JPH06247966A - 7-azaindole derivative and antiulcer agent comprising the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antiulcer agent. CONSTITUTION:This compound is expressed by formula I [R is (1-4C alkyl- substituted)phenyl, halogen-substituted phenyl, indolyl, etc.; R1 and R2 are H, 1-4C alkyl, (1-4C alkoxy-substituted)phenyl, nitrile, etc.; R3 to R5 are H, OH, 1-4C alkyl(oxycarbonyl), etc.; X is CH2CH2, COO, C0CH2, etc., with the proviso that the case where X-R is CH2CH2Ph and R3 to R5 are H or only H and alkyl, is removed], e.g. 3-phenyl-1-phenethyl-7-azaindole. The compound expressed by formula I is obtained by reacting a compound expressed by formula II with a compound expressed by the formula Z-X-R (Z is halogen, mesyloxy, tosyloxy, OH, etc).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 7-azaindole derivative, a pharmaceutically acceptable addition salt thereof with an acid, and an antiulcer drug containing the addition salt as an active ingredient.

[0002]

2. Description of the Related Art 7-Azaindole derivatives are described in J. Med.
Chem. 15 (1972) 1168, JP-A 1-500834 and the like report, but the 7-azaindole derivative of the present invention and its use as an antiulcer drug are not known at all.

On the other hand, the drugs currently used as antiulcer drugs include gastric acid secretion inhibitors such as H ₂ -inhibitors represented by cimetidine and omeprazole which inhibits proton pump, and drugs having a gastric mucosal protective action. Many drugs are known, and these are used depending on the patient's symptoms.

[0004]

However, it is known that these known drugs have problems in terms of efficacy and side effects. For example, H ₂ represented by cimetidine
-The presence of refractory ulcers with inhibitors, the occurrence of carcinoids and diazepam for omeprazole,
There is a problem such as interaction with other drugs such as reduction of hepatic clearance of phenytoin, and improvement is desired.

[0005]

As described above, conventional drugs have drawbacks such as limited use methods due to their effects and side effects. Therefore, as a result of earnest research based on these findings, the present inventors have found that the following indole derivatives have a remarkable antiulcer effect, and completed the present invention.

According to the present invention, the following formula (I)

[Chemical 15] [In the formula, R represents phenyl, C ₁ -C ₄ alkyl-substituted phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, halogen-substituted or nitro-substituted phenyl, indolyl or pyridyl, and R ₁ and R ₂ are independently of each other. , Hydrogen, C ₁
-C ₄ alkyl, phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, aralkyl, nitrile, or represents carbamyl, or R ₁ and R ₂ together form a ring -
(CH ₂ ) ₄ -or

[Chemical 16] R ₃ , R ₄ and R ₅ independently of one another are hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxycarbonyl, NHR ₆ (R ₆ represents phenyl or aralkyl). Or phenyl, X is CH
₂ CH ₂ , COO, COCH ₂ , CH ₂ CO, CONH, C
OCH ₂ O, COOCH _2, or represents a CH ₂ CH (OH) group, provided that, -X-R is a CH ₂ CH ₂ Ph,
A novel 7-azaindole derivative represented by R ₃ R ₄ and R ₅ is hydrogen or only hydrogen and alkyl are provided, and its addition salt with a pharmaceutically acceptable acid. To be done.

R, R ₁ in the compound represented by the formula (I),
Specific examples of the C ₁ -C ₄ alkoxy-substituted phenyl contained in R ₂ include a phenyl group in which 2-, 3- or 4-position is substituted with methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy and the like. C in R
₁ -C ₄ alkyl-substituted 2-position in the specific examples of the phenyl, 3- or 4-position is methyl, ethyl, propyl, butyl, isopropyl, phenyl group substituted with isobutyl.

Specific examples of C ₁ -C ₄ alkyl in R ₁ and R ₂ include methyl, ethyl, propyl, butyl, isopropyl and isobutyl.

Further, specific examples of C ₁ -C ₄ alkyloxycarbonyl for R ₃ , R ₄ and R ₅ include methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,
Butyloxycarbonyl, and the like.

Examples of the aralkyl in R ₁ , R ₂ and R ₆ include benzyl and phenethyl.

The compounds of formula (I) of the present invention are prepared according to Can. J. Ch.
em. 44 (1966) 2455 A, H. Kelly & J. Parrick, Chem. H
eterocycle comp. 8 (1972) 594 LN Yakhonotiv et.a
l. It can be synthesized by the method shown in the following Reaction-1 using known raw materials described in the literature such as the above and the raw materials synthesized according to those methods.

Reaction-1

[Chemical 17] When X is CH ₂ CH ₂ or CH ₂ CO in Reaction-1, Z means halogen such as chloro or bromine, mesyloxy or tosyloxy, and the reaction uses a base such as sodium hydride, THF, DMF, etc. In an inert solvent. The reaction temperature is preferably ice-cooling to the reflux temperature of the solvent used.

In reaction-1, X is COO, C
OCH _2, COCH ₂ O, the Z in the case of CO ₂ CH ₂ group chlorine, halogen bromine, etc., hydroxy, or R-X-
O- means an acid anhydride, and when it is other than hydroxy, NaH, triethylamine, pyridine, NaOH, K
TH using a base such as OH, Na ₂ CO ₃ , K ₂ CO ₃
The reaction is carried out using a solvent such as F, CH ₂ Cl ₂ , DMF, water or a mixed solvent thereof. When using a mixed solvent, a phase transfer catalyst such as n-Bu ₄ N-HSO ₄ may be further added. The reaction is carried out under ice cooling to the reflux temperature of the solvent.

