KR950010186B1 - N-heterocyclryl-4-piperidinamine derivatives - Google Patents

Abstract

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Description

N-heterocyclyl-4-piperidinamine derivatives

The present invention relates to N-heterocyclyl-4-piperidinamine derivatives and methods for their preparation.

US Pat. No. 4,219,559 describes a number of 1-substituted N-heterocyclyl-4-piperidinamines as compounds with useful antihistamine properties. This patent document also introduces a number of N-heterocyclyl-4-piperidinamines in which the 1-position of the piperidine moiety is unsubstituted or substituted with alkyloxycarbonyl or phenylmethoxycarbonyl groups as useful intermediates. Doing. Many of these compounds are also described in J. Med. Chem. 1985, 28, pp. 195-1933, 1934-1942 and 1943-1947. In addition, J. J. Med. Chem. 1985, 28, 1934-1943] Preparation and antihistamine properties of compound 1-[(4-fluorophenyl) methyl] -4- (4-piperidinyl) -1H-benzimidazol-2-amine dihydrobromide This is described. The latter compound is known as the active metabolite of astemisol. Astemizole: a New, Non-sedative, Long-acting H ₁ -antagonist, Med. Publ. Found. Symp. Ser. 84, 25-34 (1984).

US Patent Nos. 4,556,660 and European Patent Application Publication Nos. 145,037, 144,101 and 151,824 are compounds having useful antihistamine and serotonin antagonistic properties, including N-heterocyclyl-4 having a 1-substituted piperidine moiety. The family of piperidineamines is also described and the N-heterocyclyl-4-piperidineamine unsubstituted 1-position of the piperidine moiety is described as an intermediate.

European Patent Application Publication No. 151,826 also describes a number of 4- (bicyclic heterocyclyl) methyl and -heteropiperidine with useful antihistamine and serotonin antagonistic properties.

The present invention relates to a composition containing the above-mentioned N-heterocyclyl-4-piperidinamine having a hydrogen atom, an alkyloxycarbonyl or phenylmethoxycarbonyl group at the position of the piperidine moiety as an active ingredient. Using a method for treating an allergic disease.

The present invention relates to an antiallergic composition comprising at least one pharmaceutically acceptable inert carrier and an antiallergic effective amount of at least one of the following general formula (I) compounds, a pharmaceutically acceptable acid addition salt or stereochemical isomer thereof as an active ingredient It is about.

Wherein L is hydrogen, C _1-6 alkyloxycarbonyl or phenylmethoxycarbonyl, and A ¹ = A ² -A ³ = A ⁴ is a structural formula -CH = CH-CH = CH- (a), -N = CH-CH = CH- (b), -CH = N-CH = CH- (c), -CH = CH-N = CH- (d) or -CH = CH-CH = N- (e) Are divalent radicals and one or two hydrogen atoms of the radicals (a) to (e) are each independently substituted with halo, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl or hydroxy R is selected from the group consisting of hydrogen and C _1-6 alkyl, R ¹ is substituted with hydrogen, C _1-10 alkyl, C _3-6 cycloalkyl, Ar ¹ and 1 or 2 Ar ¹ radicals Is selected from the group consisting of C _1-6 alkyl, R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, (C _1-6 alkyl) -CO—, (C _1-6 alkyloxy) -CO and Ar ² -C _1-6 alkyl, Ar ¹ is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkyl- Phenyl optionally substituted with up to 3 substituents each independently selected from the group consisting of CO-; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Pyridinyl; Pyrazinyl; Is selected from the group consisting of thiazolyl and imidazolyl optionally substituted with C _1-6 alkyl, Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 Alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl, and (C _1-6 alkyl) -CO It is selected from the group consisting of phenyl optionally substituted with up to 3 substituents each independently selected from the group consisting of

The term "halo" as used in the above definitions refers to fluoro, chloro, bromo and iodo generically; The term “C _1-6 alkyl” refers to straight or branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl , Hexyl and the like, "C _1-10 alkyl" means a C _1-6 alkyl radical as defined above and its higher homologue having 7 to 10 carbon atoms, and "C _3-6 cycloalkyl" means cyclopropyl, cyclobutyl , Cyclopentyl or cyclohexyl is generically referred to.

