KR870001647B1 - Process for preparing five membered heterocyclie ring containing n-(bicyclic heterocyclyl)-4-piperidinamines - Google Patents

Abstract

N-heterocyclyl-4-piperidineamine is prepd. for use as an antihistamine. Compd. (I-a) [R1=C1-4 alkyl substd. by halo phenyl; R7=hydrogen, C1-4 alkyl; alk=C1-4 alkane diyl! is prepd. by cyclization of compd. (II) in inert solvent. Cyclodesulfurizing compd. (III) [R1, R10=C1-4 alkyl substd. by halophenyl; alk=C1-4 alkane diyl! gives compd. (I-b). The cyclodesulfurizing agent is iodomethane, and this reaction is perfomed in methanol or ethanol.

Description

Method for preparing N- (bicycle heterocycle) -4-piperidinamine having a 5-membered heterocycle ring

The present invention relates to novel N-heterocyclyl-4-piperidineamines, pharmaceutically acceptable acid addition salts and stereochemical isomers thereof represented by the following general formula (I).

In the general formula (I), A ¹ = B ² = C ³ = D ⁴ is a divalent radical having the following general formula (a), (b), (c), (d) or (e), One or two hydrogen atoms in the radical may be substituted independently from halo, lower alkyl, lower alkyloxy, trifluoromethyl or hydroxy; R is selected from the group consisting of hydrogen and lower alkyl, R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, Ar ¹ and lower alkyl substituted with one or two Ar ¹ groups; R ² is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, (lower alkyl) -CO—, (lower alkyloxy) -CO and Ar ² lower alkyl; L is selected from the group consisting of radicals of the following general formulas (f), (g) and (h), where n is an integer of 0 or 1 or 2, and s is 0 or 1 to 6 inclusive integers, Alk is lower alkanediyl, Y is O, S, NR ³ or a direct bond, X is O, S, CH-No ₂ or NR ⁴ and Z is O, S, NR ⁵ or a direct bond, And Het may be optionally condensed as an optionally substituted benzine ring as an optionally substituted 5 membered heterocycle ring having one or more nitrogen atoms, and this Het is linked to C _S H _2S on a carbon atom, and R ³ described above. Is a hydrogen, lower alkyl, (Ar ² ) lower alkyl, 2-lower alkyl-oxy-1,2-dioxoethyl or a group of formula-C (= X) -R ⁶ , wherein R ⁶ is hydrogen, lower alkyl, Ar ² , Ar ² -lower alkyl, lower alkyloxy, Ar ² -lower alkyloxy, mono- or di (lower alkyl) amino, Ar ² -amino, Ar ² -lower alkylamino or Ar ² loweralkyl (lower alkyl) Amino and R ⁴ described above is hydrogen , Lower alkyl, cyano, nitro, Ar ² -sulfonyl, lower alkylsulfonyl, lower alkylcarbonyl or Ar ² -carbonyl; In addition, R ⁵ described above is hydrogen or lower alkyl, provided that (t) Het is 1 when (i) A ¹ = A ² = A ³ = A ⁴ is a divalent lentical of the following general formula (a) or (b): Is not-(lower alkyl) pyrrolyl, and (ii) A ¹ = A ² = A ³ = A ⁴ is a divalent radical of the following general formula (a) or (b), and L is S is O and Y is In the case of radicals of the general formula (g) which is NR ³ , Het is not 1H-benzimidazol-2-yl; And Ar ¹ is halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, mercapto, amino, mono- and di (lower alkyl) amino, carboxyl, lower car Phenyl optionally substituted with up to 3 substituents each independently selected from the group consisting of alkyloxycarbonyl and lower alkyl-CO-; Teethyl; Halothienyl; Furanyl; Lower alkyl substituted furanyl; Pyridinyl; Selected from the group consisting of thiazolyl and imidazolyl optionally substituted with lower alkyl; And Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, mercapto, amino, mono- and di (lower alkyl) amino, carboxyl, lower alkyl. It is selected from the group consisting of phenyl optionally substituted with up to 3 substituents each independently selected from the group consisting of oxy carbonyl and (lower alkyl) -CO.

US Pat. No. 4,219,559 describes several N-heterocyclyl-4-piperidinamines having the following general formula and these compounds are useful as antihistamines.

The compounds of the present invention are fundamentally different from these prior art compounds by the nature of the 1-piperidinyl substituents and are essentially different from the prior art compounds in the fact that the present compounds are not only powerful histamine antagonists but also powerful serotonin antagonists. .

As used in the preceding definitions, the term "halo" refers to fluoro, chloro, bromo and iodine collectively; The term "lower alkyl" refers to straight chains having 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-diethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like Side chain saturated hydrocarbon group; "Alkyl" means lower alkyl as described above and their higher derivatives having 7 to 10 carbon atoms; The term “cycloalkyl” refers to cycloprofil, cyclobutyl, cyclopentyl and cyclohexyl; In addition, "lower alkanediyl" means a divalent straight or branched chain alkanediyl group having 1 to 6 carbon atoms.

The Het ring in the compound of formula (I) may be unsaturated or partially saturated or fully saturated.

Compounds of formula (I) wherein Het is a heterocycle substituted with a hydroxy mercapto or amino group may comprise, in its structure, a keto-inol tautomerge or a vinylloggue thereof and consequently these compounds are The inol form may of course be present in keto form.

Preferred compounds within the scope of the present invention are those wherein Het is thiazolyl, 4,5-dihydrothiazolyl, oxazolyl, imidazolyl, tetrazolyl, 1,3,4-thiadiazolyl, benzimidazolyl, benzothiazolyl Selected from the group consisting of benzoxazolyl and indole, and each of the Het groups, if possible, lower alkyl, Ar ¹ , Ar ¹ -lower alkyl, amino, (aminoiminomethyl) amino, mono- and di (lower alkyl); ) Compounds optionally substituted with up to two substituents selected from the group consisting of amino, Ar ¹ -amino, nitro and pyrimidinyl.

Particularly preferred compounds are those in which L is a radical of formula (g) or (h) as Het mentioned above as a preferred compound.

More particularly preferred compounds are those wherein Het is thiazolyl or imidazolyl and L is radical of formula (g) or (h).