Next, when Z is hydroxy, the reaction is carried out using dicyclohexylcarbodiimide (DCC), but it is preferred to use a base such as pyridine or paradimethylaminopyridine together. The reaction is carried out under ice cooling to the reflux temperature of the solvent.

Further, in the formula (I), when X is CONH, in Reaction-1, O = C = NR (isocyanate).
At this time, a base such as NaH is used, and TH
The reaction is carried out in an inert solvent such as F or DMF from under ice cooling to the reflux temperature of the solvent.

In the compound of formula (I) of the present invention, X is CH.
_In the case of ₂ CH ₂ , as shown in Reaction-2, JCS Perk
in I (1975) 1910 A. Brodrick et. al., J.
Heterocycle Chem. 26 (1989) 1029 MO Mo
A 2-amino-pyrrole derivative is also used as a starting material and is synthesized by a method similar to the known method described in the literature such as nnet et. al.

Reaction-2

[Chemical 18] In this Reaction-2, when R ₃ ′ and R ₅ ′ in the compound of formula V are hydrogen or C ₁ -C ₄ alkyl, the ketal and acetal thereof are used. In Reaction-2, according to a known method, the reaction is carried out in a solvent such as MeOH or EtOH using concentrated hydrochloric acid as a catalyst. The reaction is preferably carried out at the reflux temperature of the solvent.

As a specific example of the reaction-2, the reaction when ethoxymethylene malonic acid ester is used is shown in the reaction-3.

Reaction-3

[Chemical 19] In Reaction-3, concentrated hydrochloric acid is used as a catalyst, EtOH, MeOH
At a reflux temperature using a solvent such as. The product produced by the reaction can be optionally substituted according to the following Reaction-4.

Reaction-4

[Chemical 20] In reaction-4, first, the compound of formula (VII) is refluxed in POCl ₃ to convert the 4-position hydroxy group into a chloro form. If this is reduced in acetic acid using zinc, Y can be converted to a hydrogen compound. The chlorinated form can be obtained by reacting a substituted amine with a base such as NaH without solvent or using an inert solvent such as DMF, where Y is a substituted amino group, (NHR ₆ )
(In the formula, R ₆ represents phenyl or aralkyl).

Specific examples of the compound of the present invention are as follows.

1) 1-phenethyl-3-phenyl-7
-Azaindole 2) 3-Verdyl-1-phenethyl-7-azaindole 3) 1-phenethyl-7-azaindole 4) 1-phenacyl-3-phenyl-7-azaindole 5) 1- (2-hydroxy- 2-phenylethyl)-
3-Phenyl-7-azaindole 6) 1- (4-nitrophenyloxycarbonyl)-
3-Phenyl-7-azaindole 7) 5-phenoxycarbonyl-6,7,8,9-tetrahydro-pyrido [2,3-b] indole 8) 3-phenyl-1-phenylacetyl-7-azaindole 9 ) 5-Phenylacetyl-4,5-diaza-indeno [3,2-b] indene 10) 1-phenoxycarbonyl-3-phenyl-7-
Azaindole 11) 1-phenyloxyacetyl-3-phenyl-7
-Azaindole 12) 3- (4-methoxyphenyl) -2-methyl-1
-Phenylacetyl-7-azaindole 13) 5-phenylacetyl-6,7,8,9-tetrahydro-pyrido [2,3-b] indole 14) 1-benzyloxycarbonyl-3-phenyl-
7-azaindole 15) 1- (2-methylphenyl) acetyl-3-phenyl-7-azaindole 16) 1- (4-methylphenyl) acetyl-3-phenyl-7-azaindole 17) 1- (4 -Chlorophenyl) acetyl-3-phenyl-7-azaindole 18) 1- (2-chlorophenyl) acetyl-3-phenyl-7-azaindole 19) 1- (4-methoxyphenyl) acetyl-3-phenyl- 7-azaindole 20) 1- (2-methoxyphenyl) acetyl-3-phenyl-7-azaindole 21) 1- (4-nitrophenyl) acetyl-3-phenyl-7-azaindole 22) 3-benzyl- 1- (4-methylphenyl) acetyl-7-azaindole 23) 5- (4-methoxyphenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 24) 1- (3-indolyl) acetyl-3-phenyl-
7-azaindole 25) 3-phenyl-1- (2-pyridyl) acetyl-
7-azaindole 26) 1- (4-methylphenyl) acetyl-7-azaindole 27) 2,3-dimethyl-1- (4-methoxyphenyl) -7-azaindole 28) 2,3-dimethyl-1 -(4-Methoxyphenyl) -7-azaindole 29) 5- (2-methylphenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 30) 5- (4-methylphenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 31) 5- (2-methoxyphenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 32) 5- (2-chlorophenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 33) 5- (4-chlorophenyl) acetyl-6,7,
8,9-Tetrahydro-pyrido [2,3-b] indole 34) 3-phenyl-1-phenylcarbamoyl-7-
Azaindole 35) 1- (4-chlorophenyl) carbamoyl-3-
Phenyl-7-azaindole 36) 5-phenylcarbamoyl-6,7,8,9-tetrahydro-pyrido [2,3-b] indole 37) 5- (4-chlorophenyl) carbamoyl-6,
7,8,9-Tetrahydro-pyrido [2,3-b] indole 38) 3-Cyano-5-ethoxycarbonyl-4-hydroxy-1-phenethyl-7-azaindole 39) 4-anilino-3-cyano- 5-Ethoxycarbonyl-1-phenethyl-7-azaindole 40) 4-Benzylamino-3-cyano-5-ethoxycarbonyl-1-phenethyl-7-azaindole 41) 3-Cyano-5-ethoxycarbonyl-1- Phenethyl-7-azaindole 42) 3-carbamoyl-5-ethoxycarbonyl-1
-Phenethyl-7-azaindole 43) 3-cyano-4-methyl-6-phenyl-1-phenethyl-7-azaindole 44) 3-cyano-6-methyl-4-phenyl-1-phenethyl-7-aza Indole

The compound of formula (I) of the present invention can be converted into an addition salt with a pharmacologically acceptable acid, if desired, and these acid addition salts are also included in the scope of the present invention. . Examples of acid addition salts include hydrochloric acid, hydrobromic acid,
Examples thereof include salts with inorganic acids such as sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, succinic acid, oxalic acid, malic acid and tartaric acid.

