JP3265695B2 - 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel and pharmaceutically useful 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound, its isomer and its pharmaceutically acceptable acid addition salt.

[0002]

2. Description of the Related Art One of the causes of hypertension and coronary and cerebral circulatory dysfunction, which have become major social problems as adult diseases, is abnormal contraction of smooth muscle. It is known that contraction is triggered by an increase in the intracellular concentration of calcium ions. Elevated intracellular concentrations of calcium ions include (1) those via membrane potential-dependent calcium channels, (2) those released from intracellular calcium storage sites, and (3) those via receptor-dependent channels. However, it is said that excessive calcium ions in cells cause spasm of coronary arteries and cerebral blood vessels, and these vasospasms are one of the causes of myocardial infarction, angina and cerebral infarction. Is considered one. Therefore, use of calcium antagonists is currently being attempted for the treatment of hypertension, coronary / brain and peripheral circulatory disorders. However, calcium antagonists exhibit antagonism to membrane potential-dependent calcium channels, but hardly any antagonism to calcium influx into other cells or calcium release from storage sites. As a compound having not only an inhibitory effect on the membrane potential-dependent smooth muscle contraction suppressed by a conventional calcium antagonist but also an intracellular calcium antagonistic effect, WO 90/05723 describes a certain compound. Trans-4-amino (alkyl) -1-pyridylcarbamoylcyclohexane compound, its optical isomer, its pharmaceutically acceptable acid addition salt has a sustained coronary / cerebral / renal blood flow increasing action, It is disclosed that it is useful as an agent for preventing and treating cardiovascular diseases such as coronary, brain and kidney. An object of the present invention is to provide a compound having an effect of increasing coronary, cerebral, renal and peripheral arterial blood flow which is more potent, longer lasting, and less toxic than conventional compounds.

[0003]

The present inventors have made intensive studies and as a result, have found that the 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound of the present invention, its isomer and its pharmaceutically acceptable nature. The inventors have found that an acid addition salt can achieve the above object, and have completed the present invention.
Furthermore, the compound of the present invention exhibited an experimental asthma-suppressing effect of guinea pig by inhalation of histamine and a contraction-inhibiting effect by acetylcholine in a guinea pig-excluded tracheal specimen, and was also found to have an anti-asthmatic effect.

That is, the present invention provides a compound represented by the general formula (I)

[0005]

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Wherein R is hydrogen, alkyl, -NR '
R "(where R 'and R" are the same or different and each represents hydrogen,
Represents alkyl, phenylalkyl, and phenyl. And R ¹ represents hydrogen, alkyl, phenylalkyl, phenyl, nitro or cyano, or R and R ¹ may be bonded to each other to further have an oxygen atom, a sulfur atom and a substituent in the ring. R ² represents hydrogen, alkyl or phenylalkyl, R ³ and R ⁴ represent the same or different hydrogen and alkyl, and A represents a single bond. , Represents an alkylene, and X is ＣC
(R ⁷⁾ - (wherein, R ⁷ is hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, -NReRf (wherein, Re, Rf are the same or different and each is hydrogen, alkyl, -COR ^9, - COOR ^{9 '} ,
—SO ₂ R ^{9 ′} (where R ⁹ represents hydrogen, alkyl, phenyl or phenylalkyl, and R ^{9 ′} represents alkyl, phenyl or phenylalkyl), or Re and Rf
Represents a group which forms a heterocyclic 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. ), Cyano,
Azide, hydrazino optionally having substituent (s), -CO
OR ^10, -CONR ¹¹ R ^{12 (wherein, R 10, R 11, R} 12
Represents hydrogen, alkyl, phenyl, or phenylalkyl. ). ), = N-, and R ⁵ and R ⁶ together represent the formula (1): -C (Ra) = C (Rb)-(a) -N = C (Rb)-(b) -C ( Ra) = N- (c) -N (Ra)-(d) (where Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, -NReRf (where Re, Rf
Is as defined above. ), Cyano, azide, hydrazino optionally having substituent (s), -COOR ¹⁰ , -CONR
¹¹ R ¹² (where R ¹⁰ , R ¹¹ , and R ¹² have the same meanings as described above), or Ra and Rb together form at least one of a nitrogen atom, a sulfur atom, and an oxygen atom in the ring And a group forming a 5- to 6-membered aromatic ring which may be hydrogenated, which may contain Or (2) Formula -N (Rc) -C (= Rd)-(e) -C (= Rc) -N (Rd)-(f) (where Rc and Rd are taken together. Nitrogen atom in the ring
A group forming a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one of a sulfur atom and an oxygen atom. ) R ⁸ is hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro,
—NReRf (where Re and Rf are as defined above), cyano, azide, hydrazino optionally having a substituent, —COOR ¹⁰ , —CONR ¹¹ R ¹² (where
R ¹⁰ , R ¹¹ and R ¹² are as defined above. ), And n represents 0 or 1. However, when R ⁵ and R ⁶ together represent the formula (a), X is = C (R ⁷ )-, and
Any one of Ra, Rb, R ⁷ and R ⁸ is halogen,-
NReRf, azido, optionally substituted hydrazino, -COOR ^10, or shows a -CONR ¹¹ R ^12, R
a and Rb together represent a group that forms a 5- to 6-membered hydrogenated aromatic ring which may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom in the ring. . A 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound, an isomer thereof and a pharmaceutically acceptable acid addition salt thereof.

For example, among the compounds of the general formula (I) of the present invention, (1) R ⁵ and R ⁶ together represent the formula (a), X represents ＣC (R ⁷ )-, And Ra, Rb, R
^One of R ⁷ and R ⁸ is halogen, —NReRf, azide, hydrazino optionally having substituent (s), —COO
R ¹⁰ and —CONR ¹¹ R ¹² , or (2) R ⁵ and R ⁶ together represent the formula (a), and X represents （C (R ⁷ ) —, pyrrolopyridine, pyrazolopyridine Compounds that form a condensed ring such as are preferred.

