JP3275389B2 - 4-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-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 smooth muscle contractility. It is known that contraction is induced 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. Is not uniform,
An excess of these calcium ions is said to cause spasm of coronary arteries and cerebral blood vessels, and these vasospasms are considered to be one of the causes of angina, myocardial infarction and cerebral infarction. 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 action on membrane potential-dependent smooth muscle contraction suppressed by a conventional calcium antagonist but also an intracellular calcium antagonistic action, WO
No. 90/05723 discloses certain trans-4-types.
An amino (alkyl) -1-pyridylcarbamoylcyclohexane compound, an optical isomer thereof, or a pharmaceutically acceptable acid addition salt thereof has a sustained coronary / cerebral / renal blood flow increasing effect, and is used as an antihypertensive agent and a coronary / cerebral agent. -It is disclosed that it is useful as a prophylactic / therapeutic agent for diseases of the circulatory system such as the kidney. An object of the present invention is to provide a compound having a coronary, cerebral, renal and peripheral arterial blood flow increasing effect with reduced toxicity, which is more potent and longer lasting than those of conventional compounds.

[0003]

[Means for Solving the Problems] Under such circumstances,
As a result of intensive studies, the present inventors have found that the 4-amino (alkyl) cyclohexane-1-carboxylic acid amide compound of the present invention, its isomer and its pharmaceutically acceptable acid addition salt can achieve the above object. To complete 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.

The present invention has a general formula

[0005]

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[Wherein R ¹ and R ² are the same or different and each is hydrogen, alkyl or cycloalkyl which may have a substituent on a ring, cycloalkylalkyl, phenyl,
Represents aralkyl, piperidyl or pyrrolidinyl, R ¹ and R ² together represent alkylidene or phenylalkylidene, or an oxygen atom, sulfur atom or substitution in the ring together with the nitrogen atom to which R ¹ and R ² are bonded. A group forming a heterocyclic ring which may have a nitrogen atom which may have a group, R ³ and R ^{4 each} represent hydrogen or alkyl, A represents a single bond or alkylene, and X represents ＣC
(R ⁷ ) — or ＮN—, and R ⁵ and R ⁶ together form the formula —CRa = CRb— (a) —NRa—C (＝ Rb) — (b) —N = CRb— (c ) -C (= Ra) -NRb- (d) -CRa = N- (e) -NRa- (f) (where Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl) , nitro, -NRcRd in (wherein, Rc, Rd are the same or different and each is hydrogen, alkyl, -COR ^9, -COO
R ⁹ ′ or —SO ₂ R ⁹ ′ (where R ⁹ represents hydrogen, alkyl, phenyl or aralkyl, and R ⁹ ′ represents alkyl, phenyl or aralkyl) or Rc and Rd are And a 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 a nitrogen atom. ), Cyano, azide, hydrazino optionally having substituent (s), -COOR
¹⁰ , -CONR ¹¹ R ¹² (where R ^10-12 represents hydrogen, alkyl, phenyl or aralkyl), 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. . However, when the formula (b) or (d) is indicated, Ra,
Rb is a group which always forms a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom in the ring. ), Wherein R ⁷ and R ⁸ are the same or different and are hydrogen,
Halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, -NReRf (wherein, Re, Rf are the same or different and each is hydrogen, alkyl, -COR ^9, -C
OOR ⁹ ′, —SO ₂ R ⁹ ′ (where R ⁹ represents hydrogen, alkyl, phenyl or aralkyl, and R ⁹ ′ represents alkyl, phenyl or aralkyl), or Re and Rf are bonded. Oxygen atom in the ring with the nitrogen atom
And a group forming a heterocyclic ring which may contain a sulfur atom or a nitrogen atom which may have a substituent. ), Cyano, azide, hydrazino optionally having substituent (s),-
COOR ^10, -CONR ¹¹ R ¹² (wherein, R ^10-12 are hydrogen, alkyl, phenyl,. Showing an aralkyl) indicates, n represents 0 or 1. However, when R ⁵ and R ⁶ are of the formula (a), X is = C (R ⁷ )-and R
a, Rb, R ⁷ , or R ⁸ is one of —NRcRd;
-NReRf, azide, which may have a substituent hydrazino, -COOR ^10, or shows a -CONR ¹¹ R ^12, R
a and Rb are a group which together form a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom; Show. The present invention relates to a 4-substituted amino (alkyl) cyclohexane-1-carboxylic acid amide compound according to claim (1), an isomer thereof and a pharmaceutically acceptable acid addition salt thereof.

The symbols in the general formula (I) will be described by definition. Halogen is chlorine, bromine, fluorine or iodine, and alkyl is 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms.
Linear or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, Haloalkyl is 2-ethylhexyl, nonyl, decyl or the like, and the above-mentioned alkyl is substituted with 1 to 5 halogens, and is trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3 , 3-pentafluoropropyl and the like; alkoxy is a linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy. , Tertiary butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc., and cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl moiety is a cycloalkyl having 3 to 7 carbon atoms, and the alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl Etc.), wherein cyclopropylmethyl, cyclobutylmethyl,
Cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptyl Butyl, cyclopropylhexyl, cyclopentylhexyl, cyclohexylhexyl, cycloheptylhexyl and the like, and alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, and is methylene, ethylene, trimethylene, tetramethylene or the like. Methylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, diethylmethyl , Propylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltrimethylene, dimethyltetramethylene, etc., and aralkyl is a compound having alkyl having 1 to 4 carbon atoms as an alkyl portion thereof, and benzyl, 1-phenylethyl , 2-phenylethyl, 3-phenylpropyl, 4-
Phenylalkyl such as phenylbutyl, alkylidene is a linear or branched alkylidene having 1 to 6 carbon atoms, and is methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene,
Phenylalkylidene and the like are referred to as phenylalkylidene, in which the alkylidene moiety is an alkylidene having 1 to 6 carbon atoms, such as benzylidene, phenylethylidene, phenylpropylidene, phenylbutylidene, phenylpentylidene, and phenylhexylidene.

[0008] Further, the compound may have 3 carbon atoms which may have a substituent.
As substituents of up to 7 cycloalkyl, phenyl, aralkyl, piperidyl, and pyrrolidinyl, halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, -NRcRd (where Rc and Rd are the same or different and are hydrogen, alkyl, -COR ⁹ , -COOR ⁹ ',-
Represents SO ₂ R ⁹ ′, or Rc and Rd represent 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. 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, alkoxy, aralkyl and haloalkyl are as defined above, and acyl is acetyl, propionyl, butyryl, valeryl, pivaloyl, benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl and the like. As a substituent of the hydrazino which may have a substituent, alkyl,
Aralkyl, nitro, cyano and the like. Here, alkyl and aralkyl are as defined above.

R ¹ and R ² , Rc and Rd or Re and Rf
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 it is bonded include a 5- to 6-membered ring, Are preferable, and specific examples thereof include pyrrolidinyl, piperidyl, piperazinyl, morpholino, and thiomorpholino. Examples of the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, haloalkyl and the like. Here, alkyl, aralkyl and haloalkyl are as defined above.

R ⁵ and R ⁶ are represented by formulas (a), (c), (e),
In the case of the single ring shown in (f), it represents pyridine, pyrimidine, pyridazine, triazine, pyrazole, and triazole.

Further, R ⁵ and R ⁶ are represented by the formula (a):
When a condensed ring is formed by showing (b) and (d), pyrrolopyridine (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, imidazopyridine (1H-imidazo [4,5-b] pyridine, etc.), pyrrolopyrimidine (1H-pyrrolo [2,3-d] 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., pyrrolo triazine (pyrrolo [1, 2-
a] -1,3,5-Triazine, pyrrolo [2,1-f]
-1,2,4-triazine, etc.), pyrazolotriazine (pyrazolo [1,5-a] -1,3,5-triazine etc.), triazolopyridine (1H-1,2,3-triazolo [4, 5-b] pyridine), triazolopyrimidine (1,2,4-triazolo [1,5-a] pyrimidine,
1,2,4-triazolo [4,3-a] pyrimidine, 1
H-1,2,3-triazolo [4,5-d] pyrimidine, etc., cinnoline, quinazoline, quinoline, pyridopyridazine (pyrid [2,3-c] pyridazine etc.), 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, pyrimido [5,4-d] pyrimidine etc.), pyrazinopyrimidine (pyrazino [2,3-d] Pyrimidine), naphthyridine (such as 1,8-naphthyridine), tetrazolopyrimidine (such as tetrazolo [1,5-a] pyrimidine), thienopyridine (such as thieno [2,3-b] pyridine),
Thienopyrimidine (thieno [2,3-d] pyrimidine etc.), thiazolopyridine (thiazolo [4,5-b] pyridine, thiazolo [5,4-b] pyridine etc.), thiazolopyrimidine (thiazolo [4,5 -D] pyrimidine, thiazolo [5,4-d] pyrimidine, etc., oxazolopyridine (oxazolo [4,5-b] pyridine, oxazolo [5,4-b] pyridine etc.), oxazolopyrimidine (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-d] pyrimidine, etc., 2,3-dihydropyrrolopyridine (2,3-dihydro-1H-pyrrolo [2,3-b] Lysine, 2,3-dihydro -1H-
Pyrrolo [3,2-b] pyridine, etc.), 2,3-dihydropyrrolopyridine (2,3-dihydro-1H-pyrrolo [2,3-d] pyrimidine, 2,3-dihydro-1H-
Pyrrolo [3,2-d] pyrimidine), 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, Wherein the carbon atom may be carbonyl, for example, 2,3-dihydro-2-oxopyrrolopyridine,
2,3-dihydro-2,3-dioxopyrrolopyridine,
7,8-dihydro-7-oxo-naphthyridine, 5,
6,7,8-tetrahydro-7-oxonaphthyridine and the like are also included. Also, these rings are halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro,
-NRcRd, cyano, formyl, acyl, aminoalkyl, mono- or dialkylaminoalkyl, azide,
It may be substituted with a substituent such as —COOR ¹⁰ , —CONR ¹¹ R ¹² , or hydrazino which may have a substituent.

