JP2864489B2 - Asthma treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for asthma comprising a 4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound, an optical isomer thereof and a pharmaceutically acceptable acid addition salt thereof.

[0002]

BACKGROUND OF THE INVENTION WO 90/05723 describes certain trans-4-amino (alkyl) -1-amines.
Pyridylcarbamoylcyclohexane compounds, their optical isomers, and their pharmaceutically acceptable acid addition salts have a sustained coronary, cerebral and renal blood flow increasing action, and are used as antihypertensive agents and circulatory systems such as coronary, cerebral and renal It is disclosed that it is useful as an agent for preventing and treating diseases.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have proposed a 4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound containing the above-mentioned trans form, which has a sustained coronary / cerebral / renal blood flow increasing action. The present inventors have found that optical isomers and pharmaceutically acceptable acid addition salts thereof are useful for treating asthma, and have completed the present invention.

[0004]

That is, the present invention provides a compound of the general formula

Embedded image (Wherein R ¹ and R ² are the same or different and each represents hydrogen,
Alkyl having 1 to 10 carbons, alkanoyl having 2 to 5 carbons, formyl, alkoxycarbonyl having 1 to 4 carbons, amidino, or 3 to 7 carbons which may have a substituent on the ring Cycloalkyl, cycloalkylcarbonyl having 3 to 7 carbon atoms, phenyl, phenylalkyl, benzoyl, naphthoyl, phenylalkoxycarbonyl, benzylidene, pyridylcarbonyl, piperidyl, pyrrolidylidene or pyridylidene,
Or R ¹ and R ² are a group forming a 5- or 6-membered ring which may contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring together with the nitrogen atom to which it is bonded. Or a group which forms phthalimide with a nitrogen atom bonded thereto, R ³ represents hydrogen, alkyl having 1 to 4 carbons, R ⁴ represents hydrogen, alkyl having 1 to 4 carbons, ⁵ represents hydrogen, a hydroxyl group, alkyl having 1 to 4 carbon atoms, or phenylalkoxy; R ⁶ represents hydrogen, 1 carbon atom;
A represents 4 alkyl, A represents a single bond, linear alkylene having 1 to 5 carbon atoms or alkylene substituted with alkyl having 1 to 4 carbon atoms, and n represents 0 or 1. )
The present invention relates to a therapeutic agent for asthma comprising a 4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound represented by the formula (I), an optical isomer thereof and a pharmaceutically acceptable acid addition salt thereof.

Further, as a preferred compound as a therapeutic agent for asthma of the present invention, a compound represented by the following general formula:

Embedded image (Wherein R ^1a and R ^2a are the same or different and are hydrogen, or phenylalkyl, phenylalkoxycarbonyl or R ^1a and R ^{2a which} may have a substituent on the ring are substituted on the ring together. R ⁷ and R ⁸ are the same or different and represent hydrogen or alkyl having 1 to 4 carbons; R ^3a represents hydrogen, a hydroxyl group, 1 to 4 carbons; Represents 4 alkyls, R ^5a ,
R ^6a is the same or different and represents hydrogen or alkyl having 1 to 4 carbons. 4-aminoalkyl- represented by
Examples include 1-pyridylcarbamoylcyclohexane compounds, optical isomers thereof, and pharmaceutically acceptable acid addition salts thereof.

In the present specification, alkyl having 1 to 10 carbon atoms means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. 2 to 5 alkanoyls include acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pivaloyl, valeryl, etc., and alkoxycarbonyls having 1 to 4 carbon atoms are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy. Carbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl and the like; cycloalkyl having 3 to 7 carbon atoms means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloalkyl having 3 to 7 carbon atoms; Carbonyl is cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, phenylalkyl is benzyl, phenylethyl, phenylpropyl, phenylbutyl, etc., and phenylalkoxycarbonyl is phenylethoxycarbonyl, phenylpropoxy. Carbonyl, phenylbutoxycarbonyl, etc., pyridylcarbonyl is 2-pyridylcarbonyl, nicotinoyl, isonicotylnoyl, piperidyl is 2-piperidyl, 3-piperidyl, 4-piperidyl, pyrrolidylidene is 2-pyrrolidylidene, 3-pyrrolidylidene and piperidylidene are 2-piperidylidene, 3-piperidylidene and 4-piperidylidene, each having 5 to 6 members together with a nitrogen atom. And the like are pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino and the like, phenylalkoxy is benzyloxy, phenylethoxy, phenylpropoxy, phenylbutoxy and the like, and linear alkylene having 1 to 5 carbon atoms is Methylene, ethylene, trimethylene,
Alkylene in which tetramethylene and pentamethylene are substituted with alkyl having 1 to 4 carbon atoms is methylmethylene,
Propylene, methyl trimethylene, dimethyl ethylene,
Dimethyltetramethylene, ethylethylene, dimethyltrimethylene and the like, and alkyl having 1 to 4 carbon atoms represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like, respectively.

The substituents which may be possessed in each symbol of [Chemical Formula 2] include halogen such as chlorine, iodine, bromine and fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl. Alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc. having 1 to 4 carbon atoms, benzyl, phenylethyl, phenylpropyl, phenylbutyl, etc. Phenylalkyl, nitro, amino and the like.

