JPH03218356A - Trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane compound and its medicinal use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides novel and pharmaceutically useful trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane compounds, their pharmaceutically acceptable acid addition salts, and their pharmaceutically acceptable acid addition salts. Concerning medicinal use.

[Question B to be solved by the prior art and the invention] One of the causes of hypertension and coronary/cerebral circulation disorders, which are major social problems as adult diseases, is abnormality in smooth muscle contractility. It is known that contraction is induced by an increase in the intracellular concentration of calcium ions. There are three ways to increase the intracellular concentration of calcium ions: 1) via membrane potential-dependent calcium channels, 2) released from intracellular calcium storage sites, and 3) via receptor-dependent channels. Not like that. In addition, when these calcium ions are in excess, it is said to cause constriction of coronary arteries and cerebral blood vessels, and constriction of these blood vessels is thought to be one of the causes of myocardial infarction, angina pectoris, and cerebral infarction. .

Therefore, attempts are currently being made to use calcium channel blockers to treat hypertension and coronary/cerebral circulation disorders. However, although calcium antagonists exhibit an antagonistic effect on membrane voltage-dependent calcium channels, they hardly exhibit an antagonistic effect on calcium influx into other cells or calcium release from storage sites.

On the other hand, JP-A-62-54 describes N-(o-carboxy- or alkoxycarbonyl-substituted phenyl)-trans-4-guanidinomethylcyclohexane carboxamide derivatives having anti-ulcer activity.

However, it is not known that these compounds have antihypertensive effects and coronary/cerebral circulation improving effects.

[Means to solve the problem]

The present inventors conducted extensive studies with the aim of developing a compound that not only has an antagonistic effect on membrane potential-dependent calcium channels on which conventional calcium antagonists act, but also has an intracellular calcium antagonistic effect.

As a result, trans-4-amino(alkyl)1-pyridylcarbamoylcyclohexane compounds and their pharmaceutically acceptable acid addition salts have the above-mentioned effects, and have useful antihypertensive effects and coronary/cerebral/renal circulation improving effects. The present invention has been completed based on the discovery that the present invention has the following properties.

That is, the present invention provides the general formula P6 [wherein R1 and R2 are the same or different, hydrogen,
Alkyl having 1 to 10 carbon atoms, alkanoyl having 2 to 5 carbon atoms, formyl, alkoxycarbonyl having 1 to 4 carbon atoms, amidino, or 3 carbon atoms which may have a substituent on the ring ~7 cycloalkyl, 3 to 7 carbon atoms
cycloalkyl carbonyl, phenyl, phenylalkyl, henzoyl, naphthoyl, phenyl alkoxy carbonyl, henzylidene, pyridyl carbonyl, piperidyl, pyrrolidylidene or piberylidene, or R', R2 are bonded A group that forms, together with a nitrogen atom, a 5- to 6-membered ring that may contain an oxygen atom, a sulfur atom, or a nitrogen atom that may have a substituent in the ring, or forms a phthalimide together with a bonded nitrogen atom R3 is hydrogen, carbon number 1-
4 alkyl, R4 represents hydrogen, alkyl having 1 to 4 carbon atoms, RS represents hydrogen, hydroxyl group, alkyl having 1 to 4 carbon atoms, phenylalkoxy, R6 represents hydrogen,
represents alkyl having 1 to 4 carbon atoms, A represents a single bond, linear alkylene having 1 to 5 carbon atoms, or alkylene substituted with alkyl having 1 to 4 carbon atoms, n represents O or 1 . ] trans-4-amino(alkyl)- represented by
The present invention relates to a 1-pyridyl hamoyl hexane compound, optical isomers thereof, pharmaceutically acceptable acid addition salts thereof, and pharmaceutical uses thereof.

Furthermore, the present invention relates to a preventive and therapeutic agent for circulatory system diseases, which contains a compound represented by general formula (1) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

In this specification, alkyl having 1 to 10 carbon atoms refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, hebutyl,
Octyl, nonyl, decyl, etc., alkanoyl with 2 to 5 carbon atoms include acetyl, propionyl, isoprobionyl, butyryl, isobutyryl, bivaloyl, valeryl, etc., and alkoxycarbonyl with 1 to 4 carbon atoms include methoxycarbonyl. , ethoxycarbonyl, propoxycarbonyl, isoproboxycarbonyl, ptoxylponyl, isobutoxylponyl, tertiary butoxycarbonyl, etc. Cycloalkyl having 3 to 7 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Heptyl is cycloalkylcarbonyl having 3 to 7 carbon atoms, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, phenylalkyl is henzyl, phenylethyl, phenylpropyl, phenylbutyl, etc. Phenylalkoxycarbonyl refers to phenylethoxycarbonyl, phenylbutoxycarbonyl, phenylbutoxycarbonyl, etc., biridylcarbonyl refers to 2-pyridylcarbonyl, nicotinoyl, isonicotinoyl, and biveridyl refers to 2-piperidyl, 3-piperidyl, 4-piperidyl, etc. - Piveridyl, pyrrolidylidene refers to 2-pyrrolidylidene, 3-pyrrolidylidene, piperidylidene refers to 2-piperidylidene, 3-biperidylidene, 4-biperidylidene, and a group forming a 5- to 6-membered ring with a nitrogen atom refers to pyrrolidinyl,
Piperidino, biverazinyl, morpholino, thiomorpholino, etc.; phenylalkoxy includes henzyloxy, phenylethoxy, phenylpropoxy, phenylbutylene, etc.; linear alkylene with 1 to 5 carbon atoms includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, etc. , Alkylene substituted with an alkyl having 1 to 4 carbon atoms refers to methylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltetramethylene, ethylethylene, dimethyltrimethylene, etc., substituted with an alkyl having 1 to 4 carbon atoms. are methyl, ethyl, provil,
Indicates isopropyl, butyl, isobutyl, tertiary butyl, etc., respectively.