In order to simplify the structural notation of the compound of formula (I) and the specific precursors and intermediates thereof, the following formula is represented by the symbol D.

Compounds of formula (I) are generally prepared by reacting the intermediates of formula (II) with the piperidine of formula (III) according to known alkylation reactions.

In formulas (II) and (III), Het is operating as described above, and Q ¹ and Q ² are combined with Het during the alkylation reaction to formula (f), (g) and (h) Select to form two groups.

For example, the compound of general formula (I) is a piperidine of general formula (III) wherein Q ² is hydrogen, that is, a piperidine of general formula (III-a), It can be prepared by N-alkylation as a reagent of II), that is, a compound of the general formula (II-a).

In the compound of formula (II-a), W represents a suitable leaving group such as halo such as chloro, bromo or iodine or a sulfonyloxy group such as methylsulfonyloxy or 4-methylphenyl sulfonyloxy.

In addition, R is a radical of general formula (f), Y is a radical of general formula (g) not directly bonded to Y 'or Z is a radical of general formula (h) not directly bonded to Z' Compounds represented by the same general formulas (Ia-1), (I-as) and (I-a-3), which are the compounds of I), may be substituted with piperidine of general formula (III-b) It can be prepared by alkylation with a reagent of).

, HY'-Alk-또는

의 기이다.In general formula (III-b), Q <^2a> is respectively a general formula

, HY'-Alk-or

It is the flag of.

In formula (II-b), W 'is the same as described in the previous definition of W, and when S is O, it may also represent lower alkyloxy or lower alkylthiodi.

Compounds of general formula (I-a-2) are also Q in which the Q ² is a piperidine of general formula (III), ie, piperidine represented by general formula (III-c), which is a group of the general formula -Alk-W. ¹ can be prepared by alkylation with a reagent represented by formula (II), ie, a reagent represented by formula (II-c), which is a group of formula -C _s H _2s -Y'H.

The compound of the general formula (I) which is a group of the general formula hHet-C _s H _2s -ZC (= X) -Y'-Alk, that is, the compound represented by the general formula (I-a-4) may also be represented by the general formula (III) piperidine of -c) is a reagent of general formula (II) wherein Q ² is a group of the general formula -C _s H _2s -ZC (= X) Y, H, that is, a reagent represented by general formula (II-d) It can be prepared by N-alkylation reaction.

Alkylation reactions include, but are not limited to, fire-resistant hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Lower alkanols such as methanol, ethanol, 1-butanol and the like; Ketones such as 2-propanone, 4-methyl-2-pentanone and the like; Ethers such as 1.4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; N, N-dimethylformamide (DMF); N, N-dimethylacetamide (DMA) nitrobenzene; 1-methyl-2-pyrrolidinone; Dimethyl sulfoxide (DMSO); It is conveniently carried out in an insoluble organic solvent such as and analogs thereof.

Alkaline metal carbonates or bicarbonates, sodium hydrides or suitable bases such as, for example, N, N-diethylethanamine or N- (1-methylethyl) -2-propanamine are added to release the reaction during the reaction. Acid can be recovered. In some cases the addition of an iodide salt, preferably an alkali metal iodide, is suitable. The reaction rate can be increased at a somewhat elevated temperature.

Compounds of formula (I) can also be prepared by desulfurization cyclization of suitable thiourea derivatives of the following formula (IV).

This desulphurization reaction involves the reaction of methanol, ethane, and a suitable reaction inert organic solvent such as lower alkanols, such as 2-propanol and the like, with the general formula (IV) compounds with a suitable alkyl halide, preferably methane iodide. You can proceed.

Otherwise, the desulfurization ring reaction may be carried out by reacting the compound of formula (IV) with a suitable metal oxide or metal salt in a suitable solvent according to a known method. For example, the compound of formula (I) may be selected from (IV) as a suitable Hg (II) or Pb ((e) such as, for example, HgO, HgCl ₂ , Hg (OA _C2 , PbO or Pb (OA _C ) ₂ ) _2. II) can be easily prepared by reaction with oxides or salts thereof.

In certain cases it may be appropriate to add a small amount of sulfur to the reaction mixture.

Methanediamine, in particular N, N'-methanetetramilbis [cyclohexaneamine], can be used as the desulfurization ring.

L is Z is Z ', Y is NH, and X is O or S, wherein X is a radical of general formula (h) represented by X', that is, general formula (I- The compound of b-1) can generally be prepared by reacting an isocyanate or isothiocyanate of formula (VI) with a reagent of formula (V).

A compound of formula (I) wherein L is a radical of formula (h) wherein Z is NH, Y is Y 'and X is X', ie, the compound represented by formula (Ib-2), is represented by formula (VI) Isocyanate or isothiocyanate may be prepared by reacting with piperidine of general formula.

The reactions of compounds (V) and (IV) and (iii) and (iii) generally proceed in a suitable reaction inert solvent such as ether such as tetrahydrofuran and the like. The compound of the general formula (I) wherein L is a direct bond and Z is a radical of general formula (h) wherein X 'is a compound represented by general formula (I-c) Lidine can be prepared by reacting with a reagent of the general formula.

The reaction of compound (i) and (iii) can generally proceed according to the following known esterification or amidation reaction. For example, carboxylic acids can be converted to reactive derivatives, such as anhydrides or carboxylic acid halides, and reacted directly with compound (i); Compound (i) and (iii) are reacted with a suitable amide or ester-producing reagent such as dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide and the like.

These reactions proceed most advantageously in suitable solvents such as ethers such as tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, trichloromethane or protic polar solvents such as N, N-dimethylformamide. A base addition such as N, N-diethylethanamine is suitable.

The compound of the general formula (I) wherein L is a direct bond and Y is a radical of general formula (g) wherein O is a compound represented by general formula (I-d) Alkenylene may be prepared by reacting piperidine of formula (III-a) with agitation, preferably in a suitable solvent, and heating the reactants together if necessary.

Compounds of formula (I) may also be prepared according to the process for preparing five-membered ring heterocycle compounds or similar methods thereof, which are held in the art. Several such cyclization methods are described below.

