d ₆ , δ): 1.61 (m, 2),

1.80 (n, 2), 3.28 (n, 4), 3.46 (br t, 4, J - 12.1), 3.59 (br d,

2, J = 10.2), 4.08 (br 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 (br 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 (br s, 1). ¹³ C NMR (DMSO-d 6): 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.

- 117 Analysis a

calcd

calcd: C 53 → θ 2; Η 5 »54; IT 17.12%;

Found: C, 53.95; Ξ 5.57; H, 17.05%.

Example 43 (a) Preparation of IT- [4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] -butyl] -2- (methylanino) -benzamide hydrochloride

This compound was prepared according to the procedure described in Example 36 for 0.92 g (5.17 mmol) of T-methylisatinic anhydride (Aldrich Chemical Company) and 1.5 g (5.17 mmol, 1.0 equiv) of [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b). The free base was purified by flash chromatography eluting with ethyl acetate. After preparation, the hydrochloride was recrystallized from ethanol / ether and dried in a vacuum oven to give 1.22 g (51%) of a pale beige solid, m.p. 169-173 ° C. 1 H NMR (DMSO-d ₆ , δ): 1.58 (a, 2), 1.81 (a, 2), 2.77 (s, 3), 3.30 (a, 4),

3.48 (br d, 3, J - 13.8), 3.58 (br d, 3, J - 12.9), 4.07 (br d,

2, J - 14.8), 6.56 (t, 1, J - 7.4), 6 _? 63 (d, 1, J - 8.3), 7, 29 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.5), 7.57 (d, 1, J = 7, 2), 7.61 (d, 1, J = 7.4), 7.64 (br s, 1), 8.13 (t, 2, J = 8.3), 8.41 (br t, 1, J = 5.4), 11.00 (br s, 1). ¹³ C NMR (DMSO-d _g, S): 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.

• »

- 118 Analysis for Cg ^ Hg ^ N ^ OS.HCl:

date; C, 60.05; H, 6.57; 15.22%; Found: C, 60.09; H, 6.60; 1T 15.13%.

Example 44 (a) Preparation of (O) -cis-2- (ethoxycarbonyl) -1-cyclohexanecarboxylic acid

A round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 10.0 g (64.9 mmol) of cis-1,2-cyclohexanedioic anhydride (Aldrich Chemical Company) and 2.76 mL (2.18 g).

A mixture of methanol (68.1 mmol, 1.05 eq) was heated in an oil bath to 100 ° C for one hour, allowed to cool to room temperature and the excess methanol was evaporated in vacuo to give 12.0 g (100%) as an oil. m.p. 65-66 ° C. _η

H

NMR (CDCl ₃ , δ) -1.35-1.65 (a, 4), 1.80 (a, 2), 2.03 (a. 2), 2.86 (a, 2), 3, 68 (s, 3). ¹³ C NMR (CDCl ₃ , δ): 23.63, 23.75, 25.96,

26.26, 42.34, 42.48, 51.71, 174.04, 179.71.

( ") -Cis-2- (hydroxymethyl)

- Preparation of 1-c-cyclohexane carbonyls αv-methyl ester

Flame-dried round bottom flask with stirrer, drip funnel and nitrogen inlet, 11.7 g (63.0 mmol) (-) - cis

- 119

To a solution of -2-methoxycarbonyl-1-cyclohexanecarboxylic acid and 35.0 ml of anhydrous THE was added 69.0 ml (69.0 ol, 1.1 eq.) In a slow syringe, under ice-cooling and stirring, over 25 minutes. 1 M TH3 borane solution (Aldrich Chemical Company) was added. The solution was allowed to cool to room temperature overnight with stirring, then cooled in an ice-water bath and 55.0 ml of distilled water and 17.0 g of potassium carbonate were added.

After separating the aqueous and organic phases, the aqueous phase was extracted with more ethyl acetate and the title compound was a colorless oil.

NMR (CDCl ₃ , δ): 1.30-1.75 (a, 7), 1.89 (a, 1), 1.97 (t, 1, J = 6.0), 2.02 (a). , 1), 2.76 (a, 1), 3.63 (a, 2), 3.68 (s, 3). ¹³ C NMR (CDCl ₃ , δ: 23.55, 26.22, 26 _; 34, 40.65, 42.32, 51.44, 64.27, 175.75.

contempt for C _Q H ^ gO ^ calcd date: C, 62.77; H, 9.36%; found: C, 62.69; H, 9.35%.

(c) Preparation of 2-Pomylbenzoic acid mecyl and ester

7.20 g (41.8 mmol) of methyl (α) -cis-2- (hydroxymethyl) 120-methyl) -1-cyclohexanecarboxylic acid in a three-necked three-necked magnetic flask equipped with a thermometer and a nitrogen inlet flask, 42.0 of DI.IS0, 200.0 mL of DHI and 29.1 mL (21.2 g, 209 mmol, 5 equiv.) in ice-water cooled in three equal portions at 26.5 g (167 mmol, 4.0 equiv.) Sulfur trioxide-pyridine complex (Aldrich Chemical Company) is added. After stirring for 90 minutes, 200.0 ml of distilled water are added, the aqueous and organic phases are separated and the aqueous phase is extracted with DKL1. The combined organic phase is evaporated to give a pale orange liquid which is partitioned between distilled water and ether. The organic phase is dried over magnesium sulfate, filtered and evaporated. That's how it got

7.45 g of a pale yellow, oily crude product

The residue was purified by hexane / hexane to give 4.98 g (70%) of the title compound as a colorless liquid.

(d) (I) -cis-4a, 5,6,7,8,8a-Hexahydro-1 (2H) -phthalazinone and (I) -trans-4a, 5,5S, 7,8,8a-hexahydro- Preparation of 1 (2H) -Phthalazinone (mmol) 2-formylbenzoic acid methyl ester,

120 ml of 95% ethanol and 9.0 g (154 mmol, 2.2 eq.) Of hydrazine hydrate (as a solution)

Reflux with 85% reflux and nitrogen inlet for one minute at reflux, cool to room temperature and evaporate in vacuo. Their Nam is dismantled. The organic phase is dried over magnesium sulfate,

121 were filtered, evaporated to give 7.79 g (74%) of a pale yellow oily compound which was used without further purification.

(e) (-) - cis-2 (chlorobutyl) -4a, 5,6,7,8,8a-hexahydro-

-1 (2H) -Phthalazinone and (%) trans-2- (4-chlorobutyl)

Preparation of -4a, 5,6,7,8,8a-hexahydro-1 (2E) -phthalazinone

In a round-bottomed flask equipped with a flame-dried 500 ml three-necked magnetic stirrer, a nozzle inlet and a stoppered dropping funnel, 3.07 g (103 mmol, 2 equiv.) Of sodium hydride (80% oil dispersion) was washed three times with hexane. Add 0 ml of anhydrous DIJ ?. 7.79 g (51.2 mmol) of (-) - cis-4a, 5,6,7,8,8a-hexahydro-1 (2H) -phthalazinone and (1) -trans-4a, 5 are added to the suspension under ice-cooling. A solution of 6,7,8,8a-hexahydro-1 (2E) -phthalazinone (77:23) in 40.0 ml of anhydrous DEP is added slowly. After the addition was complete, 6.47 mL of 1-bromo-4-chlorobutane (Aldrich Chemical Company) was added dropwise (9.65 g, 56.5 mmol, 1.1 eq.). After 15 minutes, the excess sodium hydride was quenched by the addition of 30 mL of distilled water and the solvent was evaporated in vacuo. Wash the residue with water, mix with kernel

122 pts are obtained in the form of a colorless oil and the trans product of 3.78 is also obtained in the form of a colorless oil.

The value of the cis compound is 0.13 and that of ^the trans product is 0.20.

The cis isomer:? K-HI® (CBCl?): 1.25-1.71 (m,?), 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 (h, 1, J = 1.0, 2.6). ¹³ C El ® (CBCl ^S): 22.71, 23.25, 23.51, 24.29, 24.93, 29.15, 54.04, 57.06, 44.95, 46.10, 149.21, 167.55Analysis of glA-jOCl:

Calculated: C, 59.38; H, 7.89; % 11.54%; Found: 0, 59.28; II, 7.91; iT 11.48%.

Trans isomer A: ΗHL (CDClC, S): 1.28 (m, 4), 1.79 (m, 7), 2.10 (m, 2), 2.54 (m, 1). ), 3.56 (m, 2), 3.73 (m, 1), 3.34 (m, 1), 7.02 (s, 1). ^lr> C ®.® (CDC1 ₅ S): 25.03, 25.21, 25.54, 25.66, 28.42, 29.67, 37.52, 39.92, 44.61, 47 , 14, 150.53, 168.66.

Analysis of the formula:

date; c, 59.38; H, 7.89; N, 11.54%;

Found: C, 59.20; II, 7.35; 1T 11.43%.

(f) (t) -cis-2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -4a, 5,5,7,8,8a-hexahydro Preparation of -l (2Ξ) -Phthalazinone Chlorine

1.05 g (4.33 mmol) of (-) - cis-2- (4-chlorobutyl) -4a, 5,6,7,8,8a-hexahiaro in a round-bottomed flask equipped with a magnetic stirrer, reflux condenser and (2H-Phthalazinone, 1.04 g (4.76 mmol, 1.1 eq) 3- (1-piperazinyl) -1,2-benzisothiazole, 0.725 mL (0.526 g, 5.20 mmol, 1 2 eq.) Of triethylamine and

The reaction mixture was heated under reflux for 6 hours. At this point in time, according to TLC, the reaction was not complete, so 0.19 g (0.2 eq) of 3- (1-piperazinyl) -1,2-benzisothiazole and 0.12 ml (87 mg, 0, Triethylamine (86 mmol, 0.2 eq) was added and the reaction mixture was refluxed for the next day

The reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo, and the residue was taken up in DCM and washed with saturated potassium carbonate solution.

The organic phase was dried over magnesium sulfate and evaporated to give 2.54 g of an orange oil. This crude product was purified by flash chromatography eluting with 2: 1 ethyl acetate: hexane to give 1.05 g of a yellow oily free base.

To a solution of this free base in ethyl acetate was added 2.47 mL of a 1 L ethereal hydrogen chloride solution (1.0 eq), and the hydrochloride thus obtained was recrystallized from ethanol. Yield: 0.58 g (29%) of the white solid hydrochloride of cin containing 10% of the trans isomer, m.p. 191-195 ° C (with decomposition).

1 H NMR (DMSO-d ₆ , δ) _: 1.32 (n, 1), 1.46 (n, 3), 1.58 (m, 5), 1.73 (m,

3), 2.73 (m, 1). 3 ₇ 25 (m, 4), 3.46 (br d, 2, J - 12.4), 3.55 (br d, 3, J - 14.7), 3.70 (m, 2), 4.06 (br 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 (r, 2, J -8.1),

10.83 (br s, 1). 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.

- 124 Analysis for the formula 02 ^ Η ^ _Ί N ^ OS.HCl: Calculated: G 59.79; H, 6.98; / 15.16%;

Found: C, 59.32; H, 7.02; 15.08%.

Example 45 · (a) (I) -urans-2-f4-E4- (1,2,3-Benzisothiazol-3-yl) -1-piperazinyl] -outhyl-4a, 5,6,7,8,3a-hexahydro -1 (2Ξ) -Phthalazinone hydrochloride

2.92 g (13.3 mmol, 1.5 equiv.) Of 5- (1-piperazinyl) -1,2-benzisothiazole, 2.16 ml (1.57 g) in a round-bottomed flask equipped with an air-tight stirrer, a reflux condenser and a nitrogen inlet. refluxed at.

h under nitrogen at reflux condenser Foreza the reaction time of the test according VEK _Me üovábbi not therefore 0.450 g (2.05 mmol, 0.2 eq.) of 3- (1-ρ1Ρθrazinil) -l, 2-benzisothiazole and 0.72 ml (0.52 g, 5.14 mmol,

Triethylamine (0.5 eq.) Was added and the reaction mixture was cooled to reflux temperature and ethyl acetate was added. Up to 5.2 times an orange oily product is obtained, giving ayers a free base. To a solution of this base in ethyl acetate was 6.41 mL

- 125 -

Ether HCl in ether (1.0 eq) was added and the resulting hydrochloride was crystallized from a stand to give 2.24 g (47%) of the cin hydrochloride as an off-white solid, m.p. 186-138 ° C.

Si NMR (DMSO-d6, $) * 1.21 (m, 4), 1.61 (br q, 2, J 6.6) 1.71 (n, 4), 1.97 (m, 2) , 2.19 (m, 2), 3.24 (n, 4), 3.47 (br t, 2, J _- 13 0), 3.54 (br d, 2, J - 11.1) , 3.69 (td, 2, J 2 _Z 5, 6 _Z 5), 4.06 (br d, 2, J - 13.7), 7.16 (d, 1, J - 1.1), 7.48 (ddd, 1, J = 1.1. 7.0. 8, D, 7.60 (ddd, 1, J - 1.1, 7.0, 8.0), 8.12 (t , 2, J = 7.9), 10.8 (br s, 1). ¹³ C NMR (DMSO-d 6, δ):

20.14, 24.45, 24.65, 24.87, 25.35, 27.59, 36.68, 38.82, 46.25,

46.30, 50.41, 55.15, 121.13, 123.95, 124.56, 126.91, 128.06,

151.05, 152.06, 162.15, 168.07.

Analysis: Calculated for C ?? H ?? O? 3.1131: C, 59.79; H, 6.98; IT 15.16%; Found: C, 59.85; 6 6.97; 15.12%.

Example 46 (a) Preparation of 2- (4-Bromobutyl) -1,3 (2H, 4H) -isoquinolindione

In a three-necked round-bottom flask equipped with a reflux condenser and a addition funnel, 15 g (92.5 mmol) of homophthalic anhydride (Aldrich Chemical Company) and 3.54 mL (8.26 g, 92.5 mmol, 1 eq) were added.

A mixture of 4-amino-1-butanol was added in an oil bath at 150 ° C. The reaction mixture was poured slowly into 170 g of crushed ice with 150 g of crushed ice. The viscous organic material is separated from the ice and ethanol is added to give a white solid. Removal of the solvent in vacuo gave a yellow solid which was recrystallized from ethanol to give 17.1 S (62%) pale yellow, m.p. 87-39 ° C.

The product is obtained according to Iara cin, m.p.

1 H NMR (CDCl 3 S): 1.88 (m, 4),

7.26 (d, 1 'J' 7.5), 7.58. (cd, J, 7.4, 1.4), ¹³ C NMR (CDCl _{3 ,?} ) _? 26.26, 29.64, 32.55,

6.5), 4.02 (t, 4, J - 7.0), 4.03 (s, 2),

3.43

1. J

8.20

35.88, 164.32, found:

C, 52.79;

H, 4.30; N, 4.74%.

(b) 2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -1,3 (2H, 4H) -isoquinolinedione hydrochloride bridge in a round-bottomed flask equipped with a reflux condenser and nitrogen inlet. g (33 mmol) 2- (4

-bromobutyl) -1,3 (2H, 4H) -isoquinolindione, 7.96 g (36.3 mmol,

2-benzisoliazole, 5.52 mL (4.0 g,

39.6 mmol (1.2 eq) triethylamine and 50.0 ol are refluxed for 3.5 hours. First, the bleaching agent was ethyl acetate: hexane 2: 1 * «·· * ·« «« 4

A mixture of 127 and then pure ethyl acetate was used

11.9 g of the free base are obtained

The free base was treated with ethyl acetate hydrochloric acid (1.0 orange as an oil, 27.4 mL of 13 algae equiv.), And the resulting hydrochloride was recrystallized from aqueous ethanol to give 6.57 g (40%). m.p. 190-195 ° C.

NMR (DMSO-d6, .6): 1.64 (a, 2),

1.75 (a, 2), 3.10-3.60 (a, 4), 3.91 (q, 2, J - 6.8), 4.05 (br d, 2, J - 13, 0), 7.55 (a, 4), 8.12 (a, 4), 10.60 (br s, 1). ¹³ C NMR (DMSO-d 6, δ): 20 _r 57, 24.66, 36.02, 38.53, 46.32, 50.44, 55.12,

121.13, 123.94, 124.57, 124.84, 126.90, 127.20, 127.48, 127.93,

128.06, 133.46, 135.41, 152.06, 162.15, 164.53, 170.08.

Analysis for S.UCl.O.pHgO:

Calculated: C, 60.05; 3, 5.88; 3, 11.67; Hg0, 1.37%; Found: C 60, pO; 3, 5.35; 3, 11.74; HgO, 1.79%.

Example 47 (a) Preparation of 2- [4- (1,4-benzisothiazol-p-yl) -1-piperazinyl] butyl] -1,4 (23, pH) phthalazinedione hydrochloride

In a flame-dried, three-necked round bottom flask with magnetic stirrer, reflux and nitrogen inlet, sodium hydride (0.102 g, 5.39 mmol, 1 eq.) As an 80% oil dispersion) was washed three times with 10 mL of anhydrous Di. Cover with T. The suspension was cooled in an ice-water bath, 0.549 g (3.59 omol) of phthalic hydrazide and

1.2 g (3.39 mmol, 1, G equiv.) 8- (1, 2-benzisothiazol-3-yl) -5,8- ··· · · * · · · · · · · «· · 4 · · 4 4 4 4 · * * * *

12S-Diazaspiro [4.53 cyano-5-onium bromide] was added and the reaction mixture was refluxed the next day.

The reaction mixture was cooled in an ice-water bath and the excess sodium hydride was quenched with 5.0 mL of distilled water.

The solvent was evaporated in vacuo and the residue was dried over EtOAc, filtered and evaporated to give 0.63 g of crude product which was combined with an additional 1.3 g of crude product from a previous batch. The aqueous phases from both reactions were also combined and washed with DKLI. The DELI solution was filtered and concentrated in vacuo to give 0.34 g of crude product. The crude product (1.70 g total weight) was purified by thin-layer chromatography, eluting with 94: 6 Dili / methanol to give 0.64 g of the free base as a white solid. To its chloroform solution 1.47 ml 1 l ·; ethereal hydrogen chloride solution (1.0 eq) was recrystallized from aqueous ethanol to give 0.429 g (13%) of a white solid, m.p. 242-245 ° C (dec.). while).

1 H NMR (DMSO-d 6,; 1.81 (br s, 4), 3.26 (n, 4), 3.45 (br t, 2, J 12.0), 3.57 (br d, 2 J - 11.5), 4.06 (m, 4), _t 7. 41 (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 (br s, 1), 11.70 (br s, 1). ¹³ C NMR (DMS0-d _fi £): 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.

···· · »·« • ·

Example 48 (a) Preparation of 3,4-Dihydro-1H-2-benzopyran-1-ol

The title compound was treated with B.

Bonad ies and R.

[J. Org. Chem. 49: 1647 (1984). In a 1 liter flame-dried round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet, 32.3 ml (35.0 g, 0.261 mol) of 3,4-dihydro-1H-2-benzopyran (Aldrich Chemical Company), 56.3 g (0.261 mol), A mixture of 1 eq. Of pyridinium chlorochromate (aldrich Chemical Company) and 100.0 ml of anhydrous BKI.I is heated in an oil bath to 60-70 ° C. After 2 hours and then 4 hours, an additional 1 equivalent of pyridinium chlorochromate is added to the reaction mixture, which is refluxed until the following day.

the dark brown-orange residue was washed with Dlul.

ékesí-

The organic phase was evaporated to give 37 g of an orange oil.

This gave 20.2 g (52%) of the title compound as a colorless oil.

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), δ , 40 (tn, 1, J - 7.6), 7.54 (td, 1, J - 7.5, 1.3), 8.10 (dd, 1, J - 1.0, 7.8) ). ¹³ C NMR (CDCl 3 S) 27.82, 67.31, 125.30, 127.24, 127.68, 130.38, 133.67, 139.55,

165.13.

• «

130 -

(b) Compound 2- (4-Chlorobutyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-1-one was prepared according to the procedure described in Example 34, step (c). 0.46 g (2.85 mmol) 2,3,4,5-ethanedahydro-1H-2-benzazepin-1-one [Preparation of 3,4-dihydro-1H-2-benzopyran-1-one 17. 17. Gilman, see Synthetic Commun. 12, 573 (1982)] with 0.339 ml (0.586 g, 3.42 mmol, 1.2 equiv.) Of 1-bromo-4-chlorobutane gave 0.40 g (58%) of the title compound as an orange solid. , oily textiles.