The compound of the formula [2] of the present invention also includes pharmaceutically acceptable acid addition salts, hydrates or various solvates formed together with inorganic acids, organic acids and the like. When an asymmetric carbon is present in the compound of the formula [2] of the present invention, optical isomers and racemic forms thereof may exist, but the present invention includes all of them.

The compound of the formula [2] of the present invention can be easily produced, for example, by the method described in the specification of WO 90/05723.

Method 1 General formula

Embedded image (Wherein each symbol has the same meaning as described above) and a carboxylic acid compound represented by the following formula:

Embedded image (Wherein each symbol is as defined above). Reactive derivatives of carboxylic acid compounds include acid halides such as acid chlorides, acid anhydrides, mixed acid anhydrides formed from ethyl chloroformate and the like, methyl esters and esters such as ethyl esters, and dicyclohexylcarbodiimide. And reactive derivatives generated from such carbodiimides. The reaction is carried out in the presence of a solvent inert to the reaction, but usually, tetrahydrofuran, ethyl acetate,
Organic solvents containing no hydroxyl group, such as benzene, toluene, carbon tetrachloride, chloroform, methylene chloride and dimethylformamide, are used. The reaction is carried out at an arbitrary temperature, for example, -10 to 200 ° C, preferably 0 to 80 ° C. In the case of a non-reactive reactive derivative (eg, ester) as a raw material, a high reaction temperature is used. In the case of highly reactive derivatives (eg mixed acid anhydrides), lower reaction temperatures are used.

Method 2 Among the compounds of the formula 2, one of R ¹ and R ² is hydrogen and the other is other than hydrogen, a compound of the general formula

Embedded image (Wherein each symbol has the same meaning as described above), and can be produced by reacting an amine compound represented by the following formula with a carboxylic acid compound or a reactive derivative thereof, a halide compound, an aldehyde compound or a ketone compound.

The carboxylic acid compound used in this reaction is represented by the formula R ⁷ —COOH (VI) (where R ⁷ is hydrogen, alkyl having 1 to 4 carbon atoms or carbon atom which may have a substituent) A cycloalkyl, phenyl, or pyridyl of the number 3 to 7), and the reactive derivative thereof is a compound formed from an acid halide, an acid anhydride, a mixed acid anhydride, an ester, or a carbodiimide. Derivatives, etc., and the halide compound is represented by the formula R ⁸ -Hal (VII) (wherein R ⁸ is alkyl having 1 to 10 carbons or 3 to 7 carbons which may have a substituent) cycloalkyl, phenyl, and Hal is chlorine, iodine, fluorine, a compound represented by showing the bromine.), aldehyde compound, wherein R ⁹ -CHO (VIII) (wherein, R ⁹ is hydrogen, Prime 1-9 alkyl, a compound represented by.) Showing the phenyl which may have a substituent, the ketone compound of the formula

Embedded image (Wherein R ¹⁰ and R ¹¹ are the same or different and each have 1 to 9 carbon atoms)
Or R ¹⁰ and R ¹¹ represent cycloalkyl having 3 to 7 carbon atoms which may have a substituent by bonding to a carbonyl group. ).

When reacting the compound of the formula [6] with a carboxylic acid or a reactive derivative thereof, the reaction can be carried out under the same conditions as in the method 1, but the compound of the formula [6] is reacted with a ketone or aldehyde. When reacting with
Usually, a dehydration reaction is carried out with a solvent which is hardly miscible with water, for example, benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane and the like. At this time, it is also advantageous to add a small amount of an acid such as paratoluenesulfonic acid. Further, it can also be produced by subjecting an alkylidene obtained by dehydration condensation and a benzylidene compound optionally having a substituent to a reduction reaction.

The reduction reaction is usually carried out in an alcohol such as methanol, ethanol, isopropyl alcohol, or the like.
It can be performed at 10 to 100 ° C, preferably 0 to 40 ° C. As the reducing agent, sodium borohydride, a small amount of hydrochloric acid, hydrobromic acid, a reducing agent such as sodium cyanoborohydride in the presence of an acid such as acetic acid,
When there is no effect on other groups of the target compound, the compound can also be produced by performing a reductive amination reaction using a catalytic reduction method using Raney nickel, palladium carbon, platinum oxide or the like.

Method 3 Among the compounds of the formula 2, R ¹ and R ² represent phenylalkyl or piperidyl which may have a substituent, and R ¹ and R ² have a substituent. Benzylidene or piperidylidene which may be optionally subjected to a reduction reaction. The reduction reaction is usually performed in an alcohol such as methanol, ethanol, or isopropyl alcohol at -10 to 100C.
Preferably, it can be carried out at 0 to 40 ° C. It is preferable to use sodium borohydride as the reducing agent, but if it does not affect other groups of the target compound, catalytic reduction with palladium carbon, platinum oxide, or the like can be performed.

Method 4 Of the compounds of the formula (2), those compounds which form a 5- to 6-membered ring together with the nitrogen atom to which R ¹ and R ² are bonded are represented by the general formula

Embedded image Or general formula

Embedded image (In the formulas [Chem. 8] and [Chem 9], Y is oxygen, sulfur or an optionally substituted nitrogen, and Z is halogen (chlorine, bromine, etc.), sulfonyloxy (methanesulfonyloxy, p -Reactive derivatives of alcohols such as toluenesulfonyloxy.) And a compound in which both R ¹ and R ^{2 in} Chemical Formula ² are hydrogen. The reaction can be performed using the same conditions as in Method 2.