The divalent radicals used to describe these cyclization reactions have the meanings of the following general formulas (i), (j) or (k).

For example, a compound of the general formula (I), that is, a compound represented by general formula (I-e), in which Het is an optionally substituted imidazolyl group, may be a suitable N- (2,2-diseride group of general formula (VII). Prepared by cyclization of an alkyl oxyethyl) imideamide derivative.

In the scheme, R ⁷ , R ⁸ and R ⁹ are each independently an optional substituent of the imidazole ring.

The cyclization can be conveniently carried out in a suitable solvent in the presence of a suitable acid such as, for example, hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid. The reaction rate can be increased at elevated temperatures.

In addition, the compounds of the general formula (I), in which Het is a substituted 1H-benzimidazol-2-yl group, that is, the compound represented by the general formula (I-f), are subjected to desulfurization reaction of a suitable derivative of general formula (XII). It can be prepared by.

In the above scheme, R ¹⁰ and R ¹¹ are each independently an optional substituent of the benzimidazol-2-yl ring.

This desulfurization ring reaction can be carried out according to the same method as described above for preparing compound (I) from compound (IV).

The compound of formula (I), that is, a compound represented by formula (I-g), wherein Het is an optionally substituted oxazolyl group, may be prepared by reacting a reagent of formula (XIII) with an intermediate of formula (XIV). .

In the above scheme, R ¹² and R ¹³ are each independently an optional substituent of the oxazole ring.

The reaction of compound (XIII) with (XIV) is free in a suitable solvent or solvent mixture in the presence of a suitable base such as alkali or alkaline metal hydroxides, carbonates, bicarbonates and the like, such as sodium hydroxide, sodium carbonate, potassium bicarbonate and the like. Proceeds. Examples of suitable solvents or solvent mixtures include water, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 2-propanone and the like and mixtures thereof.

Compounds of the general formula (I) wherein Het is an optionally substituted thiazoli group may be prepared according to various condensation reactions, and are sometimes represented by the following formulas (I-h), (I-) and (I-j). To yield a compound.

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ -NH are each independently an optional substituent of the thiazole ring.

The cyclization reaction of compounds (XV) with (XVI) and (XVII) with (XVIII) can be carried out by aromatic hydrocarbons such as benzine and methylbenzene; Aliphatic or alicyclic hydrocarbons such as hexane and cyclohexane; Lower alkanols such as methanol and ethane; Kenones such as 2-propanone and 4-methyl-2-pentanone; Ethers such as 1,4-dioxane, 1,1'-oxybisethane and tetrahydrofuran; Halogenated hydrocarbons such as trichloromethane and the like; N, N-dimethylformamide (DMF); It proceeds advantageously in a suitable inert organic solvent such as N, N-dimethylacetamide (DMA) and the like.

Alkali metal carbonates or bicarbonates, sodium hydrides or appropriate organic bases such as, for example, N, N-diethylethanamine or N- (1-methylethyl) -2-propanamine are added to recover the acid generated during the reaction. can do. Under certain conditions it is suitable to add an iodide salt, preferably an alkali metal iodide. The reaction rate can be increased at a somewhat elevated temperature.

The cyclization reaction of compounds (XIX) and (XVIII) can be advantageously carried out according to the same reaction conditions used in the preparation of compounds (I-h) and (I-i), provided that the reaction mixture contains ammonia or For example, ammonium salts such as ammonium are replenished.

A compound of formula (I) wherein N is a group of the formula -NH-Alk- and Het is an optionally substituted 4,5-dihydro-2-thiazolyl ring, wherein X 'is a reagent of formula (XX). It can be manufactured by condensation as an intermediate of general formula (VI), which is S, that is, compound (VI-a).

This condensation reaction is advantageously carried out according to the same reaction conditions described in the production method of the compounding rule (I-h) or (I-i).

Compounds of general formula (I), in which L is a radical of general formula (g), i.e. compounds represented by general formula (I-l), may also be used as ethers such as tetrahydrofuran, 1,1'-oxybisethane and analogs. The intermediate (XXI) can be prepared in a suitable solvent by reducing it as a suitable metal complex hydride such as lithium aluminum hydride.

In the above scheme, Alk 'is the same as Alk's definition under the condition that one methylene functional group is lacking.

Compounds of general formula (I) can also be interconverted according to known methods of functional group conversion. Some examples are described later.

Compounds of the general formula (I) with nitro substituents are prepared by stirring the starting material nitro compound in a hydrogen-containing medium in the presence of a suitable amount of suitable catalysts such as charcoal, platinum, charcoal-platinum palladium, raninickel and similar catalysts. By heating it can be converted to their corresponding amines. Examples of suitable solvents include methanol, ethanol and the like. The halo atom substituted on the aryl group is substituted by hydrogen in the presence of a suitable catalyst, such as charcoal-attached palladium and similar catalysts, and in a suitable solvent under a hydrogen stream, by stirring the starting material and heating it if necessary, under known hydrogenolysis. You can.

These haloatoms can also be substituted with lower alkyloxy or lower alkylthio substituents by reacting the starting halo compound with an alkali or alkaline earth metal salt or a suitable alcohol or thioalcohol in a suitable alcohol or thioalcohol, or preferably in a suitable solvent.

Compounds of formula (I), wherein L is a radical (g) where Y is NH, react the starting amine with a suitable carboxylic acid or derivatives thereof such as acid halides, acid anhydrides and the like, where L is N-CO It can be converted into a compound of formula (I) which is a radical (g) which is (lower alkyl) or N-CO (Ar ² ).

Compounds of formula (I), wherein L is radical (g) wherein Y is NH, reacts the starting amine with a suitable isocyanate or isothiocyanate in a suitable solvent so that L is Y is N-CO (lower alkylamino), Compound of general formula (I) which is a radical (g) which is CO-NH-Ar ² , N-CS (lower alkylamino) or N-CS-NH-Ar ² . Can be reduced.

In all the above-mentioned formulations and in all the formulations described below, the reaction product can be separated from the reaction mixture and further purified according to methods known in the art if further desired.

