SK280125B6 - 1,2-benzazoles and pharmaceutical preparations based thereon - Google Patents

Abstract

Disclosed are 1,2-benzazoles of general formula (I), wherein: R is hydrogen or C1-6 alkyl; R1 and R2 each independently are hydrogen, halo, hydroxy, C1-6 alkyloxy or C1-6 alkyl; X is O, S; Alk is C1-4 alkanediyl; and Q is a residue of the formula (a) or (b), where the general symbols are as defined in the Claim 1 and their pharmaceutically acceptable acid additional salts and pharmaceutical preparations on their basis. Compounds of the formula (I) exhibit useful antipsychotic properties and are useful in the treatment of a variety of disorders in which serotonin release is of predominant importance.

Description

Technical field

The present invention relates to 1,2-benzazoles and pharmaceutical compositions thereof. The compounds of the invention have useful antipsychotic properties and therefore can be used in the treatment of various disorders in which serotonin release is of paramount importance.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,352,811 and 4,458,076 disclose 3-piperidyl-1,2-benzisoxazoles and 3-piperidyl-1,2-benzisothiazoles having antipsychotic and analgesic properties. The compounds of this invention differ from these known compounds by the nature of the substituent at the 1-position of the piperidine ring.

SUMMARY OF THE INVENTION

The present invention provides 1,2-benzazoles of formula (I)

and pharmaceutically acceptable acid addition salts thereof, wherein R is hydrogen or (C 1 -C 6) alkyl;

R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6) alkoxy and (C 1 -C 6) alkyl;

X represents oxygen or sulfur;

Alk is C 1 -C 4 alkanediyl; and Q is a radical of formula (a)

where

Y ¹ and Y ² are each independently oxygen or sulfur;

R ³ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, nitro, cyano, hydroxy, C 1 -C 10 alkylcarbonyloxy, amino, mono- and di (alkyl) (C1-C6) amino in each of the alkyl radicals, (C1-C10) alkylcarbonylamino, phenylmethoxy and azido;

R ⁴ represents hydrogen or halogen; or a radical of formula (b)

where

R ⁵ is hydrogen or C 1 -C 6 alkyl;

Z is -S-, -CH ₂ - or

-CR ⁶ = CR ⁷ -, wherein R ^e and R ⁷ are each independently hydrogen or C 1 -C 6 alkyl; and

A is a divalent radical of the formula -CH ₂ -CH ₂ -, -CH ₂ -C ₂ -CH ₂ - or -CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen, halogen, amino or alkyl having 1; up to 6 carbon atoms.

In these definitions, the generic term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "C 1 -C 6 alkyl" refers to a straight or branched chain saturated hydrocarbon radical of 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl , hexyl and the like. The term "C 1 -C 4 alkanediyl" refers to a straight or branched chain C 1 -C 4 alkanediyl group such as methylene, ethylene, propylene, butylene and the like. The term "C 1 -C 10 alkyl" refers to a C 1 -C 6 alkyl group as defined above and its higher C 7 -C 10 homologues, such as heptyl, nonyl and the like.

Preferred compounds of the invention are those wherein Q is a radical of formula (a) wherein R ³ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, hydroxy, amino, or azido, and R ⁴ represents hydrogen; or wherein Q is a radical of formula (b), wherein R ⁵ is C 1 -C 6 alkyl and A is a bivalent radical of formula -CH ₂ -CH ₂ , -CH ₃ -CH ₂ -CH ₂ - or -CR ^S = CR ⁹ - wherein R ⁸ and R ⁹ are independently H, C 1 -C 6 alkyl.

Of these preferred compounds, particularly preferred those compounds wherein R is H, R ¹ is hydrogen or halo and R ² is hydrogen, halogen, hydroxy or C 1 -C 6 alkyl.

Of the compounds described in the preceding paragraph, particular preference is given to those wherein Q is a radical of formula (a), wherein R ³ is hydrogen, halogen or methyl and Y ¹ is oxygen; or wherein Q is a radical of formula (b), wherein -Z-A- is a radical of formula -S-CH 2 -CH 2 -; -S- (CH 2) 5; -S-CR ⁸ = CR ⁹ -; wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; -CH-CH-CR ³ -CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; or -CH ₂ -CH ₂ -CH ₂ -CH ₂ -.

Of the compounds referred to in the previous paragraph, particular preference is given to those compounds, wherein R ¹ is H and R ² is hydrogen, halogen, hydroxy or methoxy.

The most preferred compounds of the invention are those selected from the group consisting of 3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) 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-piperidyl) ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and their pharmaceutically acceptable acid addition salts.