Method 5 Among the compounds of the formula 2, compounds in which R ¹ and R ² are both hydrogen can be produced by a reaction using the following compounds. (I) Among the compounds of the formula ² , the production reaction from a compound in which R ¹ and R ² are alkoxycarbonyl and aralkyloxycarbonyl having 1 to 4 carbon atoms is 3 to 35%, preferably 15 to 30%. % Of acetic acid in the presence of hydrogen bromide at 0 to 50 ° C., preferably at about 5 to 30 ° C., whereby both R ¹ and R ² of the To a compound.

In particular, among the compounds of the formula 2, R ¹
And a compound in which R ² is an alkoxycarbonyl having 1 to 4 carbon atoms, in a suitable organic solvent which does not affect the reaction, for example, alcohol (methanol, ethanol, isopropyl alcohol, etc.), ether (tetrahydrofuran, etc.) By stirring and, if necessary, heating in the presence of a base, for example, an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate (sodium hydroxide, potassium carbonate, sodium bicarbonate, etc.). The target compound can be produced. Further, in the case of a compound in which R ¹ and R ² are phenylalkoxycarbonyl among the compounds of the formula ² , in an appropriate organic solvent which does not affect the reaction, palladium carbon or the like can be obtained. Hydrogen, hydrazine, formic acid, formic acid in the presence of a suitable catalyst Such as by using ammonium, it can also be produced by performing reductive decomposition reaction at room temperature or under, if necessary under pressure.

(Ii) Of the compounds of the formula (2), R ¹ ,
The production reaction from a compound forming phthalimide together with the nitrogen atom to which R ² is bonded is carried out using acetone, tetrahydrofuran or a water-containing solvent thereof in the presence of sodium sulfide hydrate at -5 ° C. to room temperature, Preferably, stirring is performed at 0 to 5 ° C., and the obtained intermediate is subjected to a dehydration reaction in dicyclohexylcarbodiimide or trifluoroacetic acid in the presence of triethylamine. The obtained intermediate was further stirred at -20 ° C with anhydrous hydrazine in tetrahydrofuran to obtain R ¹ and R
² together can be converted to the compound is hydrogen.
Further, the phthaloyl compound can be directly converted into an amino compound in an alcohol in the presence of hydrazine.

(Iii) Among the compounds of the formula 2, R ¹
And preparation from compounds in which R ² is benzylidene, pyridylidene or pyrrolidylidene. The reaction can be carried out at room temperature or at 30 ° C. in the presence of a dilute acid solution having a concentration which does not affect other substituents, such as 5% hydrochloric acid, 5% sulfuric acid or the like. It can be produced by heating and stirring at ６０60 ° C., and a solvent such as an alcohol can be used during the reaction. Further, among the compounds of the formula 2, R ¹ and R
^A compound in which both are hydrogen can also be produced by subjecting the nitrile compound to a reduction reaction.
The reaction can be carried out by a general reduction method using a reagent which does not affect other substituents, for example, Raney nickel, hydrazine and the like.

Method 6 In the compound of the formula 2, R ¹ is alkyl or phenylalkyl having 1 to 4 carbon atoms and R ² is alkyl, phenyl or phenylalkyl having 1 to 4 carbon atoms; R ¹ ,
An oxygen atom in the ring together with the nitrogen atom to which R ² is attached,
A group forming a 5- or 6-membered ring which may contain a sulfur atom or a nitrogen atom which may have a substituent,
^The compound in which ⁵ is not a hydroxyl group is obtained by reacting a compound in which R ⁵ is not a hydroxyl group in the chemical formula with sodium nitrite or potassium nitrite in the presence of hydrochloric acid, sulfuric acid, formic acid, and acetic acid.

Embedded image (In the formula, R ^{5 ′} represents a group other than a hydroxyl group in R ⁵ , and other symbols are as defined above.) The hydroxy is represented by thionyl chloride, phosphorus oxychloride, phosphorus trichloride Reacting with a halogenating agent such as phosphorus pentachloride, phosphorus tribromide or the like, or reacting with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in the presence of a dehydrohalogenating agent to form a reactive derivative of the corresponding alcohol And then the general formula

Embedded image (Wherein, R ^{1 ′} represents alkyl having 1 to 4 carbon atoms and phenylalkyl, R ^{2 ′} represents alkyl having 1 to 4 carbon atoms, phenyl and phenylalkyl, or R ^{1 ′} and R ^{2 ′} Represents a group forming a 5- to 6-membered ring which may contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring together with the nitrogen atom to which it is bonded.) It can be produced by reacting an amine compound. The reaction is carried out in the presence of a suitable base, for example, an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate (sodium hydroxide, potassium carbonate, sodium bicarbonate and the like), an organic base such as pyridine and triethylamine. Do.

The isomers included in the compound of the formula [2] of the present invention can be isolated from the racemate by a conventional method or can be produced by using each isomer raw material.

The compound of the formula [2] thus obtained can be separated and purified from the reaction mixture by a method known per se, such as recrystallization or chromatography. Further, the compound of the formula (2) can form a pharmaceutically acceptable acid addition salt according to a conventional method. Acids used to form acid addition salts include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) and organic acids (acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, etc.) It can be selected as appropriate. In addition, these salts are prepared according to a standard method.
It is converted to the corresponding free base by reaction with an alkali such as, for example, sodium hydroxide or potassium hydroxide. Furthermore, it can also be a quaternary ammonium salt.