In addition, the substituents that may be present in each symbol of general formula (r) include halogens such as chlorine, iodine, bromine, and fluorine, methyl, ethyl, proyl, isopropyl, butyl, isobutyl, and tertiary butyl. Alkyl having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isobroboxy,
It represents alkoxy having 1 to 4 carbon atoms such as butoxy, imbutoxy, tertiary butoxy, phenylalkyl such as benzyl, phenylethyl, phenylpropyl, phenylbutyl, nitro, amino, and the like.

The compound of general formula (1) of the present invention also includes pharmaceutically acceptable acid addition salts, hydrates, and various solvates formed with inorganic acids, organic acids, etc.

When an asymmetric carbon exists in the compound of general formula (1) of the present invention, optical isomers, racemic forms thereof, etc. may exist, and the present invention encompasses all of these.

The compound of general formula (1) of the present invention can be synthesized by the method shown below.

A carboxylic acid compound or a reactive derivative thereof represented by the general formula R3 (in the formula, each symbol has the same meaning as above) and the general formula [blank below] 12 R6 (in the formula, each symbol has the same meaning as above) A method of reacting with an aminopyridine compound represented by (same meaning).

Reactive derivatives of carboxylic acid compounds include acid halides such as acid salts, acid anhydrides, mixed acid anhydrides formed from ethyl chloroformate etc., esters such as methyl ester, ethyl ester etc., dicyclohexyl Examples include reactive derivatives produced from carbodiimide, such as carbodiimide.

The reaction is carried out in the presence of a solvent inert to the reaction, but
Usually, organic solvents containing no hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, and dimethylformamide are used. The reaction can be carried out at any temperature, for example from -10 to
200"C1 is preferably carried out at 0 to 80°C,
A high reaction temperature is used when the starting material is a reactive derivative that is not very reactive (for example, an ester), and a low reaction temperature is used when the raw material is a reactive derivative that is highly reactive (for example, a mixed acid anhydride).

Square I Compounds of general formula (1) in which one of Rl and R2 is hydrogen and the other is other than hydrogen are represented by the general formula (in the formula, each symbol has the same meaning as above). It can be produced by reacting an amine compound with a carboxylic acid compound or its reactive derivative, a halide compound, an aldehyde compound, or a ketone compound.

The carboxylic acid compound used in this reaction has the formula: Shows 7 cycloalkyl, phenyl, and pyridyl.

A halide compound is a compound represented by the formula R'-1 { al
(Vl) (wherein R8 is alkyl having 1 to 10 carbon atoms, or 3 to 7 carbon atoms which may have a substituent)
cycloalkyl and phenyl, and Hal represents chlorine, iodine, and fluorine. ), and the aldehyde compound is 2R9-CHO (■) (in the formula,
R9 represents hydrogen, alkyl having 1 to 9 carbon atoms, or phenyl which may have a substituent. )) ] 5, and a ketone compound is a compound represented by the formula represents a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent.

When the compound of general formula (IV) is reacted with a carboxylic acid or a reactive derivative thereof, it can be carried out using the same conditions as in Method I, but when the compound of general formula (IV) and a ketone or aldehyde are reacted, When reacting, the dehydration reaction is usually carried out with a solvent that is difficult to miscible with water, such as benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, etc. At this time, it is also advantageous to add a small amount of an acid such as para-toluenesulfonic acid.

It can also be produced by subjecting algylidene obtained by dehydration condensation and hengelidene compounds which may have 1 6 substituents to a reduction reaction.

The reduction reaction can usually be carried out in an alcohol such as methanol, ethanol, or isobrobyl alcohol at 10 to 100°C, preferably 0 to 40°C.

In addition, reducing agents such as sodium borohydride, sodium cyanoborohydride in the presence of a small amount of an acid such as hydrochloric acid, hydrobromic acid, or acetic acid, and furthermore, If not, use a catalytic reduction method using Raney nickel, palladium on carbon, platinum oxide, etc.
It can also be produced by performing a reductive amination reaction.

Fangdian 1 Among the compounds of general formula (I), compounds in which Rl and R2 represent phenylalkyl or biperidyl, which may have a substituent, are penzylidene or biperidyl, where Rl and R2 may have a substituent. It can be produced by subjecting a compound that is biverylidene to a reduction reaction.

The reduction reaction can be carried out usually in an alcohol such as methanol, ethanol or isobrobyl alcohol at 10 to 100°C, preferably 0 to 40°C.

Further, as the reducing agent, it is preferable to use sodium borohydride, but catalytic reduction with palladium carbon, platinum oxide, etc. can also be carried out if other groups of the target compound are not affected.

Compound 1 Among the compounds of the general formula (1), compounds in which Rl and R2 are groups forming a 5- to 6-membered ring together with the nitrogen atom to which they are bonded are the compounds of the general formula or the general formula [formula (IX), (X ), Y is oxygen, sulfur, or nitrogen which may have a substituent, and Z is halogen (chlorine,
bromine, etc.), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy, etc.).

Rl and R2 of the compound represented by and general 2N)
can be produced by reacting with a compound in which both are hydrogen.

The reaction can be carried out using conditions similar to method 2.

Among the compounds of general formula (1), a compound in which R and R2 are both hydrogen can be produced by a reaction using each of the following compounds.

(i) Among the compounds of general formula (1), the production reaction from compounds in which Rl and R2 are alkoxycarbonyl and aralkyloxycarbonyl having 1 to 4 carbon atoms is 3 to 35%, preferably << is 15 ~30% acetic acid in the presence of hydrogen bromide, 0-50°C, preferably 5-3
By stirring or standing at around 0°C, the compound of general formula (1) can be converted to a compound in which both Rl and R2 are hydrogen.