When the compound represented by the general formula (I) is used as a medicine, it can be made into various dosage forms. That is, this preparation can be orally administered in the form of liquid preparation such as tablets, dragees, hard capsules, soft capsules, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of injection solution.

In preparing these formulations, conventional additives for formulation, such as excipients, stabilizers, preservatives,
A solubilizer, a wetting agent, an emulsifier, a lubricant, a sweetening agent, a coloring agent, a flavoring agent, a tonicity adjusting agent, a buffering agent, an antioxidant and the like can be added to prepare a formulation.

The administration method and dose of the antiulcer agent of the present invention are not particularly limited and may be appropriately selected depending on various formulation forms, sex of patients and degree of disease. The daily dose of the active ingredient is It is 1 mg to 2000 mg.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these are merely for illustrating the present invention and do not limit the present invention.

Example-1 3-phenyl-1-phenethyl-7-azaindole 3-phenyl-7-azaindole (0.5 g), Na
Add H (60% nujol, 0.11g) to DMF at room temperature for 1
Stir for 5 minutes. After cooling with ice water, phenethyl bromide (0.48 g) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, evaporated, and purified with a silica column. 2% ethyl acetate / chloroform 0.46 g (59.8) of the title compound at the outflow.
%) Was obtained. _{mp 87~88 ℃ PMR (CDCl 3)} ; 3.20 (2H, t, J = 7), 4.58 (2H, t, J = 7), 7.12-
7.15 (4H, m), 7.21-7.30 (4H, m), 7.42 (2H, t, J = 8), 7.54
(2H, dd, J = 2,8), 8.21 (1H, dd, J = 2,8), 8.38 (1H, dd, J = 2,
5) MASS (EI); 299 (M ⁺⁺ 1,90%), 208, 194 (100%), 152, 9
1

Example-2 3-Benzyl-1-phenethyl-7-azaindole In the same manner as in Example-1, 3-benzyl-7-azaindole (0.55 g) to the title compound 0.24 g (29.1).
%) Was obtained. Yellow oil PMR (CDCl ₃ ); 3.12 (2H, t, J = 7), 4.00 (2H, s), 4.47 (2H, t,
J = 7), 6.68 (1H, s), 6.98 (1H, dd, J = 5,8), 7.08 (2H, d, J =
7), 7.17-7.28 (8H, m), 7.71 (1H, dd, J = 2,8), 8.30 (1H, d
d, J = 2,5) MASS (EI); 313 (M ^{+ +} 1,85%), 222 (100%), 208

Example-3 1-Phenethyl-7-azaindole In the same manner as in Example-1, 7-azaindole (1.0
From g), 0.87 g (46.2%) of the title compound was obtained. Oil PMR (CDCl ₃ ); 3.16 (2H, t, J = 7), 4.53 (2H, t, J = 7), 6.36 (1
H, d, J = 3), 6.96 (1H, d, J = 3), 7.06 (1H, dd, J = 5,8), 7.11
(2H, d, J = 8), 7.19-7.28 (3H, m), 7.89 (1H, dd, J = 2,8), 8.
34 (1H, dd, J = 2,5) MASS (EI); 222 (M ⁺ , 10%), 131, 118

Example-4 1-phenacyl-3-phenyl-7-azaindole In the same manner as in Example-1, 3-phenyl-7-azaindole (1.27 g) and phenacyl chloride (1.03).
From g), 0.81 g (39.3%) of the title compound was obtained. _{mp 155~157 ℃ PMR (CDCl 3)} ; 5.84 (2H, s), 7.16 (1H, dd, J = 5,8), 7.30 (1
H, t, J = 7), 7.45 (3H, t, J = 8), 7.53 (2H, t, J = 7), 7.63-7.6
8 (2H, m), 8.10-8.12 (2H, m), 8.26 (1H, dd, J = 2,8), 8.33 (1H, dd, J = 2,5) MASS (EI); 313 (M ⁺ + 1,85%), 208 (100%), 105

Example-5 1- (2-hydroxy-2-phenyl-ethyl) -3-
Phenyl-7-azaindole 1-phenacyl-3-phenyl-7-azaindole (0.45 g) in methanol solution under water cooling with NaBH.
Add ₄ (0.6 g). After stirring at room temperature for 1 hour, water is added and the mixture is extracted with chloroform. The extract is dried over anhydrous sodium sulfate, evaporated and purified on a silica column. 1
5-20% acetic acid ethyl ester / chloroform 0.33 g (86.1%) of the title compound was obtained at the outflow. Oil PMR (CDCl ₃ ); 4.49 (1H, dd, J = 8,14), 4.58 (1H, dd, J = 3,1
4), 5.21 (1H, dd, J = 3,8), 5.66 (1H, brs), 7.16 (1H, dd, J =
5,8), 7.23-7.44 (9H, m), 7.56 (2H, d, J = 8), 8.23 (1H, dd,
J = 2,8), 8.32 (1H, dd, J = 2,5) MASS (EI); 315 (M ^{+ +} 1,90%), 209, 208 (100%), 131

