JPH05194401A - 4-amino@(3754/24)alkyl)cyclohexan-1-carboxylic acid amide compound - Google Patents

Abstract

PURPOSE:To provide the subject new toxic compounds having a strong and long-acting effect on increase of the blood flow volume in the corona, the brain, the kidney and the peripheral arteria and useful as an antihypertensive agent, a medicine for preventing and treating diseases of the circulatory system such as the corona, the brain or the kidney or a medicine for treating asthma. CONSTITUTION:Compounds of formula I [R<1> to R<4> are H or an alkyl and R<1> to R<2> may be a cycloalkyl, phenyl, etc.; A 15 single bond or an alkylene; X is CR<7> or N; R<5>, together with R, forms CRa=CRb, N=CRb, formula II, III, etc.; Ra, Rb and R<7> are H, a halogen, an alkyl, an alkoxy, etc., and Ra and Rb may be a group which can form a 5- to 6-membered aromatic ring, etc., in combination (Ra and Rb in formulae II and III must be the above-mentioned group); n is 0 or 1], isomers thereof or their pharmaceutically permissible acid adduct salts, e.g. trans-N-(6-amino-4-pyrimidyl)-4- aminomethylcyclohexanecarboxamide dihydrochloride 3/2 hydrate. The above- mentioned compound can be produced by reacting a compound of formula IV or its reactive derivative with a compound of formula V.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art One of the causes of hypertension and coronary / cerebral circulatory disorders, which have become a major social problem as an adult disease, is abnormal smooth muscle contractility. It is known that contraction is induced by an increase in intracellular concentration of calcium ions. Increase in intracellular concentration of calcium ion is (1) mediated by membrane potential-dependent calcium channel, (2) released from intracellular calcium storage site, (3) mediated by receptor-dependent channel, etc. , But not uniform,
When these calcium ions are excessive, it is said to cause spasms 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, the use of calcium antagonists is currently being attempted for the treatment of hypertension and coronary / cerebral and peripheral circulatory disorders. However, calcium antagonists show antagonism of membrane potential-dependent calcium channels, but almost no antagonism of calcium influx into other cells and calcium release from storage sites. As a compound having an intracellular calcium antagonistic effect as well as an inhibitory effect on a membrane potential-dependent smooth muscle contraction suppressed by a conventional calcium antagonist, International Publication WO
No. 90-05723 describes certain trans-4-
Amino (alkyl) -1-pyridylcarbamoylcyclohexane compounds, optical isomers thereof, and pharmaceutically acceptable acid addition salts thereof have a continuous coronary / cerebral / renal blood flow increasing action, and are antihypertensive agents and coronary / cerebral -It is disclosed that it is useful as a preventive / therapeutic agent for cardiovascular diseases such as kidney. It is an object of the present invention to provide a compound having a stronger, longer-lasting action, a reduced toxicity, and a coronary, cerebral, renal and peripheral arterial blood flow increasing action as compared with conventional compounds.

[0003]

[Means for Solving the Problems] Under these circumstances,
As a result of intensive studies by the present inventors, 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. It came to complete the present invention by finding out. Further, it was also found that the compound of the present invention exhibits an experimental asthma suppressive action by histamine inhalation and a contractile suppressive action by acetylcholine in a guinea pig excised trachea specimen, and has also been proved to have an anti-asthma action.

The present invention has the general formula

[0005]

[Chemical 2]

[Wherein R ¹ and R ² are the same or different and are hydrogen, alkyl or cycloalkyl optionally having a substituent on the ring, cycloalkylalkyl, phenyl,
Aralkyl, piperidyl or pyrrolidinyl, R ¹ and R ² together represent alkylidene and phenylalkylidene, and R ¹ and R ² together with the nitrogen atom to which they are attached have an oxygen atom, a sulfur atom or a substituent in the ring. Represents a group forming a heterocycle which may have a nitrogen atom which may have a group, R ³ and R ⁴ represent hydrogen or alkyl, A represents a single bond or alkylene, and X represents ═C
(R ⁷⁾ - or = N- are shown, R ^5, 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) (wherein Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl. , Nitro, -NRcRd (wherein Rc and Rd are the same or different and are hydrogen, alkyl, -COR ⁹ , -COO.
R ⁹ ′, —SO ₂ R ⁹ ′ (wherein R ⁹ represents hydrogen, alkyl, phenyl and aralkyl, R ⁹ ′ represents alkyl, phenyl and aralkyl), or Rc and Rd are combined. A group forming a heterocyclic ring which may include an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring together with the nitrogen atom present. ), Cyano, azido, optionally substituted hydrazino, —COOR
¹⁰ , -CONR ¹¹ R ¹² (wherein R ^10-12 represents hydrogen, alkyl, phenyl, aralkyl) or R
a and Rb represent together a group forming 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. . However, when the formula (b) or (d) is shown, Ra,
Rb represents a group which, together with each other, 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. ), 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 ′ (wherein R ⁹ represents hydrogen, alkyl, phenyl and aralkyl, R ⁹ ′ represents alkyl, phenyl and aralkyl), or Re and Rf are bonded to each other. Oxygen atom in the ring, together with the nitrogen atom
It represents a group forming a heterocycle which may contain a sulfur atom or a nitrogen atom which may have a substituent. ), Cyano, azido, optionally substituted hydrazino, −
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 is
a, Rb, R ⁷ or R ⁸ is any 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 together a group which 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. Show. ] The 4-substituted amino (alkyl) cyclohexane- 1-carboxylic acid amide compound of Claim (1) represented by these, its isomer, and its pharmaceutically acceptable acid addition salt.

