FI103406B - 3-piperatsinyylibentsatsolijohdannainen - Google Patents

Description

, 103406 3-Piperazinylbenzazole Derivative Divided from U.S. Patent Application No. 8937015, U.S. Patent Nos. 4,452,799, 4,524,206 and 4,590,196 disclose some 3-piperidinyl-1,2-benzisoxazoles and -1,2-benzisothiazoles having psychotropic, sedative and analgesic properties. U.S. Patent 4,804,663 describes 3-piperidinyl-1,2-10 benzisoxazoles and -1,2-benzisothiazoles as antipsychotics. U.S. Pat. And EP-A-0281309 describe piperazinyl derivatives having anti-psychotic properties. EP-A-0135781, published April 3, 1985, discloses some 3-piperidinylindat-15 cell derivatives having antipsychotic and analgesic properties. EP-A-0302423 describes 1-phenyl-3-piperazinyl-1H-indazole derivatives which are useful as analgesic, anticonvulsant and antidepressant drugs.

The present invention relates to a compound of formula (III-a) H R 1 '(III-a 1') 25 HN NJ Is ^^ 1 * * * * * an acceptable acid addition salt or a stereochemically isomeric form thereof, wherein R 1 is hydrogen or halogen.

• · ·

The compounds of formula (III-a) are useful as intermediates in the preparation of valuable 3-piperazinylbenzazole derivatives of the formula (I) and pharmaceutically acceptable acid addition salts thereof, (i) q-ch2-ch2-n-N2-N1; wherein R 1 is hydrogen, halogen or C 1-6 alkyl; X is O, S or NR 3; wherein R 3 is hydrogen or phenyl; and 10 Q is a radical of the formula R 8 s R 1> V R 6 V 'N. .R6 .S N R6

>. .-ΜΛ '' -vöC OÖC

r9 o '"Π, κ υ oo (M) (b-2) (b-3) R10 n R6 S / N .R6 <ύχ rlrr'" -Cör Π '· p9' '> r \ N TT' " ··

0 o O

(b-4) (b-5) (b ~ 6) 25 R15

s & X

wherein R6 is hydrogen or C1-6 alkyl; R7 and R8 are each independently hydrogen or C1-6 alkyl; R9 and R10 are each independently hydrogen; halogen, amino or C 1-8 alkyl; R 11 is hydrogen or C 1-8 alkyl; and R 15 is hydrogen or hydroxy; wherein the radicals of formula (b-3), (b-4) and (b-7) in the bivalent ring groups of the cabbage, one or two hydrogen atoms of -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - may be replaced by C 1-8 alkyl.

In the above definitions, the term halogen means fluorine, chlorine, bromine and iodine; C 1-6 alkyl means straight or branched saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like radicals.

Depending on the nature of the various substituents, the compounds of formula (I) may have multiple asymmetric carbon atoms. Unless otherwise stated or indicated, the chemical designation of the compounds indicates a mixture of all possible stereochemically isomeric forms and said mixtures contain all diastereomers and enantiomers of the parent molecular structure. The absolute configuration of each chiral center can be indicated by the stereochemical graphs R and S, and said R and S designation are based on the rules set forth in Pure Appl. Chem. 1976, 45, 11-30.

Stereochemically isomeric forms of the compounds of formula (I) are, of course, within the scope of the invention.

• · ·

Pure stereoisomeric * chemical isomeric forms of the compounds of formula (I) may be obtained by methods well known in the art. Diastereoisomers may be separated by physical separation methods such as selective crystallization and chromatography, e.g.

countercurrent separation, liquid chromatography and the like; and the enantiomers may be separated from one another by the selective crystallization of their diastereoisomeric salts with optically active acids. Pure stereochemically isomeric forms may also be obtained from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction exhibits stereospecificity.

Most preferred compounds of formula (I) are those wherein X is O or NH; and / or R 1 is hydrogen or 6-fluoro.

Compounds of formula (I) may be prepared by reacting piperazine benzazole of formula (III) with an alkylating reagent of formula (II). In formula (II), W is a reactive leaving group such as a halogen, e.g., chlorine, bromine or iodine, or a sulfonyloxy group, e.g., methanesulfonyloxy, 4-methylbenzenesulfonyl-yloxy, or the like.