(c) 2- {4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] -

Preparation of butyl-2,4,5,5,5-tetralidro-1E-2-benzazepin-1-one hydrochloride was prepared according to the procedure described in Example 34, step d). 0.40 g (1.59 mmol) of 2- (4-chlorobutyl) -2,5,4,5-tetrahydro-1H-2-benzazepin-1-one and 0.52 g (2.59 mmol) of 1.5 eq.) Of 3- (1-miperazinyl) -1,2-benzisothiazole gives 0.45 g of free base,

which is purified by flash chromatography

0.1%.

the hydrochloride is dried in a hot oven. This gave 227 mg (30%) of the title hydrochloride, which was beige. m.p. 215-217 ° C (dec.).

···· ··· * * ·· 1 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

1 H NMR (DMSO-d 6, 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 (br d, 2, J - 13 _r 0), 7.25 (dd, 1, J - 1.2, 7.5), 7.33 (cd, 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 (br s, 1). ¹ C NMR (DMSO-d6, δ) P

45.69,, 29.30,

46.35, 50.46, 55.23,

128.24,

20.61.

121.15,

130.51,

25.55

123.95, 124.57, 126.59,

136.25, 137.09, 152.06,

29.58, 45.59,

126.91, 127.94, 128.07,

162.16, 169.78.

Elemsás

11.39%;

uS-3.1

6.67;

EXAMPLE (a) T- {4- [4- (1,2-Benzisothiazol-5-yl) -piperidino] -butyl} -phthalimide was added and 1 mL of 2 x 2 · · ··· ·· ** · · «· * · • * 4 · ··« ··· · · * · * • «4 4 4 ··· • · · 44« 4 44444

Adjust to 10 by adding 132 alkaline solutions. The organic products were extracted with Dluil, the solution was dried over magnesium sulfate, filtered and evaporated. This gave 4.22 g (91%) of the title compound as an orange oil.

1 H NMR (CDCl ₃ ,?): 1.57 (a, 7),

2.10 (a, 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) ).

(b) Preparation of 2-Amino-η 4 -14- (1,2-benzisothiazol-5-yl) piperidino-n-butylbenzamide hydrochloride Compound h was prepared according to the procedure of Example 36. 0.68 g (4.15 romol) of isatic anhydride (Aldrich Chemical Company) 1.2 g (4.15 mmol, 1.0 equiv) of 3-yl- (4-aminobutyl) -4-piperidinyl] -1 1.38 g of free mark was reacted with 2-benzisol azole by flash chromatography using ethyl acetate: hexane 2: 1 as eluent,

0, l _z j ürietiltartalmazó as eluent.

Stopping the hydrochloride from water-containing ethanol

beige-

1.0 g (59%) of the title compound are obtained, m.p. 239-240 ° C.

NMR (DMSO-d6, S3x1.58 (m, 2),

1.78 (m, 2), 2.23 (a, 4), 3.14 (m, 4), 3.27 (q, 2, J = 6.3), 3.65 (m, 3) , 6.40 (br s, 2), 6.51 (ddd, 1, J = 1.3, 7.0, 8.4), 6.69 (dd, 1, J - 0.9, 8, 2), 7.13 (ddd, 1, J - 1.6, 7.1, 8.7), 7.52 (m, 2), 7.63 (ddd, 1, J - 1.0, 7 , 0, 8.0), 8.22 (d, 1, J - 8.1), 3.27 (d, 1, J - 8.1), 8.29 (a, 1), 10.0 (br s, 1). ¹³ C NMR (DMSO-d _g, S) t 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 0 ₂ ^ Η ₂ θΝ ^ 05.HC1:

· * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·

date: C 62.08; H 6 57; 1Ϊ 12.59 ′ found: C 62.11; H 6 61; ?

Example 50 (a) Preparation of E [4- [4- (1,3-Benzisothiazol-3-yl) -1-piperazinyl] butyl] carbamoyl} phenylacetal

In a 200 ml flame-dried round-bottomed flask equipped with a magnetic stirrer, a separatory funnel and a nitrogen inlet, 3.0 g (10.4 mmol) of 3- (4-aminobutyl-1-piperazinyl) -1,2-benzisothiazole. Example 13 (b)], a mixture of 1.74 mL (1.26 g, 12.5 mmol, 1.2 equiv) of triethylamine and 50.0 mL of DK was cooled in an ice-water bath and 2.06 g A solution of acetylsalicylic acid chloride (10.4 mmol, 1.0 equiv) in Aldrich Chemical Company (OKI) (20 mL) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 15 min, followed by cold saturated sodium hydrogen The organic phase is dried over magnesium sulfate, filtered and evaporated to give p.8 g of an orange crude product which is purified by flash chromatography.

Elution using a 95: 5 mixture of DILI and methanol to give the product of 2.93 S cin, which is the title compound and? 17- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butybutyl; Mixture of 2-hydroxybenzamide.

(b) Preparation of 17β-4- [4- (1,2-3-benzisothiazol-3-yl) -1-piperazinyl] butyl-2-hydroxybenzamide hydrochloride

2.93 S, 11- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -carbamoyl-phenylacetate and 17- {4- '4- (' 1,2-Benzisothiazole «4 · • · · · · · · · · · · · · ·

• ·· • ·

- A mixture of 134 -3-yl) -1-piperazinyl] butyl] -2-hydroxybenzamide and 30 µl of methanol was charged with a 300 ml magnetic stirrer, a addition funnel and a nitrogen inlet tube.

1.1 eq.) Of sodium methanolate (Aldrich Chemical Company) are obtained in the form of a base. The base was added with ethereal hydrogen chloride in ether (1.0 equiv),

2.32 g (50% relative to acetylsalicylic acid chloride) of II - {% - Γ4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -2-hydroxybenzamide hydrochloride are obtained. off-white solid

- - · lg

NMR (DMSO-dg): 5 1.63 (n, 2), L _Y 80 (m, 2), 3.27 (m, 6H), 3.47 (br t, 2, J - 12.7), 3.59 (br d, 2, J

13.5), 6.89 (m, 2), 7.40 (ddd, 1, J)

1, J {dd, 1, J

5.5), 10.80 (br

25,99,

121.14. 160.09,

1.1, 6.9, 8.1), 7.60

1.4, 7.9).

s, 1),

46.35.

124.57, 126.90, 169.03.

38.38.

123.95,

162.16,

- 1.7, 7.2, 8.8), 7.47, J - 1.1, 7.0, 8.1),

J = 8.4), 8.98 (br t, 1.13)

11.3), 4.07 (br d, 2, J (ddd,

7.90

1 H NMR (DMSO-d 6): 20.60,

118.43,

152.05, (ddd,

8.12 (t, 2,

12.68 (s, 1).

50.44, 55.06, 115.07, 117.31,

127.69, 128.07, 133.59,

Analysis for formula 022 ^ 256 ^ 028.HCl:

Calculated: C, 59.11; H, 6.09; 12.53%;

Found: C, 59.00; II 6.10; H, 12.47%.

- 155

Example 51 (a) Preparation of N - [4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] butyl] benzamide hydrochloride

The free base corresponding to the title compound was prepared according to Example 50, step (a). 1.5 g (5.17 mmol, 1.0 equiv) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole See Example 13, Step b) 0 Acylation with 6 ml (0.727 g, 5.17 mmol) of benzoyl chloride for 1 hour gives the free base (1.49 g), which is purified by flash chromatography. Elution was carried out with ethyl acetate containing 0.1% triethylamine. To a solution of the free base in ethyl acetate was added 3.8 ml of a solution of hydrogen chloride in ether (II) and the hydrochloride thus obtained was recrystallized from ethanol to give 1.04 g of the title compound as a beige solid, m.p. 201.5 ° C.

1 H NMR (DMSO-d 6 δ S): 1.61 (a, 2), 1.80 (a, 2), 3.27 (a, 6), 3.47 (br t, 2, J - 12.6 ), 3.59 (br d, 2, J - 11.7), 4.08 (br d, 2, J 13.4), 7.50 (a, 4), 7.60 (t, 1, J - 7.6), 7.87 (a, 2), 8.13 (t,

2, J = 8.4), 8.58 (br t, 1, J = 5.5), 10.72 (br s, 1). ¹³ C NMR (DMSO-d6?: 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 of ^G 22 ^ 26 ^ 4 ^0S,? - for ^G :

calcd: C, 61.31; H, 6.31; 17 13.00%; Found: C, 51.27; H, 6.54; 17 12.98%.

. (

I · * • «

- 156 -

EXAMPLE 52 (a) Preparation of H- (4-Chlorobutyl) -1T-methylbenzamide

This compound was prepared according to the procedure described in Example 34, step (c). 355 (22.2 mmol) H-methylbenzamide (Aldrich. Chemical Company) with 2.81 mL (4.19 g, 24.4 mmol, 1.1 equiv.) Of 1-bromo-4-chlorobutane ( Aldrich Chemical Gompany).

The crude reaction mixture was extracted with DKI.I and purified with son.

Elution with 2: 1 ethyl acetate: hexane gave 3.02 g (60%) of a pale yellow oily title compound.

(b) Preparation of N- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -1-methylbenzamide hydrochloride

This compound was prepared in a similar manner to that described in Example 34, step d). 1.50 g (6.65 mmol) of u-methyl-IT- (4-chlorobutyl) -beazamide 1.1 g (7.3 mmol, 1.1 equiv) of 3- (1-piperazinyl) -1 , With 2-benzisothiazole, refluxed overnight to give 3.64 g of crude free base

gyromskromatoí cleaned with graphics. Elution with ethyl acetate and hexane 2: 1 0.1% triethylamine is used, 1.40 g of the free base are obtained in the form of a yellow oil.

in. This was used to obtain the hydrochloride, which was recrystallized from ethanol-ether to give 0.76 g (26%) of the title hydrochloride as a white solid, m.p. 151-174 ° C.

hi NMR (DMSO-d _g, S): 1.57-1.83 (m, 4), 2.98 (n, 4), 3.26 (ni, 4) _3? 55 ( _m , 5) · 4.07 (br 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 (br s, 1). ¹³ C NMR (DMSO-d _g, £): 20.29, 23.68, 36.91, 45.74, 46.27, 50.40, 5 ^ 5.22, 121.14, 123.95,

124.56, 129.15, 136.70, 152.06, 162.17, 170Λ5.

I:

Calculated for ^C 23 ^H 28 ^ 4 ^0s * ^iI ^:

- 157 Analysis a

C, 62.08;

H, 6.57;

I'T 12.59%;

found

C, 62.01;

H, 6.56;

N, 12.55%.

reset

With magnetic stirrer, nitrogen inlet and

5.18 mmol (1.5 eq.) Of triethylamine and 10.0 mL of DKLi

A solution of benzoyl chloride (Aldrich Ohemical Company) in DKM (10.0 mL) was added dropwise. The reaction mixture was stirred for 30 minutes

1.4 g of a pale yellow solid are obtained, which is purified by flash chromatography. 0.1% triethylamine was added as eluent. The solvent was removed in vacuo and recrystallized from the resulting ethanol to give 0.915 g, m.p.

···· ···· eV ve • · e ♦ V • e ·· ve ♦ ·· • · ·· «·· t

- 158 ^X H NMR _(DMSO-d6, S): 1.60 (a, 2), 1.79 (a, 2), 3.15 to 3.37 (a, 5), 3 _r 45 (br ε, 3, J - 12.7), 3.59 (br d, 2, J - 12.0), 4.08 (br d, 2, J 12.9), 7.48 (ddd, 1 , J = 1.0, 7.1, 8.1), 7.55, (da, 2, J = 8.6), 7.60 (ddd, 1, J = 1.2, 7.0, 8.2), 7.90 (da, 2, J - 8.7), 8.13 (t, 2, J - 8.2), 8.68 (br t, 1, J - 5.5) , 10.59 (br s, 1). Nuclear Magnetic Resonance Spectrum (DMSO-d6, δ) 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.

Slashing the σ ₂₂ Ξ ₂₅ ΙΤ ₄ 0301.Η01.0.5 calculating bt

C, 55.69;

¢: 0th

f. " THE ! <U cx _ =. X u

r- r. example (the) Preparation of II- [4- (4- (1,2-benzisolazol-3-yl) -1-piperazinyl] butyl} -3,4-dichlorobenzamide hydrochloride This the compound was prepared according to the procedure described in Example 55 ·.

1.0 g (5.45 mmol) of 3- [4- (aminobuoyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b), 0.524 g (0.721 ml) (5.18 mmol, 1.5 equiv) of triethylamine and 0.723 g (3.45 mmol, 1.0 equiv) of 3,4-dichlorobenzoyl chloride (Aldrich Chemical Company). The crude reaction mixture was flash chromatographed.

bad base we get. Convert this base to hydrochloride water LTUL Θ G 8.0 0 X O C il crystallize; dried in a vacuum oven, s 0.08 g (51%) of a pale beige solid bridge rokloridoh m.p. 2C8-210 ° C (with decomposition).

···· · »·· ·· ·· · • · • · • 99 • * · " ·· · · · • • · · 9 9 • · • ·· · · · * · 99 · · ·

- 159 1 H NMR (DMSO-d 6, δ) δ 1.61 (ο, 2). 1.82 (m, 2). 3.27 (m, 6), 3.52 (η, 4). 4.07 (br d, 2, J 13.4), 7 _T 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 (br s, 1). ¹³ C NMR (DMSO-d 6, $): 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.

Claiming Ο ^ Η ^ Ι ^ ΟΒΟΙρ.ΞΟΙ:

found:

C, 52.86; H, 5.04; ΪΪ 11.21%;

52.94; H, 5.09; N, 11.16%.

Example 55 (a) Preparation of H-pt- [4- (2,1-Benzisothiazol-5-yl) -1-piperazinyl] -butyl} -4-methoxybenzamide hydrochloride according to the procedure of Example 53, 1.0 g (5.45 mmol) of 5- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b), 0.524 g (0.721 mL, 5.18 mL) mmol (1.5 eq.) of triethylamine and 0.589 S (3.45 mmol, 1.0 eq.) of p-anisoyl chloride (Aldrich Chemical Company). The crude reaction mixture was purified by flash chromatography.

A 93: 7 mixture of D 2 IN and methanol was used to obtain 0.73 3 pale beige blue solid free bases. From this, hydrochloride is produced,

The solid was recrystallized from a solid and dried in a vacuum oven to give 0.287 g (18%) of the title compound as a beige solid, m.p. 171-173 ° C (with decomposition).

···· · * ··························•

· · ·

140 NMR _(DMSO-fi, t C): 1:59, l _f 78 (a-2), 3.26 (a, 6), 3.49 (br d, 2, J - 12.1), (m 2). 3.58 (br d, 2, J - 13.8), 3.81 (s, 3), 4.07 (br d, 2, J - 13.4), 7.00 (da, 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 (da, 2, J - 8.9), 8.13 (t, 2, J - 8.3), 8.45 (t, 1, J - 5.6), 10.81 ( br s, 1). ¹³ C NMR (DMSO-d _g <f): 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 a

Share HC1 with one of the following tre:

060,00; 116.39; n 12.19%

Example 56 (a) Preparation of Ν '- (4- [4- (1,2-Benzisoyl-thiazol-5-yl) -1-piperazaziryl] -butyl] -4- (trifluoromethyl) -benzamide hydrochloride

3- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (1.0 g, 3.45 mmol) was prepared according to the procedure described in Example 53 (b). ), 0.524 g (0.721 mL,

5.18 mmol (1.5 eq.) Of triethylamine and 0.720 g (0.515 mL, 3.45 mmol, 1.0 eq.) Of 4- (trifluoromethyl) benzoyl chloride (Aldrich).

Chemical Company)

After the addition of 4- (trifluoromethyl) benzoyl chloride, the ice-water bath was stirred

Using 141 ethyl acetate, 0.57 g of solid free base is obtained. This was used to prepare the hydrochloride, which was recrystallized from ethanol to give 0.26 g (15%) of a solid cinnamid hydrochloride, m.p. 205-207 ° C (with decomposition).

NMR (DMSO-d6, A): 1.62 (m, 2), 1.83 (m, 2), 3.15-3.40 (m, 6), 3.50 (br t, 2, J - 13.0), 3.59 (br d, 2, J - 11.6), 4.08 (br 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 (br t, 1, J 5.5), 10.95 (br s, 1). ¹³ C NMR _(DMSO-fi, S): 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 _? 04th

5.25;

11.25%;

Example 57 (a) Preparation of 17- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -4-tert-butylbenzamide hydrochloride

5.18 mmol (1.0 eq.) Of triethylanine and 0.679 g (0.674 mL, 5.45 mmol, 1.0 eq.) Of tert-butylbenzoyl chloride (Alorich Chemical Company). The free base

0.560 g) was converted to the hydrochloride and recrystallized from ethanol.

- 142 after all. Yield: 0.251 g (15%) of the title beige hydrochloride, m.p. 220.5-222 ° C (with decomposition).

'Ή NMR (DMSO-dg, i') · 1.31 (s, 9), 1.60 (m,

2), 1.82 (a, 2), 3.25 (m, 6), 3.55 (m, 4), 4.08 (br 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 (n, 2), 8.55 (t, 1 , J = 5.7), 11.06 (br s, 1). ¹³ C NMR (DMSO-d 6, S): 20.82, 26.55, 31.15, 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 formula 0261 ^ 11 ^ 03.1101:

Calculated: C, 64.11; H, 7.24; % 11.50%;

C, 64.00; H, 7.25; IT 11.45%.

Example 58 (a) Preparation of IT- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl-4- (phenylazo) benzamide hydrochloride

3- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (1.24 g, 4.27 mmol) was prepared as described in Example 55 (b). 0.648 g (0.893 µl, 1.5 equiv.) of triethylamine and 1.05 g (4.27 mmol, 1.0 equiv.) of p-phenylazo) benzoyl chloride (available from: Kodak). The reaction mixture was stirred for 1 hour after the addition of p- (phenylazo) benzoyl chloride. The free base was purified by flash chromatography eluting with ethyl acetate / hexane 3: 1, 0.1% triethylamine.

A mixture of 143 was added, followed by ethyl acetate containing 0.1% triethylamine and finally a teaspoon to give 1.42 g of an orange solid and an orange solid which was converted to hydrochloride and water-containing ethanol. It is recrystallized. 0.589 g (26%) of an orange solid, m.p. 225-227 ° C.

1.82 (a, 2), 3.36 (a, 8),

2, J - 11.9), 7.49 (ta, 1,

First

of the title hydrochloride,

NMR (DMSO-d6, S): 1.67 (a, 2), (br d, 2, J = 10.4), 4.11 (br d,

7.6), 7.64 (a, 4), 7j98 (a, 4), 8.14 (a, 4), 8.82 (br t,

5.6), 10.50 (br s, 1).

46.36, 50.45, 55.12 ,.

123.97, 124.58, 126.91, 127 ^ 45, 129.52, 131.98, 132.61, 136.64, 155.71, 162.17, 165.18, 165.39.

Analysis calculated for C ₂ gE _X Q 1; gOS.ECl 62.85;

¹³ C NMR (DMSO-d

119.43, 119, 91, 121.16, 122.30,

127.95, 128.09. 128.50,

151.82, 152.07, 153.15,

3.63

J J 9): 20.65, 26.22, 38.56,

122.68,

128.84,

153.46,

H, 5.84;

N, 15.71%;

H, 5.85;

N, 15.63%.

Example 59 · (a) Preparation of 4-Acetamido-N- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butylsarnaria hydrochloride

In a flame-dried 100 ml three-necked flask equipped with a magnetic stirrer, a nitrogen inlet, a thermometer and a rubber partition, 0.742 g (4.14 mmol) of 4-acetanebenzoic acid (0.503 g, 0.693 ml, 4.97 mmol) were added.

1.2 eq.) Of triethylamine and 20.0 ml of anhydrous TEF were weighed.

The reaction mixture was cooled to -15 ° C with dry ice and isopropanol stirrers, followed by 0.565 g (0.537 mL, 4.14 mmol, 1.0 eq.) Of isobutyl chloroformate (Aldrich Chemical).

