DE3686341T2 - 1,2-BENZISOXAZOLE-3-YL AND 1,2-BENZISOTHIAZOL-3-YL 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

US Patents 4,352,811 and 4,458,076 describe 3-piperidinyl-1,2-benzisoxazole and 3-piperidinyl-1,2-benzisothiazole with antipsychotic and analgesic properties.

EP-A-0 110 435 describes ((bis(aryl)methylene)-1-piperidinyl)alkyl-pyrimidinones which are useful in the treatment of psychosomatic disorders. EP-A-0 070 053 describes bicyclic pyrimidin-5-one derivatives which are psychotropic agents.

The compounds of the present invention differ from those of the prior art by their substitution at the 1-position of the piperidine residue.

The present invention relates to 1,2-benzazoles having the formula:

and to the pharmaceutically acceptable acid addition salts or possible stereochemically isomeric forms thereof, wherein

R is hydrogen or C₁₋₆alkyl;

R¹ and R² are each independently members of the group consisting of hydrogen, halogen, hydroxy, C₁₋₆alkyloxy and C₁₋₆alkyl ;

X stands for O or S;

Alk is C₁₋₄alkanediyl; and

Q is a remainder of the formula

wherein

Y¹ and Y² each independently represent O or S;

R³ represents a member selected from the group consisting of hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C₁₋₆alkylcarbonyl)oxy, amino, mono- and di(C₁₋₆alkyl)amino, (C₁₋₆alkylcarbonyl)amino, phenylmethoxy and azido;

R⁴ is hydrogen or halogen; or

a remainder of the formula

means in which

R⁵ is hydrogen or C₁₋₆alkyl;

Z has the meaning -S-, -CH₂-, or -CR⁶=CR⁷-;wherein the radicals R⁶ and R⁷ each independently of one another denote hydrogen or C₁₋₆alkyl; and

A represents a divalent radical -CH₂-CH₂-, -CH₂-CH₂-CH₂- or -CR⁸=CR⁹-, wherein R⁸ and R⁹ each independently represent hydrogen, halogen, amino or C₁₋₆alkyl.

In the above definitions, the term "halogen" is generic for fluorine, chlorine, bromine and iodine;

"C₁₋₆alkyl" is intended to include straight and branched saturated hydrocarbon radicals having 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl;

"C₁₋₄alkanediyl" is intended to include divalent straight or branched chain alkanediyl radicals having 1 to 4 carbon atoms, such as methylene, ethylene, propylene, butylene; and

"C₁₋₁₀alkyl" is intended to include C₁₋₆alkyl radicals as previously defined and their higher homologues containing 7 to 10 carbon atoms, such as heptyl and nonyl.

Preferred compounds within the compound are those in which Q is a radical of formula (a) in which R³ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, hydroxy, amino or azido and R⁴ is hydrogen or in which Q is a radical of formula (b) in which R⁵ is C₁₋₆alkyl and A is a divalent radical -CH₂-CH₂-, -CH₂-CH₂-CH₂- or -CR⁸=CR⁹- in which R⁸ and R⁹ are each independently of one another hydrogen or C₁₋₆alkyl.

Particularly preferred compounds are those preferred compounds wherein R is hydrogen, R¹ is hydrogen or halogen and R² is hydrogen, halogen, hydroxy or C₁₋₆alkyloxy.

More particularly preferred compounds are those particularly preferred compounds wherein Q is a radical of formula (a) wherein R³ is hydrogen, halogen or methyl and Y¹ is O; or Q is a Radical of formula (b) in which -ZA- is -S-CH₂-CH₂-, -S-(CH₂)₃-, -S-CR⁸=CR⁹- in which R⁸ and R⁹ each independently of one another are hydrogen or methyl, is -CH=CH-CR⁸=CR⁹- in which R⁸ and R⁹ each independently of one another are hydrogen or methyl, or is -CH₂-CH₂-CH₂-CH⁹-CH⁹-.