Compounds of general formula (I) have basic properties and consequently these compounds include hydrochloric acid such as hydrochloric acid and bromic acid, and inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and the like; Or acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxobiropanic 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, benzene Non-toxic therapeutic activity by treating with a suitable acid such as organic acids such as sulfonic acid, 4-methylbenzenesulfonic acid, cyclohexane sulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like acids Can be converted to acid addition salts. In contrast these salt forms can be converted to the free base form by treatment with alkali.

In the above preparations some intermediates and starting materials are known compounds and some are novel compounds. These compounds can be prepared according to known methods or by analogous methods thereof. Several such methods are described in more detail below.

The intermediate of general formula (III-a) is subjected to desulfurization ring reaction according to the same method as described above for preparing compound (I) from compound (IV) using thiourea derivative of general formula (XXII) as starting material. It can then be advantageously prepared by removing the protecting group P in the intermediate of the general formula PD (XXII) thus obtained.

In the general formula (XXII), P is a suitable protecting group such as lower alkyloxycarbonyl, Ar ² -CH ₂ -O-CO-, Ar ² -CH _2-, and the like.

Removal of protecting group P in compound (XXII) can be carried out in a generally known manner, ie by hydrolysis in alkaline or acidic aqueous medium.

Intermediates of formulas III-b) and (III-c) may be prepared by reacting the corresponding intermediates of formula III-a with appropriate reagents according to known N-alkylation methods.

For example, an intermediate of general formula (III-b) in which Q ^2a represents a group of the general formula H ₂ N—CH ₂ —Alk′—, that is, compound (III-b-1) may also be represented by general formula (III-a) The intermediate of is reacted with a nitrile of the general formula (XXII) according to a known N-alkylation method, and then the nitrile (XXIII) thus obtained is subjected to known nitrile-amine reduction methods such as catalytic hydrogenation and the like. It can be prepared by conversion to the corresponding amine (III-b-1).

In the above compounds (XXIV), (XXV), and (III-b-1), Alk 'is identical to the definition of Alk under the condition that one methylene functional group is lost. The intermediate of general formula (III-b), wherein Q ^{2a is} Alk-NH ₂ , reacts reagent (XXVI) with (III-a) according to a known N-alkylation method, and the intermediate (XXVII) thus produced is reacted. It can be prepared by conversion to the free amine according to known deprotection methods.

Intermediates of formula (III-b), in which Q ^2a represents a group of the formula HY'-CH ₂ CH _2- , ie intermediate (III-b-3), also represent compounds (III-a) in a suitable solvent. It can be prepared by stirring with the reagent of (XXVIII) and heating these reactants together if necessary.

Intermediate of general formula (III-b), ie, intermediate (III-b), wherein Q ^2a is a group of general formula HX-Alk, converts functional group Y'H to a suitable separator with 0 'and also thionyl chloride, phosph Foryl chloride and analogs thereof can be converted to intermediates of formula (III-c) by converting hydroxy functional groups to chlorine atoms.

Intermediates of general formula (III-b-2) are also reacted with a hydroxylated amine with a suitable corresponding carbonyl-oxidized form compound which is thus obtained to reduce the oxime according to known methods, i.e., catalytic hydrogenation and similar reduction. Can be prepared from this corresponding carbonyl-oxidized form compound.

In any of these reactions, intermediates in which R ¹ or R ² or R ³ or R ⁴ are hydrogen may be R ¹ or R ² according to known N-alkylation, N-acylation or reductive N-alkylation methods. And or R ³ and or R ⁴ can be converted to a corresponding intermediate that is not hydrogen.

Intermediates of formula (XXII) and intermediates of formula (XXII), in which R ² is hydrogen, ie intermediate (XXII-a), are piperidine of formula (XXIV-a) or (XXIX-b). Prepared by reacting XXX-a) or (XXX-b) with an aromatic reagent.

Radial of general formula (i) where K is s = 0, s = 0 or Y of non-direct bond hand Radical of general formula (j) or general formula (k) of which s = 0 and Y are not direct bond hand Where is an intermediate of formula (XI) wherein K is represented by K ', that is, the intermediate of formula (XI-a) is a piperidine of formula (III-b) wherein Q ^2a is a -K'H group. That is, it can be prepared by reacting the piperidine represented by the general formula (III-b-4) with the intermediate of the general formula (XXXI).

In the above scheme, V represents a suitable leaving group such as lower alkylthio, lower alkyloxy, halo and the like.

Intermediates of formula (XXXI) can be prepared according to known methods such as alkylating a suitable thiourea derivative with a suitable alkyl halide when V is lower alkylthio.

Intermediates of the general formula (XII), wherein K is -NH-Alk-, i.e., the intermediate represented by the general formula (XII-a), are suitable aryl derivatives of one way (XXXII). It can be advantageously prepared by reacting with an intermediate, ie an intermediate of formula (VI-a).

Intermediates of formula (XIV) can be prepared by subjecting the intermediate of formula (III-a) to an N-alkylation reaction with a nitrile of formula NC-K-W according to known N-alkylation methods.

In addition, intermediates of the general formula (XIV), in which K is the general formula -NH-Alk, ie, the intermediate represented by the general formula (XIV-a), also represent a cyanogen halide of the general formula (XXXIII), wherein Q ^2a is a general formula H _2, an intermediate of formula (III-b) represents N-Alk- group, that is reacted with an intermediate represented by the general formula (III-b-2) can be produced.

Intermediates of formula (XVI), wherein K is formula -NH-Alk, can be prepared by reacting intermediate (VI-a) with an ammonium salt such as ammonia or ammonium chloride and the like in the presence of a suitable solvent.

Intermediates of the general formula (XVIII), wherein W is a halogen group, i.e., the intermediate represented by the general formula (XVIII-a), may react compound N-alkylation with a reagent of the general formula R ¹⁷ -CH ₂ -CO-KW. It can be prepared by the halogenation of the intermediate (XXXIV) that can be produced.

Intermediates of formula (XXI) may be prepared by N-alkylation of intermediate (III-a) with a suitable reagent of the formula Het-C _s -H _2s -Y-Alk'-CO-W.

It can be seen from the above general formula (I) that the compound of the present invention may have several asymmetric carbon atoms in these structures.