In particular, among the compounds of general 2〇), R' and R2
In the case of a compound in which is an alkoxycarponyl having 1 to 4 carbon atoms, it can be dissolved in a suitable organic solvent that does not affect the reaction, such as alcohol (methanol, ethanol, isopropyl alcohol, etc.), ether (tetrahydrofuran, etc.). bases, such as alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates (
The target compound can be produced by stirring and heating if necessary in the presence of sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc., and furthermore, among the compounds of general formula (I), Rl and R2 In the case of a compound in which is phenylalkoxycarbonyl, use hydrogen, hydrazine, formic acid, ammonium formate, etc. as a hydrogen source in the presence of a suitable catalyst such as palladium on carbon in a suitable fa-containing solvent that does not affect the reaction. It can also be produced by carrying out a reductive decomposition reaction at room temperature or, if necessary, under pressure.

(ii) Among the compounds of general formula (1), the production reaction from the compound that forms phthalimide together with the nitrogen atom to which Rl and R2 are bonded is carried out using acetone, tetrahydrofuran, or their water-containing solvents. Stirring is carried out in the presence of sodium hydrate at -5°C to room temperature, preferably 0 to 5'C, and the resulting intermediate is dehydrated in dicyclohexylcarbodiimide or trifluoroacetic acid in the presence of triethylamine. Do this. By further stirring the obtained intermediate with anhydrous hydrazine in tetrahydrofuran at -20°C, R
' and R2 are both hydrogen. It is also possible to directly convert a phthaloyl compound into an amino compound in alcohol in the presence of hydrazine.

(iii) Among the compounds of general formula (1), the production reaction from the compound in which R1 and R2 are penzylidene, piperidylidene, or pyrrolididene is performed using a dilute acid solution with a concentration that does not affect other substituents, for example, 5% hydrochloric acid. It can be produced by heating and stirring at room temperature or 30 to 60°C in the presence of 5% sulfuric acid or the like, and an alcoholic solvent can also be used during the reaction.

Furthermore, among the compounds of general formula (1), R+ 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 that does not affect other substituents, such as Raney nickel and dorazine.

In the compound of general formula (1), R1 is alkyl or phenylalkyl having 1 to 4 carbon atoms, R2 is alkyl having 1 to 4 carbon atoms, phenyl, phenylalkyl, or Rl
, R2 forms 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 R2 is bonded,
In the compound where R5 is not a hydroxyl group, R5 in the general formula (TV)
A compound in which 5 is not a hydroxyl group is reacted with sodium nitrite or potassium nitrite in the presence of hydrochloric acid, sulfuric acid, formic acid, and acetic acid to form a compound of the general formula K0 (wherein R5" represents a group other than a hydroxyl group in R5, and other symbols has the same meaning as above), and this hydroxyl is treated with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, or phosphorus tribromide, or
React with methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. in the presence of a dehydrohalogenating agent to form the corresponding reactive derivative of the alcohol, and then,
General formula 23 (wherein, Rl= represents alkyl having 1 to 4 carbon atoms, phenylalkyl, R2= represents alkyl having 1 to 4 carbon atoms,
phenyl, phenylalkyl, Rl=, R2'
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. ) can be produced by reacting an amine compound represented by:

The reaction is carried out in the presence of a suitable base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate (sodium hydroxide, potassium carbonate, sodium bicarbonate, etc.), an organic base such as pyridine, triethylamine, etc. Let's do it.

Further, the isomers included in the compound of general formula (1) of the present invention can be isolated from the racemate by a conventional method, or can be produced by using raw materials for each isomer.

The compound of general formula (I) thus obtained can be separated and purified from the reaction mixture by methods known per se, such as recrystallization and chromatography.

Furthermore, the compound of general formula (1) 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. These salts can also be converted to the corresponding free bases according to conventional methods, for example by reaction with an alkali such as sodium hydroxide or potassium hydroxide. Furthermore, it can also be made into a quaternary ammonium salt.

Among the compounds of general formula (I), preferred compounds include Rl
and R2 are both hydrogen, and examples thereof include optical isomers and pharmaceutically acceptable acid addition salts thereof.

Further, among the compounds of general formula (1), preferred compounds include trans-4-aminomethyl-1(4-pyridyl-lupamoyl)cyclohexane, trans-4-aminomethyl-trans-1-methyl-1-(4- pyridylcarbamoyl)cyclohexane, trans-4-aminomethylcis2-methyl-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans -4-aminomethyl-1(2-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl-1-(3-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl-1-[(3-hydroxy-2pyridyl) ) carbamoyl] cyclohexane,
trans-4-aminomethyl-1-(3-methyl-4pyridylcarbamoyl)cyclohexane, 4(trans-
4-aminomethylcyclohexylcarbonyl)amino-
2,6-dimethylpyridine N-oxide, trans-4
-aminomethyl-1(2-methyl-4-pyridylcarbamoyl)cyclohexane, trans-4-(2-aminomethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(1-amino-1- methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(l-aminopropyl)-1-(4
-pyridylcarbamoyl)cyclohexane, (+i}trans-4-(1-aminopropylkl-(4-pyridylcarbamoyl)cyclohexane, (-)-trans-4
-(1-aminobyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-4(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (-)-trans-4-( 1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and its pharmaceutically acceptable acid addition salts.

[Actions and Effects of the Invention] Next, the actions and effects of the compounds of the present invention will be specifically explained using pharmacological experiments. The test compounds used are as follows.

Test compound A: trans-4-aminomethyl 1-(4-
pyridylcarbamoyl)cyclohexane dihydrochloride Test compound B: trans-4-aminomethylcis-2-
Methyl-1-(4-pyridylcarpamoyl)cyclohexane dihydrochloride monohydrate Test compound C: trans-4
-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane dihydrochloride monohydrate Pharmacology Experimental Example 1 Antihypertensive effect Group 1 3-5 males with spontaneous hypertension weighing 350-450 g 30 μ/kg of the test compound dissolved in 0.5% hydroxybutylene methyl cellulose was orally administered to rats, and systolic blood pressure was measured 3 hours after administration by the tail cuff method to examine antihypertensive effects. The results are shown in Table 1.

