HU195793B - Process for the production of new derivatives of 1,2-benziazol -3-il and medical compositions containing thereof as active substance - Google Patents

Abstract

Piperidine derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts are new. R = H or 1-6C alkyl; R1 and R2 = H, halo, OH, 1-6C alkoxy or 1-6C alkyl; X = O or S; Alk = 1-4C alkanediyl; Q = a gp. of formula (a) or (b); Y1 and Y2 = O or S; R3 = H, halo, 1-6C alkyl, 1-6C alkoxy, CF3, NO2, CN, OH, 2-11C alkenoyloxy, NH2, mono- or di(1-6C alkyl)amino, 2-11C alkanoylamino, benzyloxy or azido; R4 = H or halo, R5 = H or 1-6C alkyl; Z = S, CH2 or C(R6) = C(R7); R6 and R7 = H or 1-6C alkyl; A = CH2CH2, CH2CH2CH2 or C(R8)=C(R9); R8 and R9 = H, halo, NH2 or 1-6C alkyl. More specifically, R = H; R1 = H or halo; R2 = H, halo, OH or 1-6C alkoxy; R3 = H, halo or Me; Y1 = O; Z-A = SCH2CH2, S(CH2)3; S-CR8=CR9, CH=CH-CR8=CR9 or (CH2)4; R8 and R9 = H or Me. 2 Cpds. (I) including 3-(2-(4-(6-fluoro -1,2-benzioxazol-3-yl)-1 piperidinyl)ethyl)-6,7,8,9 -tetrahydro-2-methyl-4H -pyrido(1,2-a) pyrimidin-4-one (Ia) are specifically claimed.

Description

The present invention relates to novel 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives and to pharmaceutical compositions containing them as active ingredients. The compounds of the present invention and their acid addition salts have potent anti-psychotic activity and are useful in the treatment of various complaints associated with serotonin release.

U.S. Patent Nos. 4,352,811 and 4,458,076 disclose 3-piperidinyl-1,2-benzisoxazoles and 3-piperidinyl-1,2-benzisothiazoles with antipsychotic and analgesic properties.

The compounds of the present invention differ from those described in the prior art in that they are substituted at the 1-position of the piperidyl group.

The present invention provides 1,2-benzazoles of formula I and pharmaceutically acceptable acid addition salts thereof, wherein:

X is O or S; or X is O or S; and

i) if X is O and Q is present,

(a) a group of the general formula disease R ¹ is halogen, alk is C 1-4 alkylene, Y ¹ is oxygen or sulfur, Y ² is oxygen or sulfur; and Irish obsession is hydrogen, C 1-4 alkyl, hydroxy, or C 1-4 alkoxy, if X is a sulfur atom and Q is a group of formula (a) then R ' is hydrogen, alk is C 1-4 alkylene, Y ¹ and Y ² is an oxygen atom, and R ' obsession is a hydrogen sub, if X is O and Q is Lentes group, where (b) Z. meaning -CHa- THE or -CH 2 -CH 2 -CH 2 - Z is -CR * = CR ⁷ -, and THE represents -CR ': CR ⁸ -, wherein

R * and R ⁷ meaning independently H or 1 - 4 saints C powder and the alkyl R * and R ⁸ meaning each other- irrespective of its location hydrogen, C 1 -C 4 al- alkyl obsession halogen, then

15 R ^l is hydrogen, halogen, hydroxy or a C 1-4 alkoxy group, alk C 1-4 20 R ^s alkylene; and is C 1-4 alkyl, or arc) if X is sulfur and Q is present- (b) a group of the general formula wherein 25 · Z is -CH 2 and THE is -CH 2 -CH 2 -CH 2 then R ' is hydrogen or 30 alk .halogénatom, is C 1-4 alkylene, and R ⁵ C 1-4 or alkyl 35 v) if X is O and Q is Lentes where a group of the formula: Z is sulfur and 40 THE is -CH2-CH2-, -CH2-

A divalent group of formula -CH 2 -CH 2 - or -CH = CR ⁸ wherein

R * is hydro 45 or C 1 -C 4 alkyl,

then R ¹ is hydrogen, halo 50 or a C 1-4 alkoxy group, alk is C 1-4 alkylene and 55 R ' is C 1-4 alkyl.