Preferred compounds of formula (I) for use as active ingredients in the compositions of the present invention are those in which A ¹ = A ² -A ³ = A ⁴ is a divalent radical of formula (a) or (b), and R ¹ is Ar ¹ Substituted with C _1-6 alkyl.

Particularly preferred compounds of formula (I) for use as active ingredients in the compositions of the present invention are those in which A ¹ = A ² -A ³ = A _t is a divalent radical of formula (a) or (b) and R is hydrogen R ¹ is hydrogen or C _1-6 alkyl and R ¹ is phenyl optionally substituted with up to two substituents independently selected from the group consisting of halo, hydroxy and C _1-6 alkyl; Pyridyl; Imidazolyl; Thienyl; Halothienyl; Furanyl; Furanyl substituted C _1-6 alkyl; Especially preferred are compounds wherein C _1-6 alkyl is substituted with one selected from the group consisting of thiazolyl and pyridinyl, wherein R ¹ is furanylmethyl or (C _1-6 alkyl) furanylmethyl compound.

The most preferred compound of general formula (I) to be used as an active ingredient in the composition of the present invention is 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazole [4,5-b] pyridin-2-amine or a pharmaceutically acceptable acid addition salt thereof. Compounds of formula (I) and their preparation are known and are described, for example, in US Pat. Nos. 4,219,559 and 4,556,660.

In addition to the methods described in the above patents, the compounds of general formula (I) may also be prepared by a number of novel methods which constitute another embodiment of the present invention.

The compound of the general formula (I) can be prepared by reacting the piperidine derivative of the general formula (II) with the benzimidazole derivative of the general formula (III), and then optionally decarboxylation the reaction.

In Formulas (II) and (I-a), L ¹ has the same meaning as L except hydrogen, and in Formulas (II) and (III), each of Q ¹ and Q ² represents a compound (II) and During the reaction with the compound (III), a group is selected such that -NR ² -is formed which connects the piperidine and benzimidazole sites. For example, Q ¹ may be a radical —NHR ² and Q ² may be a radical —W, or conversely, Q ¹ may be a radical —W ′ and Q ² may be a radical —NHR ² .

In formulas (III-a) and (II-b), W and W 'are halo, such as chloro, bromo or iodo or sulfonyloxy groups, such as methylsulfonyloxy or 4-methylphenylsulfonyloxy It may be a suitable leaving group, while W may also be alkyloxy or alkylthio.

The reaction of compound (II-a) with (III-a) and the reaction of compound (II-b) with (III-b) include aromatic 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; Dimethyl sulfoxide (DMSO); Easily in an inert organic solvent such as 1-methyl-2-pyrrolidinone or the like. Suitable base or organic bases, such as alkali metal carbonates or hydrogen carbonates, sodium hydride, for example N, N-diethylethanamine or N- (1-methylethyl) -2-propanamine, are added to free the reaction process. You can extract the acid. In some cases it is suitable to add iodide salts, preferably alkali metal iodides. Slightly warming up may speed up the reaction. On the other hand, Q ¹ may be an oxo radical, and Q ² may be a radical —NHR ² .

The reaction of compound (II-c) with (III-b) is easily carried out by treating the mixture of reactants with a suitable reducing agent in a suitable reaction-inert organic solvent. The reaction mixture may be stirred and / or heated to accelerate the reaction rate. Preferably, the piperidine of formula (II-c) is first reacted with benzimidazole amine of formula (III-b) to form an enamine, which is optionally isolated and further purified, and then the en The amine is reduced. Examples of suitable solvents include water; C _1-6 alkanols such as methanol, ethanol, 2-propanol and the like; Cyclic ethers such as 1,4-dioxane and the like; Halogenated hydrocarbons such as chlorchloromethane and the like; N, N-dimethylformamide; N, N-dimethylacetamide; Dimethyl sulfoxide and the like; Or mixtures of these solvents. Examples of suitable reducing agents are metals or metal hydrides such as sodium borohydride, lithium aluminum hydride, or hydrogen, with hydrogen being preferably used in the presence of a suitable catalyst such as palladium on charcoal, platinum on charcoal and the like. It may be advantageous to add a suitable catalyst poison, such as thiophene, to the reaction mixture to prevent unwanted further hydrogenation of certain functional groups in the reactants or reaction products.