Company) and after 5 minutes stirring at 1.20 g (4.14 mmol, 1.0 equiv.) Of silicate for 1 hour and then return to room temperature;

carbonate solution abal. The organic extract was filtered using a map mixture to give a solution of 0.74 g of a white, navy product in 1.57 mL of 1 K hydrogen chloride solution (1.0 eq). The solvent was evaporated in vacuo to give a crystalline water-soluble ethanolic salt, and the salt was an opaque solid; we get, it is.

1.59 (m, 2), 2.07 (s, 3), 3.25 (n,

3.59 {br d, 2, J

- 7.5), 7.60 (t,

- 8.6), 8.13 (t, 1), 10.68 (br s, 38.34, 46.40,

126.95, 127.98, 128.12, 128.75, 168 ^ 66.

- 11.4), 4.08 (br

1, J = 7.6),

2, J = 8.3),

I). ¹³

50.49. 55.18;

NMR

6), 3.46 (br t, 2, d, 2, J (d, 2, J (br t, 1, J (DMSO-d

13.4), 7.48 (t, • 8.7), 7.82 (d,

5.2), 10.23 24.09, 118.01, 121.19, 124.00,

141.84, 152.11, 162.20,

7.66

8.46

C NMR (DMSO-d _g 20.67,

12.9)

1, J

2, J (s,

26.37, 124.61, 165.73, • ·

• · »summary le tre found

C, 59.06;

H, 6.20;

r 14.35%;

C, 58.99;

Ν 14.43:

(a) 4 - [(tert-3-isocycloyl) amino] -benzoic acid is prepared in a flask equipped with 10.0 g of 5% soda solution and 40.0 ml of 1,4-dioxane 500 with stirring and addition funnel!

place: Fluka) Drip a solution of 40.0 ml of 1,4-diisane with stirring

Stir 1,4-di. The solvent was evaporated in vacuo and the white was evaporated. The pH of the organic product was 11 1V.

1 H NMR (CDCl ₃ , δ): 1.50 (s, 9), 7.58 (d, 2, J - 8.8), 7.86 (d, 2, J - 8.8), δ , 76 (br s, 1), 12.67 (br s, 1).

- 146 ···· ·· ««

(b) Preparation of H- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl} -4 - [(tert-butoxycarbonyl) -amino] -benzamide hydrochloride

This compound was treated with the same procedure as in Example 59, 2.05 g (8.65 mmol) of 4 - [(tereroxycarbonyl) amino] benzoic acid, 1.05 g (1.45 mL, 10.4 mmol, 2 eq.) Of triebylamine, 1.18 g (1.12 ml. 8.65 mmol, 1.0 eq.) Of isobutyl chloroformate and 2.51 3 (8.65 mmol, 1.0 eq.) eq.) prepared using 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b).

The crude reaction mixture was purified by flash chromatography.

of ethyl acetate containing 0.78 g of a white solid free base. The impure fractions were combined and purified by flash chromatography using Dili / methanol 9: 1 as eluent to give 0.40 g of a white solid free base. The free bases from each column were combined, dissolved in a mixture of ebanol and chloroform, and 2.41 ml

Add 3 N hydrochloric acid (1.0 eq).

After removal of the solvent, the hydrochloride was recrystallized from ethanol to give 0.644 g (14%) of a beige solid zinc compound, m.p. 205-203 ° C (foaming).

1 H NMR (DMSO-d 6 ₎ δ 1.49 (s, 9), 1.60 (m, 2),

1.80 (m. 2), 3.10-3.54 (m, 8), 3.59 (m, 2), 4.08 (br d, 2, J 12.5), 7.55 ( a, 4), 7.80 (d, 2, J - 8.8), 8.14 (m, 2), 8.45 (br t, 1, J - 5.4), 9.64 (s) , 1), 10.80 (br s, 1). ¹³ C NMR (DMSO-d _g $)

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.

- 147 ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Analysis: Calculated for C I^H O ^N S.O.HCl: C, Η 6.64; H, 12.82%;

Found: C, 59.45; Ξ 6.65; IT 12.92%.

(a) Preparation of 5 - [(tert -Butoxycarbonyl) amino] benzoic acid according to the procedure described in Example 60 (a), 5.0 g (36.5 mmol) of 3-amino- benzoic acid (Aldrich Chemical

Conpany), 25 µl of 5% soda solution and 19.9 g (91.1 omol, 2.5 eq.) Of di-tert-butyl dicarbonate (Pinka). After 65 hours, the reaction mixture was worked up

7.48 g (86%) of the title compound

NMR (CDCl ₃ , 1): 1.49 as a white solid.

____ · .. hi______________ (s, 9), 7.37 (ε, 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 (br s, 1), 12.92 ( br s, 1).

(b) IT- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -3 - [(tert-butoxycarbonyl) amino] -benzanide hydrochloride hydrate production

This compound was prepared according to the procedure of Example 59, 2.45 g (10.3 mmol) of 3 - [(tert-butoxycarbonyl) amino] benzoic acid, 1.25 g (1.72 mL, 12.4 mmol). 1.2 eq.) Of triethylamine, 1.41 g (1.34 mL, 10.3 mmol, 1.0 eq.) Of isobutyl chloroformate and 3.0 g (10.3 mmol) of , Eq.) Using 5- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b) · · ··· ···· · · · · · · · · · · · · · · · · · · · · ·

- 143 Let's bring it out. After 20 hours, transfer the reaction mixture into a separatory funnel, wash the organic product with saturated potassium carbonate solution, dry over magnesium sulfate, filter, and evaporate. The crude free base thus obtained is purified by flash chromatography. eluting

Using a 95: 5 mixture of din and methanol, 2.82 g of a white solid free base are obtained. To a solution of 1.0 g of the free base (1.96 mmol) in chloroform is added 1.96 ml of 1 IT ethereal hydrogen chloride solution (1.0 equiv.) And the hydrochloride thus obtained is recrystallized from a mixture of ethanol and ether. so

0.46 g (23%) of the title compound is obtained as a white solid hydrochloride, m.p. 159-144 ° C (foaming).

hydrate

NMR (DMSO-d6, 9: 1.48 (s, 9), 1.59 (m, 2), 1.80 (m, 2), 3.16-3.54 (n, 8), 3, 59 (br d, 2, J - 11.8), 4.08 (br 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 (br t,

1, J = 5.6). 9.49 (s, 1), 10.72 (br s, 1). ¹³ C NMR (DMSO-d _g, S):

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 of Cg ^ -IT ^ U ^ S.ECl 0.75 HgO:

calcd: C, 57.95; H, 6.75; i; 12.51; ~ ₂ 0, 2.41%; Found: C, 57; H, 6.74; 17, 12.61; EgO, 2.44%.

Example 62 (a) Preparation of 4-Anino-IT- {4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] benzamide hydrochloride ···· ··· ·

- 149 mg (1.57 nmol) of 17- [4- [4- (1,2-Zisothiazol-5-yl) -1-piperazinyl] butynyl (800 mg, 1.57 nmol) in a 500 ml round-bottomed flask with a magnetic stirrer and nitrogen inlet. } -4- (tert -butoxycarbonylamino) benzamide (see Example 60, step b), 1.5 mL of anisole, 15.0 mL of anhydrous chloroform and 15.0 mL of trifluoroacetic acid After stirring for 30 minutes at room temperature and evaporating the solvent in vacuo, the crude oily residue was dissolved in ethyl acetate, washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and evaporated to give the crude amine as a yellow solid. Purified using 0.2% triethylamine in ethyl acetate as the eluent to give an oily amine base of 0.37 S. The amine in ethyl acetate and DKLI yielded 0.90 ml of a solution of 1 LT ether in ether (1.0 eq.). ), the solvent was removed in vacuo and the

hydrochloride from water-containing ethanol gave 200 mg (29%) of the title compound as a tan solid hydrochloride, m.p. 213.5-214.5 ° C.

Si NMR (DMSO-d 6): 1.56 (η, 2), 1.77 (m. 2), 3-27 (m. 6), 3.45 (br t, 2. J 12.5). . 3.59 (br d, 2, J - 11.9), 4.08 (br d, 2, J - 13.2), 5.61 (br 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 (br s, 1). ¹³ C NMR (DMSO-d ₆ , S) δ 20.65, 26.52, 38.11, 46.37, 50.44, 55.15, 112.43, 121.16, 123.96, 124, 58, 126.91, 128.08, 128.62, 151.44, 152.06, 162.18, 166.20.

Analysis for 0 ₂₂ ^ 27 ^ 5 ⁰³ · Η01:

calcd: 0 59.25; H, 6.33; 17 15.70%;

Found: C, 59.05; H 6.52; 17 15.62%.

• «·· •« ·· · • ·

- 150 -

Example 63 (a) Preparation of 3- N - {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -benzamide hydrochloride hydrate

This compound was prepared according to the procedure described in Example 62, 1,77 S (5,7-indol) -1'-T- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} - 3 - [(tert-butoxycarbonyl) amino] benzamide (see Example 61, step b), 3.0 mL of anisole, 30.0 mL of anhydrous chloroform and 30.0 mL of trifluoroacetic acid ( purchased from EI.I Scientific). The crude amine base

followed by ethyl acetate containing 0.2% triethylamine to give 1.16 g of an orange oily free base. This gives the hydrochloride, which is recrystallized from ethanol / ether to give 0.31 g (20%) of the solid title hydrochloride hydrate, m.p. 122-130 ° C (foaming).

1 H NMR (DMSO-d 6, δ): 1.59 (m, 2), 1.80 (m, 2), 3.05-3.75 (m, .10), 4.08 (br d, 2). , J = 13.0), 6.10 (br 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 (br t, 1, J = 5.5), 10.77 (br s, 1). ¹³ C NMR (DMSO-d ₆ , S): 20.66, 26.35, 38.36, 46.40,

50.49, 55.20, 114.21, 115.93, 117.63, 121.21, 124.05, 124.64,

126.98, 128.14, 128.72, 135.61, 146.36, 152.13, 162.22, 166.77.

Analysis calculated for C2 H20 N4 O3 O1.0.5 H2 O: C, 56.07; H, 6.42; Ν 15.59; Hg0, 1.98%; Found: 0, 58.17; H, 6.41; ΪΤ 15.25; N, 2.35%.

···· ·· «« ·

- 151 -

Example 64 (a) 17- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -5-bromo-2,6-dimethoxybenzene amide Ilidro chloride produces; dig a

In a 100 ml 3-neck, round-bottomed flask equipped with a flame-dried magnetic stirrer, a nitrogen inlet, a addition funnel and a thermometer, place 1.48 g (5.6'9 mmol) of 3-bromo-2,6-dihydroxybenzoic acid (2 6-dimethyl oxybenzoic acid) was obtained by the method of P, P. Doyle et al., J. Med.

At the end of this time, 0.03 ml of Llp was added and the temperature was maintained at 65 ° C for 2 hours with the solvent; it is removed in vacuo, the residue is taken up in 20.0 mL of chloroform and 1.5 g (5.17 mmol, 0.9 eq) of 3- [4- (4-aminobutyl) -1-piperazine-1,2 A mixture of benzisothiazole (see Example 13, step b), 12.0 mL of chloroform and 0.785 g (1.08 mL, 7.76 mmol, 1.4 equiv) of triethylamine was added. The reaction mixture was stirred at room temperature

The organic solution was washed with saturated potassium carbonate solution,

· · · * * * * · · · · · · »

To a solution of the free base in ethyl acetate was added 2.72 mL of a 1'T ethereal hydrogen chloride solution (1.0 eq.). The solvent was removed in vacuo and the hydrochloride was recrystallized from ethanol to give 0.867 g (27%) of the title hydrochloride as a white solid, mp 220-221 ° C (with decomposition).

1 H NMR (DMSO-d 6, ≤ 4): 1.56 (m, 2),

1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4), 3.78 (s, 6), 4.08 (br 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) _Z 9), 7.60 (tn, 1, J = 8.1), 8.13 (t, 2, J - 8.9),

8.38 (br t, 1, J = 5.6), 10.92 (br s, 1). ¹³ C NMR (DMSO-d 6, <);

20.36, 36.23, 38.01, 46.29, 50.39, 55.07, 56.12, 61.72, 10 ^ 7,

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.

contamination with Cg ^^^ l ^ O-SBr.HCl sum of tre: Found: C, 50.58; H, 5.31; Π 9.83%; Found: 0, 50.69; H, 5.32; i? 9.80%.

Example 65 (a) Preparation of 2-Acetamido-IT-4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butybenzamide hydrochloride

This compound was prepared in a similar manner to that described in Example 53, using 1.3 g (3.17 mmol) of 2-amino-n-4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] -. butyl benzobarine (see Example 36), 0.48 g (0.36 mL, 4.73 mmol, 1.5 equiv.) of triethylamine and 0.25 g (0.226 mL, 3.17 mmol). (0 eq.) In acetyl chloride.

The reaction mixture was stirred in an ice-water bath for 1 hour, then allowed to warm to room temperature and after 18 hours ···

• ·· ···· 999 · · * ·· • · · · · ₄ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ›·› ● ●…

- 155 processed. The free base is purified by thin-layer chromatography. Elution with ethyl acetate containing 0.1% triethylamine afforded 1.09 g of an oily free base. To a solution of the free base of 1.04 (2.30 mmol) in ethyl acetate was added 2.50 mL of a 1 ΪΤ uL hydrochloric acid solution (1.0 eq). The solvent was removed in vacuo and the hydrochloride thus obtained was recrystallized from ethanol. as beige solid hydrochloride according C, 359 g (56% of theory), mp .: 189.5 to 190.5 ° C NMR (DMSO-d _g, £): _z l 67 (m, 2), 1, 84 (m,

2), 2.10 (s, 3), 3.10-3.75 (m, 10), 4.09 (br d, 2, J - 12.9), 7 _Z 16 (tn, 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 (br t, 1, J - 5.2), 10.86 (br s, 1), 11.24 (br s, 1). 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 of the formula:

calcd: C> 9506; H, 6.20; ΙΪ 14.55%; Found: 0, 59.13; ü6,25; iT 14.41%.

Example 66 (a) Preparation of 2- {4- [4- (1,2-bis-isothiazol-3-yl) -piperidine-5-butyl] - (3H) -1-isoquinolinone hydrochloride

In a 100 mL round-bottomed flask equipped with a reflux condenser, a magnetic stirrer, and nitrogen inlet flask, 1.25 g (5.73 mmol) of 3- (4-piperidinyl) -1,2-benzisothiazole, 1.54 g (6.33 g)

- 154 mmol, 1.2 eq.) Of 2- (4-chlorobutyl) -1-isoindolinone, [see Example 3 (a)], 1.45 g (2.0 mL, 14.33 mmol). (2.5 eq.) Of triethylamine and 25.0 ml of acetonitrile was refluxed for 2 days and the solvent was evaporated in vacuo. The crude reaction mixture was purified by flash chromatography to give 1.55 g of the free base. To the solution of the free base was added hydrogen chloride (1-17 g, 1.0 eq), and the solvent was removed in vacuo and the hydrochloride thus obtained was crystallized from ethanol. Yield: 1.15 g (45%) of pale beige blue solid title hydrochloride, m.p. 211-214 ° C (with decomposition). ·. 1 H NMR (DMSO-d 6, δ): 1.74 (n, 4), 2.22 (m, 4), 3.13 (n, 4), 3.59 (t, 4, J

- 6 _Z 1), 3.65 (η, 1), 4.52 (s, 2), 7.51 (η, 1), 7.54 (ddd, 1, J 1.1, 7.0, 8.1), 7.63 (n, 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 (br s, 1). ¹³ C NMR (DMSO-d 6 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 ^σ 24 '^ 27 ^ 3θ ⁸ - ^ 61 Calculated: C 65.21; H, 6.38; 17 9.51%;

Found: C, 65.31; H, 6.41; 17 9.51%.

67 · and 68.

Example 17a [a] 17- [4- [4- (1,3-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -3-bromo-2-hydroxy-6-methoxybenzamide hydrochloride; - ^ 4- [4- (1,2-Benzisothiazol-3-yl) -l-pi • · · · · · · · · · ·

- 155 perazinyl] butyl] -3-bromo-6-hydroxy-2-methoxybenzamide hydrochloride

4.99 g (9.35 mmol) of IT- {4- [4- (1,2-benzisothiazol-5-yl) - 4.99 g (9.35 mmol), in a 250 ml flame-dried round-bottomed flask, fitted with a magnetic stirrer, a nitrogen inlet funnel and a pressure equalizing addition funnel, is charged. -piperidine ^, azinyl] butyl] -3-bromo-2,6-dimethoxybenzamide (see Example 64, step a) and 75.0 ml of anhydrous Dini in 9.25 ml of 1 17 ethereal hydrogen chloride (9.25 mmol, 0.99 eq) was added followed by 9.55 mL of a solution of boron tribromide in dichloromethane (9.55 mL, 1.0 mL). dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then cooled in an ice water bath and 50 mL of 11 M ammonium hydroxide was added. The solids were dissolved by addition of DSM and water.

The phases were separated, washed with water, dried over magnesium sulfate and evaporated.

3.61 g of a sticky yellow crude product are obtained. This raw,

Sulfur (2.06 g) was used in a 97: 3 mixture of DKM and methanol

T- {4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] butyl] -3-bromo-2-hydroxy-6-methoxybenzaric acid is obtained (using ethyl acetate as an oil). 13 g of minor isomer are obtained, chemically 17- [4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] -3-bromo-6-hydroxy-2- methoxybenzanide (tan solid, IL = 0.54).

156 hydrochloric acid was prepared by dissolving the individual free amine base in ethyl acetate and adding 1 equivalent of 1 L ethereal hydrogen chloride solution.

Example 67

Recrystallization of the hydrochloride of the major (major) isomer from aqueous ethanol gave 1.67 g (32%) of IT- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -3-bromo. -2-hydroxy-6-methoxybenzamide hydrochloride (light pink solid), m.p. 191-192,5 ° C.

NMR (DMSO-d6, δ) ·

1.54-1.90 (a, 4), 3.05-3.70 (a, 10), 3.94 (s, 3), 4.07 (br d, 2, (d, 1,

J-6.2), 25.95, 121.17. 159.27, ^w O, QU {U, J.

J-9.0), 8.11 (d, 1.10.75 (br s, 38. 58, 46.35,

123.99, 124.60, 126.95, 128.10,

162.21, 168.79.

, /, <»/ (A, 1), i, & o

J-7.6), 8.14 (d, 1, J-7.9),

1), 14.87 (s, 1). ¹³ C NMR (DMSO-d _g , S): 10.62,

50.44, 55.04, 56.69, 102.30, 103, 14, 104.76,

136.07, 152.10, 158.08,

η. 1). 7.6

8.93 {t, 1, ο ₂₃ η ₂₇ ^ ο ^ .ηοι

C, 49.69;

sum total was calculated

H, 5.08;

found:

49.79;

H, 5.11;

il 9.93%.

Example 68 The hydrochloride of the n-isomer isomer

and dried in a very good vacuum, Abderhalden apparatus, 76 mg (2%) of 11- (4- L4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] -3-bromo-6-hydroxy- 2-Methoxybenzamide hydrochloride (white solid), m.p. 185-187 ° C.

• ·

NMR (DMSO-d 6,?): 1.60 (n, 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 (br t, 1, J-5.2). 10.65 (br s, 1),

10.99 (s, 1). ¹³ C NMR (DMS0-d _g, S), 20.50, 26.17, 38.14, 46.44, 50.55.

55.27, 61.66, 104.70, 114.00, 119.20, 121.19, 124.04, 124.63, 126.99,

128.13, 133.81, 152.13, 154.34, 156.85, 162.24, 165.15.

- 157 -

Analysis for Cg ^ HgryE ^ O ^ SBr.HCl combine this into a formula: Calculated: C, 49.69; H, 5.08; Π 10.08%; Found: C, 49.73; H, 5.07; 17 10.00%.