Compounds of formula (I) may generally be prepared by reacting a suitable reactive ester of formula (II) with an appropriately substituted piperidine of formula (III). In the reactive ester of formula (II), W is a reactive ester residue, for example halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group, for example methylsulfonyloxy, (4-methylphenyl) sulfonyloxy and the like.

(II)

The reaction of a compound of formula (II) with a compound of formula (III) is conveniently carried out in an inert organic solvent, for example an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene and the like; in a lower alkanol such as methanol, ethanol, 1-butanol and the like; in a ketone such as 2-propanone, 4-methyl-2-pentanone and the like; in ether, for example

1,4 dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; Ν, Ν-dimethylformamide (DMF); N, N-dimethylacetamide (DMA); nitrobenzene; 1-methyl-2-pyrrolidone and the like. A suitable base, for example an alkali metal or alkaline earth metal carbonate, bicarbonate, hydroxide, alkoxide or hydride, for example sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, hydride, may be added to capture the acid that is released during the reaction. sodium or the like, or an organic base such as a tertiary amine such as N, N-diethylctanamine, N- (1-methylethyl) -2-propanamine, 4-ethylmorpholine and the like. In some cases, an iodide salt, for example an alkali metal iodide, is also added. The reaction rate can be encouraged by slightly elevated temperatures.

The compounds of formula (I) may also be prepared by methods known per se for the preparation of compounds having a Q moiety in their structure.

For example, compounds of formula (I) wherein Q is a radical of formula (a), which compounds are characterized by formula (Ia), can be prepared by cyclizing the corresponding 2-aminobenzamide or 2-aminobenzenethioamide of formula (IV-a) with urea or thiourea.

urea or thiourea

Compounds of formula (I-a) may also be prepared by cyclization of a suitable 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)

IV-c (v)

---) (I-a).

These cyclization reactions are conveniently carried out by mixing and optionally heating the reactants together, optionally in the presence of a suitable solvent inert to the reaction and having a relatively high boiling point, such as aliphatic or aromatic hydrocarbons such as petroleum ether, dimethylbenzene and the like. .

In the above reaction schemes, R ¹⁰ and R ^{10 and} independently of each other are suitable leaving groups such as C 1 -C 6 alkoxy, amino and C 1 -C 6 mono- and di (alkyl) amino in each of the alkyl groups residues.

Compounds of formula (I) wherein Q is a radical of formula (b), which are characterized by formula (Ib), may be prepared by conventional cyclization procedures suitable for the preparation of pyrimidin-4-ones, for example by reaction of an amine of formula (Ib). VI) with a cyclizing agent of formula (VII) or cyclization of a compound of formula (VIII) with an amine of formula (IX)

ft__ (VIII)

II θ (IX)

These cyclization reactions are usually carried out by stirring the reactants together, optionally in the presence of a suitable solvent inert to the reaction, such as an aliphatic, alicyclic or aromatic hydrocarbon such as hexane, cyclohexane, benzene and the like; pyridine; Ν, Ν-dimethylformamide and similar amides. The reaction rate can be encouraged by elevated temperatures. In some cases, it is particularly preferred to carry out the reaction at the reflux temperature of the reaction mixture.

In the above reaction schemes, each of L and L ^{1 is} independently a suitable leaving group, such as, for example, C 1 -C 6 alkoxy, hydroxy, halogen, amino, C 1 -C 6 mono- and di (alkyl) amino. alkyl radicals and the like.

By the same cyclization procedure, compounds of formula (I-b) can also be obtained by cyclizing an intermediate of formula (IX) with a reagent of formula (X).

N in c A + (ix) cyclization (I-b).

SK 280125 Β6

Compounds of formula (I-b) wherein Z is sulfur, which compounds are characterized by formula (I-b-1), can also be prepared by cyclizing 2-mercaptopyrimidinone of formula (XI) with a reagent of formula (XII)

In the general formula (XII), W 'has the same meaning as the above-mentioned W symbol.

Compounds of formula (I-b-1) wherein A is a radical of formula

While these compounds may be characterized by the general formula (I-b-1-a), they may also be prepared by cyclizing the 2-mercaptopyrimidinone of the formula XI with a reagent of the formula XIII

o (xiii) (i-b-l-a)

The cyclization reactions leading to compounds of formula (Ib-1) or (Ibla) can generally be carried out by stirring the mixture of reactants, optionally in the presence of a suitable solvent inert to the reaction, such as aliphatic, alicyclic or aromatic hydrocarbons such as hexane, cyclohexane, benzene and the like; pyridine; Ν, Ν-dimethylformamide and similar amides. The reaction rate can be encouraged by slightly elevated temperatures. In some cases, the reaction is preferably carried out at the reflux temperature of the reaction mixture.

