JP2961891B2 - Benzamide compounds and their pharmaceutical uses - Google Patents

Description

The present invention relates to novel and pharmaceutically useful benzamide compounds, isomers thereof and pharmaceutically acceptable acid addition salts thereof, and pharmaceutical uses thereof.

"Background of the Invention" Abnormal smooth muscle contractility is considered to be one of the causes of hypertension and coronary and cerebral circulation disorders (angina pectoris, cerebral infarction, etc.), which have become major social problems as adult diseases. . The contraction-relaxation of smooth muscle is regulated mainly by the increase or decrease of intracellular calcium.As a result, calcium influxed into smooth muscle cells binds to calmodulin and activates myosin light chain phosphatase. It is phosphorylated, and it is said to contract smooth muscle (myosin phosphorylation theory). For this reason, many calcium antagonists that reduce intracellular calcium and dilate blood vessels have been developed and widely used for treating hypertension, angina, and the like.

However, in recent years, sustained contraction, a characteristic of smooth muscle such as blood vessels and trachea, cannot be explained by the myosin phosphorylation theory alone, suggesting the involvement of a contraction mechanism that is independent of intracellular calcium concentration and a mechanism that enhances calcium sensitivity. Have been. This is supported by the presence of ineffective smooth muscle contractions and diseases (such as cerebral vasospasm and asthma) for which calcium antagonists are ineffective. Drugs that reduce intracellular calcium alone are not enough to treat diseases with smooth muscle contractions Therefore, development of a new smooth muscle relaxant is desired.

By the way, as benzamide compounds, JP-A-62-158252 and JP-A-62-158253 have been used as cardiotonic agents, J. Med. Chem., 14, 963 (1971) as an antiulcer agent, and intestinal peristalsis inhibitor In Spanish Patent No. 456,989, etc., but there is no report on smooth muscle relaxing action.

On the other hand, in WO93 / 05021, a 4-amino (alkyl) cyclohexane-1-carboxylic acid amide compound is
It is disclosed that it is a powerful and persistent antihypertensive agent, and is useful as a prophylactic / therapeutic agent for diseases of the circulatory system such as coronary / brain / renal and peripheral arteries, and a therapeutic agent for asthma.

An object of the present invention is to have a strong smooth muscle relaxing action, as well as having a hypotensive action and a cerebral / coronary vasodilatory action similar to conventional calcium antagonists, and also have a continuous renal and peripheral circulation improving action, An object of the present invention is to provide an orally administrable compound which also suppresses vasoconstriction caused by various agonists unlike calcium antagonists.

DISCLOSURE OF THE INVENTION As a result of intensive studies, the present inventors have found that the benzamide compound of the present invention, its isomer and its pharmaceutically acceptable acid addition salt can achieve the above object, and completed the present invention. I came to.

Furthermore, it was found that the compound of the present invention exhibited an experimental asthma-suppressing effect on guinea pigs by histamine inhalation, a contraction-inhibiting effect by acetylcholine in a guinea pig isolated trachea specimen, and also had an anti-asthmatic effect.

The present invention has the general formula [Wherein, R represents hydrogen, alkyl or cycloalkyl optionally having a substituent on the ring, cycloalkylalkyl, phenyl or aralkyl, or Wherein R ⁶ is hydrogen, alkyl or a formula: —NR ⁸ R ⁹ (where R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, aralkyl or phenyl), and R ⁷ is hydrogen , Alkyl, aralkyl, phenyl, nitro or cyano, or R ⁶ and R ⁷ are combined to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. And a group forming a good heterocyclic ring.).

R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to form an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom. .

R ² and R ³ are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, Represents carbamoyl, alkylcarbamoyl or azide.

R ⁴ represents hydrogen or alkyl.

R ⁵ is pyridine, pyrimidine, pyridazine, triazine, pyrazole, triazole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine,
Pyrazolopyrimidine, imidazopyrimidine, pyrrolotriazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, cinnoline, quinazoline, quinoline, pyridopyridazine, pyridopyrazine, pyridopyrimidine, pyrimidopyrimidine, pyrazinopyrimidine, naphthyridine, tetrazolo Pyrimidine, thienopyridine, thienopyrimidine, thiazolopyridin, thiazolopyrimidine, oxazolopyridin, oxazolopyrimidine, furopyridine, furopyrimidine, 2,3-dihydropyrrolopyridine, 2,3-dihydropyrrolopyrimidine, 5,6,7, 8-tetrahydropyrido (2,3-d) pyrimidine, 5,6,7,8-tetrahydro-1,8-naphthyridine and a nitrogen-containing heterocyclic ring selected from the group consisting of 5,6,7,8-tetrahydroquinoline Wherein the nitrogen-containing heterocycle is hydrogenated To form an aromatic ring that may be at a carbon atom in the ring carbonyl and nitrogen-containing heterocyclic ring may have a substituent.

A is the formula (Wherein R ¹⁰ and R ¹¹ are the same or different and are hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl,
Indicates carboxy or alkoxycarbonyl. Alternatively, R ¹⁰ and R ¹¹ represent a group which forms a cycloalkyl by bonding. l, m, and n each represent 0 or an integer of 1 to 3. ). And a pharmaceutically acceptable acid addition salt thereof.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable excipient; ), A drug for treating hypertension, a drug for treating angina, a drug for treating asthma, a drug for treating renal and peripheral circulatory disorders, or a drug for suppressing cerebral vasospasm containing the compound, isomer or pharmaceutically acceptable acid addition salt thereof. provide.

 The definition of each symbol in this specification is as follows.

The alkyl in R and R ¹ is a linear or branched alkyl having 1 to 6 carbon atoms, and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl. , Pentyl, hexyl and the like, and alkyl having 1 to 4 carbon atoms is preferable.

Shows R, cyclopropyl and cycloalkyl of R ^1, cyclobutyl, cyclopentyl, cyclohexyl, a number 3-7 cycloalkyl carbon such cycloheptyl.

The cycloalkylalkyl in R and R ¹ is a cycloalkyl moiety having 3 to 7 carbon atoms,
The alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl,
Butyl, pentyl, hexyl, etc.) which is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl,
Cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylhexyl, cyclopentylhexyl, cyclohexylhexyl, cyclo Heptylhexyl and the like.

The aralkyl in R and R ¹ has an alkyl moiety having 1 to 4 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl. Indicates phenylalkyl.

The substituents of cycloalkyl, cycloalkylalkyl, phenyl, and aralkyl which may have a substituent on the ring of R and R ¹ are halogen (chlorine, bromine, fluorine, iodine), alkyl (R, R ¹ ), Alkoxy (linear or branched alkoxy having 1 to 6 carbon atoms, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary) Butoxy, pentyloxy, hexyloxy, etc.) aralkyl (same as aralkyl in R and R ¹ ), haloalkyl (alkyl in which R ¹ and R ¹ are substituted with 1 to 5 halogen atoms, and fluoromethyl , Difluoromethyl, trifluoromethyl,
It indicates 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like. ), Nitro, amino, cyano,
Azide and the like.

R and R ¹ are combined with an adjacent nitrogen atom to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent, in the ring; 6 to 6-membered rings and these bonding rings are preferred, and specifically, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, 1-imidazolyl,
Examples thereof include 2,3-dihydrothiazol-3-yl and the like.
Examples of the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, haloalkyl and the like. Wherein the alkyl, aralkyl, haloalkyl has the same meaning as indicated R, in R ^1.

The halogen, alkyl, alkoxy and aralkyl in R ² and R ^{3 have} the same meanings as those described for R and R ¹ .

Acyl in R ² and R ³ is alkanoyl having 2 to 6 carbon atoms (acetyl, propionyl, butyryl, valeryl,
Pivaloyl), benzoyl, or phenylalkanoyl having an alkanoyl moiety of 2 to 4 carbon atoms (phenylacetyl, phenylpropionyl, phenylbutyryl, etc.).

The alkylamino in R ² and R ³ is an alkylamino having a linear or branched alkyl having 1 to 6 carbon atoms in the alkyl moiety, and is methylamino, ethylamino, propylamino, or isopropylamino. Butylamino, isobutylamino, secondary butylamino, tertiary butylamino, pentylamino, hexylamino and the like.

Acylamino in R ² and R ³ is alkanoyl having 2 to 6 carbons as acyl, acylamino having an alkanoyl moiety having a phenylalkanoyl having 2 to 4 carbons, such as acetylamino, propionylamino, Butylylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetylamino, phenylpropionylamino, phenylbutyrylamino and the like.

The alkylthio in R ² and R ³ is an alkylthio having a linear or branched alkyl having 1 to 6 carbon atoms in the alkyl portion, and is methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio. , Secondary butylthio, tertiary butylthio, pentylthio, hexylthio and the like.

The aralkyloxy represented by R ² and R ³ has aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion thereof, and includes benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, And phenylpropyloxy, 4-phenylbutyloxy and the like.

The aralkylthio in R ² and R ³ has an aralkyl having an alkyl having 1 to 4 carbon atoms in the alkyl portion, and includes benzylthio, 1-phenylethylthio, 2-phenylethylthio, and 3-phenylpropyl And luthio, 4-phenylbutylthio and the like.

The alkoxycarbonyl in R ² and R ³ has a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms in the alkoxy moiety, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl. , Butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The alkylcarbamoyl in R ² and R ³ is a group having 1 carbon atom.
Carbamoyl mono- or di-substituted with 4 alkyl, such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, butylcarbamoyl, dibutylcarbamoyl and the like.

The alkyl in R ⁴ has the same meaning as the alkyl in R and R ¹ .

The nitrogen-containing heterocyclic ring represented by R ⁵ represents, in the case of a single ring, pyridine, pyrimidine, pyridazine, triazine, pyrazole or triazole, and in the case of a condensed ring, pyrrolopyridine (1H-pyrrolo [2,3-b] pyridine, 1H -Pyrrolo [3, 4
-B] pyridine, 1H-pyrrolo [3,4-b] pyridine, etc., pyrazolopyridine (1H-pyrazolo [3,4-b] pyridine, 1H-pyrazolo [4,3-b] pyridine, etc.), imidazo Pyridine (1H-imidazo [4,5-b] pyridine and the like), pyrrolopyrimidine (1H-pyrrolo [2,3-d] pyrimidine, 1H-pyrrolo [3,2-d] pyrimidine, 1H-pyrrolo [3,4 -D] pyrimidine), pyrazolopyrimidine (1H-pyrazolo [3,4-d] pyrimidine, pyrazolo [1,5
-A] pyrimidine, 1H-pyrazolo [4,3-d] pyrimidine, etc.), imidazopyrimidine (imidazo [1,2-a]
Pyrimidine, 1H-imidazo [4,5-d] pyrimidine, etc.), pyrrolotriazine (pyrrolo [1,2-a] -1,3,5-
Triazine, pyrrolo [2,1-f] -1,2,4-triazine), pyrazolotriazine (pyrazolo [1,5-a] -1,
3,5-triazine, etc.), triazolopyridine (1H-1,
2,3-triazolo [4,5-b] pyridine, etc.), triazolopyrimidine (1,2,4-triazolo [1,5-a] pyrimidine, 1,2,4-triazolo [4,3-a] Pyrimidine, 1H-1,
2,3-triazolo [4,5-d] pyrimidine, etc.), cinnoline, quinazoline, quinoline, pyridopyridazine (pyrid [2,3-c] pyridazine etc.), pyridopyrazine (pyrid [2,3-b] pyrazine etc.) ), Pyridopyrimidine (pyrid [2,3-d] pyrimidine, pyrido [3,2-d] pyrimidine, etc.), pyrimidopyrimidine (pyrimido [4,5
-D] pyrimidine, pyrimide [5,4-d] pyrimidine, etc.), pyrazinopyrimidine (pyrazino [2,3-d] pyrimidine, etc.), naphthyridine (1,8-naphthyridine, etc.), tetrazolopyrimidine (tetrazolo [1 , 5-a]
Thienopyridines such as pyrimidine (thieno [2,3-b]
Pyridine, etc.), thienopyrimidine (thieno [2,3-
d] pyrimidine), 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), furopyridine (furo [2,3-b] pyridine, furo [3,2-b] pyridine etc.), furopyrimidine (furo [2,3-d] pyrimidine,
Furo [3,2-d] pyrimidine and the like, 2,3-dihydropyrrolopyridine (2,3-dihydro-1H-pyrrolo [2,3-b] pyridine, 2,3-dihydro-1H-pyrrolo [3, 2-b] pyridine, etc.), 2,3-dihydropyrrolopyrimidine (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, the carbon atom in the ring may be carbonyl. For example, 2,3-dihydro-2-oxopyrrolopyridine, 2,3-dihydro-2,3-dioxopyrrolopyridine, 7,8-dihydro-7-oxo-1,8-naphthyridine, 5,6,7 , 8-Tetrahydro-7-oxo-1,8-
Naphthyridine and the like are also included.

Also, these rings are halogen, alkyl, alkoxy, aralkyl, haloalkyl, nitro, amino, alkylamino, cyano, formyl, acyl, aminoalkyl, mono- or dialkylaminoalkyl, azido, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, It may be substituted by a substituent such as hydrazino which may have a substituent.

Examples of the substituent of the hydrazino which may have a substituent, an alkyl, aralkyl, nitro, and and cyano, alkyl, aralkyl R, has the same meaning alkyl, and aralkyl in R ^1, for example, Methylhydrazino, ethylhydrazino, benzylhydrazino and the like are exemplified.

The alkyl in R ⁶ has the same meaning as the alkyl in R and R ¹ . Further, the alkyl in R ⁸ , R ⁹ , R ^8a , R ^9a , R ^8b , R ^9b is the same as the alkyl in R and R ¹ , and R ⁸ , R ⁹ , R ^9
8a, aralkyl in R ^9a is as defined aralkyl R, in R ^1.

The alkyl in R ⁷ , R ^7a and R ^7b has the same meaning as the alkyl in R and R ¹ , and the aralkyl in R ⁷ and R ^7a has the same meaning as the aralkyl in R and R ¹ .

R ⁶ and R ⁷ , R ^6a and R ^7a , R ^6b and R ^7b or R ^6c and R ^7c are combined and further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring The group which forms a heterocyclic ring which may be used is imidazol-2-yl, thiazole-
2-yl, oxazol-2-yl, imidazoline-2
-Yl, 3,4,5,6-tetrahydropyridin-2-yl,
3,4,5,6-tetrahydropyrimidin-2-yl, 1,3-oxazolin-2-yl, 1,3-thiazolin-2-yl or halogen, alkyl, alkoxy, haloalkyl,
Benzoimidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl and the like which may have a substituent such as nitro, amino, phenyl and aralkyl are exemplified. Here, halogen, alkyl, alkoxy, haloalkyl, aralkyl has the same meaning as indicated R, in R ^1.

Examples of the substituent on the nitrogen atom which may have a substituent include alkyl, aralkyl, haloalkyl and the like. Wherein the alkyl, aralkyl, and haloalkyl the same meaning as in R, in R ^1.

Hydroxyalkyl in R ¹⁰ , R ¹¹ , R ^10a , R ^11a , R ^10b , and R ^11b is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms substituted with 1 to 3 hydroxy groups. For example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl and the like. R ¹⁰ , R ¹¹ , R
^10a , R ^11a , R ^10b , alkyl in R ^11b is the same as the alkyl in R, R ¹ , R ¹⁰ , R ¹¹ , R ^10a , haloalkyl in R ^11a , alkoxycarbonyl is the same as those shown in R, R ¹ It is synonymous, and aralkyl in R ¹⁰ and R ¹¹ is synonymous with aralkyl in R and R ¹ . R ¹⁰ and R ¹¹ , R
^{Cycloalkyl 10a} and R ^11a or R ^10b and R ^11b is formed by bonding is also synonymous with cycloalkyl R, in R ^1.

The present invention also includes pharmaceutically acceptable acid addition salts, hydrates or various solvates formed with the inorganic acid or organic acid of compound (I). In addition, when having a carboxyl group, sodium salt, potassium salt, calcium salt,
Metal salts such as aluminum salts and salts with amino acids such as lysine and ornithine are also included.