Decarboxylation of compound (I-a) to prepare piperidine compound of formula (I-b) is carried out by treating the starting compound of formula (I-a) with an acid or a base in a suitable solvent. can do. Suitable acids or bases may include hydrochloric acid, for example hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, and the like, which acid is preferably used in aqueous solution or mixed with acetic acid, for example. Suitable bases are alkali metal hydroxides, hydrides or alkoxides in aqueous or alcoholic media.

In all of the above and below processes, the reaction product can be isolated from the reaction mixture and, if necessary, further purified according to methods generally known in the art.

Compounds of general formula (I) have basic properties and are therefore suitable acids, such as hydrochloric acid, such as hydrochloric acid, hydrobromic acid and the like, inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and the like; Or acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E ) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, Treatment with organic acids such as benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid can be converted to therapeutically active non-toxic acid addition salt forms.

Conversely, the salt form can be converted to the free base form by treatment with alkali.

Intermediates and starting materials in the above production methods are known compounds that can be prepared according to methods known in the art for preparing the compounds or similar compounds.

From the compounds of general formula (I), it is clear that the compounds of the present invention may have several asymmetric carbon atoms in their structure. Each of these chiral centers may exist in R- and S- configuration, and these R- and S- notations are described in the literature “R. S. Cahn, C. Ingold and V. Prelog in Angew. Chem., Int. Ed. Engl., 5, 385, 511 (1966) ”.

Pure stereochemically isomeric forms of the compounds of general formula (I) can be obtained using processes known in the art. Diastereomers can be separated by physical separation methods such as fractional crystallization and chromatography techniques, such as countercurrent distribution, and enantiomers can be separated from one another by fractionally determining their diastereomeric salts with optically active acids.

Provided that the reaction occurs stereospecifically, pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the suitable starting materials. Cis and trans diastereomeric racemates can be further divided into their optical isomers cis (+), cis (-), trans (+) and trans (-) using methods known to those skilled in the art. have.

Stereochemically isomeric forms of the compounds of formula (I) are meant to be included within the scope of the invention as a matter of course.

Another feature of the invention R ¹ is C _1-6 alkyl-and the C _1-6 alkyl substituted with substituted furanyl, said C _1-6 alkyl-substituted furanyl is 5-methyl-2-furanyl It is a fact that compounds of general formula (I), which are not represented by general formula (I-c), and pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof are novel compounds.

The compounds of the preferred novel ^R-1 is ^a 3- or 4- (C _1-6 alkyl) substituted with 2-furanyl 2- (C _1-6 alkyl) C _1- substituted-3-furanyl _It is a compound of the general formula (I-c) which is ₆ alkyl.

Particularly preferred novel compounds are methyl wherein R ^1-a is substituted with 3- (C _1-6 alkyl) -2-furanyl, R ² is sorghum, R is hydrogen, and A ¹ = A ² -A ³ = A ⁴ is a compound wherein CH = CH-CH = CH or N = CH-CH = CH.

Some of the compounds of formula (I) which can be used as active ingredients in the compositions and methods of treatment according to the invention are listed in the following table for the purpose of illustration, not limitation.

TABLE 1

TABLE 2

*: cis + trans isomer

TABLE 3

*: (+)-[R- (R *, R *)]-2,3-dihydroxybutanedioate (2: 3)

TABLE 4

The use of the compounds of formula (I), their pharmaceutically acceptable acid addition salts or possible stereochemically isomeric forms in the compositions of the invention is based on their useful pharmacological properties. More particularly, they are active as antihistamines, and this activity is clearly demonstrated by the results obtained in the "Protection of Rats from Compound 48 / 80-Induced Death" test. In addition, these compounds have no soothing effect, an unwanted side effect often caused by antihistamines. In addition to antihistamine properties, these compounds also exhibit serotonin-antagonism.