The symbols in the general formula (I) will be described below by definition. Halogen is chlorine, bromine, fluorine or iodine, and alkyl is straight or branched alkyl having 1 to 6 carbon atoms. In addition, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl and the like. Trifluoromethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3
-Alkoxy such as pentafluoropropyl is a straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, butoxy, isobutoxy, secondary butoxy, Tertiary butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like, alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, methylene, ethylene, trimethylene, Examples include tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, diethylmethylene, propylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltrimethylene, dimethyltetramethylene, and the like. Phenylalkyl has alkyl having 1 to 4 carbon atoms as its alkyl moiety, and includes benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,
Represents phenylbutyl, etc., as a substituent on the aromatic ring of phenyl or phenylalkyl, halogen, alkyl,
Alkoxy, phenylalkyl, haloalkyl, nitro, -NReRf (wherein Re, Rf are the same or different and each is hydrogen, ^{alkyl, -COR 9, -COOR 9 ',} -S
O ₂ R ^{9 ′} or a heterocyclic 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 Re and Rf are bonded. The group to be formed is shown. ), Cyano, azide, formyl, acyl,
—COOR ¹⁰ , —CONR ¹¹ R ¹² or hydrazino which may have a substituent. Here, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl have the same meaning as described above, and acyl is acetyl,
And propionyl, butyryl, valeryl, pivaloyl, benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl and the like.

The substituent of the hydrazino which may have a substituent includes alkyl, phenylalkyl, nitro,
And cyano. Here, alkyl and phenylalkyl are as defined above. Examples of the group forming a heterocyclic 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 Re and Rf are bonded are 5 to 6 members Rings and these bonded rings are preferred, and specific examples include pyrrolidinyl, piperidyl, piperazinyl, morpholino, and thiomorpholino. Further, as the substituent on the nitrogen atom which may have a substituent, alkyl, phenylalkyl,
Haloalkyl and the like. Here, alkyl, phenylalkyl and haloalkyl are as defined above.

The group in which R and R ¹ combine to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom and a nitrogen atom which may have a substituent is imidazol-2-yl, Thiazol-2-yl, oxazol-2-yl,
Imidazolin-2-yl, 3,4,5,6-tetrahydropyridin-2-yl, 3,4,5,6-tetrahydropyrimidin-2-yl, oxazolin-2-yl, thiazolin-2-yl or halogen, Benzimidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, indole-2- which may have a substituent such as alkyl, alkoxy, haloalkyl, nitro, amino, phenyl and phenylalkyl. Ill. Here, halogen, alkyl, alkoxy, haloalkyl and phenylalkyl are as defined above. Examples of the substituent on the nitrogen atom which may have a substituent include alkyl, phenylalkyl, haloalkyl and the like. Here, alkyl, phenylalkyl and haloalkyl are as defined above. R ⁵ and R ⁶ together form formulas (a), (b),
In the case of a single ring represented by (c) or (d), it represents pyridine, pyrimidine, pyridazine, triazine, pyrazole, triazole and the like.

When R ⁵ and R ⁶ together form a condensed ring of the formulas (a), (e) and (f), pyrropyridine (1H-pyrrolo [2,3-b Pyridine, 1H-pyrrolo [3,2-b] pyridine, 1H-pyrrolo [3,4-b] pyridine, etc., pyrazolopyridine (1H-pyrazolo [3,4-b] pyridine, 1H-pyrazolo [4 , 3-b] pyridine, etc.), imidazopyridine (1H-imidazo [4,5-b] pyridine etc.), pyrrolopyrimidine (1H-pyrrolo [2,3-b] pyrimidine, 1H-pyrrolo [3,2-d] Pyrimidine, 1H-pyrrolo [3,4-d] pyrimidine, etc.), pyrazolopyrimidine (1H-pyrazolo [3,4-d] pyrimidine, pyrazolo [1,5-a] pyrimidine, 1H-pyrazolo [4,
3-d] pyrimidine, etc.), imidazopyrimidine (imidazo [1,2-a] pyrimidine, 1H-imidazo [4,
5-d] pyrimidine, etc.), pyrrolotriazine (pyrrolo [1,2-a] -1,3,5-triazine, pyrrolo [2,1-f] -1,2,4-triazine), pyrazolotriazine ( Pyrazolo [1,5-a] -1,3,5-triazine and the like, and triazolopyridine (1H-1,2,2,3).
3-triazolo [4,5-b] pyridine and the like, and triazolopyrimidine (1,2,4-triazolo [1,5-
a] Pyrimidine, 1,2,4-triazolo [4,3-
a] pyrimidine, 1H-1,2,3-triazolo [4,
5-d] pyrimidine, etc.), cinnoline, quinazoline,
Quinoline, pyridopyridazine (eg, pyrido [2,3-c] pyridazine), pyridopyrazine (pyrid [2,3-
b] pyrazine, etc.), pyridopyrimidine (pyrido [2,
3-d] pyrimidine, pyrido [3,2-d] pyrimidine, etc., pyrimidopyrimidine (pyrimido [4,5-d]
Pyrimidine, pyrimide [5,4-d] pyrimidine, etc., pyrazinopyrimidine (pyrazino [2,3-d] pyrimidine, etc.), naphthyridine (1,8-naphthyridine, etc.), tetrazolopyrimidine (tetrazolo [1,5-
a] pyrimidine, etc.), thienopyridine (thieno [2,
3-b] pyridine, thienopyrimidine (thieno [2,3-d] pyrimidine, etc.), thiazolopyridine (thiazolo [4,5-b] pyridine, thiazolo [5,4
-B] pyridine, etc.), thiazolopyrimidines (thiazolo [4,5-d] pyrimidine, thiazolo [5,4-d] pyrimidine etc.), oxazolopyridines (oxazolo [4,5-b] pyridine, oxazolo [5 , 4-b] pyridine, etc.), oxazolopyrimidines (oxazolo [4,5-d] pyrimidine, oxazolo [5,4-d]
Pyrimidine, etc.), furopyridine (furo [2,3-b]
Pyridine, furo [3,2-b] pyridine, etc., furopyrimidine (furo [2,3-d] pyrimidine, furo [3,2-b]
2-d] pyrimidine), 2,3-dihydropyrrolopyridine (2,3-dihydro-1H-pyrrolo [2,3-
b] pyridine, 2,3-dihydro-1H-pyrrolo [3,
2-b] pyridine), 2,3-dihydropyrrolopyrimidine (2,3-dihydro-1H-pyrrolo [2,3-
d] pyrimidine, 2,3-dihydro-1H-pyrrolo [3,2-d] pyrimidine, etc.), 5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine, 5,6
7,8-tetrahydro-1,8-naphthyridine, 5,
6,7,8-tetrahydroquinoline and the like. When these rings form a hydrogenated aromatic ring, the carbon atom in the ring may be carbonyl, for example, 2,3-dihydro-2-oxo. Pyrrolopyridine, 2,3
-Dihydro-2,3-dioxopyrrolopyridine, 7,8
-Dihydro-7-oxonaphthyridine, 5,6,7,8
-Tetrahydro-7-oxonaphthyridine and the like are also included. Also, these rings are halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, -NR
eRf, cyano, formyl, acyl, aminoalkyl,
Mono- or dialkylaminoalkyl, azide, -CO
It may be substituted by a substituent such as OR ¹⁰ , —CONR ¹¹ R ¹² , and hydrazino which may have a substituent. Here, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, -NReRf, acyl,-
COOR ¹⁰ , —CONR ¹¹ R ¹² , and optionally substituted hydrazino have the same meanings as described above, and aminoalkyl includes aminomethyl, aminoethyl, aminopropyl, aminobutyl and the like, and mono or dialkylamino Alkyl includes methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylaminopropyl, dimethylaminopropyl, methylaminobutyl, dimethylaminobutyl and the like.