R 1 Q-CH 2 -CH 2 -W + H-N 2 - (I)

20 <Π> {IIQ

Said N-alkylation reaction may conveniently be carried out in a reaction inert organic solvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; lower alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, and the like; in ether, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydro-2H-furan and the like; in a dipolar aprotic solvent, e.g. N, N-dimethylformamide, N, N-dimethylacetamide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; or in a mixture of said solvents. A suitable base such as, for example, alkali metal or alkaline earth metal carbonate; hydrocarbonate, hydroxide, alkoxide or hydride, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride and the like, or organic bases such as N, amine, e.g. N- (1-methylethyl) -2-propanamine, 4-ethylmorpholine and the like can be used to collect the acid released during the reaction. In some cases, it is convenient to add an iodide salt, preferably an alkali metal iodide. Slightly elevated temperatures may accelerate the reaction. In this and the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methods well known in the art such as extraction, distillation, crystallization by grinding and chromatography.

Compounds of formula (I) wherein X is oxygen or NR3 and said X is X1 and said compounds of formula (I-a) may also be obtained by cyclization of an intermediate of formula 20 (VI) after treatment with a suitable base in a reaction inert solvent.

W2 r1 R1,> R vl / ·: ·· __, Ν-χΉ] -. / __K n ': · ... 25 0-ch2-ch2-N ^ NC- ° · “2 · ™ 2-Ν_: '' -i (VI) (lu) • · · • · · · ·

In formula (VI), W 2 is a suitable leaving group, such as halogen, e.g., fluorine or chlorine, or a nitro group. Suitable bases for said cyclisation include, for example, alkali and alkaline earth metal carbonates, hydrocarbons, hydroxides, alkoxides or hydrides, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium hydroxide, , or organic bases such as amines, e.g. N, N-diethylethanamine, 4-ethylmorpholine and the like. Suitable solvents include, for example, aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like hydrocarbons; lower alkanols, e.g. methanol, ethanol, 1-butanol and the like; ketones, e.g. 2-propanone, 4-methyl-2-pentanone and the like ketones; ethers, e.g., 1,4-dioxane, tetrahydrofuran, and the like; dipolar aprotic solvents, e.g. N, N-di-10-methylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone and the like, or mixtures of these solvents. In order to increase the reaction rate, the temperature of the reaction mixture may be increased, and in particular said cyclization reaction may be carried out at the reflux temperature of the reaction mixture.

The compounds of formula (I) have basic properties and can therefore be converted into their therapeutically active non-toxic acid addition salts by treatment with appropriate acids, for example, inorganic acids, e.g. hydrochloric, hydrobromic and the like, sulfuric acid, nitric acid: Y, phosphoric acid and the like; or organic acids such as, for example, acetic, propionic, hydroxyacetic, 2-hydroxypropionic, 2-oxopropionic, oxalic, propane, amber, (Z) -2-maleic, ( E) -2-fumaroyl, 2-hydroxymeric resin, 2,3-dihydroxymeric resin, 2- • 4-hydroxy-1,2,3-propanetricarboxyl, methanesulfone, · · · * · * ethanesulfone -, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexane sulfamide, 2-hydroxybenzoic, 4-amine, · N · 30 -no-2-hydroxybenzoic and the like acids. On the contrary • «· Y the salt form can be converted to the free base form .j. by treatment with a base.

The term acid addition salt as used herein also includes solvates which can also be formed from a compound of formula (I). Examples of such solvents include, for example, hydrates, alcoholates, and the like.

Some of the intermediates and starting materials used in the above preparations are known compounds that can be prepared by methods known in the art of chemistry to prepare said or similar compounds. For example, some intermediates of formula (III) and (V) are described in U.S. Patent Nos. 4,452,799, 4,524,206 and 4,590,196, and in EP-A-10,0302423, intermediates of formula (II) and their preparation are described in U.S. Pat. Other intermediates may be prepared according to methods known in the chemical art for the preparation of similar compounds, some of which are given hereinbelow.

The new intermediates of formula (IIIa) may be obtained by deprotecting an intermediate of formula (XXII).