Example 69 (a) Preparation of IT-p1- (4-) 6-Eru.or-1,2-berisoisoxol-3-yl) -piperidino] -butyl-phthalimide hydrochloride

In a 100 mL round bottom flask equipped with a magnetic stirrer, 1.64 g (7.45 mmol) of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoaxole, 2.63 g (9.51 mmol, 1.25 eq. IT) (4-Bromobutyl) phthalimide (Aldrich Chemical Company), 1.13 g (1.56 mL, 11.2 mmol, 1.5 'equiv.) And 30 mL of acetonitrile were weighed.

The flask was fitted with a reflux condenser and a nitrogen inlet tube

the answer will be placed in a dohler

saturated

• · · • ·

- 158 as poppy seeds were adsorbed onto silica gel and obtained by solid chromatography.

1.9 g of an oil are obtained, which is soon obtained as a yellow solid, which is obtained with 1N diethylene chloride hydrochloride in ethanol to give 1.39 g (41%) of the title product as a solid, m.p. dg, 5): 1.68 (a, 2), 1.78 (a, 2),

3.47 (a, 1), 3.62 (a, 4), 7.34 (dt, 1,

J = 9.1, 1.8), 7.88 (a, 4), 8.20 (a, 1), (DMS0-d _fi, S): 20.97, 25.71, 27.16, 31

97.67, 98.03, 112.90, 113.24, 117.00

A solution of (131.99, 134.71, 160.43, 162.40, 163.45) (1.0 eq.) Was recrystallized from water with a light beige color, 229 ° C.

NMR

2.27 (a, 4), 3.10 (a, 4),

J-2.0, 8.9), 7.73 (dd, 1,

10.55 (br s, 1). ¹³ C NMR

52, 37.21, 51.60, 55.78,

123.36, 124.15, 124.30,

163.64, 165.69, 168.32.

Analysis calculated for _{CΖ 0ΖΖΖΗΖΖ} ^ _Ζ ^ ^ ^ΗΗ: C, 62.95; H, 5.50; 17 9.18%; Found: 0, 53.05; H, 5.52; 17 9.14%.

Example 70 (a) Preparation of IT-} 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -2,2,2-trifluoroacetamide

Equipped with a magnetic stirrer, a thermometer, a metering tube and a nozzle for the inlet 1,

you• · ·

- 3- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (6.9 g) in a 250 ml round bottom flask with a 159 neck (see Figure 13).

(b)] and 50.0 mL of anhydrous DELI solution was cooled in an ice bath and 6.53 S (4.40 mL, 31.1 mmol, 1.5 equiv.) of trifluoroacetic anhydride in 20.0 mL of DKLI. solution was added dropwise over 30 minutes

After stirring for 2 hours, 50 ml of saturated potassium carbonate solution was added slowly to the cold reaction edge. The reaction mixture was transferred to a separatory funnel and the organic material was extracted with DEI.I. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6.87 g (36%) of a cinnam orange oil. This crude product is used without.

¹ H NMR (CDCl ₃ , δ): 1.71 (br s, 4), 2.51 (br t, 2, J-6.2), 2.71 (t, 4, J-4.8), δ , 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).

into a round-bottomed flask in the form of a 0.587 S (19.6 mmol) sodium oily dispersion.

is added to the hybrid. The resulting slurry was cooled in an ice-water bath

160 -3-yl) -1-piperazinyl] butyl} -2,2,2-trifluoroacetamide (6.87 g, 17.8 mmol) in 50.0 mL THB slowly over 35 min. add to it. The ice-water bath was removed and 2.55 g (1 _} 1 ml, 17.8 mmol) of methyl iodide in 20 ml of anhydrous TEU were added dropwise. The orange solution was allowed to warm to room temperature and stirred for 4 days. It is removed in sodium. The residue is divided between water and DEH,

nal wash. It's organic phase also 0, magnesium sulphate tony s closes tiny, hi their, evaporate, so orange, oily raw temples we get. This raw free base is fast-

cr om tography with ethyl acetate as eluent! 4.55 g (64%) of the title compound are obtained as a white solid. . .

1 H NMR (CDCl 3, δ: 1.59 (a, 2), 1.71 (a, 2), 2.47 (t, 2, J-7.0), 2.68 (a, 4), 3.04 and 3.14 (2 singlets, 3, NCH2 tautomers), 3.45 (a, 2), 3.58 (a, 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).

(c) 3- {4- [4- (Ethylamino) butyl] -1-piperazinyl} -1,2-

Preparation of benzisothiazole

In a 250 ml round-bottomed flask equipped with a magnetic stirrer

2.0 g (5.0 mmol) of 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl} -H-methyl-2,2,2-trifluoroacetaria A mixture of 50 ml of methanol and 20.0 ml of 7% aqueous potassium bicarbonate solution was stirred at room temperature for 6 hours, then methanol was removed in vacuo and the organic phase was extracted with

I

- 161 extracted.

The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give the title compound as a yellow oily crude product which was used without further purification.

(d) 2-Amino-1- {4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] · -IT-methylbenzamide hydrochloride Prep.

With magnetic stirrer and nitrogen inlet

IU

In a 100 mL round bottom flask, 1.4 g (4.6 mmol) of 5- {4- [4- (methylamino)

butyl] -1-piperazinyl] -1,2-benzisothiazole, 0.750 g (4.6 mmol,

1.0 eq.) Isatinic anhydride (Aldrich Chemical Company) and

The mixture of ethanol (25.0 ml) was stirred under nitrogen at room temperature for 1 hour and then left without stirring for another 6 hours. The reaction mixture was concentrated in vacuo to give a brownish-orange liquid crude product. This free base is purified by flash chromatography;

Elution with 0.1% triethylamine in ethyl acetate gave 1.06 g of the free base. 1.06 g (2.50 mmol) of the free base in ethyl acetate

2.5 mL of 1.0 N ethereal hydrogen chloride solution (1.0 eq) was added.

The solvent was removed in vacuo and the solid residue was recrystallized from ethanol and ether.

0.625 g (50%) of a cin yellowish solid are obtained, m.p. 186-189 '

NMR (DMSO-d6, δ) 3.61 (br s, 4), 2.93 (s, 3), 2.95-3.72 (m, 10),

4.07 (br d, 2, J-12.0), 5.13 (br 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, • ·

- 162 J-1.0, 6.9, 8.0), 8.13 (t, 2, J-8.2), 10.85 (br s, 1). 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 633 ^ 299OS.ECl:

Calculated: C, 60.05; H, 6.57; N, 15.22%; Found: 0, 59.98; H, 6.60; 17 15.13%.

Example 71 (a) Preparation of 3-Hydroxy-1,2-bis-isoxazole

This compound was prepared by the method of R. Priary and R. R. Sunday [J. Heterocyclic. Chem. (Aldrich Chemical Company) and 1750 ml of anhydrous THE. During processing, the crude product precipitates as a beige solid precipitate; Recrystallization from ethyl acetate gave 15.7 g of an off-white solid. The second generation gave an additional 9.4 g of product, giving a total yield of 25.1 g (60%).

1 H NMR (DMSO-d 6, S): 7.34 (ddd, 1, J-1.6, 6.3, 8.0), 7.61 (n, 2), 7.78 (d, 1, J-7.7), 12.39 (br s, 1).

(b) Preparation of 3-Elor-1,2-benzisoxazole

Flame-dried JOO nl round bottom flask equipped with a magnetic stirrer, equipped with a addition funnel and a nitrogen inlet flask, weighed 24.3 g (0.184 mol) of 3-hydroxy-1,2-bezisoxazole and 18.6 g (25.6 ml, 0.184 mol) of , 0 eq) dry triethylamine • ·

- To a mixture of 165 was added dropwise phosphorus oxychloride (62.1 g, 37.8 mL, 0.405 mol, 2.2 eq.) Under ice-cooling. The reflux was removed, the flask was refluxed and the reaction was continued in an oil bath at 150 ° C for the next day. Then the oil bath; The mixture was removed and the pale brown liquid product was allowed to cool to room temperature and the reaction mixture was slowly poured into 500 ml of ice-water with stirring. After warming to room temperature, transfer the reaction mixture to a separatory funnel and add 250 mL of DELI.

250

Dry over magnesium sulfate, filter, and evaporate to give 28.3 g (100%) of crude product as a pale orange liquid. This crude product was used without further purification.

(DESO-dg,): 7.56 (ttm, 1, J = 7.2), 7.35 (m, 3).

(c) Preparation of 1- (1,2,3-benzisoxazol-3-yl) piperazine

In a 500 mL round bottom flask equipped with a reflux condenser and a nitrogen inlet, 28.3 g (0.184 mol) of 3-chloro-1,2-benzisoxazole, 95.1 g (1.10 mol, 6.0 eq.) Of piperazine and A mixture of 10.0 ml of toluene in an oil bath for 18 hours was poured into 155 ml of ice-cold hot orange reaction mixture, and the organic products were extracted from the heterogeneous aqueous mixture with

22.3 g of a pale orange liquid product are obtained. To this crude product was added 6.0 mL of ethyl acetate and the solution was cooled to reflux.

- 164 beings. The precipitated dark orange solid product was filtered, spatulated, washed with ethyl acetate and ether and air dried. This gave 10.1 g of a mustard solid which was used without further purification.

The ilffi _{CDLlS0-d6, 6):} 2.91 (m, 4), 3.42 (m, 4), 7.31 (η 1),

7.59 (d, 2, 1 = 3.5), 7.99 (<3, 1, J = 8.0).

(d) Preparation of 1'T- [4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] butyl] phthalimide hydrochloride

In a round-bottomed flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen inlet, 4.0 g (19.7 mmol)

1- (1,2-Benzisoxazol-3-yl) piperazine, 6.66 g (23.6 mmol, 1.2 equiv) of H- (4-bromobutyl) phthalinide (Aldrich Chemical Company), ml boil with stirring, then remove the oil bath and a

Transfer the reaction mixture to a separatory funnel and add saturated potassium.

carbonate solution and 200 ml of ethyl acetate

eluting

ethyl acetate gave the pure product as a viscous yellow oil. The free base (5.89 g, 14.6 mmol) was dissolved in a mixture of ethyl acetate and DELI, 14.6 mL of 1 IT ethereal hydrogen chloride solution (1.0 eq) was added, and the solvent was evaporated in vacuo. The hydrochloride thus obtained is recrystallized from aqueous ethanol. 0.71 g (8.2%) of the title compound is obtained as an off-white solid, m.p. 257-259 ° C (with decomposition).

NMR (DMSO-d _g, S): 1.71 (m, 4), 3.21 (n, 4);

3.55 (m, 6), 4.14 (br d, 2, J-13.2), 7.38 (η, 1), 7.65 (d, 2, J-3.7), 7 , 90 (m, 4), 8.06 (br d, 1, J-8.0), 10.62 (br s, 1). ¹³ C NMR (DMSO-d 6, $): 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 Cg ^ Hg ^ H ^ O-.HCl:

calcd: C, 62.65; H, 5.71; IT 12,715;

Found: 0, 62.51; II, 5.68; IT 12.65%.

Example 72 (a) Preparation of 5- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisoxazole

This compound was prepared according to the procedure described in Example 15 (b), 13- (4- [4- (1,2-Benzisoxazol-5-yl) -1-piperazinyl] butyl) (4.04 g, 9.99 mmol). —1'talimide See Step 71 (d)],

0.87 g of 55% hydrazine hydrate (14.99 mmol, 1.5 equiv.) And 50 mL of methanol were added

Re action air;. 'Et 2.5

- 166 acid hydrazide by-products are not precipitated. A further 0.87 g (1.5 eq.) Of hydrazine was added and the reaction mixture was refluxed for an additional 1 hour. Workup gave 2.1 g (77%) of the hyers product as an oil sterile which solidified on standing.

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 (vol.2,

J-6.5), 3.60 (t, 4, J-5.0), 7.22 (a, 1), 7.46 (a, 2), 7.70 (d, 1,

J = 8.0).

The above crude product was used without further purification.

(b) Preparation of 2-Amino-iT- {4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] butyl} hydrochloride

3- (4- (4-Aminobutyl) -1-piperazinyl) -1,2-benzisozazole (1.0 g, 3.65 mmol), 0.656 g (4.02 (1.1 eq.) Of isatinic anhydride and 10 ml of ethanol.

A 19: 1 mixture gives a 1.37 S viscous, yellow, oily free base. The hydrochloride was prepared from the strain, which was recrystallized from water-containing ethanol and sealed in a vacuum oven. 1.08 g (60%) of the title compound are obtained as a pale tan solid, m.p. 249-252 ° C.

NMR _(DMS0-d6, S): 1.58 (a, 2), 1.79 (a, 2), 3.29 (a, 6), 3.56 (in, 4), 4.14 ( a, 2), 6.45 (br s, 2), 6.53 (t, 1, J-7.6), 6.71 (d, 1, ^J -8.0), 7.15 (t , 1, J-7 _; 7), 7.37 (a, 1), 7.52 (d, 1, J-7.2), 7.65 * · · · (d, 2, J-3, 7), 8.06 (d, 1, J-8.2), 8.30 (br t, 1, J-5.4), 10.79 (br s, 1). 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.

• »· · ·« V • 4 • · ··

- 167 Analysis for .EC1:

Calculated: C, 61.46; Ξ 6.56; 17 16.29%;

Found: C, 51.57; H, 6.54; 17 16.34%.

Example 75 (a) DT-£ 2- [1- [4- [4- (1,3-Benzisothiazol-3-yl) -1-piperazinyl] butyl] amino] carbonyl] phenyl} carbamic acid ethyl Preparation of ester hydrochloride

In a 50 ml round-bottomed flask, flame-dried, 1.5 g (5.66 mmol) of 2-amino-17- [4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl} benzamide (see Example 36), a mixture of 0.463 g (0.638 mL, 4.58 mmol, 1.25 eq) of triethylamine and 10 mL of anhydrous chloroform was placed in an ice-water bath under nitrogen,

Ethyl chloroformate (0.437 g, 0.385 mL, 4.03 mmol, 1.1 eq) dissolved in anhydrous chloroform was added dropwise.

After the addition is complete, the cooling bath is removed and a

additional 0.57 g (0.51 µl, 5.66 mmol, 1.0 equiv.) of triethylamine and 0.4 g (0.35 mL, 5.66 mmol, 1.0 equiv.) of ethyl acetate adding the solution (chloroformate) in several portions,

liter was washed with sodium bicarbonate solution, the layers were washed.

163 were separated and the aqueous phase was extracted with DKLI. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. concentrated. Thus 1.74 g of an orange oily product are obtained.

Punk. This free base purification by thin layer chromatography: az elution with ethyl acetate and hexane 2: 1, 0.1% triethylamine content mixture. followed by 0.1% triethylamine

tariffs; Applying ethyl acetate gives 0.49 S of an oily free base. 0.46 g (0.96 mmol) of free base in DKI and ethyl

Acetate (0.96 mL, 1 L) (1.0 eq), hydrochloride was filtered and dried in vacuo. Yield: 0.385 g (20%) of a white solid, m.p. 195-195.5 ° C.

NMR

(DMSO-d 6,?): 1.24 (T. 3 J - 7.2), 1.62 (n, 2), 1.83 (B 2) 3.26 (?, 6), 3.47 (M, 2) 3.61 (n, 2), 4.07 (m, 2), 4.14 (Q, 2, J - 7.2), 7.10 (tn, First 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 (You, 2, J -

8.4), 8.20 (dd, 1, J = 0.9, 8.3), 8.89 (br t, 1, J = 5.5), 10.85 (br s, 1), 10.97 (s, 1). ¹³ C NMR (DMSO-d 6, S): 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, 152.91, 162.24, 168.36.

Analysis for 1L-0-.3.H01:

Calculated: C, 57.96; H, 6.23; % 13.52%;

Found: C, 58.07;

H, 6.28; 17 13.47%.

···· ··········································································································································· (ν • •·ν ν • νν ν

- 169 -

Example 74 (a) Preparation of N- [4- (1,2-Benzisothiazol-3-yl) -1-piperazilyl] -butyl] -3-bromo-2,6-dihydroxybenzamide hydrochloride

In a 100 ml round-bottomed flask, flame dried, 2.4 g (1.46 ml) of anhydrous toluene and 1.2 g (5.15 mmol) of 3-bromo-2,6-dihydroxy

was prepared by bromination of benzoic acid [dihydroxybeazoic acid with elemental bromine, E

Doyle et al. (J. Chem. Removed in vacuo and 15 ml of anhydrous

To the resulting suspension, 1.5 g (5.15 mmol) of 3- [4- (4-aninobutyl)

-1-piperazinyl] -1,2-benzisothiazole [15. Example 15 (step b)] After isolating 15 ml of zis, the aqueous phase is extracted with Dlu.I.

The organic extract was combined, dried over magnesium sulfate, and dried. 0.705g (1.39 ···· ······································································································· ··· «« ····

- Adding 170 chlorine time readers. The hydrochloride was filtered, washed with ether and dried in a vacuum oven to give 0.454 g (16%) of an off-white solid, m.p. 228-230 ° C (with decomposition).

hi NMR (DMSO-d _g, S): 1.62 (a, 2), 1.77 (a, 2);

3.00-3.70 (a, 10), 4.05 (n, 2), 6.49 (d, 1, J = 8.8), 7.48 (un,

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 (br s, 1), 10.50 (br s, 1), 11.85 (br s, 1),

14.81 (br s, 1). ^ij C NMR (DMS0-d _g $): 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.

Example 75 (a) Preparation of 6-Fluoroisatinic anhydride

250 nl spherical tube with magnetic stirrer

3.0 g (19.3 mmol) of 2-anino-6-fluorobenzoic acid (available from

Maybridge Chemical Conpany), a mixture of 15.0 g (75.8 mmol, 5.9 eq.) Of trichloromethyl (chloroformate) (Johnson Ill. Chemical Conpany) and 60 ml of anhydrous 1,4-dioxane with nitrogen gas. cover and reflux for 6 hours. The reaction mixture was allowed to cool to room temperature and evaporated.

IgC gave 3.8 g of the title compound as an off-white crude product which was used without further purification.

NMR (DMSO-d6, S): 6.97 (d, 1, J-8.2), 7.06 (dd, 1, J-8.4,

10.7), 7.73 (a, 1), 11.90 (br s, 1).

· · · · · · · · · · · ···

- 171 (b) Preparation of 2-Amino-H- {4- (4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] -6-fluorobenzamide hydrochloride

Flame-dried 500 ml round-bottomed flask

To a solution of 6-fluoroisatinic anhydride (1.5 g, 8.28 mmol) in anhydrous TElF (40 mL) was added 3- [4- (4-8 g) (8.28 mmol, 1.0 eq.) A solution of (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 15, step b) in 25 ml of anhydrous THF was added and the reaction mixture was stirred at room temperature for the next day, free base by column chromatography

Elution with a 19: 1 mixture of LEI and methanol gave a 2.79 yellow, oily free base. The free base was dissolved in ethyl acetate and 6.53 mL (1.0 eq) of a 1 N HCl solution was added. The resulting hydrochloride was recrystallized from aqueous ethanol to give 2.0 (52%) of a beige solid, m.p. 218-220 ° C.

NMR (DMSO-d6, δ): 1.57 (m, 2), 1.80 (m, 2), 3.10-3.75 (m, 10), 4.10 (br d, 2, J - 13.1), 5.89 (br 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 (br s, 1). ¹³ C NMR (DMSO-d _g $); 20.75, 26.38, 38.39,

46.57, 50.66, 55.38, 101.81, 102.27, 107.65, 108.01, 111.63,

111.68, 121.49, 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 822¾ ^ ¾ ^ ^3.0 ° calcd: C, 56.95; H, 5.86; 1T 15.09%;

Found: C, 57.06; H, 5.95; % 14.94%.

example (a)

250

- 172 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

Preparation of 3-fluoro-isatinic anhydride and 6-fluoro-isatinic anhydride in a flame-dried round-bottom flask with 50 ml of anhydrous chloroform, 10.0 g (60.2 mmol) of 5-fluorophthalic anhydride

1.0 eq.) (Aldrich Chemical Company) azidotrimethylsilane was not observed and refluxed for a further 3.5 hours and 10 ml of 95% ethanol was added. Examination of the milky olefin shows that this product is p-ulu-or

60:40 mixture of 6-fluoro isomer.