Each of these chiral centers may exist in R- and S-configurations, which are named R.S. Chan, C. Ingeld and V. Prelog et al. Chem., Int. Ed. In accordance with the law described in Eng 1., 5,385, 511 (1966).

Pure stereochemically isomeric forms of the compounds of formula (I) can be obtained using known methods. Diastereomers can be separated according to chromatographic methods such as countercurrent distribution and physical separation methods such as screening crystallization, and colonies can be separated from one another by screening and crystallizing their diastereoisomers using optically active acids. .

Pure stereochemically isomeric forms can also be prepared starting from the corresponding pure stereoisomeric forms of suitable starting materials under the conditions that the reaction proceeds with steric properties.

Cis and trans diastereomeric racemates are further classified into their optical isomers, namely cis (+), cis (-), trace (+) and trace (-) using methods known in the art. Can be separated.

Stereochemically isomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

The following examples are intended to illustrate the invention and are by no means intended to limit the scope of the invention. Acids not otherwise mentioned are those based on the tannery weight.

EXAMPLE

A. Preparation of Intermediates

Example 1

12.5 parts N- (2,2-dimethoxyethyl) -N '-[2- [2-[[1-[(4-fluorophenyl) methyl] -1 H-benzimidazol-2-yl] amino] The mixture of -1-piperidinyl] ethyl] guanidine monohydro iodide and 100 parts of 10% operational aqueous solution is refluxed with stirring for 1 hour. The reaction mixture is poured into crushed ice and the whole solution is treated with aqueous sodium hydroxide solution.

The product is extracted with dichloromethane and the extract is dried, filtered and evaporated. Solid residue is crystallized in 4-methyl-2-pentanone. The product was filtered off and dried to give 2.3 parts (28%) of 1-[(4-fluorophenyl) methyl] -N- [1- [2- (1H-imidazol-2-ylamino] ethyl-4 -Piperidinyl] -1H-benzimidazol-2-amine, melting point 226.5 ° C. (Compound 79).

In a similar manner, the following compounds are also prepared.

1-[(4-fluorophenyl) methyl] -N- [1- [2-[(1-methyl-1H-imidazol-2-yl) amino] ethyl] -4-piperidinyl-1H-benz Imidazole-2-amine hemihydrate: melting point 85.0 ° C. (compound 80).

1-[(4-fluorophenyl) methyl] -N- [1- [2-[[1- (1-methylethyl) -1H-imidazol-2-yl] amino] ethyl] -4-piperidi Nil] -1H-benzimidazol-2-amine monohydrate; Melting point 90.8 ° C. (Compound 81); and

1-[(4-fluorophenyl) methyl] -N- [1- [2-[[1-[(4-fluorophenyl) methyl] -1 H-imidazol-2-yl] amino] ethyl]- 4-piperadinyl] -1H-benzimidazole-2-aminecyclohexanesulfate (1: 3) dihydrate: melting point 230-250 ° C. (decomposition) (compound 82).

Example 2

40 parts N- [2-[[(3,4-dichlorophenyl) methyl] amino] phenyl] -N '-[2- [4-[[1-[(4-fluorophenyl) methyl] -1 H- Benzimidazol-2-yl] amino] -1-piperidinyl ethyl thiourea, a mixture of 60 parts water temperature (II), 0.1 parts sulfur and 400 parts ethanol was stirred and refluxed overnight. The reaction mixture is filtered through Hyflo and the filtrate is evaporated. The residue is crystallized in ethanol. The product was filtered off and dried to 17 parts (45%) of 1-[(3,4-dichloro phenyl) methyl] -N- [2- [4-[[1-[(4-fluorophenyl) methyl ] -1H-benzimidazol-2-yl] amino] -1-piperidinyl] ethyl] -1H-benzimidazol-2-amine. Melting point 113.2 ° C. (compound 83).

Example 3

1.95 parts [2- [4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] amino] -1-piperidinyl] ethyl] cyanamide, 45 parts To a stirred mixture of tetrahydrofuran and 50 parts of water is added a solution of 3.7 parts of 1-hydroxy-2-propanone (= 50%). 5 parts 2N sodium hydroxide solution is added dropwise. After the dropwise addition, stirring is continued at room temperature for 2 hours. The reaction mixture is poured into water and the product is extracted with trichloromethane. The extract is filtered off and evaporated. The residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (96: 4 vol. Ratio) saturated with ammonia as eluent.

Pure fractions are collected and the eluent is evaporated. The residue was crystallized in acetotrile to yield 1.3 parts (6%) of 1-[(4-fluorophenyl) methyl] -N- [1- [2-[(4-methyl-2-oxazolyl) amino] ethyl ] -4-piperidinyl] -1H-benzimidazol-2-amine. Melting point 178.1 ° C. (compound 84).

Example 4

4.3 parts N- [2- [4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] amino] -1-piperidinyl] ethyl] thiourea, 2.1 To a stirring mixture of negative potassium carbonate and 45 parts tetrahydrofuran is added dropwise a solution in which 0.9 parts of 1-chloro-2-propanone is dissolved in a small amount of tetrahydrofuran. After the dropwise addition, stirring at room temperature is continued for one night. The reaction mixture is filtered through Hyflo and the filtrate is evaporated.

The residue was crystallized in acetonitrile. The product was filtered off and dried to give 3.8 parts (81%) of 1-[(4-fluorophenyl) methyl] -N- [1- [2-[[4- (4-pyridinyl-2-thiazolyl) ) Amino] ethyl]-4-piperidinyl] -1H-benzimidazol-2-amine. Melting point 184 ° C. (Compound 85).

In a similar manner, the following compounds are also prepared.

1-[(4-fluorophenyl) methyl] -N- [1- [2-[[4- (4-pyridinyl-2-thiazolyl) amino] ethyl] -4-piperidinyl] -1H- Benzimidazol-2-amine. Melting point 195-212 ° C. (Compound 86); And 1-[(4-fluorophenyl) methyl] -N- [1- [2-[[4- (2-pyridinyl-2-thiazolyl) amino] ethyl] -4-piperidinyl] -1H -Benzimidazol-2-amine. Melting point 151.5 ° C. (Compound 87).