The present invention also includes pharmaceutically acceptable acid addition salts, hydrates or various solvates formed with the inorganic or organic acid of compound (I). When the compound has a carboxyl group, a metal salt such as a sodium salt, a potassium salt, a calcium salt, and an aluminum salt, and a salt with an amino acid such as lysine and ornithine are also included. The present invention also includes the cis or trans geometric isomer of compound (I) or a mixture thereof. When an asymmetric carbon is present, optical isomers and racemic forms thereof may exist, but the present invention includes all of them.

The compound (I) of the present invention can be synthesized by the following method.

[Method 1] General formula (II)

[0015]

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(Wherein each symbol is as defined above) and a carboxylic acid compound represented by the formula (III):

[0017]

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(Wherein each symbol has the same meaning as described above).

The reactive derivative of the carboxylic acid compound includes acid halides such as acid chlorides, acid anhydrides, mixed acid anhydrides formed from ethyl chloroformate, etc., methyl esters, and the like.
Reactive derivatives generated from esters such as ethyl esters and carbodiimides such as dicyclohexylcarbodiimide are exemplified. The reaction is carried out in the presence of a solvent inert to the reaction, but usually does not contain hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, dimethylformamide, and dimethylimidazolidinone. Organic solvents are used. The reaction can be performed at any temperature, for example, -10 to 2
The reaction is carried out at a temperature of 00 ° C., preferably 0 to 80 ° C., but in the case of a reactive derivative (eg an ester) having a low reactivity, a high reaction temperature is used, and a reactive derivative having a large reactivity (eg a mixed acid) is used. (Anhydride), lower reaction temperatures are used. Further, if necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine or the like is used as a deoxidizing agent. Further, the compound of the general formula (II) can be easily synthesized by the following synthesis method.

That is, the general formula (IV)

[0021]

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(Wherein each symbol is as defined above) and a compound represented by the general formula (V)

[0023]

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(Wherein R and R ¹ are, together with the above-mentioned groups, t-butoxycarbonyl, benzyloxycarbonyl,
X represents a protecting group such as acetyl and benzoyl, and X represents oxygen,
R ⁹ ″ represents lower alkyl such as methyl, ethyl, propyl, etc., benzyl, p-nitrobenzyl, 2-thienyl, etc.) or an acid addition salt thereof. Is done.

The compound represented by the general formula (V) includes S-methylisothiourea, O-methylisourea, S-ethylisothiourea, O-ethylisourea, N, N'-S-trimethylisothiourea, N, N'- O-trimethylisourea, N, S-dimethylisothiourea, N, O-dimethylisourea, N-ethyl-S-methylisothiourea, N-
Ethyl-O-methylisourea, 2-methylthio-2-imidazole, 2-methylthio-2-benzothiazole,
2-methylthio-2-benzoxazole, 2-methylthio-2-imidazoline, 2-methoxy-2-imidazoline, 2-methylthio-3,4,5,6-tetrahydropyrimidine, 2-methylthiothiazoline, N, N'- Dibenzyloxycarbonyl-S-methylisothiourea,
N, N'-diacetyl-S-methylisothiourea, ethylformimidate, methylformimidate, methylacetimidate, ethylacetimidate, ethylN
-Methylformimidate, methyl N-methylformimidate and the like, and the acid addition salts thereof include hydroiodide, hydrobromide, hydrochloride, sulfate, p-toluenesulfonate and the like. can give.

In the reaction, water, alcohols such as methanol and ethanol alone or mixtures thereof with water, polar solvents such as dimethylformamide, dioxane and tetrahydrofuran or mixtures thereof with water are generally used as preferred solvents. The amount of the compound represented by the formula (V) is preferably 1 to 10 moles, and the reaction is preferably carried out at any temperature, for example, 0 to 100 ° C. If necessary, potassium carbonate as a deoxidizing agent,
It is preferable to use an inorganic base such as sodium carbonate, potassium hydroxide and sodium hydroxide or an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine.

The carboxylic acid compound of the general formula (IV) wherein R ² is hydrogen, which is a raw material for synthesis of the present invention, is a compound of Chemical and Pharmaceutical Bulletin (Chem. Phar).
m. Bull.), Vol. 27, p. 2735 (1979), or Vol. 27, p. 3039 (1979). In the case where the carboxylic acid compound is not tranexamic acid, the compound can be synthesized by the following method.

[0028]

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(In the formula, Ac represents an amino protecting group such as acetyl, and other symbols are as defined above.)

That is, after protecting the amine compound of the formula (g) with an amino-protecting group (such as an acetyl group), an acetyl group is introduced into the aromatic ring by a Friedel-Crafts reaction, and the carboxyl compound of the formula (k) is subjected to a haloform reaction. Obtaining an acid compound, then
By reducing the aromatic ring by catalytic reduction and deprotecting by alkali hydrolysis, a compound in which R ² is hydrogen in the carboxylic acid compound of the general formula (IV) can be synthesized. R ² is alkyl, a compound showing a phenylalkyl in a manner known per se, R ² is prepared by alkylating or phenylalkyl of the compound is hydrogen.

The cis-form or trans-form of the carboxylic acid compound of the general formula (IV) can be obtained, for example, by subjecting the carboxylic acid compound of the formula (l) to a usual column chromatography and recrystallization method. Obtaining a cis form of the compound,
Further, the trans-form of the carboxylic acid compound of the formula (l) is obtained by esterifying the carboxylic acid compound of the formula (l) by a usual method and isomerizing the ester by using a base (sodium methoxide, potassium butoxide, etc.). Then, each isomer can be obtained by deprotection according to the method described above.