5-Fluoro-isatinic anhydride

7.24 (dt, 1, J = 4.7, 8.1), 7.68 (ddd,

7.76 (dt, 1, J = 7.9, 0.9)

For 6-fluoroisatinic anhydride (DLISO-άθ, with 500 observed signals)

The above mixture is further stirred.

- 175 (b) 2-Amin o- 1T- | Preparation of 4- [4- (1,2-benzisolazol-3-yl) -1-piperazinyl] butyl] -3-fluorobenzamide hydrochloride

In a 100 mL round bottom flask, 50 mL of THE, 2.55 g (8.80 mmol)

3- [4- (4-Aminobutyl) -1-piperazinyl-1,2-benzisothiazole; and

A mixture of 3-fluoro-6-fluoroisatinic anhydride (1.59 g, 8.80 mmol, 1.0 equiv.) In 60:40 mixture was stirred at room temperature for 10 minutes and then the solvent was removed on a rotary evaporator. The viscous oil-like residue was flash chromatographed on ethyl · ethyl acetate.

0.8 g of the title compound is obtained. The free base is dissolved in ethyl acetate, 1.89 ml

17 yrs

The resulting hydrochloride was recrystallized twice from ethanol to give 0.36 g (15% relative to 3-fluoro-isatinic anhydride) of the title hydrochloride as yellowish crystals, m.p. 175-176 ° C.

1 H NMR (DMSO-d 6, 200 MHz; δ): 1.59 (m, 2), 1.80 (m, 2), 3.18-3.66 (n, 10), 4.09 (br d). , 2, J - 13.3), 4.30 (br 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 ( tn, 1, J = 7.7), 7.62 (tn, 1, J)

7.4), 8.14 (t, 2, J - 6.9), 8.48 (br t, 1, J - 5.6), 10.72 (br s, 1). ¹³ C NMR (DMSO-d6, 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 a

combine zigzag tre:

Calcd. C, 56.95; H, 5.87; II 15.09%;

Found: C, 56.95; Ξ 5.95; N, 15.05%.

Example 77 (a) 2 - [(tert-Butoxycarbonyl) amino] benzoic acid

In a 1 L round bottom flask was cooled in an ice bath a mixture of 25 g (0.182 mol) of 2-aminobenzoic acid and 100 ml of 1,4-diosan, followed by slow addition of 99.5 g (0.456 mol, (5 eq.) Of di-tert-butyl dicarbonate in 120 mL of 1,4-dioxane was added. After the addition was complete, the cooling filter was removed and the reaction mixture was stirred at room temperature for 67 hours to give a viscous brownish-orange solution.

This solution was diluted with water (140 mL) and a

Set to 2. Transfer the reaction to a separatory funnel. The isolated product after filtration was dried to give 38.16 g (88%) of the cin-compound.

Si NMR (CDC1 _3, S):

1.55 (s, 9), 7.05 (tm, 1, J - 7.7), 7.58 (tn, 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 (br s, 1).

• · · • ·

- Preparation of 175 (b) 2 - [(tert -Butoxycarbonyl) on amine ο] H- (4-hydroxybutyl) -benzamide in a 1 liter, three-necked, round-bottomed flask fitted with an addition funnel and nitrogen inlet. 37.94 g (0.160 mol) of 2 - [(tert

-outoxycarbonyl-amino] -benzoic acid, 19.46 g (26.8 mL, 0.192 equiv) of isobutyl chloroformate (Aldrich Chemical Company) are added dropwise. The temperature during the addition is maintained between -15 ° C and -50 ° C. After the addition was complete, the slurry was kept under stirring for 5 minutes and then slowly treated with 14.5 g (14.8 µl, 0.161 mol, 1.0 equiv.) Of 4-amino-1-butanol (Aldrich Chemical Company) in 50 ml of anhydrous A solution of THF was added dropwise and the reaction mixture was stirred for 50 minutes at -15 ° C to -30 ° C. At this time, the cooling residue was removed and the solution was stirred at room temperature for an additional 18 hours, ethyl acetate was added and the organic phase was saturated with ethyl acetate, the organic phases were combined, dried over magnesium sulfate and the crude product was a light yellow oil. cin.

1 H NMR (CDCl 3, δ): 1.52 (s, 9). 1.72 (a, 4), 3.48 (q, 2, J = 6.2),

3.75 (n, 2), 6.59 (br s, 1), 6.97 (ta, 1, J = 7.5), 7.42 (a, 2),

8.36 (dd, 1, J = 0.9, 8.9), 10.22 (br s, 1).

- 176 - (c) Preparation of 2 - [(tert-3-butoxycarbonyl) amino] -1T- [4 - [(methylsulfonyl) oxy] butylbenzamide

In a 500 mL round-bottomed flask, 14.0 g (45.3 mmol) of 2 - [(tert-butoxycarbonyl) amino] -1- (4-hydroxybutyl) benzamide and

Anhydrous methanesulfonyl chloride (10.38 g, 7.0 mL, 90.6 mmol, 2.0 eq.) (Alorich Chemical Company) was added dropwise to 100 ml of anhydrous pyridine under ice-water cooling, and the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. stir for 1 hour. 3

the reaction mixture was evaporated to give an orange oil which was purified by addition of ethyl acetate and saturated sodium bicarbonate solution.

After separating the Λ layers, the aqueous phase is extracted with ethyl acetate, the combined organic solution is washed with water, dried over magnesium sulfate, and filtered and evaporated to give 18.19 g of an orange crude product. 3 crude mesylate derivatives with column chromatography as eluent

and hexane

A 1: 1 mixture was used to give 11.46 (657) of the title compound as a pale orange oil;

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), δ> 27 (br s, 1), 6 , 99 (tm, 1, J - 8.2), 7.42 (d, 1, J - 7.9), 7.44 (m, 1), 8.36 (da, 1, J - 8, 4), 10.13 (br s, 1).

• · »·· • · * ·· ·· ··«

- 177 - (d) Preparation of 3- (1-Piperazyl) -1,2-benzisothiazole-1,1-dioxide

In a 500 ml round-bottomed flask, 16.93 g of 2-chlorobenzisothiazole-1,1-dioside (84 mmol) (see European Patent Application 0 196 096) is covered with piperazil (Alcrich Chemical nitrogen gas) and then heated. age mixture solidifies This crude

A mixture of 43.5 g (0.505 mol, 6.0 eq.) Of Company) and 9 ml of toluene was heated at 160-170 ° C (room temperature) for 22 hours, after separation of the reaction mixture between chloroform and water, the organic phase was washed three times with 400 ml of water.

Filtration and evaporation gave the title compound as a tan solid (7.24 g, 34%).

NMR (CDCl ₃ , δ): 1.74 (br s, 1), 3.08 (t, 4, J - 5.1). 4.03 (vol. 4, J = 5.0), 7.68 (n, 2). 7.84 (dd, 1.

J = 1.2, 6.9), 7.97 (dd, 1, J = 1.8, 6.9).

The zinc product was used without further purification.

(e) N- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -2 - [(tert-buto-2-carbonyl) amino] -benzamide-3,3- production of dioxide

In a flame-dried 500 mL spherical ion beaker, 3.2 g (12.7 mmol) of 5- (1-piperazinyl) -1,2-benzisothiazole-1,1-dioxide, 5.0 g (12.9 mmol, 02 eq.) 2 - [(tert-Buto2'carbonyl) amino] -N- [4 - [(methylsulfonyl) oxy] butyl] -benzamide, 1.60 g (2.2 ml, 1, 58 mmol (1.25 eq.) Of triethylamine and 75 ml of anhydrous aceto. ! · ♦ · • · · ·

The mixture of 173 nitrile was refluxed under nitrogen for 1 hour, and the orange solution was washed with a separating solution of sodium bicarbonate. After separation of the organic phase, the aqueous phase was extracted with ethyl acetate, and the combined organic solution was dried over magnesium sulfate, dried and evaporated to give a yellowish glassy product (6.09) which was purified by thin-layer chromatography. Elution afforded 4.53 g (62%) of the title compound as a pale beige glassy product.

ΜΛ (a) Cl _3. , S). _; 1. 52 (s, 9),

1.64 (m, 4), 2.47 (br t, 2, J - 6.5), 2.63 (br t, 4, J - 5.0),

3.48 (br q, 2, J = 6.2), 4.03 (br c, 4, J = 4.9), 6.50 (br s, 1),

6.98 (t, 1, J - 7.6), 7.41 (d, 1, J - 7.7), 7.43 (η, 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 (br s, 1).

(f) Preparation of 2-Amino-17- [4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl-butyl-benzamide-S, S-dioxide hydrochloride

In a 500 mL round bottom flask, 40 mL trifluoroacetic acid, 100 mL chloroform, 3 mL anhydrous anisole and 4.58 g (7.98 mmol) of 17- {4- [4- (1,2-benzisothiazol-3-yl) - A mixture of 1-piperazinyl-butyl-2 - [(tert -butoxycarbonyl) amino] -zzamide-3, 5d oxide was stirred at room temperature for 50 minutes, then the reaction mixture was concentrated received orange fluid in DKlI • ·

- wash with a saturated sodium bicarbonate solution.

After separation of the organic phase, the aqueous phase is extracted twice with DKCl. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. This gave an orange, liquid crude product which was purified by column chromatography. Elution with 97: 5 ethyl acetate: methanol followed by 96: 4 gave 5.06 g of the free base. 1.95 g of the free base (4.42 mmol) are dissolved in DI2i, 4.64 mL (1.05 eq) of a 1T aqueous hydrogen chloride solution are added, and the hydrochloride thus formed is recrystallized twice from aqueous ethanol to give 0.85 g (54%) of a pale beige solid title hydrochloride, m.p. 259-261 ° C (with decomposition).

h1 NMR (DMSO-d6, [delta]) ·

1.58 (a, 2), 1.78 (a, 2), 3.00-3.80 (m. 8), 3.95 (br s, 2), 4.68 (br s, 2) , 6.54 (t, 1, J - 7.4), 6.71 (d, 1, J - 8.1), 7.15 (ta, 1, J - 7.6), 7.51 ( da, 1, J = 7.4), 7.87 (a, 2), 8.09 (a, 1),

8.30 (a, 2). ¹³ C NMR (DMSO-d _g £); 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 ca ' ¹ .

LiS (tc-spectrum) (ion spray): m / z (relative intensity) 442 (IE ⁺ , 100).

Analysis for C _oo H „ _n iT | -0-, S.HCl

Calc'd. C, 55.53; H, 5.91; 1. 14.67%; Found: C, 55.08; n 6.00; 7T 14.58%.

130 -

Example 78 (a) Preparation of 1,4-Dihydro-2H-5,1-benzothiazine-2,4-dithione

In a flame-dried 500 mL round-bottomed flask, a mixture of 5.0 g (18.59 mmol) of isatinic anhydride, 18.0 g (40.49 mmol, 2.2 equiv.) Of phosphorus pentasulfide and 100 mL of xylene was refluxed for 19 hours. Boil, then strain and wash the filtrate with the washings by evaporation in vacuo to give a red-brown solid crude product which is prepared in ethyl acetate (5: 1).

7.4).

8.2).

Capric NMR (DMSO-dg,?) In 2.44 g (63%) as a solid: 7.43 (t, 1, J

7.56 (d, 1, J = 8.2), 7.90 (t, 1, J = 7.7), 8.33 (d, 1, J (b) 2-Amino-17- (4 - Preparation of [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] buti thiobenzamide hydrochloride

40 ml of anhydrous THE and L measured in a 1 liter round bottom flask

To a mixture of 2.9 (13.7 omol) 1,4-dihydro-2H-3,1-benzothiazine-2,4-dithione was slowly added 4.2 g (14.4 mmol, 1.05 equiv.) Under nitrogen. - A side of [4- (4-aminobutyl) -1-piperazinyl-1,2-benzisothiazole (see Example 15, step b)] in anhydrous THF (55 mL) was added and the reaction mixture was stirred at room temperature for 50 minutes. Then another 1.0 g (5.45 • ·

- 181 mmol (0.25 eq.) Of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisolazole in 10 ml of anhydrous THE and stirred for 15 minutes, the suspension is filtered and the filtrate is evaporated. 7.6 g of an orange-red oil-like residue are obtained. This residue was combined with 0.65 g of crude product obtained in a previous experiment and partitioned by successive flash chromatography.

mixture. Further purification was carried out in a Harrison Research chromatotron using a gradient elution of 100% DE11 as eluent followed by ΕΪΠ.Ι and methanol 99: 1.

finally, a 97: 5 mixture of DI3: 1 and methanol gave 0.718 g of a yellow oily free base. The free base (0.718 g, 1.69 mmol) was dissolved in ethyl acetate, treated with ethereal hydrogen chloride (1.69 mL, 1.0 eq), filtered, washed with ethyl acetate and ether, then with ethyl acetate. recrystallization gave 0.229 g (2.7%) of the title compound as a yellow solid, m.p. 198-201 ° C.

NMR (DMSO-d6, δ): 1.78 (a, 4), 3.05-3.80 (a, 10), 4.10 (br d, 2, J 12.7), 5.74 ( br s, 2), 6.59 (t, 1, J - 7.5), 6.74 (d, 1, J 8.0), 7.08 (a, 2), 7.50 (t, 1, J - 7.7), 7.63 (t, 1, J - 7.6), 8.15 (t, 2, J - 7.2), 10.30 (a, 1), 10, 83 (a, 1). ¹³ C NMR (DMSO-d 6, S): 21.74, 25.35, 45.37, 47.32, 51.43, 56.10,

118.78, 122.18, 124.98, 125.59, 127.93, 128.49, 129.11,

130.98, 143.37, 153.08, 163.20, 197.17.

CILIS (core syncope with chemical ionization): m / z): 426 (ΐ.Ή-?, 100).

118.56,

129.37, (relativ inten • ·· · · «·· * ·· ··· *

Analyze and a

calcd

calcd: C, 57.19; H, 6.11; ΐϊ 15.16%;

Found: 056.95; H, 6.17; N, 14.98%.

Example 79 (a) 17- (4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl-2 - [(tert-butoxycarbonyl) -anino] - benzamide; Preparation of S-oxide

In a 250 mL round-bottomed flask, 1.48 g (6.29 mmoles) of 3- (1-piperazinyl) -1,2-benzisothiazole-1-oxide [see J. Led. Chem. 34, 5316 (1991) 1, 2.52 g (6.52 mmol, 1.04 eq.) Of 2 - [(tert-butoxycarboxyl) amine] - N- [4 - (Methanesulfonyl oxy) butyl] η zamide (see Example 77, step c), 0.762 g (1.05 mL, 7.53 mmol).

A mixture of ethyl acetate (1.2 eq.) And acetonitrile (50 mL) was refluxed for 24 hours under nitrogen, the orange slurry was transferred to a separatory funnel, ethyl acetate was added and the solution was washed with saturated sodium bicarbonate solution. After separating the layers, the aqueous phase was extracted twice more with ethyl acetate.

The combined organic solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3.08 g of an orange residue. This crude product was purified by flash chromatography.

Elution was carried out with a 97: 5 mixture of BIO / methanol and then a 95: 5 mixture. so

1.9 g (57%) of a beige glassy title compound are obtained.

- 183 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 (brs,

1), 6.97 (ddd, 1, J = 1.1, 7.3, 7.8), 7.41 (d, 1, J - 7.6), 7.42 (a, 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 (br s, 1).

(b) Preparation of 2-Amyloxy- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butybutamide-S-oxide hydrochloride hydrate

A mixture of trifluoroacetic acid (17.0 ml) was stirred at room temperature for 30 minutes, then the reaction mixture was evaporated and the crude product was dissolved in DELI. After selecting a saturated sodium bicarbonate solution, the aqueous phase was extracted twice more with DKLI. The combined organic solution was dried over magnesium sulfate, filtered and evaporated. The crude product was partially purified by flash chromatography.

first with DI1.I and methanol

A mixture of 97: 3 and 95: 5 was used to obtain 2.41 g of a tan-orange oil, which was further purified by flash chromatography. A gradient elution was carried out with mixtures of 98-95% Dlyl and 2-5% methanol to give 0.57 S free base as a white, glassy ··· · product, which was dissolved in DELI, 1.54. A solution of hydrochloric acid (77 mL) (1.0 eq.) was added and the hydrochloride thus obtained was filtered and dried. 0.47 S (27%) of the title hydrochloride hydrate is a hygroscopic, off-white solid, m.p. 208-213 ° C (with decomposition).

NMR (DMSO-d6, S): 1.58 (a, 2), 1.79 (a,

2), 3.17 (a, 2). 3.28 (a, 2), 3.45 (a, 2), 3.58 (br s, 2), 3.73 (br s, 2), 4.67 (br 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 (a, 2 ), 8.09 (a, 1), 8.22 (a, 1), 8.32 (br t, 1, J = 5.3), 11, 25 (br s, 1). ¹³ C NMR (DMSO-d 6,?): 20.65, 26.28, 38 _z 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 ca ' ¹ .

I.IS (ion spray): m / z (relative intensity): 426 (EH,

100).

Analysis

Ü _{2 For} S .1101 .HgO:

Calc'd: C, 55.05; H, 6.30; K, 14.59; H ₂ 0, found:

C, 55.28; H, 5.21; 17 14.53; ΕΟ, Ο,

3.75%;

4.07%.

Example 80 (a) 77- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -2- {[iT- (9H-fluoren-9-yl). Preparation of methoxy) carbonyl-L-valyl] amine p-benzamide

In a 300 mL round bottom flask, 2.39 S (5.84 mmol) of 2-amino-1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -benzanide ( See Example 36) for a biphasic mixture of 60 ml of anhydrous chloroform and 60 ml of 5% aqueous soda solution, 3.3 g (9.22 mmol).

185 - 1.58 eq.) Of N - [(9H-fluoren-9-ylmethoxy) carbonyl] - L-valyl chloride (prepared by the method of L.A. Carpino et al., J. Org. Ghem. 51: 3734 (1986); A solution of N - [(9H-fluoren-9-ylmethoxy) carbonyl] -L-valine] in chloroform (60 mL) was added. The biphasic reaction mixture was stirred at room temperature for 10 minutes, then transferred to a separatory funnel, chloroform added, the organic phase separated, dried over magnesium sulfate, filtered and evaporated. 6.48 g of a pale yellow oily crude product are obtained, which is purified by flash chromatography. Elution with 95: 5 ethyl acetate: methanol

4.5 g (95%) of a white glassy title compound are obtained.

1 H NMR (CDCl 3? 1.00 (d, 3, J - 6.9), 1.07 (d, 3, J - 6.8), 1.64 (m,

4), 2.36 (m, 3), 2.62 (n, 4), 3.38 (m, 2), 3.53 (br t, 4, J 4.8), 4.37 (n). , 4), 5.55 (d, 1, J - 8.6), 6.83 (br s, 1), 7.10 (t, 1, J - 7.6), 7.30 (n, 4), 7.48 (t, 4, J - 7.1), 7.66 (t, 2, J -

8.1), 7.82 (n, 4), 8.61 (d, 1, J = 8.3), 11.59 (br s, 1).

(b) N- {2- [IT- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl] -carbamoyl] -phenyl} -L-valinamide trifluoroacetate preparation of hydrate

In a 500 mL round-bottomed flask, 3.57 g (4.88 mmol) of 1- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -2- [H- ( 9H-Fluoro-en-9-ylmethoxy-carbonyl] -L-valyl] -amine-benzamide, 100 ml of chloroform, 50 ml of 4-aminomethylpiperidine (Aldrich Chemical Company) under nitrogen at room temperature for 30 minutes. After stirring, the reaction mixture was transferred to a separatory funnel and 150 ml of chloroform was added. Organic wood • ·

The mixture is washed three times with 250 ml of water each time, dried over magnesium sulfate, filtered and evaporated. 5.67 g of a yellow oily crude product are obtained. This free base was purified by column chromatography on silica gel; Elution with 85:15 ethyl acetate: methanol gave 2.13 g of the free base as a viscous oil. An aliquot of the free base (1.17 g) was further purified by semi-preparative HPLC (Vydac C-18 column) eluting with a gradient of 9: 1 in water containing 0.1% trifluoroacetic acid and 0.1% trifluoroacetic acid.

We finish with a 1: 9 ratio.