Example 5

1.3 parts 1-chloro-2-propanone, 5 parts N- [2- [4-[[1- (2-furanylmethyl) -1H-benzimidazol-2-yl] amino] -1-piperidi Nil] ethyl] Thiourea, a mixture of 3 parts potassium carbonate and 68 parts N, N-dimethylacetamide is stirred at room temperature overnight. Water is added and the product is extracted with 4-methyl-2-propanone. The extract is dried, filtered and evaporated. The oily residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 volume ratio) as eluent.

Pure fractions are collected and the eluent is evaporated. Let the residue be converted to hydrochloride in 2-propanol. The salts were separated by filtration and dried overnight under vacuum at 110 ° C. for 3.8 parts of 1- (2-furanylmethyl) -N- [1- [2-[(4-methyl-2-thiazolyl_amino] ethan] Obtain 4-piperidinyl-1H-benzimidazol-2-amine trihydrochloride monohydrate Melting point 238.5 ° C. (Compound 88).

Example 6

4.3 parts N- [2- [4-[[1-[(4-fluorophenyl) methyl-1H-benzimidazol-2-yl] amino] -1-piperidinyl] ethyl] thiourea, 2.1 parts To a stirred mixture of potassium carbonate and 40 parts of methanol is added dropwise a solution of 2 parts of 2-bromo-1-phenylethanone in methanol. After the dropwise addition, stirring is continued for one night at room temperature. The reaction mixture is filtered through Hyflo and the filtrate is evaporated. The residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (90:10 volume ratio) as eluent. Pure fractions are collected and the eluent is evaporated. The residue was crystallized in acetonitrile to give 2.5 parts of 1-[(4-fluorophenyl] methyl] -N- [1-2-[(4-phenyl-2-thiazolyl) amino] ethan] -4-piperidinyl -1H-benzimidazol-2-amine is obtained, melting point 176.2 ° C (compound 89).

Example 7

1.2 parts N- (aminothioxomethyl) guadidine, 6.3 parts 1-bromo-4- [4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] Amino] -1-piperidinyl]-2-buta stirs a mixture of dihydrobromide and 120 parts methanol at room temperature overnight. The precipitate was filtered off and dried to give 3.6 parts (49%) of N- [4- [2- [4-[[1-[(4-fluorophenyl) methyl] -1 H-benzimidazole-2- Il] amino] -1-piperidinyl] ethyl] -2-thiazolyl] guanidine trihydrobromide. Melting point 282.8 ° C. (Compound 90).

In a similar manner, the following compounds are also prepared.

N- [1- [2- (2-amino-4-thiazolyl) ethyl] -4-piperidinyl) -1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-amine : Melting point 01.0 ° C. (Compound 91).

1-[(4-fluorophenyl) methyl) -N- [1- [2- (2-phenyl-4-thiazolylethyl] -4-piperidinyl] -1H-benzimidazol-2-amine di Hydrochloride monohydrate Melting point 258.1 ° C. (Compound 92).

1-[(4-fluorophenyl) methyl) -N- [1- [2- (2-phenyl-4-thiazolylethyl] -4-piperidinyl] -1H-benzimidazol-2-amine mono Hydrate, melting point 113.3 ° C. (Compound 93).

N- [1- [2- (2-amino-5-methyl-4-thiazolyl) ethyl] -4-piperidinyl] -1 [(4-fluorophenyl) methyl] -1 H-benzimidazole- 2-amine. Melting point 214.4 ° C. (Compound 94).

1-[(4-fluorophenyl) methyl] methyl] -N- [1- [2- (5-phenyl-2-phenyl-4-thiazolylethyl] -4-piperidinyl] -1H-benzimi Dazol-2-amine monohydrate, melting point 127.4 ° C. (Compound 95); and

1-[(4-fluorophenyl) methyl] -N- [1- [2- [2- (phenylamino) -4-thiazolyl] ethyl] -4-piperidinyl] -1 H-benzimidazole- 2-amine trihydroclyde: melting point 233.4-237.9 ° C. (Compound 96).

Example 8

A mixture of 1.5 parts isothiocyanatomethane and 150 parts methanol saturated with ammonia is stirred at room temperature for 1 hour. The whole solution was evaporated and 9.7 parts of 4-bromo-1- [4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl [amino] -1- Piperidinyl-3-pentanone and 120 parts methanol are added. Stirring is continued one night at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The whole solution is alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was crystallized in acetonitrile to give 5.2 parts (72.5%) of 1-[(4-fluorophenyl) methyl] -N- [1- [2- [5-methyl-2- (methylamino) -4-thia Zolyl] ethyl] -4-piperidinyl] -1H-benzimidazol-2-amine is obtained. Melting point 181.8 ° C. (Compound 97).

The following compounds are also prepared following the same preparation and using the same large amounts of suitable starting materials.

1-[(4-fluorophenyl) methyl] -N- [1- [2- [2- (methylamino) -4-thiazolyl] ethyl] -4-piperidinyl] -1 H-benzimidazole- 2-amine: melting point 157.9 ° C. (Compound 98).

Example 9

1.2 parts 2-chloroethanamine, 4.1 parts 1- (4-fluorophenylmethyl) -N- [1- (2-isothiocyanatoethyl) -4-piperidinyl] -1 H-benzimidazole- A mixture of 2-amine, 2.2 parts sodium carbonate and 135 parts tetrahydrofutanlan is stirred at room temperature for 3 hours. The mixture is heated to reflux and further stirred at reflux for one night. The reaction mixture is filtered and the filtrate is evaporated. The residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 5 vol. Ratio) saturated with ammonia as eluent. Pure fractions are collected and the eluent is evaporated. The residue was crystallized twice in acetonitrile to give 1 part N- [1- [2- [4,5-dihydro-2-thiazolyl) amino] ethyl] -4-piperidinyl] -1] [(4- Fluorophenyl) methyl] -1H-benzimidazol-2-amine is obtained: Melting point 147.6 ° C. (Compound 99).

The beneficial antihistamine properties of the compounds of formula (I) can be demonstrated in the following test methods.