Table 1 28 Pharmacology Experiment Example 2 Effect on Coronary Blood Flow Two to three adult mongrel dogs per group were anesthetized by intravenously administering 30 μg/kg body weight of sodium bentobarbital, and the method of Yago et al. [Japan Pharmacology Magazine, Volume 57, 380
Page (1961)], the left coronary artery was perfused.
The blood flow was measured. 10-300 μg of test compound was administered intracoronarily.

The effect of the test compound on coronary blood flow was determined when 3 μg of nifedipine [dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydrobiridine-3,5-dicarboxylate] was administered intracoronarily. ED, the dose required to increase coronary blood flow to half the effect of. (μ
g) and the results are summarized in Table 2.

In addition, the half-life (Tz, minutes) was also determined as the duration of the effect.

[Margin below]

Table 2 Pharmacology Experiment Example 3 Effect on vertebral artery blood flow Two adult mongrel dogs in one group were anesthetized by intravenously administering bentobarbital sodium 25 cm/kg body weight, the right vertebral artery was perfused, and the blood flow was measured. did. Test compounds were administered into the vertebral artery.

Papaverine hydrochloride (II (3,4-dimethoxyphenyl))
methyl)-6.7-dimethoxyisoquinoline hydrochloride) 1
The effect of the test compound is that the maximum blood flow increase rate when 00 μg is administered to the vertebral artery is 100%.
ED + the dose required to achieve 0%. . (μg)
The results are summarized in Table 3. In addition, the half-life (T'A.min) was also determined as the duration of the effect.

Table 3 Acute Toxicity Experiment Test compounds A, B, and C were intraperitoneally administered to ddY mice and observed for 5 days. No deaths were observed after intraperitoneal administration of 100 μ/kg.

As is clear from the above experimental examples and various pharmacological experiments,
The compound of the present invention (■), its optical isomer 31, and its pharmaceutically acceptable acid addition salts have coronary and cerebral blood flow increasing effects similar to calcium antagonists, which are not seen in conventional calcium antagonists. It also has the effect of increasing renal blood flow.

In addition, its blood flow increasing effect lasts for a long time, and its blood pressure lowering effect is strong (high ceiling). Furthermore, it is effective not only against vascular curvature induced by in-vivo calcium agonist-like substances such as endothelin, but also against vascular curvature caused by calcium ionophores without the action of calcium antagonists.

Therefore, the compounds of the present invention are useful as antihypertensive agents and agents for preventing and treating diseases of the circulatory system, such as those of the coronary, brain, and kidneys.

When the compound of the present invention is used as a medicine, it is mixed with an effective amount thereof and appropriate pharmacologically acceptable excipients, carriers, diluents, and other pharmaceutical formulation additives to form tablets, granules, powders, and capsules. It can be administered orally or parenterally in the form of tablets, injections, ointments, suppositories, and the like.

The dosage may vary depending on the patient's age, weight, symptoms, etc., but it is usually administered orally at 50% per day for adults.
~500 μm, which can be administered once or divided into several doses.

〔Example〕

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 4-aminopyridine 1 5. While cooling and stirring 4 g of triethylamine, 20.6 g of dichloromethane, and 165 g of dimethylacetamide in ice water, 50 ml of dichloromethane containing 53 g of trans-4-penzyloxyrupoxamide methylcyclohexane and rupoyl chloride was added. The solution is added dropwise from a dropping funnel at a temperature of 5 to 10°C over a period of 1 hour. After stirring at the same temperature for 3 hours,
Heat to 50-55°C and react for 8 hours. After cooling the reaction mixture, it was poured into water, and the dichloromethane layer was washed with an aqueous sodium bicarbonate solution, dried, and concentrated to obtain 68 g of solid. When ethyl acetate is added to this solid and the resulting crystals are collected by filtration, trans-4-henzyloxyrupoxamidomethyl 1-(4-pyridylhamoyl)cyclohexane having a melting point of 178-183°C is obtained. When this compound is converted into a hydrochloride, a hydrochloride dihydrate having a melting point of 270°C (decomposition) is obtained.

Example 2 Trans-4-penzyloxycarboxamidomethyl-
1-(4-pyridylhamoyl)cyclohexane 25
g and 500 g of 30% hydrogen bromide acetic acid solution at room temperature,
If left for 22 hours, crystals will gradually precipitate. The crystals were collected by filtration and washed with ethanol and ether to give trans-4-aminomethyl-
1-(4pyridylcarhamoyl)cyclohexane dihydrobromide is obtained as crystals. The crystals are dissolved in ice water and made alkaline with concentrated sodium hydroxide solution, and the precipitated crystals are collected by filtration, washed with water, and dried to obtain a basic compound with a melting point of 148°C. This basic compound is dissolved in ethanol, an ethanol solution of oxalic acid is added, and the precipitated crystals are collected by filtration and washed with ethanol and ether to obtain dioxalate having a melting point of 221'c (decomposed). Melting point of dihydrochloride 292°C (decomposition) Example 3 Trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane 2.33 g, 99% formic acid 15
When d and 18 d of acetic anhydride are added and stirred, the inner bath heats up to 36°C. After refluxing this mixture for 10.5 hours,
Pour into ice water and make alkaline with potassium carbonate and concentrated sodium hydroxide aqueous solution. Add chloroform to the precipitated tar and collect the resulting crystals by filtration, wash with water, and dry.
When dissolved in ethanol and added with an ethanol solution of oxalic acid, crystals will precipitate. When these crystals are filtered and dried,
Trans-4-formamidomethyl-1-(4-pyridylcarbamoyl)cyclohexane oxalate dihydrate having a melting point of 204-207°C (decomposed) is obtained.