Preferred compounds are those more particularly preferred compounds wherein R¹ is hydrogen and R² is hydrogen, halogen, hydroxy or methoxy .

The most preferred compounds are selected from the group consisting 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 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 the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) can generally be prepared by reacting a corresponding reactive ester of formula (II) with a correspondingly substituted piperidine of formula (III). In the reactive ester (II), W represents a reactive ester radical, such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group, for example methylsulfonyloxy, (4-methylphenyl)sulfonyloxy.

The reaction of (II) with (III) can be carried out in a simple manner in an inert organic solvent such as an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene; a lower alkanol, for example methanol, ethanol, 1-butanol; a ketone, for example 2-propanone, 4-methyl-2-pentanone; an ether, for example 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran; , -dimethylformamide (DMF); , -dimethylacetamide (DMA); nitrobenzene; 1-methyl-2-pyrrolidinone. The addition of a suitable base, such as an alkali or alkaline earth metal carbonate, hydrogen carbonate, hydroxide, alkoxide or hydride, for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride, or an organic base such as a tertiary amine, for example , -diethylethanamine, -(1-methylethyl)-2-propanamine, 4-ethylmorpholine, can be used to absorb the released in the course of the reaction. Acid may be used. In some cases the addition of an iodide salt, preferably an alkali metal iodide, is appropriate. Slightly elevated temperatures may promote the reaction rate.

The compounds of formula (I) can also be prepared by methods known from the literature for the preparation of compounds which contain radicals of formula Q within their structure.

For example, the compounds of formula (I) wherein Q represents a radical of formula (a), which compounds are represented by formula (Ia), can be prepared by cyclizing a corresponding 2-amino-benzamide or 2-amino-thiobenzamide of formula (IV-a) with urea or thiourea. +Urea or thiourea

The compounds of formula (Ia) can also be prepared by cyclizing a corresponding intermediate of formula (IV-b) with an amine of formula (V)

or by cyclizing an isocyanate or isothiocyanate of formula (IV-c) with a primary amine of formula (V).

These cyclization reactions are conveniently carried out by stirring and, if desired, heating the reactants together, optionally in a suitable reaction-inert solvent with a relatively high boiling point, such as in aliphatic and aromatic hydrocarbons, for example petroleum ether, dimethylbenzene.

In the above reaction schemes, R¹⁰ and R10-a each independently represent a suitable leaving group such as C₁₋₆alkyloxy, amino and mono- and di(C₁₋₆alkyl)amino.

The compounds of formula (I) wherein Q denotes a radical of formula (b), which compounds are represented by formula (Ib), can be prepared by cyclization methods known from the literature for the preparation of pyrimidin-4-ones, for example by reacting an amine of formula (VI) with a cyclizing agent of formula (VII) or by cyclizing a reagent of formula (VIII) with an amine of formula (IX).

These cyclization reactions can generally be carried out by stirring the reactants together, if desired in the presence of a suitable reaction-inert solvent, such as an aliphatic, alicyclic or aromatic hydrocarbon, for example hexane, cyclohexane, benzene; pyridine; , -dimethylformamide. Elevated temperatures can be used to promote the reaction rate. In some cases it may be advantageous to carry out the reaction at the reflux temperature of the reaction mixture.

In the above reaction schemes, L and L¹ each independently represent a suitable leaving group such as (C₁₋₆alkyl)oxy, hydroxy, halogen, amino, mono- and di(C₁₋₆alkyl)amino.

By the same cyclization method, the compounds of formula (Ib) can also be prepared by cyclizing an intermediate of formula (IX) with a reagent of formula (X). Cyclization reaction

The compounds of formula (Ib) wherein Z is S, which compounds are represented by formula (Ib-1), can also be prepared by cyclizing a 2-mercaptopyrimidinone of formula (XI) with a reagent of formula (XII). Cyclization reaction

In (XII) W' has the same meaning as previously described for W.

The compounds of formula (Ib-1) wherein A is

which compounds are represented by the formula (Ib-1-a), can also be prepared by cyclizing a 2-mercaptopyrimidinone of the formula (XI) with a reagent of the formula (XIII).