The amine compound of the general formula (III), which is another synthetic raw material, is described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol.
1258 (1982), 32, 945 (1989), Janard of heterocyclic chemistry (J. Heterocycl. Chem.), 20,
295 (1983), Vol. 9, 235 (1
972), Vol. 1, p. 42 (1964), Journal of the American Chemical Society (J. Am. Chem. Soc.), Vol. 77, p. 2256 (1
955) and Jurunal Organicheskoy
Kimi (Zhurnal Organicheskoi Khimii), Vol. 9, No. 12
It can be synthesized by the method described on page 66 (1973).

[Method 2] General formula (VI)

[0034]

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(Wherein each symbol is as defined above), and an amine compound (synthesized by the method described in Japanese Patent Application No. 3-255689) and a compound of the general formula (V) It can be synthesized by subjecting it to a condensation reaction. The reaction can be carried out under the same conditions as in the reaction of compounds (IV) and (V) in Method 1. Further, when R in the general formula (I) is -N
The compound of R′R ″ can be synthesized by the following two methods.

[Method 3] The compound of the general formula (VI) and the iso (thio) represented by the general formula (VII) R ¹ NC = X (VII) (wherein each symbol is as defined above) General formula (VIII) obtained by reacting with a cyanate compound

[0037]

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(Wherein each symbol is as defined above) and a (thio) ureido compound (VIII) represented by the general formula (I
X) (R ⁹ ) m -X ¹ (IX) wherein R ⁹ represents alkyl or phenylalkyl, and X ¹ represents halogen (chlorine, bromine, iodine, etc.) or sulfonyloxy (methanesulfonyloxy, p-toluene Sulfonyloxy, trifluoromethanesulfonyloxy, etc.), and m represents 1 or 2. With a suitable alkylating agent represented by the general formula (X)

[0039]

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After derivation to a compound represented by the formula (wherein each symbol is as defined above), R′R ″ NH (XI) (wherein each symbol is as defined above) The compound of formula (I) wherein R is -NR'R "can be synthesized by reacting with an amine derivative represented by the formula:

As the isocyanate or isothiocyanate compound represented by the general formula (VII) shown herein, methyl isocyanate, methyl isothiocyanate, ethyl isocyanate, ethyl isothiocyanate, phenyl isocyanate, phenyl isothiocyanate and the like are exemplified. When R ¹ is hydrogen, sodium isocyanate, sodium isothiocyanate, ammonium thiocyanate and the like are particularly used.

Suitable alkylating agents of the general formula (IX) include methyl iodide, ethyl iodide, benzyl bromide,
-Nitrobenzyl bromide, 2-thienyl bromide, dimethyl sulfate, diethyl sulfate and the like. Further, as the amine derivative of the general formula (XI), ammonia,
Methylamine, ethylamine, propylamine, aniline, benzylamine, phenethylamine, N-methyl-
N-benzylamine and the like.

The reaction between compounds (VI) and (VII) is carried out with methanol,
An alcoholic solvent such as ethanol or a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, chloroform or methylene chloride is used. The reaction temperature is preferably from 0 to 200 ° C, particularly preferably from room temperature to 100 ° C. For some compounds, the reaction is accelerated by adding an organic base such as pyridine or triethylamine. When R ¹ is hydrogen, the reaction is carried out in an acidic aqueous solution such as hydrochloric acid or sulfuric acid.

In the reaction between the compounds (VIII) and (IX), a solvent such as acetone, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylimidazolidinone is used. The reaction temperature is preferably from 0 to 150 ° C, particularly preferably from room temperature to 100 ° C. In some cases, a base such as sodium hydride, potassium carbonate, or sodium methoxide can be used.

In the reaction between the compounds (X) and (XI), no solvent or an alcoholic solvent such as methanol or ethanol or a polar solvent such as tetrahydrofuran, acetonitrile or dimethylformamide is used. It is preferable to use 0.5 to 1.5 equivalents of the amine derivative of the compound (XI) with respect to the compound (X).
You may use 0 equivalent. The reaction temperature is -20 to 150C, preferably 0 to 100C. This reaction can be promoted by adding 0.01 to 10 equivalents, preferably 0.1 to 3 equivalents of a base or a metal salt. As such a base, an inorganic base such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate, or an organic base such as pyridine, triethylamine or 4-dimethylaminopyridine is used, and the organic base itself can be used as a solvent. The metal salts include copper chloride, copper bromide, copper acetate,
Copper sulfate, mercury acetate and the like are used. Compound (VII)
The desired compound of the general formula (I) can be obtained by directly reacting the compound (XI) with the compound (XI) according to the reaction between the compounds (VII) and (VIII).

[Method 4] A cyanide compound represented by the general formula (XII) X ² —CN (XII) (where X ² represents a halogen such as chlorine or bromine) And the resulting general formula (X
III)

[0047]

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(Wherein each symbol has the same meaning as described above), and the cyanamide compound represented by the general formula (XI) is reacted with an amine derivative of the general formula (XI) so that R in the general formula (I) is -NR '.
The compound of R ″ can be synthesized.

The reaction between the compounds (VI) and (XII) uses a solvent such as tetrahydrofuran, ether, acetone, methanol, ethanol, acetonitrile, dimethylformamide, dimethylimidazolidinone, chloroform, dichloromethane and the like. The reaction temperature is preferably -20 to 150C, particularly preferably 0 to 80C. This reaction was performed with potassium acetate,
Inorganic bases such as sodium acetate, potassium carbonate and sodium carbonate, and organic bases such as pyridine, triethylamine and 4-dimethylaminopyridine are used.

The reaction between the compounds (XIII) and (XI) is carried out in an inorganic solvent or an alcoholic solvent such as methanol or ethanol, or a polar solvent such as acetone, tetrahydrofuran, dioxane or dimethylformamide. General formula
The amine derivative of (XI) is preferably used in an amount of 0.8 to 1.5 equivalents to the cyanamide compound (XIII), but may be used in an amount of 155 to 10 equivalents when the reaction is not hindered.
In this reaction, the base is used in an amount of 0.01 to 10 equivalents, preferably 0.1 to 10 equivalents.
It is promoted by adding 1-3 equivalents. As such a base, it is advantageous to use an organic base such as pyridine, triethylamine and 4-dimethylaminopyridine, and an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen carbonate.