Explaining each symbol of the general formula (I) by definition, halogen means chlorine, bromine, fluorine and iodine, and alkyl means 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms.
Individual straight chain or branched chain alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-Ethylhexyl, nonyl, decyl and the like, and haloalkyl is the above alkyl substituted with 1 to 5 halogens, and is trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3. , 3-pentafluoropropyl, etc., and alkoxy is a linear or branched alkoxy having 1 to 6 carbon atoms, and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy. , Third grade butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like, and cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl having 3 to 7 carbon atoms, and cycloalkylalkyl. The cycloalkyl part is a cycloalkyl having 3 to 7 carbon atoms, and the alkyl part is a linear or branched alkyl having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl). And the like), 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 can be mentioned. Alkylene is a linear or branched alkylene having 1 to 6 carbon atoms and is methylene, ethylene, trimethylene or tetra. Methylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, diethylmethyle , Propylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltrimethylene, dimethyltetramethylene and the like, and aralkyl means an alkyl group having an alkyl group having 1 to 4 carbon atoms such as benzyl and 1-phenylethyl. , 2-phenylethyl, 3-phenylpropyl, 4-
Phenylalkyl such as phenylbutyl and alkylidene are linear or branched alkylidene having 1 to 6 carbon atoms, and include methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene,
Hexylidene and the like, and phenylalkylidene is an alkylidene having an alkylidene portion having 1 to 6 carbon atoms, and includes benzylidene, phenylethylidene, phenylpropylidene, phenylbutylidene, phenylpentylidene, phenylhexylidene and the like.

Further, the number of carbon atoms which may have a substituent is 3
~ 7 cycloalkyl, phenyl, aralkyl, piperidyl, pyrrolidinyl substituents are halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, -NRcRd (wherein Rc and Rd are the same or different and are hydrogen, alkyl, -COR). ⁹ , -COOR ⁹ ',-
SO ₂ R ⁹ ′, or Rc and Rd are heterocyclic rings which may contain an oxygen atom, a sulfur atom and a nitrogen atom which may have a substituent in the ring together with the nitrogen atom to which they are bonded. The group to be formed is shown. ), Cyano, azido, formyl, acyl, —COOR ¹⁰ , —CONR ¹¹ R ¹² or hydrazino which may have a substituent.

Here, halogen, alkoxy, aralkyl and haloalkyl have the same meanings as described above, and acyl includes acetyl, propionyl, butyryl, valeryl, pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutyryl. Alkyl is a substituent of hydrazino which may have a substituent,
Examples include aralkyl, nitro and cyano. Here, alkyl and aralkyl have the same meanings as described above.

R ¹ and R ² , Rc and Rd or Re and Rf
As 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 is bonded, a 5- or 6-membered ring, these And a specific example thereof is pyrrolidinyl, piperidyl, piperazinyl, morpholino, thiomorpholino and the like. Further, examples of the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl and haloalkyl. Here, alkyl, aralkyl and haloalkyl have the same meanings as described above.

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

Further, R ⁵ and R ⁶ are represented by the formula (a),
When (b) and (d) are shown to form a condensed ring, pyrrolopyridine (1H-pyrrolo [2,3-b] pyridine, 1H
-Pyrrolo [3,2-b] pyridine, 1H-pyrrolo [3,3
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-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 and the like), 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 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 (pyrido [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 (1,8-naphthyridine, etc.), tetrazolopyrimidine (tetrazolo [1,5-a] pyrimidine, etc.), thienopyridine (thieno [2,3-b] pyridine, etc.),
Thienopyrimidines (thieno [2,3-d] pyrimidines etc.), thiazolopyridines (thiazolo [4,5-b] pyridines, thiazolo [5,4-b] pyridines etc.), thiazolopyrimidines (thiazolo [4,5 -D] pyrimidine, thiazolo [5,4-d] pyrimidine and the like), oxazolopyridine (oxazolo [4,5-b] pyridine, oxazolo [5,4-b] pyridine and the like), 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 [2,2]). 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), 2,3-dihydropyrrolopyridine (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, and when these rings form a hydrogenated aromatic ring, The carbon atom therein may be carbonyl, such as 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. In addition, 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 a pharmaceutically acceptable acid addition salt of compound (I) formed with an inorganic acid or an organic acid, a hydrate or various solvates. When it has a carboxyl group, it also includes metal salts such as sodium salt, potassium salt, calcium salt and aluminum salt, and salts with amino acids such as lysine and ornithine.

The present invention also includes cis or trans geometric isomers of compound (I) or a mixture thereof. When an asymmetric carbon is present, optical isomers, racemates thereof, etc. may be present, but the present invention includes all of them. The compound (I) of the present invention can be synthesized by the method shown below.

Method 1 General formula (II)

[0016]

[Chemical 3]

[Wherein each symbol has the same meaning as defined above] and a carboxylic acid compound or a reactive derivative thereof represented by the general formula (III)

[0018]

[Chemical 4]

A method of reacting with an amino compound represented by the formula (wherein each symbol has the same meaning as defined above).

The reactive derivative of a carboxylic acid compound means an acid halide such as an acid chloride, an acid anhydride, a mixed acid anhydride formed from ethyl chloroformate, a methyl ester,
Examples thereof include esters such as ethyl ester and reactive derivatives produced from carbodiimide 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 containing no hydroxyl group such as benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, dimethylformamide and dimethylimidazolidinone are used. The reaction may be performed at any temperature, for example, -10 to 200 ° C,
It is preferably carried out at 0 to 80 ° C., but as a raw material, a reactive derivative (eg ester) which is not so reactive
In the case of, 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. Furthermore, if necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine is used as a deoxidizing agent. If necessary, the amino group of the general formula (II) can be protected by an amino protecting group such as benzyloxycarbonyl or t-butoxycarbonyl for the reaction. 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 synthetic raw material of the present invention, is a chemical and pharmaceutical bulletin (Chem.Pharm.Bull.), Vol. 27, page 2735 (1979). Or Vol. 27, No. 303
It 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, it can be synthesized by the following method.

[0023]

[Chemical 5]

(In the formula, Ac represents an amino-protecting group such as acetyl, and other symbols have the same meanings as described above.)

That is, after protecting the amine compound of the formula (i) with an amino protecting group (acetyl group or the like), an acetyl group is introduced into the aromatic ring by Friedel-Crafts reaction and the carboxylic acid of the formula (iv) is reacted by the haloform reaction. An acid compound is obtained, and then an aromatic ring is reduced by catalytic reduction and deprotected by alkaline 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- 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 ordinary column chromatography and recrystallization. A cis form of the compound
By esterifying the carboxylic acid compound of (iv) by a conventional method and isomerizing it by using a base (sodium methoxide, potassium butoxide, etc.), the formula
It can be obtained by obtaining the trans isomer of the carboxylic acid compound of (iv) and then deprotecting each isomer according to the above method.