The appropriate fractions were combined, evaporated and the residue was dissolved in water and methanol and lyophilized. 0.87 g (48%) of a white powdery cin is obtained.

1 H NMR (DMSO-d _g , S): δ 1.01 (t,

6. J - 6.5), 1.60 (a, 2), 1.77 (a, 2), 2.18 (a, 1), 3.30 (a, 8),

3.61 (a, 2), 3.95 (a, 1), 4.10 (a, 2), 7.25 (t, 1, J - 7.7). 7.48 (ta, 1, J = 7.5), 7.58 (a, 2), 7.76 (d, 1, J = 7.8), 8.13 (t, 2,

J - 9.0), 8.24 (d, 1, J - 8.4), 8.40 (br s, 1), 8.89 (br c, 1, J

-4.8), 10.33 (br s, 1), 11.48 (s, 1). ¹³ C NMR (DMS0-d _g, £):

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.

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

- 187 -

Example 81 (a)? -? - [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -2- [[(9 H -fluoren-9)] Preparation of -yl-niethoxy-carbonyl] -D-valyl-4-amino-4-benzamide

This compound was prepared according to the procedure described in Example 80, step (a).

2.35 g (5.7 nmol (see Example 56; 2-amino-η 4 - [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] -butyl}) —Benzamide (see Example 56), IT - [(9H-fluoren-9-ylmethoxy) carbonyl] -D-valyl chloride (5.22 g, 9.0 mmol, 1.58 eq.) 120 ml of anhydrous chloroform and 60 ml of 5% aqueous soda solution.

IT - [(9H-fluoren-9-ylmethoxy) carbonyl] -D-valine was prepared by BACHEL1.

We got it from California.

The crude product is purified

yielding a solid title compound.

NMR (COCl ₃ , $) -1.01 (d, 3, J 6.8), 1.07 (d, 3, J - 6.8), 1.64 (a, 4), 2.36 ( a, 3), 2.62 (br t, 4, J - 4.5), 3.42 (a, 2), 3.53 (br t, 4, J - 4.8), 4.37 (a, 4), 5.55 (d, 1, J = 8.6), 6.80 (br s, 1), 7.10 (t, 1, J -7.2), 7.36 (tn, 4, J = 4.4), 7.48 (tn, 4, J = 7.6), 7.67 (t, 2, J = 8.2),

7.80 (a, 4), 8.62 (da, 1, J = 8.9), 11.58 (br s, 1).

(b) 1 '- {2- [1- [4- (4- (1,2-Benzisothiazol-3-yl) -1-pip) ^; Preparation of 3-azinoyl-butyl] -carbamoyl] -phenyl} -D-valinamide trifluoroacetate hydrate

This compound was prepared in Example 80.

5.47 g (4.75 mmol) of IT- [4- [4- (1,2-benzisothiazol-3-yl) -1- = piperazinyl] butyl] -2- [17- (9 1-Fluoren-9-ylmethoxy) carbonyl] -D-valyl-4-aminobenzamide, 100 ml of chloroform and 50 ml of 4- (aminomethyl) -

Purification by column chromatography eluting with 85:15 ethyl acetate: methanol gave 1.99 free base as a viscous oil. A 0.65 g portion of this free base was purified on a top preparative column to give 0.54 g (57%) of the title compound as a white powder. 1 sec

1 H NMR (DMSO-d 6, δ) η, 01 (ε, 6, ^J - 6.5), 1.60 (a, 2), 1.78 (a, 2), 2.18 (a, 1) , 3.32 (a, 8),

3.62 (a, 2), 3.95 (a, 1), 4.10 (br d, 2, J = 10.5), 4.56 (brs,

3), 7.24 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.7), 7.58 (a, 2), 7.77 (d, 1, J = 7.5), 8.13 (a, 2), 8.23 (d, 1, J = 8.1), 8.34 (brs,

3), 8.90 (br c, 1, J = 5.3), 10.54 (br s, 1), 11.49 (s, 1).

NMR (DMSO-d6, S): 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.

Example 82 (a) Preparation of IT- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -2- (tert-butoxycarbonylamino) benzamide

In a 250 ml round-bottomed flask fitted with a magnetic stirrer and a separatory funnel, 5 µ 3 (8.06 mmol) of 2-amino-1'- [4- (1,2-benzisothiazol-5-yl) -1- pipmnazinyl-3-butyl} -benzamide (see Example 36), 4.41 g (20.2 mmol, 2.5 eq) of di (tert-butyl) in 10 ml of 1,4-dioxane and 10 ml of 5% aqueous soda solution. -buiil) ~ di ···· · «·· ·· • · ♦ • · · ·« · · · · · *

A solution of 18 9 carbonate (Alarich Chemical Company) in 10 µl 1,4-dioxane was added dropwise and the reaction mixture was stirred at room temperature for 45 hours. A further solution of 1.76 g (8.06 g, 1.0 equiv.) Of di (terbutyl) dicarbose in 10 ml of 1,4-dioxane was added to the reaction mixture, and the resulting suspension was Stir for 5 days. At this time, the reaction mixture is filtered, the filtrate is transferred to a separatory funnel, ethyl acetate and water are added, the organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated to give the crude product as an orange liquid.

Yield: 6.56 g. This crude carbamate was purified by thin layer chromatography to give 3.39 g (83%) of the title compound as a yellow oil.

NMR (CDCl ₃ , δ): δ-52 (s, 9), 1.71 (n, 4), 2.50 (br t, 2, J = 6.4),

2.67 (br t, 4, J - 4.9), 3.48 (b, 2), 3.55 (br t, 4, J - 4.9), 6.74 (a, 1), 6.98 (ta, 1, J - 7.6), 7.42 (a, 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 (br s, 1) J (b ) Preparation of N- [4- (4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -2 - [(terbutoxycarbonyl) amino] benzamide, S, S trioxide

A solution of 4.49 g (13.0-15.6 mmol, 2.0-2.4 equiv.) Of 50-60% m-chloroperoxybenzoic acid (Aldrich Oaenical Company) in 50 mL of DKU was added. , 32 g (6.51 mmol) of 1T - {* 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazilyl] butyl] -2 - [(tert-butoxycarbonyl) amine ] to a solution of nz amide in 50 ml DKU,

The reaction mixture was stirred at room temperature for 1.5 minutes. The solution is then transferred to a separatory funnel, DIII and saturated aqueous sodium bicarbonate solution are added, the organic phase is separated off and the aqueous phase is separated off.

Extract twice with DELI. The combined organic layers were dried over magnesium sulfate and, after filtration, evaporated to give 4.6 g of a yellow glassy title compound. This crude product was purified by flash chromatography using a 4: 1 mixture of 'DELI and methanol as eluent.

2.28 g (59%) of the title compound are obtained as a pale yellow solid.

1 H NMR (CDCl ₃ , δ -): 1.5O (s, 9), 1.84 (a, 2), 2.08 (a, 2), 3.33 (a, 6),

3.50 (a, 2), 4.48 (a, 4), 6.95 (t, 1, J - 7.7), 7.40 (ta, 1, J 8.0), 7.71 (a) , 4), 7.94 (d, 1, J = 6.7), 8.20 (br s, 1), 8.32 (d.

1, J = 8.8), 10.40 (s, 1).

(c) Preparation of 2-Amino-IT - [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl-butylbenzamide] -N, S, S-trioxide hydrochloride

In a 500 mL round bottom flask, 2.28 g (5.87 mmol) of IT- [4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] -2 - [( To a _{mixture of} tert-butoxycarbonylamino-benzamide-1Τ, S, S-trioxide, 4.0 ml of anhydrous anisole and 50 ml of anhydrous chloroform was added 5.0 ml of trifluoroacetic acid. The reaction mixture was stirred under nitrogen for 30 minutes at room temperature and then with 15 ml of trifluoro

Acetic acid was added to the reaction mixture and the solution was stirred for 30 minutes. Chloroform was added to the mixture, followed by slow addition

- Cool, saturated sodium bicarbonate solution is added at 191 bar. The mixture was transferred to a response funnel and the organic phase was separated.

The aqueous phase was extracted with chloroform.

the organic layers were combined, dried over magnesium sulfate, filtered and evaporated. The product thus obtained was subjected to Thin Elution with methanol (4: 1) as a eluent by thin-layer chromatography to give 0.686 g of a pale yellow, glassy free base. This free base (0.686 g, 1.55 mmol) was dissolved in a mixture of Di and methanol (1.55 mL, 1.0 eq) and 1 L of HCl was added. The hydrochloride thus obtained was recrystallized from water-containing echoes as 0.51 g.

of the title compound as a beige solid, m.p.

226-228 ° C.

Si NMR (DMSO-d6, S); 1.61 (m, 2). 1.91 (m, 2). 3.32 (a, 2), 3.96 (a, 8),

4.75 (br 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 (a, 2), 8, 10 (a, 1). 8.31 (dm, 2, J = 6.2). 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 .

LE (ion spray): m / z (relative intensity) 458 (L + T, 80), 480 (Lh-αTa) ⁺ , 100.

Analysis for ^ 2 ^ 27 ^ 5648.HCl:

Calculated: 0 55.49; H, 5.71; 1 '14.18; Cl, 7.18%;

Found: 55.57; H, 5.75; 14.14; Cl, 7.23%.

.:

*

- 192 -

Example 83 (a) Preparation of 2-Amino-11-yl-1- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -benzamide oxide hydrochloride

In a 250 mL round-bottomed flask, 3.28 g (8.01 mmol) of 2-amino-17β -4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] '} - a mixture of dry glaze (see Example 36) and 75 mL of anhydrous DKL1 was stirred under nitrogen and cooled to -78 ° C with dry ice / acetone. In a pear shaped flask, 2.30 g (6.7-8.0 mmol, 8-1.0 equiv) of 50-60% m-chloroperoxybenzoic acid

The m-chloroperoxybenzoic acid was covered with nitrogen gas, anhydrous DKLI was added and the solution was cooled to -40 ° C with a mixture of dry ice and acetone. At this temperature, some of the m-chloroperoxybenzoic acid remains insoluble. The supernatant was transferred through a cannula to the cold benzamide solution, the residue

extracted.

The combined organic phase was washed with magnesium sulfate and concentrated by filtration to

5.57 g of a beige solid crude product are obtained and the crude free base is subjected to flash chromatography (17: 5, dichloromethane / methanol) to give a beige solid. This solid product was DELI / gs

I ···· «» · «·« ··. · * · · · · ·· »·« «« ·,. * ·· ·· · · »· ···« · _βΛ *

- 195 saturated; üátrium hydrogen carbonate oldaf; between them. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. 0.991 g of a beige solid free base are thus obtained. The free base (0.986 g, 2.52 mmol) was dissolved in a mixture of DELI and methanol, 2.32 mL (1.0 eq) of a solution of hydrogen chloride in 17 ether was added and the resulting hydrochloride was recrystallized from aqueous ethanol (0.470 g, 13%). m.p. 177.5-173.5 ° C (with decomposition). i

1 H NMR (DMSO-d 6, S): 1.61 (n, 2), 1.91 (m, 2), 3.29 (br c, 2, J = 6.8),

3.66 (m, 2), 3.90 (m, 6), 4.10 (br 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 (br t, 1, J = 5.6). ¹³ C NMR (DMSO-d 6, S): 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 _r 30.

LIS (ion spray): m / z (relative intensity) 426 (ΜΗ *, 100).

Analysis for CogEgrjm ^ OgS.ECl:

calcd: C, 57.19; H, 6.11; 1-15.16%; Found: C, 57.29; H, 6.13; ii 15.10%.

Example 84 (a) Preparation of 2- [2- (tert-Buto-carbonyl) -bridase in o] benzoic acid

In a 500 mL round bottom flask, 7.5 g (40.0 mmol) of 2-hyrazinobenzoic acid hydrochloride (Aldrich Chemical Company), 40 mL, 1.4 ···· ···························································································

- a mixture of 194-dioxane and 75 ml of 571 aqueous soda solution with ice water

The flask was then fitted with an addition funnel and a solution of di-tert-butyl dicarbonate (9.6 g, 44.0 mmol, 1.1 eq.) In 1,4-dioxane (20 mL) was added slowly.

The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. At this time, an additional 0.99 g (4.54 mmol) was added

0.11 eq) of a solution of tert-butyl dicarbonate and 10 µl of 1,4-dioxane are added slowly to the reaction mixture, and the reaction mixture is stirred for a further 26 hours and then concentrated. An orange-red residue is obtained. To this is added 200 ml of water and the mixture is cooled in two ice water baths. The pH was adjusted to 1 by the addition of aqueous 1T hydrochloric acid and the solution was thoroughly triturated with ethyl acetate extracts and hexane and dried in a vacuum oven. 9.13-8% (91%) of the title compound are yellow-beige solid.

NMR (DMSO-d _g, S): 1.43 (s, 9H), 6.77 (t, 1, J - 5.7), 6.88 (d, 1, J

- 8.2), 7.45 (cn, 1, J - 7.7), 7.83 (dd, 1, J - 1.5, 7.9), 8.89 (s, 1), 9 , 07 (br s, 1), 12.98 (br s, 1).

(b) Preparation of H- {4- [4- (1,3-Benzisothiazol-5-yl) -1-piperazinyl] butyl} -2- [2- (tert-butoxycarbonyl) hydrazino] benzanide

In a flame-dried 10G nl round-bottom flask, 2.57 g (10.2 mmol) of 2-L 2-tert-butoxycarbonylhydrazino] benzoic acid, 50 ml of anhydrous THE and 1.25 g (1.70 ml, , 2 mmol, 1.2 equiv.) Viz195 ···· »··· ·· ·» · · · · · · · · · ·

... · · · · ·· ··· "· "· the

It is cooled with stirring in a dry ice / isopropanol mixture. Isobutyl chloroformate (1.39 g, 1.52 mL, 1.0 eq.) Was added and the mixture was stirred for one minute and then cooled to -20 to -35 ° C.

Tii'r. -ί reel, gate k,

3.0),

NMR (CDCl ₃ , δ): 1.45 (s, 9), 1.68 (br t, 4, J)

2.49 (br t, 2, J = 6.8). 2.67 (br ε, , 4, J - 4.8), 3. , 45 {br q . 2, J "( > .0), 3.55 (br t, 4, J -4.8), 6.32 (br s, 1), 6 _? 61 (m, 1). 6.78 (tn, 1, J - 7.5), 7.01 (d, 1, J = 8.2), 7.35 (m, 3), 7.47 (Cm 1, J - 7 5). 7.81 (d, 1, J - 8.0), 7.90 (d, 1. J - 8.0) 8.76 (br s, 1)

.X ···

(ο) 17- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -2-hydrazinobenzamide dihydrochloride hydrate

Extract with 2.85 g (5.43 mmol) of 17- [4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl} 2- [2- (tert-chloroform) in a 500 mL round bottom flask. The combined organic phases were obtained as a colorless liquid. The crude product was solidified by column chromatography and the yellow oily free base was dissolved in DKH and

6.3 µl of a solution of gene chloride was added

The dihydrochloride thus obtained was obtained as a golden yellow solid, m.p.

226 ° C.

····? ♦ ·· ·· * · • · · · · · · · _Λ ·· ·· · · · · • · · · · · · · · · · ·· ·· ·· "··

- 197 hl NMR (DMSO-d6-S): 1.62 (a, 2), 1.83 (β, 2), 3.17 (a, 2), 3.29 (q, 2, J , 8, 6.6), 3.37 (a, 2), 3.54 (br s, 4), 4.05 (br s, 2),. 6.99 (t, 1, J 7.5), 7.12 (d, 1, J - 8.0), 7.46 (a, 2), 7.58 (t, 1, J - 7, 6)

7.73 (dd, 1, J = 1.3, 7.5), 8.06 (br s, 1), 8.09 (d, 1, J - 8.2), 8.13 (d, 1, J - 8.2), 8.78 (t, 1, J - 5.6), 9.18 (s, 1), 10.27 (br s, 3), 11.18 (br s, 1). ¹³ C NMR (DMSO-d _g £.): 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 '.

I.1S (by chemical ionization); n / z (relative intensity): 425 (LET, 10), 291 (100).

Analysis for C ₂₂ H _{2 S} N _c 0S.2.HC1.0.5H ₂ 0:

date; 6 52.17; H, 6.17; N, 16; Cl, 14.00; HgO 1.78%; Found: 0, 52.23; H, 6.34; H, 16.30; Cl, 14.04; HgO 2.05%.

Example 85 (a) Preparation of 3-Aminobenzo [d] thiophene-2-carboxylic acid methyl ester

This compound was prepared by the method of J. R. Beck [J. Org. Chem. 32, 5224 (1972)]. 50.0 g (0.538 mole) of 2-Nenobenzonitrile (Aldrich Chemical Company), 35.2 mL (56.4 g, 0.345 mmol, 1.11 eq.) Of methylthioglycolate (Aldrich Chemical Company), 400 ml ΒΙ.Π? and 57.4 g / 187 ml of aqueous potassium hydroxide solution afforded 56.1 g (52%) of the title compound as a pale beige solid.

1 H NMR (CDCl ₃ , δ): 3.90 (s, 3), 5.92 (br s, 2), 7.37 (ddd, 1, J = 1.3, 7.0, 8.2), 7.48 (ddd, 1, J = 1.5,

7.0, 8.2), 7 _Z 64 (ddd, 1, J -0.8, 1.5, 8.0), 7.74 (ddd, 1, J 0.8, 1.2, 8 , 0).

- 198 (b) Preparation of BenzoK thiophen-3-amine in a 1 L round bottom flask 32.09 & (0.155 mol) 3-amino-2-pyrrolidinone and 3θ, 83 g (43.0 µL, 0.3θ8 mol, 2.50 eq.)

1-Methylpiperazine (Aldrich Chemical Company) is light orange. the solution was cooled to 180-185 ° C for 3 to 5 hours under nitrogen and the residue was partially purified to give a flash chromatography solution which was further purified by column chromatography; Elution with DKLI gave 20.1 g (87%) of the title compound as a liquid liquid.

1 H NMR (CDCl ₃ , δ): 3.84 (br s, 2),

6.34 (s, 1), 7.38 (m, 2), 7.61 (m, 1), 7.80 (m, 1).

(C)

1- (Benzol [b] thiophen-3-yl) -piperazine in a yOC mL flask was 15.86 g (0.106 mol) of benzo [b] thiophen-3-s.min, 21.07 g (0.245 mol, 2.3 eq). piperazine and t are heated under nitrogen and allowed to stand overnight at room temperature.

At this time, the reaction mixture was concentrated and

The elution

We start with 100% DLI, DELI and methanol 85:15

(199) to give 14.41 g (62%) of the title compound as a yellow solid.

4i NMR _(DMSO-d6, S):

2.95 (m, 8), 6.89 (s, 1), 7.38 (m, 2), 7.75 (m, 1), 7.92 (m, 1).

(d) 1T-? 4 - '(4- (Benzo [b] thiophen-3-yl) -1-piperazinyl] -

Preparation of butyl-butyl chloride hydrochloride

In a 250 mL round-bottomed flask, 5.23 g (24.0 mmol) of 1- (benzopho] thiophen-5-yl) piperazine, 8.18 g (29.0 mmol, 1.21 equiv.) Of iT- (Brem butyl) phthalimide (Aldrich Chemical Company) 5.63 g (5.0 mL)

A mixture of 35.9 mmol, 1.5 eq.) Of triethylamine and 100 ml of acetonitrile under nitrogen at reflux for 2 hours.

boil.

The reaction mixture is transferred to a separatory funnel,

BIE.I was added and the solution was separated with a saturated sodium hydroxide organic layer, and the aqueous layer was extracted with DKH. The combined organic solution was washed with brine, separated, dried over magnesium sulfate, and filtered and evaporated to give 13.26 g of crude product as an orange oil which was purified by flash chromatography.

Elution with ethyl acetate / hexane (1: 1) gave 8.5 g of a yellow solid free base. The free base (1.55 S, 3.39 mmol) was dissolved in ethyl acetate and 5.70 mL (1.0 eq) of 1 H ethereal hydrogen chloride was added. The hydrochloride thus prepared was recrystallized from aqueous ethanol to give 1.30 g of a white solid, m.p.