Example-6 1- (4-nitrophenyloxycarbonyl) -3-phenyl-7-azaindole 3-phenyl-7-azaindole (0.58 g), N
To a solution of Et ₃ (2.09 ml) in methylene chloride, under ice cooling, 4
-Nitrophenyl chloroformate (0.72 g) was added and stirring was continued for 3 hours. Water was added to the reaction solution, extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and then evaporated. Purification with a silica column gave 0.6 g (56%) of the title compound in the 3% ethyl acetate / chloroform outlet. _{mp 130~135 ℃ PMR (CDCl 3)} ; 7.36 (1H, dd, J = 5,8), 7.43 (1H, t, J = 7), 7.5
2 (2H, t, J = 7), 7.58 (2H, d, J = 9), 7.67 (2H, d, J = 7), 7.67
(2H, d, J = 7), 7.98 (1H, s), 8.22 (1H, dd, J = 1,8), 8.37 (2
H, d, J = 9), 8.60 (1H, dd, J = 1,5) MASS (EI); 360 (M ^{+ +} 1,10%), 316, 193 (100%)

Example-7 5-phenyloxycarbonyl-6,7,8,9-tetrahydro-pyrido [2,3-b] indole 6,7,8,9-tetrahydro-in the same manner as in Example-6.
Pyrido [2,3-b] indole (0.52 g), phenyl chloroformate (0.45 ml) to 0.71 g (80 g)
%) Of the title compound was obtained. Oil _{PMR (CDCl 3); 1.86-1.96 (} 4H, m), 2.67 (2H, m), 3.11 (2H,
m), 7.20 (1H, dd, J = 5,8), 7.25-7.46 (5H, m), 7.73 (1H, dd, J = 1,8), 8.44 (1H, dd, J =
1,5) MASS (EI); 292 (M ⁺ , 25%), 249 (100%), 221,199, 171

Example-8 1-Phenylacetyl-3-phenyl-7-azaindole In the same manner as in Example-6, 3-phenyl-7-azaindole (1.0 g) and phenylacetyl-chloride (0.
86 ml) gave 0.85 g (52.8%) of the title compound. mp 112-120 ℃ PMR (CDCl ₃ ); 5.03 (2H, s), 7.26-7.50 (9H, m), 7.62 (2H,
d, J = 8), 8.14-8.19 (2H, m), 8.48 (1H, dd, J = 2,5) MASS (EI); 313 (M ^{+ +} 1,60%), 236, 194, 166, 139 , 91
(100%) IR (neat); 1715, 1600

Example-9 5-phenylacetyl-4,5-diaza-indeno [3,
2-b] Indene To a solution of NaH (60% nujol, 0.4 g) in anhydrous DMF was added 4,5-diaza-indeno [3,2-b] indene (0.62 g) under ice-water cooling. After stirring for 15 minutes, phenylacetyl chloride (0.40 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated. Purification with a silica column and ethyl acetate / hexane (1: 3) gave 0.14 g (14%) of the title compound at the outflow. mp 142〜146 ℃ PMR (CDCl ₃ ); 3.72 (2H, s), 5.13 (2H, s), 7.20-7.40 (6H,
m), 7.45 (2H, m), 7.51 (1H, d, J = 7), 7.89 (1H, dd, J = 1,7),
8.37 (1H, dd, J = 1,5), 8.43 (1H, d, J = 7) MASS (EI); 325 (M ^{+ +} 1,25%), 206 (100%), 91

Example 10 1-Phenyloxycarbonyl-3-phenyl-7-azaindole 3-phenyl-7-azaindole (0.58 g) was added to 7.
5% aq. To the mixture of NaOH and methylene chloride was added phenyl chloroformate (0.45 ml) with vigorous stirring while cooling with ice water. The mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with chloroform. It was washed with water, washed with brine, dried over anhydrous magnesium sulfate, and then evaporated. Purify on a silica column to give 0.79 g (84%) of the title compound in the outlet of ethyl acetate / hexane (1: 2). _{mp 103~104 ℃ PMR (CDCl 3)} ; 7.3-7.53 (9H, m), 7.66 (2H, d, J = 8), 8.02 (1
H, s), 8.21 (1H, dd, J = 1,8), 8.60 (1H, dd, J = 1,5) MASS (EI); 314 (M ⁺ , 10%), 270 (100%), 193, 77

Example-11 1-Phenyloxyacetyl-3-phenyl-7-azaindole In the same manner as in Example-10, 3-phenyl-7-azaindole (0.5 g) and phenyloxyacetyl chloride (0.5 g). 42 ml) gave 0.06 g (7%) of the title compound. mp 144-146 ℃ PMR (CDCl ₃ ); 5.92 (2H, s), 7.02 (1H, t, J = 7), 7.08 (2H, s
d, J = 8), 7.25-7.42 (4H, m), 7.50 (2H, t, J = 8), 7.65 (2H, dd, J = 2,8), 8.19-8.22 (2H,
m), 8.46 (1H, dd, J = 2,5) MASS (EI); 329 (M ^{+ +} 1,20%), 207, 194 (100%)

Example-12 2-Methyl-1-phenylacetyl-3- (4-methoxyphenyl) -7-azaindole 3- (4-methoxyphenyl) -2-methyl-in the same manner as in Example-10. 7-Aza Indore (0.71
g) and phenylacetyl chloride (0.44 ml) gave 0.20 g (19%) of the title compound. _{mp 143~148 ℃ PMR (CDCl 3)} ; 2.63 (3H, s), 3.87 (3H, s), 5.08 (2H, s),
7.02 (2H, d, J = 9), 7.19 (1H, dd, J = 4,7), 7.20-7.40 (7H,
m), 7.77 (1H, dd, J = 1,7), 8.36 (1H, dd, J = 1,4) MASS (EI); 357 (M ^{+ +} 1,10%), 238 (100%), 223 , 91