In the above definitions, halogen means fluorine, chlorine, bromine and iodine.

Alatt C 1-4 -alkyl, saturated, linear or branched,

6Q refers to hydrocarbon groups having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-methyl-ethyl, 1,1-dimethylethyl, propyl, butyl, and the like.

C 1-4 alkylene is understood to mean straight or branched C 1-4 divalent alkylene groups such as methylene, ethylene, propylene, butylene and the like.

Preferred compounds of the present invention are those wherein Q is a group of formula (a) wherein

R ³ is hydrogen, C 1-4 alkyl,

C 1-4 alkoxy or hydroxy;

obsession

Q is a group of formula (b) wherein:

meaning C 1-4 alkyl; and meaning -CH-chi, CH2 CH2-CH2 or -CH = CR'- general is bivalent group, where R ' meaning hydro- atom obsession C 1-4

alkyl group.

Particularly preferred are those preferred compounds wherein R ^l is hydrogen or halogen.

Even more preferred are the compounds having the formula

Q is a group of formula (a) wherein

R ³ is hydrogen or methyl; and

Y * is oxygen;

obsession

Q is a group of Formula (b) wherein -Z-A- is -S-CH2-CH2-, -S- (CHab-, -S-CH-CR'-);

let group where R ⁹ meaning hydro- genius or me- or -CH butyl and; = CH-CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are from each other independently hydro-

a gene atom or a methyl group; or -CH2-CH2-C12-CH2.

More preferred of the above preferred compounds are those having the formula

R * is hydrogen.

Most preferred compounds are 3- [2- [4- (5-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl- 4H-Pyrido [1,2-a] pyrimidin-4-one cs 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one, and pharmaceutically acceptable acid addition salts thereof.

In general, the compounds of formula (I) may be prepared by reacting a suitable reactive ester of formula (II) or an acid addition salt thereof with an appropriately substituted piperidine of formula (III) or an acid addition salt thereof.

The reactive ester of formula (II) in W is a reactive ester group such as a halogen atom such as chlorine, bromine or iodine or a sulfonyloxy group such as methylsulfonyloxy, (4-methylphenyl) sulfonyloxy - or a similar group.

The reaction of the compounds of formula (Π) and (III) in an inert organic solvent such as an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like, an alkanol such as methanol, ethanol, 1-butanol and the like;

a ketone such as 2-propanol, 4-meth; I-2-pentanone and the like; an ether such as 1,4-dioxane-1,1'-oxybisethane, tetrahydrofuran and the like; Ν, Ν-dimethylformamide ban; N, N-dimethyl acetamide; nitrobenzene; It can be carried out in 1-methyl-2-pyrrolidone and the like.

For the capture of the acid liberated during the reaction, a suitable base such as an alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, alkoxidol or hydride such as sodium carbonate, sodium bicarbonate, potassium carbonate, hydroxide, sodium methoxide, sodium hydride and the like; or an organic base such as a tertiary amine such as Ν, Ν-diethylethanamine, N- (1-methylethyl) -2-propanamine, 4-ethylmorpholine and the like.

In some cases, the addition of an iodine salt, preferably an alkali metal iodide, may be advantageous. The reaction rate can be accelerated by increasing the temperature.

The compounds of formula (I) according to the invention are basic and therefore can be converted into pharmaceutically acceptable non-toxic acid addition salts by treatment with the appropriate acid.

Suitable acids include inorganic acids such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid and the like), sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid-2-hydroxypropanoic acid, 2-oxopropionic acid, ethanedioic acid, propanedioic acid, butenedioic acid, (Z) -2-butanedioic acid, ( E) -2-Butenedioic acid-2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2 -hydroxybenzoic acid and the like. Conversely, salts can be converted to the free base by treatment with a base.

Many of the intermediates and starting materials used in the above process are known compounds which are known in the art, or by the preparation of similar compounds, 4,335,127, 4,342,870, 4,443,451 and

U.S. Patent 4,485,107. Other intermediates may be prepared by methods known in the art for the preparation of similar compounds, some of which are described below.

The intermediates of formula (III) may generally be prepared from a benzoylpiperidine of formula (XIV) wherein halo is preferably fluorine, in a manner known in the art, for example by reacting a benzoylpiperidine of formula (XIV) with hydroxylamine; and cyclizing the resulting oxime of formula XV in a manner known in the art. There is thus obtained an intermediate of formula (IIIa) in which X is oxygen. The above intermediate is represented by the general formula (IIIa).