The following compounds are exemplified as the compound of the present invention.

(1) trans-4-benzyloxycarboxamidomethyl-1- (4-pyridylcarbamoyl)
Cyclohexane, melting point 178-183 ° C; hydrochloride salt 1 /
Dihydrate, melting point 270 ° C (decomposition) (2) trans-4-aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane, melting point 148 ° C; dihydrobromide, melting point 267 ° C (decomposition); 2 Oxalate, melting point 221 ° C (decomposition); dihydrochloride, melting point 292 ° C (decomposition) (3) trans-4-formamidomethyl-1- (4-
Pyridylcarbamoyl) cyclohexane ・ oxalate ・
Hemihydrate, melting point 204-207 ° C (decomposition) (4) trans-4-dimethylaminomethyl-1- (4
-Pyridylcarbamoyl) cyclohexane dihydrochloride
1/2 hydrate, melting point 280-283 ° C (5) N-benzylidene-trans- (4- (4-pyridylcarbamoyl) cyclohexyl) methylamine, melting point 142-145 ° C (6) trans-4-benzylaminomethyl -1- (4
-Pyridylcarbamoyl) cyclohexane dihydrochloride
3/4 hydrate, melting point 266-268 ° C (decomposition) (7) trans-4-isopropylaminomethyl-1-
(4-pyridylcarbamoyl) cyclohexane dioxalate 1/2 hydrate, melting point 227 ° C (decomposition) (8) trans-4-nicotinoylaminomethyl-1-
(4-pyridylcarbamoyl) cyclohexane / hydrobromide / hydrochloride / 1/2 hydrate, melting point 256 [deg.] C. (decomposition) (9) trans-4-cyclohexylaminomethyl-1
-(4-pyridylcarbamoyl) cyclohexane / 2 oxalate, melting point 231 ° C (decomposition) (10) trans-4-benzyloxycarboxamide-1- (4-pyridylcarbamoyl) cyclohexane,
Melting point 213 to 215 ° C (11) trans-4-amino-1- (4-pyridylcarbamoyl) cyclohexane dihydrobromide, melting point 2
85 ° C (decomposition) (12) trans-4- (1-aminoethyl) -1-
(4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, melting point 286-287 ° C (decomposition) (13) trans-4-aminomethyl-cis-2-methyl-1- (4-pyridylcarbamoyl) cyclohexane Dihydrochloride monohydrate, melting point 280-282 ° C (decomposition); 7/4 oxalate, melting point 222 ° C (decomposition) (14) (+)-trans-4- (1-benzyloxycarboxamidopropyl) ) -1- (4-Pyridylcarbamoyl) cyclohexane / hydrochloride / monohydrate, [α] ²³
_D = + 18.7 ° (c = 1, ethanol), melting point 210
° C (15) (-)-trans-4- (1-benzyloxycarboxamidopropyl) -1- (4-pyridylcarbamoyl) cyclohexane / hydrochloride / monohydrate, [α] ²³
_D = -18.5 ° (c = 1, ethanol), melting point 208
° C (16) (+)-trans-4- (1-aminopropyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, [α] ²⁵ _D = + 4.6 ° (c
= 1, ethanol), melting point 238 ° C (decomposition) (17) (-)-trans-4- (1-aminopropyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, [ α] ²⁵ _D = −4.4 ° (c
= 1, ethanol), melting point 235 ° C. (decomposition) (18) (−)-trans-4- (1-benzyloxycarboxamidoethyl) -1- (4-pyridylcarbamoyl) cyclohexane, [α] ²³ _D = −8 .4 ° (c =
0.4, ethanol), melting point 192 ° C (19) (+)-trans-4- (1-benzyloxycarboxamidoethyl) -1- (4-pyridylcarbamoyl) cyclohexane, [α] ²³ _D = + 8.1 ° (C =
1, ethanol), melting point 190 ° C (20) (+)-trans-4- (1-aminoethyl)
-1- (4-pyridylcarbamoyl) cyclohexane.
Dihydrochloride / hemihydrate, [α] ²³ _D = + 4.6 ° (c =
1, methanol), melting point 276 [deg.] C. (decomposition) (21) (-)-trans-4- (1-aminoethyl)
-1- (4-pyridylcarbamoyl) cyclohexane.
Dihydrochloride / hemihydrate, [α] ²³ _D = -4.9 ° (c =
0.7, methanol), melting point 279 [deg.] C. (decomposition) (22) trans-4- (4-chlorobenzoyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane oxalate 1/2 hydrate, 204 ° C. (decomposition) (23) trans-4-aminomethyl-1- (2-pyridylcarbamoyl) cyclohexane dihydrochloride, melting point 2
45 ° C (decomposition) (24) trans-4-benzyloxycarboxamidomethyl-1- (2-pyridylcarbamoyl) cyclohexane, melting point 133-137 ° C (25) trans-4-methylaminomethyl-1- (4
-Pyridylcarbamoyl) cyclohexane / 2-oxalate, melting point 211-212 ° C (decomposition) (26) trans-4- (2-phenylethyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (27) trans-4 -(N-acetyl-N-methylamino) methyl-1- (4-pyridylcarbamoyl) cyclohexane (28) trans-4-cyclohexylcarbonylaminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (29) trans-4- Hexylaminomethyl-1-
(4-pyridylcarbamoyl) cyclohexane (30) trans-4-diethylaminomethyl-1-
(4-pyridylcarbamoyl) cyclohexane (31) trans-4- (4-benzyl-1-piperazinyl) methyl-1- (4-pyridylcarbamoyl) cyclohexane (32) trans-4- (1-piperazinyl) methyl-
1- (4-pyridylcarbamoyl) cyclohexane (33) trans-4-morpholinomethyl-1- (4-
Pyridylcarbamoyl) cyclohexane (34) trans-4-thiomorpholinomethyl-1-
(4-pyridylcarbamoyl) cyclohexane (35) trans-4-guanidinomethyl-1- (4-