• · · · »· ♦

NMR (DMSO-d6, δ): 3.52 (br s, 4), 3.20 (m, 6). 3.61 (a. 6),

7.11 (s, 1), 7.42 (a, 2), 7.88 (a, 4), 7.89 (d, 2, J - 2.7),

10.56 (br s, 1). ¹³ C NMR (DMSO-d _g, S) t 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.

200 -

Example 86 (a) Preparation of 4- [4- (Benzo [b] thiophen-5-yl) -1-piperazinyl] butylanine

In a 100 mL round bottom flask, 5.52 g (8.59 mmol) of IT- {4- [4-benzoyl] thiophen-5-yl) -1-piperazinyl] butyl} -phthalimide (see Example 85 (d)) step), a mixture of 0.75 g (12.87 mmol, 1.55 eq.) of 555 hydrazine hyalate and 25 ml of methanol is refluxed for 105 minutes. The suspension was allowed to cool to room temperature and water (25 mL) was added. The reaction mixture was quenched by addition of aqueous hydrochloric acid 117 to pH 2

The solid product thus obtained is filtered off with water

phase was extracted with DKI.I.

The organic phases are desalted, filtered again and concentrated to give 2.00 g (82%) of a pale yellow oily compound, m.p.

201 - solidifies on standing and turns into a tan solid.

1 H NMR (CDCl 3, δ) δ, 22 (br s, 2), 1.56 (m, 4), 2.46 (t, 2, J = 7.4), 2.73 (m, 6). , 3.18 (br t, 4, J - 4.6), 6.62 (s, 1), 7.34 (n, 2), 7.77 (n, 2).

(b) Preparation of 2-Amino-I: 7- £ 4- [4- (Benzo CbJ-thiophen-5-yl) -1-piperazinyl] butyl} -benzarnium hydrochloride • In a 100 mL round bottom flask, 1.79 S ( 5.18 mmol) 4- [4- (benzo [b] thiophen-5-yl) -1-piperazinyl] butylamine, 1.21 g (7.42 mmol, 1.2 equiv) of isatinic anhydride and 25 ml The mixture was stirred at room temperature under nitrogen for 1.5 hours

separated,

extracting the aqueous phase with H 2 O. The combined organic solution was dried over magnesium sulfate, filtered and evaporated to give 5.41 g of an orange crude product. Purify the free base by thin layer chromatography using 2.7 g of a colorless, oily free base as eluent. The free base (2.21 g, 5.41 mmol) was dissolved in ethyl acetate and 5.41 mL (1.0 eq.) Of ethereal hydrogen chloride was added. Recrystallization from the resulting hydethanol gave 1.38 g (50%) of the title hydrochloride as a solid, m.p. 210-212 ° C.

off-white, 1H-NMR (DMSO-d6, δ): 1.61 (a, 2), 1.82 (a, 2), 3.06-3.46 (a, 8), 3.61 ( br d, 4, J = 10.7), 6.43 (br s, 2), 6.54 (ε, 1, J = 7.4), 6.71 (d,

1, J - 8.0), 7.12 (s, 1), 7.16 (ε, 1, J - 8.2), 7.43 (a, 2), 7.53 (d, 1, j - 7.8), 7.83 (a, 1), 7.97 (a, 1), 8.33 (br ε, 1, J 5.3), 10.72 (br s, 1). ¹³ C NMR (DMSO-d _g, 8): 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.

202 -

Example 87 (a) Preparation of N- [4- [4- (1,2-Benzisolazol-3-yl) -1-piperazinyl] butyl-3-chloro-5-ethyl-2,6-dimethylbenzene hydrochloride

In a oven-dried 300 ml round-bottomed flask, 100 ml of toluene and 4.32 g (* 17.6 mmol) of 5-chloro-5-ethyl-2,6-methylmethylbenzoic acid were prepared according to the procedure of J. Paul et al. . Chem., 29, 61-69 (1936)] was added to a mixture of thionyl chloride (4.15 ml, 5.67 g, 47.6 mmol, 2.7 eq.) Under nitrogen and the pale yellow reaction mixture to 75 ³ 0

Dissolve in ml of anhydrous chloroform with nitrogen over the solution. example (□)

203], a solution of anhydrous chloroform (20 mL) was added to the acid chloride solution followed by 2.14 g (2.94 mL, 2.10 mmol).

k. The resultant viscous orange wash is washed with the organic phase and the organic phase is washed with magnesium sulfate (1.0 mL) and the ether salt (1.0 mL) is crystallized from ethanol / ether and dried in a vacuum oven.

powdery,

NMR (DMSO-d6, S): 1.16 (t, 3, J = 7.5), 1.60 (o, 2), 1.83 (br s, 2), 2.58 (q, 2) , J = 7.5), 3.20-3.63 (a, 10),

3.74 (s, 3), 3.78 (s, 3), 4.10 (br 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). ¹³ C NMR (DMSO- _g , $): 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.

- found 204 formulas:

56.31;

Ξ 6.18; N, 10.08%.

(a) into 1Γ- (4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-3-butyl-3-chloro-5-ethyl-6-hydroxy-2-methoxy) η z amide hydrochloride and 17- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl-3-chloro-5-ethyl-2-hydroxy-6-methoxybenzamide hydrochloride preparation of hydrate

2.07 g (4.0 mmol) of 1T- [4- [4- (1,2-benzisothiazol-3-yl'-1-piperazinyl) butyl] -3-chloro-5-ethyl-2,6- dimethoxybenzamide (see Example 87, step (a)) was mono-demethylated following the procedure of Examples 67 and 68. The two isomers thus obtained were eluted with ethyl acetate: hexane (2: 1). hexane 2: 1 mixture of 5-alklór eüil-2-hydroxy-6-methoxybenzamide _(Rf value of 0.11 when

(205: 2: 1 ethyl acetate: hexane) as a small isomeric pale orange oil. The saline two isomeric chloro chlorine is prepared separately by freeing the free amine base in ether and 1 eq. 1 TT ethereal hydrogen chloride oil was added.

Example 83

The hydrochloride of the major isomer was recrystallized from a mixture of ethanol and ether and dried in a vacuum oven to give 0.76 g (55%) of IT- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] - butyl 1- [5-chloro-5-ethyl-6-hydroxy-2-methoxybenzarine hydrochloride, off-white powder, m.p. 179-181 ° C.

Si NMR (DMSO-d6, δ): 1.12 (t,

3, J = 7.3), 1.64 (o, 2), 1.81 (m, 2), 2.52 (m, 3), 3.20-3.60 (m, 9), 3 , 82 (s, 3), 4.06 (br d, 2, J - 12.3), 7.38 (s, 1), 7.47 (m,

1), 7.60 (c, 1, J - 7.5), 8.12 (t, 2, J - 6.6), 8.83 (br t, 1, J - 5.1), 11 , 25 (br s, 1), 13.60 (s, 1). ¹³ C NMR (DMSO-d _g, £):

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 a

Calc'd: C, 55.65;

sum of tre:

H, 5.93; 17 10.38%;

c 55.56, H 5.99; Π 10.29%.

Example 89

The hydrochloride of the minor isomer

It was crystallized from 95% ethanol and dried in vacuo to give 0.156 g (7%) of 1- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] major-3-chloro-

206 -5-ethyl-2-hydroxy-6-diethyl: i-bisamide amide hydrochloride in the form of off-white, off-white crystals of punk, m.p. 171i / y. i

1 H NMR (DMSO-d 6, δ): 1.15 (C, 3, J = 7.6), 1.62 (a, 2), 1.81 (a, 2), 2.52 (q, 2 , J 7.6), 3.20-3.62 (a, 10), 3.72 (s, 3), 4.08 (br 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 (br t, 1, J = 5.6). 10.63 (br s, 1), 12.64 (s,

1). ¹³ C NMR (DMSO-d 6, 75.43 MHz, 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 _oc -H -.- H 2y y ^ calculated: Calcd for H ₂ O -SO ₂ .KCl.1.25 H ₂ O: 0 53.45; H, 6.19; H, 9.97; H ₂ 0 4.00%; found: 0 53.46; Ξ 6.14; 17.99; H ₂ 0 4.02%.

Example 90

Preparation of -Amin o-tert-4- [4- (1,2-benzisothiazol-yl) -1-piperazinyl-butyl} - γ-methoxybenzamate hydrochloride

This compound was prepared according to the procedure described in Example 75, step (b). y, y5 g (0.017 mol) of 3-methoxyisatinic anhydride (prepared from 2-amino-3-netoxybenzoic acid (Aldrich Ohemical Company) according to the procedure described in Example 99) and 5.33 g (0.017 mol, 1.0). eq.) 5- [4- (4-Aminobutyl) -1-piperazinyl] -1,2-benzisothiazole gave 5.41 g of the title compound as the free base. A portion (1.94 g) was dissolved in ethanol (mL) and treated with hydrogen chloride (4.4 mL, 1.0 eq) in ether.

The hydrochloride thus obtained · · ·

Recrystallization from a mixture of 207 ethanol and isopropanol gave 1.93 S (65%) of a cinch-white crystals, m.p. 156-138 ° C.

NMR (DMSO-d6, 200 MHz, g): 1.59 (m, 2), 1.80 (n, 2), 3.12-3.60 (a, 6), 3.81 (s, 3 ), 4.09 (brd,

2, J - 12.9), 6.13 (br s, 1), 6.54 (t, 1, J - 8.0), 6.91 (d, 1, J7.6), 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 _r 33 (br t, 1, J - 5 _t 4), 10.89 (br s, 1).

¹³ C NMR (DMSO-d 6,?): 75.43 MHz,?); 21.68, 27.29, 39.04, 47.38, 51.48,

56.20, 56.54, 112.83, 114.92, 115.40, 120.73, 122.18, 124.98, 125.59,

127.93, 129.11, 140.50, 147.88, 153.09, 163.18, 169.79.

LE (by chemical ionization / CH 2 O, 50 mA / sec):

LI + 1, base (440).

Analysis for C ^ Hg ^ i ^ OgS.HCl:

date: C 59.03; H, 6.35; Π 14.71; s, 6.74; cl 7.45%; found: c 57.94; H, 6.42; rn 14.57; S c, / 1; cl 7.55%.

Example 91

live. 0.99 g (33 mmol) of 3- [4- (4-aminobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b), 0.52 g (0 72 ml, 5.1 mmol, 1.5 eq.) Of triethylamine and 0.70 g (3.4 mmol, 1.0 eq.) Of 2-nitrobenzoyl chloride (Aldrich Chemical Company), The crude reaction mixture was purified by flash chromatography.

using ethyl acetate containing 0.94 g of yellow solid free base.

- We get 208. The ester was converted to the hydrochloride, crystallized from ethanol-ether and dried in a vacuum oven to give the title hydrochloride as an off-white powder (0.66 g, 41%), m.p. 214-215 ° C.

1 H NMR (DMSO-d 6, 200 MHz ₎ δ: - 1.61 (n. 2), 1.85 (n, 2), 3.28 (n, 6), 3.56 (m, 4), 4.09 (br d, 2, J - 13.5), 7.48 (dd, 1, J - 7.2, 7.8), 7.72 (n, 4), 8.06 (d, 1, J - 8.0), 8.15 (t, 2, J - 7.0), 8.83 (br t, 1, J - 5.5), 11.29 (br s, 1).

Nuclear Magnetic Resonance Spectrum (DMSO-d6, 75.43 MHz, λmax 21.44, 26.95, 39.32, 47.30, 51.39,

56,06,122,18,124.86, 124.99, 125.59, 127.94, 129.09, 130.07,

131.63, 133.57, 134.55, 148 _z 01, 153.09, 163.20, 166.42.

Analysis of the formula:

calcd: 0 55.51; H, 5.50; 17 14.71%;

Found: C, 55.55; H, 5.55; 17 14.72%.

Example 92 (a) Preparation of 2-Amiao-cC, c £, cC-trifluoro-p-toluic acid

5.00 g (21.3 mmol) · 2-nitro-o, c, o C-trifluoro-p-toluic acid (Aldrich Chemical Company) in 100 mL of abs. ethanol solution in 50 ml of abs.

ethanol and 100 mg into a 5% palParr 5% charcoal apparatus

The solution is filtered through a millipore AP filter, the filtrate is concentrated by rotary evaporation and the residue is dried under vacuum. This is obtained without further purification.

• · · «« · ·

• <* • · ·

- Preparation of 209 (b) 2-Amino-1- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -4- (trifluoromethyl) benzamide hydrochloride

20 ml of anhydrous pyridine in a 100 ml round-bottomed flask,

1.35 g (6.5 mmol) of 2-amino-c, 10C, cC-trifluoro-p-toluic acid and 2.00 g (6.5 mmol, 1.0 eq) of 3- [4- (4- aninobutyl) -1-piperazinyl] -1,2-benzisothiazole (see Example 13, step b) was added thereto, then poured and mass-opened in vacuo.

Water (200 mL) was added to the residue and the solution was evaporated to dryness. To the resulting brown solid product was added 200 mL of u-ol and the solvent was removed on an organic evaporator. This process was repeated two more times in each case with 200 ml of toluene. To the rest. 200 ml of distilled water are added and the solution is alkalized by the addition of one IT soda solution.

This aqueous solution was extracted three times with 200 mL of ethyl acetate

dried on sulfate,

Toluene (200 mL) was added and the combined organic layer was filtered with magnesium and evaporated. The residue and the solvent were repeated on a rotary evaporator twice, in each case adding 200 ml of toluene. The crude product thus obtained, starting with pure ethyl acetate, was carried on with a 1:99 mixture of methanol and ethyl acetate ············ 9% and ending with a 2:98 mixture of methanol and ethyl acetate. 1.45 g of the free amine base are obtained, which is dissolved in ethanol and 3.04 ml of a 1 IT solution of hydrogen chloride are added. Ancient crystallization of hydrochloride (15%) from ethanol containing cinic acid 0.512 g

RINTEL, white, cri , s t low os product we get, op. : 205-207 1H NMR (DMSO-dg, 200 MHz, S): 1.60 (a. 2), 1.80 ( ". 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, First J - 7, 5), 7.71 (d, 1 J - 8.3), 8.14 (a,

2), 8.57 (br t, 1. J - 5.4). 10.94 (br s, 1). C NMR (DMSO-d

75.43 MHz (£): 20.75, 26.22, 38.21,46,45,50,55,55,22, 110.09,

110.13, 110.18, 110.23, 112.29, 112.35, 112.40, 112.45, 117.88, 121.24, 122.23, 124.04, 124.66, 125, 84, 127.00, 128.17, 129.34, 131.38, 131.79, 149.66. 152.16, 162.24, 167.88.

Ϊ.Ϊ8 (with chemical ionization / Clí, 50 mA / sec): II + 1, base (478).

Analysis a

calcd

date:

C, 55.74; H, 5.29; iT 13.62; S, 6.24; 01 6.90%;

u

u

C, 54.04; H, 5.38; 1T 13.57? S, 6.32; Cl, 6.92%.

93rd-98th examples

A 95 · -98. The compounds of Examples 1 to 8 are prepared from the appropriately substituted anthranilic acid precursors by the procedure of Example 92 (b).

The anthranilic acid used in this process is commercially available,

Analytical data for 2-aminobenzamides are shown below.

• · · · ·· «« 9 «• W * • · * · · · · ··· · 4 ·« V * ·· 4 ♦ Ν ·· 4 «··«

211 Example 95

Preparation of 2-Amino-E- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -3-methyl to prepare the hydrochloride Starting material 2-amino-5-methyl benzoic acid (Aldrich Chemical Company), yield 0.806 g (54%), mp 208-210 ° C.

NMR (DMSO-d6,

Ό

300 MHz, S); 1.58 (a, 2), 1.78 (a, 2), 2.08 (s, 3), 3.31 (a, 8), 3.59 (a,

2), 4.08 (br d, 2, J - 12.1), 6.21 (br 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 (br t, 1, J - 5.2), 10.58 ( br s, 1). ¹³ C NMR (DMS0-d _g, 75.43 MHz, <£): 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.

I.LS (with chemical ionization / CH 2 O, 50 m / sec): Lh-1, base (424).

Analysis for C ₂ ^ H ₂ ^ E ^ 0S.HCl:

Calc'd: C, 60.05; H, 6.57; E, 15.22; S, 6.97. Cl, 7.71%; Found: C, 60.08; H, 6.61; IT 15.12; Δ 7.06; Cl, 7.76%.

Example 94

Preparation of 2-Amino-1 - [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -5-hourly amide hydrochloride

Starting material: 2-amino-6-chlorobenzoic acid (hancaster

Synthesis Inc.), 0.75 g (24%), m.p. 211-215 ° C.

Si NMR (DMSO-d

200 MHz, 5). 1.59 (a, 2), 1.82 (a, 2), 3.15-3.61 (a, 10), 4.08 (br d, 2, J - 13.5), 5.23 (br s, 2), 6.61 (d, 1, J - 7.8), 6.66 (d, 1, J -

8.2), 7.05 (t, 1, J - 8.0), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J -

7.5), 8.14 (t, 2, J = 7.2), 8.47 (br t, 1, J = 5.3), 10.70 (br s, 1).

C NMR (DMSO-d _g, 75.43 MHz, 5); 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.

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

212

I.S. by chemical ionization (CH 2 O, 50 mA / sec): LI + 1, base (444).

Analysis for C ^ HH ^ NN ^OCl.iOl;

Calc'd: C, 55.00; Ξ 5.56; IT 14.58; S, 6.67. Cl, 14.76%; Found: C, 55.09; Ξ 5.66; 1714.55; S, 6.74. Cl, 14.66%.

Example 95

Preparation of 2-Amino-17β-4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl-5-fluorobenzamide hydrochloride Starting material: 2-Amino-5-fluoro- Benzoic acid (Food), 0.65 g (22%). mp 219-221 ° C.

1 H NMR (DMSO-d 6, 300 MHz, δ '): δ, 58 (m,

2), 1.80 (a, 2), 3.29 (a, 6), 3.45 (m, 2), 3.59 (br d, 2, J = 10.9),

4.08 (br d, 2, J - 12.6), 6.30 (br s, 2), 6.71 (dd, 1, 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 (br t, 1, J -

5.3), 10.65 (br s, 1). ¹³ C NMR (DMSO-d6, 75.43 MHz _? D 21.72, 27.17,

39.12, 47.42, 51.51, 56.21, 114 _T 36, 114 _r 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.

LIS (by chemical ionization / Cl 10, 50 mA / sec); LI + 1 base (428).

Analysis of the C ^ H ^ iT ^ EOS.HCl calculator t

C, 56.95;

found;

C, 56.84;

S, 7.01; Cl 7.75% ···· ···

Example 96

Preparation of 2-Amino-iT-pl · - [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl-butyl} -6-methylbenzamide hydrochloride Starting material 2-amino-6-methyl- benzoic acid (Aldrich Chemical Company), 1.10 g (21%), m.p. 194-196 ° C.

1 H NMR (DMSO-d

-200 MHz, λ); 1.59 (n, 2), 1.80 (n, 2), 2.21 (s, 3), 3.32 (m, 6), 3.55 (m, 4) ), 4.10 (n, 2), 4.93 (br 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 (br t, 1, J = 5.3), 10.80 (br s, 1). ¹³ C NMR (DMSO-d 6, 75.43 ΜΗζ _τ £): 20.68, 21.73, 27.27, 39.02, 47.37, .51, 56.17, 113.70, 118.82 , 122.18, 124.18, 124.99, 125.61, 127.93, .129.11, 129.76, 135.30, 146.32, 153.08, 163.20, 169.29.

I.IS (with chemical ionization / OH 2 O, 50 mA / sec): I.I + 1, oasis (424).

Analysis for -HC1:

date; C, 60.05; li 6.57; H, 15.22; S, 6.97. Cl, 7.71; Found: C, 59.99; H, 6.58; K, 15.17; S, 7.08; Cl, 7.64%.

Example 97

Preparation of 2-Amylo-IT-η 4 -L- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl-2-naphthalenecarboxylic acid amide Starting material 3- ^a- mino-2-naphthoic acid (Aldrich Chemical ConpanyJ, 0.284 g (9%), m.p. 216-218 ° C.