The compounds of formula (1) may also be interconverted by methods known per se for functional group transformation.

For example, compounds of formula (Ia) wherein R ³ is amino may be prepared from the corresponding nitrosubstituted quinazolines by known procedures for reducing nitro compounds to amino compounds. A suitable reduction process for nitro compounds to amino compounds is, for example, catalytic hydrogenation in a relatively polar solvent such as an alcohol such as methanol or ethanol in the presence of a suitable catalyst such as platinum on activated carbon. In some cases, it may be useful to add a suitable catalytic poison, such as thiophene, to the reaction mixture.

Compounds of formula (Ia) wherein R ³ is phenylmethoxy can be converted to compounds of formula (Ia) where R ³ is hydroxy by conventional catalytic hydrogenolysis procedures. Compounds of formula (Ia) wherein R ³ is amino or hydroxy can be converted to compounds of formula (Ia) wherein R ³ is C 1 -C 10 alkylcarbonylamino or C 1 -C 10 alkylcarbonyloxy in an alkyl moiety, by reacting the respective compounds with a suitable acylating agent, for example, an acyl halide or acid anhydride. Compounds of formula (Ia) wherein R ³ is an amino group can be converted to compounds of formula (Ia) where R ³ is an azido group by converting the amino group in these compounds to a diazonium group by treatment with nitrous acid or an alkali metal or alkaline zinc metal salt thereof. then the resulting diazonium group is converted to an azide group by treatment with sodium azide or any other suitable alkali metal or alkaline earth metal azide.

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

Many of the intermediates and starting compounds used in the above-mentioned preparative procedures are known compounds which can be prepared by methods known per se for the preparation of these or similar compounds. For example, the intermediates of formula (II) and methods for their preparation are described in U.S. Pat. 4,335,127, 4,342,870, 4,443,451 and 4,485,107. Other intermediates may be prepared by methods known per se for the preparation of similar compounds. Some of these preparative procedures are listed below.

Intermediates of formula (III) may generally be prepared from a benzoylpiperidine of formula (XIV)

wherein "halogen" is preferably fluorine, by methods known per se, for example by reacting a benzoylpiperidine of formula (XIV) with hydroxylamine and cyclizing the thus formed oxime of formula (XV) by methods known to produce an intermediate of formula (III) wherein X is oxygen, while

this intermediate is characterized by the general formula (IH-a)

Intermediates of formula (III) wherein X is sulfur, which intermediates may be characterized by formula (III-b)

can be prepared by a procedure analogous to that described in U.S. Pat. 4,458,076.

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

Because of this pharmacological activity, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the treatment of psychotic disorders and in the treatment of various conditions where serotonin release is of paramount importance, for example in blocking serotonin-induced contractions in bronchial tissues and vessels. , both arteries and veins. The compounds of the invention also have useful properties such as sedatives, anxiolytics, anti-aggressive agents, anti-stress agents, muscular protectants and cardiovascular protectants, and are therefore suitable for the protection of warm-blooded animals, for example in stressful situations, e.g. In addition, the compounds of the invention are useful as preservatives against endotoxin shock and as anti-diarrheal agents.

In the treatment with the compounds according to the invention, pharmaceutical preparations based on them are preferably used.

In preparing these pharmaceutical compositions, an effective amount of a particular compound used in the form of a base or an acid addition salt that forms the active ingredient of the composition is mixed to a homogeneous mixture with a pharmaceutically acceptable carrier. The carrier used may take a number of different forms depending on the type of formulation desired for administration. The pharmaceutical preparations preferably take the form of unit dosage forms suitable, preferably, for oral, rectal, percutaneous or parenteral administration. For example, any conventional pharmaceutical carriers, such as water, glycols, oils, alcohols and the like, may be used in the preparation of preparations suitable for oral administration, provided that these preparations are in the form of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, acolines, lubricants, binders, disintegrants, and the like, when such oral preparations are to take the form of powders, pills, capsules or tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form. Solid pharmaceutical carriers are naturally used in the manufacture of tablets and capsules. In parenteral formulations, the carrier typically comprises sterile water as the sole or predominant component, although other ingredients, for example, to increase the solubility of the active ingredients, may be used. In the preparation of injectable solutions, for example, saline solution, glucose solution or mixtures thereof may be used as the carrier. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the case of formulations suitable for percutaneous administration, the carrier generally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally in admixture with small amounts of any other suitable ingredients which do not have a significant deleterious effect on the skin. These additives may facilitate the administration to the skin and / or may facilitate the preparation of these preparations. Compositions of this type may be administered in a variety of ways, for example as transdermal patches, topical deposits or as an ointment.

