FI81800B - Process for preparing novel, therapeutically utilizable 1, 2-benzisoxazol-3-yl-1-piperidinylalkl pyridopyrimidinone and -tiasolopyrmidinone derivatives - 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

81800

Process for the preparation of new therapeutically useful 1,2-benzisoxazol-3-yl-1-piperidinylalkylpyridopyrimidinone and thiazolopyrimidinone derivatives 5

The invention relates to a process for the preparation of new therapeutically useful 1,2-benzisoxazol-3-yl-1-piperidinylalkylpyridopyrimidinone or thiazolopyrimidinone derivatives of the formula I

10 „oylox ©:

10 O

wherein R 1 is hydrogen, halogen, hydroxy, C 1-4 alkoxy or C 1-4 alkyl, Alk is C 2-4 alkylene; R 5 is C 1-6 alkyl; and A

20 is a group -CH = CR6-CR7 = CR8-, -S- (CH2) 2-, -S- (CH2) 3-, -S-CH = CR9- or - (CH2) 4-; wherein R 6 is hydrogen or C 1-6 alkyl; R 7 is hydrogen, halogen or C 1-6 alkyl; R 8 is hydrogen or C 1-4 alkyl and R 9 is hydrogen or C 1-4 alkyl; and pharmaceutically acceptable acid addition salts thereof.

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

Compounds having a therapeutic effect, such as those of the compounds of formula (I) having a chemical structure, have been described e.g. in Finnish patent publications 71737, 75828 and 77868, and in patent applications 843934 and 844708 (corresponding to European patent publications 144 101 and 145 037).

The new compounds of formula (I) differ from the known compounds of 2,81800 senuni in the substituent contained in the 1-position of the piperidine ring.

In the above definitions, the term halogen is a generic term for fluorine, chlorine, bromine and iodine; "C 1-4 alkyl" means straight-chain and branched saturated hydrocarbon groups containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl and butyl groups ; "C 2-4 alkenyl" means bivalent, straight-chain or branched alkenyl groups containing 2 to 4 carbon atoms, such as, for example, ethylene, trimethylene and tetramethylene groups.

Particularly preferred are those compounds of formula (I) wherein R 1 is hydrogen or halogen.

Very particularly preferred among said particularly preferred compounds are those compounds in which A is -S-CH2-CH2-, -S- (CH2) 3-, S-CH = CR9-, in which R9 is hydrogen or methyl, -CH * CH -CR7 = CR8-, wherein each of R7 and R8 is independently hydrogen or methyl, or -CH2-CH2-CH2-CH2-.

Particularly preferred among said completely different preferred compounds are those in which R 1 is hydrogen.

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

The process according to the invention for the preparation of the novel compounds of the formula (I) .. is characterized in that

I! that an ester derivative of formula II

Wherein W is a reactive ester residue such as halogen is reacted with a piperidine derivative of formula 111 3 81 800 5 10 wherein R 1 is as defined above, inert to the reaction in a solvent, and if desired, the compounds of formula (I) are converted into a therapeutically active non-toxic acid addition salt by treatment with a suitable acid or, conversely, the acid addition salt is converted into the free base by treatment with a base.

In the reactive ester of formula (II), W 20 represents a reactive ester group such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group, for example a methylsulfonyloxy or (4-methylphenyl) sulfonyloxy group or the like.

The reaction of the compound (II) with the compound (III) can be conveniently carried out in an inert organic solvent such as an aromatic hydrocarbon, for example, benzene, methylbenzene, dimethylbenzene or the like; in a lower alkanol, for example methanol, ethanol, 1-butanol or the like; in keto-30, for example 2-propanone, 4-methyl-2-pentanone or the like; in an ether, for example 1,4-dioxane, 1,1-oxybisethane, tetrahydrofuran or the like; In Ν, Ν-dimethylformamide (DMF) or N, N-dimethylacetamide (DMA); nitrobenzene, 1-methyl-2-pyr-35 rolidinone; or the like. During the reaction, a suitable base such as an alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, alkoxide or hydride, for example sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, sodium hydroxide may be added to scavenge the acid liberated during the reaction. - methoxide, sodium hydride or the like; or an organic base such as a tertiary amine, for example, N, N-diethylethanamine, N- (1-methylethyl) -2-propanamine, 4-ethylmorpholine or the like. In some conditions, it is appropriate to add an iodide salt, preferably an alkali metal iodide. Raising the temperature somewhat may increase the reaction rate.