The intermediate of formula (IIIa) wherein X is sulfur (compounds of formula (111b)) may be prepared in a manner analogous to that described in U.S. Patent No. 4,458,076.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are potent antagonists of many neurolotransmitters and therefore possess useful therapeutic properties. For example, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts possess potent psycholytic activity and antiserotonin activity.

Due to their therapeutic action, the compounds of formula I and their pharmaceutically acceptable acid addition salts are useful in the treatment of psychotic disorders and in the treatment of various diseases in which serolonin release is of primary importance. Examples include blocking the contraction of serolonin-induced airway tissue, small blood vessels, arteries, and veins. The compounds of the present invention have a sedative, anxiolytic, anti-aggressive, anti-stress, muscle-protective, cardiovascular-protective effect and are therefore suitable for the protection of warm-blooded animals, e.g., in a stressed state such as during transport or the like. In addition, the compounds of the present invention are useful in protecting against endotoxin shock and may also be used as anti-diarrheal agents.

The above pharmaceutical agents may be formulated into various pharmaceutical forms for administration. The compounds of this invention may be formulated into pharmaceutical compositions by admixing an effective amount of a compound of the invention or an acid addition salt thereof with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be selected within wide limits depending on the form of the composition for treatment. The pharmaceutical compositions preferably contain a unit dosage form for oral, rectal, percutaneous or parenteral administration. For example, when preparing an oral preparation, any conventional pharmaceutical medium, such as water, glycol, oils, alcohols, and the like, which can be used to prepare oral liquid preparations, such as suspensions, syrups, elixirs and solutions, may be used. Solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be used to provide powders, tablets, capsules. Because capsules and tablets are the easiest to administer, they are the most preferred oral dosage unit forms in which solid pharmaceutical carriers can be used.

In parenteral formulations, the carrier will usually comprise sterile water, at least partially, although other ingredients, for example, to aid solubility, may also be used.

Injectable solutions, for example, may be formulated containing a saline solution, a glucose solution, or a salt and glucose solution.

Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

In formulations suitable for percutaneous administration, the carrier optionally comprises an penetration enhancer and / or a suitable wetting agent, optionally with minor amounts of any suitable additives of a nature, which do not adversely affect the skin. The additives may facilitate the administration to the skin and / or the formulation of the desired formulation.

These compositions may be administered in a variety of ways, for example, as a transdermal topical formulation or as an ointment.

The acid addition salts of the compounds of formula (I) have a slightly increased water solubility over the corresponding base and are therefore more advantageous in the preparation of aqueous formulations.

It is particularly advantageous to formulate the above pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to physically separate, individually applicable doses, each unit containing a predetermined amount of the active ingredient required to achieve the desired therapeutic effect and the desired pharmaceutically acceptable carrier. Examples of such dosage units are tablets (coated and uncoated tablets), capsules, powders, injectable solutions or suspensions, and the like, and a separate series thereof.

Because the compounds of the present invention are useful in the treatment of psychotic disorders, warm-blooded animals suffering from a psychotic disorder are treated systemically with a mixture of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. One skilled in the art of treating psychotic disorders can easily determine the amount of effective amount from experimental results. Generally, an effective amount of 0.01 mg / kg to 4 mg / kg body weight, more preferably 0.04 mg / kg to 2 mg / kg body weight, is effective.

The invention is illustrated by the following examples, but the invention is not limited to the following examples. Unless otherwise indicated, all parts are by weight and temperatures are in C.

A) Preparation of intermediates.

Example 1

To a stirred mixture of 1,3-difluorobenzene (65 parts) 130 parts of aluminum chloride and 195 parts of dichloromethane are added dropwise a solution of 95 parts of 1-acetyl-4-piperidinecarbonyl chloride and 65 parts of dichloromethane under cooling. After the addition was complete, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was triturated, filtered and evaporated to give 48 parts (36%) of 1-acetyl-4- (2,4-difluorobenzoyl) -piperidine as a residue, (intermediate 1) 1-acetyl-4- (2). , 4-difluorobenzoyl) piperidine and 180 parts of a 6N hydrochloric acid solution are stirred and refluxed for 5 hours. The reaction mixture was concentrated and the residue was stirred with 2-propanol. The product was filtered off and dried, yielding 39 parts (83%) of (2,4-difluorophenyl) piperidinylmethanone (interm. 2).