Example-13 5-phenylacetyl-6,7,8,9-tetrahydro-
Pyrido [2,3-b] indole 6,7,8,9-Tetrahydro-pyrido [2,3-b] indole (0.52 g) and phenylacetyl chloride (0.44 ml) in the same manner as in Example-10. To 0.43g
(49%) of the title compound was obtained. mp 79-84 ℃ PMR (CDCl ₃ ); 1.84 (4H, m), 2.61 (2H, m), 3.09 (2H, m),
5.01 (2H, s), 7.17 (1H, dd, J = 5,8), 7.23-7.39 (5H, m), 7.
69 (1H, dd, J = 1,8), 8.32 (1H, dd, J = 1,5) MASS (EI); 290 (M ⁺ , 95%), 172 (100%), 144 (100%) , 91

Example-14 1-Benzyloxycarbonyl-3-phenyl-7-azaindole In the same manner as in Example-10, 3-phenyl-7-azaindole (0.97 g) and carbobenzoxylchloride (0.9%). From 86 ml, 1.28 g (78%) of the title compound was obtained. mp 98-100 ° C PMR (CDCl ₃ ); 7.28 (1H, dd, J = 5,8), 7.36-7.43 (4H, m),
7.47 (2H, t, J = 7), 7.55 (2H, d-like, J = 7), 7.60 (2H, d-lik
e, J = 7), 7.86 (1H, s), 8.16 (1H, dd, J = 1,8), 8.58 (1H, dd,
J = 1,5) MASS (EI); 329 (M ⁺⁺ 1,10%), 283, 91 (100%)

Example-15 1-((2-methylphenyl) acetyl) -3-phenyl-7-azaindole 3-phenyl-7-azaindole (1.0 g), 2-
Methylphenylacetic acid (0.77g), DCC (1.11)
g), DMAP (4-dimethylaminopyridine, 0.3
1 g) was added to methylene chloride, and the mixture was stirred at room temperature overnight.
Dilute hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes, made basic with aqueous sodium hydrogen carbonate and extracted with chloroform. Purify on a silica column and use 1% ethyl acetate / chloroform at the outflow.
Obtained 38 g (82.1%) of the title compound. _{mp 134~136 ℃ PMR (CDCl 3)} ; 2.37 (3H, s), 5.04 (2H, s), 7.17-7.31 (5H,
m), 7.39 (1H, t, J = 8), 7.49 (2H, t, J = 8), 7.64 (2H, d, J =
8), 8.19-8.21 (2H, m), 8.45 (1H, dd, J = 2,5)

Example-16 1- (4-methylphenyl) acetyl-3-phenyl-
7-Azaindole In the same manner as in Example-15, 0.74 g (63%) of the title compound was obtained from 3-phenyl-7-azaindole (0.7 g) and p-tolylacetic acid (0.54 g). mp 133-134 ℃ PMR (CDCl ₃ ); 2.32 (3H, s), 4.97 (2H, s), 7.14 (2H, d, J =
8), 7.27 (1H, dd, J = 5,8), 7.33-7.38 (3H, m), 7.46 (2H, t, J = 7), 7.60 (2H, d, J = 7),
8.14-8.16 (2H, m), 8.46 (1H, dd, J = 2,5) MASS (EI); 327 (M ^{+ +} 1,40%), 194 (100%), 166, 139, 1
05

Example-17 1- (4-chlorophenyl) acetyl-3-phenyl-
7-Azaindole 3-phenyl-7-azaindole (0.7 g) and 4-chlorophenylacetic acid (0.62) were prepared in the same manner as in Example-15.
g) gave 0.94 g (75.3%) of the title compound. _{mp 159~160 ℃ PMR (CDCl 3)} ; 4.99 (2H, s), 7.25-7.40 (6H, m), 7.48 (2H,
t, J = 8), 7.62 (2H, dd, J = 2,8), 8.14 (1H, s), 8.17 (1H, dd,
J = 2,8), 8.46 (1H , dd, J = 2,5) MASS (EI); 349 (M + +3,90%), 347 (M + + 1,99%), 194, 1
66, 125 (100%), 89

Example-18 1- (2-chlorophenyl) acetyl-3-phenyl-
7-Azaindole 3-phenyl-7-azaindole (0.7 g) and 2-chlorophenylacetic acid (0.62) were prepared in the same manner as in Example-15.
The title compound (0.89 g, 71.3%) was obtained from g). _{mp 147~148 ℃ PMR (CDCl 3)} ; 5.11 (2H, s), 7.25 (8H, m), 7.64 (2H, d, J =
8), 8.18-8.20 (2H, m ), 8.45 (1H, dd, J = 2,5) MASS (EI); 349 (M + +3,40%), 347 (M + + 1,65%), 194 (Ten
0%), 166, 125, 89

Example-19 1- (4-methoxyphenyl) acetyl-3-phenyl-7-azaindole In the same manner as in Example-15, 3-phenyl-7-azaindole (0.7 g) and 4-methoxy were prepared. Phenylacetic acid (0.6
The title compound (0.86 g, 69.8%) was obtained from g). mp 113 ℃ PMR (CDCl ₃ ); 3.79 (3H, s), 4.95 (2H, s), 6.87 (2H, d, J =
8), 7.28 (1H, dd, J = 5,8), 7.35-7.40 (3H, m), 7.47 (2H, t, J = 8), 7.62 (2H, d, J = 8),
8.15 (2H, m), 8.47 (1H, dd, J = 2,5) MASS (EI); 343 (M ^{+ +} 1,13%), 194 (100%), 121