In the present invention, when an asymmetric carbon is present, optical isomers and racemic forms thereof may exist, and the present invention includes all of them.

(1) In the present invention, R, R ¹ , R ² , R ³ ,
It is preferable that at least one selected from R ⁴ , R ⁵ and A satisfies the following definition.

R represents hydrogen, alkyl or aralkyl which may have a substituent on the ring, or (Wherein R ^6a is hydrogen or a formula: —NR ^8a R ^9a (where R ^8a ,
R ^9a is the same or different and represents hydrogen, alkyl or aralkyl. ) And R ^7a represents hydrogen, alkyl, aralkyl or phenyl. Alternatively, R ^6a and R ^7a are combined to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring.

Represents a group represented by

R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring.

Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to form an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom. .

R ² and R ³ are the same or different and represent hydrogen, alkyl, halogen, nitro, amino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, carboxy, alkoxycarbonyl, carbamoyl or azide.

R ⁴ represents hydrogen or alkyl.

R ⁵ is pyridine, pyrimidine, pyridazine, triazine, pyrazole, triazole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine,
Pyrazolopyrimidine, imidazopyrimidine, pyrrolotriazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, cinnoline, quinazoline, quinoline, pyridopyridazine, pyridopyrazine, pyridopyrimidine, pyrimidopyrimidine, pyrazinopyrimidine, naphthyridine, tetrazolo Pyrimidine, thienopyridine, thienopyrimidine, thiazolopyridin, thiazolopyrimidine, oxazolopyridin, oxazolopyrimidine, furopyridine, furopyrimidine, 2,3-dihydropyrrolopyridine, 2,3-dihydropyrrolopyrimidine, 5,6,7, 8-tetrahydropyrido (2,3-d) pyrimidine, 5,6,7,8-tetrahydro-1,8-naphthyridine and a nitrogen-containing heterocyclic ring selected from the group consisting of 5,6,7,8-tetrahydroquinoline Wherein the nitrogen-containing heterocycle is hydrogenated To form an aromatic ring that may be at a carbon atom in the ring carbonyl and nitrogen-containing heterocyclic ring may have a substituent.

A is the formula (Wherein, R ^10a and R ^11a are the same or different and represent hydrogen, alkyl, haloalkyl, hydroxyalkyl, carboxy or alkoxycarbonyl; or R ^10a and R ^11a
Represents a group which forms a cycloalkyl by bonding. l, m, n
Represents an integer of 0 or 1 to 3, respectively. ).

(2) The present invention provides a compound represented by the formula (I) wherein R, R ¹ , R ² , R ³ ,
It is particularly preferred that at least one selected from R ⁴ , R ⁵ and A satisfies the following definition.

R represents hydrogen or alkyl; (Wherein R ^6b is hydrogen or a formula: —NR ^8b R ^9b (where R ^8b ,
R ^9b is the same or different and represents hydrogen or alkyl. ) And R ^7b represents hydrogen or alkyl. Alternatively, R ^6b and R ^7b are bonded to form a group which forms a heterocyclic ring which may further have a nitrogen atom which may have a substituent in the ring. ) Represents a group represented by

R ¹ represents hydrogen or alkyl.

Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to further include a nitrogen atom which may have a substituent in the ring.

R ² and R ³ are the same or different and represent hydrogen, halogen, nitro, hydroxy, aralkyloxy, cyano, carboxy, alkoxycarbonyl, carbamoyl or azide.

R ⁴ represents hydrogen.

R ⁵ may have a substituent, pyridine, 1H-pyrrolo [2,3-b] -pyridine or 1H-pyrazolo [3,4-b]
Shows a group derived from pyridine.

A is the formula (Wherein R ^10b and R ^11b are the same or different and represent hydrogen, alkyl, hydroxyalkyl or carboxy. Alternatively, R ^10b and R ^11b represent a group which forms a cycloalkyl by bonding. Represents an integer of 0 or 1 to 3, and m
¹ represents 0 or 1. ).

(3) The formula (I), the group represented by -NRR ^1, amino, guanidino or 3-propyl guanidino is, the same or different and hydrogen as R ^2, R ^3,
Halogen, nitro, cyano or azide, R ⁴ is hydrogen, and R ⁵ is optionally substituted 4-pyridyl, 1H-pyrrolo [2,3-b] pyridin-4-yl or 1H -Pyrazolo [3,4-b] pyridin-4-yl is A
_{The, -CH 2 -, - CH (} CH 3) -, - C (CH 3) 2 -
Or —CH (CH ₂ OH) — is each a preferred group.

A is preferably located at the 4-position of benzamide.

Further, in the general formula (I), A is a group represented by the formula —CH (CH ₃ )
When the compound has an asymmetric carbon atom such as-, a compound having an absolute configuration of R exhibits preferable activity.

Desirable compounds among the compounds represented by the general formula (I) include (R) -N- (4-pyridyl) -4- (1-aminoethyl) benzamide and (R) -N- (4-pyridyl) -4- (1-aminoethyl) -3-nitrobenzamide, (R) -N- (4-pyridyl) -4- (1-aminoethyl) -3-chlorobenzamide, (R) -N- (4- (Pyridyl) -4- (1-aminoethyl) -2-nitrobenzamide, (R) -N- (4-pyridyl) -4- (1-aminoethyl) -2-chlorobenzamide, (R) -N- ( 1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-aminoethyl) benzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-aminoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-aminoethyl) -3-azidobenzamide, (R) -N- (3-iodo-1H-pyrrolo [2,3-b]
Pyridin-4-yl) -4- (1-aminoethyl) -3
-Azidobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) benzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -2-nitrobendazamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -3-azidobenzamide, (R) -N- (4-pyridyl) -4- (1-guanidinoethyl) benzamide, N- (1H-pyrazolo [3, 4-b] pyridin-4-yl) -4-guanidinomethylbenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-guanidinoethyl) benzamide, N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4-guanidinomethyl-3-humanrobenzamide, (R) -N -(1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-guanidinoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-guanidinoethyl) -2-nitrobenzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4
-(1-guanidinoethyl) benzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1- (3-propylguanidino) ethyl) benzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -3-cyanobenzamide, N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-amino-2-hydroxyethyl ) Benzamide, and (R) -N- (3-iodo-1H-pyrrolo [2,3-b]
And a compound selected from pyridin-4-yl) -4- (1-aminoethyl) benzamide.

The compounds included in the present invention are as shown in the following table. In the table, Me is methyl, Et is ethyl, nPr is n-propyl, isoPr is isopropyl, nBu is n-butyl, isoBu is isobutyl, Pen is pentyl, Hex is hexyl, Ac is acetyl, Ph is phenyl, and Bn is benzyl. , Phenetyl means 2-phenylethyl.

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

Method 1 General formula (Wherein, R, R ¹ , R ² , R ³ and A have the same meanings as described above) or a reactive derivative thereof represented by the following general formula: (Wherein, R ⁴ and R ⁵ have the same meanings as described above).

Reactive derivatives of carboxylic acid compounds include acid halides such as acid chlorides, acid anhydrides, mixed acid anhydrides formed from ethyl chloroformate and the like, esters such as methyl esters and ethyl esters, and carbodiimides such as dicyclohexylcarbodiimide. And a reactive derivative produced from the same.

The reaction is carried out in the presence of a solvent inert to the reaction, but usually contains a hydroxyl group such as tetrahydrofuran, ethyl acetate, benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, dimethylformamide, dimethylimidazolidinone. No organic solvent is used.
The reaction is carried out at an arbitrary temperature, for example, -10 to 200 ° C, preferably 0 to 80 ° C. In the case of a reactive derivative (for example, an ester) which is not very reactive, a high reaction temperature is used, In the case of highly reactive derivatives (eg mixed acid anhydrides), lower reaction temperatures are used. Further, if necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine or the like is used as a deoxidizing agent. In addition, if necessary, the general formula (IV)
Can be reacted by protecting the amino group with an amino protecting group such as benzyloxycarbonyl and tertiary butoxycarbonyl. The protecting group may be removed by a conventional method after the reaction.

The carboxylic acid compound of the general formula (IV), which is a synthesis raw material of the present invention, can be obtained from a commercially available raw material by a known method, or
It can be easily synthesized by the method described in WO93 / 05021.

The amine compound of the general formula (V), which is another synthetic raw material, can be synthesized by the method described in WO93 / 05021.

In particular, in general formula (IV), R is (Wherein, R ⁶ and R ⁷ have the same meanings as described above.) Can be easily synthesized by the following synthesis method.

That is, the general formula (Wherein R ¹ , R ² , R ³ and A have the same meanings as described above), and a compound represented by the general formula: (Wherein, R ⁶ and R ⁷ have the same meanings as described above. When R ⁶ is an amino group, it may be protected with tertiary butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, etc., and W is oxygen, A heterocyclic ring such as sulfur or pyrazole, and V represents lower alkyl such as hydrogen, methyl, ethyl, propyl, benzyl, p-nitrobenzyl, etc.) or an acid addition salt thereof. Synthesized.

Compounds represented by the general formula (VII) include S-methylisothiourea, O-methylisourea, S-ethylisothiourea, O-ethylisourea, N, N'-S-trimethylisothiourea, N, N'-O-trimethyl Isourea, N, S-dimethylisothiourea, N, O-dimethylisourea, N-ethyl-S-methylisothiourea, N-ethyl-O-methylisourea, 2-methylthio-2-benzimidazole,
2-methylthio-2-benzothiazole, 2-methylthio-2-benzoxazole, 2-methylthio-2-imidazoline, 2-methoxy-2-imidazoline, 2-methylthio-3,4,5,6-tetrahydropyrimidine, -Methylthiothiazoline, N, N'-dibenzyloxycarbonyl-S-methylisothiourea, N, N'-diacetyl-
S-methylisothiourea, ethylformimidate, methylformimidate, methylacetoimidate, ethylacetoimidate, ethyl (N-methyl) formimidate, methyl N-methylformamidate, pyrazole-1-carboxamidine, 35 -Dimethylpyrazole-
1-carboxamidine and the like, and the acid addition salts thereof include hydroiodide, hydrobromide, hydrochloride, sulfate, p-toluenesulfonate and the like.

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

Method 2 In the compound (I), one of R and R ¹ is hydrogen and the other is hydrogen or a compound other than formula (II).
A general formula wherein R and R ¹ obtained by the formula are hydrogen Wherein R ² , R ³ , R ⁴ , R ⁵ and A have the same meanings as described above, and a halide compound, an aldehyde compound or a ketone compound. Can be.

The halide compound used in this reaction is represented by the formula R ¹² -Hal (IX) (wherein R ¹² is alkyl having 1 to 6 carbons or 3 to 6 carbons which may have a substituent on a ring) Hal is a halogen, and preferably represents chlorine or bromine, wherein 7 cycloalkyl, cycloalkylalkyl, phenyl, and aralkyl are represented by the following formula:
A compound represented by the formula R ¹³ CHO (X) wherein R ¹³ represents hydrogen, alkyl having 1 to 5 carbon atoms, or phenyl or aralkyl which may have a substituent on a ring. And the ketone compound is represented by the formula (Wherein, R ¹⁴ and R ¹⁵ are the same or different and each represent alkyl having 1 to 5 carbon atoms, or phenyl or aralkyl which may have a substituent on the ring, or R ¹⁴ and R ¹⁵ are 3 to 5 carbon atoms which may be substituted with a carbonyl group
Shows 7 cycloalkyls. ).

When reacting compound (VIII) with a halide compound,
The reaction can be carried out under the same conditions as in Method 1, but it is preferable to carry out the deacidification condensation reaction in the presence of a base such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine and the like.

When reacting the compound (VIII) with an aldehyde or ketone, the dehydration condensation reaction is usually carried out under reflux with heating together with a solvent which is hardly miscible with water, for example, benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane and the like. Do. At this time, it is also advantageous to add a small amount of an acid such as paratoluenesulfonic acid.

The alkylidene and phenylalkylidene compounds obtained by the above condensation reaction can be converted to alkyl and aralkyl compounds by subjecting them to a reduction reaction.

The reduction reaction is usually carried out in an alcohol such as methanol, ethanol, or isopropyl alcohol in the range of -10 to 100.
C., preferably at 0-40C. In addition, 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, further, does not affect other groups of the target compound In case, Raney nickel, palladium carbon,
It can also be produced by performing a reductive amination reaction using a catalytic reduction method using platinum oxide or the like.

Method 3 In the compound (I), a heterocyclic ring which may contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with the nitrogen atom to which R and R ¹ are bonded ( For example, compounds that are groups that form pyrrolidinyl, piperidyl, piperazinyl, morpholino, thiomorpholino, etc.)
General formula Or [In formulas (XII) and (XIII), R ^16-23 are the same or different and are hydrogen, halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, aralkyl, haloalkyl, nitro, amino, Cyano, hydrazino which may have a substituent, Y is a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent, Z is a halogen (eg, chlorine, bromine), Shows alcohol-reactive derivatives such as sulfonylioxy (methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) However, the substituent of the formed heterocycle is 1 to 3. And the compound (VIII).

 The reaction can be performed under the same conditions as in Method 2.

Method 4 In the present invention, R of the general formula (I) is (Wherein R ⁶ and R ⁷ have the same meanings as described above). Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A have the same meanings as described above (synthesized by the method described in WO 93/05021), and It can also be synthesized by subjecting a compound of the formula (VIII) to a condensation reaction. The reaction can be carried out under the same conditions as in the reaction of compounds (IV) and (VII) in Method 1.

Further, R in the general formula (I) is (Wherein, R ⁷ , R ⁸ and R ⁹ have the same meanings as described above) can be synthesized by the following method 5 or 6.

Method 5 A compound of the general formula (XIV) and an iso (thio) represented by the general formula R ⁷ NC = X (XV) wherein R ⁷ is as defined above and X is S, O. When reacted with a cyanate compound, the general formula (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , A and X are as defined above).

Examples of the isocyanate or isothiocyanate compound represented by the general formula (XV) shown here include methyl isocyanate, methyl isothiocyanate, ethyl isocyanate, ethyl isothiocyanate, phenyl isocyanate, and phenyl isothiocyanate. ,
In particular, when R ¹ is hydrogen, sodium isocyanate, sodium isothiocyanate, ammonium thiocyanate and the like are used.

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

Then, a (thio) ureido compound represented by the formula (XVI) and a general formula R ²⁴ -X ¹ (XVII) wherein R ²⁴ represents alkyl or aralkyl, and X ¹ represents a halogen (such as chlorine, bromine, or iodine) Or sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.). With an appropriate alkylating agent represented by the general formula (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ²⁴ , A and X have the same meanings as described above).

Suitable alkylating agents of the general formula (XVII) include methyl iodide, ethyl iodide, benzyl bromide, p-nitrobenzyl bromide, dimethyl sulfate, diethyl sulfate and the like.

In the reaction between the compound of the general formula (XVI) and the compound of the general formula (XVII), a solvent such as acetone, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, and dimethylimidazolidinone is used. Reaction temperature is 0
~ 150 ° C, especially room temperature to 100 ° C, is preferred. In some cases, a base such as sodium hydride, potassium carbonate, or sodium methoxide can be used.

Then, R of the general formula (I) is reacted with the amine derivative represented by HNR ⁸ R ⁹ (R ⁸ and R ⁹ have the same meanings as described above) to obtain R in the general formula (XVIII). (Wherein, R ⁷ , R ⁸ and R ⁹ are as defined above) can be synthesized.

Examples of the amine derivative represented by HNR ⁸ R ⁹ include ammonia, methylamine, ethylamine, propylamine, aniline, benzylamine, phenethylamine, N-methyl-N-benzylamine, and the like.