The other synthetic raw material, the general formula (I
II) amine compounds are described in Journal of Medicinal Chemistry (J.Med.Chem.), Vol. 25, No. 125.
8 pages (1982), Vol. 32, p. 945 (198).
9), Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), Vol. 20, p. 295 (1983), vol. 9, p. 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).

The method of the two compounds (I), is one of hydrogen, R ¹ and R ^2, the other compounds other than hydrogen, the formula R ¹ and R ² obtained by the method 1 is hydrogen (IV )

[0029]

[Chemical 6]

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

The halide compound used in this reaction is represented by the formula (V) R ⁹ -Ha 1 (V) (wherein R ⁹ is an alkyl having 1 to 10 carbons or an optionally substituted carbon). Number 3 to 7 cycloalkyl, cycloalkylalkyl, phenyl, aralkyl,
Piperidyl and pyrrolidinyl are used, and Hal is halogen, preferably chlorine and bromine. ), And an aldehyde compound is a compound 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). Optionally represented by phenyl, aralkyl, nitrogen-protected piperidyl or nitrogen-protected pyrrolidinyl).
The ketone compound has the formula (VII)

[0032]

[Chemical 7]

(In the formula, R ¹¹ and R ¹² are the same or different and each is an alkyl having 1 to 9 carbons or phenyl which may have a substituent on the ring, aralkyl, nitrogen protected piperidyl or nitrogen protected. Is shown to be pyrrolidinyl,
R ¹¹ and R ¹² are each a cycloalkyl having 3 to 7 carbon atoms which may be bonded to a carbonyl group to have a substituent. ) Is a compound represented by.

When the compound (IV) is reacted with the halide compound, the same conditions as in Method 1 can be used, but sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine can be used. It is preferable to carry out the deoxidation condensation reaction in the presence of a base such as. In the case of reacting the compound (IV) with an aldehyde or a ketone, it is usually heated under reflux with a water-immiscible solvent such as benzene, toluene, xylene, carbon tetrachloride, chloroform and dichloromethane.
Perform a dehydration condensation reaction. At this time, it is also advantageous to add a small amount of acid such as paratoluenesulfonic acid. Further, the compounds of alkylidene, phenylalkylidene, pyrrolidylidene, and piperidylidene obtained by the above condensation reaction can be reduced to give compounds of alkyl, aralkyl, pyrrolidinyl, and piperidyl.
The reduction reaction is usually performed in an alcohol such as methanol, ethanol or isopropyl alcohol at -10 to 100.
C., preferably 0 to 40.degree. C. Also,
As the reducing agent, in the presence of sodium borohydride, a small amount of acid such as hydrochloric acid, hydrobromic acid, acetic acid, etc., a reducing agent such as sodium cyanoborohydride, and when other groups of the target compound are not affected. It can also be produced by carrying out 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), R ¹ and R ² may contain, together with the nitrogen atom to which they are bonded, an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. A compound which is a group forming a good heterocycle has the general formula (VIII)

[0036]

[Chemical 8]

Or general formula (IX)

[0038]

[Chemical 9]

[In the formulas (VIII) and (IX), R ^13-20 may be the same or different and each may have hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, cyano, or a substituent. Represents hydrazino, Y is carbon,
It is oxygen, sulfur or nitrogen which may have a substituent, and Z is an alcohol such as halogen (chlorine, bromine etc.), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy etc.). The reactive derivative is shown. However, the number of substituents of the heterocycle formed is 1 to 3. ] It can manufacture by making the compound and compound (IV) represented by these react. The reaction can be carried out 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 heterocycle which may contain a nitrogen atom which may have a sulfur atom or a sulfur atom or a nitrogen atom in the ring together with the nitrogen atom which is bonded, is represented by the compound (IV) Among them, the substituent of the heterocycle in the A part is -NR
A compound represented by the general formula (X) is prepared by reacting cRd, -NReRf, a compound other than hydrazino with sodium nitrite or potassium nitrite in the presence of hydrochloric acid, sulfuric acid, formic acid and acetic acid.

[0041]

[Chemical 10]

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

[0043]

[Chemical 11]

(Wherein R ¹ 'and R ² ' are the same or different and represent alkyl, phenyl or aralkyl, or
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 is shown. It 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 hydrogen carbonate (sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, etc.),
It is carried out in the presence of an organic base such as pyridine or triethylamine. Further, the isomers included in the compound (I) of the present invention can be isolated from the isomer mixture by a conventional method or can be produced by using each isomer raw material.

In the compound (I) of the present invention thus obtained, the amino group at the 4-position-substituted amino moiety of the cyclohexane ring and Ra, Rb, R ⁷ and R ⁸ are —NRcRd or —.
The amino group in the case of showing NReRf and the amino group in the case where R ⁵ and R ⁶ form a monocycle or the case where the substituent in the ring or the ring in the case of forming a condensed ring shows —NRcRd are ordinary amino protecting groups. Protected by formyl, acetyl, propionyl, butyryl,
1 to 1 carbon atoms such as isobutyryl, pivaloyl and valeryl
5 alkanoyl; alkoxycarbonyl having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tertiary butoxycarbonyl; cyclopropylcarbonyl, cyclobutylcarbonyl, Cycloalkylcarbonyl having 4 to 8 carbon atoms such as cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl; aroyl such as benzoyl and naphthoyl (wherein aroyl means halogen, alkyl having 1 to 6 carbons, carbon number 1 to 6)
Optionally having 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, and 1 to 6 carbons on the phenyl ring.
Optionally having a substituent such as alkoxy, aralkyl, trifluoromethyl, nitro or amino); phenylalkenyl such as styryl, cinnamyl, phenylbutenyl, phenylpentenyl or phenylhexenyl; or benzylidene, Phenylalkylidene such as phenylethylidene; group forming pyrrolidylidene, piperidylidene, phthalimide; alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl; methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, diethyl Alkylcarbamoylalkyl such as carbamoylmethyl, dimethylcarbamoylethyl; methoxymethyl, ethoxymethyi , Alkoxymethyl such as propoxymethyl, butoxymethyl and tertiary butoxymethyl; aralkyloxyalkyl such as benzyloxymethyl, p-methoxybenzyloxymethyl and o-nitrobenzyloxymethyl; allyl; cyclic ethers such as tetrahydrofuran and tetrahydropyran It may be protected by a protecting group such as.