The compounds of formula (I) are basic in nature and thus can be converted into therapeutically active non-toxic acid addition salts by treatment with suitable acids, for example inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid or the like; sulfuric acid, phosphoric acid or the like or organic acids such as acetic, propane, hydroxyacetic, 2-hydroxydropane, 2-oxopropane, ethanedicarboxylic, propanedicarboxylic, butanedicarboxylic, (Z) -2 -butenedicarboxylic, (E) -2-butenedicarboxylic, 2-hydroxybutanedicarboxylic, 2,3-dihydroxybutanediyl-carboxylic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, With 4-methylbenzenesulfonic, cyclohexanesulfamine, 2-hydroxybenzoic or 4-amino-2-hydroxybenzoic acid or the like. Accordingly, the salt can be converted to the free base form by treatment with a base.

Many of the intermediates and starting materials used are known compounds which can be prepared by methods known in the art for the preparation of said or similar compounds. For example, intermediates of formula 5,81800 van (II) and their preparations are described in U.S. Patent Nos. 4,335,127, 4,342,870, 4,443,451 and 4,485,107. Other intermediates may be prepared by methods known in the art for the preparation of similar compounds. , and for some of them the manufacturing methods are shown below.

Intermediates of formula (III) may generally be prepared from benzoylpiperidine of formula (XIV) halogen H \ / n \ / (XIV) wherein halogen is preferably fluorine following procedures known in the art, for example by reacting benzoylpiperidine (XIV) with hydroxylamine and by cyclization of the oxime (XV) 20 thus obtained halogen • OCjy * "\ - / (XV)

25 NOH

following procedures known in the art to give an intermediate of formula (III).

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are highly antagonistic to a number of neurotransmitter mediators and thus have useful pharmacological properties. For example, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts have potent antipsychotic activity and anti-serotonin activity.

Due to their pharmacological activity, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the treatment of psychoses and in the treatment of many conditions in which serotonin release is predominant, such as serotonin-induced bronchial and vascular, vascular, arterial, arterial prevention. The compounds 10 of the invention also have advantageous properties as sedatives, antianxiety, aggression and stress relievers, muscle protectors and cardiovascular protectors, and are thus suitable for providing a protective effect in warm-blooded animals, for example in stressful situations such as transport. In addition, the compounds of the invention are useful as protective agents against endotoxin shocks as well as antidiarrheal drugs.

The efficacy of the compounds of the invention as antipsychotic agents is demonstrated by test results obtained using at least one of two different test methods combined with the apomorphine, tryptamine and norepinephrine test in rats and the apomorphine test in dogs. The tests are performed following the procedures described below and a summary of the test results is shown in Table 1.

Combined Apomorphine, Tryptamine, and Norepinephrine Test in Rats (APO Rat, TRY Rat, and NOR Rat (Table 1)) The experimental animals used in this test were full-grown male Wistar rats (240 ± 10 g). after fasting overnight, the animals were administered subcutaneously (1 ml / 100 g) an aqueous solution of the test compound (time * 0) and placed in isolated 35 observation cages, 30 minutes later (time <30 min) 7 81,800 rats were given an intravenous injection of 1 , 25 mg / kg apomorphine hydrochloride (APO) and observed for one hour for the presence or absence of the following apomorphine-induced phenomena: restlessness and repeated, 5 forced chewing At the end of this 1 hour period (time = 90 min), the same animals were given an intravenous injection. 40 mg / kg tryptamine (TRY) and typical tryptamine-induced, reciprocal, convulsive seizures were noted. From 0 pretreatments (time = 120 min), the same animals were given 1.25 mg / kg norepinephrine (NOR) intravenously and any deaths were then expected for 60 minutes.