The cyclization reactions for preparing the compounds of formulae (I-b-1) and (I-b-1-a) can generally be carried out by stirring the reactants together, if desired in the presence of a suitable reaction-inert solvent, such as an aliphatic, alicyclic or aromatic hydrocarbon, for example hexane, cyclohexane, benzene; pyridine; , -dimethylformamide;. To increase the reaction rate, elevated temperatures can be useful. In some cases it can be advantageous to carry out the reaction at the reflux temperature of the reaction mixture.

The compounds of formula (I) can also be converted into one another using methods known from the literature for the conversion of functional groups.

For example, compounds of formula (I-a) in which R³ is amino can be derived from the corresponding nitro-substituted quinazolines by nitro-to-amine reduction procedures known from the literature.

A suitable nitro-to-amine reduction process is, for example, catalytic hydrogenation in a relatively polar solvent such as an alcohol, e.g. methanol or ethanol, in the presence of a suitable catalyst, e.g. platinum on carbon. In some cases it may be useful to add a suitable catalyst poison, e.g. thiophene.

The compounds of formula (Ia) in which R³ is phenylmethoxy can be converted into compounds of formula (Ia) in which R³ is hydroxy by catalytic hydrogenolysis processes known from the literature; the compounds of formula (Ia) in which R³ is amino or hydroxy can be converted into compounds of formula (Ia) in which R³ is (C₁₋₁₀alkylcarbonyl)amino or (C₁₋₁₀alkylcarbonyl)oxy by reacting the former compounds with a suitable acylating agent, for example an acyl halide or an acid anhydride; the compounds of formula (Ia) in which R³ is an amino group can be converted into compounds of formula (Ia) in which R³ is an azido group by converting the amino group is converted into a diazonium group with nitrous acid or a corresponding alkali metal or alkaline earth metal salt thereof and then converting the diazonium group into an azide group with sodium azide or another suitable alkali metal or alkaline earth metal azide.

The compounds of formula (I) have basic properties and can therefore be converted into their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, with inorganic acids such as hydrohalic acid, for example hydrochloric acid, hydrobromic acid and the like, and sulphuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid. Conversely, the acid salt form can be converted into the free base form by treatment with alkali.

Some intermediates and starting materials in the above-mentioned routes are known compounds which can be prepared by literature-known methods for preparing these or similar compounds. For example, the intermediates of formula (II) and their preparations are described in US Patents 4,335,127; 4,342,870; 4,443,451 and 4,485,107. Other intermediates can be prepared by literature-known methods for preparing similar compounds and preparative methods for some of them are given below.

The intermediates of formula (III) can generally be prepared from a benzoylpiperidine of formula

wherein halogen is preferably fluorine, can be derived by methods known from the literature, for example by reacting a benzoylpiperidine (XIV) with hydroxylamine and cyclizing the oxime thus obtained halogen

according to methods known from the literature, to form the intermediate of formula (III) in which X is O, which intermediates are represented by the formula

being represented.

The intermediates of formula (III) in which X has the meaning of S, which intermediates are represented by the formula

can be prepared by a process analogous to that described in US Patent 4,458,076.

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof are potent antagonists to a number of neurotransmitters and therefore exhibit useful pharmacological properties. For example, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts exhibit potent psychotic activity and antiserotonin activity.

Due to their pharmacological activities, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the treatment of psychotic diseases and in the treatment of a number of conditions in which serotonin release is of paramount importance, such as in the blocking of serotonin-induced contractions of bronchial tissues and of blood vessels, both arteries and veins. The present compounds also have useful properties as sedatives, anxiolytics, antiaggressors, antistress agents, muscle protectants and cardiovascular protectants and are therefore useful for protecting warm-blooded animals, for example in stressful situations, such as during transport. In addition, the present compounds are useful as protective agents against endotoxic shock and as antidiarrheal agents.