B

i ._, (XXII), 1 'n i P-N N-15- \ _y v: ·. ·. 25 • · • ·. wherein P is a protecting group, such as (C 1 -C 6 -alkyl or * 1 -C 1 -aryl) carbonyl, (C 1 -C 4 -alkyloxy or -aryl) carbonyl • 1 -C 4 or phenylmethyl, by acid or base hydrolysis or by catalytic hydrogenation. Protected according to formula (XXII)

• M

* · I

The intermediate 30 can be prepared from a thioamide of the formula • T: (xxiii) w2: "· S \ R * / S 11 rV (xxiii) PN NC- (v 'h 35 \ / 8 103406 wherein W2 is reactive as defined above a leaving group by condensing a thioamide with a hydrazine of formula NH 2 -NH 2 (XXIV) in the presence of an acid such as acetic acid and then cyclizing with a base, said thioamide of formula (XXIII) in turn being obtained from an amide of formula (XXV) W 2.

/ -Λ 8

P-N N — C — O

10 N / N H (XXV) by reaction with 2,4-bis (4-methoxyphenyl) -2,4-disulfide-1,3,2,4-dithiaphosphane (Lawesson's reagent).

The amide of formula (XXV) can be prepared by N-acylation of the mono-protected piperazine (XXVI) with a carboxylic acid of formula (XXVII) or a functional derivative thereof such as a halide, symmetric or mixed anhydride following chemically known N-acylation procedures.

\ v2 O \ _ R1 ... 25 P — Is / ^ N-H. HO-C- / ^ - (XXV)

i ·. * \ -J

• V ·: (XXVI) (XXVII) • · · • · · · ·

The compounds of formula (I), their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms are potent antagonists of nerve mediators, and in particular serotonin and dopamine mediators.

9 103406

The following examples are intended to illustrate, but not limit, the scope of the present invention. Unless otherwise stated, all parts are by weight.

A) Preparation of intermediate 5 Example 1 a) To a stirred mixture of 114 parts of 1,2-benzisoxazol-3-ol and 230 parts of phosphoryl chloride was added dropwise 160 parts of N, N-diethylethanamine (exothermic reaction). After the addition was complete, the reaction mixture was stirred overnight at 135 ° C. The mixture was poured into crushed ice and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was boiled in 2,2'-oxybispropane. The solvent was decanted off (this was repeated twice) and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions were collected and evaporated to give 60 parts (15%) of 3-chloro-7-methyl-1,2-benzisoisoxazole as a residue (intermediate 20 L).

b) To a stirred and heated (90 ° C) mixture of 120 parts of piperazine and 400 parts of 1-butanol was added dropwise 60 parts of 3-chloro-7-methyl-1,2-benzoisoxazole. After the addition was complete, stirring was continued for 6 hours at reflux temperature.

• ·. After cooling, the reaction mixture was filtered, and the filtrate was evaporated. The residue was taken up in water and the product • 1 * 1 was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on standing to give 56 parts (71.5%) of 7-methyl-3- (1-piperazinyl) -: 35 1,2-benzoisoxazole as a residue (interm. 2).

10 103406

Example 2 a) A mixture of 32 parts of ethyl 1-piperazine carboxylate, 17 parts of 3-chloro-1,2-benzisothiazole and 45 parts of N, N-dimethylacetamide was stirred for 0.5 h at 150 ° C: in. After cooling to 50 ° C, the reaction mixture was poured into ice water. The aqueous layer was decanted off and the oil layer was stirred in water. The product from the oily viscous layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by 10 column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated to give 13 parts (44%) of ethyl 4- (1,2-benzisothiazol-3-yl) -1-piperazinecarboxylate as a residue (interm. 3).

b) A mixture of 12.5 parts of ethyl 4- (1,2-benzisothiazol-3-yl) -1-piperazinecarboxylate and 187.5 parts of 48% hydrobromic acid in water was stirred for 1.5 hours at reflux temperature. After evaporation, the residue was taken up in 2-propanol and the solvent was evaporated again. The residue was dissolved in methanol. , the line was again evaporated and stirred in 2-propan-1-one. The product was filtered off and dried, yielding 11.5 parts (73%) of 3- (1-piperazinyl) -1,2-benzo-isothiazole hydrobromide (interm. 4).