Part of (2,4-difluorophenyl) - (4-piperidinyl) -ethanone hydrochloride was mixed with 12 parts of hydroxylamine hydrochloride and 120 parts of ethanol at room temperature and 10.5 parts of N, N-diethylethanamine was added. The whole mixture was stirred and refluxed for 3 hours. After cooling, the precipitated product is filtered off and filtered to give 11 parts (100%) of (2,4-difluorophenyl) - (4-piperidinyl) methanone oxime (interm. 3).

A mixture of (2,4-difluorophenyl) (4-piperidinyl) methanone, 25 parts of potassium hydroxide and 25 parts of copper water was stirred and refluxed for 2 hours. The reaction mixture was cooled and extracted with melylbenzene. The extract was dried, filtered and evaporated. Recrystallization of the residue from petroleum ether gave 6.8 parts of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (interm. 4).

Example 2 A mixture of 2 parts of 2-thiazolamine, 76 parts of 3-acetyl-4,5-dihydro-2 (3H) -furanone, 1.2 parts of concentrated hydrochloric acid and 270 parts of methylbenzene was stirred for 2 hours and refluxed. Boil using a water separator. The reaction mixture was cooled and 340 parts of phosphoryl chloride was added at 20-30 ° C. The whole is then slowly warmed to 100-110 ° C and stirred for 2 hours at this temperature. The reaction mixture was evaporated and the residue was poured into a mixture of crushed ice and ammonium hydroxide. 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 95: 5 by volume mixture of trichloromethane and methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 1,1'-oxybisethane to give 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidine-5 on (Intermediate 5).

Example 3 A mixture of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidine ethanol, 25 parts potassium carbonate, 270 parts Ν, Ν-dimethylacetamide and 75 parts water was stirred at room temperature and 36 parts 1, 3-Dibromopropane is added in one. The temperature rises to 50 ° C. The entire reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and water was added to the residue. The solid product was washed with water and dried in vacuo at 100 ° C to give 21 parts (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2 lb] [1,3] liazin-6-one, m.p. 155 ° C (interm. 6).

Following the above procedure, using an equivalent amount of starting materials

2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one; 148.7 'C (interm. 7).

Example 4 A mixture of one part acetic acid and 180 parts 67% acetic acid hydrobromic acid was stirred and refluxed. Stirring was continued overnight at reflux-611. The reaction mixture was concentrated and the solid was triturated with 2-propanone. The product was filtered and dried to give 24 (100%) copper (7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6II-pyrimido [2,1b] [1,3] thiazine-6). -on-monohydrobromide, m.p. 215 ° C (interm. 8).

Following the above procedure, 6- (2-bromo-otyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrochloride is prepared in an equivalent amount of the appropriate starting materials. ; m.p. 237.2 'C (interm. 9).

(B) Production of final products

Example 5

5.3 parts 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride, 4.4 parts 6 a mixture of -fluoro-3- (4-piperidinyl) -1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide and 90 parts of N, N-dimethylformamide at 85-90 ° C overnight. stir. After cooling, the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of Ν, Ν-dimethylformamide and 2-propanol. The product was filtered off and dried, yielding 3.8 parts (46%) of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6.7, 8,9-Tetrahydro-2-methyl-4H-pyrido [1,2-a] pyridinidin-4-one is obtained; m.p .: 170.0 'C (Compound 1 ,.