The reaction of compound (XVIII) with HNR ⁸ R ⁹ uses no solvent or an alcoholic solvent such as methanol or ethanol, or a polar solvent such as tetrahydrofuran, acetonitrile, or dimethylformamide. Compound (XVII
In contrast to I), the amine derivative of compound HNR ⁸ R ⁹ is preferably used in an amount of 0.5 to 1.5 equivalents.
5 to 10 equivalents may be used. The reaction temperature is -20 to 150C, preferably 0 to 100C. This reaction can be promoted by adding 0.01 to 10 equivalents, preferably 0.1 to 3 equivalents of a base or a metal salt. As such a base, an inorganic base such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate, or an organic base such as pyridine, triethylamine or 4-dimethylaminopyridine is used, and the organic base itself can be used as a solvent. Also,
As the metal salt, copper chloride, copper bromide, copper acetate, copper sulfate, mercury acetate and the like are used.

Further, by directly reacting the compound (XVI) with the compound (XIX) according to the reaction between the compound (XV) and (XVI), the desired R of the general formula (I) can be obtained. (Wherein, R ⁷ , R ⁸ and R ⁹ have the same meanings as described above).

Method 6 A compound of the general formula (XIV) is reacted with a cyanide compound represented by the general formula X ² —CN (XIX), wherein X ² represents a halogen such as chlorine, bromine, etc. formula ^{(Wherein, R 1, R 2, R} 3, R 4, R 5 and A has the same meaning as defined above) cyanamide compound represented by the general formula by reacting with an amine derivative of HNR ⁸ R ⁹ ( R of I) (Wherein, R ⁷ , R ⁸ and R ⁹ are as defined above) can be synthesized.

The reaction of compound (XIV) with (XIX) includes tetrahydrofuran, ether, acetone, methanol, ethanol,
Solvents such as acetonitrile, dimethylformamide, dimethylimidazolidinone, chloroform and dichloromethane are used. Reaction temperature is -20 to 150 ° C, especially 0 to 80
C is preferred. In this reaction, an inorganic base such as potassium acetate, sodium acetate, potassium carbonate and sodium carbonate and an organic base such as pyridine, triethylamine and 4-dimethylaminopyridine are used.

The reaction between compound (XX) and HNR ⁸ R ⁹ is performed in an inorganic solvent or an alcoholic solvent such as methanol or ethanol, or a polar solvent such as acetone, tetrahydrofuran, dioxane, or dimethylformamide. The amine derivative of HNR ⁸ R ⁹ is preferably used in an amount of 0.8 to 1.5 equivalents based on the cyanamide compound (XX).
1.5 to 10 equivalents may be used. In this reaction, the base is added to 0.01 to 10
It is promoted by adding an equivalent, preferably 0.1 to 3 equivalents. As such a base, it is advantageous to use an organic base such as pyridine, triethylamine and 4-dimethylaminopyridine, and an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen carbonate.

Method 7 In the compound (I), R and R ¹ are the same or different and each is alkyl, phenyl, aralkyl or (In the formula, R ^6c and R ^7c are combined to form a group which forms a heterocyclic ring which may further contain an oxygen atom, a sulfur atom and a nitrogen atom which may have a substituent in the ring.) Or R,
Compounds in which R ¹ 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 it is bonded, are compounds (VIII A) reacting a compound in which the substituent of the heterocyclic ring of R ⁵ is not amino or hydrazino with sodium nitrite or potassium nitrite in the presence of hydrochloric acid, sulfuric acid, formic acid and acetic acid; (Wherein, R ² , R ³ , R ⁴ , R ⁵ and A have the same meanings as described above), and the hydroxy is represented by thionyl chloride, phosphorus oxychloride, phosphorus trichloride, pentachloride Phosphorus, reacting with a halogenating agent such as phosphorus tribromide, or reacting with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in the presence of a deoxidizing agent to form a reactive derivative of the corresponding alcohol. Compounds having the general formula HNR ²⁵ R ²⁶ (XXII) wherein R ²⁵ and R ²⁶ are the same or different and are alkyl, phenyl, aralkyl or imidazole, triazole,
Thiazole, benzimidazole, oxazole, benzoxazole or the like nitrogen atom, sulfur atom, or a heterocyclic ring containing an oxygen atom, or R ²⁵ , R ²⁶ is bonded and pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine,
It represents a group forming a heterocyclic ring which may contain an oxygen atom, a sulfur atom and a nitrogen atom together with a nitrogen atom such as imidazole, benzimidazole, thiazole, oxazole and benzoxazole. ) Can be produced by reacting the amine compound.

The reaction is carried out using a suitable base, for example, an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate (sodium hydroxide, potassium carbonate, sodium bicarbonate and the like), and an organic base such as pyridine and triethylamine. Perform in the presence of

In particular, in the compound (I) of the present invention, a compound having a substituent on the benzene ring is obtained by nitrating a corresponding carboxylic acid or a derivative thereof with nitric acid / sulfuric acid and then subjecting the compound to various reduction reactions (for example, H ₂ / Raney Ni , Zn / AcOH, etc.). Subsequently, it is treated with sodium nitrate in the presence of an acid such as hydrochloric acid or sulfuric acid to form a diazonium salt, which can be converted into each functional group by a Sandmeyer reaction (copper chloride, copper bromide, copper cyanide, etc.). Further, the iodine body is obtained by treating with potassium iodide. In addition, the fluorine body, after converting the diazonium salt to a boric acid salt with HBF ₄ ,
It can be synthesized by heating or by treating with hydrogen fluoride pyridine. The carboxyl compound can also be obtained by hydrolyzing the nitrile compound obtained by the Sandmeyer reaction, or by directly lithiating the benzene ring and treating with carbon dioxide. Esters and amides can be easily converted from carboxylic acids according to conventional methods. The hydroxy compound can be synthesized by heating a diazonium salt in an acidic aqueous solution. Further, an alkyloxy or aralkyloxy compound can be easily synthesized by treating a hydroxy group with a corresponding alkyl halide or aralkyl halide in the presence of a base. Alkyl and aralkyl are Friedel-Craf using the corresponding alkyl, aralkyl halide and AlCl _3.
ts reaction, Gr prepared from aromatic halide and magnesium
It can be synthesized by a reaction with an ignard reagent or by a coupling reaction between an aromatic halide and a corresponding alkyl or aralkylboron compound using a palladium catalyst.

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 a benzene ring and a nitrogen-containing heterocycle (an oxygen atom, a sulfur atom, and a heterocyclic ring which may have a substituent in the ring together with a nitrogen atom).
May be protected by a common amino protecting group, for example, alkanoyl having 1 to 5 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl and valeryl; methoxycarbonyl, C2-C5 alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl; cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
Cycloalkylcarbonyl having 4 to 8 carbon atoms such as cycloheptylcarbonyl; aroyl such as benzoyl and naphthoyl (where aroyl is halogen, 1 to 6 carbon atoms)
Alkyl, alkoxy having 1 to 6 carbon atoms, aralkyl, trifluoromethyl, nitro, amino and the like, which may have a substituent); benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, Phenylalkoxycarbonyl such as phenylbutoxycarbonyl (here, phenylethoxycarbonyl is halogen on the phenyl ring, having 1 to 6 carbon atoms)
Which may have a substituent such as alkyl, alkoxy having 1 to 6 carbon atoms, aralkyl, trifluoromethyl, nitro, amino, etc.); styryl, cinnamyl, phenylbutenyl, phenylpentenyl, phenyl Phenylalkenyl such as hexenyl; or phenylalkylidene such as benzylidene and phenylethylidene; groups forming pyrrolidylidene, piperidylidene, phthalimide; alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl; methylcarbamoylmethyl; Ethylcarbamoylmethyl,
Alkylcarbamoylalkyl such as dimethylcarbamoylmethyl, diethylcarbamoylmethyl, dimethylcarbamoylethyl; methoxymethyl, ethoxymethyl,
Alkoxymethyl such as propoxymethyl, butoxymethyl, tertiary butoxymethyl; benzyloxymethyl;
It may be protected by a protecting group such as aralkyloxyalkyl such as p-methoxybenzyloxymethyl and o-nitrobenzyloxymethyl; allyl; and cyclic ether such as tetrahydrofuran and tetrahydropyran.

The amino protecting groups described above are commonly used in 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 acids (boron trifluoride ether complex, titanium tetrachloride, tin tetrachloride, aluminum chloride) , Boron tribromide, trimethylsilane iodide, etc.) or alkali (ammonia, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate,
Sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrazine, etc.).

Also, 5% palladium carbon, 10% palladium carbon, 10%
% Palladium hydroxide carbon, Raney nickel, etc. as a catalyst, catalytic reduction in liquid ammonia, reduction using metallic sodium and metallic lithium, or sodium borohydride, lithium aluminum hydride, diborane, zinc, sodium amalgam, etc. It can also be deprotected by a reduction method using as a reducing agent, and furthermore, hydrogen peroxide, potassium permanganate, 2,3-dichloro-5,6
A method using an oxidizing agent such as -dicyano-1,4-benzoquinone (DDQ) or N-bromosuccinimide can also be used.

The compound (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography.

Further, compound (I) can form a pharmaceutically acceptable acid addition salt according to a conventional method. Acids used to form acid addition salts include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic acids (acetic acid, methanesulfonic acid,
Maleic acid, fumaric acid, etc.). 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. Also,
In the compound (I), compounds having a carboxy group include metal salts (eg, sodium, potassium, calcium, aluminum), amino acids (eg, lysine, ornithine)
And a salt with

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

Pharmacological Experiment Example 1: Antihypertensive Action 30 mg / kg of a test compound dissolved in 0.5% hydroxypropylmethylcellulose was orally administered to 3 to 5 spontaneously hypertensive rats (SHR) weighing 350 to 450 g in one group. The systolic blood pressure after time is measured by the tail cuff method,
The hypotensive effect was studied. The results are shown in Table 31.

Pharmacological Experimental Example 2: Vasodilatory Action Male rabbits (weighing 1.9-3.0 kg) were anesthetized with sodium pentobarbital and then exsanguinated to kill the thoracic aorta. A ring-shaped specimen having a width of about 2 mm was prepared, and a Crabs-Henseleit solution (NaCl 117 mM; KCl 4.7 mM; CaCl ₂ 2.5) at 37 ° C.
mM; MgSO ₄ 1.2 mM; NaHCO ₃ 24.8 mM; KH ₂ PO ₄ 1.2 mM; glucose
The suspension was suspended at a load of 2 g in a Magnus tube having a capacity of 40 ml filled with 11.0 mM). A mixed gas (95% oxygen + 5% carbon dioxide) was constantly ventilated in the Magnus tube. Specimen tension was measured with an isometric transducer (TB-611T, Nihon Kohden).
Specimens were contracted with phenylephrine (10 ⁻⁶ M) and after the contraction was constant, compounds were added cumulatively and the relaxation response was observed. The relaxation reaction of the compound was calculated by setting the phenylephrine contraction to 100% and the concentration at which 50% of the phenylephrine was relaxed as IC ₅₀ (μM). The results are shown in Table 32.

Pharmacological experiment example 3: Effect on acetylcholine-induced contraction of isolated guinea pig trachea specimens Male anthropoid guinea pigs (body weight 260-390 g) were intraperitoneally administered with 100 mg / kg of sodium pentobarbital, anesthetized, exsanguinated, and trachea was removed. . The abdominal cartilage of the trachea was cut open, the ligament was cut at a width of 3 mm, and a specimen was prepared. Specimens were incubated at 37 ° C in Crabs-Henseleate solution (NaCl
117 mM; KCl 4.7 mM; CaCl ₂ 2.5 mM; MgSO ₄ 1.2 mM; NaHCO ₃ 2
The suspension was suspended at a load of 1 g in a 40-ml capacity Magnus tube filled with 4.8 mM; KH ₂ PO ₄ 1.2 mM; glucose 11.0 mM). A mixed gas (95% oxygen + 5% carbon dioxide) was constantly ventilated in the Magnus tube. Use a isometric transducer (TB-
Recording was performed on a recorder (Ti-102, Tokai Medical Science) using 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. The maximum response of papaverine (10 ⁻⁴ M) was defined as 100%, and the concentration showing a 50% relaxation reaction was calculated as IC ₅₀ (μM). Table 33 shows the results.

Pharmacological Experimental Example 4: Effect on coronary blood flow Pentobarbital sodium body weight was administered intravenously (30
mg / kg) to anesthetize 2 to 3 adult mongrel dogs per group, and the method of Yago et al. [Nippon Pharmacological Magazine, Vol. 57, 380
In accordance with page (1961)], the left coronary artery is perfused and its blood volume is measured. Administer 10-300 μg of test compound intracoronary. The effect of the test compound on coronary blood flow was determined by the administration of 3 μg of nifedipine [dimethyl 2,6-dimethyl-4- (2-nitrophenyl) 1,4-dihydropyridine-3,5-dicarboxylate] into the coronary artery. The dose required to increase coronary blood flow by half is expressed as ED ₅₀ (μg). In addition, half-life (T1 / 2,
Minute).

Pharmacological experiment 5: Brain, coronary and renal arterial blood flow increasing effect Adult mongrel dogs were treated with sodium pentobarbital (30 mg / kg
Anesthetize with iv), and perform artificial respiration (20 ml / kg, 18 times / min) with an artificial respirator (manufactured by Harvard). The left vertebral artery, the left circumflex coronary artery and the right renal artery are exposed, a blood flow probe is attached, and the blood flow is measured with an electromagnetic blood flow meter (manufactured by Nihon Kohden Corporation). The test compound is administered intravenously via a cannula placed in the femoral vein. The effect of the test compound is represented by the rate of increase from the blood flow before administration of the test compound.

Pharmacological Experimental Example 6: Peripheral arterial blood flow increasing action Male rats were treated with sodium pentobarbital (50 mg / k
Anesthetize with g ip) and fix in dorsal position. A probe is attached to the right sole, and the blood flow is measured with a laser blood flow meter (manufactured by Advance). The test compound is administered intravenously via a cannula placed in the femoral vein, and the effect on blood flow is calculated as the rate of increase from the blood flow before administration of the test compound.

The compound (I) of the present invention, an isomer thereof and a pharmaceutically acceptable acid addition salt thereof have a strong smooth muscle relaxing action and, similarly to a calcium antagonist, have a coronary and cerebral blood flow increasing action. Furthermore, it also has a renal and peripheral circulation improving effect not seen with conventional calcium antagonists. In addition, the effect of increasing the blood flow is long. Furthermore, it suppresses not only a smooth muscle contraction reaction accompanied by an increase in intracellular calcium, but also a contraction reaction due to enhancement of a calcium-sensitive mechanism of smooth muscle.

Therefore, the compound of the present invention is a potent and persistent drug for treating hypertension, a drug for treating angina pectoris, a drug for treating renal and peripheral circulatory disorders, a drug for suppressing cerebral vasospasm, etc. It is useful as a systemic disease prevention / treatment agent.

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.

In addition, the compound (I) of the present invention, its isomer and its pharmaceutically acceptable acid addition salt are highly safe and, as is clear from the results of pharmacological experiment 1, have good oral absorption. is there.

When the compound (I) of the present invention is used as a medicament, its effective amount is mixed with pharmacologically acceptable excipients, carriers, diluents and other pharmaceutical preparation additives to give tablets, granules,
It can be administered orally or parenterally in the form of powders, capsules, injections, inhalants, ointments and suppositories.

The dose may vary depending on the age, body weight, symptoms, etc. of the patient, but it is usually about 1 to 500 mg orally per day for an adult, and it can be administered once or divided into several times.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

Example 1 (R) -N- (4-pyridyl) -4- (1-
(Aminoethyl) benzamide dihydrochloride monohydrate (Compound 2, R form) (a) (R)-(+)-4- (1-benzyloxycarbonylaminoethyl) benzoic acid 2 g of dichloromethane 20 ml
1.43 ml of thionyl chloride and dimethylformamide 2 were added to the solution.
Drops were added and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of R) -4- (1-benzyloxycarbonylaminoethyl) benzoic acid chloride. next,
The crystals were dissolved in 10 ml of acetonitrile, and cooled under ice-cooling.
525 mg of aminopyridine and 1.1 of diisopropylethylamine
After dropwise addition to a 7 ml acetonitrile 20 ml solution, the mixture was 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 the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate-hexane to give (R) -N- ( 1.87 g of 4-pyridyl-4- (1-benzyloxycarbonylaminoethyl) benzamide was obtained.