Said pharmaceutical preparations are preferably formulated in a unit dosage form which facilitates administration and uniformity of dosage. The unit dosage form as used herein and in the claims means physically discrete units that are suitable as dosage units and which contain a predetermined amount of active ingredient calculated to produce the desired therapeutic effect. In addition, these units contain the desired pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored and coated tablets), capsules, pills, powders, cachets, injectable solutions or suspensions, teaspoons, tablespoons, and the like. And their separate multiples.

In the treatment of psychotic diseases in warm-blooded animals, patients are systematically administered a pharmacologically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Those of skill in the treatment of psychotic diseases can readily determine this effective amount based on the results of the above assays. An effective amount is usually from 0.01 to 4, preferably from 0.04 to 2 mg / kg body weight.

The invention is explained in more detail in the following examples. These examples are illustrative only and do not limit the scope of the invention in any way. Unless otherwise stated, all parts are by weight. The temperature is given in degrees Celsius.

DETAILED DESCRIPTION OF THE INVENTION

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 a solution of 95 parts of 1-acetyl-4-piperidinylcarbonyl chloride in 65 parts of dichloromethane with cooling. After completion of the dropwise addition, the mixture was further stirred at room temperature for 3 hours. 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. 48 parts (36%) of 1-acetyl-4- (2,4-difluorobenzoyl) piperidine are obtained as a residue (intermediate 1).

A mixture of 48 parts of 1-acetyl-4- (2,4-difluorobenzoyl) piperidine and 180 parts of 6N hydrochloric acid is 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-piperidyl) methanone hydrochloride (interm. 2).

A mixture of 12 parts of (2,4-difluorophenyl) (4-piperidyl) methanone hydrochloride, 12 parts of hydroxylamine hydrochloride and 120 parts of ethanol is stirred at room temperature and 10.5 parts of N, N-diethylethanamine are added. The resulting mixture was stirred and refluxed for 3 hours. The mixture was then cooled and the precipitated product was filtered off and dried. 11 parts (100%) of oxime (2,4-difluorophenyl) (4-piperidyl) methanone (interm. 3) are obtained.

A mixture of 11 parts of (2,4-difluorophenyl) (4-piperidyl) methanone oxime, 25 parts of potassium hydroxide and 25 parts of water is stirred and refluxed 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-piperidyl) -1,2-benzisoxazole (interm. 4).

Example 2

A mixture of 50 parts of 2-thiazolamine, 76 parts of 3-acetyl-4,5-dihydro-2- (3-halo) -furanone, 1.2 parts of concentrated hydrochloric acid and 270 parts of methylbenzene is 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 resulting mixture was slowly warmed to 100-110 ° C with stirring and stirring was continued at this temperature for 2 hours. 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 silica gel column chromatography using a 95: 5 by volume mixture of trichloromethane and methanol as eluent. The eluent was evaporated from the combined pure fractions. The residue was crystallized from a mixture of 2-propanol and 1,1'-oxybisethane. 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one (interm. 5) are obtained.

Example 3

A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of Ν, Ν-dimethyl acetamide and 75 parts of water is stirred at room temperature and 36 parts are added in one portion. 1,3-dibromopropane. As a result of the exothermic reaction, the temperature is raised to 50 ° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried at 100 ° C under vacuum. 21 parts (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one are obtained with a temperature of mp 155 ° C (interm. 6).

The same procedure was carried out using equivalent amounts of the respective starting materials. There was thus obtained 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one, m.p. 148.7 [deg.] C. (interm. 7).

Example 4

A mixture of 20 parts 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H-pyrimido [2,1b] [1,3] thiazin-6-one, 50 parts acetic acid and 180 parts 67 of a solution of hydrobromic acid in acetic acid is heated to reflux with stirring. Stirring was continued at reflux overnight. 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-bromoelyl) -3,4-dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-6-one monohydrobromide, m.p. 215 DEG C. (interm. 8).

Using the same procedure, 6- (2-bromoethyl) -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one monohydrochloride, m.p. 237, was prepared from equivalent amounts of the appropriate starting materials. , 2 ° C (interm. 9).