Following the above procedure, using equivalent amounts of the appropriate starting materials, the following compounds were prepared:

6] 2- [4- (6-Fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5- you; 165.1'C (compound 2); 3- (2- [4- (1,2-Benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-melyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 177.9 ° C (compound 3);

3 - [(2- [4- (6-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -2,7-dimethyl-4H-pyrido [l, 2-a] pyrimidine -4-one; m.p. 186.9 ° C (compound 4); 3- [2-] 4- {1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl} -6,7, 8,9-letrahidro-2-methyl-4-pyrido [l, 2-a] piriinidin-4-one; 183.1 ° C (compound 5); 3- (2- (4- (1,2-Benzisothiazol-3-yl, -1-piperidinyl) ethyl] -2,4-yl, 3H) -quinazolin-dione monohydrochloride, m.p.> 300 ° C (decomposed) (Compound 6) 3- (2- (4- (1,2-Bis-isisoliazol-3-yl) -1-piperidinyl] ethyl) -6,7,8 ₎ 9-tetrahydro-2-methyl -4H-pyrido [1,2a] pyrimidin-4-one, m.p. 145.7 ° C (compound 7) 3- [2- (4- (G-hydroxy-1,2-benzisoxazole-3) yl) -1-piperidinyl] ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 213.1 ° C (Compound 8). );

The following compounds were prepared in a similar manner:

3- [2- [4- (5-Meloxy-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-2-methyl-4H-pyrido (1,2-alpirimidin-4-one (9) . compound);

3- (2- (4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidine-4- on (compound 10).

Example 6

3.3 parts 3- (2-chloroethyl) -2-methyl-4H-pyridol, 2-a] pyrimidin-4-one, 3.3 parts b-fluoro-3- (4-piperidinyl) -1, A mixture of 2-benzisoxazole, 8 parts of sodium carbonate, 1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 3 hours. The reaction mixture was cooled, water was added and the phases were separated. The organic phase is dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a 95: 5 by volume mixture of trichloromethane and methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanol (1.2 parts (19%)) of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] - ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 170.4 ° C (compound 11).

Example 7

6.75 parts of 3- (2-chloroethyl) -2,4- (1H, 3H) -quinazolinodione, 6.6 parts of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole, A mixture of 10 parts of sodium bicarbonate, 0.1 parts of potassium iodide and 90 parts of Ν, Ν-dimethylformamide was stirred overnight at 100-110 ° C. After cooling, the reaction mixture was poured into water. After stirring, the product is filtered off and crystallized from Ν, Ν-dimethylformamide. Thus 4.8 parts (39%) of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,4- (1H, 3H) -quinazoline-dione is obtained; m.p. 253.4 'C (compound 12).

Example 8

7.4 parts 6- (2-bromoethyl) -3,7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrobromide, 4.4 parts 6-fluoro-3- ( A mixture of 4-piperidinyl) -1,2-benzisoxazole, 10 parts of sodium carbonate and 90 parts of Ν, Ν-dimethylformamide was stirred at 80-85 ° C overnight. After cooling, the reaction mixture was poured into water. The product was filtered off and purified by column chromatography on silica gel using a 95: 5 by volume mixture of trichloromethane and methanol as eluent. The pure fractions were collected and the eluent was evaporated. 2-Propanol was added to the residue. Its products were filtered off and dried, yielding 5.3 parts (62%) of 6- (2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piper-713-dinyl) methyl] - 3,7-Dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one, m.p. 231.0 DEG C. (Compound 13).

The following compounds were prepared in a similar manner:

6- [2- {4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2- a] pyrimidin-5-one; 135.0 ° C (compound 14);

7- [2- (4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl-3,4-dihydro-8-methyl-2H, 6H-pyrimido (2,1b) ] [1,3] -thiazin-6-one, m.p.

6- [2- [4- (l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5 -you; 154.5 ° C (compound 16);

3- [2- [4- (6-Fluoro-1,2-benzisothiazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1 , 2-a] pyrimidin-4-one (Compound 17); 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl) ethyl] -2,3-dihydro-2-thioxo-4 (1H) -quinazoline (18 .compound).

Example 9

5-8. The following compounds of formula (I) are also prepared as described in Examples 1 to 6:

6,7,8,9-Telrahydro-3- [2- [4- (6-methoxy-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-melyl-4H-pyrido [1 , 2-a] pyrimidin-4-one, m.p. 148.6 ° C (compound 19);

3,4-dihydro-7- (2- [4- (6-methoxy-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -8-methyl-2H, 6H-pyrimido [2, lb] [1,3] -thiazin-6-one, m.p. 174.6 ° C (compound 20);

2,3-dihydro-6- [2- [4- (6-methoxy-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl) -7-methyl-5H-thiazolo [3,2- a] pyrimidin-5-one, m.p. 175.9 ° C (compound 21);