PMR (CDCl _{3 /} TMS) δ: 1.45 (3H, d, J = 6.8 Hz), 4.84 (1
H, m), 5.03 (1H, d, J = 12Hz), 5.09 (1H, d, J = 12Hz), 5.
18 (1H, brs), 7.33 (7H, m), 7.60 (2H, d, J = 5.9Hz), 7.
77 (2H, d, J = 7.8 Hz), 8.50 (2H, d, J = 5.9 Hz) (b) (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonylaminoethyl) benzamide 1.87
g, 10 mg of palladium hydroxide carbon (300 mg) was added to methanol (20 ml), and then catalytic reduction was carried out under a hydrogen gas stream. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. A hydrochloric acid-methanol solution was added to the obtained crystals. After evaporating the solvent under reduced pressure, the obtained crystals were recrystallized from methanol-ethyl acetate to give (R) -N- (4-pyridyl) -4- (1-aminoethyl) having a melting point of 287-288 ° C. 1.0 g of benzamide dihydrochloride monohydrate was obtained.

[Α] _D = +3.2 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.53 (3H, d, J = 6.8 Hz), 4.5
(1H, brs), 7.70 (2H, d, J = 8.3Hz), 8.07 (4H, m), 8.59
(2H, d, J = 5.8 Hz), 8.69 (2H, brs), 11.18 (1H, brs) Example 2 N- (4-pyridyl) -4- (1-amino-
1-methylethyl) benzamide dihydrochloride (compound 1
3) (a) 4- (1-benzyloxycarbonylamino-1)
-Methylethyl) benzoic acid 780mg dichloromethane 10ml
Add 0.21 ml of thionyl chloride and dimethylformamide 2 to the solution.
Drops were added and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure to give 4- (1-benzyloxycarbonylamino-
Crystals of 1-methylethyl) benzoic acid chloride were obtained.
Next, the crystals were dissolved in 10 ml of acetonitrile, added dropwise to a solution of 195 mg of 4-aminopyridine and 0.5 ml of diisopropylethylamine in 10 ml of acetonitrile under ice cooling, and stirred at room temperature for 5 hours. After the reaction, water was added, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure.
N- (4-pyridyl) -4- (1-benzyloxycarbonylamino-1-methylethyl) benzamide 750 mg
I got

PMR (CDCl _{3 /} TMS) δ: 1.64 (6H, s), 5.00 (2H, s), 5.2
8 (1H, s), 7.32 (5H, s), 7.47 (2H, d, J = 8.3Hz), 7.58
(2H, d, J = 6.4Hz), 7.76 (2H, d, J = 8.3Hz), 8.51 (2H,
d, J = 6.3 Hz) (b) N- (4-pyridyl) -4- (1-benzyloxycarbonylamino-1-methylethyl) benzamide
620mg, 10% palladium hydroxide carbon 300mg methanol 20m
After the addition to l, catalytic reduction was performed under a stream of hydrogen gas. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. A hydrochloric acid-methanol solution was added to the obtained crystals. After evaporating the solvent under reduced pressure, the obtained crystals were recrystallized from methanol-ethyl acetate to give N- (4-pyridyl) -4 having a melting point of 299-300 ° C.
-(1-amino-1-methylethyl) benzamide.2
390 mg of the hydrochloride were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.67 (6H, s), 7.77 (2H, d, J
= 8.3Hz), 8.15 (2H, d, J = 8.3Hz), 8.40 (2H, d, J = 6.4H)
z), 8.75 (2H, d, J = 6.4Hz), 8.87 (2H, s), 11.80 (1H,
s) Example 3 N- (4-pyridyl) -4aminomethyl-2
-Benzyloxybenzamide monohydrochloride monohydrate (compound 52) (a) To a solution of 7.1 g of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid in 50 ml of dichloromethane, 1.55 ml of thionyl chloride and dimethylformamide 2 Drops were added, and the mixture was heated under reflux for 1.5 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of 2-benzyloxy-4-benzyloxycarbonylaminomethylbenzoic acid chloride.
Next, the crystals were dissolved in 50 ml of acetonitrile, added dropwise to a solution of 1.42 g of 4-aminopyridine and 5.27 ml of diisopropylethylamine in 50 ml of acetonitrile under ice cooling, and stirred at room temperature for 4 hours. After the reaction, water was added, extracted with chloroform, washed with water, dried, and the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give N- (4-pyridyl) -2. -Benzyloxy-4-
Crystals of benzyloxycarbonylaminomethylbenzamide were obtained.

PMR (CDCl _{3 /} TMS) δ: 4.45 (2H, d, J = 5.8 Hz), 5.14 (2
H, s), 5.15 (2H, s), 7.04 (4H, m), 7.42 (5H, m), 7.50
(5H, s), 8.24 (1H, d, J = 7.8Hz), 8.33 (1H, d, J = 6.4H
z), 10.06 (1H, s) (b) N- (4-pyridyl) -2-benzyloxy-4
-Benzyloxycarbonylaminomethylbenzamide
1.5 ml of a 25% hydrogen bromide-acetic acid solution and 3 ml of acetic acid were added to 500 mg, and the mixture was stirred at room temperature for 3 hours. After the reaction, ethyl acetate is added, and the precipitated crystals are collected by filtration under reduced pressure. 10 ml of a 2N aqueous sodium hydroxide solution was added to the crystals, extracted with chloroform, washed and dried. After evaporating the solvent under reduced pressure, a hydrochloric acid-methanol solution was added to the residue, and the mixture was concentrated again. By recrystallizing the obtained crystals from methanol-ethyl acetate,
N- (4-pyridyl) -4-aminomethyl-2-benzyloxybenzamide monohydrochloride having a melting point of 203-205 ° C.
160 mg of hydrate were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.11 (2H, s), 5.23 (2H, s),
7.19 (1H, d, J = 7.8Hz), 7.37 (3H, m), 7.55 (5H, m), 7.
71 (1H, d, J = 7.8 Hz), 8.31 (2H, brs), 8.43 (2H, d, J =
6.4 Hz), 10.52 (1H, s) Example 4 N- (4-pyridyl) -4-aminomethyl-
2-ethoxybenzamide dihydrochloride hemihydrate (compound 50) (a) N- (4-pyridyl) -4- obtained in Example 3
Aminomethyl-2-benzyloxybenzamide monohydrochloride monohydrate 4.8 g, diisopropylethylamine 5.9 m
l, chloroform 100ml and dimethylimidazolidinone
_2.5 g of Boc ₂ O was added to 50 ml of the mixture, and the mixture was stirred at room temperature for 5 hours. After the reaction, chloroform was distilled off under reduced pressure, extracted with ethyl acetate, washed with water and dried. The crystals obtained by evaporating the solvent under reduced pressure were recrystallized from methanol-ethyl acetate-hexane to give N- (4-pyridyl) -2-benzyloxy-4-tertiary-butoxycarbonylaminomethylbenzamide. 3.38 g was obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.40 (9H, s), 4.18 (2H, m),
5.19 (2H, s), 6.97 (1H, d, J = 7.8Hz), 7.18 (1H, s), 7.
35 (3H, m), 7.50 (5H, m), 7.62 (2H, m), 8.41 (2H, d, J
= 6.4 Hz), 10.43 (1H, s) (b) N- (4-pyridyl) -2-benzyloxy-4
Tertiary butoxycarbonylaminomethylbenzamide
3.38 g was catalytically reduced with 1 g of 10% palladium hydroxide carbon in a solution of 10 ml of ethanol and 70 ml of dimethylimidazolidinone under a stream of hydrogen. After the reaction, the catalyst is removed by filtration and concentrated under reduced pressure to give N- (4-pyridyl).
1.85 g of -4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide were obtained.

PMR (CDCl _{3 /} TMS) δ: 1.46 (9H, s), 4.26 (2H, m), 5.6
2 (1H, brs), 6.87 (2H, m), 7.70 (2H, d, J = 7.8Hz), 7.9
3 (2H, d, J = 8.3Hz), 8.45 (2H, d, J = 7.8Hz) (c) N- (4-pyridyl) -4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide 100m
g of dimethylformamide 10 ml solution, potassium carbonate 40 m
g and 56 mg of ethyl bromide were added, and the mixture was stirred at room temperature for 4 hours.
After the reaction, water was added, extracted with ethyl acetate, washed with water and dried,
The crystals obtained by concentration under reduced pressure were recrystallized from ethyl acetate-hexane to give N- (4-pyridyl) -4-.
Tertiary butoxycarbonylaminomethyl-2-ethoxybenzamide (60 mg) was obtained.

PMR (CDCl _{3 /} TMS) δ: 1.45 (9H, s), 1.64 (3H, t, J = 6.
8Hz), 4.28 (2H, q, J = 6.8Hz), 4.33 (2H, m), 4.96 (1H,
brs), 6.94 (1H, s), 7.01 (1H, d, J = 7.8Hz), 7.56 (2H,
m), 8.21 (1H, d, J = 8.3H), 8.51 (2H, m), 10.24 (1H,
s) (d) N- (4-pyridyl) -4-tert-butoxycarbonylaminomethyl-2-ethoxybenzamide to 60 mg
1N hydrochloric acid-dioxane (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the crystals obtained by evaporating the solvent under reduced pressure were recrystallized from methanol-ethyl acetate to give a compound having a melting point of 25.
N- (4-pyridyl) -4-aminomethyl-2-ethoxybenzamide dihydrochloride 1/2 hydrate at 1 DEG C. (decomposition) 4
0 mg was obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.36 (3H, t, J = 6.8 Hz), 4.07
(2H, m), 4.19 (2H, q, J = 6.8Hz), 7.17 (1H, d, J = 8.3H
z), 7.49 (1H, s), 7.64 (2H, d, J = 8.3Hz), 8.21 (2H, d,
J = 7.8Hz), 8.70 (2H, s), 8.74 (2H, d, J = 7.8Hz), 11.4
9 (1H, s) Example 5 (R)-(-)-N- (4-pyridyl) -4
-(1-aminoethyl) -3-nitrobenzamide.2
Hydrobromide 1/2 hydrate (Compound 125) (a) A mixture of 1.2 ml of concentrated nitric acid and 1.2 ml of concentrated sulfuric acid was added under ice-cooling.
2 g of (R) -4- (1-acetamidoethyl) benzoic acid methyl ester was added little by little. After stirring at room temperature for 5 hours, 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-hexane to give (R) -4-
1.4 g of (1-acetamidoethyl) -3-nitrobenzoic acid methyl ester was obtained.

PMR (CDCl _{3 /} TMS) δ: 1.55 (3H, d, J = 6.8 Hz), 1.95 ( ₃
H, s), 3.93 (3H, s), 5.42-5.49 (1H, m), 6.00-6.04
(1H, br), 7.57 (1H, d, J = 8.3Hz), 8.18 (1H, dd, J = 1.
4,8.3 Hz), 8.48 (1H, d, J = 1.4 Hz) (b) (R) -4- (1-acetamidoethyl) -3-
Nitrobenzoic acid methyl ester (650 mg) was dissolved in 2N hydrochloric acid and refluxed for 2 hours. After the reaction, the reaction solution was distilled off under reduced pressure,
Further, azeotropic distillation with toluene and drying gave (R) -4- (1-aminoethyl) -3-nitrobenzoic acid / hydrochloride (620 mg).

PMR (DMSO-d _{6 /} TMS) δ: 1.60 (3H, d, J = 6.4 Hz), 4.85
−4.88 (1H, br), 8.12 (1H, d, J = 8.3Hz), 8.32 (1H, dd,
J = 1.5,8.3Hz), 8.43 (1H, d, J = 1.5Hz), 8.66-8.72 (3
H, br) (c) 0.9 g of benzyloxycarbonyl chloride was added dropwise at room temperature to 10 ml of an aqueous solution containing 1 g of (R) -4- (1-aminoethyl) -3-nitrobenzoic acid / hydrochloride and 535 mg of sodium hydroxide. Then, the mixture was stirred at the same temperature for 3 hours. The reaction solution was acidified by adding concentrated hydrochloric acid, extracted with chloroform, washed with water,
After drying, the residue obtained by concentration is purified by silica gel column chromatography (chloroform: methanol = 10: 1), and 1.05 g of (R) -4- (1-benzyloxycarbonylaminoethyl) 3-nitrobenzoic acid is obtained. I got

PMR (CDCl _{3 /} TMS) δ: 1.31 (3H, d, J = 6.8 Hz), 4.93−
5.09 (3H, m), 7.28-7.37 (5H, m), 7.84 (1H, d, J = 8.3H
z), 8.25-8.29 (2H, m), 8.44 (1H, d, J = 1.5 Hz) (d) 1 g of (R) -4- (1-benzyloxycarbonylaminoethyl) -3-nitrobenzoic acid in dichloromethane
5 ml solution, thionyl chloride 5 ml, dimethylformamide 1
Drops were added and refluxed for 3 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of (R) -4- (1-benzyloxycarbonylaminoethyl) -3-nitrobenzoic acid chloride. Next, the crystals were dissolved in 14 ml of dichloromethane,
Under ice-cooling, the mixture was added dropwise to a solution of 250 mg of 4-aminopyridine and 375 mg of diisopropylethylamine in 6 ml of dichloromethane, followed by stirring at room temperature for 4 hours. After the reaction, water was added to the reaction solution, extracted with chloroform, dried, evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give (R) -N − (4-
940 mg of pyridyl) -4- (1-benzyloxycarbonylaminoethyl) -3-nitrobenzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.45 (3H, d, J = 6.8 Hz), 4.90
(1H, d, J = 12.2Hz), 4.97 (1H, d, J = 12.2Hz), 5.03-5.
09 (1H, m), 7.28-7.36 (5H, m), 7.75 (2H, d, J = 6.4H
z), 7.84 (1H, d, J = 8.3 Hz), 8.25-8.29 (2H, m), 8.44
(1H, d, J = 1.5Hz), 8.50 (2H, d, J = 6.4Hz), 10.78 (1H,
s) (e) 4 ml of a 25% hydrogen bromide-acetic acid solution was added to 400 mg of (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonylaminoethyl) -3-nitrobenzamide, and the solution was added at room temperature. Stirred for hours. After the reaction, the reaction solution was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate and recrystallized from methanol to give (R)-(-)-N-
153 mg of (4-pyridyl) -4- (1-aminoethyl) -3-nitrobenzamide / dihydrobromide / 1/2 hydrate was obtained.

[Α] _D = -7.9 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.62 (3H, d, J = 6.8 Hz), 4.91
−4.95 (1H, br), 8.15 (1H, d, J = 8.3Hz), 8.34 (2H, d, J
= 6.8Hz), 8.52 (4H, m), 8.66 (1H, d, J = 2.0Hz), 8.82
(2H, d, J = 6.8Hz), 11.78 (1H, s) Example 6 (R)-(-)-N- (4-pyridyl) -3
-Amino-4- (1-aminoethyl) benzamide.3
Hydrochloride 3/2 hydrate (Compound 127) 540 mg of (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonylaminoethyl) -3-nitrobenzamide was added to 10% palladium hydroxide carbon Using 250 mg, the mixture was stirred in a 20 ml solution of methanol at 40 ° C. for 4 hours under a hydrogen stream. After the reaction, the catalyst was removed by filtration, and the residue obtained by concentration under reduced pressure was converted into a hydrochloride using 15% hydrochloric acid-methanol, and then recrystallized from methanol to give (R)-having a melting point of 210 ° C (decomposition). (-)-N- (4-pyridyl) -3-amino-
4- (1-aminoethyl) benzamide ・ 3 hydrochloride ・ 3 /
130 mg of dihydrate were obtained.