The present invention also includes pharmaceutically acceptable acid addition salts, hydrates or various solvates formed with an inorganic acid 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. Compound (I) of the present invention can be synthesized by the following method.

Method 1 General formula (II)

[0016]

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

[0018]

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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 and the like, methyl esters, and the like.
Examples include esters such as ethyl esters, and reactive derivatives formed from carbodiimides such as dicyclohexylcarbodiimide.

The reaction is carried out in the presence of a solvent inert to the reaction, but usually, tetrahydrofuran, ethyl acetate,
Organic solvents not containing a hydroxyl group, such as benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, dimethylformamide, and dimethylimidazolidinone, are used. The reaction can be performed at any temperature, for example, -10 to 200 ° C.
The reaction is preferably carried out at 0 to 80 ° C., but is not so reactive as a raw material.
In the case of (1), a high reaction temperature is used, and in the case of a highly reactive reactive derivative (for example, a mixed acid anhydride), a low reaction temperature is used. Further, if necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine or the like is used as a deoxidizing agent. If necessary, the reaction can be carried out by protecting the amino group of the general formula (II) with an amino protecting group such as benzyloxycarbonyl and t-butoxycarbonyl. The protecting group may be removed by a conventional method after the reaction.

The carboxylic acid compound of the general formula (II), which is a raw material for the synthesis of the present invention, is described in Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 27, p. 2735 (1979). Or Vol. 27, No. 303
The compound can be synthesized by the method described on page 9 (1979), and particularly when the carboxylic acid compound of the general formula (II) is other than transamine.

[0023]

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(Wherein 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 (i) with an amino protecting group (such as an acetyl group), an acetyl group is introduced into an aromatic ring by a Friedel-Crafts reaction, and a carboxylic acid of the formula (iv) is subjected to a haloform reaction. An acid compound is obtained, and then an aromatic ring is reduced by catalytic reduction and deprotected by alkali hydrolysis to synthesize a compound in which R ¹ and R ² are hydrogen in the carboxylic acid compound of the general formula (II). can do.

The cis-form or trans-form of the carboxylic acid compound of the general formula (II) can be obtained, for example, by subjecting the carboxylic acid compound of the formula (iv) to a conventional column chromatography and recrystallization method. Obtaining a cis form of the compound;
The carboxylic acid compound of (iv) is esterified by an ordinary method, and isomerized by using a base (eg, sodium methoxide, potassium butoxide) to obtain a compound represented by the formula
It can be obtained by obtaining the trans form of the carboxylic acid compound of (iv) and then deprotecting each isomer according to the above-mentioned method.

The other synthetic raw material represented by the general formula (I
II) are described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 25, No. 125
8 (1982), Vol. 32, p. 945 (198
9), Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), Vol. 20, 295 (1983), Vol. 9, 235 (1972).
Vol. 1, p. 42 (1964), Journal of the American Chemical Society
(J. Am. Chem. Soc.), Vol. 77, p. 2256 (1955)
Year) and Zhurnal Organicheskoi Khimii, Vol. 9, 126
It can be synthesized by the method described on page 6 (1973).

Method 2 Among the compounds (I), compounds in which one of R ¹ and R ² is hydrogen and the other is not hydrogen are those represented by the general formula (IV) wherein R ¹ and R ² obtained by method 1 are hydrogen. )

[0029]

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

The halide compound used in this reaction is represented by the formula (V) R ⁹ -Ha1 (V) wherein R ⁹ is an alkyl having 1 to 10 carbon atoms or a carbon atom which may have a substituent. 3 to 7 cycloalkyl, cycloalkylalkyl, phenyl, aralkyl,
In piperidyl and pyrrolidinyl, Hal is a halogen, preferably chlorine or bromine. Wherein the aldehyde compound is represented by the formula (VI) R ¹⁰ —CHO (VI) (wherein R ¹⁰ is hydrogen, alkyl having 1 to 9 carbons or a substituent on the ring) Which may be phenyl, aralkyl, nitrogen-protected piperidyl or nitrogen-protected pyrrolidinyl.)
The ketone compound is represented by the formula (VII)

[0032]

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(Wherein R ¹¹ and R ¹² are the same or different and each have 1 to 9 carbon atoms or an optionally substituted phenyl, aralkyl, nitrogen-protected piperidyl or nitrogen-protected ring) Showing pyrrolidinyl,
R ¹¹ and R ¹² are each independently cycloalkyl having 3 to 7 carbon atoms which may be substituted with a carbonyl group. ).

The reaction of compound (IV) with a halide compound can be carried out under the same conditions as in method 1, except that sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine It is preferable to carry out the deacidification condensation reaction in the presence of a base such as When the compound (IV) is reacted with an aldehyde or a ketone, it is usually heated under reflux with a water-immiscible solvent, for example, benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, and the like.
A dehydration condensation reaction is performed. At this time, it is also advantageous to add a small amount of an acid such as paratoluenesulfonic acid. Further, by subjecting a compound of alkylidene, phenylalkylidene, pyrrolidylidene, and piperidylidene obtained by the above condensation reaction to a reduction reaction, a compound of alkyl, aralkyl, pyrrolidinyl, and piperidyl can be derived.
The reduction reaction is usually performed in an alcohol such as methanol, ethanol, or isopropyl alcohol in the range of -10 to 100.
C, preferably at 0 to 40C. Also,
As a reducing agent, sodium borohydride, a small amount of hydrochloric acid, hydrobromic acid, a reducing agent such as sodium cyanoborohydride in the presence of an acid such as acetic acid, furthermore, when there is no effect on other groups of the target compound It can also be produced by performing a reductive amination reaction using a catalytic reduction method using Raney nickel, palladium carbon, platinum oxide or the like.

Method 3 In the compound (I), an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent may be contained in the ring together with the nitrogen atom to which R ¹ and R ² are bonded. The compound which is a group forming a good heterocyclic ring has the general formula (VIII)

[0036]

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Or the general formula (IX)

[0038]

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[In the formulas (VIII) and (IX), R ^13-20 may be the same or different and may have hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, cyano, or a substituent. Represents hydrazino, Y is carbon,
Oxygen, sulfur or an optionally substituted nitrogen, and Z is an alcohol such as halogen (chlorine, bromine, etc.), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.). 2 shows a reactive derivative. However, the formed heterocyclic ring has up to 1 to 3 substituents. And the compound (IV). The reaction can be performed using the same conditions as in Method 2.

Method 4 In the compound (I), R ¹ and R ² are the same or different and each represents alkyl, phenyl or aralkyl, or R ¹ and R ²
A compound which is a 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 the compound is bonded is a compound (IV) Wherein the substituent of the heterocyclic ring in the A portion is -NR
cRd, -NReRf, a compound that 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 represented by the general formula (X):

[0041]

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(Wherein each symbol is as defined above), and the hydroxy form is represented by thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or the like. By reacting with a halogenating agent or reacting with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in the presence of a dehydrohalogenating agent to form a corresponding reactive derivative of the alcohol, then formula (XI)

[0043]

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(Wherein R ¹ ′ and R ² ′ are the same or different and represent alkyl, phenyl, aralkyl,
And a 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 R ¹ ′ and R ² ′ are bonded. The compound can be produced by reacting an amine compound represented by The reaction is carried out with 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, etc.);
The reaction is performed in the presence of an organic base such as pyridine and triethylamine. 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 compound (I) of the present invention thus obtained is characterized in that the amino group of the 4-substituted amino moiety of the cyclohexane ring, Ra, Rb, R ⁷ and R ⁸ are -NRcRd or-
The amino group in the case of NReRf and the amino group in the case where R ⁵ and R ⁶ form a single ring or the case where the substituent of the ring in the case of forming a condensed ring or -RcRd represent -NRcRd are a normal amino protecting group May be protected by, for example, formyl, acetyl, propionyl, butyryl,
1 to 1 carbon atoms such as isobutyryl, pivaloyl and valeryl
5 alkanoyls; alkoxycarbonyl having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl; cyclopropylcarbonyl, cyclobutylcarbonyl, Cycloalkylcarbonyl having 4 to 8 carbon atoms such as cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl; aroyl such as benzoyl and naphthoyl (where aroyl is halogen, alkyl having 1 to 6 carbon atoms and 1 to 6 carbon atoms)
Which may have a substituent such as alkoxy, aralkyl, trifluoromethyl, nitro and amino); phenylalkoxycarbonyl such as benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl and phenylbutoxycarbonyl ( Here, phenylethoxycarbonyl means halogen, alkyl having 1 to 6 carbons, 1 to 6 carbons on a phenyl ring.
Phenylalkenyl such as styryl, cinnamyl, phenylbutenyl, phenylpentenyl, phenylhexenyl, or benzylidene; Phenylalkylidene such as phenylethylidene; groups forming pyrrolidylidene, piperidylidene, and phthalimide; alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and dipropylcarbamoyl; methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, diethyl Alkylcarbamoylalkyl such as carbamoylmethyl and dimethylcarbamoylethyl; methoxymethyl, ethoxymethyl Alkoxymethyl such as propoxymethyl, butoxymethyl and tert-butoxymethyl; aralkyloxyalkyl such as benzyloxymethyl, p-methoxybenzyloxymethyl and o-nitrobenzyloxymethyl; allyl; cyclic ether such as tetrahydrofuran and tetrahydropyran May be protected by a protecting group such as

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 hydrogencarbonate, potassium hydrogencarbonate, 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,
Alternatively, deprotection can be performed by a reduction method using sodium borohydride, lithium aluminum hydride, diborane, zinc, sodium amalgam, or the like as a reducing agent, and further, hydrogen peroxide, potassium permanganate,
A method using an oxidizing agent such as 3-dichloro-5,6-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. Compounds having a carboxyl group in compound (I) include metal salts (such as sodium salts, potassium salts, calcium salts, and aluminum salts) and amino acids (such as lysine and ornithine).
And a salt with

[0049]

Next, the action of the compound of the present invention will be specifically described by pharmacological experiments.