• · *. Example 3 (Intermediate of the Invention) • a · Mixed and cooled mixture (10 ° C) containing 64 parts of 1- (phenylmethyl) piperazine and 360 parts of tetrahydrofuran , 32.5 * · V * 30 parts of 2,4-difluorobenzoyl chloride were added over 20 minutes.

After stirring, stirring was continued until the mixture had reached room temperature. The salt formed was filtered off and the filtrate evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol as eluent.

't I

11 103406 (95: 5 by volume). The pure fractions were collected and evaporated to give 50 parts (87.8%) of 1- (2,4-difluorobenzoyl) -4- (phenylmethyl) piperazine as a residue (intermediate 5).

5 b) A mixture of 30 parts of 1- (2,4-difluorobenzoyl) -4- (phenylmethyl) piperazine, 19 parts of 2,4-bis (4-methoxyphenyl) -2,4-disulfide-1,3, 2,4-Dithiophosphane and 174 parts of benzene were stirred and refluxed for 3 hours. The reaction mixture 10 was evaporated and the residue was dissolved in trichloromethane. The residue was purified by flash chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was allowed to stand for 2 days at room temperature-15. The product was filtered off and dried to give 25 parts (79.2%) of 1 - [(2,4-difluorophenyl) thioxomethyl] -4- (phenylmethyl) piperazine (interm. 6).

c) A mixture of 40 parts of 1 - [(2,4-difluorophenyl) thioxomethyl] -4- (phenylmethyl) piperazine, 144 parts of 1-butanol, 13 parts of hydrazine monohydrate and 24 parts of acetic acid was stirred overnight at reflux. temperature. After cooling, 50 parts of sodium carbonate were added and stirring was continued for 3 hours. time at reflux temperature. The reaction mixture was cooled to room temperature and water and methylbenzene were added. After stirring for 15 minutes, the separated organic layer was dried, filtered and evaporated.

The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (92: 8 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 12 parts (32.2%) of 6-fluoro-3- [4- (phenylmethyl) piperazinyl] -1H-indazole; m.p.

Mp 162.0 ° C (interm. 7).

12 103406 d) A mixture of 12 parts of 6-fluoro-3- [4- (phenylmethyl) piperazinyl] -1H-indazole, 1 part of Raney nickel chelate catalyst and 200 parts of methanol was hydrogenated at atmospheric pressure and At 2 ° C with two parts 5, 10% palladium on carbon catalyst. After the calculated amount of hydrogen had passed, the catalyst was filtered off through diatomaceous earth and the filtrate was evaporated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off and dried to give 7.7 parts (92.0%) of 6-fluoro-3-10 (1-piperazinyl) -1H-indazole (interm. 8).

Example 4 a) To a stirred mixture of 12.5 parts of piperazine, 3.6 parts of N, N-diethylethanamine and 75 parts of trichloromethane was added a solution of 9 parts of 2-fluoro-N-phenylbenzene-carbohydrazonoyl chloride in 75 parts of trichloromethane. All of this was stirred for 2 hours at room temperature. After addition of 5 parts potassium carbonate, the reaction mixture was stirred for 30 minutes at reflux temperature. The mixture was cooled, washed with 100 portions of water and the layers separated. The organic layer was dried, filtered and evaporated to give 6 parts (55.8%) of 1- (2-fluorobenzoyl) piperazine, 2-: phenylhydrazine as a residue (interm. 9).

b) A mixture of 4.5 parts of 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, 6 parts of 1- (2- • · *. *. (fluorobenzoyl) piperazine, 2-phenylhydrazine, · · · *, * 5.04 parts of sodium carbonate, 0.1 parts of potassium urodide 3a • * · * * 120 parts of 4-methyl-2-pentanone, was stirred overnight at reflux temperature. The inorganic salt was filtered off and the filtrate was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol · 35. The product was filtered off and dried, yielding 13 103406 2.5 parts (25.8%) of 3- [2- [4 - [(2-fluorophenyl) - (2-phenylhydrazono) methyl] -1-piperazinyl] ethyl ] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; mp. 180 ° C (interm. 10).