In addition, the compounds of formula (I), their pharmaceutically acceptable acid addition salts or stereochemically isomeric forms are of particular interest due to their useful pharmacodynamic effects. On the other hand, these compounds show rapid onset so that antihistamine effects are present almost instantaneously. On the other hand, these compounds have an effective duration of action, ie not too short and not too long without the need for frequent administration. Therefore, the dosage may be appropriately adopted depending on the progress of the symptoms.

In order to prepare a pharmaceutical composition of the present invention, an effective amount of a specific compound in the form of a base or an acid addition salt as an active ingredient is mixed in a complete mixture with a pharmaceutically acceptable carrier, which may be in various forms depending on the form of preparation desired for administration. Can be taken. These pharmaceutical compositions are preferably in a single dosage form suitable for oral, rectal, transdermal or parenteral injection. Preparation of compositions in oral dosage form includes, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; Or in the case of powders, pills, capsules and tablets, conventional pharmaceutical media such as starch, sugar, solid carriers such as kaolin, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case clearly solid pharmaceutical carriers are used. In parenteral compositions, other components, such as those for enhancing solubility, may be included, but the carrier generally consists of at least mostly sterile water. For example, an injectable solution may be prepared in which the carrier consists of saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In a composition suitable for transdermal administration, the carrier may optionally contain a penetration enhancer and / or a suitable hydrating agent, optionally with a small amount of suitable additives of a certain nature that do not cause any harmful effects on the skin. Such additives may facilitate administration to the skin and / or may be useful for preparing the desired composition. These compositions can be administered in a variety of ways, for example as a transdermal patch, spot-on or ointment.

Acid addition salts of compounds of formula (I) are obviously more suitable for the preparation of aqueous compositions, since they have increased water solubility than the corresponding base forms. It is particularly advantageous to formulate the pharmaceutical compositions described above in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein and in the claims refers to physically discrete units suited to a single dosage containing a predetermined amount of active ingredient calculated to achieve the desired therapeutic effect with the required pharmaceutical carrier. . Examples of these dosage unit forms include tablets (engraved or coated tablets), capsules, pills, powder packages, wafers, injection solutions or injection suspensions, teaspoon doses, table spoon doses, and the like, and these Of several doses.

In another embodiment of the present invention, allergy is characterized by administering an anti-allergic effective amount of the general formula (I) compound, a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof to a warm-blooded animal suffering from an allergic disease. Provided are methods for treating allergic diseases in warm-blooded animals suffering from the disease. Preferred effective amounts of the active ingredient are administered as a composition as described above. One skilled in the art can easily determine the effective amount of antiallergic from the test results presented herein. In general, an effective amount is considered to be between 0.001 and 100 mg, more preferably between 0.01 and 1 mg per kg of body weight.

EXAMPLE

A) Preparation of Intermediates

Example 1

N ² - (2- furanyl methyl) pyridine-2,3-diamine, 47.5 parts of methyl (α- amino -α- methoxymethyl) carbamate, 36.5 parts, 34.5 parts and stirring 450 parts of methylbenzene and a mixture of acetic acid Heat at 65-68 ° C. for 16 hours. The reaction mixture is evaporated. 140 parts of potassium hydroxide, 50 parts of water and 400 parts of 2-propanol are added to the residue and stirring is continued for 16 hours under reflux. The reaction mixture is concentrated to 1/4 volume. 500 parts of water are added and 2-propanol is removed by azeotropic distillation. After stirring for 1 hour at room temperature, the product is filtered off and washed two times with 20 parts of water and three times with 12 parts of 2-propanone followed by crystallization with 1,2-dichloroethane. The product was filtered and dried at 50 ° C. under vacuum to give 27.3 parts (51.0%) of 3- (2-furanylmethyl) -3H-imidazo [4,5-b] pyridin-2-amine having a melting point of 193.3 ° C. do.