Example 4 35 A mixture of 2.33 g of trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane, 37% formalin and 3.1 g of 85% formic acid was heated for 2.5 g on an oil bath.
After refluxing for a period of time and cooling, ice water is added, the mixture is made alkaline with an aqueous solution of potassium carbonate and sodium hydroxide, and extracted with chloroform. After drying the chloroform layer, concentrate &
1. 93 g of solid are obtained. When this solid is dissolved in ethanol under heating and 25% ethanolic hydrochloric acid is added, crystals are precipitated. The crystals are collected by filtration and washed with ethanol and petroleum ether to give trans-4-dimethylaminomethyl-1-(4-
(pyridylcarbamoyl) cyclohexane dihydrochloride hydrate is obtained.

Example 5 A mixture of 4.4 g of trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohegyosan, 2 g of henzaldehyde, and 10 ml of toluene was placed in a eggplant-shaped flask and refluxed, and a theoretical amount of water was distilled off. let After 3.5 hours, activated carbon was added and filtered, and the filtrate was concentrated to give a solid. Isobrobyl ether and ethyl acetate were added to this, and the crystals were collected by filtration, washed with ethyl acetate, and dried. can get.

5.6 g of this N-penzylidene compound in ethanol,
Sodium borohydride 0. When 66 g of trans-4-benzylaminomethyl-1-(4
-pyridylcarbamoyl)cyclohexane dihydrochloride
A 3/4 hydrate is obtained.

Example 6 3 g of trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane dihydrobromide, 10 g of methanol, and 10 d of acetone are added with 3 g of sodium cyanoborohydride while stirring under water cooling. 5
After stirring for 3 hours at ~10°C, stir for an additional 3 hours at room temperature. The reaction mixture is concentrated below 30°C. The residue was poured into water, extracted with butanol, the organic layer was concentrated, the concentrate was dissolved in methanol, a methanol solution of oxalic acid was added, and the precipitated crystals were collected by filtration, giving a melting point of 227"C.
(Decomposition) of trans-4-isopropylaminomethyl-1-(4-pyridylcarbamoyl)cyclohexane.
Dioxalate dihydrate is obtained.

Example 7 Trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane dihydrobromide 6 g, pyridine 10 (1+j! and dimethylacetamide 100
Cool the mixture on ice and add nicotinic acid chloride hydrochloride 3.
Add 5g. After gradually increasing the internal temperature, the mixture was stirred at room temperature for 20 hours. The mixture is concentrated, chloroform is added, insoluble matter is filtered off, and the solvent is concentrated. Further, isopropyl alcohol is added to the residual viscous oil, the liquid is separated by decantation, and then concentrated. Add ethanol, collect the crystals by filtration, and recrystallize with a mixed solvent of methanol and ethanol to obtain trans-4-nicotinoylaminomethyl-1-(4-pyridylrubamoyl)cyclohexane with a melting point of 256°C (decomposition). Hydrobromic acid/hydrochloride/dihydrate is obtained.

Example 8 3.95 g of trans-4-aminomethyl-1-(4-pyridylcarhamoyl)cyclohegisan dihydrobromide
, 1.6 g of cyclo xyl bromide, 4.5 g of potassium carbonate and 100 mN of dimethylformamide at 70%
Stir at °C for 48 hours. The solvent was distilled off, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated, chloroform is added to the residue, and the resulting crystals are collected by filtration. When these crystals are dissolved in ethanol, oxalic acid is added, heated, and then cooled, fine crystals are precipitated. When the crystals are collected by filtration and further recrystallized from aqueous ethanol, the melting point is 23.
1°C (decomposition) of [・Lance-4-cyclohegysylaminomethyl-1. -(4-pyridylcarbamoyl)cyclohexane dioxalate is obtained.

Example 9 4-aminopyridine 5.3g,}ethylamine 39 1 3. While cooling and stirring 7 g of dichloromethane, 35 ml of dichloromethane, and 50 ml of dimethyl acetamide in ice water, add 20 g of trans-4-henzyloxyrupoxamide, 20 g of dichloromethane, and 6 ml of dichloromethane.
0 relative solution is added dropwise. After the dropwise addition, the mixture was stirred at 15-20°C for 2 hours, and then at 50-55°C for 4 hours. After the reaction,
After cooling the reaction mixture, it was poured into ice water, and the dichloromethane layer was washed with a 5% aqueous sodium bicarbonate solution, washed with water, dried, and concentrated to obtain trans-4 with a melting point of 213-215°C.
19 g of henzyloxylupoxamide-1-(4-pyridylcarbamoyl)cyclohexane are obtained as crystals.

Examples: O trans-4-henzyloxylupoxamide 1 (
4-pyridylcarhamol)/ , :y +5 . −
・Kizan 19g and 25% hydrogen bromide acetic acid solution 500g
Let stand for 16 hours. Pour the reaction solution into 2 liters of ether. The precipitated crystals were collected by filtration, washed with ether and acetone, and then washed with 40% ethanol stirred at 50-60°C to give trans-4-amino-1 (decomposed) with a melting point of 285°C. 15 g of 4-pyridylhamoyl)cyclohexane dihydrobromide are obtained.

Example 11 Trans-4-(1-henzyloxyrupoxamide ethyl)-1-(4-pyridylcarpamoyl)cyclohexane hydrochloride monohydrate 2.0 g ethanol 100 d
1.5 ml of 10% hydrochloric acid and 4 g of 10% palladium-carbon (containing 53.8% water) are added to the suspension, and catalytic reduction with hydrogen is carried out at 15-20°C under normal pressure. After confirming the completion of the reaction by silica gel thin layer chromatography, the catalyst is filtered off and the filtrate is concentrated under reduced pressure to obtain a viscous oil. When an acetone-methanol mixture is added, trans-4-(l
1.4 g of -aminoethyl l-1- (4-pyrisylcarbamoyl)cyclohexane dihydrochloride hydrate is obtained.