Example 5 a) A mixture of 98 parts of 2,4-difluorobenzaldehyde, 49 parts of hydroxylamine monohydrochloride, 160 parts of methanol and 80 parts of 2-propanol saturated with hydrochloric acid was stirred at reflux temperature for 4 hours. The reaction mixture was concentrated in vacuo and triturated with 2,2'-oxybispropane. The product was filtered off and dried to give 60 parts (45.0%) of 2,4-difluorobenzaldehyde, oxime hydrochloride (interm. 11).

B) A stirred and cooled (-10 ° C) mixture of 58 parts of 2,4-difluorobenzaldehyde, oxime hydrochloride and 750 parts of trichloromethane was bubbled with chlorine for 30 minutes. Excess chlorine was removed by a stream of nitrogen, and 42 parts of N, N-diethylethanamine were added to the solution. After the addition was complete, stirring was continued while allowing the reaction temperature to rise to room temperature. The precipitate was filtered off. The filtrate was cooled to -20 ° C and added to a stirred and cooled (-10 ° C) solution of 86 parts of pipette. 25 Racines in 900 parts trichloromethane over 10 minutes. The reaction mixture was stirred overnight at room temperature. The mixture was then heated to 30 ° C and filtered.

• · ·; The filtrate was concentrated in vacuo at 25 ° C. Excess piperazine was removed by washing twice with 100 parts water.

: * Γ: 30 The separated organic layer was dried, filtered and concentrated in vacuo. The concentrated residue was ground *. 2,2'-oxybispropane. The solid product was filtered off · · · ';; and dried to give 50 parts (69.1%) of 1 - [(2,4-difluorophenyl) (hydroxylimino) methyl] piperazine: 35 (interm. 12).

14 103406 c) A mixture of 8 parts of 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrobromide, 4, 8 parts of 1 - [(2,4-difluorophenyl) (hydroxyimino) methyl] piperazine, 8 parts of sodium hydrogencarbonate-5 and 180 parts of 4-methyl-2-pentanone were stirred at reflux for 20 hours. The reaction mixture was filtered off hot and the filtrate evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane-10 and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was concentrated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.4 parts (50.5%) of 6- [2- [4 - [(2,4-difluorophenyl) - (hydroxyimino) methyl] -1-piperazin-15-yl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one (interm. 13).

Example 6

A mixture of 58 parts of 5-methyl-1,3,4-thiadiazol-2-amine, 76 parts of 3-acetyl-4,5-dihydro-2 (3H) -fura-20 nonone, 1.2 parts 12N Hydrochloric acid solution and 540 parts of methylbenzene were stirred at reflux for 2 hours using a water separator. After cooling to room temperature, 340 parts were added dropwise; phosphoryl chloride at 20-40 ° C (cooling was; Vi 25 necessary to maintain this temperature). This size *. the woman was gradually heated to reflux temperature: 95 ° C. Hydrogen chloride gas began to develop. Then, 100 parts of the mixture were distilled off and the residue was stirred at reflux for 2 hours. Cooling • · · V; After 30 hours, the reaction mixture was evaporated and the residue was poured

IM

: ice / ammonium hydroxide mixture, stirring simultaneously; The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and 15 103406 methanol (95: 5 by volume) each time as the eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,21-oxybispropane to give 11.8 parts of 6- (2-chloroethyl-2,7-dimethyl-5H-1,3,4-thiadiazolo [3,2-5a] -pyrimidine-5). mp 118 ° C (interm. 14).

Example 7 a) A mixture of 50 parts of 5-methyl-3-isooxazolamine, 70 parts of 3-acetyl-4,5-dihydro-2 (3H) -furanone, 435 parts of methylbenzene and 16 parts of polyphosphoric acid -10 poles, stirred at reflux for 3 hours, using a water separator. The reaction mixture was concentrated in vacuo to give 99 parts (95.1%) of 4,5-dihydro-3- [1- (5-methyl-3-isooxazolyl) imino] ethyl] -2 (3H) -furanone as an oily residue (interm. 15).