Further, compounds of the formula (I) in which R and R ¹ are bonded to form a group forming a heterocyclic ring which may further have an oxygen atom, a sulfur atom and a substituent in the ring are as follows: It can be synthesized by a method.

[Method 5] In the compound (VI), R ² is hydrogen and the substituent of the heterocyclic ring in the portion A is —NReR
f, a compound which is not hydrazino is reacted with sodium nitrite or potassium nitrite in the presence of hydrochloric acid, sulfuric acid, formic acid and acetic acid to obtain a compound of the general formula (XIV)

[0053]

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(Wherein each symbol has the same meaning as described above), and the hydroxy form is represented by thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or the like. The compound is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in the presence of a halogenating agent or in the presence of a dehydrohalogenating agent to form a corresponding reactive derivative of an alcohol.

[0055]

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(Wherein R and R ¹ are combined to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom, and a nitrogen atom which may have a substituent in the ring) Indicates that
R ^{2 ′} is the same or different and represents alkyl, phenyl or phenylalkyl. The compound can be produced by reacting an amine compound represented by The reaction is carried out using a suitable base, for example, an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate (sodium hydroxide, potassium carbonate, sodium bicarbonate and the like), and an organic base such as pyridine and triethylamine. Perform in the presence of The isomers included in the compound (I) of the present invention can be isolated from a mixture of isomers by a conventional method, or can be produced by using each isomer raw material.

The thus-obtained compound (I) of the present invention comprises an amino group in the 4-substituted amino moiety of the cyclohexane ring, an amino group in the case where Ra, Rb, R ⁷ and R ⁸ represent —NReRf. When R ⁵ and R ⁶ form a single ring or form a condensed ring, the substituent in the ring or the ring is-
The amino group in the case of representing NReRf may be protected by a usual amino protecting group, for example, alkanoyl having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl and valeryl; methoxycarbonyl, ethoxy C2 to C5 alkoxycarbonyl such as carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl; cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl Aroyl such as benzoyl and naphthoyl (where aroyl is halogen, alkyl having 1 to 6 carbons) Which may have a substituent having 1 to 6 carbon atoms such as alkoxy, phenylalkyl, trifluoromethyl, nitro and amino); benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, phenylbutoxycarbonyl Such as phenylalkoxycarbonyl (where phenylethoxycarbonyl is a halogen on the phenyl ring,
Alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, phenylalkyl, trifluoromethyl, nitro,
Which may have a substituent such as amino);
Phenylalkenyl such as styryl, cinnamyl, phenylbutenyl, phenylpentenyl and phenylhexenyl; or phenylalkylidene such as benzylidene and phenylethylidene; a group forming pyrrolidylidene, piperidylidene, phthalimide; methylcarbamoyl;
Alkylcarbamoyl such as ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl; alkylcarbamoylalkyl such as methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, diethylcarbamoylmethyl, dimethylcarbamoylethyl; methoxymethyl,
Ethoxymethyl, propoxymethyl, butoxymethyl,
Alkoxymethyl such as tertiary butoxymethyl; benzyloxymethyl, p-methoxybenzyloxymethyl,
It may be protected by a protecting group such as aralkyloxyalkyl such as o-nitrobenzyloxymethyl; allyl; cyclic ether such as tetrahydrofuran and tetrahydropyran.

The above-mentioned amino-protecting groups may be selected from common acids (hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, bromic acid / acetic acid, hydrochloric acid / dioxane, hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, etc.) and Lewis Acid (boron trifluoride ether complex, titanium tetrachloride, tin tetrachloride, aluminum chloride, boron tribromide, trimethylsilane iodide, etc.) or alkali (ammonia, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate) , Sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrazine, etc.). A catalytic reduction method using 5% palladium carbon, 10% palladium carbon, 10% palladium hydroxide carbon, Raney nickel or the like as a catalyst, a reduction method using metallic sodium or metallic lithium in liquid ammonia, or sodium borohydride; It can also be deprotected by a reduction method using lithium aluminum hydride, diborane, zinc, sodium amalgam or the like as a reducing agent. Further, hydrogen peroxide, potassium permanganate, 2,3-dichloro-5,6
A method using an oxidizing agent such as -dicyano-1,4-benzoquinone (DDQ) or N-bromosuccinimide can also be used.

The compound (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, chromatography and the like. Further, compound (I) can form a pharmaceutically acceptable acid addition salt according to a conventional method. The acid used to form the acid addition salt is appropriately selected from inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) and organic acids (acetic acid, methanesulfonic acid, maleic acid, fumaric acid, etc.). be able to.
In addition, these salts are converted to the corresponding free bases by a conventional method, for example, by reaction with an alkali such as sodium hydroxide or potassium hydroxide. Furthermore, it can also be a quaternary ammonium salt. In the compound (I), the compound having a carboxyl group can be a salt with a metal salt (eg, sodium, potassium, calcium, aluminum) or an amino acid (eg, lysine, ornithine).

[0060]

The compound (I) of the present invention, its isomers and its pharmaceutically acceptable acid addition salts have a coronary and cerebral blood flow increasing effect similarly to calcium antagonists, It also has an effect on increasing renal and peripheral arterial blood flow, which is not seen in E. coli. In addition, the effect of increasing blood flow is long, and the effect of lowering blood pressure is also strong. Furthermore, it is effective not only for vasoconstriction induced by an in vivo substance such as endothelin, but also for vasoconstriction caused by calcium ionophore or phorbol ester in which a calcium antagonist does not act. Therefore, the compounds of the present invention are useful as potent and persistent antihypertensive agents and agents for preventing and treating diseases of the circulatory system such as coronary, cerebral, renal and peripheral arteries. Furthermore, the compounds of the present invention exhibit an experimental asthma-suppressing effect of guinea pigs by histamine inhalation, and a contraction-inhibiting effect of histamine and acetylcholine in guinea pig isolated trachea specimens, and are also useful as therapeutic agents for asthma.

When the compound (I) of the present invention is used as a medicine, its effective amount is mixed with pharmacologically acceptable excipients, carriers, diluents and other additives for pharmaceutical preparations.
It can be administered orally or parenterally in the form of tablets, granules, powders, capsules, injections, ointments, suppositories and the like. The dose may vary depending on the age, weight, symptoms, etc. of the patient.
５００500 mg, which can be administered once or in several divided doses.