The above-mentioned amino-protecting group is a common acid (hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, hydrobromic acid / acetic acid, hydrochloric acid / dioxane, hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, etc.) or Lewis acid. 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.).

Further, a catalytic reduction method using 5% palladium carbon, 10% palladium carbon, 10% palladium hydroxide carbon, Raney nickel, etc. as a catalyst, a reduction method using sodium metal or lithium metal in liquid ammonia,
Alternatively, it can be deprotected 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, 2,
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 and chromatography. 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 into the corresponding free bases by a conventional method, for example, by reaction with an alkali such as sodium hydroxide or potassium hydroxide. Further, a quaternary ammonium salt can be used. Further, the compound having a carboxyl group in the compound (I) includes metal salts (sodium salt, potassium salt, calcium salt, aluminum salt, etc.), amino acids (lysine, ornithine, etc.).
It can also be salted with.

[0049]

ACTION AND EFFECT OF THE INVENTION Next, the action of the compound of the present invention will be specifically described by a pharmacological experiment.

Pharmacological Experiment Example 1 Spontaneously Hypertensive Rats (SH-350g)
In (R), catheters for blood pressure measurement and drug administration were previously inserted into the carotid artery and jugular vein, respectively, and 0.3 mg / kg of the test compound was intravenously administered under no anesthesia and restraint to examine the effect on blood pressure. . Blood pressure was automatically measured and analyzed via the left transducer. The results are shown in Table 1.

[0051]

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

Pharmacological Experiment 2 A male rabbit (body weight: 1.9 to 3.0 kg) was anesthetized with sodium pentobarbital, and then bled to death, and the thoracic aorta was extracted. A ring-shaped specimen with a width of about 2 mm was prepared, and Krebs-Henseleit solution (NaCl 117 mM; KCl 4.7 mM; C) at 37 ° C was prepared.
aCl ₂ 2.5 mM; MgSO ₄ 1.2 mM; NaHCO ₃ 24.8 mM; KH ₂ PO ₄ 1.2
It was suspended with a load of 2 g in a Magnus tube having a volume of 40 ml filled with mM; glucose 11.0 mM). Inside the Magnus pipe is always
A mixed gas (95% oxygen + 5% carbon dioxide) was bubbled. Specimen tension is isometric transducer (TB-611
T, Nihon Kohden). The sample was contracted with phenylephrine (10 ⁻⁶ M), and after the contraction was constant, the compound was cumulatively added and the relaxation reaction was observed. In the relaxation reaction of the compound, the phenylephrine contraction was defined as 100%, and the concentration at which 50% of the compound could be relaxed was calculated as IC ₅₀ (μM). The results are shown in Table 2.

[0053]

[Table 2] Table 2 ─────────────────────────────── Compound Compound Vasorelaxant (μM) ───── ────────────────────────── Example 3 0.09 Example 4 0.08 Example 6 0.12 Example 7 0.19 ───────────────────────────────

Pharmacological Experiment 3: Effect on Coronary Blood Flow Anesthetize 2-3 hybrid dogs per group by intravenous administration of sodium pentobarbital 30 mg / kg body weight, and the method of Yago et al. , Volume 57, 38
The left coronary artery was perfused and its blood volume was measured according to page 0, (1961). 10 to 300 μg of the test compound was administered intracoronarily. The effect of test compounds on coronary blood volume was nifedipine [dimethyl-2,6-dimethyl-4-
(2-Nitrophenyl) -1,4-dihydropyridine-
3,5-dicarboxylate] 3 μg was expressed as ED ₅₀ (μg) for the dose required to increase coronary blood to half the effect of intracoronary administration, and the results are summarized in Table 3. In addition, the half-life (T1 /
2 minutes).

[0055]

[Table 3] Table 3 ─────────────────────────────── Compound Compound coronary blood flow increasing action (ED ₅₀ ; μg) (T1 / 2; min) ─────────────────────────────── 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 Experiment 4: Effect on contraction of guinea pig isolated trachea specimen by acetylcholine Male Hartley guinea pig (body weight 260 to 390 g)
Pentobarbital sodium (100 mg / kg) was intraperitoneally administered to the mouse to anesthesia, the blood was killed, and the trachea was removed. The ventral cartilage of the trachea was cut open, and the ligament portion with a width of 3 mm was cut to prepare a specimen. Krebs-Henseleate solution (NaCl 117 mM; KCl 4.7 mM; CaCl ₂ 2.5 mM; MgS) at 37 ° C
O ₄ ; 1.2mM; NaHCO ₃ 24.8mM; KH ₂ PO ₄ 1.2mM; glucose 1
It was suspended with a load of 1 g in a Magnus tube having a capacity of 40 ml filled with 1.0 mM). The mixed gas (95
% Oxygen + 5% carbon dioxide gas) was aerated. The tension of the sample was recorded on a recorder (Ti-102, Tokai Medical Science) using an isometric transducer (TB-611T, Nihon Kohden). The sample was contracted with acetylcholine (10 ⁻⁶ M), and after the contraction was constant, the compound was cumulatively added and the relaxation reaction was observed. The relaxation reaction of the compound is papaverine (10 ^-4 M)
The maximum reaction was determined as 100%, and the concentration showing 50% relaxation reaction was calculated as IC ₅₀ (μM). The results are shown in Table 4.

[0057]

[Table 4] Table 4 ─────────────────────────────── Compound Bronchodilator (IC ₅₀ ; μM) ── ───────────────────────────── Example 3 0.06 Example 4 0.09 Example 6 0.17 Example 7 0.31 ────────────────────────────────

Pharmacological Experiment 5: Effect of Histamine Inhalation on Guinea Pig Experimental Asthma Method of Suyama (Allergy, Vol. 15, pp. 549, 196)
6 years), a female Hartley guinea pig weighing 490 to 630 g was placed in the aerosol inhaler to obtain 0.2%.
A histamine solution (histamine hydrochloride, Hanai Chemical Co., Ltd.) was sprayed with an ultrasonic neprizer (TUR-3200, Nihon Kohden Kogyo Co., Ltd.) and the protective effect 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 inhalation was measured. The results are shown in Table 5.