[Α] _D = -6.1 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.46 (3H, d, J = 6.3 Hz), 4.60
−4.64 (1H, br), 7.41 (1H, s), 7.48−7.51 (1H, m), 7.
56 (1H, d, J = 7.8Hz), 8.37 (2H, d, J = 6.9Hz), 8.40-8.
70 (2H, br), 8.75 (2H, d, J = 6.9Hz), 11.66 (1H, s) Example 7 (R)-(+)-N- (4-pyridyl) -4
-(1-aminoethyl) -3-chlorobenzamide.2
Hydrobromide (Compound 141) (a) (R) -4- (1-acetamidoethyl) -3-
1 g of nitrobenzoic acid methyl ester was stirred at room temperature for 3 hours under a hydrogen stream in a 20 ml methanol solution using 0.3 g of 10% palladium hydroxide carbon. After the reaction, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.89 g of (R) -3-amino-4- (1-acetamidoethyl) benzoic acid methyl ester.

PMR (DMSO-d _{6 /} TMS) δ: 1.30 (3H, d, J = 6.9Hz), 1.82
(3H, s), 3.78 (3H, s), 4.93-5.01 (1H, m), 5.31-5.3
3 (2H, br), 7.11 (1H, dd, J = 1.4,8.3Hz), 7.17 (1H, d, J
= 8.3Hz), 7.27 (1H, d, J = 1.4Hz), 8.26 (1H, d, J = 8.3H)
z) (b) To a solution of 193 mg of sodium nitrite in 2 ml of concentrated sulfuric acid was added dropwise at room temperature a solution of (R) -3-amino-4- (1-acetamidoethyl) benzoic acid methyl ester (600 mg) in acetic acid (6 ml). Stir for 30 minutes. The reaction solution was treated with copper (I) chloride 55
0 mg of a concentrated hydrochloric acid solution (6 ml) was added dropwise to the solution under ice-cooling.
Stirred for hours. After the reaction, the reaction solution was poured into ice water, extracted with chloroform, washed with water, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give (R) -4- (1-acetamidoethyl) -3-chlorobenzoic acid methyl ester 46
0 mg was obtained.

PMR (CDCl _{3 /} TMS) δ: 1.46 (3H, d, J = 6.8 Hz), 1.99 ( ₃
H, s), 3.89 (3H, s), 5.33-5.40 (1H, m), 5.92-5.98
(1H, br), 7.36 (1H, d, J = 8.3Hz), 7.87 (1H, dd, J = 1.
5,8.3 Hz), 8.00 (1H, d, J = 1.5 Hz) (c) (R) -4- (1-acetamidoethyl) -3-
Chlorobenzoic acid methyl ester (630 mg) was added to 2N hydrochloric acid (15 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, azeotropically dried with toluene, and dried to obtain 700 mg of (R) -4- (1-aminoethyl) -3-chlorobenzoic acid / hydrochloride.

PMR (DMSO-d _{6 /} TMS) δ: 1.51 (3H, d, J = 6.8 Hz), 4.67
−4.74 (1H, m), 7.89 (1H, d, J = 8.3Hz), 7.95−7.99 (2
H, m), 7.80-7.86 (3H, br) (d) 10 ml of an aqueous solution containing 690 mg of (R) -4- (1-aminoethyl) -3-chlorobenzoic acid / hydrochloride and 410 mg of sodium hydroxide at room temperature Then, 750 mg of benzyloxycarbonyl chloride was added dropwise, and the mixture was stirred for 3 hours. After the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and extracted with chloroform. The residue obtained by drying and distilling off the solvent under reduced pressure is subjected to silica gel column chromatography (chloroform: methanol =
30: 1) to give (R) -4- (1-benzyloxycarbonylaminoethyl) -3-chlorobenzoic acid (680 mg).

PMR (DMSO-d _{6 /} TMS) δ: 1.31 (3H, d, J = 6.8 Hz), 4.93
−5.06 (3H, m), 7.28−7.37 (5H, m), 7.56 (1H, d, J = 8.
(3Hz), 7.85-7.90 (2H, m), 8.12 (1H, d, J = 7.9Hz) (e) (R) -4- (1-benzyloxycarbonylaminoethyl) -3-chlorobenzoic acid 680 mg of dichloromethane To the 7 ml solution, 5 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by stirring at room temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of (R) -4- (1-benzyloxycarbonylaminoethyl) -3-chlorobenzoic acid chloride. Next, the crystals were dissolved in 12 ml of dichloromethane, added dropwise at room temperature to a solution of 187 mg of 4-aminopyridine and 267 mg of diisopropylethylamine in 5 ml of dichloromethane, and stirred for 1 hour. After the reaction, water was added to the reaction solution, extracted with chloroform, washed with water and dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and purified by (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonyl) 650 mg of (aminoethyl) -3-chlorobenzamide were obtained.

PMR (CDCl _{3 /} TMS) δ: 1.43 (3H, d, J = 6.8 Hz), 5.03-
5.17 (3H, m), 5.27-5.31 (1H, br), 7.24-7.42 (5H,
m), 7.59 (2H, d, J = 6.4Hz), 7.63 (1H, m), 7.78 (1H,
s), 8.27-8.31 (1H, br), 8.52 (2H, d, J = 6.4 Hz) (f) (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonylaminoethyl)- 7 ml of 25% hydrogen bromide-acetic acid solution was added to 630 mg of 3-chlorobenzamide,
Stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether and recrystallized from methanol to give (R)-(+)-N- (4-pyridyl) -4 having a melting point of> 300 ° C. 243 mg of-(1-aminoethyl) -3-chlorobenzamide dihydrobromide were obtained.

[Α] _D = +4.0 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.52 (3H, d, J = 6.8 Hz), 4.76
−4.84 (1H, m), 7.88 (1H, d, J = 8.3Hz), 8.12 (1H, d, J
= 8.3Hz), 8.19 (1H, d, J = 2.0Hz), 8.30 (2H, d, J = 6.9H)
z), 8.53-8.57 (3H, br), 8.79 (2H, d, J = 6.9Hz), 11.5
8 (1H, s) Example 8 N- (4-pyridyl) -3-aminomethylbenzamide dihydrochloride monohydrate (compound 21) (a) Chlorine was added to a solution of 10 g of 3-cyanobenzoic acid in 100 ml of dichloromethane. 10 ml of thionyl and 1 drop of dimethylformamide were added, and the mixture was refluxed for 3 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain 3-cyanobenzoic acid chloride. Next, this oily substance was dissolved in 25 ml of dichloromethane, added dropwise to a solution of 5 g of 4-aminopyridine and 8.9 g of diisopropylethylamine in 50 ml of dichloromethane, and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and recrystallized from chloroform-methanol-ether to give N- (4-pyridyl) -3.
5.3 g of cyaminobenzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 7.81 (1H, t, J = 7.8Hz), 8.16
(1H, d, J = 7.8Hz), 8.34-8.37 (3H, m), 8.55 (1H, s),
8.77 (2H, d, J = 7.3Hz), 11.90 (1H, s) (b) N- (4-pyridyl) -3-cyanobenzamide
2g, Raney nickel 0.5g, 2M sodium hydroxide solution
A solution of 8 ml of ethanol in 20 ml was stirred at room temperature for 5 hours under an initial pressure of hydrogen of 10 atm in an autoclave. After the reaction, the catalyst was removed by filtration, and the solution obtained by concentrating under reduced pressure to 1/3 was diluted with water and extracted with chloroform: methanol = 10: 1. The residue obtained by drying and distilling off the solvent under reduced pressure is subjected to silica gel chromatography (chloroform: methanol = 10: 1).
Was purified. The obtained oily substance was converted into a hydrochloride with 15% hydrochloric acid-methanol and recrystallized from methanol-ether to give N- (4-pyridyl) -3-aminomethylbenzamide dihydrochloride having a melting point of 273-276 ° C. 620 mg of salt monohydrate was obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.13-4.16 (2H, m), 7.64 (1
H, t, J = 7.8Hz), 7.79 (1H, d, J = 7.8Hz), 8.10 (1H, d, J
= 7.8Hz), 8.30 (1H, s), 8.42 (2H, d, J = 6.8Hz), 8.43
−8.55 (3H, br), 8.76 (2H, d, J = 6.8Hz), 11.83 (1H,
s) Example 9 (R)-(+)-N- (1H-pyrrolo [2,3-
b] pyridin-4-yl) -4- (1-aminoethyl)
Benzamide dihydrochloride 3/2 hydrate (Compound 230) (a) In a 15 mL dichloromethane solution of 1.2 g of (R) -4- (1-benzyloxycarbonylaminoethyl) benzoic acid, 0.9 mL of thionyl chloride, dimethylformamide One drop was added and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of (R) -4- (1-benzyloxycarbonylaminoethyl) benzoic acid chloride. next,
The crystals were dissolved in 10 ml of acetonitrile, and 4-amino-
After dropwise adding a solution of 240 mg of 1H-pyrrolo [2,3-b] pyridine and 520 mg of diisopropylethylamine in 10 ml of acetonitrile, the mixture was stirred at room temperature for 8 hours. The precipitated crystals were collected by filtration, dried, and dissolved in methanol (7 ml).
0 mg was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, water was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with ethyl acetate. The crystals obtained by drying and distilling off the solvent under reduced pressure are washed with ethyl acetate, and washed with (R) -N- (1H-pyrrolo [2,3-
b] 330 mg of pyridin-4-yl) -4- (1-benzyloxycarbonylaminoethyl) benzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.33-1.40 (3H, m), 4.72-
4.78 (1H, m), 4.98−5.04 (2H, m), 6.78−6.82 (1H, m
m), 7.32-8.16 (13H, m) (b) 200 mg of (R) -N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4 (1-benzyloxycarbonylaminoethyl) benzamide , 15% hydrochloric acid-methanol 1
80% of 10% palladium hydroxide carbon was added to a mixture of 6 ml of methanol and 6 ml of methanol, followed by stirring at 40 ° C. for 1 hour under a hydrogen stream. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. The obtained crystals were recrystallized from methanol-ether to give (R)-(+)-N- (1H-pyrrolo [m] having a melting point of 286 [deg.] C. (decomposition). (2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide.dihydrochloride.3 / 2 hydrate (120 mg) was obtained.

[Α] _D = +6.1 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.54 (3H, d, J = 6.8 Hz), 4.50
−4.54 (1H, m), 7.11 (1H, br), 7.55 (1H, br), 7.70 (2
(H, d, J = 8.3Hz), 8.02-8.06 (3H, m), 8.33 (1H, br), 8.
62 (3H, br), 10.99 (1H, br) Example 10 (R)-(+)-N- (1H-pyrazolo [3,4
-B] pyridin-4-yl) -4- (1-aminoethyl) benzamide dihydrochloride monohydrate (compound 238) (a) (R) -4- (1-benzyloxycarbonylaminoethyl) To a solution of 1.11 g of benzoic acid in 10 ml of dichloromethane were added 2 ml of thionyl chloride and one drop of dimethylformamide, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of (R) -4- (1-benzyloxycarbonylaminoethyl) benzoic acid chloride. next,
The crystals were dissolved in 10 ml of acetonitrile, and 4-amino-
320 mg of 1H-pyrazolo [3,4-b] pyridine dihydrochloride and 880 mg of diisopropylethylamine in 10 ml of acetonitrile
After dropping into a mixture of 3 ml of -dimethylimidazolidinone, the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration, dried, dissolved in 7 ml of methanol, added with 80 mg of sodium methoxide, and stirred at room temperature for 30 minutes. After the reaction, water was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with ethyl acetate. Drying,
The crystals obtained by evaporating the solvent under reduced pressure are washed with ethyl acetate and washed with (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-benzyl) 310 mg of (oxycarbonylaminoethyl) benzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.37 (3H, d, J = 6.8 Hz), 4.73
−4.79 (1H, m), 4.97 (1H, d, J = 12.2Hz), 5.03 (1H, d, J
= 12.2Hz), 7.33-7.37 (5H, m), 7.49 (2H, d, J = 8.3H
z), 7.71 (1H, d, J = 5.4 Hz), 7.90-7.95 (3H, m), 8.39
-8.42 (2H, m), 10.76 (1H, s), 13.53 (1H, s) (b) (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- To a mixture of (1-benzyloxycarbonylaminoethyl) benzamide (300 mg), 15% hydrochloric acid-methanol (3 ml) and methanol (14 ml) was added 10% palladium hydroxide / carbon (100 mg), and the mixture was stirred at 40 ° C. for 1 hour under a hydrogen stream. After the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. The obtained crystals were recrystallized from methanol-ether to give (R)-(+)-N- (1
H-pyrazolo [3,4-b] pyridin-4-yl) -4-
120 mg of (1-aminoethyl) benzamide dihydrochloride monohydrate was obtained.

[Α] _D = +4.4 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.54 (3H, d, J = 6.9 Hz), 4.94
−4.55 (1H, m), 7.72 (2H, d, J = 8.3Hz), 7.85 (1H, b
r), 8.07 (2H, d, J = 8.3 Hz), 8.55 (1H, br), 8.71 (3H, b
r), 11.27 (1H, br) Example 11 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-guanidinomethylbenzamide dihydrochloride monohydrate (compound 482) (a) Thionyl chloride was added to a solution of 2.85 g of 4-benzyloxycarbonylaminomethylbenzoic acid in 12 ml of dichloromethane.
2 ml and 1 drop of dimethylformamide were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of 4-benzyloxycarbonylaminomethylbenzoic acid chloride. Next, the crystals were dissolved in 5 ml of acetonitrile and added dropwise to a mixture of 1.09 g of 4-amino-1H-pyrazolo [3,4-b] pyridine / 2 trifluoroacetate and 1.7 g of diisopropylethylamine in 10 ml of acetonitrile and 5 ml of dimethylformamide. Thereafter, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and acetonitrile was distilled off under reduced pressure, then extracted with ethyl acetate, dried, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (10 ml), and sodium methoxide was added.
80 mg was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform: methanol = 10: 1. The crystals obtained by drying and distilling off the solvent under reduced pressure are washed with ethyl acetate and washed with N- (1H-pyrazolo [3,4-b] pyridine-
540 mg of 4-yl) -4-benzyloxycarbonylaminomethylbenzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.29 (2H, br), 5.06 (2H,
s), 7.30-7.40 (5H, m), 7.44 (2H, d, J = 7.8Hz), 7.69
(1H, d, J = 4.9Hz), 7.91-7.97 (3H, m), 8.39-8.44 (2
H, m), 10.77 (1H, br), 13.53 (1H, br) (b) N- (1H-pyrazolo [3,4-b] pyridine-4-
Yl) -4-benzyloxycarbonylaminomethylbenzamide 540 mg, 15% hydrochloric acid-methanol 3 ml and methanol 10 ml were mixed with 10% palladium hydroxide carbon 250m
g was added and stirred at 40 ° C. for 2 hours under a hydrogen stream. 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 N-
(1H-pyrazolo [3,4-b] pyridin-4-yl) -4
330 mg of -aminomethylbenzamide dihydrochloride were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.11-4.16 (2H, m), 7.7.70
(2H, d, J = 8.3Hz), 7.89 (1H, br), 8.08 (2H, d, J = 8.3H)
z), 8.55-8.80 (5H, m), 11.37 (1H, m) (c) N- (1H-pyrazolo [3,4-b] pyridine-4-
Il) -4-Aminomethylbenzamide dihydrochloride 330m
g, diisopropylethylamine 500 mg meanol 5 ml
-Pyrazole-1- in a mixture of 5 ml of dimethylformamide
284 mg of carboxamidine hydrochloride was added, and the mixture was stirred at room temperature under a nitrogen stream for 8 hours. After the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 3: 1) to obtain white crystals. The crystals were converted to the hydrochloride with 15% hydrochloric acid-methanol and recrystallized from methanol-ether to give a m.p.
N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4-guanidinomethylbenzamide at 54 DEG C. (decomposition)
205 mg of dihydrochloride monohydrate were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.52 (2H, br), 7.40 (2H, b
r), 7.50 (2H, d, J = 8.3 Hz), 7.85 (1H, br), 8.03 (2H,
d, J = 8.3 Hz), 8.34 (1H, br), 8.55 (2H, br) Example 12 N- (4-pyridyl) -4-guanidinomethylbenzamide monohydrochloride monohydrate (Compound 395) N- (4-pyridyl) -4-aminomethylbenzamide dihydrochloride 550 mg, diisopropylethylamine 950 mg
540 mg of pyrazole-1-carboxamidine hydrochloride was added to a 7 ml solution of methanol, and the mixture was stirred at room temperature for 6 hours under a nitrogen stream. After the reaction, the reaction solution was concentrated to half the volume under reduced pressure, and ethyl acetate was added to precipitate crystals. The crystals were collected by filtration and recrystallized from methanol-ethyl acetate to give a melting point of 244-248 ° C.
333 mg of N- (4-pyridyl) -4-guanidinomethylbenzamide monohydrochloride monohydrate was obtained.