Pharmacological Experimental Example 1 Spontaneously hypertensive rats weighing 350 to 450 g (SH
In R), a catheter for blood pressure measurement and drug administration was inserted into the carotid artery and the jugular vein in advance, and 0.3 mg / kg of the test compound was intravenously administered under anesthesia and unrestrained to examine the effect on blood pressure. . Blood pressure was automatically measured and analyzed via the left transducer. Table 1 shows the results.

[0051]

Table 1 Table 1 Compound dose (mg) Antihypertensive effect (mmHg) (SHR iv) 実 施 Example 3 0.3 -62 Example 4 0.3-77 Example 6 0.3-96 Example 7 0.3-53 ────────────────────────── ─────────

Pharmacological Experimental Example 2 A male rabbit (weighing 1.9 to 3.0 kg) was anesthetized with sodium pentobarbital, and was then bled to death and the thoracic aorta was isolated. A ring-shaped specimen having a width of about 2 mm was prepared, and a Krebs-Henseleit solution (NaCl 117 mM; KCl 4.7 mM; C
aCl ₂ 2.5 mM; MgSO ₄ 1.2 mM; NaHCO ₃ 24.8 mM; KH ₂ PO ₄ 1.2
The suspension was suspended at a load of 2 g in a Magnus tube having a capacity of 40 ml and containing 1 mM of glucose; The inside of the Magnus tube is always
A mixed gas (95% oxygen + 5% carbon dioxide gas) was passed. The specimen tension is measured using an isometric transducer (TB-611).
T, Nihon Kohden). The specimen was contracted with phenylephrine (10 ⁻⁶ M), and after the contraction was constant, the compound was cumulatively added, and the relaxation reaction was observed. The relaxation reaction of the compound was calculated as IC ₅₀ (μM), where phenylephrine contraction was defined as 100% and its 50% relaxable concentration was calculated. Table 2 shows the results.

[0053]

Table 2 Table 2 Compound Vasodilator action (μM) ────────────────────────── Example 3 0.09 Example 4 0.08 Example 6 0.12 Example 7 0.19 ───────────────────────────────

Pharmacological Experimental Example 3: Effect on coronary blood flow Two to three mongrel dogs per group were anesthetized by intravenously administering 30 mg / kg body weight of pentobarbital sodium, and the method of Yago et al. , Vol. 57, 38
In accordance with page 0, (1961), the left coronary artery was perfused and its blood volume was measured. 10 to 300 μg of the test compound was administered into the coronary artery. The effect of the test compound on coronary blood volume was nifedipine [dimethyl 2,6-dimethyl-4-
(2-nitrophenyl) -1,4-dihydropyridine-
The dose required to increase coronary blood to half the effect of 3 μg of [3,5-dicarboxylate] intracoronary administration was expressed as ED ₅₀ (μg), and the results are summarized in Table 3. In addition, half-life (T1 /
2, min).

[0055]

Table 3 Table 3 ─────────────────────────────── compounds coronary blood flow increasing action (ED _50; μg) (T1 / 2; minute) ─────────────────────────────── Example 3 8.8 (2.7) Implementation Example 4 7.0 (3.8) Example 6 4.3 (3.0) Example 7 20.0 (6.7) ─────────────

Pharmacological Experimental Example 4: Effect on acetylcholine-induced contraction of isolated guinea pig trachea specimen Male Hartley guinea pig (body weight 260-390 g)
Was administered intraperitoneally with 100 mg / kg of sodium pentobarbital, and after anesthesia, blood was killed and the trachea was removed. The ventral cartilage of the trachea was cut open, the ligament was cut at a width of 3 mm, and a specimen was prepared. Specimens were prepared at 37 ° C. Krebs-Henseleate solution (NaCl 117 mM; KCl 4.7 mM; CaCl ₂ 2.5 mM; MgS
O ₄ ; 1.2 mM; NaHCO ₃ 24.8 mM; KH ₂ PO ₄ 1.2 mM; glucose 1
The suspension was suspended at a load of 1 g in a 40-ml capacity Magnus tube filled with 1.0 mM). The mixed gas (95
% Oxygen + 5% carbon dioxide). The tension of the specimen was recorded on a recorder (Ti-102, Tokai Medical Science) using an isometric transducer (TB-611T, Nihon Kohden). The specimen was contracted with acetylcholine (10 ⁻⁶ M), and after the contraction was constant, the compound was cumulatively added, and the relaxation reaction was observed. Relaxation reaction of compound is papaverine (10 ^-4 M)
Is defined as the maximum response, and the concentration showing a 50% relaxation reaction was calculated as IC ₅₀ (μM). Table 4 shows the results.

[0057]

Table 4 Table 4 Compounds Bronchodilator effect (IC ₅₀ ; μM) ───────────────────────────── Example 3 0.06 Example 4 0.09 Example 6 0.17 Example 7 0.31 mm

Pharmacological Experiment Example 5: Effect of histamine inhalation on guinea pig experimental asthma Suyama's method (Allergy, Vol. 15, p. 549, 196)
6 years), a female Hartley-type guinea pig weighing 490 to 630 g was placed in an aerosol inhaler, and 0.2%
A histamine solution (histamine hydrochloride, Hanoi Chemical) was sprayed with an ultrasonic nebulizer (TUR-3200, Nippon Koden Kogyo Co., Ltd.), and the protective action was examined using rollover as an index. For inhalation of the test compound, a guinea pig was placed in the aerosol inhaler and dissolved in physiological saline to a predetermined concentration. The test compound solution is sprayed for 5 minutes. Then, histamine was immediately inhaled, and the delay time of the rollover time due to difficulty in inhaling was measured. Table 5 shows the results.

[0059]

[Table 5] Table 5 ─────────────────────────────── Compound concentration (%) Average rollover time (sec) ─ ────────────────────────────── Example 3 0.01 152.4 ± 12.2 0.1 235.4 ± 40.2 ───────────────────────────────

Acute toxicity experiment The test compound (Examples 3 and 6) was intraperitoneally administered to ddY mice and observed for 5 days.
There were no deaths with intraperitoneal administration of / kg.

The compound (I) of the present invention, an isomer thereof and a pharmaceutically acceptable acid addition salt thereof have a coronary and cerebral blood flow increasing effect similarly to a calcium antagonist, and furthermore, these compounds do not show the same effect as conventional calcium antagonists. It also has a renal and peripheral arterial blood flow increasing effect. 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 compound of the present invention exhibits an experimental asthma-suppressing effect of guinea pigs by histamine inhalation and a contraction-inhibiting effect of acetylcholine in a guinea pig isolated trachea sample, and is also useful as a therapeutic agent for asthma.

When the compound (I) of the present invention is used as a medicament, its effective amount is mixed with a pharmacologically acceptable excipient, carrier, diluent 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 dosage may vary depending on the patient's age, body weight, symptoms, etc., but is usually 5 to 5 mg orally per adult daily.
The dose is about 500 mg, which can be administered once or divided into several times.

[0063]

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) A mixture of 4.7 g of 4,6-diaminopyrimidine, 500 ml of ethanol and 200 ml of water was added with 13.25 ml of 1N sodium hydroxide under ice cooling with ice water. Further, 26.5 ml of 1 N hydrochloric acid was added dropwise, and then 4.5 g of benzyloxycarbonyl chloride was added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to precipitate crystals. The crystals are collected by filtration and chloroform: methanol (5: 1).
To give 2.4 g of N-benzyloxycarbonyl-4,6-diaminopyrimidine having a melting point of 194 ° C. (B) 1.7 g of N-benzyloxycarbonyl-4,6-diaminopyrimidine, 2.9 ml of triethylamine and 40 ml of 1,3-dimethyl-2-imidazolidinone
Was cooled with ice water, and while stirring, a solution of 2.6 g of trans-4-benzyloxycarboxamidomethylcyclohexanecarbonyl chloride in 20 ml of 1,3-dimethyl-2-imidazolidinone was added dropwise.
Stirred for hours. When the reaction solution was poured into water, a yellow gum-like insoluble material precipitated. This was washed with cold water, dried and concentrated, ethyl acetate was added, and the resulting crystals were collected by filtration, and the trans-N- (6-benzyloxycarboxamide-4 having a melting point of 187 ° C was used.
-Pyrimidyl) -4-benzyloxycarboxamide 1.6 g of methylcyclohexanecarboxamide were obtained. (C) Catalytic reduction was carried out by passing hydrogen gas through a 50 ml methanol solution containing 800 mg of the compound obtained in (b), 0.5 ml of concentrated hydrochloric acid and 400 mg of 10% palladium-carbon. The reaction was completed at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to precipitate crystals. The crystals were collected by filtration and recrystallized from ethanol to give a melting point of 245.
150 mg of trans-N- (6-amino-4-pyrimidyl) -4-aminomethylcyclohexanecarboxamide dihydrochloride 3/2 hydrate at ２４247 ° C. was obtained.