7-chloro-3- [2- [4- (l-6-fluoro, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl) -2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one, m.p. 203.8 ° C (compound 22);

3- [2- (4- (6-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl) -2,6,8-trimethyl-4H-pyrido [l, 2-a] pyrimidine-4-η, m.p. 155.1 ° C (compound 23);

3- (3- [4- (6-Fluoro-1,2-bonisoxazol-3-yl) -1-piperidinyl] propyl] -2-methyl-4H-pyrido [1,2-a) pyrimidine-4- on, m.p. 141.3 ° C (compound 24); 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6-melyl-2,4 (1H, 3H) -quinazolinedione, m.p. , 5 C (compound 25);

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,6-dimethyl-4H-pyridole, 2-a] pyrimidine-4- on, m.p. 193.6 ° C (compound 26);

3- [2- [4- (5-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [ 1,2-a] pyrimidin-4-one, m.p.

compound);

3- [3- [4- (6-fluoro-1,2-bonisoxazol-3-yl) -1-piperidinyl] propyl] -2,4 (1H, 3H) -quinazolidinedione, m.p. 7 C (compound 28);

3- [3- [4- (6-fluoro-I, 2-benzisoxazol-3-yl) -l-piperidinyl] propyl] -6,7,8,9-letrahidro-2-methyl-4H-pyrido [ 1,2-a] pyrimidin-4-one, m.p. 133.1 ° C (compound 29);

6- [2- [4- (5-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2- a] pyrimidin-5-one, m.p. 109.1 ° C (compound 30);

7- (2- [4- (5-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2, 1b] [1,3] thiazin-6-one, m.p. 108.3 ° C (compound 31);

3- [4- [4- (6-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] butyl] -2-methyl-4H-pyrido [l, 2-a) pyrimidin-4- on, m.p. 140.9 ° C (compound 32); 3- [2- [4- (5-fluoro-2-benzisoxazol-3-yl) -l-piperidinyl] ethyl-2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one 158.0 ° C (compound 33); 7-bromo-3- [2- [4- (6-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl) -2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one, m.p. 185.9 ° C (compound 34);

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,8-dimethyl-4H-pyrido [1,2-a] pyrimidine -4-on, m.p. 182.2 ° C (compound 35); 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-2-thioxo-4 (1H) -quinazolinone, m.p. 198.1 ° C (Compound 36); 3- [2- [4- (5-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,4 (1H, 3H) -quinazolinedione, m.p. 2 'C (Compound 37);

6- (2- [4- [5-fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl] ethyl] -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5- on, m.p. 123.6 ° C (compound 38); 3- [4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butyl] -2,4 (1H, 3H) -quinazolidinedione, m.p. 7 C (compound 39);

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6-hydroxy-2,4 (1H, 3H) -quinazolidinedione, m.p. 290 ° C (compound 40); and

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6-methoxy-2,4 (1H, 3H) -quinazolidinedione, m.p. 300 ° C (compound 41).

Example 10

4.2 parts 3- (2-chloroethyl) -2,4 (1H, 3H) -quinazolinodione, 4.5 parts 3- (4-piperidinyl) -1,2-benzisothiazole monohydrochloride, 6 parts sodium A mixture of carbonate, 0.1 parts of potassium iodide and 90 parts of N, N'-dimethylformamide was stirred overnight at 100 ° 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 concentrated. The residue was purified by column chromatography over silica gel, eluting with 95: 5 trichloromethane: methanol. The pure fractions were collected and the solvent was distilled off. The residue was converted into the hydrodicloride ee in 2-propanol. The salt was filtered off and crystallized from N.N-dimethylformamide. The product was filtered and dried.

-815

1.5 parts of 3- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperidinyl] ethyl] -2,4 (1H, 3H) -quinazolin-dione monohydrochloride are obtained, 300 ⁴ C (compound 6).

C) Pharmacological Examples

The psychotic activity of the compounds of the invention was demonstrated by the following experimental data using at least two different assays. The combined apomorphine, tryptamine and norepinephrine assays were performed in rats and the apomorphine assay in dogs. The assays were performed as follows and the experimental data are summarized in Table 1.