Example-20 1- (2-methoxyphenyl) acetyl-3-phenyl-7-azaindole In the same manner as in Example-15, 3-phenyl-7-azaindole (0.7 g) and 2-methoxy were prepared. Phenylacetic acid (0.6
The title compound (0.93 g, 75.4%) was obtained from g). mp 132-134 ℃ PMR (CDCl ₃ ); 3.78 (3H, s), 4.94 (2H, s), 6.91-6.98 (2H,
m), 7.24-7.39 (4H, m), 7.47 (2H, t, J = 8), 7.46 (2H, d, J =
8), 8.16-8.19 (2H, m), 8.45 (1H, dd, J = 2,5) MASS (EI); 343 (M ^{+ +} 1,90%), 194 (100%), 148, 121

Example-21 1- (4-nitrophenyl) acetyl-3-phenyl-
7-Azaindole In the same manner as in Example-15, 3-phenyl-7-azaindole (2.0 g) and 4-nitrophenylacetic acid (1.87) were prepared.
The title compound was obtained from g). _{mp 173~174 ℃ PMR (CDCl 3)} ; 5.14 (2H, s), 7.32 (1H, dd, J = 5,8), 7.40 (1
H, t, J = 7), 7.49 (2H, t, J = 7), 7.62-7.64 (4H, m), 8.15 (1
H, s), 8.18-8.29 (3H, m), 8.47 (1H, dd, J = 2,5) MASS (EI); 358 (M ^{+ +} 1,6%), 194 (100%)

Example-22 3-benzyl-1- (4-methylphenyl) acetyl-
7-Azaindole In the same manner as in Example-15, 3-phenyl-7-azaindole (0.57 g) and 4-methylphenylacetic acid (0.4
The title compound (0.62 g, 66.4%) was obtained from 1 g). mp 116-117 ℃ PMR (CDCl ₃ ); 2.32 (3H, s), 4.01 (2H, s), 4.91 (2H, s),
7.11-7.15 (3H, m), 7.19-7.32 (7H, m), 7.68 (1H, dd, J = 2,
8), 7.77 (1H, s), 8.38 (1H, dd, J = 2,5) MASS (EI); 341 (M ^{+ +} 1,70%), 209, 131 (100%), 105

Example-23 5- (4-methoxyphenyl) acetyl-6,7,8,9
-Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-tetrahydro-pyrido [2,3-b] indole (0.34g), 4- in the same manner as in Example-15.
The title compound (0.05g, 8%) was obtained from methoxyphenylacetic acid (0.33g). mp 115-117 ° C PMR (CDCl ₃ ); 1.83 (4H, m), 2.61 (2H, m), 3.09 (2H, m),
3.78 (3H, s), 4.93 (2H, s), 6.85 (2H, d, J = 8), 7.17 (1H, dd, J = 5,8), 7.30 (2H, d, J = 8),
7.69 (1H, d, J = 8), 8.32 (1H, d, J = 5) MASS (EI); 321 (M ^{+ +} 1,50%), 172, 144 (100%), 121

Example-24 1- (3-indolyl) acetyl-3-phenyl-7-
Azaindole 3-phenyl-7-azaindole (0.7 g) and 3-indoleacetic acid (0.63 g) were prepared in the same manner as in Example-15.
From this, the title compound (0.76 g, 76.7%) was obtained. _{mp 153~154 ℃ PMR (CDCl 3)} ; 5.17 (2H, s), 7.13-7.22 (2H, m), 7.29 (1H,
dd, J = 5,8), 7.35-7.39 (3H, m), 7.47 (2H, t, J = 8), 7.61 (2
H, d, J = 8), 7.79 (1H, d, J = 8), 8.06 (1H, brs), 8.16-8.18
(2H, m), 8.50 (1H, dd, J = 2,5) MASS (EI); 352 (M ^{+ +} 1,50%), 194 (100%), 157, 130

Example 25 3-Phenyl-1- (2-pyridyl) acetyl-7-azaindole 2-pyridylacetic acid hydrochloride (0.62 g) and N-hydroxysuccinimide (0.42 g) in DMF solution. DCC
(0.82 g) is added and the mixture is stirred at room temperature. 3-phenyl-7-azaindole (0.7 g), 4-
Dimethylaminopyridine (0.92 g) was added and the mixture was stirred for 20 hours. The precipitated crystals were removed by filtration, aqueous sodium hydrogen carbonate was added, the mixture was extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, and then evaporated. Purification with a silica column gave the title compound (0.13 g, 11.5%) at the outlet of 10% ethyl acetate / chloroform. PMR (CDCl ₃ ); 5.22 (2H, s), 7.20 (1H, dd, J = 5,8), 7.25-7.
28 (1H, m), 7.36-7.50 (4H, m), 7.63-7.70 (3H, m), 8.16 (1
H, d, J = 7), 8.20 (1H, s), 8.42 (1H, dd, J = 2,5), 8.59 (1H,
d, J = 5) MASS (EI); 314 (+ 1,70%), 194 (100%), 167

Example 26 1- (4-Methylphenyl) acetyl-7-azaindole In the same manner as in Example-15, 7-azaindole (1.0
The title compound (1.76 g, 83%) was obtained from g) and 4-methylphenylacetic acid (1.27 g). mp 93-95 ℃ PMR (CDCl ₃ ); 2.32 (3H, s), 4.94 (2H, s), 6.59 (1H, d, J =
4), 7.13 (2H, d, J = 8), 7.21 (1H, dd, J = 5,8), 7.31 (2H, d, J
= 8), 7.87 (1H, dd, J = 2,8), 7.99 (1H, d, J = 4), 8.41 (1H, d
d, J = 2,5)