B) To a stirred mixture of 98 parts of 4,5-dihydro-3- [1- (5-methyl-3-isooxazolyl) imino] ethyl] -2 (3H) -furanone, 348 parts of methylbenzene and 300 parts of trichloromethane, was added dropwise to 150 parts of phosphoryl chloride. After the addition was complete, stirring was continued for 3 hours at reflux temperature. The reaction mixture was concentrated to half its volume and the residue was poured into crushed ice. This entity was discussed

I »I

ammonium hydroxide solution, and the product was extracted twice with 240 parts of 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The residue was dissolved in trichloromethane, filtered over silica gel, and the filtrate was concentrated in vacuo. The residue was crystallized from a mixture of methylbenzene and 2,2'-oxybispropane to give 96 parts (88.2%) of 6- (2-chloro-3O-ethyl) -2,5-dimethyl-7H -iso-branches solo- [2,3-a] -pyrimidin-7-one; mp. 165 ° C (interm. 16).

• · · \ B) Preparation of Final Compounds 11 'Example 8

A mixture of 5 parts of 3- (2-chloroethyl) -35,6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidine-16 103406 4-one monohydrochloride, parts of 3- (1-piperazinyl) -1,2-benzisothiazolidine hydrochloride, 8 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone were stirred for 20 hours at reflux temperature. The reaction mixture was filtered and the filtrate evaporated. The residue was purified by flash chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the (E) -2-butenedioate salt in 2-propanol. The salt was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 7.4 parts (85%) of 3- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl-ethyl-6,7,8,9 -tetrahydro-2-methyl-4H-pyrido-15 [1,2-a] pyrimidin-4-one (E) -2-butenedioate (1: 1); mp.

186.0 ° C (compound 1).

Example 9

A mixture of 7.4 parts of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] thiazin-6-one monohydrobromide, 4 , 4 parts of 7-methyl-3- (1-piperazinyl) -1,2-benzisoxazole, 10 parts of sodium carbonate and 94 parts of N, N-dimethylformamide were stirred overnight at 90 ° C. After cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was eluted. The residue was crystallized from 4-30 methyl-2-pentanone The product was filtered off and dried to give 3.8 parts (44.6%) of 3,4-dihydro-8-methyl- 7- [2- [4- (7-Methyl-1,2-benzoisoxazol-3-yl) -1-piperazinyl] ethyl] -2H-6H-pyrimido [2,1-b] thiazin-6 -: one, mp 170.9 ° C (compound 2).

IV 103406

Example 10

A solution of 4.4 parts of 6- [2- [4 - [{2,4-difluorophenyl) (hydroxyimino) methyl] -1-piperazinyl] ethyl] -2,3-dihydro-7-methyl -5H-Thiazolo [3,2-a] -pyrimidin-5-one in 45 parts of tetrahydrofuran was stirred at room temperature. 0.5 parts of a 50% sodium hydride dispersion were gradually added. After the addition was complete, 108 parts of methyl benzene was added and the reaction mixture was stirred for 18 hours at reflux temperature. After cooling, 10 parts of ethanol were added followed by 3 parts of acetic acid. This whole was stirred for 10 minutes. The mixture was treated with ammonium hydroxide and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.8 parts of 20 (91.4%) of 6- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperazinyl] ethyl] - 2,3-dihydro-7-methyl-5H-thiazolo [1,2,3a] pyrimidin-5-one; mp. 193.0 ° C (compound 3).

Example 11 '· u A mixture of 2.5 parts of 3- [2- [4 - [(2-fluorophenyl) - (2-phenylhydrazono) methyl] -1-piperazinyl] - • · · • * Ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, 1: ·: part of potassium carbonate and 27.8 parts of 1,2-ethane glycol, stirred overnight at reflux temperature. The reaction mixture was cooled and then poured into water. The product 30 was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent 18 103406 was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The salt was filtered off and dried to give 0.7 parts (25.5%) of 2-methyl-3- [2- [4- (1-phenyl-1H-indazol-3-yl) -1-piperazinyl] ethyl] -4H-5 pyrido [1,2-a] pyrimidin-4-one; mp. 260.0 ° C (dec.) (Compound 4).