[0062]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Example 1 (a) 21.2 g of isothiourea sulfate was dissolved in 40 ml of water, and 46 ml of 2N sodium hydroxide solution was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, a solution of trans-4-aminomethylcyclohexanecarboxylic acid dissolved in 100 ml of hot water was added dropwise, and the mixture was stirred at room temperature for 24 hours. After the reaction, the reaction solution was cooled, and the precipitated crystals were collected by filtration. After washing well with cooling water and drying, 18.5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid was obtained.
325 ° C

(B) Trans-4-guanidinomethylcyclohexanecarboxylic acid (82.36 g) was dissolved in 1,2-dichloroethane (500 ml), and diisopropylethylamine (210 ml) and chlorotrimethylsilane (153) were added thereto.
Then, the mixture was stirred at 40 ° C. for 1.5 hours. After cooling,
210 ml of diisopropylethylamine and 172 ml of benzyl chloroformate were added, and the mixture was stirred under ice cooling for 1 hour and further at room temperature for 3 hours. The reaction solution was adjusted to pH 2 with 1N hydrochloric acid.
After extracting with dichloromethane, the organic layer was concentrated under reduced pressure to obtain 202 g of a red solid. This red solid was washed with dichloromethane and dried to obtain trans-4-
125.9 g of (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid were obtained. 140-142 ° C

(C) 60 g of trans-4- (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid was dissolved in 300 ml of dichloromethane, and 14 ml of thionyl chloride and 1 m of dimethylformamide were dissolved.
was added and stirred at room temperature for 1 hour. When the solvent was distilled off under reduced pressure, 63 g of trans-4- (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid chloride was obtained quantitatively as white crystals.

(D) 4-amino-1H-pyrrolo [2,3
-B] 2.46 g of pyridine in 100 ml of acetonitrile
, 6.5 ml of diisopropylethylamine was added, and the mixture was stirred at 40 ° C. Trans-4-
19.86 g of (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid chloride
Was added and stirred at 50 ° C. for 2 hours. Further, 6 ml of diisopropylethylamine and 15.03 g of trans-4- (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid chloride were added, and 50
Stirred at C for 2 hours. The solvent was distilled off under reduced pressure, and the obtained reaction mixture was dissolved in 100 ml of methanol. 1.05 g of sodium methoxide was added to this solution,
And stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, 200 ml of chloroform was added, and the solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and trans-N- (1H-pyrrolo [2,3-
b] 3.61 g of pyridin-4-yl) -4- (1-benzyloxycarbonylguanidinomethyl) cyclohexanecarboxamide were obtained. 160-162 ° C

(E) 3.3 g of trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-benzyloxycarbonylguanidinomethyl) cyclohexanecarboxamide was added to 100 ml of dioxane and 100 ml of dimethylformamide. Dissolve in 50 ml of mixed solvent,
500 mg of 10% palladium hydroxide carbon was added. The mixture was stirred at room temperature for 11 hours while passing hydrogen gas. The catalyst is filtered off,
The filtrate was concentrated. After the residue was dissolved in 15% hydrochloric acid-methanol, the solvent was concentrated under reduced pressure. The obtained yellow solid was recrystallized from ethyl acetate-methanol to give trans-N-
(1H-pyrrolo [2,3-b] pyridin-4-yl)-
4-guanidinomethylcyclohexanecarboxamide 2
1.5 g of hydrochloride monohydrate were obtained. 250 ° C (decomposition)

Example 2 (a) 3.3 g of 4-amino-1H-pyrazolo [3,4-b] pyridine dihydrochloride was added to 30 m of dimethylformamide.
and 150 ml of acetonitrile, and 16.7 ml of diisopropylethylamine was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, trans-4- (1,3-dibenzyloxycarbonylguanidinomethyl) cyclohexanecarboxylic acid chloride 1 synthesized in Example 1 (c) 1
A solution of 9.3 g of acetonitrile in 50 ml was added dropwise, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained reaction mixture was dissolved in 100 ml of methanol. To this solution was added sodium methoxide 860 m under ice cooling.
g was added and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and extracted with chloroform. Washing with water,
After drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography, and trans-N- (1
H-pyrazolo [3,4-b] pyridin-4-yl) -4
-(3-benzyloxycarbonylguanidinomethyl)
2.5 g of cyclohexanecarboxamide were obtained.

NMR (DMSO / TMS) δ: 1.30
2.20 (9H, m), 2.40 (1H, m), 3.
06 (2H, br.d), 5.09 (2H, s), 7.
32 (6H, br.s), 7.84 (1H, d, J = 5
Hz), 8.31 (1H, s), 8.35 (1H, d,
J = 5Hz)

(B) In a 200 ml autoclave, trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (3-benzyloxycarbonyl) synthesized in Example 2 (a) Guanidinomethyl) cyclohexanecarboxamide (2.5 g), 10% palladium hydroxide-carbon (300 mg), dimethylformamide (10 ml) and methanol (60 ml) were added, and the mixture was treated under an initial hydrogen pressure of 10 atm.
Stirred at ４０40 ° C. for 1 hour. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. The obtained crystals were dissolved in 10 ml of methanol, and 5 ml of 10% hydrochloric acid-methanol was added under ice cooling. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methanol-ethyl acetate-water to obtain trans-N- (1H
-Pyrazolo [3,4-b] pyridin-4-yl) -4-
1.4 g of guanidinomethylcyclohexanecarboxamide dihydrochloride monohydrate was obtained. 262-264 ° C

The following compounds can be synthesized according to the method of any of the above Examples 1 and 2.

(1) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide, melting point 175 ° C.
(Decomposition) (2) trans-N- (1-methylpyrrolo [2,3-
b] pyridin-4-yl) -4- (guanidinomethyl)
Cyclohexanecarboxamide dihydrochloride monohydrate,
236-239 ° C. (3) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (2-imidazolin-2-yl) aminomethylcyclohexanecarboxamide hydroiodide Melting point 275 ° C (decomposition) (4) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-methylguanidinomethyl) cyclohexanecarboxamide (5) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-butylguanidinomethyl) cyclohexanecarboxamide (6) trans-N- (1H-pyrrolo [2,3-b] pyridine-4 -Yl) -4- (1,2-dimethylguanidinomethyl) cyclohexanecarboxamide (7) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (2 -Butyl-1-methylguanidinomethyl) cyclohexanecarboxamide (8) trans-N- (3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (9) trans -N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (2-imitazoline-2-
Yl) aminomethylcyclohexanecarboxamide (10) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (1-methylguanidinomethyl) cyclohexanecarboxamide