[0059]

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

Acute Toxicity Experiment Each test compound (Examples 3 and 6) was intraperitoneally administered to a ddY mouse and observed for 5 days.
No cases of death were observed with the intraperitoneal administration of 1 kg / kg.

The compound (I) of the present invention, isomers thereof and pharmaceutically acceptable acid addition salts thereof have a coronary and cerebral blood flow increasing action similar to calcium antagonists, and are not found in conventional calcium antagonists. It also has a renal and peripheral arterial blood flow increasing action. Further, the blood flow increasing action is long lasting and the blood pressure lowering action is also strong. Furthermore, it is effective not only for vasoconstriction induced by substances in the body such as endothelin but also for vasoconstriction caused by calcium ionophore or phorbol ester, which does not act on calcium antagonists. Therefore, the compound of the present invention is useful as a potent and persistent antihypertensive agent and a preventive / therapeutic agent for cardiovascular diseases such as coronary, cerebral, renal and peripheral arteries. Furthermore, the compound of the present invention exhibits an experimental asthma-suppressing action on guinea pigs by inhaling histamine and a contraction-suppressing action by acetylcholine on guinea pig isolated trachea specimens, and is also useful as a therapeutic agent for asthma.

When the compound (I) of the present invention is used as a medicine, it is mixed with an effective amount thereof and an additive for pharmaceutical preparation such as a pharmacologically acceptable excipient, carrier, diluent and the like,
It can be administered orally or parenterally in the form of tablets, granules, powders, capsules, injections, ointments and suppositories. The dose may vary depending on the age, weight and symptoms of the patient, but usually 5 to 5 times per day for adults as oral administration.
The amount is about 500 mg, which can be administered once or divided into several times.

[0063]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 (a) A mixture of 4.7 g of 4,6-diaminopyrimidine, 500 ml of ethanol and 200 ml of water was ice-cooled with ice-water, and 13.25 ml of 1N sodium hydroxide was added. Further, 26.5 ml of 1N 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 were collected by filtration and chloroform: methanol (5: 1).
Recrystallization was performed to obtain N-benzyloxycarbonyl-4,6-diaminopyrimidine (2.4 g) having a melting point of 194 ° C. (B) N-benzyloxycarbonyl-4,6-diaminopyrimidine 1.7 g, triethylamine 2.9 ml and 1,3-dimethyl-2-imidazolidinone 40 ml
Was cooled with ice water, and a solution of 20 g of 1,3-dimethyl-2-imidazolidinone containing 2.6 g of trans-4-benzyloxycarboxamidomethylcyclohexanecarbonyl chloride was added dropwise while stirring, and at room temperature, 1.5
Stir for hours. When the reaction solution was poured into water, a yellow gum-like insoluble material was precipitated. This was washed with cold water, dried, concentrated, ethyl acetate was added, the obtained crystals were collected by filtration, and trans-N- (6-benzyloxycarboxamide-4 having a melting point of 187 ° C was collected.
1.6 g of -pyrimidyl) -4-benzyloxycarboxamide methylcyclohexanecarboxamide was obtained. (C) Hydrogen gas was passed 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 to carry out catalytic reduction. 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 are collected by filtration and recrystallized from ethanol, melting point 245
Obtained 150 mg of trans-N- (6-amino-4-pyrimidyl) -4-aminomethylcyclohexanecarboxamide dihydrochloride 3/2 hydrate at ˜247 ° C.

Example 2 (a) Trans-4-benzyloxycarboxamide methylcyclohexane 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 dichloromethane solution containing 1.86 g of carbonyl chloride was added dropwise over 30 minutes. After stirring at room temperature for 3 hours, it was heated to 45 to 50 ° C. and reacted for 3 hours. After cooling the reaction solution, it 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 was obtained. (B) Compounds 33 mg and 30 obtained according to (a)
5 ml of a% hydrobromic acid acetic acid solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, ether was added, and the obtained crystals were thoroughly washed with ether. Recrystallized with ethanol, trans-N- (1H- with a melting point of 262 ° C (decomposition).
24 mg of pyrrolo [2,3-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide was obtained.

Example 3 (a) (R)-(+)-1-phenylethylamine 30
g in 200 ml of chloroform under ice-cooling, acetic anhydride 3
8.4 g was added dropwise. After the reaction, ice water was added and 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 obtain (+)-N.
32.2 g of-(1-phenylethyl) acetamide was 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 to 185 with aluminum chloride.
g was added in small portions. After stirring at the same temperature for 1 hour, 50 ~
The mixture was stirred at 60 ° C for 3 hours. After the reaction, the reaction solution was poured into ice water and extracted with chloroform. The crystals obtained by washing with water, drying and concentration under reduced pressure were recrystallized from ethanol-isopropyl ether to give (+)-N- (1- (4-
62.8 g of acetylphenyl) ethyl) acetamide was 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 = 8Hz),
7.90 (2H, d, J = 8Hz)

After adding 760 ml of 10% sodium hypochlorite 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, 50- The mixture was stirred at 70 ° C for 1 hour. After the reaction, the solvent was distilled off under reduced pressure and the obtained residue was poured into ice water. Crystallization occurred when acidified with concentrated hydrochloric acid. This is 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 = 8Hz) 7.
95 (2H, d, J = 8Hz)

(+)-4- (1-acetamidoethyl)
Benzoic acid 51.2 g, 5% ruthenium carbon 35.4 g, 28% ammonia water 220 ml solution, in an autoclave, hydrogen initial pressure 70 atm, 90 ° C for 3 hours, 150 ° C for 3 hours.
Stir for hours. After the reaction, the catalyst was filtered off and concentrated under reduced pressure to obtain 53.5 g of (+)-4- (1-acetamidoethyl).
A cis / trans mixture of cyclohexanecarboxylic acids was obtained. Then, 33 ml of 31% hydrochloric acid methanol solution,
200 ml of methanol was added and 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 by purification under silica gel column chromatography was used to purify (+)-4- (1-acetamidoethyl) cyclohexanecarboxylic acid methyl ester cis.
38.0 g of trans mixture (2: 1) was 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 tertiary 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 = 7Hz),
1,98 (3H, s), 3.66 (3H, s), 5.7
4 (1H, m)