Pyridylcarbamoyl) cyclohexane (36) trans-4- (1-benzyl-4-piperidinyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (37) trans-4- (2-nitrophenyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (38) trans-4- (2-aminophenyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (39) trans-4-butylaminomethyl-1- (4
-Pyridylcarbamoyl) cyclohexane (40) trans-4-cyclopentylaminomethyl-
1- (4-pyridylcarbamoyl) cyclohexane (41) trans-4- (N-benzyl-N-methylamino) methyl-1- (4-pyridylcarbamoyl) cyclohexane / 2 oxalate monohydrate, melting point 206 ~ 2
08 ° C (decomposition) (42) trans-4- (4-methylcyclohexyl)
Aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (43) trans-4- (2-methylcyclohexyl)
Aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (44) trans-4- (1-benzyl-4-piperidylidene) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (45) trans-4- (4- Piperidyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (46) trans-4- (4-fluorobenzoyl) aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane (47) trans-4- [2- ( 3,4-dimethoxyphenyl) -1-methylethyl] aminomethyl-1- (4
-Pyridylcarbamoyl) cyclohexane (48) trans-4- (N-benzyl-N-ethylamino) methyl-1- (4-pyridylcarbamoyl) cyclohexane (49) trans-4-ethylaminomethyl- (4-pyridylcarbamoyl) Cyclohexane (50) trans-4-aminomethyl-1- (3-pyridylcarbamoyl) cyclohexane dihydrochloride, melting point 2
50 ° C. (decomposition) (51) trans-4-aminomethyl-1-[(3-benzyloxy-2-pyridyl) carbamoyl] cyclohexane (52) trans-4-aminomethyl-1-[(3-hydroxy-2 -Pyridyl) carbamoyl] cyclohexane dihydrochloride monohydrate, mp 195-200 ° C (53) trans-4-benzyloxycarboxamidomethyl-1- (3-pyridylcarbamoyl) cyclohexane, mp 180-183 ° C (54 ) Trans-4-Benzyloxycarboxamidomethyl-1-[(3-benzyloxy-2-pyridyl)
Carbamoyl] cyclohexane, melting point 192-195 ° C (55) trans-4-phthalimidomethyl-1- (4
-Pyridylcarbamoyl) cyclohexane ・ hydrochloride ・ 1
Hydrate, mp 246-248 ° C (56) trans-4-benzyloxycarboxamidomethyl-1- (3-methyl-4-pyridylcarbamoyl) cyclohexane, mp 185-190 ° C (decomposition) (57) trans-4- Aminomethyl-1- (3-methyl-4-pyridylcarbamoyl) cyclohexane dihydrochloride, mp 285-287 ° C (decomposition) (58) 4- (trans-4-benzyloxycarboxamidomethylcyclohexylcarbonyl) amino-2,
6-dimethylpyridine-N-oxide, melting point 180-1
83 [deg.] C (decomposition) (59) 4- (trans-4-aminomethylcyclohexylcarbonyl) amino-2,6-dimethylpyridine-
N-oxide dihydrobromide, melting point 278-280 ° C
(Decomposition) (60) trans-4-aminomethyl-1- (2-methyl-4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, melting point 265-268 ° C (decomposition) (61) trans-4 -(1-benzyloxycarboxamidoethyl) -1- (4-pyridylcarbamoyl) cyclohexane / hydrochloride / monohydrate, mp 198-200
° C (decomposition) (62) trans-4-aminomethyl-trans-2-
Methyl-1- (4-pyridylcarbamoyl) cyclohexane (63) trans-4-aminomethyl-trans-3-
Methyl-1- (4-pyridylcarbamoyl) cyclohexane (64) trans-4-aminomethyl-cis-3-methyl-1- (4-pyridylcarbamoyl) cyclohexane (65) trans-4-aminomethyl-cis-4- Methyl-1- (4-pyridylcarbamoyl) cyclohexane (66) trans-4- (1-amino-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, melting point 313 -315 ° C (decomposition); dihydrochloride, melting point 310 ° C (decomposition); dihydrobromide, melting point 271 ° C (decomposition) (67) trans-4- (2-aminoethyl) -1-
(4-pyridylcarbamoyl) cyclohexane dihydrochloride, melting point 260-263 ° C (decomposition) (68) trans-4-aminomethyl-cis-2-ethyl-1- (4-pyridylcarbamoyl) cyclohexane (69) trans- 4- (2-aminopropyl) -1-
(4-Pyridylcarbamoyl) cyclohexane (70) trans-4- (2-amino-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane / fumarate / hemihydrate, melting point 185-187
° C (decomposition) (71) trans-4- (1-aminopropyl) -1-
(4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, melting point 286-288 ° C (decomposition) (72) trans-4-amino-cis-2-methyl-1
-(4-pyridylcarbamoyl) cyclohexane (73) trans-4-aminomethyl-trans-1-
Methyl-1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride dihydrate, mp 165-170 ° C (decomposition) (74) trans-4-benzylaminomethyl-cis-
2-methyl-1- (4-pyridylcarbamoyl) cyclohexane dioxalate / 3/2 hydrate, melting point 190 ° C
(Decomposition) (75) trans-4- (1-benzyloxycarboxamide-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane hydrochloride, melting point 210 ° C. (decomposition); Mp 154-155 ° C. (76) trans-4-benzyloxycarboxamidomethyl-1- (N-methyl-4-pyridylcarbamoyl) cyclohexane oxalate monohydrate, mp 13
2 ° C. (decomposition) (77) trans-4- (1-acetamido-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane / hemihydrate, melting point 250-253 ° C. (78) trans- 4- (1-amino-2-methylpropyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride, melting point 301-303 ° C (decomposition)