Protection of rats from compound 48 / 80-induced lethality

Oligomer mixture 48/80, which is an oligomeric mixture obtained by condensation of 4-methoxy-N-methylbenzeneethanamine with formamide, is known as a powerful histamine releaser (Int. Arch. Allergy, 13, 336 (1958)).

Protection from Compound 48 / 80-induced lethal cyclic shock is considered a simple way to quantitatively measure the antihistamine activity of a test compound. Wistar male rats of the sigmoids of 240-260 body weight are used in the experiment. After fasting overnight, the mice are transferred to a controlled laboratory (temperature = 21 ± 1 ° C, relative humidity = 65 ± 5%). These mice are administered subcutaneously or orally with a test compound or solvent (0.9% NaCl solution). One hour after administration, 48/80 of freshly dissolved Compound 48 is injected intravenously at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight). In a control experiment in which 250 solvent-treated animals were injected with a standard dose of Compound 48/80, less than 2.8% of animals survived after 4 hours. Therefore, survival rate after 4 hours was regarded as a safe criterion of drug administration protection effect.

The ED ₅₀ value of the compound of formula (I) is listed in column 1 of Table 1. This ED ₅₀ value refers to the value expressed in mg / kg body weight of the test compound which protects 50% of the test animal at 48/80 induction mortality.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts are also potent serotonin antagonists. The performance of the title compound as a serotonin antagonist is clearly demonstrated as a result obtained by testing the antagonism of the title compound against serotonin effect and following the test.

Antagonism of Seratonin Effect in Gastric Lesions

A. Methods Induced with Compound 48/80.

Compound 48/80 (obtained oligomer mixture by condensation of 4-methoxy-N-methylbenzeneethanamine with formamide) is a potent release that releases vasoactive amines such as histamine and serotonin from endogenous stores, for example. Jay. Mice injected with Compound 48/80 show persistent blood flow changes on different blood vessels; Symptom of developing lip and ear within 5 minutes after compound injection; The mice will be shocked within 30 minutes. This shock following death can be prevented if mice are pretreated with H1 antagonists. However, mice treated with 48/80 compounds and protected from shock as antagonists can exhibit all the symptoms of intensive gastric activity because they cannot inhibit the stimulating effects on gastric secretions; Visual necropsy reveals an enlarged stomach with abnormal contents and rough coarse red spots corresponding to the site of collapsed glands that appear throughout the mucosa. Many known serotonin antagonists such as methyregird, cyproheptadine, cinnaserine, myanserine, fifamferon, spiferon, pizotifen and metergoline, as well as growth of the ears and limbs, as well as lesions and abnormalities in the gastric area The above expansion can be completely prevented.

B. Method

Fasting male rats of Wister's wintering at 220-250 g body weight overnight. But water was available. The test compound is administered orally in the form of a solution or suspension in an aqueous medium. The test compound is also administered to the control rat and the blank rat. After 1 hour, all rats are administered subcutaneously with a dose of 2.5 mg / kg of 5- [4- (diphenylmethyl) -1-piperazinylmethyl] -1-methyl-1H-benzimidazole-2-methanol. . Two hours after oral or subcutaneous administration of the test compound, Compound 48/80 (dissolved 0.25 mg / ml vertically in water) is injected intravenously (dose 1 mg / kg) in all rats except for the blank rats.

Four hours after intravenous injection of Compound 48/80, the mice are dissected to separate the stomach. The stomach is then visually inspected for expansion and its contents (blood, latex, food) and thoroughly washed. Visually examined lesions are separated into grades of 0 to +++. At this time, 0 is a state in which the lesion cannot be detected at all by the naked eye, and +++ represents a state covered with red rough spots of more than half of the gastric gland.

Column 2 of Table 1 lists the dose (ED ₅₀ value) of the compound of the general formula (I) in which 50% of the rats showed no gastric enlargement as well as gastric lesions (ED ₅₀ value).

The compounds listed in Table 1 below illustrate only the useful pharmacological properties of all compounds within the scope of formula (I), and it is clear that the present invention is by no means limited to these compounds.

TABLE 1

In view of their antihistamine and serotonin antagonistic properties, the compounds of formula (I) and acid addition salts thereof are very useful for the treatment of allergic diseases such as allergic rhinitis, allergic conjunctivitis, chronic dart, and allergic asma. do.

In view of their useful pharmacological properties, the title compound can be prepared in various formulation forms depending on the purpose of administration. That is, in the preparation of the pharmaceutical composition of the present invention, as an active ingredient, an effective amount of a specific compound is combined with a carrier for a drug tongue in the form of a base or an acid addition salt, and the carrier is in a wide range of forms depending on the type of preparation required for administration. Can change. These pharmaceutical compositions are preferably prepared in unit dosage form suitable for oral, rectal or parenteral injection. For example, when the composition is formulated in oral dosage form, oral liquid preparations such as suspensions, syrups, extracts and solutions may be prepared by conventional pharmaceutical media such as water, glycols, oils, alcohols and the like; In the case of powders, pills, capsules and tablets, conventional solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrating agents and the like can be used. Because of their ease of administration, tablets and capsules are in the most advantageous oral dosage form, in which case solid drug carriers are used.

In the case of parenteral compositions, the carrier may contain other ingredients such as dissolution aids, but is usually composed of most sterile water rolls. For example, injectable solutions consist of a saline solution, a glucose solution or a mixture of these saline and glucose solutions. It may be prepared using an injection suspending agent or a suitable liquid carrier, suspension or the like. The acid addition salt of compound (I) is more preferably prepared in an aqueous solution composition in view of increasing water solubility compared to the corresponding base form.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form that is easy to administer and that can maintain a constant dosage. Dosage unit form as used herein refers to a physical division unit suitable as a unit dosage, each division unit contains a calculated amount of the active ingredient in combination with the required drug carrier to achieve the required therapeutic effect have. Examples of such dosage unit forms include tablets (scoad tablets or dragees), capsules, pills, powdered pockets, wafers, injectable solutions, injection suspensions, tea spoons, spoons, and the like, and their multiples.

The following preparations are illustrated in the form of dosage units suitable for systemic administration of typical pharmaceutical compositions to animal and human patients in accordance with the present invention. These examples are intended to illustrate the present invention, not to limit the scope of the present invention.