Table 1 shows the ED50 values of some of the compounds tested. In this context, the ED50 value means the dose that protects 50% of the animals from the effects induced by apomorphine, tryptamine or norepinephrine. Apomorphine test in dogs (APO dog) The method used is described in P.A.J. Janseen and C.J.E. Niemegeers, Arzneim-Forsch. (Drug Res.) 20 9 (1959) 765-767. The compounds listed in Table 1 were administered subcutaneously to beagle dogs at various doses, and 1 hour later the animals were administered a standard dose of 0.31 mg / kg (subcutaneously) apomorphine.

Table 1 shows the ED50 values of the few compounds tested. In this context, the ED50 value refers to the dose that prevents vomiting in 50% of the animals.

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In view of the advantageous pharmacological properties of the compounds of formula (I), they may be formulated into a wide variety of pharmaceutical forms for administration. To prepare pharmaceutical compositions, an effective amount of a particular active compound of formula (I), which may be in the form of a free base or an acid addition salt, is admixed with a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form. These pharmaceutical compositions are preferably in the form of indivisible dosages suitable for administration preferably oral, rectal, transdermal or parenteral injections.

Those skilled in the art of treating psychoses will readily be able to determine an effective amount of a compound of formula (I) based on the test results presented herein. It is generally considered that an effective amount would be 0.01-4 mg / kg body weight, more preferably 0.04-2 mg / kg body weight.

The following examples illustrate the invention. Unless otherwise indicated, all parts are by weight and all temperatures are in degrees Celsius. Experimental Part A) Preparation of intermediates Example 1 To a stirred mixture of 65 parts of 1,3-difluorobenzene, 130 parts of aluminum chloride and 195 parts of dichloromethane was added dropwise, while cooling, a solution of 95 parts of 1-acetyl -li-4-piperidinecarbonyl chloride in 65 parts of dichloromethane. After the addition was complete, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 parts (36%) of 35 l-acetyl-4- (2,4-difluorobenzoyl) piperidine (intermediate 1).

10 81 800

A mixture of 48 parts of 1-acetyl-4- (2,4-difluorobenzoyl) piperidine and 180 parts of 6 N hydrochloric acid solution was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was stirred in 2-propanol. The product was filtered off and dried, yielding 39 parts (83%) of (2,4-difluorophenyl) (4-piperidinyl) methanone hydrochloride (interm. 2).

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

A mixture of 11 parts of (2,4-difluorophenyl) - (4-piperidinyl) methanone oxime, 25 parts of potassium hydroxide and 25 parts of water was stirred and refluxed for 20 hours. The reaction mixture was cooled and extracted with methylbenzene. The extraction solution was dried, filtered and evaporated. The residue was crystallized from petroleum ether, yielding 6.8 parts of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (interm. 4).

25 Example 2

A mixture of 50 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 and refluxed for 2 hours using a water separator. The reaction mixture was cooled and 340 parts of phosphoryl chloride were added at 20-30 ° C. The whole mixture was slowly heated to 100-110 ° C and stirring was continued 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. Extract H 81800 toluene was dried, filtered and evaporated. The residue was purified by chromatography on a column of silica gel using adsorbent and trichloromethane-methanol (95: 5 by volume) 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] pyrimidin-5-one ( intermediate 5).

Example 3 A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidiethanol, 25 parts of potassium carbonate, 270 parts of N, N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane, raising the temperature to 50 ° C. The whole mixture was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried under reduced pressure at 100 ° C to give 21 parts (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-20 pyrimido [2,1- b] [1,3] thiazin-6-one (intermediate 6); mp.