(79) cis-4-aminomethyl-1-
(4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate, melting point 186 ° C (decomposition) (80) cis-4-benzyloxycarboxamide-1
-(4-pyridylcarbamoyl) cyclohexane, melting point 161 ° C (decomposition) (81) cis-4-amino-1- (4-pyridylcarbamoyl) cyclohexane dihydrobromide, melting point 267
° C (decomposition); 1/4 hydrate, melting point 146-149 ° C (decomposition) (82) cis-4-formamido-1- (4-pyridylcarbamoyl) cyclohexane 1/4 hydrate, melting point 2
32 ° C (decomposition) (83) cis-4-benzyloxycarboxamide-1
-(4-pyridylcarbamoyl) cyclohexane dioxalate monohydrate, melting point 213 to 214 ° C (decomposition) (84) cis-4- (1-aminoethyl) -1- (4-
Pyridylcarbamoyl) cyclohexane ・ dihydrochloride ・ 1
Hydrate, melting point 255-257 ° C (decomposition) (85) cis-4- (1-amino-1-methylethyl)
-1- (4-pyridylcarbamoyl) cyclohexane.
Dihydrochloride, melting point 289 ° C (decomposition) (86) cis-4-aminomethyl-cis-2-methyl-
1- (4-pyridylcarbamoyl) cyclohexane.2
Hydrochloride monohydrate, melting point: 258 to 260 ° C (decomposition) (87) cis-4-aminomethyl-cis-2-methyl-
1- (3-pyridylcarbamoyl) cyclohexane.2
Hydrochloride 1/2 hydrate, melting point 255-257 ° C (decomposition)

When the compound of the present invention is used as a medicine, the compound is mixed with an effective amount of a pharmacologically acceptable excipient, carrier, diluent and other additives for a pharmaceutical preparation to prepare a tablet,
It can be administered orally or parenterally in the form of granules, powders, capsules, injections, aerosols, ointments, suppositories and the like.

The dose may vary depending on the age, body weight, symptoms, etc. of the patient, but it is usually about 5 to 500 mg orally per day for an adult, and it may be administered once or divided into several doses. Can be.

[0029]

The present invention will be specifically described below with reference to examples and formulation examples.

Example 1 cis-4-benzyloxycarboxamide-1- (4-
Pyridylcarbamoyl) 25% in 48 g of cyclohexane
500 g of a hydrogen bromide acetic acid solution is added, and it is left still for 15 hours.
The reaction is poured into 2 liters of ether. The precipitated crystals are collected by filtration and washed with ether and acetone.
Washing with ethanol heated to 60 ° C. gave a melting point of 26.
28 g of cis-4-amino-1- (4-pyridylcarbamoyl) cyclohexane dihydrobromide at 7 ° C (decomposition)
Is obtained.

Example 2 cis-4-amino-1- (4-pyridylcarbamoyl)
2.2 g of cyclohexane, 15 ml of 99% formic acid and 18 ml of acetic anhydride are mixed and refluxed for 10 hours. The reaction solution is poured into ice water and made alkaline with potassium carbonate and concentrated aqueous sodium hydroxide. Chloroform was added to the precipitated tar, the precipitated crystals were collected by filtration, washed with water and dried,
Cis-4-formamide-1- with a melting point of 232 ° C. (decomposition)
(4-pyridylcarbamoyl) cyclohexane 1/4
1.6 g of hydrate are obtained.

Example 3 cis-4-amino-1- (4-pyridylcarbamoyl)
A mixture of 6.4 g of cyclohexane, 3.1 g of benzaldehyde and 100 ml of toluene is placed in an eggplant-shaped flask and refluxed, and the theoretical amount of water is distilled off. After reacting for 3.5 hours, activated carbon is added and the mixture is filtered, and the filtrate is concentrated to obtain a solid. A mixed solution of isopropyl ether and ethyl acetate (1: 1) was added thereto, and the crystals were collected by filtration, washed with ethyl acetate, and dried. N-benzylidene-cis- (4-pyridylcarbamoyl) having a melting point of 235 ° C. (decomposition) was obtained. 6.8 g of cyclohexylamine are obtained.

Example 4 N-benzylidene-cis- (4-pyridylcarbamoyl) cyclohexylamine (6.0 g) was added to sodium borohydride (1.1 g) in ethanol, and the reaction was carried out in a conventional manner to give a melting point of 213 to 214. Cis-4-benzylamino-1- (4-pyridylcarbamoyl) cyclohexane dioxalate monohydrate 2.2 ° C (decomposition) 2.2
g is obtained.