Example 11

Λζ pooled apomorphine (APÓ), triptanine (TRY) and norepinephrine (NOR) studies in rats 25

Adult male Wistar rats (240 t 10 g) were used as the test animal. After fasting overnight, the animals were treated subcutaneously (time = 0) with an aqueous solution of the test compound (1 ml / 100 g) and placed in separate observation chambers. Thirty minutes thereafter (time = 30 minutes), 1.25 mg / kg apomorphine hydrochloride (APO) was injected into the rats and observed for one hour for aporaorphine-induced phenomena, movement, and the presence or absence of celerotypic chewing. At the end of this 1 hour period (time = 90 minutes), 40 mg / kg tryptamine (TRY) is injected intravenously into the same animals and typical tryptamine-induced bilateral tonic movements are observed. Two hours after pretreatment (time = 120 minutes), finally, the same animals were treated intravenously with 1.25 mg / kg morepinephrine (NOR) and mortality was assessed up to 60 minutes later.

Table 1 shows the ED50 values of the test compounds. The ED50 value is the dose that protects 50% of the animals from apomorphine, tryptamine or norepinephrine-induced phenomena.

Apomorphine Assay in Dogs (APOdog)

P. A. J. Janssen and C. J. E. Niemegeers, Arzneim. - Forsch. (Drug Slit). 9, 765-767 (1959)]. The compounds listed in Table 1 are administered subcutaneously to the English Blood at various doses and the animals are treated with 0.31 mg / kg (subcutaneous) apomorphine 1 hour after treatment.

Table 1 shows the ED50 values of the test compounds. The ED50 value represents the dose that protects 50% of the animals from vomiting.

The compounds listed in Table 1 are listed for the purpose of silence, but are intended only to illustrate the pharmacological activity of the compounds of formula (I).

Table 1

Compound F Dso (Λ PO) rat EDso (TRY) rat EDso (NOR) rat EDso (APO) l-dog sama mg / kg s. c. mg / kg s. c. mg / kg s. c. mg / kg s. c. duration First 0:08 0:08 0:16 1 hour 0008 2 o'clock 0005 4 o'clock 0015 8 hours 0018 16 o'clock 0:02 Second 0:02 0005 0:31 1 hour 0004 4 o'clock 0008 16 o'clock 0:16 11th 0:02 0:01 0:16 1 hour 0015 4 o'clock 0:03 13th 0:02 0:02 0:08 1 hour 0015 4 o'clock 0:06 14th 0:02 0005 0:31 1 hour 0004 4 o'clock 0004 15th 0:08 0:01 0:31 1 hour 0015 4 o'clock 0:06

-917

Claims (6)