B) Preparation of the Final Compound

Example 2

22.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 3- (2-furanylmethyl) -3H-imidazo [4,5-b] pyridin-2-amine, 21.4 parts, methylbenzene 360 parts And 0.1 part of 4-methylbenzenesulfonic acid are stirred for 4 days at reflux using a water separator. After cooling to 50 ° C., 64 parts of ethanol and 3.8 parts of sodium tetrahydroborate are added little by little to the reaction mixture. After the addition is complete, stirring is continued at 50 ° C. for 2 hours. After cooling, the mixture is decomposed with 3.5 parts of acetic acid. Water is added to the mixture with stirring to separate the layers. The aqueous layer is extracted with methylbenzene. The combined methylbenzene layers were dried, filtered and evaporated to ethyl 4-[[3- (2-furanylmethyl) -3H-imidazo [4,5-b] pyridin-2-yl] as an oily residue. Amino] -1-piperidinecarboxylate (Compound 56) is obtained.

Example 3

Ethyl 4-[[3- (2-furanylmethyl) -3H-imidazo [4,5-b] pyridin-2-yl] amino] -1-piperidinecarboxylate, 50 parts of potassium hydroxide, 2 Propanol is stirred at a mixture of 400 parts and 20 drops of water and refluxed for about 5 hours. The reaction mixture is evaporated and water is added to the residue. The product is extracted twice with 4-methyl-2-pentanone. The combined extracts are dried, filtered and then evaporated. The solid residue is stirred in 1-1'-oxybisetane. The product was filtered and dried to give 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine (compound 140) having a melting point of 159.0 ° C. 34 parts (85%) are obtained.

Example 4

A mixture of 9.8 parts of ethyl 4-amino-1-piperidinecarboxylate and 15 parts of 2-chloro-1- (4-fluorophenylmethyl) -1H-benzimidazole is heated to 120 ° C. The mixture is stirred at 120 ° C. for 43 hours. After cooling, 100 parts of trichloromethane are added and the whole is stirred thoroughly. The mixture is washed with water. The aqueous layer is separated and the glass mixture is filtered and then evaporated. The solids are combined and dissolved in 100 parts of water, followed by 100 parts of 20% sodium hydroxide solution. The precipitate was filtered and dried at 50 ° C. under vacuum to ethyl 4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] amino] -1-piperi having a melting point of 181 ° C. 12.1 parts (40.5%) of deancarboxylate (Compound: 21) are obtained.

Example 5

Stir a mixture of 3.2 parts of ethyl 4- [1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-ylamino] -1-piperidinecarboxylate and 300 parts of 48% hydrobromic acid solution And reflux for 1 hour. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product was filtered and dried to give 1-[(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazol-2-amine dihydrobromide (Compound 112) 3.3 with a melting point of 290.2 ° C. 3.3 Part (82%) is obtained.

All other compounds listed in Tables 1-4 can be obtained by similar preparation methods.

C) Pharmacological Example

The useful antihistamine properties of the general formula (I) compounds which can be used as active ingredients in the preparations according to the invention can be demonstrated by the following test procedure.

Example 6

[Protection of Rats from Compound 48 / 80-Induced Lethality]

A mixture of oligomers obtained by condensation of compound 48/80, 4-methoxy-N-methylbenzeneethanamine and formaldehyde is known as an effective histamine releaser (see Int. Arch. Allergy. 13, 336 (1958). The protective effect from compound 48 / 80-induced lethal circulatory collapse is a simple way to quantitatively measure the antihistamine activity of a test compound: inbred Wistar male rats weighing 240-260 g. The mice are fasted overnight and then transferred to a laboratory with a temperature of 21 ± 1 ° C. and a relative humidity of 65 ± 5%, and the test compound or solvent (0.9% NaCl solution) is added to the test mice. Subcutaneous or oral administration One hour after administration, Compound 48/80 immediately dissolved in water is injected intravenously into mice at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight). 2.8% or less after 4 hours in solvent-treated animals . The injection of compound 48/80 the quantity standard dose of the animals survived after 4 therefore sees the survival time in the safety standards of the protection effect of the ED ₅₀ dose of the Formula (Ⅰ) compound-values are shown in Table 5 The ED ₅₀ -value is the value (mg / kg body weight) in which the test compound complements 50% of the test animals from Compound 48 / 80-induced lethality.