(+)-Trans-4- (1-acetamidoethyl) cyclohexanecarboxylic acid methyl ester 6
To a solution of 3 g of methanol in 250 ml, 10 ml of water and 66 g of potassium hydroxide were added, 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 diluted sulfuric acid. The precipitate was filtered off under reduced pressure, and the filtrate containing (+)-trans-4- (1-aminoethyl) cyclohexanecarboxylic acid was added to a filtrate containing 41.8 sodium hydroxide aqueous solution 41.8.
After adding ml under ice-cooling, 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, whereby crystals were precipitated. (+)-Trans-4- (1-benzyloxycarboxamidoethyl) having a melting point of 125 to 126 ° C. when collected by filtration under reduced pressure and dried.
25.9 g of cyclohexanecarboxylic acid was 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 the solution of (+)-trans-4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxylic acid 6 g in dichloromethane 60 ml was added thionyl chloride 5 ml and dimethylformamide 1 drop, 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, this crystal was dissolved in 40 ml of acetonitrile, and 4-amino-1H-pyrrolo [2,3-
b] Pyridine 1 g and diisopropylethylamine 4.7
After adding dropwise to a 50 ml solution of 50 ml of acetonitrile, the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration, dried, dissolved in 200 ml of dimethylformamide and 100 ml of methanol, and 460 mg of sodium methoxide was added to 40
The mixture was stirred at 0 ° 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 = 3Hz), 7.35 (6H,
s), 7.80 (1H, d, J = 5Hz), 8.06
(1H, d, J = 5Hz), 9.80 (1H, s)

(+)-Trans-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide 2.6 g, 10% palladium hydroxide Carbon 50
0 mg, 15% hydrochloric acid methanol 4 ml methanol 70
The ml solution is stirred for 1 hour at room temperature under an initial hydrogen pressure of 5 atm in an autoclave. After the reaction, the catalyst was filtered off and the crystals obtained by concentrating under reduced pressure were recrystallized from ethanol to give (+)-trans-N- with a melting point of 220 to 223 ° C.
(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 48% aqueous sodium hydroxide solution in 1,000 ml of toluene was cooled with ice.
After dropping 62 g of acetyl chloride, the mixture was stirred at room temperature for 5 hours.
After the reaction, the mixture was neutralized with saturated potassium carbonate aqueous solution and extracted with ethyl acetate. After washing with water and drying, distilling off the solvent under reduced pressure,
102.3 g of N- (1-methyl-1-phenylethyl) acetamide was 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)
To a solution of 25 g of acetamide and 16.6 g of acetyl chloride in 75 ml of dichloroethane, aluminum chloride 4 was added under ice cooling.
1.5g was added in small portions. After stirring at the same temperature for 1 hour,
It stirred at 50-60 degreeC for 1 hour. After the reaction, the reaction solution was poured into ice water and extracted with chloroform. The crystals obtained by washing with water, drying and concentration under reduced pressure were recrystallized from ethyl acetate-isopropyl ether to give N- (1- (4-
20.4 g of acetylphenyl) -1-methylethyl) acetamide was 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) and sodium hydroxide (3.9 g) in a solution of methanol (250 ml) was added dropwise with 10% sodium hypochlorite (240 ml) at 50 to 70 ° C.
It was stirred for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, the resulting residue was poured into ice water, and subsequently 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)

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

Cis of 4- (1-acetamido-1-methylethyl) cyclohexanecarboxylic acid methyl ester
To a solution of the trans mixture (30.8 g) in methanol (150 ml) was added potassium tertiary butoxide (30.0 g).
Heated to reflux for hours. After the reaction, the residue obtained by concentration under reduced pressure was poured into ice water and neutralized with concentrated hydrochloric acid. Extracted with chloroform, washed with water, dried, concentrated under reduced pressure and recrystallized from precipitated crystals to give trans-4- (1-
Acetamide-1-methylethyl) cyclohexhesanecarboxylic acid methyl ester 24.5 g was 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 methylethyl) cyclohexanecarboxylic acid methyl ester in 100 ml of 4N potassium hydroxide was heated under reflux for 50 hours. After the reaction, under ice cooling, 11.6
2 ml of benzyloxycarbonyl chloride was added dropwise at the same temperature, followed by stirring at room temperature for 5 hours. After the reaction, add concentrated hydrochloric acid to the reaction solution under ice cooling,
Crystals precipitated upon acidification. The crystals are collected by filtration under reduced pressure and dried to give a trans-form having a melting point of 83 to 85 ° C.
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 trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxylic acid (6.2 g) in dichloromethane (65 ml) was added thionyl chloride (5.2 ml) and dimethylformamide (1 drop), and the mixture was heated under reflux for 1 hour. did. After the reaction, the solvent is distilled off under reduced pressure to obtain crystals of trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarbonyl chloride. Next, this crystal was dissolved in 50 ml of acetonitrile, and 4-amino-1H- under ice cooling.
After dropping 1 g of pyrrolo [2,3-b] pyridine and 5.4 ml of diisopropylethylamine into 50 ml of acetonitrile, the mixture was stirred at room temperature for 5 hours. After the reaction, water was added, the mixture was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to obtain crystals. 60 ml of dimethylformamide, 6 ml of methanol
Dissolve in 0 ml, and under ice cooling, sodium methoxide 281
mg was added, and the mixture was 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 concentrating, 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 = 3Hz), 7.35 (6H, s),
7.80 (1H, d, J = 6Hz), 8.06 (1H,
d, J = 6 Hz), 9.76 (1H, s)

Trans-N- (1H-pyrrolo [2,3-
b] Pyridin-4-yl) -4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide 1.6 g, 10% palladium hydroxide on carbon 2
A 50 ml solution of 50 mg and 4 ml of a 15% hydrochloric acid-methanol solution in 50 ml of methanol was stirred in an autoclave at a hydrogen initial 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-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 was obtained. PMR (DMSO-d ₆ /TMS)δ:0.80-2.
20 (10H, m), 1.21 (6H, s), 7.30
(1H, d, J = 3Hz), 7.59 (1H, d, J =
3 Hz), 8.07 (2H, brs), 8.22 (1
H, d, J = 6Hz), 8.30 (1H, d, J = 6H)
z), 10.91 (1H, s), 12.68 (1H, b
rs) Corresponding dihydrobromide trihydrate, mp 225-228
℃