The active ingredient (A.I.) used throughout these examples represents a compound of formula (I), possible stereochemical isomers thereof or pharmaceutically acceptable acid addition salts.

Example 10

Oral drops

500 g of active ingredient (A.I.) are dissolved in 0.5 L 2-hydroxypropanoic acid and 1.5 L polyethylene glycol at 60-80 ° C. After cooling to 30-40 ° C., 35 L of polyethylene glycol is added thereto and the mixture is stirred well. Then, an oral drop containing 10 mg of active ingredient per ml was added thereto by adding a solution of 1750 g of sodium saccharin dissolved in 2.5 liters of purified water and adding 2.5 cocoa flavor and polyethylene glycol residue to 50 liters while stirring. Obtain the first solution. The obtained solution is filled into a suitable container.

Example 11

Oral solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 L of boiled purified water. To 3 liters of this solution, 10 g of 2,3-dihydroxybutanedioic acid is first dissolved, followed by 23 g of the active ingredient (A.I.). The latter solution is mixed with the remaining amount of the electronic solution, and 12 L of 1,2,3-propanetriol and 3 L of 70% sorbitol solution are added thereto. 40 g sodium saccharin is dissolved in 0.5 L water and 2 ml raspberry and 2 ml gooseberry essence are added.

The latter solution is mixed with the electronic solution and the remaining amount of water is added to make a volume of 20 l to obtain an oral solution containing 20 mg of active ingredient per order (5 ml). Fill the obtained solution into a suitable container.

Example 12

Capsule

20 g of active ingredient (A.I.), 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 are vigorously stirred together. The resulting mixture is then filled with 20 mg of active ingredient in 1000 suitable hard gelatin capsules, respectively.

Example 13

Film coating

Preparation of Purified Nose

A mixture of 100 g of active ingredient (A.I.), 570 lactose and 200 starch is mixed well and then wetted with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml water. The wet powder mixture is sieved, dried and sieved again. Next, 100 g of microcrystalline cell lurose and 15 g of hydrogenated hydrogenated oil are added thereto.

The whole solution is mixed well and pressed to make tablets to yield 10,000 tablets each containing 10 mg of active ingredient.

Cloth operation

A solution obtained by dissolving 5 g of ethyl cellulose in 150 ml dichloromethane is added to a solution of 10 g of methyl cellulose in 75 ml of modified ethanol. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added thereto.

10 g of polyethylene glycol is melted and dissolved in 75 ml dichloromethane. The latter solution is added to the electronic solution followed by 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension (Opaspray K-1-2109) and homogenization of the whole solution. do.

The mixture thus obtained is coated on stir core with a coating apparatus.

Example 14

Injection medicine

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are 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 (A.I.) are added thereto while stirring. The solution is cooled to room temperature and a residual amount of water for injection is added to obtain 1 L of a solution containing 4 mg of active ingredient (A.I.) per ml.

Filter sterilize this solution (U. S.P.XVII p.811) and fill it with sterile containers.

Example 15

Suppository

3 g of active ingredient (A.I.) is dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 g of surfactant and 330 g of residual triclylide are melted together. The latter mixture is mixed well with the electronic solution. The mixture thus obtained is poured into a mold at a temperature of 37-38 ° C. to prepare 100 suppositories each containing 30 mg of active ingredient.

The present invention also relates to a method for treating allergic diseases of warm-blooded animals suffering from allergic diseases by administering an amount of an anti-allergic effective amount of the general formula (I) compound or a pharmaceutically acceptable acid addition salt thereof.

Suitable daily dosages for patients range from 0.1 to 100 mg, preferably 1 to 50 mg.

Claims (7)

A method for producing a compound of the general formula (I-e), an acid addition salt thereof, or a stereochemical isomer thereof by closing the imidide derivative of the general formula (VII) in an inert solvent.

The above formulas R ¹ is a C _1-4 alkyl substituted with halo-phenyl, R ₇ is a C _1-4 alkyl substituted with hydrogen, C _1-4 alkyl, halo-phenyl, Alk is C _1-4 alkynyl It's Dyle. A method of preparing an acid addition salt or a stereochemical isomer thereof by cyclodesulfurizing a thioide derivative of general formula (XI) in an inert solvent with an alkali halide, a metal oxide or a metal salt. .

In the above formula, R ¹ is C _1-4 alkyl substituted with halophenyl, C ¹⁰ is C _1-4 alkyl substituted with phenyl which may be substituted with halogen atoms of 2 or less, and Alk is C _1-4 alkyndiyl to be. A method for producing a compound of general formula (I-g), an acid addition salt thereof or a stereochemical isomer thereof by condensation reaction of a compound of general formula (XIV) with a compound of general formula (XIII) in an inert solvent.

In the above general formula, R ¹ is C _1-4 alkyl substituted with halophenyl, R ¹² is C _1-4 alkyl, and Alk is C _1-4 alkyndiyl. A method for producing a compound of formula (I-h), an acid addition salt thereof, or a stereochemical isomer thereof by condensing a compound of formula (XVI) with a compound of formula (XV) in an inert solvent.

In the above formula, R ¹ is C _1-4 alkyl or furanyl substituted with halophenyl, R ¹⁴ is C _1-4 alkyl or pyridinyl, and Alk is C _1-4 alkyndiyl. Compound of Formula (XVIII) with Formula (XVII). A method for producing a compound of formula (I-j), an acid addition salt thereof, and a stereochemical isomer thereof by condensation reaction of a compound of formula (XVIII ′) with an isocyanide of formula (XIX) in an inert solvent.

Wherein R ¹ is C _1-4 alkyl substituted with halophenyl, R ¹⁷ is hydrogen or C _1-4 alkyl, R ¹⁸ is C _1-4 alkyl, and Alk is C _1-4 alkyndiyl . A method for producing a compound of formula (I-k), an acid addition salt thereof or a stereochemical isomer thereof by condensation reaction of a compound of formula (IV-a) with a compound of formula (XX) in an inert solvent.

In the formula above, R is C _1-4 alkyl substituted with halophenyl and Alk is C _1-4 alkyndiyl.