B. Preparation of the final compounds

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-piperidyl) -1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of Ν, di-diemethylformamide are stirred at 85-90 overnight. C. After cooling, the reaction mixture was poured into water. The product is filtered off and crystallized from a mixture of Ν, Ν-diemethylformamide 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-piperidyl) ethyl) -6, 7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 170.0 ° C (compound 1).

Using the same procedure, the following shall also be prepared from equivalent amounts of the relevant starting materials:

6- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl) ethyl] -7-methyl-5H-thiazolo [3,2-a] pyrimidine- 5-one, mp 165.1 ° C (compound 2);

3- (2- (4- (1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p.

177.9 ° C (compound 3);

3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -2,7-dimethyl-4H-pyrido [1,2-a] pyrimidin-4 -one mp 186.9 ° C (compound 4);

3- (2- (4- (1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] 183.1 ° C (compound 5); 3- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperidyl) ethyl) -2,4 monohydrochloride (1H, 3H) quinazolinedione with a melting point greater than 300 ° C (dec.) (compound 6);

3- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperidyl) ethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] ] pyrimidin-4-one, mp 146.7 ° C (compound 7) and 3- [2- (4- (6-hydroxy-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] - 6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 213.1 ° C (compound 8).

In a similar manner were prepared: 3- [2- (4- (5-methoxy-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (compound 9) a

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

Example 6

A mixture of 3.3 parts of 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, 3.3 parts of 6-fluoro-3- (4-piperidyl) -1 2-benzisoxazole, 8 parts of potassium carbonate, 1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone are stirred and refluxed for 3 hours. The reaction mixture was cooled, water was added and the layers were separated. The organic phase is dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a 95: 5 by volume mixture of trichloromethane and methanol as eluent. The eluent was evaporated from the combined pure fractions. The residue was crystallized from 4-methyl-2-pentanone. 1.2 parts (19%) of 3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -26 were obtained.

-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p.

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-piperidyl) -1,2-benzisoxazole, 10 parts of bicarbonate sodium, 0.1 part potassium iodide and 90 parts Ν, Ν-dimethylformamide were stirred and heated at 100-110 ° C overnight. After cooling, the reaction mixture was poured into water. The mixture is stirred and the product is filtered off and crystallized from Ν, Ν-dimethylformamide. 4.8 parts (39%) of 3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -2,4- (1H, 3H) are obtained. of quinazolinedione, mp 253.4 ° C (compound 12).

Example 8

A mixture of 7.4 parts of 6- (2-bromomethyl) -3,7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-fluoro-monohydrobromide, 4.4 parts of 6-fluoro-3- (4-piperidyl) -1,2-benzisoxazole, 10 parts sodium carbonate and 90 parts Ν, Ν-dimethylformamide were stirred at 80-85 ° C overnight. After cooling, the reaction mixture was poured into water. The product was filtered off and purified by silica gel column chromatography using a 95: 5 by volume mixture of trichloromethane and methanol as eluent. The eluent was removed from the combined pure fractions. To the residue was added 2-propanol. The product was filtered off and dried, yielding 5.3 parts (62%) of 6- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -3, 7-dimethyl-5H-thiazolo [3,2-a] pyrimidin-5-one, mp 231.0 ° C (compound 13).

Similarly, the following shall be prepared:

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

7- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -3,4-dihydro-8-methyl- (2H, 6H) -pyrimido [2 12-b] [1,3] thiazin-6-one, mp 169.3 ° C (compound 15);

6- [2- (4- (1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -2,3-dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidine- 5-one, mp 154.5 ° C (compound 16);

3- [2- (4- (6-fluoro-1,2-benzisothiazol-3-yl) -1-piperidyl) ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1] , 2-a] pyrimidin-4-one (compound 17) and 3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) ethyl] -2,3- dihydro-2-thioxo-4 (1H) -quinazolinone (compound 18).

C. Pharmacological Examples

The efficacy of the compounds of the invention as psychotic agents is evidenced by the experimental data found in at least one of the two test procedures below. These procedures are the combined apomorphine-tryptamine-noradrenaline test in rats and the apomorphine test in dogs. The tests are carried out according to the experimental procedure described below and the measured data are summarized in the table.