Example-27 2,3-Dimethyl-1- (4-methylphenyl) acetyl-7-azaindole 4-methylphenylacetic acid (3.0 g), DCC (2.06)
A solution of g) in methylene chloride is stirred overnight at room temperature. The insoluble matter is filtered off and the filtrate is evaporated. Crude acid anhydride (2.
75 g) was obtained. Separately, a solution of 2,3-dimethyl-7-azaindole (0.7 g) in THF was cooled with ice water under N 2 atmosphere.
aH (60% nujol, 0.21 g) was added and the mixture was stirred for 10 minutes. This reaction solution is added dropwise to the THF solution of the crude acid anhydride obtained above under cooling with ice water. After stirring at room temperature for 2.5 hours, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and then evaporated.
Purified by silica column and 0.87 g at the chloroform outlet.
(65.2%) of the title compound was obtained. mp 81 ℃ PMR (CDCl ₃ ); 2.11 (3H, s), 2.28 (3H, s), 2.54 (3H, s), 4.
95 (2H, s), 7.07-7.12 (3H, m), 7.23-7.25 (2H, m), 7.63 (1
H, dd, J = 2,8), 8.27 (1H, d, J = 4)

Example-28 2,3-Dimethyl-1- (4-methoxyphenyl) acetyl-7-azaindole 2,3-Dimethyl-7-azaindole (0.7 g) was prepared in the same manner as in Example-27. , 4-Methoxyphenylacetic acid (3.32 g) to the title compound (0.57 g, 40.4 g)
%)was gotten. mp 82-83 ℃ PMR (CDCl ₃ ); 2.16 (3H, s), 2.56 (3H, s), 3.78 (3H, s), 4.
94 (2H, s), 6.85 (2H, d, J = 8), 7.17 (1H, dd, J = 5,8), 7.28
(2H, d, J = 8), 7.70 (1H, dd, J = 2,8), 8.31 (1H, dd, J = 2,5) MASS (EI); 295 (M ⁺ + 1,85%), 146 (100%), 121

Example-29 5- (2-methylphenyl) acetyl-6,7,8,9-
Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-Tetrahydro-pyrido [2,3-b] indole (0.52 g), o-in the same manner as in Example-27.
Trilylacetic acid (0.9 g) gave 0.28 g (31%) of the title compound. mp 102-103 ℃ PMR (CDCl ₃ ); 1.85 (2H, m), 2.33 (3H, s), 2.63 (2H, m), 3.
10 (2H, m), 4.98 (2H, s), 7.15-7.22 (5H, m), 7.71 (1H, dd, J = 2,8), 8.30 (1H, dd, J =
2,5) MASS (EI); 305 (M ⁺⁺ 1,100%), 172, 144, 105

Example-30 5- (4-methylphenyl) acetyl-6,7,8,9-
Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-tetrahydro-pyrido [2,3-b] indole (0.34 g), 4-in the same manner as in Example-27.
The title compound (0.27 g, 4 g) was obtained from trilylacetic acid (1.2 g).
4%) was obtained. mp 116-118 ℃ PMR (CDCl ₃ ); 1.83 (4H, m), 2.31 (3H, s), 2.61 (2H, m), 3.
08 (2H, m), 4.96 (2H, s), 7.12 (2H, d, J = 8), 7.16 (1H, dd, J = 5,8), 7.26 (2H, d, J = 8),
7.68 (1H, d, J = 8), 8.32 (1H, d, J = 5) MASS (EI); 305 (M ^{+ +} 1,100%), 172 (100%), 144

Example-31 5- (2-methoxyphenyl) acetyl-6,7,8,9
-Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-Tetrahydro-pyrido [2,3-b] indole (0.34g), 2-
The title compound (0.37g, 58%) was obtained from methoxyphenylacetic anhydride (1.26g). mp 90-95 ℃ PMR (CDCl ₃ ); 1.84 (4H, m), 2.64 (2H, m), 3.10 (2H, m), 3.
78 (3H, s), 4.90 (2H, s), 6.92 (2H, m), 7.16 (1H, dd, J = 5,7), 7.22-7.25 (2H, m), 7.
70 (1H, dd, J = 1,7), 8.30 (1H, dd, J = 1,5) MASS (EI); 321 (M ^{+ +} 1,100%), 173 (100%), 144 (100
%), 121, 91

Example-32 5- (2-chlorophenyl) acetyl-6,7,8,9-
Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-Tetrahydro-pyrido [2,3-b] indole (0.34 g), 2-as described in Example 27.
Chlorophenylacetic anhydride (0.65g) to 0.17g
(26%) of the title compound was obtained. mp 123-125 ° C PMR (CDCl ₃ ); 1.85 (4H, m), 2.64 (2H, m), 3.11 (2H, m), 5.
07 (2H, s), 7.18 (1H, dd, J = 4,7), 7.24-7.26 (2H, m), 7.34
(1H, m), 7.42 (1H, m), 7.71 (1H, dd, J = 1,7), 8.31 (1H, dd,
J = 1,4) MASS (EI) ; 327 (M + +3,30%), 325 (M + + 1,80%), 290, 1
72 (100%), 144 (100%)

Example-33 5- (4-chlorophenyl) acetyl-6,7,8,9-
Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-tetrahydro-pyrido [2,3-b] indole (0.34 g), 4-in the same manner as in Example-27.
Chlorophenylacetic acid (1.36 g) to give the title compound (0.3
5 g, 77%) was obtained. mp 115-117 ° C PMR (CDCl ₃ ); 1.84 (4H, m), 2.61 (2H, m), 3.08 (2H, m), 4.
97 (2H, s), 7.18 (1H, dd, J = 4,7), 7.25-7.35 (4H, m), 7.69
(1H, dd, J = 1,7 ), 8.31 (1H, dd, J = 1,4) MASS (EI); 327 (M + +3,15%), 325 (M + + 1,50%), 225 (Ten
0%), 172 (100%), 144