Example 5 (a) 13.8 g of 1-benzyl-4-hydroxy-1H-pyrazolo [3,4-b] pyridine was added to 6 g of phosphorus oxychloride.
0 ml and 20 mg of phosphorus pentachloride 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 resulting residue is poured into ice water. Neutralize with 2N aqueous sodium hydroxide solution, collect the precipitated crystals by filtration, dry and recrystallize from ethyl acetate-hexane to give 1-benzyl-
4-chloro-1H-pyrazolo [3,4-b] pyridine 1
3.5 g was obtained. PMR (CDCl _{3 /} TMS) δ: 5.71 (2H,
s), 7.12 (1H, d, J = 5Hz), 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. The residue obtained by washing with water, drying, and 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 (1H, d, J = 5Hz), 7.31
(5H, s), 8.10 (1H, s), 8.46 (1
H, d, J = 5Hz)

4-azido-1-benzyl-1H-pyrazolo [3,4-b] pyridine 2.7 g, 10% palladium hydroxide on carbon 1.0 g, 15% hydrochloric acid-methanol 1 ml in a solution of 40 ml of methanol was placed in an autoclave. The mixture was stirred for 5 hours at 40 to 50 ° C. under an initial hydrogen pressure of 10 atm. After the reaction, the catalyst was filtered off and concentrated under reduced pressure. The precipitated crystals were recrystallized from methanol-ethyl acetate to give 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 = 5Hz), 8.13 (1H,
s)

(B) 4-amino-1H-pyrazolo [3,
4-b] pyridine dihydrochloride 270 mg, diisopropylethylamine 0.68 ml 1,3-dimethyl-2-
20 ml solution of imidazolidinone under ice cooling, trans-4
A solution of benzyloxycarboxamide methylcyclohexanecarbonyl 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 resulting residue, and the mixture was extracted with ethyl acetate. After washing with water, drying, and concentration under reduced pressure, the residue obtained is purified by silica gel column chromatography, and trans-N- (1H-pyrazolo [3,4-
b] Pyridin-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 = 5Hz), 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% of 25% hydrobromic acid acetic acid solution 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 melting points 261 to 262.
330 mg of trans-N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4-aminomethylcyclohexanecarboxamide dihydrobromide hemihydrate at 300C.
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 = 5Hz),
8.93 (1H, s), 11.31 (1H, brs)

Example 6 4-Amino-1H-pyrazolo [3,4-b] pyridine
Dihydrochloride 390 mg, diisopropylethylamine 1.
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. And 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, drying, and concentration under reduced pressure, the resulting residue is purified by silica gel column chromatography to obtain (+)-trans-N- (1H-pyrazolo [3,4-b] pyridine-
There was obtained 550 mg of 4-yl) -4- (1-benzyloxycarboxamidoethyl) cyclohexanecarboxamide. 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 = 5Hz), 8.35 (1H, d, J = 5H)
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, 15% hydrochloric acid-methanol solution 1 ml of methanol 1.
The 5 ml solution was stirred in an autoclave at a hydrogen initial pressure of 5 atm at room temperature for 1 hour. After the reaction, the catalyst was filtered off, and the crystals obtained by concentrating under reduced pressure were recrystallized from ethanol to give (+)-trans-N- (1H-
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 = 5Hz),
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
l-acetonitrile 100 ml solution under ice cooling, trans-4- (1-benzyloxycarboxamido-1-methylethyl) cyclohexanecarbonyl chloride 3.9
A 20 ml solution of acetonitrile containing g is added dropwise, and the mixture is 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, drying, and concentration under reduced pressure, the residue obtained 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), a solution of 10% palladium hydroxide on carbon (300 mg) in methanol (60 ml) was autoclaved under hydrogen initial pressure of 5 atm. The mixture was stirred at room temperature for 1 hour. After the reaction, the catalyst was filtered off and the crystals obtained by concentrating under reduced pressure were 1
5 ml of 5% hydrochloric acid-methanol solution is added. Then, the crystals obtained by concentrating again were recrystallized from methanol-ethyl acetate to give trans-N- with a melting point of 278 to 279 ° C.
(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 = 5Hz),
8.85 (1H, s), 11.09 (1H, brs)

Example 8 (a) 2-Amino-2-chloropyridine (2 g) was dissolved in dimethylformamide (20 ml), and sodium azide (1.31 g) and ammonium chloride (1.07 g) were added thereto.
The mixture was stirred at 10 ° C for 10 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 4-amino-2 having a melting point of 220 ° C. (decomposition).
-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, 8Hz), 8.78 (1H,
d, J = 8Hz)

(B) 0.41 g of 4-amino-2-azidopyridine was dissolved in 20 ml of dimethylformamide,
To this, add 1 ml of diisopropylethylamine, and add 40
Stir at 0 ° 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, and the mixture was added at 50 ° C. for 24 hours.
Stir 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 184-186 ° 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 = 8Hz), 10.55 (1
H, brs)

(C) Compound 200m obtained in (b)
50 m of methanol containing 0.5 g of 15% hydrochloric acid-methanol and 100 mg of 10% palladium hydroxide on carbon
The 1-solution was stirred in an autoclave at a hydrogen initial pressure of 10 atm for 5 hours at room temperature. 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 then (R)-at 225 ° C (decomposition).
(+)-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 4-amino-1H-pyrazolo [3,4-d] pyrimidine (700 mg), triethylamine (1.08 ml) and 1,3-dimethyl-2-imidazolidinone (20 ml) was cooled with ice. , 4-benzyloxycarboxamidomethylcyclohexanecarbonyl chloride 1.76 g in dichloromethane 5 ml solution was added dropwise,
Stir at room temperature for 5 hours. After the reaction, the reaction solution was poured into water and extracted with chloroform. The residue obtained by washing with saturated aqueous sodium hydrogen carbonate and water, drying and concentration was used for silica gel column chromatography (chloroform: methanol =
10: 1) to obtain trans-N- (1H-pyrazolo [3,4-d] pyrimidin-4-yl) -4-benzyloxycarboxamide methylcyclohexanecarboxamide (530 mg). 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) 530 mg of the compound obtained in Example 3 (a) was added to 10 m of a 25% hydrobromic acetic acid solution under ice cooling.
1 was added, 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 obtained crystal was 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-aminomethyl cyclohexane carboxamide dihydrobromide 1/4 hydrate 200 mg was obtained.