All of the compounds listed in Table 1 were prepared according to the preparation procedures described in Examples 6-9, as shown in the column titled, e.g., ## STR4 ##. · · «• 19 19 103 103 19 103406 TABLE 1 o

Yh- | dis_ Eg Time X R1 Physical No Data te 10

Δ 8 - (CH 2) 2 - O H mp 229.8 ° C

6 - 8 - (CH 2) 3 - O H mp.210.0 ° C

7 8 - (CH 2) 2- S H mp. 230.1 ° C

8 8 - (CH 2) 2 O 5 -Cl HCl / sec. 264, 0 ° C

9 - (CH 2) 2 -NH 6 -F mp, 257 ° C

15 10 8 - (CH 2) 2 -NH H

20 TABLE 2 25: o • t * • · • «« · · _ __ - - - -

I I I

Combined Ex. -2-A- Time X R1 Physical ··· te # # of data 3o ------- · '11 8 -CH = CH-CH = CH- - (CHo) 2- SH (E) -2-butenedioate

• (2: 3) / color 202.9 ° C

12 8 -CH = CH-CH = CH- - (CH 2) 2 -O 5 -Cl 149 9 * C

20, 103406

Comb., Eg -Ζ-Λ- Time X Rl Physical No. Data

5 -13 8 -CH = CH-CH = CH- - (CH 2) 2 O H m.p.

14 9 -CH = CH-CH = CH- - (CH 2) 2: O 7 -CH 3 m.p. 154,6eC

10 -CH = CH-CH = CH- - (CH 2) 2- O 6 -F mp 204 (2 ° C)

16 -CH = CH-CH = CH- (CH 2) 2 -NH 6 -F mp 243.8 ° C

17 8 - (CH 2) 4 - (CH 2) 2 O H sp. 152.2 ° C

18 8 - (CH 2) 4 - (CH 2) 2 O 5 -C 1 - (> -2-butenedioate)

(1: 1) / mp. 197.4 ° C

10 19 9 - (CH 2) 4 - (CH 2) 2 O 7 -CH 3 m.p. 169.2 = 0

20 10 - (CH 2) 4 - (CH 2) 2 O 6 -F m.p. 188.7 ° C

21- (CH 2) 4 - (CH 2) 2 -NH 6 -F mp 249.5 ° C

22 8 -S- (CH 2) 3- - (CH 2) 2 OH m.p. 194.3 = 0

23 8 -S- (CH 2) 3 - (CH 2) 2 O 5 -Cl m.p. 166.8 ° C

24 8 -S- (CH 2) 3 - (CH 2) 2 -SH m.p. 162.8 ° C

25-S- (CH 2) 3 - (CH 2) 2 O 6 -F m.p.210.1 ° C

15 26 8 -S- (CH 2) 2 - (CH 2) 2 S H (E) -2-butenedioate

l, L i L (1: 1) / m.p. 223.8 ° C

27 8 -S- (CH 2) 2 - (CH 2) 2 O H m.p. 192.1 ° C

28 8 -S- (CH 2) 2 - (CH 2) 2 O 5 -C

i z L (1: 1) / m.p. 185.7 ° C

29 8 -S- (CH 2) 2 - (CH 2) 2 -NH 6 -F SP-264.6 ° C

8 -S-CH = CH- (CH 2) 2 S H (E) -2-butenedioate

Z1 (1: 1) / m.p. 232.7 ° C

20 31 8 -S-CH = CH- (CH 2) 2 O H m.p.210.8 ° C

32 -S-CH = CH- (CH 2) 2 -O-5-Cl m.p.120.4 ° C

33 9 -S-CH = CH- (CH 2) 2 - O 7 -CH 3 m.p. 149.6 ° C

34 10 -S-CH = CH- (CH 2) 2 -O 6 -F mp 217.0 ° C

35 8 -S-CH = C (CH 3) - - (CH 2) 2 - S H [f * 0 ^

36 8 -S-CH = C (CH 3) - - (CH 2) 2 - O 5 -Cl m.p. 163.9 ° C

25 S 8 -S-CH = C (CH 3) - (CH 2) 2 O H m.p.

! ·. *: 38 9 -S-CH = C (CH 3) - - (CH 2) 2 - O 7 -CH 3 m.p. 159.8 ° C

39 10 -S-CH = C (CH 3) - - (CH 2) 2 -O 6 -F mp 214.8 ° C

· * 40 8 -S-CH = C (CH 3) - - (CH 2) 2 -NH 6 -F mp 266.9 ° C

41 -CH = CH-CH = CH- (CH 2) 2 -NH H m.p. 202.0 ° C

42 8 -CH = CH-C (CH 3) = CH- - (CH 2) 2 O H m.p.