Example 5 (1) While cooling and stirring a mixture of 1.18 g of 4-aminopyridine, 1.3 g of triethylamine, 10 ml of dichloromethane and 12 ml of dimethylacetamide in ice water, cis-4- (1-benzyloxycarboxamide-1- 3. methylethyl) cyclohexanecarbonyl chloride
A solution of 23 g in 15 ml of dichloromethane was added to 5-10
It is added dropwise at a temperature of ° C. over a period of 40 minutes. After stirring at the same temperature for 3 hours, the mixture is heated to 50 to 55 ° C. and reacted for 6 hours. After cooling, the reaction mixture was poured into water, and the dichloromethane layer was washed with an aqueous solution of sodium hydrogen carbonate, dried and concentrated to give oily cis-4- (1-benzyloxycarboxamide-1-yl).
4.8 g of methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane are obtained. (2) To a solution of 2.5 g of cis-4- (1-benzyloxycarboxamido-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane in 100 ml of ethanol, 3.5 ml of 10% hydrochloric acid and 10% palladium-
2.0 g of carbon (containing 53.8% of water) is added, and catalytic reduction with hydrogen is performed at 15 to 20 ° C. under normal pressure. After confirming the completion of the reaction by silica gel thin layer chromatography, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain a viscous oil. When an acetone-methanol mixture was added thereto, cis-4- (1-amino-melting point having a melting point of 289 ° C (decomposition) was obtained.
1.2 g of 1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride are obtained.

Formulation Example 1: Tablets Compound of the present invention 10.0 mg Lactose 50.0 mg Corn starch 20.0 mg Crystalline cellulose 29.7 mg Polyvinylpyrrolidone K30 5.0 mg Talc 5.0 mg Magnesium stearate 0.3 mg 120.0 mg The present invention The compound, lactose, corn starch and crystalline cellulose are mixed, kneaded using a polyvinylpyrrolidone K30 size solution, and granulated through a 20-mesh sieve.
After drying at 50 ° C. for 2 hours, the mixture was passed through a 24 mesh sieve, and talc and magnesium stearate were mixed.
Using a 7 mm diameter punch, make 120 mg tablets per tablet

Formulation Example 2: Capsule Compound of the present invention 10.0 mg Lactose 70.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone K30 2.0 mg Talc 2.7 mg Magnesium stearate 0.3 mg 120.0 mg Compound of the present invention, lactose, Corn starch and crystalline cellulose are mixed, kneaded using polyvinylpyrrolidone K30 size solution, and granulated through a 20-mesh sieve.
After drying at 50 ° C. for 2 hours, the mixture was passed through a 24 mesh sieve, and talc and magnesium stearate were mixed.
Fill hard capsules (No. 4) to make 120 mg capsules.

Formulation example 3: aerosol 0.1 to 0.2 g of the compound of the present invention, 10 g of ethanol and 10 g of water were added and dissolved, and dichlorodifluoromethane 7 was added.
9.8 to 79.9 g are sealed in a spray pressure container to produce an aerosol.

[0038]

Functions and Effects of the Invention The usefulness of the therapeutic agent for asthma of the present invention will be described below with reference to experimental examples. Each compound in the experimental examples shows the following compounds. Compound A: trans-4-aminomethyl-1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride Compound B: trans-4-aminomethyl-cis-2-methyl-1- (4-pyridylcarbamoyl) cyclohexane.2 Hydrochloride monohydrate Compound C: trans-4- (1-aminoethyl) -1-
(4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate Compound D: (+)-trans-4- (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride / 1 Dihydrate Compound E: (-)-trans-4- (1-aminoethyl) -1- (4-pyridylcarbamoyl) cyclohexane.dihydrochloride.1 / 2 hydrate Compound F: (+)-trans -4- (1-Aminopropyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate Compound G: trans-4- (1-amino-1-methylethyl) -1- (4 -Pyridylcarbamoyl) cyclohexane dihydrochloride monohydrate Compound H: (-)-trans-4- (1-aminopropyl) -1- (4-pyridylcarbamoyl) cyclohexane.2 Acid salt monohydrate Compound I: trans-4-benzyloxycarboxamidomethyl-1- (4-pyridylcarbamoyl) cyclohexane hydrochloride 1/2 hydrate Compound J: trans-4-benzylaminomethyl-1 −
(4-pyridylcarbamoyl) cyclohexane dihydrochloride / 3/4 hydrate Compound K: N-benzylidene-trans-((4-pyridylcarbamoyl) cyclohexyl) methylamine Compound L: cis-4- (1-aminoethyl ) -1- (4
-Pyridylcarbamoyl) cyclohexane dihydrochloride
Monohydrate Compound M: cis-4- (1-amino-1-methylethyl) -1- (4-pyridylcarbamoyl) cyclohexane dihydrochloride

Experimental Example 1: Effect of histamine inhalation on experimental asthma in guinea pigs Histamine asthma was treated according to the method of Suyama (Allergy, Vol. 15,
549, 1966). Weight 490-630
g of a female Hartley-type guinea pig was placed in an aerosol inhaler, and a 0.2% histamine solution (histamine hydrochloride,
(Hanai Chemical Co., Ltd.) with an ultrasonic nebulizer (TUR-32)
00, Nihon Kohden Kogyo Co., Ltd.) and examined the protective action using rollover as an index. The test compound is inhaled by placing a guinea pig in the aerosol inhaler and spraying a test solution dissolved in physiological saline to a predetermined concentration for 5 minutes. Then
Histamine was immediately inhaled, and the lag time of the rollover time due to difficulty in absorption was measured. Table 1 shows the results.