Example 12 1-Lan-4-henzyloxycarbamoylmethylcis-2-methyl-1-(4-pyridylcarbamoyl)
Dissolve 5.5 g of cyclohexane hydrochloride monohydrate in 100 d of ethanol, add 3.0 g of concentrated hydrochloric acid, add 3.08 g of 10% palladium-carbon to this solution, and perform catalytic reduction with hydrogen under normal pressure. .

After the reaction, the end point of the reaction is confirmed by thin layer chromatography, and the reaction solution is filtered. The solvent of the filtrate was distilled off under reduced pressure,
The resulting oil was dissolved in ethanol-a7ton (11) and left overnight in the cold to give trans-4-aminomethylcys-2-methyl- with a melting point of 280-282°C (decomposition).
1-(4-pyridylcarbamoyl)cyclohexane・2
3.0 g (yield 74%) of hydrochloride monohydrate is obtained.

12-4 Melting point of oxalate 222°C (decomposition) Example 13 Using trans-4-(1-henzyl-lupoxamidoprobyl)-1-cyclohexanecarboxylic Mol(-)-α-phenethylamine, When optical splitting is performed, (+)
-1 to Lance-1-(1 benzyloxycarboxamidoprobyl)-1 cyclohexanecarboxylic acid is obtained.

[α] 631122.4° (c=1, ethanol),
Melting point: 140°C. This (+) monocarboxylic acid is converted into acid chloride by a conventional method, and is condensed with 4-aminopyridine in the same manner as in Example 1. When treated, (+)-trans-
4-(1-penzyloxycarpoxamide biru)-
1-(4-pyridylcarbamoyl)cyclohexane hydrochloride monohydrate is obtained.

[α) P= + 1 8. 7° (c=1, ethanol), melting point 210°C Example 14 According to Example 13, 1.Lance-4-(1-penzyloxycarboxamidopropyl)-1-cyclohexanecarboxylic acid was converted to D-(+) When optical resolution is carried out using monoα-phenethylamine, (-)trans-4-(1-penzyloxycarboxamidoprobyl)-1-cyclohexanecarboxylic acid is obtained. [(r)g'-22.
6° (C-1 ethanol), melting point 142°C 43 This (-) monocarboxylic acid is converted into acid chloride, condensed with 4-aminopyridine, and treated to form ()-trans-4-(1-penzyl Oxycarboxamide drug)
-1-(4-pyridylcarbamoyl)cyclohexane・
Hydrochloride monohydrate is obtained. [α]ii'= 18
．． 5° (c=1, ethanol), melting point 208°C Example 15 Same as Example 11, (+)-1-Lansu-4(1-penzyloxyrupoxamidobyl)L-(4-pyridylcarbamoyl)cyclohexane・When hydrochloride monohydrate is treated by catalytic reduction with hydrogen under normal pressure,
(+)-}Lance 4-(1-aminobutipill l1-(4
-pyridylcarbamoyl)cyclohexane dihydrochloride
A monohydrate is obtained. [α) g5= +4. e゜
(c-1, ethanol), melting point 238°C (decomposition) Example 16 Same as Example 11, (1)-trans-4(1-penzyloxycarboxamide butopyr) 44 =1-(4- pyridylcarhamoyl)cyclohexane,
When the hydrochloride monohydrate is treated by catalytic reduction with hydrogen under normal pressure, (-)-1-trans-4-(1-aminobyl)-1-(4-pyridylrubamoyl)cyclohexane.2 Salt i1.monohydrate is obtained. [α)P=
4.4° (c-1 ethanol), melting point 235°C (decomposition) Example 17 Trans-4-(1-penzyloxycarboxamidoethyl)-1-cyclohexanecarboxylic acid was converted into I,-
(1) When optical resolution is performed using 1α-phenethylamine, (-)1}Lance-4-(1benzyloxycarboxamidoethyl)-1=cyclohexanecarboxylic acid is obtained. [α]63=-4. 7° (c = 0
．． 1. (ethanol) This (-) monocarboxylic acid was converted into acid chloride by a conventional method, and in the same manner as in Example 1, 4
-Condensation with aminopyridine and treatment yields (-)-trans-4-(1-penzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl)cyclohexane. [α) M3-8.4° (c = 0.
4, ethanol), melting point 192°C Example 18 Trans-4-(1-penzyloxycarpoxamidoethyl)-1-cyclohexanecarboxylic acid was converted to
) Optical resolution using -α-phenethylamine yields (+)-trans-4-(lbenzyloxycarboxamidoethyl)-1cyclohexanecarboxylic acid. [α] p= + 4. 5° (c = 0.
5, ethanol) This (+) monocarboxylic acid is converted into an acid chloride by a conventional method, and then condensed with 4-aminopyridine and treated in the same manner as in Example 1, resulting in (+)-trans-4-(1- (penzyloxycarboxamide ethyl)
-1-(4-pyridylcarbamoyl)cyclohexane is obtained. [α) M3-+8.1' (c-1, ethanol), melting point 190°C Example 19 Same as Example 11 (+)-} Lance-4-(1-henzyloxycarpoxamide ethyl) -Trans-4-(1-1) cyclohexane is catalytically reduced with hydrogen under normal pressure.
-aminoedinole)1-(4-pyridylhamoyl)cyclohexane dihydrochloride dihydrate is obtained. (
α〕63=+4. 6゜ (c=1, methanol)
, melting point 276'c (decomposition) Example 20 In the same manner as in Example 11, (-)-trans-4-(1-penzyloxycarboxamidoethyl)-1(4-pyridylcarbamoyl)cyclohexane was dissolved under normal pressure. When catalytic reduction with hydrogen is performed and treated, (1)-trans-4-(1
-aminoethyl)1- (4-pyridylcarbamoyl)
Cyclohexane dihydrochloride dihydrate is obtained. [α
]63=-4. 9° (c = 0.7.
methanol), melting point 279'C (decomposition) Using the method of any of the above examples, the following compounds are obtained.