PMR (DMSO-d _{6 /} TMS) δ: 4.49 (2H, d, J = 6.3 Hz), 7.43
(2H, br), 7.47 (2H, d, J = 8.3Hz), 7.96 (2H, d, J = 6.4H
z), 8.02 (2H, d, J = 8.3Hz), 8.21 (1H, br), 8.55 (2H,
d, J = 6.4 Hz), 10.95 (1H, br) Example 13 (R)-(+)-N- (4-pyridyl) -4
-(1-aminoethyl) -3-fluorobenzamide.
Dihydrobromide (Compound 139) (a) (R) -3-Amino-4- (1-acetamidoethyl) benzoic acid methyl ester 2 g of hydrogen fluoride pyridine
To a 20 ml solution, add 640 mg of sodium nitrite under ice cooling,
Stirred at room temperature for 1 hour. After the reaction, pour the reaction solution into ice water,
The residue obtained by extraction with chloroform, washing with water, drying and concentration was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give (R) -4- (1
-Acetamidoethyl) -3-fluorobenzoic acid methyl ester 690 mg was obtained.

PMR (CDCl _{3 /} TMS) δ: 1.48 (3H, d, J = 6.8 Hz), 1.97 ( ₃
H, s), 3.88 (3H, s), 5.22-5.29 (1H, m), 6.05 (1H, b
r), 7.32 (1H, t, J = 7.8Hz), 7.66 (1H, dd, J = 1.5,11.2H
z), 7.75 (1H, dd, J = 1.5, 8.3 Hz) (b) (R) -4- (1-acetamidoethyl) -3-
690 mg of methyl fluorobenzoate was added to 15 ml of 2N hydrochloric acid, and the mixture was refluxed for 3 hours. After the reaction, the reaction solution was distilled off under reduced pressure, further azeotropically dried with toluene, and dried to obtain (R) -4- (1-
Aminoethyl) -3-fluorobenzoic acid / hydrochloride 620mg
I got

PMR (DMSO-d _{6 /} TMS) δ: 1.53 (3H, d, J = 6.8 Hz), 4.63
(1H, br), 7.70 (1H, d, J = 10.7Hz), 7.84 (2H, m), 8.79
(3H, br), 13.38 (1H, br) (c) 10 ml of an aqueous solution containing 610 mg of (R) -4- (1-aminoethyl) -3-fluorobenzoic acid hydrochloride and 390 mg of sodium hydroxide at room temperature Benzyloxycarbonyl chloride (710 mg) was added dropwise, and the mixture was stirred for 4 hours. After the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and extracted with chloroform.
The residue obtained by drying and distilling off the solvent under reduced pressure is purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give (R) -4- (1-benzyloxycarbonylaminoethyl) -3-fluoro 520mg benzoic acid
I got

PMR (DMSO-d _{6 /} TMS) δ: 1.33 (3H, d, J = 7.3 Hz), 4.93
−5.03 (3H, m), 7.30−7.35 (5H, m), 7.47 (1H, t, J = 7.
8Hz), 7.58 (1H, d, J = 10.8Hz), 7.74 (1H, d, J = 8.3H)
z), 8.02 (1H, d, J = 7.8 Hz) (d) To a solution of 520 mg of (R) -4- (1-benzyloxycarbonylaminoethyl) -3-fluorobenzoic acid in 7 ml of dichloromethane, 7 ml of thionyl chloride, dimethyl One drop of formamide was added and stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain crystals of (R) -4- (1-benzyloxycarbonylaminoethyl) -3-fluorobenzoic acid chloride. Next, the crystals were diluted with dichloromethane 12
The solution was added dropwise to a solution of 140 mg of 4-aminopyridine and 210 mg of diisopropylethylamine in 5 ml of dichloromethane at room temperature, followed by stirring for 1 hour. After the reaction, water was added to the reaction solution,
Extracted with chloroform, washed with water and dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 2: 1), and purified by (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonyl) 560 mg of (aminoethyl) -3-fluorobenzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.36 (3H, d, J = 7.3 Hz), 4.99
(3H, m), 7.34 (5H, m), 7.55 (1H, t, J = 7.8Hz), 7.75
(4H, m), 8.09 (1H, d, J = 7.8Hz), 8.47 (2H, d, J = 5.4H
z), 10.57 (1H, s) (e) (R) -N- (4-pyridyl) -4- (1-benzyloxycarbonylaminoethyl) -3-fluorobenzamide in 550 mg, 25% hydrogen bromide-acetic acid 8 ml of the solution was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the crystals obtained by evaporating the solvent under reduced pressure were washed with ether and recrystallized from methanol to give (R)-(+)-N having a melting point of 294 ° C (decomposition).
-(4-pyridyl) -4- (1-aminoethyl) -3-
360 mg of fluorobenzamide dihydrobromide were obtained.

[Α] _D = +4.2 ゜ (methanol, c = 1) PMR (DMSO-d _{6 /} TMS) δ: 1.54 (3H, d, J = 6.9 Hz), 4.74
(1H, m), 7.83 (1H, t, J = 7.8Hz), 7.98 (2H, m), 8.33
(2H, d, J = 6.8Hz), 8.51 (3H, br), 8.80 (2H, d, J = 6.8H)
z), 11.57 (1H, s) Example 14 N- (4-pyridyl) -4-aminomethylbenzamide dihydrochloride, mp 300-310 ° C (compound 1) Example 15 N- (4-pyridyl)- 4-aminomethyl-
2-hydroxybenzamide dihydrochloride hemihydrate,
Melting point 279 ° C (decomposition) (compound 46) Example 16 N- (4-pyridyl) -4- (2-aminoethyl) benzamide dihydrochloride hemihydrate, melting point 286 ° C
(Decomposition) (compound 18) Example 17 N- (4-pyridyl) -4-aminomethyl-
3-nitrobenzamide dihydrobromide hemihydrate, melting point 284 ° C (decomposition) (compound 53) Example 18 N- (4-pyridyl) -3-amino-4-aminomethylbenzamide Example 19 (S)-(-)-N- (4-pyridyl) -4
-(1-Aminomethyl) benzamide dihydrochloride, melting point
278-279 ° C, [α] _D = -5.6 ゜ (methanol, c = 1)
(Compound 2, S-isomer) Example 20 (S) -N-(-)-N- (4-pyridyl)
-2- (1-aminoethyl) benzamide dihydrochloride,
Melting point 193-195 ° C, [α] _D = -3.2 ゜ (methanol, c =
1) (Compound 34, S form) Example 21 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -3-amino-4- (1-aminoethyl) benzamide Example 22 N- (1H-pyrrolo [2,3-b] -pyridine-
4-yl) -3-amino-4- (1-aminoethyl) benzamide Example 23 N- (4-pyridyl) -4- (1-aminoethyl) -3-fluorobenzamide Example 24 N- (4- Pyridyl) -4- (1-amino-
1-methylethyl) -3-fluorobenzamide Example 25 N- (4-pyridyl) -4- (1-aminoethyl) -3-chlorobenzamide Example 26 N- (4-pyridyl) -4- (1- Amino-
1-methylethyl) -3-chlorobenzamide Example 27 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-chlorobenzamide Example 28 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-Chlorobenzamide Example 29 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-chlorobenzamide Example 30 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-amino-1-methylethyl) -3
-Chlorobenzamide Example 31 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-fluorobenzamide Example 32 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-Fluorobenzamide Example 33 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-fluorobenzamide Example 34 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-amino-1-methylethyl) -3
-Fluorobenzamide Example 35 N- (4-pyridyl) -4- (1-aminoethyl) -3-bromobenzamide Example 36 N- (4-pyridyl) -4- (1-amino-
1-Methylethyl) -3-bromobenzamide Example 37 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -3-bromobenzamide Example 38 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-bromobenzamide Example 39 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-bromobenzamide Example 40 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-amino-1-methylethyl) -3
-Bromobenzamide Example 41 N- (4-pyridyl) -4- (1-aminoethyl) -3-methylbenzamide Example 42 N- (4-pyridyl) -4- (1-amino-
1-methylethyl) -3-methylbenzamide Example 43 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-methylbenzamide Example 44 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-Methylbenzamide Example 45 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-methylbenzamide Example 46 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-amino-1-methylethyl) -3
-Methylbenzamide Example 47 N- (4-pyridyl) -4- (1-aminoethyl) -3-ethylbenzamide Example 48 N- (4-pyridyl) -4- (1-amino-
1-Methylethyl) -3-ethylbenzamide Example 49 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-ethylbenzamide Example 50 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-ethylbenzamide Example 51 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-ethylbenzamide Example 52 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-amino-1-methylethyl) -3
-Ethylbenzamide Example 53 N- (4-pyridyl) -4- (1-aminoethyl) -3-propylbenzamide Example 54 N- (4-pyridyl) -4- (1-aminoethyl) -3-cyano Benzamide Example 55 N- (4-pyridyl) -4- (1-amino-
1-Methylethyl) -3-cyanobenzamide Example 56 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-aminoethyl) -3-
Cyanobenzamide Example 57 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-methylethyl)-
3-cyanobenzamide Example 58 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4-aminoethyl-3-cyanobenzamide Example 59 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-cyanobenzamide Example 60 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminomethylethyl) -3-cyanobenzamide Example 61 N- (4-pyridyl) -4- (1-aminoethyl) -3-aminomethylbenzamide Example 62 N- (4 -Pyridyl) -4- (1-aminoethyl) -3-methoxybenzamide Example 63 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-aminoethyl) -3-methoxybenzamide Example 64 N- (1H-pyrazolo [2,3-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-methoxybenzamide Example 65 N- (4-pyridyl) -4- (1-aminoethyl) -2-methylbenzamide Example 66 N- (1H- Pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -2-methylbenzamide Example 67 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -2-methylbenzamide Example 68 N- (4-pyridyl) -4- (1-aminoethyl) -2-fluorobenzamide Example 69 N- (1H-pyrazolo) [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -2-fluorobenzamide Example 70 N (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-Aminoethyl) -2-fluorobenzamide Example 71 (R)-(+)-N- (4-pyridyl) -4
-(1-aminoethyl) -2-chlorobenzamide.2
Hydrobromide monohydrate, melting point 248 ° C (decomposition), [α]
_D = + 4.7 ° (methanol, c = 0.5) (Compound 142) Example 72 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -2-chlorobenzamide Example 73 N (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-Aminoethyl) -2-chlorobenzamide Example 74 N- (4-pyridyl) -4- (1-aminoethyl) -2-bromobenzamide Example 75 N- (1H-pyrazolo [ 3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -2-bromobenzamide Example 76 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -2-bromobenzamide Example 77 N- (4-pyridyl) -2-amino-4-
(1-Aminoethyl) benzamide Example 78 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -2-amino-4- (1-aminoethyl) benzamide Example 79 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -2-amino-4- (1-aminoethyl) benzamide Example 80 N- (4-pyridyl) -4- (1-amino-
2-Fluoroethyl) benzamide Example 81 N- (4-pyridyl) -4- (1-amino-
2,82,2-Trifluoroethyl) benzamide Example 82 N- (4-pyridyl) -4- (1-amino-
Cyclopropyl) benzamide Example 83 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-1-cyclopropyl)
Benzamide Example 84 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Amino-1-cyclopropyl) benzamide Example 85 N- (4-pyridyl) -4- (1-amino-
1-propyl) benzamide Example 86 N- (4-pyridyl) -4-aminomethyl-
3,5-Difluorobenzamide Example 87 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-aminomethyl-3,5-difluorobenzamide Example 88 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4-aminomethyl-3,5-difluorobenzamide Example 89 N- (4-pyridyl) -4-aminomethyl-
3,5-dimethylbenzamide Example 90 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-aminomethyl-3,5-dimethylbenzamide Example 91 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4-aminomethyl-3,5-dimethylbenzamide Example 92 N- (4-pyridyl) -4- (1-aminoethyl) -3-carbamoylbenzamide Example 93 N- (1H-pyrazolo [3 , 4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-carbamoylbenzamide Example 94 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-carbamoylbenzamide Example 95 N- (4-pyridyl) -4- (1-aminoethyl) -3-methylcarbamoylbenzamide Example 96 N- (1H- Pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Aminoethyl) -3-methylcarbamoylbenzamide Example 97 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-Aminoethyl) -3-methylcarbamoylbenzamide Example 98 N- (4-pyridyl) -4- (1-aminoethyl) -3-methylthiobenzamide Example 99 N- (4- Pyridyl) -4- (1-aminoethyl) -3-methylsulfonylbenzamide Example 100 N- (1H-2,3-dihydropyrrolo [2,3-
b] pyridin-4-yl) -4- (1-aminoethyl)
Benzamide Example 101 N- (1H-2,3-Dihydro-2-oxopyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide Example 102 N- (1H-3 -Methylpyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide Example 103 N- (1H-2,3-dimethylpyrrolo [2,3-
b] pyridin-4-yl) -4- (1-aminoethyl)
Benzamide Example 104 N- (1H-3-methylpyrazolo [3,4-b]
Pyridin-4-yl) -4- (1-aminoethyl) benzamide Example 105-a N- (2-amino-4-pyridyl)-
4- (1-Aminoethyl) benzamide Example 105-b N- (2-acetylamino-4-pyridyl) -4- (1-aminoethyl) benzamide Example 106 N- (4-pyridyl) -4- ( 1-Aminomethyl-1-methylethyl) benzamide Example 107 N- (4-pyridyl) -4- (2-amino-2-methylpropyl) benzamide Example 108 2- (1-aminoethyl) -5- ( 4-pyridylcarbamoyl) benzoic acid Example 109 2- (1-aminoethyl) -5-((1H-
Pyrrolo [2,3-b] pyridin-4-yl) carbamoyl) benzoic acid Example 110 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4-guadininomethylbenzamide Example 111 N- (1H-2,3-dihydropyrrolo [2,3-
b] pyridin-4-yl) -4-guanidinomethylbenzamide Example 112 N- (1H-2,3-dimethylpyrrolo [2,3-]
b] pyridin-4-yl) -4-guanidinomethylbenzamide Example 113 N- (1H-2,3-dihydro-2-oxopyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylbenzamide Example 114 N- (1H-3-methylpyrrolo [2,3-b] pyridin-4-yl) -4-guanidinomethylbenzamide Example 115 N- (1H-3-methylpyrazolo [3,4-b]
Pyridin-4-yl) -4-guanidinomethylbenzamide Example 116 N- (4-pyridyl) -4- (1-guanidinoethyl) benzamide Example 117 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-Guanidinoethyl) benzamide Example 118 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (1-guanidinoethyl) benzamide Example 119 N- (4-pyridyl) -4- (1-guanidino-1-methylethyl) benzamide Example 120 N- (1H-pyrazolo [3,4 -B] pyridine-
4-yl) -4- (1-Guanidino-1-methyl) benzamide Example 121 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-Methylguanidino) methylbenzamide Example 122 N- (4-pyridyl) -4- (3-ethylguanidino) methylbenzamide Example 123 N- (1H-pyrazolo [3,4-b] Pyridine-
4-yl) -4- (3-ethylguanidino) methylbenzamide Example 124 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-Ethylguanidino) methylbenzamide Example 125 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (3-Propylguanidino) methylbenzamide Example 126 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-Propylguanidino) methylbenzamide Example 127 R-(+)-N- (1H-pyrrolo [2,3-b]
Pyridin-4-yl) -4- (1- (3-propylguanidino) ethyl) benzamide dihydrochloride dihydrate;
Melting point 205-210 ° C (decomposition), [α] _D = + 9.3 ゜ (methanol, c = 0.5) (compound 456). Example 128 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (3-butylguanidino) methylbenzamide Example 129 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-butylguanidino) methylbenzamide Example 130 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (3-phenylguanidino) methylbenzamide Example 131 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-Phenylguanidino) methylbenzamide Example 132 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (3-benzylguanidino) methylbenzamide Example 133 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3-benzylguanidino) methylbenzamide Example 134 N- (1H-Pyrazolo [3,4-b] pyridine-
4-yl) -4- (3- (2-phenylethyl) guanidino) methylbenzamide Example 135 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3- (2-phenylethyl) guanidino) methylbenzamide Example 136 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (3,3-dimethylguanidino) methylbenzamide Example 137 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (3,3-dimethylguanidino) methylbenzamide Example 138 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (2,3-dimethylguanidino) methylbenzamide Example 139 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (2,3-dimethylguanidino) methylbenzamide Example 140 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (2,3-Diethylguanidino) methylbenzamide Example 141 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (2,3-Diethylguanidino) methylbenzamide Example 142 N- (1H-pyrazolo [3,4-b] pyridine-
4-143) -4- (Imidazolin-2-yl) aminomethylbenzamide Example 143 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (imidazolin-2-yl) aminomethylbenzamide Example 144 N- (1H-pyrrolo [3,4-b] pyridine-4
-Yl) -4- (Imidazol-2-yl) aminomethylbenzamide Example 145 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (Imidazol-2-yl) aminomethylbenzamide Example 146 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (pyrimidin-2-yl) aminomethylbenzamide Example 147 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (pyrimidin-2-yl) aminomethylbenzamide Example 148 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (thiazol-2-yl) aminomethylbenzamide Example 149 N- (1H-pyrrolo [2,3-b] pyridine-4
-Yl) -4- (thiazol-2-yl) aminomethylbenzamide Example 150 (R)-(-) N- (1H-pyrrolo [2,3-
b] pyridin-4-yl) -4- (1-aminoethyl)
-3-azidobenzamide dihydrobromide 1/2 hydrate (compound 555) (a) (R) -3-amino-4- (1-acetylaminoethyl) benzoic acid methyl ester 1.38 g, To a mixture of concentrated hydrochloric acid 3 ml and water 9 ml, under ice cooling, 440 mg of sodium nitrite was added, and after stirring at the same temperature for 30 minutes, 420 mg of sodium azide
Was added and stirred for 30 minutes. After the reaction, the mixture was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off to give white (R) -4- (1-acetylaminoethyl).
Crystals of -3-azidobenzoic acid methyl ester were obtained.