In view of their useful pharmacological properties, the present compounds can be formulated in various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of the present invention, a pharmaceutically effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is placed in intimate admixture with a pharmaceutically acceptable carrier, which carrier can take a wide variety of forms depending upon the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form, preferably suitable for administration by the oral, rectal, percutaneous route or by parenteral injection. For example, in preparing compositions in oral dosage form, any of the conventional pharmaceutical media may be used, such as water, glycols, oils, alcohols in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders and disintegrants in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers will of course be used. For parenteral compositions, the carrier will normally comprise, at least in large part, sterile water, although other ingredients may be included, for example to increase solubility. For example, injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose solutions. Injectable suspensions may also be prepared, in which case suitable liquid carriers and suspending agents may be used. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration aid and/or a suitable wetting agent, optionally in combination with suitable additives of any kind in small proportions, which additives do not have a noticeable adverse effect on the skin. These additives can facilitate administration to the skin and/or can contribute to the preparation of the desired compositions. These compositions can be administered, for example as a transdermal patch, as a spray or as an ointment. Due to their increased water solubility compared to the corresponding base form, acid addition salts of (I) are obviously more suitable for the preparation of aqueous compositions.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form due to ease of administration and uniformity of dosage. Unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unit doses, each unit containing, together with the required pharmaceutical carrier, a predetermined amount of active ingredient calculated to achieve the desired therapeutic effect. Examples of such unit dosage forms are tablets (including split or coated tablets), capsules, pills, sachets, wafers, injectable solutions or suspensions, teaspoonful, tablespoonful amounts and discrete multiples thereof.

In the following examples, all parts are by weight unless otherwise specified, and all temperatures are in Celsius.

EXPERIMENTAL PART A) Production of intermediate products: 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 a solution of 95 parts of 1-acetyl-4-piperidinecarbonyl chloride in 65 parts of dichloromethane with cooling. 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 phase was dried, filtered and evaporated to give 48 parts (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (intermediate 1¹).

A mixture of 48 parts of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 180 parts of a 6N hydrochloric acid solution was stirred and heated to reflux for 5 hours. The reaction mixture was evaporated and the residue was stirred in 2-propanol. The product was filtered off and dried and gave 39 parts (83%) of (2,4-difluorophenyl)(4-piperidinyl)methanone hydrochloride (intermediate 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 ,-diethylethanamine were added. The whole was stirred and heated to reflux for 3 hours. After cooling, the precipitated product was filtered off and dried to give 11 parts (100%) of (2,4-difluorophenyl)(4-piperidinyl)methanone oxime (intermediate 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 heated to reflux for 2 hours. The reaction mixture was cooled and extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was crystallized from petroleum ether to give 6.8 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (intermediate 4).

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 for 2 hours using a water separator and heated to reflux. The reaction mixture was cooled and 340 parts of phosphoryl chloride were added at a temperature of 20-30°C. The whole 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. 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 a mixture of 2-propanol and 1,1¹-oxybisethane to give 36 parts of 6-(2-chloroethyl)-7-methyl-5-thiazolo[3,2-a]pyrimidin-5-one (intermediate 5).

Example 3:

A mixture of 30 parts 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts potassium carbonate, 270 parts , -dimethylacetamide and 75 parts water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added in one batch; the temperature rose to 50 °C. The whole 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 in vacuo at 100 °C to give 21 parts (58%) of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2,6-pyrimido-[2,1-b][1,3]thiazin-6-one; mp 155 °C (intermediate 6).

Using the same method and equivalent amounts of the corresponding starting materials, the following was also produced:

2,3-Dihydro-6-(2-hydroxyethyl)-7-methyl-5-thiazolo[3,2-a]pyrimidin-5-one; m.p. 148.7ºC (intermediate 7).

Example 4:

A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2,6-pyrimido[2,1-b][1,3]thiazin-6-one, 50 parts of acetic acid and 180 parts of 67% hydrobromic acid in acetic acid was 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-propanone. The product was filtered and dried to give 24 parts (100%) of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2,6-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide; mp 215 °C (intermediate 8).