1 H NMR (DMSO-d

200 MHz, δ): 1.62 (m, 2), 1.84 (m, 2), 3.33 (m, 8), 3.59 (m, 2), 4.12 (br d, 2) , J - 12.7), 6.11 (br 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 (br t, 1, J = 5.2), 10.69 (br s, 1). ¹³ C NMR (DMSO-d 6, 50.29 MHz, S): 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, 1.28.45, 128.70, 128.90, 135.90, 146.02,

152.48, 162.58, 169.11.

- 214

I.IS (chemical ionization / CH 2 OH, 50 mA / sec): ii + 1, base (460).

Analysis for C ^ H ^ lTySO.HCl:

Calculated: C, 62.95; H'6,10; N, 14.12; S, 6.46. Cl, 7.15%; Found: C, 62.88; H 6.14; i'T 14.05; S, 6.53; Cl, 7.21%.

Example 98

Preparation of 2-Amyloxy-4- [4- (1,2-bis-isothiazol-3-yl) -1-piperazinyl] butyl] -5-methoxy-bisamide hydrochloride Starting material 2-Amino-5-methoxy-benzoic acid (which

By reduction of 2-nitro-5-methoxybenzoic acid (Apin Chemicals Ltd.), prepared according to the procedure described in Example 92, step (a) (yield 0.513 g, 10%), m.p. 150 ° C (dec.); .

Hl NMR (DMS0-d _g, 200 MHzj5): 1.60 (m, 2), l _r 79 (n, 2), 3.37 (w, 12), 3.71 (s, 3), 3, 88 (m, 2), 6.67 (d, 1, J - 8.8), 6.86 (dd, 1, J - 2.7, 8.8), 7.10 (d, 1, J - 2.7) , 7.48 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 8.12 (d, 1, J - 7.5), 8.15 (d, I, J -

7.5), 8.37 (br t, 1, J -4.7). ¹³ C NMR (DMSO-d _g, 75.43 MHz, £); ^s 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.

I.IS (with chemical ionization / CH 2, 50 mA / sec): Ll + 1, base (440) »

Analysis for C ^ HggiT ^ UgS.HCl:

Calculated: C, 58.03; II, 6.35; II, 14.71; S, 6.74. Cl, 7.45%; Found: C, 58.09; H, 6.34; N, 14.62; S, 6.82; Cl, 7.39%.

Example 99 (a) Preparation of 4-Eluoro-isatinic anhydride

0.97 g (6.25 mmol) of 2-amino-4-fluorobenzoic acid [4-fluoro-2-nitrobenzoic acid (Sigma-Aldrich Library of Eare Chemicals)]

215 reduced by the procedure described in Example 92 (a)], 20 ml of anhydrous 1,4-dioxane and 5.0 g (25.2 ol, 4.0 eq) of trichloromethyl - (chlorine). formate (Johnson-LIatthey Chemical Company) was refluxed in a 100 mL round-bottom flask for 11 hours, then cooled and stirred at room temperature overnight.

The solvent was removed on a rotary evaporator to give 1.18 g (more than 100% crude) of the cinic compound as an off-white solid.

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 (br s, 1)

next

without purification.

(b) Preparation of 2-Amino-IT-N- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] butyl] -4-fluorobenzamide hydrochloride.

This compound was prepared according to the procedure described in Example 75, step (b). 1.18 g (6.51 mmol) of 4-fluoroisatinic anhydride and 2.0 g (6.51 mmol, 1.0 equiv) of 5- [4- (4-aminobutyl) -1-piperazinyl-1 Yield 1.51 g (43%) of the title compound as a pale yellow solid, mp 254-236 ° C.

NMR (DMSO-d6, 330 MHz, δ): 1.53 (m, 2), 1.78 (n, 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 (dd, 1, J = 2.5, 7.2), 6.75 (br s, 2), 7.47 (t, 1, J -7.5),

7.60 (n, 2), 8.12 (t, 2, J = 8.3), 8.32 (br t, 1, J = 5.3), 10.90 (br s, 1). ¹³ C NMR (DMSO-d _g, 75.43 MHz, £); 21.66, 27.25, 39.02,

47.37, 51.47, 56.17, 102.14, 102.33, 102.45, 102 _r 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.

«· • · · ·

- 216 MS (with chemical ionization / CH 2 O, 50 mA / sec): M + L, base (428)

Analysis for Cgg ^ gg ^ ⁰ ^ ² · HCl:

Calculated: C, 56.95; H, 5.86; X, 15.09; S, 6.91. Cl, 7.64%;

C, 56.89; H, 5.85; N, 15.10;

S, 6.90; Cl, 7.61%.

Example 100 (a) Preparation of 5- [1- (4-Aminobutyl-4-piperidinyl) -6-fluoro-1,2-benzisoxazole

In a 100 mL round bottom flask, 1.04 g (2.47 mmol) of N-E 4- [4- (6-fluoro-1,2-benzisoxazol-5-yl) -pip® ^{: c (} 3ino] butyl } -f thalimide (see Example 69), a mixture of 0.24 g (4.24 mmol, 1.67 equiv.) of hydrazine hydrate (as a 50% aqueous solution) and 15 mL of methanol was removed after 1 hour. After allowing the reaction mixture to cool, distilled water (50 mL) was added and the solution was adjusted to pH 1 with 1 L hydrochloric acid solution. The suspension was filtered, the precipitate washed with water and the pH of the filtrate

pseudonym iumcarb ο n án - solves by adding t.

The basic and extracted three times with 100 ml of DKE.

The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. 0.58 g (81%) of the title compound is obtained as a pale yellow oily substance.

¹ HNMR (CDCl ₃ ,):

1.54 (a, 4), 1.80 (br s, 2), 2.10 (m.6), 2.41 (br t, 2.J-7.2), 2.74 (br t, 2) , J - 6.4) 3.08 (n, 3), 7.05 (dt, 1, J - 2.1, 8.9), 7.23 (dd, 1, J - 5.1, 8,). 7).

(b) Preparation of 2-Alloyo-IT- {4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperino] butybutyrimide hydrochloride

0.58 g (1.99 mmol) of 3- [1- (4-amino-butyl) -4-piperidinyl] -6-fluoro-1,2-beazisoxazole, 0.525 g (1.99 mmol, 1.0 eq.). A mixture of isatinic anhydride and 12 ml of ethanol was stirred in a 25 ml round-bottomed flask under nitrogen for 3 hours and then concentrated. This gives a brown-orange oily product which solidifies on standing. The crude free base was purified by flash chromatography using 0.1% ethyl acetate as eluent to give 0.69 g of an oily free base. The free base (0.69 g, 1.68 mole) was dissolved in ethyl acetate and treated with 1.68 mL (1.0 mL of ca.

0.51 3 (57%) of an off-white solid, title compound, m.p. 242.5-245 ° C (with decomposition).

1 H NMR (DMSO-d 6, δ); 1.57 (n, 2), 1.78 (8.2), 2.25 (m, 4), 3.12 (m, 4)

3.27 (m, 2), 3.47 (m, 1), 3.62 (br d, 2, J = 12.0), 6.39 (br s, 2),

6.51 (tm, 1.J-7.4), 6.69 (dd, 1.J -0.9, 8.1), 7.13 (un, 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 (n, l), 8.29 (n, l), 10.3 (br s, 1). ¹³ C NMR (DMSO-d ₆ , δ): 20.81, 26.44. 26/91, 31.26, 38.07, 51.27, 55.65,

97.72, 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.

found:

Claims

Claims (20)

Claims - 218 - 1. A compound of formula (I). compounds, their physiologically acceptable salts, their physiologically acceptable solvates, and their physiologically functional oxides - wherein in formula (I): -Γ R ^x is Ov is C 1 -C 6 alkoxy substituted with one or G; hydroxy, -IT (K, ^) g, nitro, 3 (O) R ^. wherein n is 0, 1 or 2; nitrile; COlTtR ^, COr \ COgR ^, CO-aryl, azido, benzyloxy, -πΛτ (Ε ⁴ ) 2, -ZiR ^ COgR ^, -ζ® ⁴ π = ο (η ⁴ ) 2, -ιςε ^ · (C = o) ch (it (r ⁴ ) ₂ ) r ⁴ or -HR (C = O) R. group; R ² C 1-6 alkoxycarbonyl; 3? - 219 R ^{4 is} hydrogen or C 1-6 alkyl; R? is - 1T = C- or -O = 17-; R 4 is hydrogen or C 1-6 alkyl; R ⁸ , R ⁸ , R 6, R ¹⁰ , and R ¹¹ are the same or different and are hydrogen or halogen; nitro; C 1-6 alkyl optionally substituted with one or more halo; C 1 -C 6 alkoxy optionally substituted with one or more halo; hydroxy; 3 (0), R ^{4 is a} general formula wherein n is 0, 1 or 2; nitrile oport; CO 2 H (R ⁴ ) 2, CCR ⁴ , COgpS CO-aryl, azido, benzyloxy, 17 (R ⁴ ) 2, -R ⁴ 17 (R ⁴ ) 2, -πΛτ = ο (η ⁴ ) 2 , - ⁴ (c = o) oh (it (r ⁴ ) 2) r ⁴ , -1S ⁴ (C = O) R ⁴ , - R ⁴ CO ² R ⁴ ; C 1-6 alkoxy-carbonylamino or Ph 17 = 17; or R? and R ⁸ and R ⁸ and R ⁶ and R ⁶ and Β θ respectively and R ·· ¹ * may also represent a group of formula (e) wherein V is O or S; Z is a C 4 -C 3 alkylene group optionally interrupted by a group -S (O) - wherein n is 0, 1 or 2; Σ is nitrogen or carbon; and 7 is a group of formula (d) wherein - 220 A is CR ⁴ or nitrogen, B is oxygen, 21 R 4 or 8 (0), Z1 ip wherein n and R * are as defined above and R 'is hydrogen or halogen. Compounds according to claim 1, salts, solvates or derivatives thereof, wherein in the formula (I), the n-nitrogen adjacent to the group Z, in the monocyclic six-membered ring, is present in oxidized form. Compounds according to claim 1 or 2, their salts, solvates or derivatives, wherein Y is -CH, ϊ ₂ -, -CH ₂ CH ₂ -, -CHgCHgCIIg-, 7 is -21 = H; and in each case represents a double bond; z R 1 is -CO ₂ Bt or hydrogen; and ZL R * represents a hydrogen atom or a methyl group. THE 3. or derivatives thereof, characterized in that: R - is hydrogen; R ² is -Cl ₁₂ -, -Ch ₂ Cl ₂ -, -CH 8 CH ₉ Cl ₁ - or-2T = iT; and 3 4 R and R are hydrogen. r- In Figure 4. their salts, solvates- - 221 - Compounds according to claim 1 or 2, their salts, solvates or derivatives, characterized in that Y is a group of the general formula (b), and 3 is hydrogen, chlorine, fluorine or di-Cl; or a methyl, hydroxy, methoxy or nitro group; and S.5 is -C = N-. Compounds according to claim 6, their salts, solvates and their derivatives, characterized in that Jelent 'represents hydrogen, fluorine, methyl, nitro or methoxy. Compounds according to claim 7, or a salt, solvate or derivative thereof, characterized in that 3 "represents a hydrogen atom or a nitro group. Compounds according to claim 1 or 2, their salts, solvates or derivatives, characterized in that Ί represents a group of the formula (c) and represents a hydrogen atom or a metal group; is hydrogen; IE ₂ , iTHIIe, hydroxy, methoxy or BHAc. represents a chlorine or bromine atom; lIHCOgterc-Bu HH or a group of formula _2; is hydrogen or bromine; methoxy, trifluoromethyl, t-Bu, n-I7 = Ph, ÜHAc, NHCOg t-Bu or 1Ή ₂ group; is hydrogen or bromine or chlorine; or a nitro group and represents a hydrogen atom, a methoxy group or a hydroxy group. - L ρθ ^ 10 - U ai • · · - 222 - Compounds according to claim 9, their salts, solvates or derivatives, characterized in that: R 7 is -H, R 'is -H, »methoxy, β üFAc or 3HHe; R is hydrogen or bromine; is hydrogen or bromine; R 1 is hydrogen or bromine; ^-1 R * ^- represents hydroxyl or methoxy group 11. A compound according to claim 10, or a salt, solvate or derivative thereof, wherein r8, R0 and R10 are hydrogen; R &lt; 4 &gt; is a hydroxy group and R &lt; 1 &gt; 7, 8 below; 'R' is methoxy, R 'is hydrogen, R' is bromine, R '' is hydrogen and R 'is hydroxy. 12. Compounds according to any one of claims 1 to 3, salts, solvates or derivatives thereof, characterized in that Z is a C 4 -C 6 alkylene group. 13 · The first to twelve. Compounds according to any one of claims 1 to 3, salts, solvates or derivatives thereof, characterized in that j represents a group of the formula (d), 3 represents a-3 group; ^{7 is} -O-; es R "hydrogen or fluorine" A ~ _Λ (J · 14. A compound according to claim 13, or a salt, solvate or derivative thereof, wherein: R3 is -H and R is hydrogen. ····· ♦ ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 223 15. 2- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -butyl} -1-isooldolinone; H - [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -3,4-dihydro-1 (2H) -isoquinolinone; 2-amino-1H-4- [4- (1,2-benzisothiazol-3-yl) piperazino] butyl} benzamide; 6- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl]. -6,7-thiaro-5H-pyrrolo [3,4-b] pyridine-5,7- <3 ion; 17 - [beta] - [4- (1,2-benzisothiazol-3-yl) -piperidino] butyl] phthalimide; 17-zis [4- (1,2-beazisothiazol-3-yl) -1-piperazilyl] butyl} -2-methylamino-butyramide; 1 T -B 4 - [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} benzamide; 2-yl- £ 4- [4- (l, 2-benzisothiazol-3-yl) ^-l-pipe, azinil] butyl} benzamide; (R) -Cis-2- [4- (4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl) -4a, 5,6,7,8,8a-hexahydro-1 (2H) ) -phthalazinon; iT-4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-butyl} -3-bromo-2-hydroxy-6-methoxy; 2-Amino-IT- {4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl-butyl} -benzamide; 2-amino-1H-4- [4-benzo [b] thiophen-3-yl) -1-piperazinyl] butylbenzamide, and the physiologically acceptable salts and solvates thereof, and their physiologically functional derivatives and its oxides. • * - 224 16. ΐί- ^ yl- [4- (l, 2-benzisothiazol-3-yl) -l-hump ^era3 i3il] -butyl .. -3-bromo-2-hydroxy-6-carboxy-methyl-benzamide; 0-17- 2-amine; 4- [4- (l, 2-benzisothiazole triazolo ol-3-yl) -l-piperidine ^ ^a3 ióil2 -buöiiy-benzamide; 2-amino-IT- [4- [4- (1,2-benzisoxazol-5-yl) -1-piperazinyl] -butyl] -benzanide; 2-amino-17β- [4- (benzo [b] hiophen-p-yl) -1-piperazinyl butyl] -benzamide; 7- {4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -3-bromo-2-hydroxy-6-methoxybenzanide, and its solvates and h-oxides; physiologically acceptable functional derivatives thereof. 17. 2-Amino-17- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butylbenzamide hydrochloride. 18th 3- £ 4- [4- (1,2-Be n z i z o t thiazol-5-yl) -p ipe r id i n o] -bu 111 ^. phthalimide; (3) -cis-2- {4- [4- (1,2-benzisothiazol-5-yl) -1-piperazinyl] -butyl] -4a, 4,5,6,7,8,8a-hexahydro- l (2'í) -phthalazinon; ··. (1) Trans-2- [4- (4- (1,2-Benzisothiazol-p-yl) -1-piperazinyl] butyl-4a, 5,6,7,8,8a-hexahydro-1 (2H) -phthalazinone ; and 3- {4- [4- (6-Fluoro-1,2-benzisoxazol-5-yl) -piperidino] butyl} -phosphate. ···· "·· • · · · · · · · · · · ·· • · · · • · · · · · · · · ·· ·· ♦ - 225 Compounds of formula (I) according to claim 1 or claim 2 or physiologically -Ο · use of ^their functional derivatives ⁱⁿ medicine. 20. [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl-butyl} -4-nitrophthalimide; 3-} 4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] butyl] -4- (3H) -quinazolinone ·, 2-} 4- [4- (1,2-Benzisothiazol-5-yl) -1-piperazinyl] butyl} -1 (2H) -phalazinone ·, 2-} 4- [4- (1,2-Benzisothiazol-5-yl) -1,3,3 (2H, 4H) -isoquinolinone; IT-p- [4- (1,2-Benzisothiazol-5-yl] -piperidino] butyl} piperazinyl] butyl} thalimide; (In IL 'ace • · · ·· ü You are an I ancestor 226 2. your (I) false oxies or physiological behavior, personality disorders, vomiting and The dj or IT-oxy according to claim 1 or claim 2 or the physiological composition according to claim 23. The diolated zophrenia of claim 1 or claim 2. - 227 - Use of any of the compounds of Claim 20 of Claim 20 for Cut, 'Salt, Solvate, Anti-E and Cut 27- The process of formula (a) in formula (I) has the meaning (a) wherein the dashed line (p? alkyl; optionally one or more halo groups having coe (r ⁴ ) ₂ , OOE ⁴ , IX Λ lx -χεέ (? 7) ₂ , -iíp7 cut:? -er ⁴ (c = o) e ^{4 is} -C ⁴ -, -CH ₂ -E = E- or - (O = 0) HE ⁴ is hydrogen, C 1-6 alkyl or. Ί 1. Ϊ? o5 alL cr; 223 out of ⁷ views: hydrogen or halogen; nitro; optionally a va _: Ov is C-C alk alkyl; optionally one or more of the formula (C 5) -alkoxy alkoxy 2; nibrilcsoport; ΓΊ Q or R ² and R ² may also represent R ⁸ and a group where S is sulfur; is a C 4 -C 8 alkylene group represented by n Ο, 1 or 2; or C 4 -C 8 -alkenylalkynylene; is carbon; and x represents a halogen atom, reacting a compound of formula II with a compound of formula IH wherein L represents a leaving group; or reacting a compound of formula (II) with a compound of formula (IV) wherein A is a suitable anion and R ^1p is -CH 8) - or - (CH 8) 3 -; or a compound of formula (V) Reacting Y ---- Z --- L, wherein L represents a leaving group, with a compound of formula VI; or cyclizing a compound of formula (VII) with a compound of formula (VIII) wherein L is a leaving group, or is CH ₂ O or Z; A compound of Formula (ZZ) wherein R 'is a signal / 1 π (Z -CHg- or -IT (R ') - (O = V) -, and R- is 5 R group or -C = C- group or a general (Z ") ^w Ov 'Ov: - 2yO CH. 17 7 - wherein R ⁽ is R), 2 2 i -SL- or CH ₂ -L is a group L-chloro-cut-bromo. denotes a methoxy or a hydroxy group and L je represents a general port, V denotes a hydroxy group 'ö ν' when T represents a group of formula (a), (b) or (c) 7 8 Q ion ^- b. and R ", ~ R, R, R, Η or R" - represents ii (R ') ₂ ^or SV 1 "; (ρ / *) ₂ , then the corresponding (alkoxycarbonyl) amino derivatives hiőrolizáljuk; or cutV = Ί. j r> a _x u sseuiin-_3v * then the appropriate and, if appropriate, one 251 ··········································································································································· alol Z represents a C 4 -C 8 alkenylene or C 4 -C 8 alkylene group where Z is a C 4 -C 8 alkenylene to form a compound of formula I wherein Y is a group of formula (c) and V represents a sulfur atom; and is of the formula (I). yielding a compound having Italános. ken.1Λ - Claim 252 Belt and / or Heavens They Are Aggressive ADVOPAT ^ ' ⁷ ^ Shit Λ.η * T.. our OFFICE K / 'EiiiiBELA ys /, Imi business drinker Post Address: 1251 Bp / PL < First í> U-i 4 72309 y, γ — z — n x — w {I 'j V_7 ^{V 1} (id) (iig) (iik) ADVOPATENT PATENT OFFICE CHRISTMAS BÉLA patent attorney ^l östácIíürÍ251 Pf. 11th ADVOPATENT PATENT OFFICE CHRISTMAS BÉLA 6th Patent Attorney Post Address: 1251 Bp.Pf. 11th