[0040]

[Table 1]

Experimental Example 2: Effect on histamine-induced contraction of guinea pig isolated trachea specimen Male Hartley guinea pig (weight: 260-390 g)
With sodium pentobarbital (100 mg / kg
i. p. ) After anesthesia, the patient was exsanguinated and the trachea was removed. The ventral cartilage of the trachea was cut open and the ligament was cut at a width of 2 mm. Five sections were ligated to prepare a chain specimen. Specimens were prepared at 37 ° C. in Krebs-Hansereit solution (NaCl 117 mM; KCl
4.7 mM; CaCl ₂ 2.5 mM; MgSO ₄ 1.2 mM; NaHCO ₃ 24.8 mM; KH
₂ PO ₄ 1.2mM; glucose 11.0mM)
Was suspended under a load of 1 g in the Magnus tube of the above. A mixed gas (95% oxygen + 5% carbon dioxide) was constantly ventilated in the Magnus tube. Determine the length of the sample with an isotonic transducer (ME-
4012, MEC) using a recorder (Ti-10)
2, Tokai Medical Science). Histamine (10 ^-5
After contraction was constant at M), the compound was cumulatively added and the relaxation reaction was observed. The relaxation reaction of the compound was defined as 50% with the maximum response of papaverine (10 ^-4 M) as 100%.
Was calculated as IC ₅₀ (μM). Table 2 shows the results.

[0042]

[Table 2]

Experimental Example 3: Effect on acetylcholine-induced contraction of isolated guinea pig trachea specimen Male Hartley-type guinea pig (weight: 260-390 g)
With sodium pentobarbital (100 mg / kg
i. p) Blood was killed after anesthesia, and the trachea was removed. The ventral cartilage of the trachea was cut open and the ligament was cut at a width of 2 mm.
Five sections were ligated to prepare a chain specimen. Specimen is 37
C. Krebs-Hanseleate solution (NaCl 117 mM; KCl 4.7 m
M; CaCl ₂ 2.5 mM; MgSO ₄ 1.2 mM; NaHCO ₃ 24.8 mM; KH ₂ PO
_The suspension was suspended at a load of 1 g in a 40-ml capacity Magnus tube filled with ₄ 1.2 mM; glucose 11.0 mM). A mixed gas (95% oxygen + 5% carbon dioxide) was constantly ventilated in the Magnus tube. Determine the length of the sample with an isotonic transducer (ME-4
012, MEC) using a recorder (Ti-102,
Tokai Medical Science). Specimen was acetylcholine (10
^-6 M), and after the contraction was constant, the compound was cumulatively added and the relaxation reaction was observed. The relaxation reaction of the compound was defined as 50% with the maximum response of papaverine (10 ^-4 M) as 100%.
The concentration showing a% relaxation reaction was calculated as IC ₅₀ (μM). Table 3 shows the results.

[0044]

[Table 3]

Acute toxicity test The test compounds A, B, and C were intraperitoneally administered to ddY strain mice, respectively, and observed for 5 days. No deaths were observed by intraperitoneal administration of 100 mg / kg.

Therefore, the 4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound represented by the formula [2], its optical isomer and its pharmaceutically acceptable acid addition salt are useful as a therapeutic agent for asthma. is there.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07D 213/75 C07D 213/75 213/89 213/89 401/12 401/12 413/12 413/12 (56) Reference Document JP-A-3-218356 (JP, A) Pharm. Sci. Vol. 2, p. 243-251 (1990) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/00-31/54

Claims (1)

(57) [Claims] 1. A compound of the general formula (Wherein R ¹ and R ² are the same or different and each represents hydrogen,
Alkyl having 1 to 10 carbons, alkanoyl having 2 to 5 carbons, formyl, alkoxycarbonyl having 1 to 4 carbons, amidino, or 3 to 7 carbons which may have a substituent on the ring Cycloalkyl, cycloalkylcarbonyl having 3 to 7 carbon atoms, phenyl, phenylalkyl, benzoyl, naphthoyl, phenylalkoxycarbonyl, benzylidene, pyridylcarbonyl, piperidyl, pyrrolidylidene or piperidylidene,
Or R ^1, R ² is a group forming a nitrogen atom linked with an oxygen atom in the ring, a sulfur atom or 5-6 membered ring may be contain a nitrogen atom which have a substituent or R ³ represents hydrogen, alkyl having 1 to 4 carbons, R ⁴ represents hydrogen, alkyl having 1 to 4 carbons, and R ⁵ represents a group forming phthalimide together with the nitrogen atom bonded thereto. Hydrogen, a hydroxyl group, an alkyl having 1 to 4 carbons,
Represents phenylalkoxy; R ⁶ is hydrogen;
A represents a single bond, linear alkylene having 1 to 5 carbon atoms or alkylene substituted with alkyl having 1 to 4 carbon atoms, and n represents 0 or 1. A therapeutic agent for asthma, comprising a 4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound represented by the formula (I), an optical isomer thereof, and a pharmaceutically acceptable acid addition salt thereof.