Using the same method and equivalent amounts of the corresponding starting materials, the following was also obtained:

6-(2-Bromoethyl)-2,3-dihydro-7-methyl-5-thiazolo[3, 2-a]pyrimidin-5-one monohydrochloride; mp 237.2ºC (intermediate 9).

B) Manufacturing of final connections: Example 5:

A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl- 4-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide and 90 parts of ,-dimethylformamide was stirred overnight at 85 to 90°C. After cooling, the reaction mixture was poured into water. The product was filtered off and crystallized from a mixture of ,-dimethylformamide and 2-propanol. The product was filtered and dried to give 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-4-pyrido[1,2-a]pyramidin-4-one; mp 170.0°C (Compound 1).

Using the same method and equivalent amounts of the corresponding starting materials, the following were also prepared:

- 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-7-methyl-5 - thiazolo[3,2-a]pyrimidine-5- on; F. 165.1ºC (Compound 2);

- 3-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4-pyrido- [1,2-a]pyridimin-4-one; f. 177.9ºC (compound 3);

- 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,7-dimethyl- 4-pyrido[1,2-a]pyrimidine- 4-on; F. 186.9ºC (Compound 4);

- 3-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2- methyl-4-pyrido[1,2- a]pyrimidin-4-one; F. 183.1ºC (Compound 5);

- 3-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-2,4(1,3)quinazolinedione monohydrochloride; F 300ºC (decomposition) (compound 6);

- 3-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro- 2-methyl-4-pyrido[1,2- a]pyrimidin-4-one; F. 145.7ºC (Compound 7);

- 3-[2-[4-(6-Hydroxy-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9- tetrahydro-2-methyl-4-pyrido[ 1,2-a]pyrimidin-4-one; F. 213.1ºC (compound 8).

In a similar way, the following are produced:

- 3-[2-[4-(5-methoxy-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4- pyrido[1,2-a]pyrimidin-4-one (compound 9);

- 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4 -pyrido[1,2-a]pyrimidin-4-one (compound 10).

Example 6:

A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-4-pyrido[1,2-a]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 was stirred and heated to reflux for 3 hours. The reaction mixture was cooled, water was added and the phases were separated. The organic phase 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 4-methyl-2-pentanone and gave 1.2 parts (19%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4-pyrido[1,2-a]pyrimidin-4-one; mp 170.4°C (Compound 11).

Example 7:

A mixture of 6.75 parts of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione, 6.6 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 10 parts of sodium hydrogen carbonate, 0.1 part of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight and heated to 100-110°C. After cooling, the reaction mixture was poured into water. After stirring, the product was filtered off and crystallized from ,-dimethylformamide to give 4.8 parts (39%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,4-(1,3)-quinazolinedione; mp 253.4°C (compound 12).

Example 8:

A mixture of 7.4 parts of 6-(2-bromoethyl)-3,7-dimethyl-5-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 ,-dimethylformamide was 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 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 the residue was added 2-propanol. The product was filtered and dried to give 5.3 parts (62%) of 6-[2[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5-thiazolo[3,2-a]pyrimidin-5-one; m.p.231.0°C (Compound 13).

In a similar way, the following were also produced:

- 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7- methyl-5 -thiazolo[3,2- a ]pyrimidin-5-one; F. 135.0ºC (Compound 14);

- 7-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,4-dihydro-8- methyl-2,6-pyrimido[2, 1-b] [1,3]thiazin-6-one; f. 169.3ºC (compound 15);

- 6-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl- 5-thiazolo[3,2-a]pyrimidine- 5-on; F. 154.5ºC (Compound 16);

- 3-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9- tetrahydro-2-methyl-4-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(1 )-quinazolinone (compound 18).

C) Pharmacological examples:

The activity of the present invention as a psychotic agent is demonstrated by experimental data obtained in at least one of two different test procedures, namely the combined apomorphine, tryptamine and norepinephrine test in rats and the apomorphine test in dogs. The tests were carried out according to the methods described below and the test results are summarized in Table 1.