Example 10 To 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, under ice cooling, 1,3-Dimethyl-containing 2.4 g of (+)-trans-4- (1-methylbenzyloxycarboxamidomethyl) cyclohexanecarbonyl chloride
2-Imidazolidinone 20 ml solution was added dropwise, and the mixture was stirred at room temperature for 3 hours.
Stir for hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The residue obtained by washing with water, drying, and concentration is purified by silica gel column chromatography to obtain (+)
-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 = 6Hz),
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
A 30 ml solution of 1 of methanol 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 concentrating under reduced pressure were added 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- with a melting point of 210 to 213 ° C.
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
A solution of trans-4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarbonyl chloride (500 mg) in dichloromethane (5 ml) was added dropwise to the above solution under ice-cooling, 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 saturated aqueous sodium hydrogen carbonate solution and water, drying and concentration was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and trans-N- (1H-pyrazolo [3,3] was used. There was obtained 310 mg of 4-d] pyrimidin-4-yl) -4- (1-benzyloxycarboxamide-1-methylethyl) cyclohexanecarboxamide. 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 by (a)
5 ml of a 25% hydrobromide acetic acid solution was added to 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 obtained crystals were washed with ether and recrystallized from ethanol-ethyl acetate to give trans-melting point 260 ° C (decomposition).
N- (1H-pyrazolo [3,4-d] pyrimidine-4-
150 mg of yl) -4- (1-amino-1-methylethyl) cyclohexanecarboxamide dihydrobromide was obtained.

Others The compounds listed below can be synthesized according to any of the methods in the above Examples. (12) trans-N- (4-pyrimidinyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide tetrahydrate, melting point 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, melting point 195-197 ° C. (16) trans-N- (1-benzyl-1H-pyrazolo [3,3. 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, melting point 26
1 to 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, melting point 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 3/2 hydrate, mp 269-270 ° C (30) trans-N- (2- ( 1-pyrrolidinyl) -4
-Pyridyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide 3/1 hydrate, mp 149-1
51 ° C. (31) trans-N- (2,6-diamino-4-pyrimidyl) -4-aminomethylcyclohexanecarboxamide dihydrobromide, melting point 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 to 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-azide- 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 =
6Hz), 7.56 (1H, d, J = 6Hz), 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-aminomethylcyclohexanecarboxamide 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 (1 H, 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-tertiary butylcarbonyloxymethylpyrrolo [2,3-b] pyridin-4-yl)
-4-Aminomethylcyclohexanecarboxamide

(72) (+)-trans-N- (1-third
Butyl carbonyloxymethylpyrrolo [2,3-b]
Pyridin-4-yl) -4- (1-aminoethyl) cyclohexanecarboxamide (73) trans-N- (1-tertiary 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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location C07D 471/04 104 Z 8829-4C 105 A 8829-4C 106 C 8829-4C 108 A 8829-4C 111 8829-4C 112 Z 8829-4C A 8829-4C 113 8829-4C 114 A 8829-4C 116 8829-4C 117 N 8829-4C Z 8829-4C 118 Z 8829-4C 119 8829-4C 471/14 101 8829-4C 102 8829-4C (72) Inventor Hiroyuki Sato 3-7-25 Oyata, Iruma-shi, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory (72) Inventor Masayoshi Uehata 3-7-25 Oyada, Iruma-shi, Saitama Yoshitomi Pharmaceutical Tokyo Research Institute Co., Ltd.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ and R ² are the same or different and are hydrogen, alkyl or cycloalkyl which may have a substituent on the ring, cycloalkylalkyl, phenyl, aralkyl,
Indicates piperidyl or pyrrolidinyl, R ¹ , R ²
Together represent alkylidene or phenylalkylidene, or contain a nitrogen atom to which R ¹ and R ² are bonded together with an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. And R ³ and R ⁴ represent hydrogen or alkyl, A represents a single bond or alkylene, X represents ═C (R ⁷ ) — or ═N—, and R ⁵ , 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) (wherein Ra and Rb are the same or different and are hydrogen, halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, -NRcRd (wherein Rc and Rd are the same or different. Differently hydrogen, alkyl,- COR ⁹ , -COOR
_{^{9 ', -SO 2 R 9'}} ( wherein, R ⁹ represents hydrogen, alkyl, phenyl, aralkyl, R ⁹ 'is alkyl,
Indicates phenyl and aralkyl. ) Or Rc and Rd
Represents a group forming a heterocycle 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, optionally substituted hydrazino, -CO
OR ¹⁰ , -CONR ¹¹ R ¹² (wherein R ^10-12 is hydrogen,
It represents alkyl, phenyl or aralkyl. ) Or
Ra and Rb together form a nitrogen atom, a sulfur atom,
A group forming a 5- to 6-membered optionally hydrogenated aromatic ring which may contain at least one oxygen atom is shown. However, when the formula (b) or (d) is shown, Ra,
Rb represents a group which, together with each other, 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. ), 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 ′ (wherein R ⁹ represents hydrogen, alkyl, phenyl and aralkyl, and R ⁹ ′ represents alkyl, phenyl and aralkyl), or Re and Rf are bonded to each other. Oxygen atom in the ring with the nitrogen atom,
It represents a group forming a heterocycle which may contain a sulfur atom or a nitrogen atom which may have a substituent. ), Cyano, azido, optionally substituted hydrazino, −
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 is
a, Rb, R ⁷ or R ⁸ is any one of —NRcRd,
-NReRf, azide, which may have a substituent hydrazino, -COOR ^10, or shows a -CONR ¹¹ R ^12, R
a and Rb represent together a group forming 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. . ] The 4-amino (alkyl) cyclohexane- 1-carboxylic acid amide compound represented by these, its isomer, and its pharmaceutically acceptable acid addition salt.