(B) (R) -4- (1-acetylaminoethyl) -3
A solution of 1.6 g of azidobenzoic acid methyl ester in 25 ml of 2N hydrochloric acid was heated to reflux for 8 hours. After the reaction, the mixture was concentrated under reduced pressure and azeotroped with toluene to obtain 1.7 g of crude (R) -3-azido-4- (1-aminoethyl) benzoic acid. Next, 1.56 g of benzyloxycarbonyl chloride was added dropwise to a 25 ml aqueous solution of 0.85 g of sodium hydroxide, and the mixture was stirred at room temperature for 5 hours. After the reaction, the solution was adjusted to pH 4 with concentrated hydrochloric acid, extracted with chloroform, washed with water and dried. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give a pale yellow (R) -3-azido-4- (1-benzyloxycarbonylamino). 1.6 g of ethyl) benzoic acid were obtained.

(C) (R) -3-azido-4- (1-benzyloxycarbonylaminoethyl) benzoic acid in dichloromethane 20
4 ml of thionyl chloride, dimethylformamide 1
The mixture was added dropwise and heated under reflux for 2 hours. After the reaction, the residue obtained by evaporating the solvent under reduced pressure was azeotroped with benzene to give (R) -3-azido-4- (1-benzyloxycarbonylaminoethyl) benzoic acid chloride a yellow color. Thus, 1.65 g of crystals were obtained.

Next, 4-amino-1-tert-butoxycarbonyl-
To a solution of 1H-pyrrolo [2,3-b] pyridine in 5 ml of dichloromethane and 25 ml of acetonitrile was added 730 mg of diisopropylethylamine, and then (R) -3-azido-4-
A solution of (1-benzyloxycarbonylaminoethyl) benzoic acid chloride in 10 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added to the reaction solution, extracted with chloroform, washed with water and dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1). (R) -N- (1-tert-butoxycarbonyl-1H-pyrrolo [2,3-b] pyridine-4-yellow amorphous
2.0 g of yl) -3-azido-4- (2-benzyloxycarbonylaminoethyl) benzamide were obtained.

(D) (R) -N- (1-tert-butoxycarbonyl-
2.0 g of 1H-pyrrolo [2,3-b] pyridin-4-yl) -3-azido-4- (2-benzyloxycarbonylaminoethyl) benzamide was dissolved in 25 ml of 98% formic acid and stirred for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, 120 ml of chloroform was added to the obtained residue, and 1N sodium hydroxide (10 ml
× 2), washed with water and dried. Ethanol-ethyl acetate was added to the residue obtained by evaporating the solvent under reduced pressure to crystallize. Recrystallization from chloroform-ethanol gave (R) -N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-azido-4- (1-benzyloxycarbonylaminoethyl) benzamide. White crystal 60
0 mg was obtained.

(E) 25% hydrogen bromide in 400 mg of (R) -N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -3-azido-4- (1-benzyloxycarbonylaminoethyl) benzamide -4 ml of an acetic acid solution was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, the crystals obtained by evaporating the solvent under reduced pressure were recrystallized from ethanol-ethyl acetate to give a compound having a melting point of 21.
(R)-(-)-N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) -3-azidobenzamide at 6-219 ° C (decomposition). Dihydrobromide
285 mg of white crystals of hemihydrate were obtained.

[Α] _D = -14.4 ° (methanol, c = 0.5) Example 151 (R)-(+)-N- (4-pyridyl)-
4- (1-aminoethyl) -2-nitrobenzamide
Dihydrobromide hemihydrate, melting point 240-244 ° C (decomposition), [α] _D = +3.7 ゜ (methanol, c = 0.5) (Compound 126) Example 152 (R)- (-)-N- (4-pyridyl)-
4- (1-aminoethyl) -3-ethoxybenzamide dihydrochloride hemihydrate, melting point 288 ° C (decomposition), [α] _D
= -7.7% (methanol, c = 0.5) (Compound 121) Example 153 (R)-(+)-N- (3-iodo-1H-
Pyrrolo [2,3-b] pyridin-4-yl) -4- (1-
Aminoethyl) benzamide dihydrochloride hemihydrate (Compound 571) (R) -N- (1H-pyrrolo [2,3-b] pyridine-4
To a mixture of a 2 ml aqueous solution containing 20 mg of -yl) -4- (1aminoethyl) benzamide and 10 mg of methyl iodide was added 18 mg of chloramine-T under ice-cooling, followed by stirring at the same temperature for 1 hour. After the reaction, 0.17 ml of 5% sodium thiosulfate and 2 ml of 1N sodium hydroxide were added, and chloroform-methanol (1
0: 1), washed with water and dried. Under reduced pressure, 1 ml of a hydrochloric acid-methanol solution was added to the crystals obtained by evaporating the solvent,
After being converted into a hydrochloride, it was recrystallized from methanol-ether to give (R)-(+) having a melting point of 244-248 ° C (decomposition).
15 mg of pale yellow crystals of -N- (3-iodo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) benzamide dihydrochloride hemihydrate I got

[Α] _D = + 8.5 ° (methanol, c = 0.1) Example 154 (R)-(+)-N- (3-iodo-1H-
Pyrrolo [2,3-b] pyridin-4-yl) -4- (1-
Aminoethyl) -3-azidobenzamide, melting point 185-1
89 ° C. (decomposition), [α] _D = 13.5 ° (methanol, c = 0.
05) (Compound 556) Example 155 (R)-(-)-N- (4-pyridyl)-
4- (1-aminoethyl) -3-hydroxybenzamide dihydrochloride, mp 262-266 ° C (decomposition), [α] _D = −
7.9% (methanol, c = 0.5) (Compound 117) Example 156 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-guanidinomethyl-3-nitrobenzamide dihydrobromide monohydrate, melting point 185-189 ° C
(Decomposition) (Compound 560) Example 157 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-guanidinoethyl)-
3-Nitrobenzamide dihydrobromide monohydrate (compound 561) Melting point 265-275 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 1.60 (3H, d, J = 6.8Hz) , 4.00
−5.00 (4H, brs), 5.27 (1H, qd, J = 6.8,1.9Hz), 7.00−
7.50 (3H, m), 7.75 (1H, m), 7.83 (1H, m), 8.30-8.60
(4H, m), 8.65 (1H, d, J = 1.9Hz), 11.19 (1H, brs), 13.
00 (1H, m) Example 158 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-guanidinomethyl-2-nitrobenzamide (Compound 562) Example 159 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1- Aminoethyl) -2-
Nitrobenzamide dihydrobromide monohydrate (compound 360) (a) 0.9 g of (R)-(1- (N-benzyloxycarbonyl) aminoethyl) -2-nitrobenzoic acid in 5 ml of thionyl chloride And stirred at room temperature for 1 hour. After the reaction,
The reaction solution was concentrated under reduced pressure, and further azeotroped with toluene three times to obtain a yellow oily substance of (R)-(1- (N-benzyloxycarbonyl) aminoethyl) -2-nitrobenzoic acid chloride. Subsequently, 4-amino-1-trityl-1H
-Pyrazolo [3,4-b] pyridine 1 g, triethylamine
To a mixture of 0.74 ml and 7 ml of dichloromethane was added (R)-
Dichloromethane of (1- (N-benzyloxycarbonyl) aminoethyl) -2-nitrobenzoic acid chloride
A 5 ml solution was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. After the reaction, the reaction solution was washed with 50 ml of water and dried. The solvent was distilled off under reduced pressure to give (R) -N- (1-trityl-1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-
(N-benzyloxycarbonyl) aminoethyl) -2
1.5 g of a yellow solid of nitrobenzamide were obtained.

Melting point 159-161 ° C PMR (CDCl _{3 /} TMS) δ: 1.40 (3H, d, J = 6.2 Hz), 4.75 (1
H, m), 4.92 (1H, d, J = 2.2Hz), 5.00 (1H, d, J = 2.2Hz),
5.23 (1H, m), 7.00-7.40 (17H, m), 7.56 (2H, s), 7.90
(1H, s), 8.15 (1H, s), 8.35 (1H, m), 9.08 (1H, brs) (b) (R) -N- (1-trityl-1H-pyrazolo [3,
4-b] Pyridin-4-yl) -4- (1- (N-benzyloxycarbonyl) aminoethyl) -2-nitrobenzamide (0.5 g) was dissolved in a 25% hydrobromic acid-acetic acid solution,
Stirred at room temperature for 1.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was washed with a mixed solvent of hexane and ethyl acetate, and crystallized from a mixed solvent of methanol and ethyl acetate to give (R) -N- (1H-pyrazolo [ 3,4-b)
Pyridin-4-yl) -4- (1-aminoethyl) -2
0.31 g of pale yellow crystals of -nitrobenzamide dihydrobromide monohydrate was obtained.

Melting point 220-225 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 1.56 (3H, d, J = 6.9Hz), 4.00
−5.00 (4H, brs), 4.72 (1H, m), 7.90 (1H, m), 7.98 (1
H, d, J = 7.8Hz), 8.05 (1H, d, J = 7.8Hz), 8.44−8.56 (6
H, m), 11.61 (1H, brs) Example 160 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-guanidinoethyl)-
2-Nitrobenzamide (compound 563) (a) (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-aminoethyl) -2-nitrobenzamide.2 A mixture of 224 mg of hydrobromide monohydrate, 0.25 ml of triethylamine and 5 ml of methanol was added at room temperature to N, N'-dibenzyloxycarbonyl-S
After adding 215 mg of -methylisothiourea, the mixture was stirred at room temperature for 14 hours, and further stirred at 40 ° C for 7.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give (R) -N-
(1H-pyrazolo [3,4-b] pyridin-4-yl) -4
166 mg of a pale yellow oily substance of-(1- (2 ', 3'-dibenzyloxycarbonyl) guanidinoethyl) -2-nitrobenzamide was obtained.

(B) (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1- (2 ', 3'-dibenzyloxycarbonyl) guanidinoethyl) -2- 165 mg of nitrobenzamide was dissolved in 3 ml of a 25% hydrobromic acid-acetic acid solution and stirred at 40 ° C. for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from a mixed solvent of methanol and ethyl acetate, and further recrystallized from the same solvent to give (R) -N- (1H-pyrazolo [3,4] -B] 140 mg of white crystals of pyridin-4-yl) -4- (1-guanidinoethyl) -2-nitrobenzamide were obtained.

PMR (DMSO-d _{6 /} TMS) δ: 1.57 (3H, d, J = 6.8 Hz), 4.00
−4.50 (4H, brs), 5.20 (1H, m), 7.00−7.40 (3H, m),
7.80-9.00 (7H, m), 11.47 (1H, m), 13.00 (1H, m) Example 161 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4 -(1-aminoethyl) -2-
Azidobenzamide (Compound 558) Example 162 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) 2-azido-4- (1-guanidinoethyl) benzamide (Compound 565) Example 163 (R) -5-((1H-pyrazolo [3,4-b]
Example 164 (R) -5-((1H-Pyrazolo [3,4-b]) pyridin-4-yl) carbamoyl) -2- (1-aminoethyl) benzoic acid (compound 369)
Pyridin-4-yl) carbamoyl) -2- (1-aminoethyl) benzoic acid methyl ester (Compound 371) Example 165 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -3,5-dimethyl-4-guanidinomethylbenzamide (compound 556) Example 166 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-guanidinobenzamide dihydrobromide monohydrate (compound 567) Melting point 286-290 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 3.80-4.30 (4H, brs), 7.42
(2H, d, J = 8.7Hz), 7.60-7.80 (4H, m), 8.10 (2H, d, J
= 8.7Hz), 8.51 (1H, m), 9.96 (1H, s), 10.98 (1H, br
s) Example 167 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-aminoethyl) -3-
Nitrobenzamide dihydrobromide monohydrate (compound 359) Melting point 198-210 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 1.61 (3H, d, J = 6.9 Hz), 3.60
−4.00 (4H, brs), 5.90 (1H, m), 7.75 (1H, m), 8.05 (1
H, m), 8.31-8.48 (6H, m), 8.64 (1H, s), 11.14 (1H, br
s) Example 168 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1- (imidazole-2-
Example 169 (R) -N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-aminoethyl) -3-nitrobenzamide (Compound 526) Compound 311) Example 170 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-aminoethyl) -3-
Azidobenzamide (Compound 557) Example 171 (R) -N- (4-pyridyl) -4- (1
-Guanidinoethyl) benzamide (Compound 396) Example 172 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1-guanidinoethyl) benzamide dihydrochloride Monohydrate (Compound 511) Melting point 210-216 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 1.46 (3H, d, J = 6.8 Hz), 4.01
(4H, m), 4.91 (1H, m), 7.24 (3H, m), 7.54 (2H, d, J =
8.3Hz), 7.80 (1H, m), 8.00 (2H, d, J = 8.3Hz), 8.48 (3
H, m), 11.00 (1H, m), 13.75 (1H, m) Example 173 (R) -N- (1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-guanidino Ethyl) benzamide (Compound 118) Example 174 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4- (1-amino-2-hydroxyethyl) benzamide dihydrobromide monohydrate (compound
568) (a) To a solution of 700 mg of N-benzyloxycarbonyl-4-methoxycarbonylphenylglycine in 20 ml of methanol was slowly added 296 mg of sodium borohydride at room temperature, followed by stirring at the same temperature for 4 hours. After the reaction, 1N hydrochloric acid was added to the residue obtained by evaporating the solvent under reduced pressure, extracted with chloroform, washed with water and dried. The crystals obtained by evaporating the solvent under reduced pressure were recrystallized from ethyl acetate-hexane to give 4- (1- (N-benzyloxycarbonyl) amino-2-hydroxyethyl) benzoic acid methyl ester as a white powder. 510 mg were obtained.