Example 9: Combined apomorphine (APO), tryptamine (TRY) and norepinephrine (NOR) test in rats:

The experimental animals used in this test were adult male Wistar rats (weight 240 ± 10 g). After an overnight fast, the animals were treated subcutaneously (1 ml/100 g) with an aqueous solution of the compound under test (time point = zero) and placed in isolated observation cages. Thirty minutes later (time point = 30 minutes), 1.25 mg/kg apomorphine hydrochloride (APO) was injected intravenously and the rats were observed for one hour for the presence or absence of the following apomorphine-induced phenomena: locomotion, stereotypical chewing. After this one-hour period (time point = 90 minutes), the same animals were injected intravenously with 40 mg/kg tryptamine (TRY) and the appearance of the typical tryptamine-induced bilateral tonic convulsions was observed. Finally, two hours after pretreatment (time point = 120 minutes), the same animals were treated with 1.25 mg/kg norepinephrine (NOR) intravenously, and any mortality was assessed 60 minutes later.

Table 1 gives the ED50 values of a number of the compounds tested. In the present context, the ED50 value means the dose which protects 50% of the animals from the apomorphine-, tryptamine- or norepinephrine-induced phenomena.

Apomorphine test on dogs (APO-Dog):

The method used is described by P.A.J. Janssen and C.J.E.Niemegeers in Arzneim.-Forsch. (Drug.Res.), 9, 765 - 767 (1959). The compounds listed in Table 1 were administered subcutaneously to beagle dogs at various doses, and the animals were administered a standard dose of 0.31 mg/kg apomorphine subcutaneously one hour later.

Table 1 gives the ED50 values of some of the compounds considered here. In the present context, the ED50 value represents the dose which protects 50% of the animals from emesis.

The compounds listed in Table 1 are not intended to limit the invention thereto, but are merely intended to illustrate the useful pharmacological activities of all compounds within the scope of formula (I). TABLE 1: Compound No. ED₅₀₀ (APO) rat in mg/kg sc ED₅₀ (TRY) rat in mg/kg sc ED₅₀ (NOR) rat in mg/kg sc ED₅₀ (APO)-Dog in mg/kg sc duration

D) Composition examples:

The following formulations illustrate typical pharmaceutical compositions in unit dosage form suitable for systemic administration to animals and humans in accordance with the present invention.

The term "active ingredient" as used in these examples refers to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Example 10: ORAL DROPS

500 g of active ingredient were dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of polyethylene glycol at 60 to 80ºC. After cooling to 30 to 40ºC, 35 l of polyethylene glycol were added and the whole was stirred well. Then a solution of 1,750 g of saccharin sodium in 2.5 l of purified water was added and with stirring 2.5 l of cocoa flavor and polyethylene glycol qs to to a volume of 50 l, creating an oral drop solution containing 10 mg of active ingredient per milliliter. The resulting solution was filled into suitable containers.

Example 11: ORAL SOLUTION

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3 l of this solution, first 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of active ingredient were dissolved. The latter solution was combined with the remaining part of the former solution and 12 l of 1,2,3-propanetriol and 3 l of 70% sorbitol solution were added. 40 g of saccharin sodium was dissolved in 0.5 l of water and 2 ml of raspberry essence and 2 ml of gooseberry essence were added. The latter solution was combined with the former solution, water was added to a total volume of 20 l, creating an oral solution containing 20 mg of active ingredient per teaspoonful (5 ml). The resulting solution was filled into suitable containers.

Example 12: CAPSULES

20 g of active ingredient, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate were vigorously stirred together. The resulting mixture was then filled into 1,000 suitable hardened gelatin capsules, each containing 20 mg of active ingredient.