TABLE 5

D) Composition Examples

The following formulations illustrate representative pharmaceutical compositions in dosage unit form suitable for systemic administration to animals and humans in accordance with the present invention. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

Example 7

[Oral drops]

500 g of 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-amidazo [4,5-b] pyridin-2-amine at 60 to 80 ° C., 2-hydroxypropanoic acid Dissolve in 0.5 L and 1.5 L polyethylene glycol. After cooling to 30-40 [deg.] C. 35 l of polyethylene glycol are added and the mixture is stirred well. Then, a solution of 1750 g of sodium saccharin in 2.5 liters of purified water was added thereto, and an appropriate amount of polyethylene glycol was added to a volume of 2.5 liters and 50 liters of cocoa flavor with stirring, and 3- (2-furanylmethyl) -N- (4- An oral drop solution containing 10 mg of piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine is obtained. The solution obtained is filled in a suitable container.

Example 8

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 L of boiling purified water. 3 g of this solution was first dissolved in 10 g of 2,3-dihydroxybutanedioic acid, followed by 3-l (5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imide 20 g of polyzo [4,5-b] pyridin-2-amine are dissolved. The latter solution is combined with the remaining solution of the former, to which 12 l of 1,2,3-propanetriol and 3 l of 70% sorbitol solution are added. 40 g of sodium saccharin is dissolved in 0.5 liter of water, and 2 ml of raspberry stock solution and 2 ml of gooseberry stock solution are added. The latter solution is combined with the former solution and an appropriate amount of water is added to make a volume of 20 liters, and then 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H per teaspoon (5 ml). Obtain an oral solution containing 20 mg of imidazo [4,5-b] pyridin-2-amine. The solution obtained is filled in a suitable container.

Example 9

20 g of 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine, 6 g of sodium laurylsulfate, 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 hard gelatin suitable to contain 20 mg of 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine per unit. Fill 1000 capsules.

Example 10 Film-coated Tablets

[Production of Tablet Nuclei]

100 g of 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine, 570 g of lactose and 200 g of starch The mixture is mixed well and then wetted with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml. The hydrated powder mixture is sieved, dried and sifted again. Thereafter, 100 g of microcrystalline cellulose and 15 g of hardened vegetable oil are added thereto. The whole was mixed well and compressed with tablets to yield 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridine-2 10,000 tablets containing 10 mg of amine are obtained.

[covering]

30ml를 가하고 전체 혼합물을 균질화시킨다. 피복장치내에서 이렇게하여 수득된 혼합물로 정제핵을 피복시킨다.To a solution of 10 g of methyl cellulose in 70 ml of modified ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are then added. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. After the latter solution was added to the former solution, 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and concentrated pigment suspension (Opaspray K-1-2109

30 ml are added and the whole mixture is homogenized. The tablet nucleus is coated with the mixture thus obtained in the coating apparatus.

Example 11

[Injection solution]

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in about 0.5 liter of boiling water for injection. After cooling to about 50 ° C., the solution is stirred with lactic acid, 4 g, propylene glycol 0.05 g and 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5- b] 4 g of pyridin-2-amine are added. After the solution was cooled to room temperature, an appropriate amount of water for injection was added to a volume of about 1 liter, and 3- (2-furanylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5 per 1 ml] was added. -b] a solution containing 4 mg of pyridin-2-amine is obtained. The solution is sterilized by filtration (U.S.P. ⅩⅦ p. 811) and filled into sterile containers.

Example 12

[Canceling]

3 g of 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine was added to 2 g of 25 ml of polyethylene glycol 400. It is dissolved in a solution of 3 g of, 3-dihydroxybutanedioic acid. An appropriate amount of triglyceride is melted together to make 12 g and 300 g of surfactant. The latter mixture is mixed well with the former solution. The mixture thus obtained was poured into a mold at a temperature of 37 to 38 ° C. to yield 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4, per each 100b suppositories containing 30 mg of 5-b] pyridin-2-amine are formed.