Example 9

Combined apomorphine (APO) -, tryptamine (TRY) - and norepinephrine (NOR) test in rats

Adult Wistar rats weighing 240 + 10 g are used as test animals in this test. The animals are fasted overnight and then administered subcutaneously at a dose of 1 ml per 100 g with an aqueous solution of the test compound (time of administration is considered to be time 0). Immediately thereafter, the animals are placed in isolated observation cages. After 30 minutes (time = 30 minutes), rats are administered intravenously apomorphine hydrochloride (APO) at a dose of 1.25 mg / kg body weight, and animals are observed for 1 hour for the presence or absence of apomorphine-induced symptoms of psychomotor restlessness and stereotyped chewing. . At the end of this one-hour period (time = 90 minutes), the same animals are intravenously administered TRY at 40 mg / kg body weight and monitored for a typical tryptamine-induced bilateral tonic seizure. Two hours after administration of the test compound (time = 120 minutes), animals are challenged with 1.25 mg / kg noradrenaline (intravenous) and mortality is observed after 60 minutes.

The table gives the ED ₅₀ values of various test compounds. The _ED50 value is defined as the dose of test compound by which 50% of the animals preserved from symptoms induced by apomorphine, tryptamine and norepinephrine.

Apomorphine test in dogs

The test method is described in P. A. J. Janssen and C. J. E. Niemegeers in Arzneim-Forsch (Drug Res.), 9, 765-767 (1959). The compounds listed in the table are administered subcutaneously to beagle dogs at various doses and after one hour the animals are given a standard amount of 0.31 mg / kg body weight (subcutaneously) of apomorphine as a challenge.

The table gives the ED ₅₀ values of various test compounds. ED ₅₀ values are defined as the dose of test compound to protect 50% of the animals from emesis.

The compounds listed in the table do not limit the scope of the claimed protection and serve merely to illustrate the pharmacological activity that characterizes all compounds within the scope of formula (I).

bump and no. IĎ.-ÍWOypotkanrojJnxHíotkan EE _M (MOR} -p = txari male (mg / kg) - (mg / kg) s.c. (mg / kg) i.c. (mg / kg) duration i.č. 1 0,9β 0.00 0.16 lh 0,001 jb 0,005 <h 0,015 bh o ou spirit 0.02 2 C, 02 0,005 0.31 LH 0,004 4h 0, an ODS 14h 0.16 11 0.02 0.01 0, U U 0,015 the 0.03 13 0.02 0.02 0.0 ' lh 0,015 4Λ 0.00 H 0.02 0,005 0.31 LH 0,004 4h 0,004 15 0.04 0.01 0.31 LH $ o.ot 4h 0.06

D. Examples of preparations

The following formulations are presented as typical examples of pharmaceutical formulations in unit dosage form suitable for systematic administration to animals and humans.

In these examples, the active ingredient is a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

SK 280125 Β6

Example 10

Oral drops

500 g of the active ingredient are dissolved in 0.5 liters of 2-hydroxypropanoic acid and 1.5 liters of poly (ethylene glycol) at 60-80 ° C. After cooling to 30-40 ° C, 35 L of polyethylene glycol is added and mixed well. Then a solution of 1750 g of saccharin sodium in 2.5 l of purified water is added, and while stirring, 2.5 l of cocoa flavor and polyethylene glycol q.s. up to a total volume of 50 liters. A solution for oral drops containing 10 mg / ml of active ingredient is obtained. The resulting solution is filled into suitable containers.

Example 11

An oral solution of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate is dissolved in 4 l of boiling purified water. 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of the active ingredient are dissolved in 3 l of this solution. The resulting solution was mixed with the remainder of the first solution and 12 L of 1,2,3-propanetriol and 3 L of 70% sorbitol solution were added. 40 g of saccharin sodium are dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The resulting solution is mixed with the first solution and water is added q. with. up to 20 liters. An oral solution was obtained containing 20 mg of active ingredient in a teaspoon (5 mL). The resulting solution is filled into suitable containers.

Example 12

The capsules g of the active ingredient, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silica and 1.2 g of magnesium stearate are mixed intensively. The resulting mixture is filled with 1000 suitable hard gelatin capsules, each containing 20 mg of the active ingredient.

Example 13

Coated tablets - preparation of tablet cores

A mixture of 100 g of active ingredient, 570 g of lactose and 200 g of starch is mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone (Kollidon-k 90 ^(R) ) in approximately 200 ml of water. The moistened powder mixture is sieved, dried and sieved again. 100 g of microcrystalline cellulose Avicel ( ^R) and 15 g of hydrogenated vegetable oil (Stcrotex ^IR ) are then added. The resulting mixture is mixed well and compressed into tablets. 10,000 tablets are obtained, each containing 10 mg of the active ingredient.