(11) trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-butylguanidinomethyl) cyclohexanecarboxamide (12) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (1,2-dimethylguanidinomethyl) cyclohexanecarboxamide (13) trans-N- (1-methylpyrazolo [3,4-
b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (14) trans-N- (1-benzyloxymethylpyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide; Melting point 190-
192 ° C. (15) trans-N- (1-methoxymethylpyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (16) trans-N- (1-hydroxymethylpyrrolo [2 , 3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (17) trans-N- (1- (2,3,4,5-tetrahydrofuran-2-yl) pyrrolo [2,3-b ] Pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (18) trans-N- (1-dimethylcarbamoylpyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (19) Trans-N- (1-acetylpyrrolo [2,3-
b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (20) N ^1- [trans- (4- (1H-pyrrolo [2,
3-b] pyridin-4-yl) carbamoyl) cyclohexylmethyl] formamidine

(21) N ^1- [trans- (4- (1H-
Pyrrolo [2,3-b] pyridin-4-yl) carbamoyl) cyclohexylmethyl] acetamidine (22) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (2 -Nitroguanidinomethyl) cyclohexanecarboxamide (23) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (2-cyanoguanidinomethyl) cyclohexanecarboxamide (24) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1,2-dibenzylguanidinomethyl) cyclohexanecarboxamide (25) trans-N- (1-benzylpyrrolo [2,3-
b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (26) trans-N- (1- (p-methoxybenzyl)
Pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (27) trans-N- (3-formyl-1H-pyrrolo [2,3-b] pyridin-4-yl)- 4-guanidinomethylcyclohexanecarboxamide (28) trans-N- (3-methoxycarbonyl-1H
-Pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (29) trans-N- (2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] Pyridin-4-yl)-
4-guanidinomethylcyclohexanecarboxamide (30) trans-N- (2-chloro-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide

(31) trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (2-nitroguanidinomethyl) cyclohexanecarboxamide (32) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (2-cyanoguanidinomethyl) cyclohexanecarboxamide (33) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (1,2-dibenzylguanidinomethyl) cyclohexanecarboxamide (34) trans-N- (1-benzylpyrazolo [3,4
-B] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (35) trans-N- (1- (p-methoxybenzyl)
Pyrazolo [3,4-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (36) trans-N- (3-carboxy-1H-pyrrolo [2,3-b] pyridin-4-yl)- 4-guanidinomethylcyclohexanecarboxamide (37) trans-N- (3-cyano-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (38) trans-N- (2 , 3-Dihydro-2,3-dioxo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (39) trans-N- (2,3-dihydro-1H- Pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (40) trans-N- (2-amido 4-pyridyl) -
4-guanidinomethylcyclohexanecarboxamide 2
Hydrochloride monohydrate, melting point 240 ° C (decomposition)

(41) trans-N- (1-benzyloxymethyl-1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (2-imidazolin-2-yl) aminomethylcyclohexanecarboxamide, melting point 211-21
2 ° C. (42) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -cis-2-methyl-4-guanidinomethylcyclohexanecarboxamide (43) trans-N- (1H-pyrazolo [3,4-b]
(Pyridin-4-yl) -cis-2-methyl-4-guanidinomethylcyclohexanecarboxamide (44) (+)-trans-N- (1H-pyrrolo [2,3
-B] pyridin-4-yl) -4- (1- (1-methylguanidino) ethyl) cyclohexanecarboxamide (45) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl)- 4- (1-methyl-1-guanidinoethyl) cyclohexanecarboxamide (46) (+)-trans-N- (1H-pyrazolo [3,
4-b] pyridin-4-yl) -4- (1-methylguanidino) ethyl) cyclohexanecarboxamide (47) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (1-methyl-1-guanidinoethyl) cyclohexanecarboxamide (48) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1 -Benzylguanidinomethyl) cyclohexanecarboxamide dihydrochloride, mp2
06 ° C (decomposition) (49) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (1-benzylguanidinomethyl) cyclohexanecarboxamide (50) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-phenylguanidino Methyl) cyclohexanecarboxamide dihydrochloride monohydrate 1/2 isopropyl ether, melting point 215 ° C (decomposition)

(51) trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-phenylguanidinomethyl) cyclohexanecarboxamide (52) trans-N- (1-benzyl Oxymethylpyrrolo [2,3-b] pyridin-4-yl) -4- (1-phenylguanidinomethyl) cyclohexanecarboxamide (53) trans-N- (1H-pyrrolo [2,3-b] pyridin-4- Yl) -4- (1-Propylguanidinomethyl) cyclohexanecarboxamide, mp 213.2
15 ° C. (54) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-benzyl-2-methylguanidinomethyl) cyclohexanecarboxamide (55) trans-N- ( 1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-benzyl-2-ethylguanidinomethyl) cyclohexanecarboxamide (56) trans-N- (1H-pyrrolo [2,3-b] Pyridin-4-yl) -4- (2-ethyl-1-methylguanidinomethyl) cyclohexanecarboxamide (57) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (2-ethyl-1-methylguanidinomethyl) cyclohexanecarboxamide (58) trans-N- (1-benzyloxymethylpyrrolo [2,3-b] pyridin-4-yl)- 4- (2-benzyl-1-ethylguanidinomethyl) cyclohexanecarboxamide, melting point 198-201 ° C (59) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4-guanidinocyclohexane Carboxamide (60) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (imidazol-2-yl)
Aminomethylcyclohexanecarboxamide, melting point 24
7 ° C (decomposition)

(61) trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (imidazol-2-yl) aminomethylcyclohexanecarboxamide (62) trans-N- (1H -Pyrrolo [2,3-b] pyridin-4-yl) -4- (benzimidazole-2-
Yl) aminomethylcyclohexanecarboxamide (63) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -4- (benzimidazole-2
-Yl) aminomethylcyclohexanecarboxamide (64) trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (thiazol-2-yl) aminomethylcyclohexanecarboxamide, melting point 256
-258 ° C (decomposition) (65) trans-N- (2-acetylamino-4-pyridyl) -4-guanidinomethylcyclohexanecarboxamide (66) trans-N- (2-methylcarbamoyl-4-)
(Pyridyl) -4-guanidinomethylcyclohexanecarboxamide (67) trans-N- (2,3-dihydro-1-methylpyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (68) trans -N- (imidazo [3,2-a] pyrimidin-4-yl) -4-guanidinomethylcyclohexanecarboxamide (69) trans-N- (2,3-dimethyl-1H-pyrrolo [2,3-b] pyridine -4-yl) -4-guanidinomethylcyclohexanesancarboxamide (70) trans-N- (3-methyl-1H-pyrazolo [3,4-b] pyridin-4-yl) 4-guanidinomethylcyclohexanecarboxamide