155 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials, 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one was also prepared (intermediate 7); mp.

148.7 ° C.

Example 4

Mixture containing 20 parts of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-306-one, 50 parts acetic acid and 180 parts of a 67% acetic acid solution of hydrobromic acid were stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-pro-35 pan. The product was filtered off and dried, yielding 24 parts (100%) of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [ 1,3] thiazin-6-one monohydrobromide (intermediate 8); mp. 215 ° C.

Following the same procedure and using 5 equivalent amounts of the appropriate starting materials, 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyridimidin-5-one monohydrochloride was also prepared (interm. 9); mp. 237.2 ° C.

B) Manufacture of finished products 10 Example 5

A mixture of 5.3 parts of 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride, 4.4 parts of 6-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 were stirred overnight at 85 ° C. 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] pyrimidin-4-one (Compound 1); mp. 170.0 ° C.

Following the same procedure and using 25 equivalent amounts of the appropriate starting materials, the following were also prepared: 6- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -7-methyl-5H- thiazolo [3,2-a] pyrimidin-5-one (Compound 2); mp. 165.1 ° C; 3- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-30 methyl-4H-pyrido [1,2-a] pyrimidin-4-one (Compound 3); mp.

177.9 ° C; 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,7-dimethyl-4H-pyrido [1,2-a] pyrimidine 4-one (compound 4); mp. 186.9 ° C; 3- [2- [4- (1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetra-35-hydro-2-methyl-4H-pyrido [ 1,2-a] pyrimidin-4-one (Compound i3 81 800 5); mp. 183.1 ° C; and 3- [2- [4- (6-hydroxy-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H- pyrido [1,2-a] pyrimidin-4-one (Compound 8); mp. 213.1 ° C.

Using the same procedure and starting from 4.7 parts of 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride and 4 part of 5-methyl-3- (4-piperidinyl) -1,2-benzisoxazole monohydrochloride gave 2.7 parts (41.5%) of 6,7,8,9-tetrahydro-2-10 methyl-3- [2- [4- (5-methyl-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -4H-pyrido [1,2-a] pyrimidin-4-one; mp. 177.5 ° C.

Example 6

A mixture of 3.3 parts of 3- (2-chloroethyl) -2-15 methyl-4H-pyrido [2,1a] pyrimidin-4-one, 3.3 parts of 6-fluoro-3- (4- piperidinyl) -1,2-benzisoxazole, 8 parts of sodium carbonate, 1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone were stirred and refluxed for 3 hours. The reaction mixture was cooled, water was added, and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by chromatography on a column of silica gel using adsorbent and trichloromethane-methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone to give 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] pyridimidin-4-one (Compound 11); mp. 170.4 ° C.

30 Example 7

A mixture of 7.4 parts of 6- (2-bromoethyl) -3,7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrobromide, 4.4 parts of 6-fluoro-3- (4-Piperidinyl) -1,2-benzisoxazole, 10 parts of sodium carbonate and 90 parts of N, N-35 dimethylformamide were stirred overnight at 80-85 ° C.

After cooling, the reaction mixture was poured into water. The product was filtered off and purified by column chromatography using silica gel as adsorbent and trichloromethane-methanol (95: 5 by volume) as eluent.

The pure fractions were collected and the eluent was evaporated. 2-Propanol was added to the residue. The product was filtered off and dried, yielding 5.3 parts (62%) of 6- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -3 , 7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-10-one (Compound 13); mp. 231.0 ° C.

In a similar manner there were also prepared: 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 (Compound 14); mp. 135.0 ° C; 7- [2- [4-15 (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2 , 1-b] [1,3] -thiazin-6-one (Compound 15); mp. 169.3 ° C; 6- [2- [4- (1,2-Benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidine -5-one (Compound 20 16); mp. 154.5 ° C.