Example 2 (a) Trans-4-benzyloxycarboxamidomethylcyclohexane while cooling 400 mg of 4-amino-1H-pyrrolo [2,3-b] pyridine, 1.2 ml of triethylamine and 50 ml of dichloromethane with ice water. A 20 ml solution of dichloromethane containing 1.86 g of carbonyl chloride was added dropwise over 30 minutes. After stirring at room temperature for 3 hours, the mixture was heated to 45 to 50 ° C. and reacted for 3 hours. After cooling, the reaction solution was poured into water. The dichloromethane layer was washed with a sodium hydrogen carbonate solution, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and trans-N- (1
H-pyrrolo [2,3-b] pyridin-4-yl) -4-
970 mg of benzyloxycarboxamide methylcyclohexanecarboxamide were obtained. (B) 33 mg of the compound obtained according to (a) and 30
5 ml of a 5% hydrogen bromide acetic acid solution was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, ether was added, and the obtained crystals were sufficiently washed with ether. The crystals were recrystallized from ethanol to give trans-N- (1H-
Pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide (24 mg) was obtained.

Example 3 (a) (R)-(+)-1-phenylethylamine 30
g of chloroform in 200 ml of a solution of acetic anhydride under ice-cooling.
8.4 g was added dropwise. After the reaction, ice water was added, and the mixture was extracted with chloroform. After washing with 2N aqueous sodium hydroxide solution and water, drying and concentration under reduced pressure, the precipitated crystals are recrystallized from isopropyl ether to give (+)-N
32.2 g of-(1-phenylethyl) acetamide were obtained. [Α] _D = + 143.5 ° (ethanol, c = 1) PMR (CDCl _{3 /} TMS) δ: 1.48 (3H,
d, J = 6 Hz), 1.98 (3H, s), 5.12
(1H, m), 5.75 (1H, brs), 7.31
(5H, s)

A solution of 103 g of the obtained (+)-N- (1-phenylethyl) acetamide and 300 ml of acetyl chloride in dichloroethane was cooled on ice with aluminum chloride 185.
g was added in small portions. After stirring for 1 hour at the same temperature, 50 ~
Stirred at 60 ° C. for 3 hours. After the reaction, the reaction solution was poured into ice water and extracted with chloroform. After washing with water and drying, the crystals obtained by concentration under reduced pressure are recrystallized from ethanol-isopropyl ether to give (+)-N- (1- (4-
62.8 g of acetylphenyl) ethyl) acetamide were obtained. [Α] _D = + 162.0 ° (methanol, c =
1) PMR (CDCl _{3 /} TMS) δ: 1.46 (3H,
d, J = 6 Hz), 2.01 (3H, s), 2.58
(3H, s), 5.13 (1H, m), 6.20 (1
H, brs), 7.38 (2H, d, J = 8 Hz),
7.90 (2H, d, J = 8Hz)

760 ml of 10% sodium hypochlorite was added dropwise to a solution of 61.4 g of (+)-N- (1- (4-acetylphenyl) ethyl) acetamide and 12.6 g of sodium hydroxide in 540 ml of methanol. Stirred at 70 ° C. for 1 hour. After the reaction, the residue obtained by evaporating the solvent under reduced pressure was poured into ice water. When acidified with concentrated hydrochloric acid, crystals precipitated. This was collected by filtration under reduced pressure, washed with water, dried, and (+)-
51.2 g of 4- (1-acetamidoethyl) benzoic acid was obtained. [Α] _D = + 136.8 ° (methanol, c =
1) PMR (CD ₃ OD / TMS) δ: 1.43 (3H,
d, J = 7 Hz), 1.96 (3H, s), 5.00
(1H, m), 7.40 (2H, d, J = 8 Hz) 7.
95 (2H, d, J = 8Hz)

(+)-4- (1-acetamidoethyl)
A solution of 51.2 g of benzoic acid and 35.4 g of 5% ruthenium carbon in 220 ml of 28% aqueous ammonia was placed in an autoclave at an initial hydrogen pressure of 70 atm, 90 ° C. for 3 hours, and 150 ° C. for 3 hours.
Stirred for hours. After the reaction, the catalyst was filtered off and concentrated under reduced pressure to give 53.5 g of (+)-4- (1-acetamidoethyl).
A cis-trans mixture of cyclohexanecarboxylic acid was obtained. Subsequently, 33 ml of a 31% hydrochloric acid / methanol solution was added thereto,
200 ml of methanol was added, and the mixture was refluxed for 4 hours. After the reaction, the residue obtained by concentration under reduced pressure was poured into ice water, and extracted with chloroform. After washing with water, drying, and concentration under reduced pressure, the residue obtained is purified by silica gel column chromatography to give (+)-4- (1-acetamidoethyl) cyclohexanecarboxylic acid methyl ester.
38.0 g of a trans mixture (2: 1) were obtained. (Α) _D
= + 11.4 ° (methanol, c = 1)

(+)-4- (1-acetamidoethyl)
To a solution of 38.0 g of a cis-trans mixture of cyclohexanecarboxylic acid methyl ester in 200 ml of methanol was added 37.7 g of potassium tert-butoxide, and the mixture was heated under reflux for 60 hours. After the reaction, the residue obtained by concentration under reduced pressure was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with chloroform.
After washing with water, drying and concentration under reduced pressure, (+)-trans-4
21 g of methyl ester of-(1-acetamidoethyl) cyclohexanecarboxylic acid was obtained. [Α] _D = +4
1.6 ° (methanol, c = 1) PMR (CDCl _{3 /} TMS) δ: 0.90 to 2.30
(10H, m), 1.09 (3H, d, J = 7 Hz),
1,98 (3H, s), 3.66 (3H, s), 5.7
4 (1H, m)

(+)-Trans-4- (1-acetamidoethyl) cyclohexanecarboxylic acid methyl ester 6
10 ml of water and 66 g of potassium hydroxide were added to a solution of 3 g of 250 ml of methanol, and the mixture was heated under reflux for 50 hours. After the reaction, the residue obtained by concentration under reduced pressure was poured into ice water and neutralized with dilute sulfuric acid. The precipitate was filtered off under reduced pressure, and the filtrate containing (+)-trans-4- (1-aminoethyl) cyclohexanecarboxylic acid was added to a 4N aqueous sodium hydroxide solution (41.8).
Then, 28.5 g of benzyloxycarbonyl chloride and 41.8 ml of 4N sodium hydroxide were alternately added dropwise at the same temperature. After the reaction, concentrated hydrochloric acid was added to the reaction solution to make it acidic, and crystals were precipitated. The crystals were collected by filtration under reduced pressure and dried.
25.9 g of cyclohexanecarboxylic acid were obtained.
[Α] _D = + 7.5 ° (ethanol, c = 0.1) PMR (CDCl _{3 /} TMS) δ: 0.90 to 2.30
(10H, m), 1.10 (3H, J = 7Hz), 4.
58 (1H, brs), 5.09 (2H, s), 7.3
5 (5H, s)

(B) To a solution of 6 g of (+)-trans-4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxylic acid in 60 ml of dichloromethane were added 5 ml of thionyl chloride and 1 drop of dimethylformamide, and the mixture was heated under reflux for 1 hour. After the reaction, the solvent is distilled off under reduced pressure.
Crystals of -trans-4- (1-benzyloxycarboxamidoethyl) cyclohexanecarbonyl chloride are obtained. Next, the crystals were dissolved in 40 ml of acetonitrile, and 4-amino-1H-pyrrolo [2,3-
b] 1 g of pyridine and 4.7 of diisopropylethylamine
After dropwise addition to 50 ml of acetonitrile solution, the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration, dried, dissolved in dimethylformamide (200 ml) and methanol (100 ml), and sodium methoxide (460 mg) was added.
Stirred at C for 10 minutes. After the reaction, water was added to the residue obtained by concentration under reduced pressure to precipitate crystals. The crystals were collected by filtration, washed with ethyl acetate, and recrystallized from chloroform-methanol to give (+)-trans-N- (1H
-Pyrrolo [2,3-b] pyridin-4-yl) -4-
2.6 g of (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide was obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
10 (10H, m), 1.04 (3H, d, J = 6H
z), 3.20 (1H, m), 5.01 (2H, s),
6.80 (1H, d, J = 3 Hz), 7.35 (6H,
s), 7.80 (1H, d, J = 5 Hz), 8.06
(1H, d, J = 5 Hz), 9.80 (1H, s)

2.6 g of (+)-trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide, 10% palladium hydroxide Carbon 50
0 mg, 15% hydrochloric acid methanol 4 ml methanol 70
The ml solution is stirred in an autoclave at an initial hydrogen pressure of 5 atm at room temperature for 1 hour. After the reaction, the catalyst was filtered off, and the crystals obtained by concentration under reduced pressure were recrystallized from ethanol to give (+)-trans-N-
(1H-pyrrolo [2,3-b] pyridin-4-yl)-
1.15 g of 4- (1-aminoethyl) cyclohexanecarboxamide dihydrochloride was obtained. [Α] _D = + 3.32 °
(Methanol, c = 0.5) PMR (DMSO-d _{6 /} TMS) δ: 0.70-2.
20 (10H, m), 1.14 (3H, d, J = 6H
z), 3.05 (1H, m), 7.23 (1H, d, J
= 3 Hz), 7.55 (1H, d, J = 3 Hz), 8.
29 (1H, d, J = 6 Hz), 8.31 (1H, d,
J = 6Hz)