(71) trans-N- (2-methylamino-4-pyridyl) -4-guanidinomethylcyclohexanecarboxamide (72) trans-N- (2-ethylamino-4-pyridyl) -4-guanidinomethylcyclohexane Carboxamide (73) trans-N- (3-fluoro-4-pyridyl)
-4-guanidinomethylcyclohexanehexanecarboxamide (74) (+)-trans-N- (1H-pyrrolo [2,3
-B] pyridin-4-yl) -4- (1-guanidinoethyl) cyclohexanecarboxamide (75) (+)-trans-N- (1H-pyrazolo [3,
4-b] pyridin-4-yl) -4- (1-guanidinoethyl) cyclohexanecarboxamide

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/10 A61P 9/10 11/06 11/06 C07D 213/89 C07D 213/89 237/20 237/20 237/22 237 / 22 239/42 239/42 239/47 239/47 Z 249/14 249/14 251/14 251/14 253/06 253/06 401/00 401/00 471/04 104 471/04 104Z 105 105A 106 106C 108 108A 471/14 101 471/14 101 102 102 102 487/04 140 487/04 140 142 142 142 146 146 (72) Inventor Hiroyuki Sato 3-7-25 Koyata, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. In-house (72) Inventor Masayoshi Uehata 3-7-25 Koyata, Iruma-shi, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory (56) References JP-A-64-5661 (JP, A) JP-A-4-273821 (JP, A) Hei 3-218356 (JP, A) International Publication 90/5723 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 213/00-213/75 C07D 237/00-237 / 22 C07D 239/00-239/47 C07D 249/00-249/14 C07D 251/00-251/14 C07D 253/00-253/06 C07D 401/00 C07D 471/00-471/14 C07D 487/00- 487/04 A61K 31/00-31/505 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (I) [Wherein, R is hydrogen, alkyl, -NR′R ″ (where
R ′ and R ″ are the same or different and represent hydrogen, alkyl, phenylalkyl, or phenyl), and R ¹ represents hydrogen, alkyl, phenylalkyl, phenyl,
Represents nitro or cyano, or R and R ¹ are combined to further form an oxygen atom, a sulfur atom,
A nitrogen atom which may have a substituent (the substituent may be
Group consisting of kill, phenylalkyl and haloalkyl
Represents a group to form a heterocyclic ring which may contain are) selected from, R ² represents hydrogen, alkyl, phenylalkyl, R ^3, R ⁴ are the same or different and represents hydrogen, alkyl, A is a single X represents ＣC (R ⁷ ) — (where R ⁷ is hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, —NReRf (where Re and Rf are the same or different) Hydrogen, alkyl, -COR ⁹ , -COO
R ⁹ ′, —SO ₂ R ⁹ ′ (where R ⁹ is hydrogen, alkyl,
R ⁹ ′ represents alkyl, phenyl or phenylalkyl; ) Or
Re and Rf represent an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent in the ring together with the nitrogen atom to be bonded (the substituent is an alkyl, a phenylalkyl,
Selected from the group consisting of haloalkyl) . ), Cyano, azide,
A hydrazino which may have a substituent (the substituent is
From alkyl, phenylalkyl, nitro and cyano
) , -COOR ¹⁰ , -CONR ¹¹ R ¹²
(Here, R ¹⁰ , R ¹¹ , and R ¹² represent hydrogen, alkyl, phenyl, and phenylalkyl.) ), = N-a shows, R ^5, R ⁶ together (1) -C (Ra) = C (Rb ) - (a) -N = C (Rb) - (b) -C ( Ra) = N- (c) -N (Ra)-(d) (where Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, -NReRf (where Re, Rf
Is as defined above. ), Cyano, azide, hydrazino which may have a substituent (the substituent is an alkyl,
Selected from the group consisting of phenylalkyl, nitro and cyano
) , -COOR ¹⁰ , -CONR ¹¹ R ¹² (where,
R ¹⁰ , R ¹¹ and R ¹² are as defined above. ) Or R
a and Rb together represent a group that forms a 5- to 6-membered hydrogenated aromatic ring which may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom in the ring. . Or (2) Formula -N (Rc) -C (= Rd)-(e) -C (= Rc) -N (Rd)-(f) (where Rc and Rd are taken together. Nitrogen atom in the ring
A group forming a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one of a sulfur atom and an oxygen atom. Wherein R ⁸ has hydrogen, halogen, alkyl, alkoxy, phenylalkyl, haloalkyl, nitro, —NReRf (where Re and Rf are as defined above), cyano, azide, and a substituent. Hydrazino (the substituent
Is alkyl, phenylalkyl, nitro and cyano
Selected from the group consisting of) , -COOR ¹⁰ , -CONR
¹¹ R ¹² (where R ¹⁰ , R ¹¹ , and R ¹² have the same meanings as described above), and n represents 0 or 1. However, when R ⁵ and R ⁶ together represent formula (a), X
Is = C (R ⁷ )-and Ra, Rb, R ⁷ , R ⁸
Is halogen, -NReRf, azide, hydrazino optionally having a substituent (the substituent is
Consists of kill, phenylalkyl, nitro and cyano
Selected from the group), -COOR ^10, or shows a -CONR ¹¹ R ^12, Ra, Rb nitrogen atom in the ring together, sulfur atom, at least one of which may contain 5 to the oxygen atom It represents a group forming a 6-membered aromatic ring which may be hydrogenated. A 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound represented by the formula: or an isomer thereof and a pharmaceutically acceptable acid addition salt thereof. 2. The compound of the general formula (I) according to claim 1 ,
An agent for increasing blood flow, comprising an isomer thereof and a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 3. A compound of the formula (I) according to claim 1 ,
An antihypertensive comprising as an active ingredient its isomer and its pharmaceutically acceptable acid addition salt. 4. A compound of the formula (I) according to claim 1 ,
A vasospasm inhibitor comprising an isomer thereof and a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 5. A compound of the formula (I) according to claim 1 ,
An agent for improving coronary / brain / renal / peripheral circulation, comprising an isomer thereof and a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 6. A compound of the formula (I) according to claim 1 ,
A therapeutic agent for asthma, comprising an isomer thereof and a pharmaceutically acceptable acid addition salt thereof as an active ingredient.