(]) Trans-4-(4-chlorohenzoyl)a47 Minomethyl-1-(4-pyridylcarbamoyl)cyclohexane oxalate dihydrate, melting point 204'C (
(Decomposition) (2) trans-4-aminomethyl-1-(2-pyridylcarbamoyl)cyclohexane dihydrochloride, melting point 24
5°C (decomposition) (3) trans-4-henzyloxylupoxamidomethyl-1-(2-pyridylcarbamoyl)cyclohexane, melting point 133-137°C (4) trans-4-methylaminomethyl-1-( 4-pyridylcarbamoyl) cyclohexane dioxalate, melting point 211-212°C
(Decomposition) (5) trans-4-(2-phenylethyl)
Aminomethyl-1-(4-pyridylcarhamoyl)cyclohexane (6) trans-4-(N-acetyl-N-methylamine)methyl-1-(4-pyridylcarbamoyl)cyclohexane (7) trans-4-cyclo xylcarponylaminomethyl-1-(4-pyridylrubamoyl)48 hexane(8) trans-4-hexylaminomethyl-1(4-
pyridylcarbamoyl)cyclohexane (9) trans-4-diethylaminomethyl-1(4-pyridylcarbamoyl)cyclohexane (10) } trans-4-(4
-henjiru-1-piverazinyl)methyl-1-(4-pyridylrubamoyl)cyclohexane (11) }Ransu 4-(1-piperazinyl)methyl 1-(4-pyridylcarbamoyl]cyclohexane (12) }Ransu 4-morpholinomethyl- 1-(4
-pyridylcarbamoyl)cyclohexane (13) trans-4-thiomorpholinomethyl-1(4-pyridylcarbamoyl)cyclohexane (14) } trans-4-
Guanidinomethyl-1-(4-pyridylcarbamoyl)cyclohexane (15) } trans-4-(1-henzyl-4-biperidinyl)aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane (16) trans-4-(2-nitrophenyl )Aminomethyl-1(4-pyridylcarbamoyl)cyclohexane (17) }Ransu-4-(2-aminophenyl)aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane (18) hRansu-4-butylaminomethyl-l- (
4-pyridyl (rubamoyl) cyclohexane (19) }
Lance 4-cyclobentylaminomethyl 1-(4-pyridylcarbamoyl)cyclohexane (20) } Lance 4-(N-henjiruN-methylamino)methyl-1-(4-pyridylcarbamoyl)cyclohexane dioxalate・Monohydrate, melting point 206~
208°C (decomposition) (21) }Rance. 4-(4-methylcyclohexyl)aminomethyl-1-(4-pyridylcarbamoyl)
Cyclohexane (22) }Ransu 4- (2-methylcyclohexyl)aminomethyl-1-(4-pyridylcarbamoyl)
Cyclohexane (23) trans-4-(1-benzyl-4-biverizylidene)aminomethyl-l-(4-pyridylcarbamoyl)cyclohexane (24) }trans-4-(4-biperidyl)aminomethyl-1-(4-pyridylcarbamoyl) Cyclohexane (25) }Ransu 4-(4-fluorobenzoyl)
Aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane (26)
4-pyridylcarbamoyl)cyclohexane (27) trans-4-(N-benzy-N-ethylamino)methyl-1-(4-pyridylcarbamoyl)cyclohexane (28) l-trans-4-ethylaminomethyl-(4
pyridylcarbamoyl)cyclohexane (29) trans-4-aminomethyl-1-(3-py51 lysylcarbamoyl)cyclohexane dihydrochloride, melting point 250°C (decomposition) (30) } trans-4-aminomethyl-1-1 (3benzyloxy-2-pyridyl)carbamoyl]cyclohexane (31) trans-4-aminomethyl-1-[(3hydroxy-2-pyridyl)carbamoyl]cyclohexane dihydrochloride monohydrate, melting point 195-200 °C (32) l-Lansu 4-penzyloxycarboxamidomethyl-1-(3-pyridylcarbamoyl)cyclohexane, melting point 180-183 °C (33) I-Lansu 4-penzyloxycarboxamidomethyl-1-[
(3-penzyloxy-2-pyridyl)carbamoyl]
Cyclohexane, melting point 192-195°C (34)
4-pyridylcarbamoyl) cyclohexane, hydrochloride,
monohydrate, melting point 246-248°C (35) } Rance 4-penzyloxycarboxami 52 Domethyl-1-(3-methyl-4-pyridylcarbamoyl)cyclohexane, melting point 185-190"c (decomposition) ( 36) trans-4-aminomethyl-1-(3-methyl-4-pyridylrubamoyl)cyclohexane dihydrochloride, melting point 285-287°C (decomposed) (37) 4-(
}Lansu 4-penzyloxycarboxamidomethylcyclohexylcarbonyl)amino-2,6-dimethylpyridine-N-oxide, melting point 180-183"C (decomposition) (38) 4-(}Lansu 4-aminomethylcyclohexylcarbonyl)amino -2.6-dimethylpyridine-
N-oxide dihydrobromide, melting point 278-280°C (decomposition) (39) trans-4-aminomethyl-1-(2-methyl-4-pyridylrubamoyl)cyclohexane 2
Hydrochloride monohydrate, melting point 265-268°C (decomposition) (40) I-Ransu 4-(1-penzyloxycarboxamidoethyl)-1-(4-pyridylcarbamoyl)cyclohexane monohydrochloride 1 Hydrate, melting point 198~
200'C (decomposition) (41) l-lansu 4-aminomethyl-trans-
2Methyl-1-(4-pyridylcarbamoyl)cyclohexane (42) }Ransu 4-aminomethyl-trans-3
Methyl-1-(4-pyridylcarbamoyl)cyclohexane (43) } trans-4-aminomethyl-cis-3-methyl-1-(4-pyridylcarbamoyl)cyclohexane (44) trans-4-aminomethylcis-4-methyl -1-(4-pyridylcarbamoyl)cyclohexane (45) 4-(1-amino-l-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane dihydrochloride monohydrate, melting point 313 ~315'c (
decomposition) Corresponding dihydrochloride, melting point 310″C (decomposition) Corresponding 2
Hydrobromide, melting point 271°C (decomposition) (46) 4-(2-aminoethyl)-1(4-pyridylrubamoyl)cyclohexane dihydrochloride, melting point 260~
263°C (decomposition) (47) }Lansu 4-aminomethyl-cis-2-ethyl-1-(4-pyridylcarbamoyl)cyclohegisane (4B) }Lansu 4-(2--aminopropyl)-
1(4-pyridylcarhamoyl)cyclohexane (49
) }Ransu 4-(2-amino-1-methylethyl)
-1-(4-pyridylcarbamoyl)cyclohegysan
Fumarate dihydrate, melting point 185-187°C (decomposition) (50)
(4-pyridylhamoyl)cyclohexane dihydrochloride monohydrate, melting point 286-288"C (decomposition) (51)} Lance 4-amino-cis-2-methyl 1-
(4-pyridylrubamoyl)cyclohexane (52) }Ransu 4-aminomethyl-trans-1
55 Methyl-1-(4-pyridylhamoyl)cyclohexane dihydrochloride dihydrate, melting point 165-170°C (
decomposition) (53) }Lance 4-benzylaminomethylsis 2-methyl-1-(4-pyridylcarbamoyl)cyclohexane dioxalate 3/2 hydrate, melting point 190°C (decomposition) (54) } Lance 4-(1-penzyloxylupoxamide-1-methylethyl)-1-(4-pyridylhamoyl)cyclohexane, melting point 210°C
(Decomposition) Corresponding dihydrate, melting point 154~]55°C (55)
}Ransu 4-penzyloxylupoxamide methyl-
1-(N-Methyl-4-pyridylrubamoyl)cyclohexane oxalate hydrate, melting point 132°C (decomposition) (56) 1-acetamido-1-methylethyl)-1 -(4-pyridylcarbamoyl)cyclohexane dihydrate, melting point 250-253°C 56 Pharmaceutical formulation example Compound of the present invention 10.0 ■ Lactose
50.0 ■ Corn starch 2 0. 0 mg crystalline cellulose
2 9. 7 mg polyvinylpyrrolidone K
30 5. Omg talc
5. Omg Suar1n Magnesium
0.3120.0■ The compound of the present invention, lactose, corn starch and crystalline cellulose are mixed, kneaded using polyvinylpyrrolidone K30 paste, and granulated through a 20 mesh sieve.