Example 4 (a) A solution of 90 g of cumylamine and 70 ml of a 48% aqueous sodium hydroxide solution in 1000 ml of toluene was added under ice-cooling.
After dripping 62 g of acetyl chloride, the mixture was stirred at room temperature for 5 hours.
After the reaction, the mixture was neutralized with a saturated aqueous solution of potassium carbonate and extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off under reduced pressure.
102.3 g of N- (1-methyl-1-phenylethyl) acetamide were obtained. PMR (CDCl ₃ / TM
S) δ: 1.70 (6H, s), 1.96 (3H,
s), 5.70 (1H, brs), 7.20-7.50.
(5H, m)

N- (1-methyl-1-phenylethyl)
Aluminum chloride 4 was added to a solution of 25 g of acetamide and 16.6 g of acetyl chloride in 75 ml of dichloroethane under ice-cooling.
1.5 g was added in small portions. After stirring for 1 hour at the same temperature,
Stirred at 50-60 ° C for 1 hour. After the reaction, the reaction solution was poured into ice water and extracted with chloroform. After washing with water and drying, the crystals obtained by concentration under reduced pressure are recrystallized from ethyl acetate-isopropyl ether to give N- (1- (4-
20.4 g of acetylphenyl) -1-methylethyl) acetamide were obtained. PMR (CDCl _{3 /} TMS) δ: 1.69 (6H,
s), 1.98 (3H, s), 2.56 (3H, s),
5.82 (1H, brs), 7.46 (2H, d, J =
9Hz), 7.95 (2H, d, J = 9Hz)

N- (1- (4-acetylphenyl) -1
-Methylethyl) acetamide (20.4 g), sodium hydroxide (3.9 g), methanol (250 ml), 10% sodium hypochlorite (240 ml) were added dropwise, and then the mixture was heated to 50 to 70 ° C.
For 1 hour. After the reaction, the residue obtained by evaporating the solvent under reduced pressure was poured into ice water, and then acidified with concentrated hydrochloric acid to precipitate crystals. This was collected by filtration under reduced pressure, washed with water and dried to obtain 17.9 g of 4- (1-acetamido-1-methylethyl) benzoic acid. PMR (CDCl _{3 /} TMS) δ: 1.67 (6H,
s), 1.96 (3H, s), 7.42 (2H, d, J
= 9 Hz), 7.88 (2H, d, J = 9 Hz), 8.
11 (1H, s), 12.50 (1H, m)

17.9 g of 4- (1-acetamido-1-methylethyl) benzoic acid, 200 ml of 10% aqueous ammonia containing 60 g of 5% ruthenium carbon were placed in an autoclave.
The mixture was stirred at an initial hydrogen pressure of 70 atm and 150 to 170 ° C. for 3 hours. After the reaction, the solvent was filtered off and concentrated under reduced pressure to give 4- (1,1).
A cis-trans mixture of 1-dimethylacetamidomethyl) cyclohexanecarboxylic acid was obtained. Then 3
1% hydrochloric acid-methanol 15 ml, methanol 100 ml
Was added and refluxed for 4 hours. After the reaction, the mixture was concentrated under reduced pressure, and extracted with chloroform. After washing with water and drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give a cis-trans mixture of methyl 4- (1-acetamido-1-methylethyl) cyclohexanecarboxylate (3: 1 1) 14.0 g were obtained.

Cis-methyl 4- (1-acetamido-1-methylethyl) cyclohexanecarboxylate
To a solution of 30.8 g of the trans mixture in 150 ml of methanol was added 30.0 g of potassium tert-butoxide,
Heated to reflux for an hour. After the reaction, the residue obtained by concentration under reduced pressure was poured into ice water and neutralized with concentrated hydrochloric acid. After extracting with chloroform, washing with water, drying, and concentrating under reduced pressure, the precipitated crystals were recrystallized from methanol to give trans-4- (1-
24.5 g of acetamido-1-methylethyl) cyclohexhexanecarboxylic acid methyl ester were obtained. PMR (CDCl _{3 /} TMS) δ: 0.80 to 2.40
(10H, m), 1.26 (6H, s), 1.92 (3
H, s), 3.66 (3H, s), 5.26 (1H, b
rs)

Trans-4- (1-acetamido-1-
A solution of 24.5 g of methyl ethyl) cyclohexanecarboxylic acid methyl ester in 100 ml of 4N potassium hydroxide was heated to reflux for 50 hours. After the reaction, 11.6 under ice cooling.
Then, 20.8 g of benzyloxycarbonyl chloride was added dropwise at the same temperature, and the mixture was stirred at room temperature for 5 hours. After the reaction, concentrated hydrochloric acid was added to the reaction solution under ice cooling,
When acidified, crystals precipitated. The crystals are collected by filtration under reduced pressure and dried to give a trans-
22.1 g of 4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxylic acid was obtained. PMR (CDCl _{3 /} TMS) δ: 0.80 to 2.30
(10H, m), 1.26 (6H, s), 4.66 (1
H, brs), 5.05 (2H, s), 7.36 (5
H, s)

(B) To a solution of 6.2 g of trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxylic acid in 65 ml of dichloromethane, 5.2 ml of thionyl chloride and 1 drop of dimethylformamide were added, and the mixture was heated under reflux for 1 hour. did. After the reaction, the solvent is distilled off under reduced pressure to obtain trans-4- (1-benzyloxycarboxamido-1-methylethyl) cyclohexanecarbonyl chloride crystals. Next, the crystals were dissolved in 50 ml of acetonitrile, and the mixture was cooled under ice cooling with 4-amino-1H-
After dropwise adding a solution of 1 g of pyrrolo [2,3-b] pyridine and 5.4 ml of diisopropylethylamine in 50 ml of acetonitrile, the mixture is stirred at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure.
0 ml, and dissolved in sodium methoxide 281 under ice-cooling.
mg was added and stirred at room temperature for 1 hour. After the reaction, water was added to the residue obtained by concentration, and the mixture was extracted with ethyl acetate. After washing with water, drying and concentration, the precipitated crystals are recrystallized from chloroform-methanol to give trans-N-
(1H-pyrrolo [2,3-b] pyridin-4-yl)-
1.6 g of 4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide was obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
10 (10H, m), 1.16 (6H, s), 4.99
(2H, s), 6.80 (1H, brs), 6.85
(1H, d, J = 3 Hz), 7.35 (6H, s),
7.80 (1H, d, J = 6 Hz), 8.06 (1H,
d, J = 6 Hz), 9.76 (1H, s)

Trans-N- (1H-pyrrolo [2,3-
b] 1.6 g of pyridin-4-yl) -4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide, 10% palladium hydroxide carbon 2
A 50 ml solution of 50 mg of a 15% hydrochloric acid-methanol solution (4 ml) was stirred in an autoclave at an initial hydrogen pressure of 5 atm at room temperature for 1 hour. After the reaction, the catalyst was removed by filtration, and the crystals obtained by concentration under reduced pressure were recrystallized from ethanol-ethyl acetate to give trans-N- (1H-pyrrolo [2,3-b] having a melting point of 288 ° C. (decomposition). Pyridine-4-
930 mg of yl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide dihydrochloride monohydrate were obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
20 (10H, m), 1.21 (6H, s), 7.30
(1H, d, J = 3 Hz), 7.59 (1H, d, J =
3 Hz), 8.07 (2H, brs), 8.22 (1
H, d, J = 6 Hz), 8.30 (1H, d, J = 6H)
z), 10.91 (1H, s), 12.68 (1H, b
rs) corresponding dihydrobromide trihydrate, mp 225-228.
° C

Example 5 (a) 1-benzyl-4-hydroxy-1H-pyrazolo [3,4-b] pyridine 13.8 g was added to phosphorus oxychloride 6
0 ml and phosphorus pentachloride (20 mg) were added, and the mixture was heated under reflux for 2 hours. After the reaction, phosphorus oxychloride is distilled off under reduced pressure, and the obtained residue is poured into ice water. Neutralized with 2N aqueous sodium hydroxide solution, the precipitated crystals are collected by filtration, dried, and recrystallized from ethyl acetate-hexane to give 1-benzyl-
4-chloro-1H-pyrazolo [3,4-b] pyridine 1
3.5 g were obtained. PMR (CDCl _{3 /} TMS) δ: 5.71 (2H,
s), 7.12 (1H, d, J = 5 Hz), 7.31
(5H, s), 8.11 (1H, s), 8.42 (1
(H, d, J = 5Hz)

2.5 g of sodium azide was added to a solution of 4.7 g of 1-benzyl-4-chloro-1H-pyrazolo [3,4-b] pyridine in 50 ml of dimethylformamide, and the mixture was stirred at 100 to 120 ° C. for 1 hour. . After the reaction, the reaction solution was poured into ice water, acidified with acetic acid, and extracted with ethyl acetate. After washing with water and drying, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain 2.7 g of 4-azido-1-benzyl-1H-pyrazolo [3,4-b] pyridine. PMR (CDCl _{3 /} TMS) δ: 5.70 (2H,
s), 6.79 (1 H, d, J = 5 Hz), 7.31
(5H, s), 8.10 (1H, s), 8.46 (1
(H, d, J = 5Hz)