A process for the preparation of a compound of formula (I) wherein X is oxygen or sulfur; and if X is oxygen and Q is a group of formula (a), then R ¹ is halogen, alk is C 1-4 alkylene, Y * is oxygen or sulfur, Υ » is oxygen or sulfur; and R ³ is hydrogen, (C1-C4) -alkyl, hydroxy, or (C1-C4) -alkoxy, obsession if X is sulfur and Q is a group of formula (a), then R ' is hydrogen, alk is C 1-4 alkylene, Y ¹ cs Y ³ is an oxygen atom, and R ³ is hydrogen, obsession if X is oxygen t and Q is a group of formula (b) wherein Z meaning -CHz- THE meaning -CH 2 -CH 2 -CH 2 -, or Z -CR® represents = CR ⁷ -, and THE ^S represents -CR = CR'-, where R® and ^R7 are each independently hydrogen or C1-4 alkyl and R 'and R' are independently hydrogen, C1-4 alkyl or halogen; then R> is hydrogen, halogen, hydroxy or C 1-4 alkoxy, alk C 1-4 alkylene and R ^s is C 1-4 alkyl, obsession if X is sulfur and Q is a group of formula (b) wherein Z is -CH 2 and THE is -CH 2 -CH 2 -CH 2, then R ' is hydrogen or halogen, alk C 1-4 alkylene and R ⁵ is alkyl of 1 to 4 heteroatoms, obsession if X is oxygen and Q is a group of formula (b) wherein Z is sulfur and THE -CII2 is-CH2-, -CH2- CH2-CH2-, or -CH = CR'képletű wherein R ^B is selected from H or C1-4 hydro- alkyl, then R * is hydrogen, halogen, or C 1-4 alkoxy, alk C 1-4 alkylene € 6 R ⁵ is C 1-4 alkyl - thus, a pharmaceutically acceptable acid addition salt the manufacture, characterized in that an ester derivative of formula II in the formula W is a reactive ester residue and Q and Alk are as defined in the disclosure or an acid addition salt thereof with a piperidine derivative of general formula (III) R ¹ and X are as hereinbefore defined, or an acid addition salt thereof, in a reaction inert solvent, and if desired, converting the resultant compound of formula (I) into a pharmaceutically acceptable acid addition salt. -1019 (Priority: Mar 26, 1986) 2. A process for the preparation of a compound of formula (I): wherein X is oxygen or sulfur, Q is a group of formula (a) or (b), and if X is oxygen and Q is a group of formula (a), then R> is halogen, alk is C 1-4 alkylene, Y is> is oxygen or sulfur, Y ³ is oxygen or sulfur; and R ³ is hydrogen, obsession if X means sulfur cs Q is a group of formula (a), then R ¹ is hydrogen, alk is C 1-4 alkylene, Y ¹ and Y ³ is oxygen and R ³ is hydrogen, obsession if X is oxygen and Q is a group of formula (b) wherein Z meaning -CHz- THE is -CH 2 -CH 2 -CH 2 -, or Z is -CR ⁶ = CR ⁷ and THE is -CR ^a = CR ⁹ - wherein R ⁶ and R ⁷ are each independently hydrogen or C 1-4 alkyl, and R 1 and R ⁹ are each independently hydrogen, C 1-4 alkyl, or halogen; then R ¹ is hydrogen or halogen, alk is C 1-4 alkylene, and R ⁵ is C 1-4 alkyl, obsession iv) if X is sulfur and Q is a group of formula (b) wherein Z is -CH- and A is -CH2- CH2-CH2-, then R ^l is hydrogen or halogen, alk is C 1-4 alkylene and R ^s is C 1-4 alkyl, or v) if X is an oxygen atom, and Q is a group of formula (b) wherein Z is sulfur and THE is a bivalent radical of formula -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH = - CR ⁹ -, wherein R ⁹ is hydrogen or C 1-4 alkyl, then R ¹ is hydrogen or halogen, alk C 1-4 alkylene and R ⁵ is C 1-4 alkyl - or a pharmaceutically acceptable acid addition salt thereof. ik, 1, characterized in that an ester derivative of formula II in the formula W is a reactive ester residue and Q and Alk are as defined in the preamble - or an acid addition salt thereof with a piperidine derivative of formula (III) Π 'and X are as hereinbefore defined, or an acid addition salt thereof, in a reaction inert solvent, and if desired, converting the compound of formula (I) obtained into a pharmaceutically acceptable acid addition salt. (Priority: March 27, 1985) 3. The process of claim 2, 3- [2 - [<1- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-letrahydro For the preparation of -2-methyl-1H-pyrido [1,2-a] pyrimidin-4-one, characterized in that 3- (chloroethyl) -6,7,8,9-tetrahydro-2-melyl-4H pyrido [1,2-a] pyrimidin-4-one or its acid addition salt 6-fluoro-3- (4-piperidin -1121 nyl) -1,2-benzisoxazole in a suitable reaction inert solvent. (Priority: March 27, 1985) The process of claim 2, 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl) ethyl] -2-ethyl-4H-pyrido [ 1,2-a) pyrimidin-4-one, characterized in that 3- (2-chloro-methyl) -2-melyl-4H-pyrido [1,2-a] pyrimidin-4-one or its acid addition salt 6 -fluoro-3- (4-piperidinyl) -1,2-benzisoxazole in a suitable solvent for the reaction. (Priority: March 27, 1985) 5. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a compound of formula (I) according to claim 1, wherein Q, Alk, R * and X are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, with one or more pharmaceutically acceptable inert carriers and / or It is mixed with 5 other excipients and converted into a pharmaceutical composition. (Priority: March 26, 1986) 6. A process for the preparation of a pharmaceutical composition, wherein the active ingredient is a compound of formula (I) according to claim 2, wherein 6, Alk, R ¹ and X are as defined in claim 2, or a pharmaceutically acceptable acid addition salt thereof. one or more medicaments are admixed with a pharmaceutically acceptable inert carrier and / or other excipient and converted into a pharmaceutical composition.