After drying at 50°C for 2 hours, pass through a 24 mesh sieve, mix talc and magnesium stearate,
Using a pestle with a diameter of 7 holes, make 120 square tablets.

February 15, 1990

Claims (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen, alkyl having 1 to 10 carbon atoms, or Alkanoyl, formyl, alkoxy having 1 to 4 carbon atoms
Carbonyl, amidino, or cycloalkyl having 3 to 7 carbon atoms, which may have a substituent on the ring, or having 3 carbon atoms
represents ~7 cycloalkyl-carbonyl, phenyl, phenylalkyl, benzoyl, naphthoyl, phenylalkoxycarbonyl, benzylidene, pyridylcarbonyl, piperidyl, pyrrolidylidene or piperidylidene, or R^1, R^2 are bonded 5-6 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
Represents a group that forms a membered ring or a group that forms phthalimide together with a bonded nitrogen atom, R^3 represents hydrogen or alkyl having 1 to 4 carbon atoms, and R^4 represents hydrogen or a group having 1 to 4 carbon atoms.
~4 alkyl, R^5 represents hydrogen, hydroxyl group, alkyl having 1 to 4 carbon atoms, phenylalkoxy, R
^6 represents hydrogen, alkyl having 1 to 4 carbon atoms, A is a single bond, straight chain alkylene having 1 to 5 carbon atoms, or 1 carbon number
It represents alkylene substituted with ~4 alkyls, and n represents 0 or 1. ] trans-4-amino(alkyl)- represented by
1-Pyridylcarbamoylcyclohexane compounds, optical isomers thereof and pharmaceutically acceptable acid addition salts thereof. (2) Claim in which R^1 and R^2 are both hydrogen (
1) The described compounds, their optical isomers and their pharmaceutically acceptable acid addition salts. (3) trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl-trans-1-methyl-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl- Cis-2-methyl-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl-1-(2-pyridyl carbamoyl)cyclohexane, trans-4-aminomethyl-1-(3-pyridylcarbamoyl)cyclohexane, trans-4-aminomethyl-1-[(3-
hydroxy-2-pyridyl)carbamoyl]cyclohexane, trans-4-aminomethyl-1-(3-methyl-4-pyridylcarbamoyl)cyclohexane, 4-(
trans-4-aminomethylcyclohexylcarbonyl)amino-2,6-dimethylpyridine-N-oxide,
trans-4-aminomethyl-1-(2-methyl-4-
pyridylcarbamoyl)cyclohexane, trans-4
-(2-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(1-amino-
1-methylethyl)-1-(4-pyridylcarbamoyl)cyclohexane, trans-4-(1-aminopropyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-4-(1-aminopropyl) )−
1-(4-pyridylcarbamoyl)cyclohexane, (
-)-trans-4-(1-aminopropyl)-1-(
4-pyridylcarbamoyl)cyclohexane, (+)-
trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (-)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and pharmaceutically acceptable thereof The compound according to claim (1), which is selected from acid addition salts that can be added. (4) a therapeutically effective amount of the compound according to claim (1);
A pharmaceutical composition for preventing and treating circulatory system diseases comprising a pharmaceutically acceptable carrier.