A solution of 2.7 g of 4-azido-1-benzyl-1H-pyrazolo [3,4-b] pyridine, 1.0 g of 10% palladium hydroxide carbon, and 1 ml of 15% hydrochloric acid-methanol in 40 ml of methanol was placed in an autoclave. The mixture was stirred at an initial hydrogen pressure of 10 atm at 40 to 50 ° C for 5 hours. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. When the precipitated crystals were recrystallized from methanol-ethyl acetate, 4-amino-
1H-pyrazolo [3,4-b] pyridine dihydrochloride 1.9
g was obtained. PMR (DMSO-d _{6 /} TMS) δ: 3.16 (2
H, brs), 6.18 (1H, d, J = 5 Hz),
7.90 (1H, d, J = 5 Hz), 8.13 (1H,
s)

(B) 4-amino-1H-pyrazolo [3,
4-b] Pyridine dihydrochloride (270 mg), diisopropylethylamine (0.68 ml), 1,3-dimethyl-2-
Trans-4 was added to a 20 ml solution of imidazolidinone under ice-cooling.
A solution of benzyloxycarboxamidomethylcyclohexanecarbonyl chloride (485 mg) in dichloromethane (5 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After washing with water and drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to obtain trans-N- (1H-pyrazolo [3,4-
b] pyridine-4-yl) -4-benzyloxycarboxamide methylcyclohexanecarboxamide 370 m
g was obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
10 (10H, m), 2.90 (2H, m), 5.03
(2H, s), 7.35 (5H, s), 7.76 (1
H, d, J = 5 Hz), 8.33 (1H, d, J = 5H)
z), 8.36 (1H, s)

Trans-N- (1H-pyrazolo [3,4
-B] pyridin-4-yl) -4-benzyloxycarboxamide methylcyclohexanecarboxamide 370
mg and 10 ml of a 25% solution of hydrogen bromide in acetic acid were stirred at room temperature for 15 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crystals were washed with ether. This was recrystallized from methanol-ethyl acetate to give a melting point of 261-262.
330 ° C., trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide hemihydrate 330 mg
I got PMR (DMSO-d _{6 /} TMS) δ: 0.90-2.
22 (10H, m), 3.05 (2H, m), 8.00
(4H, m), 8.51 (1H, d, J = 5 Hz),
8.93 (1H, s), 11.31 (1H, brs)

Example 6 4-Amino-1H-pyrazolo [3,4-b] pyridine.
390 mg of dihydrochloride, diisopropylethylamine
A 10 ml solution of 1,3-dimethyl-2-imidazolidinone containing 760 mg of (+)-trans-4- (1-benzyloxycarboxamidoethyl) cyclohexanecarbonyl chloride was added dropwise to 8 ml of a 50 ml solution of dimethylimidazolidinone under ice cooling. Then, the mixture was stirred at room temperature for 5 hours.
After the reaction, the reaction solution was poured into water and extracted with ethyl acetate.
After washing with water and drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give (+)-trans-N- (1H-pyrazolo [3,4-b] pyridine-
550 mg of 4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide were obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
15 (13H, m), 5.03 (2H, s), 7.01
(1H, m), 7.37 (5H, s), 7.78 (1
H, d, J = 5 Hz), 8.35 (1 H, d, J = 5 H)
z), 8.38 (1H, s), 10.30 (1H, s)

Trans-N- (1H-pyrazolo [3,4
-B] pyridin-4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide (580 mg, 10% palladium hydroxide on carbon 200 m)
g of 15% hydrochloric acid-methanol solution 1 ml of methanol 1.
The 5 ml solution was stirred in an autoclave at an initial hydrogen pressure of 5 atm at room temperature for 1 hour. After the reaction, the catalyst was filtered off, and the crystals obtained by concentration under reduced pressure were recrystallized from ethanol to give (+)-trans-N- (1H-) having a melting point of 294 ° C. (decomposition).
Pyrazolo [3,4-b] pyridin-4-yl) -4-
(1-aminoethyl) cyclohexanecarboxamide 2
310 mg of the hydrochloride were obtained. [Α] _D = + 4.2 ° (methanol, c = 0.5) PMR (DMSO-d _{6 /} TMS) δ: 0.90-2.
25 (13H, m), 3.10 (1H, m), 7.99
(4H, m), 8.52 (1H, d, J = 5 Hz),
8.93 (1H, s), 11.20 (1H, brs)

Example 7 4-amino-1H-pyrazolo [3,4-b] pyridine 2
Hydrochloride 1.0 g, diisopropylethylamine 4.6 m
of trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarbonyl chloride 3.9 in 100 ml of acetonitrile under ice-cooling.
g of acetonitrile in 20 ml is added dropwise and stirred at room temperature for 3 hours. After the reaction, water was added to the reaction solution, and extracted with ethyl acetate. After washing with water and drying, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- ( 630 mg of 1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide was obtained. PMR (CDCl _{3 /} TMS) δ: 0.80-2.60
(10H, m), 1.26 (6H, s), 5.05 (2
H, s), 7.33 (5H, s), 7.82 (1H,
d, J = 5 Hz), 8.14 (1H, s), 8.40
(1H, d, J = 5Hz)

Trans-N- (1H-pyrazolo [3,4
-B] Pyridin-4-yl) -4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide (630 mg), 10% palladium hydroxide carbon (300 mg) in methanol (60 ml) were placed in an autoclave under an initial hydrogen pressure of 5 atm. And stirred at room temperature for 1 hour. After the reaction, the catalyst was filtered off and concentrated under reduced pressure to give 1
5 ml of a 5% hydrochloric acid-methanol solution are added. Then, the crystals obtained by reconcentration were recrystallized from methanol-ethyl acetate to give trans-N-
(1H-pyrazolo [3,4-b] pyridin-4-yl)
-4- (1-Amino-1-methylethyl) cyclohexanecarboxamide dihydrochloride hemihydrate was obtained. PMR (DMSO-d _{6 /} TMS) δ: 0.80-2.
31 (10H, m), 1.23 (6H, s), 7.98
(4H, m), 8.50 (1H, d, J = 5 Hz),
8.85 (1H, s), 11.09 (1H, brs)

Example 8 (a) 2 g of 4-amino-2-chloropyridine was dissolved in 20 ml of dimethylformamide, and 1.31 g of sodium azide and 1.07 g of ammonium chloride were added thereto.
Stirred at 10 ° C. for 10 hours. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 4-amino-2 having a melting point of 220 ° C. (decomposition) was obtained.
1.83 g of -azidopyridine were obtained. PMR (DMSO-d _{6 /} TMS) δ: 6.55 (2
H, s), 6.67 (1H, d, J = 2 Hz), 6.7.
6 (1H, dd, J = 2.8 Hz), 8.78 (1H,
d, J = 8Hz)

(B) 0.41 g of 4-amino-2-azidopyridine was dissolved in 20 ml of dimethylformamide,
To this, 1 ml of diisopropylethylamine was added, and 40
Stirred at ° C. To this solution was added dropwise 10 ml of a dimethylformamide solution containing 1.73 g of (R)-(+)-trans-4- (1-benzyloxycarboxamidoethyl) cyclohexanecarbonyl chloride.
Stirred for hours. Ethyl acetate was added to the reaction solution, washed with water, dried and concentrated. The residue was purified by silica gel column chromatography, and (R)-having a melting point of 184 to 186 ° C.
(+)-Trans-N- (2-azido-4-pyridyl)
0.52 g of -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide was obtained. [Α]
_D = + 18.20 ° (c = 0.5, methanol) PMR (DMSO-d _{6 /} TMS) δ: 0.90-2.
20 (10H, s), 1.0 (3H, d, J = 6H
z), 3.40 (1H, m), 5.00 (2H, s),
7.32 (6H, brs), 8.45 (1H, s),
9.14 (1H, d, J = 8 Hz), 10.55 (1
H, brs)

(C) Compound 200m obtained in (b)
g, methanol 50 ml containing 0.5 ml of 15% hydrochloric acid-methanol and 100 mg of 10% palladium hydroxide carbon.
The solution was stirred in an autoclave at an initial hydrogen pressure of 10 atm at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to precipitate crystals. The crystals were recrystallized from ethyl acetate-methanol, and the (R)-
(+)-Trans-N- (2-amino-4-pyridyl)
50 mg of -4- (1-aminoethyl) cyclohexanecarboxamide dihydrochloride monohydrate was obtained. [Α] _D = +
4.25 ° (c = 0.5, methanol)

Example 9 (a) A solution of 700 mg of 4-amino-1H-pyrazolo [3,4-d] pyrimidine, 1.08 ml of triethylamine and 20 ml of 1,3-dimethyl-2-imidazolidinone was added under ice cooling. A solution of 1.76 g of trans-4-benzyloxycarboxamidomethylcyclohexanecarbonyl chloride in 5 ml of dichloromethane was added dropwise,
Stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with chloroform. After washing with saturated aqueous sodium bicarbonate and water, drying and concentration, the residue obtained was subjected to silica gel column chromatography (chloroform: methanol =
10: 1) to give 530 mg of trans-N- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -4-benzyloxycarboxamide methylcyclohexanecarboxamide. PMR (CDCl _{3 /} TMS) δ: 0.90-2.30
(10H, m), 3.11 (2H, m), 4.80 (1
H, m), 5.12 (2H, s), 7.36 (5H,
s), 8.33 (1H, s), 8.82 (1H, s)

(B) To 530 mg of the compound obtained in Example 3 (a) was added 10% of a 25% hydrogen bromideacetic acid solution under ice-cooling.
1 was added and stirred at the same temperature for 1 hour. After the reaction, the solvent obtained was distilled off under reduced pressure, and the resulting crystals were washed with ether and recrystallized from ethanol-ether to give trans-N- (1H-pyrazolo [3,4-d] having a melting point of 230 ° C. (decomposition). ] Pyrimidin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide 1/4 hydrate 200 mg was obtained.