Example 13: FILM-COATED TABLETS Production of the tablet core:

A mixture of 100 g of active ingredient, 570 g of lactose and 200 g of starch was mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone (Kollidon-K 90 ) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. 100 g of microcrystalline cellulose (Avicel ) and 15 g of hydrogenated vegetable oil (Sterotex ) were then added. The whole was mixed well and pressed into tablets to give 10,000 tablets, each containing 10 mg of active ingredient.

Coating:

To a solution of 10 g methylcellulose (Methocel 60 HG ) in 75 ml denatured ethanol was added a solution of 5 g ethylcellulose (Ethocel 22 cps ) in 150 ml dichloromethane. Then 75 ml dichloromethane and 2.5 ml of 1,2,3-propanetriol was added. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former solution and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated paint suspension (Opaspray K-1-2109) were added and the whole was homogenized.

The tablet cores were coated with the mixture thus obtained in a coating device.

Example 14: INJECTABLE SOLUTION

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate were dissolved in about 0.5 l of boiling water for injection. After cooling to about 50°C, 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of active ingredient were added with stirring. The solution was cooled to room temperature and made up to a volume of 1 l with water for injection q.s. to give a solution containing 4 mg of active ingredient per ml. The solution was sterilized by filtration (U.S.P. XVII, p. 811) and filled into sterile containers.

Example 15: SUPPOSITORIES

3 g of active ingredient were dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid and 25 ml of polyethylene glycol 400. 12 g of surfactant (SPAN) and triglycerides (Witepsol 555) q.s. to 300 g were melted together. The latter mixture was well mixed with the former solution. The mixture thus formed was poured into molds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg of active ingredient.

Claims (12)