: 30 »· · • · · 103406 21

Yhdis-Ex. -Z-A- Time X Rl Physical te data

* 43 ΊΓ -CH = CH-C (CH 3) = CH- - (CH 2) 2 -NH 6 -F mp 250.8 ° C

44 8 -CH = CH-C (CH 3) = CH- - (CH 2) 2 -NH H mp 203.6 ° C

5 45 8 -C (CH 3) = CH-CH = CH- - (CH 2) 2 O H m.p. 169.7 ° C

46 8 -C (CH 3) = CH-CH = CH- - (CH 2) 2 -SH m.p. 165.0 ° C

47 8 -C (CH 3) = CH-CH = CH- - (CH 2) 2 -NH 6 -F m.p. 228.8 ° C

48 8 -CH = CH-CC 1 = CH- - (CH 2) 2 -O H m.p. 155.3 ° C

49 -CH = CH-CCl = CH- - (CH 2) 2 -NH H m.p.

50 8 -CH = CH-CBr = CH- - (CH 2) 2 OH m.p. 167.4 ° C

10 51 8 -CH = CH-CBr = CH-1 (CH 2) 2 -NH 6 -F mp.249.3 ° C

52 8 - (CH 2) 4 - (CH 2) 2 -NH H m.p.212, S ° C

53 8 -CH 2 -CH (CH 3) - (CH 2) 2 - (CH 2) 2 -NH 6 -F mp 272.8 ° C

54 8 -CH (CH 3) - (CH 2) 3 - (CH 2) 2 OH m.p. 157, S, C

55 8 -CH (CH 3) - (CH 2) 3 - (CH 2) 2 - SH m.p. 137.4 ° C

56 8 -CH (CH 3) - (CH 2) 3 - (CH 2) 2 -NH 6 -F m.p.

15 57 8 -CH 2 -C (CH 3) -CH 2 -C (CH 3) - - (CH 2) 2 -S H mp 99.7 ° C

58 8 -CHOH- (CH 2) 3 - (CH 2) 2 -NH H mp 222 (3 ° C)

59 8 -CHOH- (CH 2) 3- - (CH 2) 2 -S H m.p. 220.9 ° C

60 8 -S- (CH 2) 3 - (CH 2) 2 -NH 6 -F m.p. 255.6 ° C

61 -S- (CH 2) 3 - (CH 2) 2 -NH H mp 202.5 ° C

62 8 -S- (CH 2) 2 - (CH 2) 2 -NH H mp 214.6 ° C

20 ° 63 8 -S-CH = CH- (CH 2) 2 -NH 6 -F mp> 300 ° C (dec.)

64 8 -S-CH = CH- (CH 2) 2 -NH H m.p.

65 -S-CH = C (CH 3) - (CH 2) 2 -NH H mp 223.1 ° C

· 66 8 -S-C (CH 3) = N - (CH 2) 2 O H (2: 1) / m.p. 236.6 1C

: /; 67 8 -S-C (CH 3) = N - (CH 2) 2 -NH 6 -F m.p. 284,30C

68 8 -O-C (CH 3) = CH- - (CH 2) 2 O H m.p. 201.6 to 0

25 69 8 -0-C (CH 3) = CH- - (CH 2) 2 -S H m.p.

70 -0-C (CH 3) = CH- (CH 2) 2 -NH H m.p.215.2 ° C

V ·! 71 8 -O-C (CH 3) = CH- - (CH 2) 2 -NH 6 -F m.p. 229.4 to 229.9 ° C

• t «• · · t · •« I r • · f • 1 · · · · · · ·

Claims (1)

22 1 0 3 4 0 6 Claim A compound of the formula (III-a) 5 H R l ___ N ^ YT1! (III-a), a pharmaceutically acceptable acid addition salt thereof, or a stereochemically isomeric form thereof, wherein R 1 is hydrogen or halogen. • »1 • • • • • • • • 1 1 · · · · 23 1 0 3 4 0 6 Förening med formeln (III- a)? R <tb> Qiicj 10 that the pharmaceutical godtagbart syraadditionssalt eller en the stereochemically isomeric derivative, the R1 betecknar is eller halogen. • ll «i« i «• * i« Ml »I« • *.