Example 10 A solution of 2.0 g of 4-amino-1H-pyrazolo [3,4-d] pyrimidine and 2.6 ml of diisopropylethylamine in 130 ml of 1,3-dimethyl-2-imidazolidinone was cooled under ice-cooling. 1,3-dimethyl-containing 2.4 g of (+)-trans-4- (1-methylbenzyloxycarboxamidomethyl) cyclohexanecarbonyl chloride
20 ml of 2-imidazolidinone solution was added dropwise, and
Stirred for hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water and drying, the residue obtained by concentration is purified by silica gel column chromatography, and (+)
-Trans-N- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide 3.0
g was obtained. PMR (CDCl _{3 /} TMS) δ: 0.90-2.20
(10H, m), 1.15 (3H, d, J = 6 Hz),
5.10 (2H, s), 7.36 (5H, s), 8.5
8 (1H, s), 8.70 (1H, s) (+)-trans-N- (1H-pyrazolo [3,4-
d] Pyrimidin-4-yl) -4- (1-methylbenzyloxycarboxamidomethyl) cyclohexanecarboxamide 410 mg, 10% palladium hydroxide 200 m
of methanol in an autoclave at an initial hydrogen pressure of 5 atm at room temperature for 1 hour. After the reaction, the catalyst was removed by filtration, and the crystals obtained by concentration under reduced pressure were purified with 15% hydrochloric acid.
It was dissolved in 5 ml of a methanol solution. The crystals obtained by concentration again were recrystallized from ethanol-ethyl acetate to give (+)-trans-N-
230 mg of (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide dihydrochloride was obtained. [Α] _D = + 4.
84 ° (methanol, c = 0.5) PMR (DMSO-d _{6 /} TMS) δ: 0.96-2.
30 (10H, m), 1.14 (3H, d, J = 6H
z), 7.85 (2H, m), 8.44 (1H, s),
8.60 (1H, s)

Example 11 (a) 4-amino-1H-pyrazolo [3,4-d] pyrimidine 200 mg, triethylamine 0.29 ml and -1,3-dimethyl-2-imidazolidinone 20 ml
Was added dropwise under ice-cooling to a solution of 500 mg of trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarbonyl chloride in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours. After the reaction,
The reaction solution was poured into water and extracted with chloroform. The residue obtained by washing with a saturated aqueous solution of sodium hydrogen carbonate and water, drying and concentration was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain trans-N- (1H-pyrazolo [3, 4-d] Pyrimidin-4-yl) -4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide (310 mg) was obtained. PMR (CDCl _{3 /} TMS) δ: 0.90-2.50
(10H, m), 1.27 (3H, s), 1.29 (3
H, s), 4.69 (1H, brs), 5.06 (2
H, s), 7.35 (5H, s), 8.61 (1H,
s), 8.77 (1H, s)

(B) Compound 310 obtained according to (a)
5 mg of a 25% hydrogen bromide acetic acid solution was added to the mg under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the resulting crystals were washed with ether, recrystallized from ethanol-ethyl acetate, and purified from trans-
N- (1H-pyrazolo [3,4-d] pyrimidine-4-
Yl) -4- (1-Amino-1-methylethyl) cyclohexanecarboxamide dihydrobromide 150 mg was obtained.

In addition, the following compounds can be synthesized according to any of the methods described in the above Examples. (12) trans-N- (4-pyrimidinyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide 1/4 hydrate, mp 235-237 ° C (13) trans-N- (3-amino -4-pyridyl)-
4-aminomethylcyclohexanecarboxamide dihydrobromide 1/4 hydrate, mp 266-269 ° C (14) trans-N- (7H-imidazo [4,5-d]
Pyrimidin-6-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide hemihydrate, melting point 214-216 ° C (15) trans-N- (3H-1,2,3-triazolo [4 , 5-d] pyrimidin-7-yl) -4-aminomethylcyclohexanecarboxamide 2/3 hydrobromide, mp 195-197 ° C (16) trans-N- (1-benzyl-1H-pyrazolo [3, 4-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide, mp 267-268 ° C (17) trans-N- (1H-5-pyrazolyl) -4-
Aminomethylcyclohexanecarboxamide dihydrobromide, melting point 251-252 ° C (18) trans-N- (1H-pyrazolo [3,4-b]
(Pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide hydrobromide hemihydrate, mp 26
1-262 ° C (19) trans-N- (4-pyridazinyl) -4-aminomethylcyclohexanecarboxamide dihydrochloride 3/2
Hydrate, melting point: 258 ° C (20) trans-N- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -4-aminomethylcyclohexanecarboxamide (21) trans-N- (2-amino- 4-pyridyl)-
4-Aminomethylcyclohexanecarboxamide dihydrochloride 3/2 hydrate, melting point 260 ° C (decomposition)

(22) trans-N- (thieno [2,3-
d] pyrimidin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide hemihydrate,
Melting point 243-245 ° C (23) trans-N- (imidazo [1,2-a] pyrimidin-5-yl) -4-aminomethylcyclohexanecarboxamide (24) trans-N- (5-methyl-1,2, 4-triazolo [1,5-a] pyrimidin-7-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide, melting point 297 ° C (decomposition) (25) trans-N- (5-methyltetrazolo [ 1,5
-A] pyrimidin-7-yl) -4-aminomethylcyclohexanecarboxamide (26) trans-N- (3-cyano-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -4-aminomethylcyclohexane Carboxamide hydrobromide dihydrate, mp 245-246 ° C (27) trans-N- (pyrido [2,3-d] pyrimidin-4-yl) -4-aminomethylcyclohexanecarboxamide (28) trans- N- (4-pyridyl) -4-iminomethylaminocyclohexanecarboxamide (29) trans-N- (1H-pyrazolo [3,4-b]
(Pyridin-4-yl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide dihydrobromide trihydrate, melting point 269-270 ° C (30) trans-N- (2- ( 1-pyrrolidinyl) -4
-Pyridyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide 3/1 hydrate, melting point 149-1
51 ° C (31) trans-N- (2,6-diamino-4-pyrimidyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide, mp 288-289 ° C.

(32) (+)-trans-N- (7-methyl-1,8-naphthyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide trihydrochloride 1
Hydrate, melting point 220 ° C. (decomposition), [α] _D = + 4.65
(Methanol, c = 0.5) (33) trans-N- (1-benzyloxymethylpyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide monohydrate, melting point 11
8-120 ° C (34) (+)-trans-N- (1-methylpyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide dihydrochloride, melting point 220 ° C (Decomposition), [α] _D = + 3.20 ° (methanol, c = 1.0) (35) trans-N-benzyl-N- (2-benzylamino-4-pyridyl) -4- (1-amino -1-methylethyl) cyclohexanecarboxamide dihydrochloride, melting point 190-194 ° C (36) trans-N- (2-benzylamino-4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide ( 37) trans-N- (2-amino-4-pyridyl)-
4- (1-Amino-1-methylethyl) cyclohexanecarboxamide (38) trans-N- (2-benzoylamino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (39) trans-N- (2-azido- 4-pyridyl)-
4-aminomethylcyclohexanecarboxamide, melting point 219 ° C (decomposition) (40) trans-N- (2-acetylamino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (41) trans-N- (2-methanesulfonylamino −
4-pyridyl) -4-aminomethylcyclohexanecarboxamide

(42) trans-N- (2-methylamino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (43) trans-N- (2-dimethylamino-4-pyridyl) -4-aminomethylcyclohexane Carboxamide (44) trans-N- (2-ethylamino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (45) trans-N- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridine 4-yl) -4-aminomethyl cyclohexanecarboxamide PMR (DMSO-d ₆ /TMS)δ:0.72-2.
20 (9H, m), 2.60-3.10 (7H, m),
6.12 (1H, brs), 6.90 (1H, d, J =
6 Hz), 7.56 (1H, d, J = 6 Hz), 9.5
0 (1H, brs) (46) (+)-trans-N- (2,3-dihydro-1
H-pyrrolo [2,3-b] pyridin-4-yl) -4-
(1-aminoethyl) cyclohexanecarboxamide (47) trans-N- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-amino-1-methylethyl ) Cyclohexanecarboxamide (48) trans-N- (2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] pyridin-4-yl)-
4-aminomethylcyclohexanecarboxamide (49) (+)-trans-N- (2,3-dihydro-2
-Oxo-1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-Aminoethyl) cyclohexanecarboxamide (50) trans-N- (2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] pyridin-4-yl)-
4- (1-Amino-1-methylethyl) cyclohexanecarboxamide (51) trans-N- (2,3-dihydro-2,3-dioxo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide

(52) (+)-trans-N- (2,3-
Dihydro-2,3-dioxo-1H-pyrrolo [2,3-
b] pyridin-4-yl) -4- (1-aminoethyl)
Cyclohexanecarboxamide (53) trans-N- (2,3-dihydro-2,3-dioxo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-amino-1-methylethyl ) cyclohexanecarboxamide (54) trans-N-(2-carboxy-4-pyridyl) -4-aminomethyl cyclohexanecarboxamide PMR (CDCl ₃ /TMS)δ:0.56-2.32
(12H, m), 2.38-2.62 (2H, m),
7.34 (1H, s), 7.95 (1H, dd, J =
1.8, 5.4 Hz), 8.06-8.28 (2H,
m), 8.59 (1H, d, J = 5.4 Hz) (55) trans-N- (2-carbamoyl-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (56) (+)-trans-N -(2-carbamoyl-4
-Pyridyl) -4- (1-aminoethyl) cyclohexanecarboxamide (57) trans-N- (2-carbamoyl-4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide (58) trans- N- (2-methylcarbamoyl-4-
(Pyridyl) -4-aminomethylcyclohexanecarboxamide (59) (+)-trans-N- (2-methylcarbamoyl-4-pyridyl) -4- (1-aminoethyl) cyclohexanecarboxamide (60) trans-N- (2 -Methylcarbamoyl-4-
Pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide (61) trans-N- (2-hydrazino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide

(62) trans-N- (2- (2,2-dimethylhydrazino) -4-pyridyl) -4-aminomethylcyclohexanecarboxamide (63) (+)-trans-N- (2- (2 , 2-Dimethylhydrazino) -4-pyridyl-4-aminomethylcyclohexanecarboxamide (64) trans-N- (2- (2,2-dimethylhydrazino) -4-pyridyl) -4- (1-amino- 1-methylethyl) cyclohexanecarboxamide (65) trans-N- (3-dimethylaminomethyl-1
H-pyrrolo [2,3-b] pyridin-4-yl) -4-
Aminomethylcyclohexanecarboxamide (66) trans-N- (3-methyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide (67) trans-N- (3-formyl -1H-pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide (68) trans-N- (3-carboxy-1H-pyrrolo [2,3-b] pyridin-4- Yl) -4-aminomethylcyclohexanecarboxamide (69) trans-N- (3-methoxycarbonyl-1H
-Pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide (70) trans-N- (3-carbamoyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -4-Aminomethylcyclohexanecarboxamide (71) trans-N- (1-tert-butylcarbonyloxymethylpyrrolo [2,3-b] pyridin-4-yl)
-4-aminomethylcyclohexanecarboxamide

(72) (+)-trans-N- (1-third
Tert-butylcarbonyloxymethylpyrrolo [2,3-b]
Pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide (73) trans-N- (1-tert-butylcarbonyloxymethylpyrrolo [2,3-b] pyridin-4-yl)
-4- (1-Amino-1-methylethyl) cyclohexanecarboxamide (74) trans-N- (2- (4-methylphenylsulfonylamino) -4-pyridyl) -4-aminomethylcyclohexanecarboxamide (75) trans- N- (2-methoxycarbonylamino-4-pyridyl) -4-aminomethylcyclohexanecarboxamide (76) (+)-trans-N- (2-acetylamino-
4-pyridyl) -4- (1-aminoethyl) cyclohexanecarboxamide (77) trans-N- (2-acetylamino-4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide (78) (+)-Trans-N- (2-methylsulfonylamino-4-pyridyl) -4- (1-aminoethyl) cyclohexanecarboxamide (79) trans-N- (2-methylsulfonylamino-
4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide (80) (+)-trans-N- (2-methylamino-4
-Pyridyl) -4- (1-aminoethyl) cyclohexanecarboxamide (81) trans-N- (2-methylamino-4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide

(82) (+)-trans-N- (2-ethylamino-4-pyridyl) -4- (1-aminoethyl)
Cyclohexanecarboxamide (83) trans-N- (2-ethylamino-4-pyridyl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide (84) trans-N- (1H-pyrrolo [2,3- b] pyridin-4-yl) -cis-2-methyl-4-aminomethylcyclohexanecarboxamide (85) trans-N- (1H-pyrazolo [3,4-b]
Pyridin-4-yl) -cis-2-methyl-4-aminomethylcyclohexanecarboxamide

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 11/06 A61P 11/06 11/08 11/08 C07D 213/89 C07D 213/89 237/20 237/20 237/22 237 / 22 239/42 239/42 Z 239/47 239/47 249/14 249/14 251/14 251/14 253/06 253/06 D 401/00 401/00 471/04 104 471/04 104Z 105 105A 106 106C 113 113 113 471/14 101 471/14 101 102 102 487/04 140 487/04 140 142 142 142 146 146 491/044 491/044 (72) Inventor Hiroyuki Sato 3-7-125 Otaya, Iruma-shi, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory (72) Inventor Masayoshi Uehata 3-7-25 Koyata, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory (56) References JP-A-4-273821 (JP, A ) JP-A-3-218356 JP, A) Akira real public 64-5661 (JP, Y1) WO 90/5723 (WO, A1) (58 ) investigated the field (Int.Cl. ^7, DB name) C07D 213/00 - 213/89 C07D 237/00-237/22 C07D 239/00-239/47 C07D 249/00-249/14 C07D 251/00-251/26 C07D 253/00-253/06 C07D 257/00-257/08 C07D 401 / 00 C07D 471/00-471/14 C07D 487/00-487/04 C07D 491/044 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (I) [Wherein, R ^1, R ² are the same or different and each is hydrogen, alkyl or, on the ring, halogen, alkyl, alkoxy, A
Aralkyl, haloalkyl, nitro, -NRcRd (here
And Rc and Rd are the same or different and are hydrogen, alkyl,-
COR ⁹ , —COOR ⁹ ′, —SO ₂ R ⁹ ′ (where R ⁹
Represents hydrogen, alkyl, phenyl, aralkyl,
R ⁹ ′ represents alkyl, phenyl or aralkyl. )
Or Rc and Rd are ring together with the nitrogen atom
Oxygen atom, sulfur atom, nitrogen atom which may have a substituent
A hydrogen atom (the substituents are alkyl, aralkyl and halo)
Selected from the group consisting of alkyl)
A group that forms a heterocyclic ring. ), Cyano, azide, ho
Rumyl, acyl, -COOR ¹⁰ , -CONR ¹¹ R ¹² (this
Where R ^10-12 is hydrogen, alkyl, phenyl, aralkyl
Show ) And optionally substituted hydra
Dino (the substituents are alkyl, aralkyl, nitro and
Selected from the group consisting of
Cycloalkyl which may have a substituent, cycloalkylalkyl, phenyl, aralkyl, or shows a piperidyl or pyrrolidinyl, or shows alkylidene, phenyl alkylidene R ^1, R ² together,
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 R ¹ and R ² are bonded (the substituent may be an alkyl, aralkyl,
Represents a group to form a heterocyclic ring which may contain are) selected from the group consisting of kill, R ^3, R ⁴ represents hydrogen or alkyl, A is a single bond or alkylene, X is = C
(R ⁷ ) — or ＮN—, and R ⁵ and R ⁶ together represent the formula —CRa = CRb— (a) —NRa—C (＝ Rb) — (b) —N = CRb— (c ) -C (= Ra) -NRb- (d) -CRa = N- (e) -NRa- (f) (where Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl) , nitro, -NRcRd in (wherein Rc, Rd are the same or different and each is hydrogen, alkyl, -COR ^9, -COO
R ⁹ ′, —SO ₂ R ⁹ ′ (where R ⁹ is hydrogen, alkyl,
R ⁹ ′ represents alkyl, phenyl or aralkyl; Or Rc and Rd are, together with the nitrogen atom to which they are bound, an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent (the substituent
Consists of alkyl, aralkyl and haloalkyl
A group which forms a heterocyclic ring which may contain a heterocyclic ring. ), Cyano, azide, hydrazino optionally having substituents (the substituents being alkyl, aralkyl,
Selected from the group consisting of nitro and cyano) , -CO
OR ¹⁰ , —CONR ¹¹ R ¹² (where R ^10-12 is hydrogen,
Shows alkyl, phenyl and aralkyl. ) Or
Ra and Rb together form a nitrogen atom, a sulfur atom,
It represents a group forming a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one oxygen atom. However, when the formula (b) or (d) is indicated, Ra,
Rb is a group which always forms a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom in the ring. Wherein R ⁷ and R ⁸ are the same or different and are hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, —NReRf (where Re and Rf are the same or different and are hydrogen, alkyl, —COR ⁹ , -CO
OR ⁹ , —SO ₂ R ⁹ ′ (where R ⁹ is hydrogen, alkyl,
R ⁹ ′ represents alkyl, phenyl or aralkyl; ) Or Re and Rf are 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 (the substituent
Consists of alkyl, aralkyl and haloalkyl
A group which forms a heterocyclic ring which may contain a heterocyclic ring. ), Cyano, azide, hydrazino optionally having substituents (the substituents being alkyl, aralkyl,
Selected from the group consisting of nitro and cyano) , -CO
OR ¹⁰ , —CONR ¹¹ R ¹² (where R ^10-12 is hydrogen,
Shows alkyl, phenyl and aralkyl. ) And n
Represents 0 or 1. However, when R ⁵ and R ⁶ are of the formula (a), X is = C (R ⁷ )-, and Ra, Rb,
One of R ⁷ and R ⁸ is —NRcRd, —NReR
f, azide, hydrazino optionally having a substituent (the
Substituents are alkyl, aralkyl, nitro and cyano
Selected from the group consisting of) , -COOR ¹⁰ , -CONR
Represents ¹¹ R ¹² , or Ra and Rb are taken together, and the ring may contain at least one of a nitrogen atom, a sulfur atom and an oxygen atom, and may be a 5- to 6-membered aromatic group which may be hydrogenated. Shows a group forming a ring. A 4-amino (alkyl) cyclohexane-1-carboxylic acid amide compound, 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.