1. Chemical compound with the formula or a pharmaceutically acceptable acid addition salt thereof, wherein R is hydrogen or C₁₋₆alkyl; R¹ and R² are each independently members of the group consisting of hydrogen, halogen, hydroxy, C₁₋₆alkyloxy and C₁₋₆alkyl ; X stands for O or S; Alk is C₁₋₄alkanediyl; and Q is a remainder of the formula wherein Y¹ and Y² each independently represent O or S; R³ represents a member selected from the group consisting of hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C₁₋₆alkylcarbonyl)oxy, amino, mono- and di(C₁₋₆alkyl)amino, (C₁₋₆alkylcarbonyl)amino, phenylmethoxy and azido; R⁴ represents hydrogen or halogen; or a remainder of the formula means in which R⁵ is hydrogen or C₁₋₆alkyl; Z has the meaning -S-, -CH₂-or -CR⁶=CR⁷-; where the radicals R⁶ and R⁷ each independently of one another are hydrogen or C₁₋₆alkyl; and A represents a divalent radical -CH₂-CH₂-, -CH₂-CH₂-CH₂- or -CR⁸=CR⁹- wherein R⁸ and R⁹ each independently represent hydrogen, halogen, amino or C₁₋₆alkyl. 2. Chemical compound according to claim 1, wherein Q is a radical of formula (a) in which R³ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, hydroxy, amino or azido and R⁴ is hydrogen; or Q is a radical of formula (b) in which R⁵ is C₁₋₆alkyl and A is a divalent radical -CH₂-CH₂-, -CH₂-CH₂-CH₂- or -CR⁸=CR⁹⁹- in which R⁸ and R⁹ are each independently hydrogen or C₁₋₆alkyl. 3. A chemical compound according to claim 2, wherein R is hydrogen, R¹ is hydrogen or halogen and R² is hydrogen, halogen, hydroxy or C₁₋₆alkyloxy. 4. Chemical compound according to claim 3, wherein Q is a radical of formula (a) in which R³ is hydrogen, halogen or methyl and Y¹ is O; or Q is a radical of formula (b) in which -Z-A- is -S-CH₂-CH₂-, -S-(CH₂)₃-, -S-CR⁸=CR⁹-, in which R⁸ and R⁹ each independently of one another are hydrogen or methyl, is -CH=CH-CR⁸=CR⁹-, in which R⁸ and R⁹ each independently of one another are hydrogen or methyl, or is -CH⁸-CH⁸-CH⁸-CH⁸-CH⁸-. 5. A chemical compound according to claim 4, wherein R¹ is hydrogen and R² is hydrogen, halogen, hydroxy or methoxy. 6. A chemical compound according to claim 1, wherein the compound is 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 or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. 7. A pharmaceutical composition comprising a suitable pharmaceutical carrier and as an active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 6. 8. A pharmaceutical composition for treating psychotic disorders, comprising a suitable pharmaceutical carrier and as an active ingredient an amount effective for treating psychotic disorders of a compound according to any one of claims 1 to 6. 9. A process for the preparation of a pharmaceutical composition, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 6 is intimately mixed with suitable pharmaceutical carriers. 10. A compound according to any one of claims 1 to 6 for use as a medicine. 11. A compound according to any one of claims 1 to 6 for use as a medicine for the treatment of psychotic disorders. 12. A process for preparing a chemical compound according to one of claims 1 to 6, characterized by: a) Reacting an ester derivative of the formula Q-Alk-W (II), where W is a reactive ester residue, with a piperidine of the formula in a reaction-inert solvent; b) Cyclization of an intermediate of the formula with urea or thiourea, optionally in a reaction-inert solvent, to give a compound of the formula c) Cyclization of an intermediate of the formula wherein R¹⁰ and R10-a each independently represent a leaving group such as C₁₋₆alkyloxy, amino and mono- and di(C₁₋₆alkyl)amino, with an amine of the formula optionally in a reaction-inert solvent, to form a compound of formula (I-a); d) Cyclizing an isocyanate or isothiocyanate of the formula with an amine of formula (V), optionally in a reaction-inert solvent, to form a compound of formula (I-a); e) Reacting an amine of the formula with an α-carbonylcarboxylic acid derivative of the formula wherein L represents a leaving group such as C₁₋₆alkyloxy, hydroxy, halogen, amino, mono- and di(C₁₋₆alkyl)amino, to form a compound of the formula f) Cyclizing a reagent of the formula with a β-aminocarboxylic acid derivative of the formula wherein L and L¹ each independently represent a leaving group such as C₁₋₆alkyloxy, hydroxy, halogen, amino, mono- and di(C₁₋₆alkyl)amino to form a compound of formula (I-b); g) Cyclizing a nitrile of the formula with a β-aminocarboxylic acid derivative of the formula (IX) wherein L represents a leaving group such as C₁₋₆alkyloxy, hydroxy, halogen, amino, mono- and di(C₁₋₆alkyl)amino, to form a compound of the formula (I-b); h) Cyclizing a 2-mercaptopyrimidinone of the formula with a reagent of the formula to form a compound of formula (Ib) in which Z is S, which compounds are represented by the formula be represented; or i) cyclizing a 2-mercaptopyrimidinone of formula (XI) with a reagent of formula to form a compound of formula (Ib) in which Z is S and A is which compounds are represented by the formula being represented; j) converting the compounds of formula (I-a) as defined above under b) in which R³ is nitro, into the corresponding amino compounds by known nitro to amino reduction processes; k) converting the compounds of formula (I-a) as defined above under b) in which R³ is phenylmethoxy, into compounds of formula (I-a) in which R³ is hydroxy by known catalytic hydrogenolysis processes; l) converting the compounds of formula (I-a) as defined above under b) in which R³ is amino or hydroxy by reacting the starting compounds with an acylating agent into compounds of formula (I-a) in which R³ is (C₁₋₆alkylcarbonyl)oxy; m) converting compounds of formula (I-a) as defined above under b) in which R³ represents an amino group into compounds of formula (I-a) in which R³ represents an azido group by converting the amino group into a diazonium group and then converting this diazonium group into an azide group; or if desired, converting the compounds of formula (I) into one another according to known group transformation methods and if desired converting the compounds of formula (I) into a therapeutically effective non-toxic acid addition salt form by treatment with an appropriate acid or, conversely, converting the acid addition salt with alkali into the free base form; and/or preparing stereochemically isomeric forms thereof.