PMR (CDCl _{3 /} TMS) δ: 3.86 (1H, m), 3.89 (3H, s), 3.9
2 (2H, d, J = 8Hz), 4.88 (1H, brs), 5.08 (2H, m), 7.20
-7.50 (17H, m), 8.00 (2H, d, J = 8Hz) (b) 4- (1- (N-benzyloxycarbonyl) amino-2-hydroxyethyl) benzoic acid methyl ester
0.418 ml of diisoprolethylamine and 740 mg of trityl bromide were added to a solution of 500 mg of dichloromethane in 20 ml of dichloromethane, and the mixture was stirred at room temperature for 9 hours. After the reaction, water was added to the reaction solution, extracted with dichloromethane, washed with water and dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 890 mg of methyl 4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzoate. Light yellow crystals were obtained.

PMR (CDCl _{3 /} TMS) δ: 3.44 (2H, d, J = 8Hz), 3.88 (3H,
s), 4.87 (1H, brs), 5.02 (2H, m), 5.48 (1H, brs), 7.1
5-7.40 (22H, m), 7.97 (2H, d, J = 8Hz) (c) 890 mg of methyl 4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzoate, 20 ml of methanol To a mixture of and 5 ml of dioxane, a 5 ml aqueous solution of 62 mg of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. After the reaction, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give 4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzoic acid
330 mg were obtained.

PMR (CDCl _{3 /} TMS) δ: 3.38 (2H, brs), 4.90 (1H, br
s), 5.08 (2H, m), 5.55 (1H, brs), 7.15-7.45 (22H,
m), 8.04 (2H, d, J = 8 Hz) (d) To a solution of 4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzoic acid (200 mg) in dichloromethane (10 ml), thionyl chloride (0.035 ml) was added. Pyridine (0.04 ml) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction,
The reaction solution was concentrated under reduced pressure, and azeotroped with toluene three times to give 4- (1- (N-benzyloxycarbonyl) amino-
Crystals of 2-trityloxyethyl) benzoic acid chloride were obtained. Subsequently, a mixture of 130 mg of 4-amino-1-trityl-1H-pyrazolo [3,4-b] pyridine, 0.8 ml of diisopropylethylamine and 10 ml of dichloromethane was added to a mixture of 4 ml.
-(1- (N-benzyloxycarbonyl) amino-2
A solution of (trityloxyethyl) benzoic acid chloride in 5 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours.
After the reaction, the mixture was extracted with chloroform, washed with water and dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to give N- (1-trityl-1H-pyrazolo [3,4-b] pyridin-4-yl)
260 mg of pale yellow oil of -4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzamide was obtained.

PMR (CDCl _{3 /} TMS) δ: 3.37 (2H, brs), 4.80 (1H, br
s), 5.04 (2H, m), 5.50 (1H, brs), 7.10-7.40 (35H,
m), 7.68 (1H, d, J = 4Hz), 7.75 (2H, d, J = 8Hz), 8.00
(2H, d, J = 8Hz), 8.04 (1H, s), 8.60 (1H, brs), 8.64
(1H, d, J = 4Hz) (e) N- (1-trityl-1H-pyrazolo [3,4-b]
10 ml of a 25% hydrobromic acid-acetic acid solution was added to pyridin-4-yl) -4- (1- (N-benzyloxycarbonyl) amino-2-trityloxyethyl) benzamide, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and amorphous crystals obtained by adding ethyl acetate were crystallized from methanol ethyl acetate to give pale yellow amorphous crystals N- (1H-pyrazolo [3,4-
b] 60 mg of pyridin-4-yl) -4- (1-amino-2-hydroxyethyl) benzamide dihydrobromide monohydrate were obtained.

Melting point 214-216 ° C (decomposition) PMR (DMSO-d _{6 /} TMS) δ: 4.36 (2H, d, J = 4Hz), 4.77
(1H, m), 7.69 (2H, d, J = 8Hz), 7.79 (1H, brs), 8.08
(2H, d, J = 8Hz), 8.45 (1H, brs), 8.62 (3H, brs), 10.9
1 (1H, brs) Example 175 N- (1H-pyrazolo [3,4-b] pyridine-
4-yl) -4-Aminomethyl-3,5-dimethylbenzamide (Compound 559) Example 176 2-amino-2- (4-((1H-pyrazolo [3,4-b] pyridin-4-yl) Example 177 N- (1H-Pyrazolo [3,4-b] pyridi-4
-Yl) -4-aminomethyl-3-nitrobenzamide dihydrobromide dihydrate, mp 205-207 ° C (compound
572) Example 178 N- (1H-pyrazolo [3,4-b] pyridine-
Example 179 (R) -N- (1H-pyrazolo [3,4-b] pyridin-4-yl) -4- (1- (4-yl) -4-aminomethyl-2-cyanobenzamide (compound 573) Aminoethyl) 2-cyanobenzamide (Compound 392) Formulation Example 1: Tablet Compound of the present invention 10.0 mg Lactose 50.0 mg Corn starch 20.0 mg Crystalline cellulose 29.7 mg Polyvinylpyrrolidone K30 5.0 mg Talc 5.0 mg Magnesium stearate 0.3 mg 120.0 mg The present invention The compound, lactose, corn starch and crystalline cellulose were mixed, kneaded using polyvinylpyrrolidone K30 size solution, and granulated through a 20-mesh sieve. 50
After drying at 2 ° C. for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and a tablet of 120 mg was produced using a 7 mm diameter punch.

Formulation Example 2: Capsule compound of the present invention 10.0 mg lactose 70.0 mg corn starch 35.0 mg polyvinylpyrrolidone K30 2.0 mg talc 2.7 mg magnesium stearate 0.3 mg 120.0 mg The compound of the present invention, lactose, corn starch and crystalline cellulose are mixed, and polyvinyl alcohol is mixed. The mixture was kneaded using a pyrrolidone K30 size liquid and granulated through a 20-mesh sieve. 50
After drying at 2 ° C. for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and the mixture was filled in hard capsules (No. 4) to produce 120 mg of capsules.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/445 A61K 31/445 31/47 31/47 31/505 31/505 31/52 31/52 31/53 31/53 31/535 31/535 C07D 213/81 C07D 213/81 215/14 215/14 239/42 239/42 239/48 239/48 401/12 401/12 403/12 403/12 413/12 413/12 417/12 417/12 471/04 471/04 473/34 473/34 487/04 141 487/04 141 144 144 144 145 145 (72) Inventor Keiji Yamagami 3-7-25 Koyada, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd.Drug Discovery Research Laboratories (72) Inventor Hiroyuki Sato 955 Komatsuri, Yoshitomicho, Chikugami-gun, Fukuoka Yoshitomi Pharmaceutical Co., Ltd.

Claims (12)

(57) [Claims] (1) General formula [Wherein, R represents hydrogen, alkyl or cycloalkyl optionally having a substituent on the ring, cycloalkylalkyl, phenyl or aralkyl, or Wherein R ⁶ is hydrogen, alkyl or a formula: —NR ⁸ R ⁹ (where R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, aralkyl or phenyl), and R ⁷ is hydrogen , Alkyl, aralkyl, phenyl, nitro or cyano, or R ⁶ and R ⁷ are combined to further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. And a group which forms a good heterocyclic ring.). R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring. Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to form an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom. . R ² and R ³ are the same or different and are hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, Represents carbamoyl, alkylcarbamoyl or azide. R ⁴ represents hydrogen or alkyl. R ⁵ is pyridine, pyrimidine, pyridazine, triazine,
Pyrazole, triazole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, pyrrolotriazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, cinnoline, quinazoline, quinoline,
Pyridopyridazine, pyridopyrazine, pyridopyrimidine, pyrimidopyrimidine, pyrazinopyrimidine, naphthyridine, tetrazolopyrimidine, thienopyridine, thienopyrimidine, thiazolopyridine, thiazolopyrimidine, oxazolopyridine, oxazolopyrimidine, furopyridine, furopyrimidine, 2,3-dihydropyrrolopyridine, 2,3-dihydropyrrolopyrimidine, 5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine, 5,6,7,8-tetrahydro-1,8- Shows a nitrogen-containing heterocyclic ring selected from the group consisting of naphthyridine and 5,6,7,8-tetrahydroquinoline, and when the nitrogen-containing heterocyclic ring forms a hydrogenated aromatic ring, the carbon atom in the ring is It may be carbonyl, and the nitrogen-containing heterocyclic ring may have a substituent. A is the formula (Wherein R ¹⁰ and R ¹¹ are the same or different and are hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl,
Indicates carboxy or alkoxycarbonyl. Alternatively, R ¹⁰ and R ¹¹ represent a group which forms a cycloalkyl by bonding. l, m, and n each represent 0 or an integer of 1 to 3. ). ] The benzamide compound represented by these, its isomer, or its pharmaceutically acceptable acid addition salt. 2. In the general formula (I), R, R ¹ , R ² , R ³ ,
The benzamide compound according to claim 1, wherein at least one selected from R ⁴ , R ⁵ and A satisfies the following definition, an isomer thereof, or a pharmaceutically acceptable acid addition salt thereof. R represents hydrogen, alkyl or aralkyl which may have a substituent on the ring, or (Wherein R ^6a is hydrogen or a formula: —NR ^8a R ^9a (where R ^8a ,
R ^9a is the same or different and represents hydrogen, alkyl or aralkyl. ) And R ^7a represents hydrogen, alkyl, aralkyl or phenyl. Alternatively, R ^6a and R ^7a are combined to form a heterocyclic ring which may further contain an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent in the ring. ) Represents a group represented by R ¹ represents hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl which may have a substituent on the ring. Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to form an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent together with an adjacent nitrogen atom. . R ² and R ³ are the same or different and represent hydrogen, alkyl, halogen, nitro, amino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, carboxy, alkoxycarbonyl, carbamoyl or acid. R ⁴ represents hydrogen or alkyl. R ⁵ is pyridine, pyrimidine, pyridazine, triazine,
Pyrazole, triazole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, pyrrolotriazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, cinnoline, quinazoline, quinoline,
Pyridopyridazine, pyridopyrazine, pyridopyrimidine, pyrimidopyrimidine, pyrazinopyrimidine, naphthyridine, tetrazolopyrimidine, thienopyridine, thienopyrimidine, thiazolopyridine, thiazolopyrimidine, oxazolopyridine, oxazolopyrimidine, furopyridine, furopyrimidine, 2,3-dihydropyrrolopyridine, 2,3-dihydropyrrolopyrimidine, 5,6,7,8-tetrahydropyrido [2,3-d] pyrimidine, 5,6,7,8-tetrahydro-1,8- Shows a nitrogen-containing heterocyclic ring selected from the group consisting of naphthyridine and 5,6,7,8-tetrahydroquinoline, and when the nitrogen-containing heterocyclic ring forms a hydrogenated aromatic ring, the carbon atom in the ring is It may be carbonyl, and the nitrogen-containing heterocyclic ring may have a substituent. A is the formula (Wherein, R ^10a and R ^11a are the same or different and represent hydrogen, alkyl, haloalkyl, hydroxyalkyl, carboxy or alkoxycarbonyl; or R ^10a and R ^11a
Represents a group which forms a cycloalkyl by bonding. l, m, n
Represents an integer of 0 or 1 to 3, respectively. ). 3. The compound of the formula (I) wherein R, R ¹ , R ² , R ³ ,
The benzamide compound according to claim 1, wherein at least one selected from R ⁴ , R ⁵ and A satisfies the following definition, an isomer thereof, or a pharmaceutically acceptable acid addition salt thereof. R represents hydrogen or alkyl; (Wherein R ^6b is hydrogen or a formula: —NR ^8b R ^9b (where R ^8b ,
R ^9b is the same or different and represents hydrogen or alkyl. ) And R ^7b represents hydrogen or alkyl. Alternatively, R ^6b and R ^7b are bonded to form a group which forms a heterocyclic ring which may further have a nitrogen atom which may have a substituent in the ring. ) Represents a group represented by R ¹ represents hydrogen or alkyl. Alternatively, R and R ¹ represent a group which forms a heterocyclic ring which may combine with an adjacent nitrogen atom to further include a nitrogen atom which may have a substituent in the ring. R ² and R ³ are the same or different and are hydrogen, halogen, nitro,
Hydroxy, aralkyloxy, cyano, carboxy,
Represents alkoxycarbonyl, carbamoyl or azide. R ⁴ represents hydrogen. R ⁵ represents a group derived from pyridine, 1H-pyrrolo [2,3-b] pyridine or 1H-pyrazolo [3,4-b] pyridine which may have a substituent. A is the formula (Wherein R ^10b and R ^11b are the same or different and represent hydrogen, alkyl, hydroxyalkyl or carboxy. Alternatively, R ^10b and R ^11b represent a group which forms a cycloalkyl by bonding. Represents an integer of 0 or 1 to 3, and m
¹ represents 0 or 1. ). 4. A compound of the formula (I) wherein (R) -N- (4-pyridyl) -4- (1-aminoethyl) benzamide and (R) -N- (4-pyridyl) -4- ( 1-aminoethyl) -3-nitrobenzamide, (R) -N- (4-pyridyl) -4- (1-aminoethyl) -3-chlorobenzamide, (R) -N- (4-pyridyl) -4 -(1-aminoethyl) -2-nitrobenzamide, (R) -N- (4-pyridyl) -4- (1-aminoethyl) -2-chlorobenzamide, (R) -N- (1H-pyrrolo [ 2,3-b] pyridine-4-
Yl) -4- (1-aminoethyl) benzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-aminoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-aminoethyl) -3-azidobenzamide, (R) -N- (3-iodo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1- Aminoethyl) -3-
Azidobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-aminoethyl) benzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-aminoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-aminoethyl) -2-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-aminoethyl) -3-azidobenzamide, (R) -N- (4-pyridyl) -4- (1-guanidinoethyl) benzamide, N- (1H-pyrazolo [3,4 -B] pyridin-4-yl)
-4-guanidinomethylbenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-guanidinoethyl) benzamide, N- (1-pyrazolo [3,4-b] pyridin-4-yl)
-4-guanidinomethyl-3-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-guanidinoethyl) -3-nitrobenzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-guanidinoethyl) -2-nitrobenzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1-guanidinoethyl) benzamide, (R) -N- (1H-pyrrolo [2,3-b] pyridine-4-
Yl) -4- (1- (3-propylguanidino) ethyl) benzamide, (R) -N- (1H-pyrazolo [3,4-b] pyridine-4
-Yl) -4- (1-aminoethyl) -3-cyanobenzamide, N- (1H-pyrazolo [3,4-b] pyridin-4-yl)
-4- (1-amino-2-hydroxyethyl) benzamide, and (R) -N- (3-iodo-1H-pyrrolo [2,3-b] pyridin-4-yl) -4- (1-amino The benzamide compound according to claim 1, which is a compound selected from ethyl) benzamide, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. 5. A therapeutic agent for hypertension comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 6. A therapeutic agent for angina pectoris, comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 7. A remedy for asthma comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 8. A remedy for renal and peripheral circulatory disorders, comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 9. A cerebral vasospasm inhibitor comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 10. A smooth muscle relaxant comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 11. A cerebral / coronary vasodilator comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof. 12. A drug for increasing the blood flow of the brain, coronary, renal or peripheral blood, comprising the benzamide compound according to claim 1, its isomer or a pharmaceutically acceptable acid addition salt thereof.