Claims (13)

An antiallergic composition comprising as an active ingredient at least one pharmaceutical carrier and at least one effective amount of an antiallergic compound of formula (I), a pharmaceutically acceptable acid addition salt thereof or a granular isomer thereof

Wherein L is hydrogen, C _1-6 alkyloxycarbonyl or phenylmethoxycarbonyl, and A ¹ = A ² -A ³ = A ⁴ is a structural formula -CH = CH-CH = CH- (a), -N Is a divalent radical of = CH-CH = CH- (b), and one or two hydrogen atoms of these radicals (a) and (b) are each independently of each other halo, C _1-6 alkyl, C _1-6 alkyl May be substituted with oxy, trifluoromethyl or hydroxy, R is selected from the group consisting of hydrogen and C _1-6 alkyl, R ¹ is C _1-6 alkyl substituted with Ar ¹ , and R ² is From the group consisting of hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, (C _1-6 alkyl) -CO-, (C _1-6 alkyloxy) -CO- and Ar ² -C _1-6 alkyl Ar ¹ is selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di -(C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkyl-CO- Phenyl optionally substituted with up to 3 substituents each independently selected; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Pyridinyl; Pyrazinyl; Is selected from the group consisting of thiazolyl and imidazolyl optionally substituted by C _1-6 alkyl, Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _{1- 6} alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di- (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and (C _1-6 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 CO-. The compound of claim 1, wherein R is hydrogen, R ² is hydrogen or C _1-6 alkyl, and Ar ¹ is each independently selected from two or more substituents selected from the group consisting of halo, hydroxy and C _1-6 alkyl. Phenyl optionally substituted by; Pyridyl; Amidazolyl; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; An antiallergic composition that is tazozolyl or pyrazinyl. The compound of claim 1, wherein the compound is 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine Phosphorus antiallergic composition. Warm blood except humans, characterized by systemic administration of an anti-allergic effective amount of a compound of the general formula (I), a pharmaceutically acceptable acid addition salt thereof, or a stereochemical isomer thereof to a warm-blooded animal, except for those suffering from allergic diseases How to treat allergic diseases in animals.

Wherein L is hydrogen, C _1-6 alkyloxycarbonyl or phenylmethoxycarbonyl, and A ¹ = A ² -A ³ = A ⁴ is a structural formula -CH = CH-CH = CH- (a), -N = CH-CH = CH- (b), -CH = N-CH = CH- (c), -CH = CH-N = CH- (d) or -CH = CH-CH = N- (e) Are divalent radicals, and one or two hydrogen atoms of the radicals (a) to (e) are each independently of one another by halo, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl or hydroxy; And R is selected from the group consisting of hydrogen and C _1-6 alkyl, R ¹ is selected from hydrogen, C _1-10 alkyl, C _3-6 cycloalkyl, Ar ¹ and 1 or 2 Ar ¹ radicals. It is selected from the group consisting of C _1-6 alkyl substituted by, R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, (C _1-6 alkyl) -CO-, Is selected from the group consisting of (C _1-6 alkyloxy) -CO- and Ar ² -C _1-6 alkyl, Ar ¹ is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl , C _1-6 alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkyl Phenyl optionally substituted with up to 3 substituents each independently selected from the group consisting of -CO-; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Pyridinyl; Pyrazinyl; Is selected from the group consisting of taazolyl and imidazolyl optionally substituted by C _1-6 alkyl, Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _{1- 6} alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl, and (C _1-6 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 CO-. The method of claim 4, wherein A ¹ = A ² -A ³ = A ⁴ is a divalent radical of formula (a) or (b) and R ¹ is C _1-6 alkyl substituted by Ar ¹ . The method of claim 5, wherein R ¹ is furanylmethyl or (C _1-6 alkyl) furanylmethyl. A compound of formula (I-c), a pharmaceutically acceptable acid addition salt thereof, or a stereochemical isomer thereof:

Wherein L is hydrogen, C _1-6 alkyloxycarbonyl or phenylmethoxycarbonyl, and A ¹ = A ² -A ³ = A ⁴ is a structural formula -CH = CH-CH = CH- (a), -N = CH-CH = CH- (b), -CH = N-CH = CH- (c), -CH = CH-N = CH- (d) or -CH = CH-CH = N- (e) Are divalent radicals, and one or two hydrogen atoms of the radicals (a) to (e) are each independently of one another by halo, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl or hydroxy; may be substituted, R is selected from the group consisting of hydrogen and C _1-6 alkyl, R ^1-a is C _1-6 alkyl-substituted with C _1-6 alkyl substituted by a furanyl, provided that the C _1-6 alkyl-substituted furanyl is not 5-methyl-2-furanyl, R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, (C _1-6 alkyl) -CO-, (C _1-6 alkyloxy) -CO- and Ar ² -C _1-6 alkyl, Ar ¹ is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl , C _1-6 alkyloxy, C ₁ Each independently from the group consisting of _-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkyl-CO- Phenyl optionally substituted with up to 3 substituents selected; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Pyridinyl; Pyrazinyl; Is selected from the group consisting of thiazolyl and imidazolyl optionally substituted by C _1-6 alkyl, Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _{1- 6} alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl, and (C _1-6 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 CO-. The method of claim 7 wherein, R ^1-a is 3-or 4- (C _1-6 alkyl) -2-furanyl or 2-substituted by a C _1- (C _1-6 alkyl) -3-furanyl ₆ alkyl. The piperidine of general formula (II) is reacted with benzimidazole of general formula (III) in a reaction-inert solvent, and the L ¹ group of the compound of general formula (I-a) obtained as necessary is subsequently decarboxylated. A process for preparing a compound of formula (I), a pharmaceutically acceptable acid addition salt thereof, or a stereochemical isomer thereof, characterized by inactivation.

Wherein L is hydrogen, C _1-6 alkyloxycarbonyl or phenylmethoxycarbonyl, and A ¹ = A ² -A ³ = A ⁴ is a structural formula -CH = CH-CH = CH- (a), -N = CH-CH = CH- (b), -CH = N-CH = CH- (c), -CH = CH-N = CH- (d) or -CH = CH-CH = N- (e) Are divalent radicals, and one or two hydrogen atoms of the radicals (a) to (e) are each independently of one another by halo, C _1-6 alkyl, C _1-6 alkyloxy, trifluoromethyl or hydroxy; May be substituted, R is selected from the group consisting of hydrogen and C _1-6 alkyl, R ¹ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, Ar ¹ and 1 or 2 Ar ¹ radicals; Is selected from the group consisting of C _1-6 alkyl substituted by R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, (C _1-6 alkyl) -CO—, (C _1-6 alkyl) Oxy) -CO- and Ar ² -C _1-6 alkyl, Ar ¹ is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyl Group consisting of oxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkyl-CO- Phenyl optionally substituted with up to 3 substituents each independently selected from among; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Pyridinyl; Pyrazinyl; Is selected from the group consisting of thiazolyl and imidazolyl optionally substituted by C _1-6 alkyl, Ar ² is halo, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _{1- 6} alkyloxy, C _1-6 alkylthio, mercapto, amino, mono- and di (C _1-6 alkyl) -CO-, carboxyl, C _1-6 alkyloxycarbonyl, and (C _1-6 alkyl ) Is selected from the group consisting of phenyl optionally substituted with up to three substituents independently selected from the group consisting of -CO-, L ¹ has the same meaning as L, but is not hydrogen, general formula (II) And in (III) Q ¹ is -NHR ² , Q ² is -W, Q ¹ is -W, R ² is -NHR ² , Q ¹ is = O, Q ² is -NHR ² , W is a reactive leaving group. The antiallergic composition of claim 2, wherein R ¹ is furanylmethyl or (C _1-6 alkyl) furanylmethyl. The compound of claim 5, wherein R is hydrogen, R ² is hydrogen or C _1-6 alkyl, and Ar ¹ is independently selected from two or more substituents selected from the group consisting of halo, hydroxy and C _1-6 alkyl. Phenyl optionally substituted by; Pyridyl; Imidazolyl; Thienyl; Halothienyl; Furanyl; C _1-6 alkyl-substituted furanyl; Thiazolyl or pyrazinyl. The compound of claim 4, wherein the compound is 3-[(5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine How to be. The compound of claim 2, wherein R ^1-a is methyl substituted by 3- (C _1-6 alkyl) -2-furanyl, R ² is hydrogen, R is hydrogen, A ¹ = A ² -A ³ = A ⁴ is a radical of the formula —CH—CH—CH═CH— (a) or —N═CH—CH═CH— (b).