Coated tablets - Coating

To a solution of 10 mg methylcellulose (Methocel 60 HG ^(R)) in 75 ml of denatured ethanol is added a solution of 5 g of ethylcellulose (Ethocel 22 cps ^<R) ) in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol is melted and the melt is dissolved in 75 ml of dichloromethane. The second solution was added to the first and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated dye suspension (Opasspray Kl-2109 ^(R) ) were added to the mixture and the resulting mixture was homogenized. The tablet cores are coated with the resulting mixture in a coating machine.

Example 14

Solution for injection

1.8 g of methyl 4-hydrobenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in approximately 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 the active ingredient are added with stirring. The solution was cooled to room temperature and water for injection was added to a volume of 1 liter. A solution is obtained containing 4 mg of active ingredient per ml. The solution is sterilized by filtration (USP XVII page 811) and filled into sterile containers.

Example 15

The suppositories g of the active ingredient are dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid in 25 ml of polyethylene glycol 400. Separately, 12 g of a surfactant (SPAN ( ^R) ) and triglyceride (Witepsol 555 ^R ) qs are admixed with 300 g. The resulting melt is mixed well and added to the solution described. The resulting mixture was poured into molds at 37-38 ° C. This gives 100 suppositories each containing 30 mg of the active ingredient.

Claims (14)