Example 8

By proceeding as described in Example 5 and starting from 5.5 parts of 3- (4-chlorobutyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride 25 and 4.8 parts of 6-fluoro-3 - (4-piperidinyl) -1,2-benzisoxazole monohydrochloride 1.8 parts of 3- [4- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] butyl] were obtained. 2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one; mp. 140.9 ° C.

Example 9 By proceeding as described in Example 5 and starting from 4.2 parts of 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4 -one monohydrochloride and 3.5 parts of 6-methoxy-3- (4-piperidinyl) -1,2-benzisoxazole gave 0.9 parts of 6,7,8,9-tetrahydro-3- [2- [ 4- (6-methoxy-1,2-benzisoxazol-3-yl) -1- 81,800 piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; mp. 148.6 ° C.

Example 10

Following the procedure described in Example 5 and starting from 5.1 parts of 7-chloro-3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 5.1 parts parts of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole were obtained 3.9 parts of 7-chloro-3- [2- [4- (6-fluoro-1,2-benzisoxazol-3- yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyr-10-do- [1,2-a] pyrimidin-4-one; mp. 203.8 ° C.

Example 11

By proceeding as described in Example 5 and starting from 5 parts of 3- (2-chloroethyl) -2,6,8-trimethyl-4H-pyrido [1,2-a] pyrimidin-4-one and 5.1 parts of 6-15 fluorine -3- (4-piperidinyl) -1,2-benzisoxazole monohydrochloride was obtained in 2.8 parts of 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl ] ethyl] -2,6,8-trimethyl-4H-pyrido [1,2-a] pyrimidin-4-one; mp. 155, LEC.

Claims (3)

1. A process for the preparation of novel therapeutically useful baral, 2-benzisoxazol-3-yl-1-piperidinylalkylpyridopyrimidinone and thiazolopyrimidinone derivatives of formula I wherein R 1 is hydrogen, halogen, hydroxy, C 1-4 alkoxy or C -alkyl, Alk is C 2-4 alkylene; R 5 is C 1-4 alkyl; and A is a group -CH = CR6-CR7 * CR8-, -S- (CH2) 2-, -S- (CH2) 3-, -S-CH = CR9- or - (CH2) 4-; wherein R 6 is hydrogen or C 1-4 alkyl; R 7 is hydrogen, halogen or C 1-6 alkyl; R 8 is hydrogen or C 1-4 alkyl and R 9 is hydrogen or C 1-4 alkyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that an ester derivative of formula II is reacted R is a reactive ester residue, such as halogen, with a piperidine derivative of formula III ". O-XX II ie 81800 wherein R1 represents the same as above, in a reaction inert solvent, and, if desired, transfers compounds of formula (I) to form of a therapeutically active non-toxic acid addition salt by treating them with a suitable acid, or vice versa, transfer an acid addition salt to a free base by treating it with a base. 2. Process for Preparation of 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-10 tetrahydro-2 methyl 4H-pyrido [1,2-a] pyrimidin-4-one or a pharmaceutically acceptable acid addition salt thereof, characterized in that 3- (2-chloroethyl) -6,7,8,9-tetrahydro-reaction is reacted. 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one or an acid addition salt thereof with 6-fluoro-3-15 (4-piperidinyl) -1,2-benzisoxazole or an acid addition salt thereof in a reaction inert solvent, and, if desired, transfer the thus obtained product into the form of a therapeutically active non-toxic acid addition salt by treating it with a suitable acid, or conversely, transferring an acid addition salt to a free base by treating it with a base. 3. Process for Preparation of 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one or a pharmaceutically acceptable acid addition salt thereof, characterized in that 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one is reacted or an acid addition salt thereof with 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole or an acid addition salt thereof in a reaction inert solvent and, if desired, transfer the thus obtained compound as a therapeutically active compound. non-toxic acid addition salt by treating it with a suitable acid, or conversely, transferring an acid addition salt to a free base by treating it with a base. 35