PATENT CLAIMS 1,2-Benzazoles of the general formula (I) wherein R is hydrogen or (C 1 -C 6) alkyl; R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6) alkoxy and (C 1 -C 6) alkyl; X represents oxygen or sulfur; Alk is C 1 -C 4 alkanediyl; and Q represents a radical of formula (a) wherein Y ¹ and Y ² are each independently oxygen or sulfur; R ³ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, nitro, cyano, hydroxy, C 1 -C 10 alkylcarbonyloxy, amino, mono- and di (alkyl) (C1-C6) amino in each of the alkyl radicals, (C1-C10) alkylcarbonylamino, phenylmethoxy and azido; R ⁴ represents hydrogen or halogen; or a radical of formula (b) About where R ⁵ is hydrogen or C 1 -C 6 alkyl; Z is -S-, -CH ₂ - or -CR ⁶ = CR ⁷ -, wherein R ⁶ and R ⁷ are each independently hydrogen or C 1 -C 6 alkyl; and A is a bivalent radical of the formula -CH ₂ -CH ₂ -, -CH ₂ -C ₂ -CH ₂ - or -CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen, halogen, amino or alkyl; 1 to 6 carbon atoms; and pharmaceutically acceptable acid addition salts thereof. The 1,2-benzazoles of formula (I) according to claim 1, wherein R is hydrogen; R ¹ represents hydrogen or halogen; R ² is hydrogen; X represents oxygen or sulfur; Alk is C 1 -C 4 alkanediyl and Q is a radical of formula (a) as set forth in claim 1, wherein Y ¹ and Y ² are each independently oxygen or sulfur; R ³ represents hydrogen; and R ⁴ is hydrogen; or Q is a radical of formula (b) as set forth in claim 1, wherein R ⁵ is hydrogen or C 1 -C 6 alkyl; Z is -S-, -CH 2 - or -CR ⁶ = CR ⁷ -, wherein R ⁶ and R ⁷ are each independently hydrogen or C 1 -C 6 alkyl; and A is a bivalent radical of formula -CH 2 -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen, halogen, amino or alkyl; and pharmaceutically acceptable acid addition salts thereof. The 1,2-benzazoles of claim 1 of formula (I) wherein Q is a radical of formula (a) wherein R ³ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, trifluoromethyl, hydroxy, amino or azido and R ⁴ is hydrogen; or wherein Q is a radical of formula (b), wherein R ⁵ is C 1 -C 6 alkyl and A is a divalent radical of formula -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen or C 1 -C 6 alkyl. A compound according to claim 3, wherein R is hydrogen, R ¹ is hydrogen or halogen and R ² is hydrogen, halogen, hydroxy or (C 1 -C 6) alkoxy. The 1,2-benzazoles of claim 4 of formula (I) wherein Q is a radical of formula (a) wherein R ⁵ is hydrogen, halogen or methyl and Y 1 is oxygen; or wherein Q is a radical of formula (b), wherein -ZA- is a radical of formula -S-CH ₂ -CH ₂ -; -S- (CH ₂ ) ₃ -; -S-CR ⁸ = CR ⁹ -; wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; -CH = CH-CR ⁸ = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; or -CH 2 -CH 2 -CH 2 -CH 2 -. A compound according to claim 5, wherein R ¹ is hydrogen and R ² is hydrogen, halogen, hydroxy or methoxy. The 1,2-benzazoles of claim 1 selected from the group consisting of 3- [2- (4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl) 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)) - l-piperidyl) ethyl] -2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one. Pharmaceutical composition for the treatment of psychotic diseases, characterized in that, in addition to the inert carrier, the active ingredient comprises a pharmaceutically effective amount of 1,2-benzazole according to claim 1 of the general formula (I) R is hydrogen or (C 1 -C 6) alkyl; R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, hydroxy, (C 1 -C 6) alkoxy and (C 1 -C 6) alkyl; X represents oxygen or sulfur; Alk is C 1 -C 4 alkanediyl; and Q is a radical of formula (a) Y ¹ and Y ² are each independently oxygen or sulfur; R ³ is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, nitro, cyano, hydroxy, C 1 -C 10 alkylcarbonyloxy, amino, mono- and di (alkyl) (C1-C6) amino in each of the alkyl radicals, (C1-C10) alkylcarbonylamino, phenylmethoxy and azido; R ⁴ represents hydrogen or halogen; or a radical of formula (b) About where R ⁵ is hydrogen or C 1 -C 6 alkyl; Z is -S-, -CH ₂ - or -CR ⁶ = CR ⁷ -, wherein R ⁹ and R ⁷ are each independently hydrogen or C 1 -C 6 alkyl; and A is a divalent radical of the formula -CH ₂ -CH ₂ -, -CH ₂ -C ₂ -CH ₂ - or -CR ^S = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen, halogen, amino or alkyl having 1; up to 6 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 8, characterized in that, in addition to the inert carrier, it comprises, as active ingredient, a pharmaceutically effective amount of 1,2-benzazole according to claim 2, wherein R represents hydrogen; R ¹ represents hydrogen or halogen; R ² is hydrogen; X represents oxygen or sulfur; Alk is C 1 -C 4 alkanediyl and Q is a radical of formula (a) as set forth in claim 1, wherein Y ¹ and Y ² are each independently oxygen or sulfur; R ³ represents hydrogen; and R ⁴ is hydrogen; or Q is a radical of formula (b) as set forth in claim 1, wherein R ⁵ is hydrogen or C 1 -C 6 alkyl; Z represents a group of formula -S-, -CH ₂ - or -CR ⁶ = CR ⁷ -, wherein R ^a and R ⁷ are independently H, C 1 -C 6 alkyl; and A is a divalent radical of formula -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CR ^S = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen, halogen, amino or alkyl; or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 8, characterized in that it contains, as active ingredient, 1,2-benzazole according to claim 1, wherein Q is a radical of formula (a), wherein R ³ is hydrogen halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, trifluoromethyl, hydroxy, amino or azido and R ⁴ is hydrogen; or wherein Q is a radical of formula (b), wherein R ⁵ is C 1 -C 6 alkyl and A is a divalent radical of formula -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CR ^S = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen or C 1 -C 6 alkyl. Pharmaceutical composition according to claim 10, characterized in that it contains, as active ingredient, the 1,2-benzazole according to claim 1, wherein R represents hydrogen, R ¹ represents hydrogen or halogen and R ² represents hydrogen, halogen, hydroxy or (C 1 -C 6) alkoxy. Pharmaceutical composition according to claim 11, characterized in that it comprises, as active ingredient, 1,2-benzazole according to claim 1 of the general formula (I), wherein Q represents a radical of the general formula (a), wherein R ³ represents hydrogen, halogen or methyl and Y ¹ is oxygen; or wherein Q is a radical of formula (b), wherein -ZA- is a radical of formula -S- (CH 2) 3 -; -S-CR ^a = CR ⁹ -; wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; -CH = CH-CR ^S = CR ⁹ -, wherein R ⁸ and R ⁹ are each independently hydrogen or methyl; or -CH ₂ -CH ₂ -CH ₂ -CH ₂ - · Pharmaceutical composition according to claim 12, characterized in that it contains, as active ingredient, 1,2-benzazole according to claim 1 of the general formula (I), wherein R ¹ represents hydrogen and R ² represents hydrogen, halogen, hydroxy or methoxy. 14. A pharmaceutical composition according to claim 8, wherein the active ingredient is 1,2-benzazole selected from the group consisting of 3- [2- (4- (6-fluoro-1,2-benzisoxazole-3)). -yl) -1-piperidyl) ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 3- [2- (4- (6 fluoro-l, 2-benzisoxazol-3-yl) -l-piperidinyl) ethyl] -2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one.