Example-34 3-Phenyl-1-phenylcarbamoyl-7-azaindole 3-phenyl-7-azaindole (0.19 g) T
NaH (60% nujol, 0.05 g) was added to the HF solution under ice cooling, and 10 minutes later, phenyl isocyanate (0.11 m) was added.
l) was added and stirred for 1 hour. The reaction solution was evaporated, ethyl acetate was added to the residue, and insoluble crystals were collected by filtration to obtain 0.24 g (78%) of the title compound. _{mp 175~178 ℃ PMR (CDCl 3)} ; 7.17 (1H, t-like, J = 7), 7.33 (1H, dd, J = 5,
8), 7.36-7.44 (3H, m), 7.50 (2H, t-like, J = 7), 7.67 (2H,
d-like, J = 7), 7.75 (2H, d-like, J = 7), 8.27 (1H, s), 8.28 (1H, dd, J = 1,8), 8.44 (1H, dd, J = 1,5), 12.04 (1H, br
s) MASS (EI); 314 (M ⁺⁺ 1,3%), 194 (100%)

Example-35 1- (4-chlorophenyl) carbamoyl-3-phenyl-7-azaindole In the same manner as in Example-34, 3-phenyl-7-azaindole (0.58 g) and 4-chlorophenylisocyanate were used. 0.87 g (84%) of the title compound was obtained from the nato (0.46 g). mp 154-158 ° C PMR (CDCl ₃ ); 7.33 (1H, dd, J = 5,8), 7.37 (2H, d, J = 9), 7.3
8 (1H, t, J = 7), 7.50 (2H, t, J = 7), 7.66 (2H, d, J = 7), 7.70
(2H, d, J = 9), 8.23 (1H, s), 8.28 (1H, d, J = 8), 8.43 (1H, d,
J = 5), 12.08 (1H, brs) MASS (EI); 350 (M ^{+ ＋} 3,4%), 348 (M ⁺ + 1,12%), 194 (100
%), 153

EXAMPLE-36 5-Phenylcarbamoyl-6,7,8,9-tetrahydro-pyrido [2,3-b] indole 6,7,8,9-tetrahydro-pyrido in the same manner as in Example-34. From [2,3-b] indole (0.52 g) and phenyl isocyanate (0.33 ml), 0.76 g (87)
%) Of the title compound was obtained. _{mp 115~120 ℃ PMR (CDCl 3)} ; 1.85-1.95 (4H, m), 2.67 (2H, m), 3.31 (2H,
m), 7.12 (1H, t, J = 7), 7.20 (1H, dd, J = 5,8), 7.38 (2H, t, J
= 7), 7.70 (2H, d, J = 7), 7.78 (1H, dd, J = 1,8), 8.27 (1H, d
d, J = 1,5), 12.48 (1H, brs) MASS (EI); 291 (M ⁺ , 50%), 172 (100%), 144, 119

Example-37 5- (4-chlorophenyl) carbamoyl-6,7,8,
9-Tetrahydro-pyrido [2,3-b] indole 6,7,8,9-Tetrahydro-pyrido [2,3-b] indole (0.52 g), 4-in the same manner as in Example-34.
0.6 from chlorophenyl isocyanate (0.46 g)
6 g (68%) of the title compound was obtained. _{mp 154~155 ℃ PMR (CDCl 3)} ; 1.94 (4H, m), 2.66 (2H, m), 3.28 (2H, m), 7.
21 (1H, dd, J = 5,7), 7.32 (2H, d, J = 9), 7.65 (2H, d, J = 9),
7.78 (1H, dd, J = 1,7), 8.26 (1H, dd, J = 1,5), 12.55 (1H, br
s) MASS (EI); 328 (M ^{+ +} 3.5%), 326 (M ⁺ + 1,20%), 172 (100
%), 144

Example-38 3-cyano-5-ethoxycarbonyl-4-hydroxy-1-phenethyl-7-azaindole 2-amino-3-cyano-1-phenethyl-pyrrole (5.35 g), diethylethoxymethylene A solution of malonate (6.02 g) in ethanol was heated to reflux for 14 hours. The solvent is evaporated, diphenyl-ether is added to the residue and heated at 220 ° C. for 1.5 hours. After allowing to cool, hexane is added to the reaction solution, insoluble crystals are collected by filtration, and the crystals are purified by a silica column. 5.18 g (58.2%) of the title compound was obtained at the outlet of 5% ethyl acetate / chloroform. _{mp 192~194 ℃ PMR (CDCl 3)} ; 1.46 (3H, t, J = 7), 3.15 (2H, t, J = 7), 4.46-
4.55 (4H, m), 7.00-7.04 (2H, m), 7.10 (1H, t, J = 8), 7.23-
7.36 (3H, m), 8.82 (1H, s), 11.99 (1H, s) MASS (EI); 335 (M ⁺ , 20%), 290, 231, 185 (100%), 91 IR (nujol); 3120, 2220, 1680, 1630

Example-39 3-Cyano-4-methyl-6-phenyl-1-phenethyl-7-azaindole 3-Cyano-6-methyl-4-phenyl-1-phenethyl-7-azaindole 2-amino Concentrated hydrochloric acid (0.1 ml) was added to an ethanol solution of -3-cyano-1-phenethyl-pyrrole (2.0 g) and benzoylacetone (1.53 g), and the mixture was heated under reflux for 4 hours. The reaction solution was evaporated, saturated aqueous sodium hydrogen carbonate was added to the residue, extracted with chloroform, and purified with a silica column. 3-Cyano-4-methyl-6 was added to the chloroform outlet.
-Phenyl-1-phenethyl-7-azaindole (1.87g, 58.5%), 2% acetic acid ethyl ester /
3-chloro-6-methyl-4-phenyl-1-phenethyl-7-azaindole (1.1
7 g, 36.6 g) were obtained. 3-Cyano-4-methyl-6-phenyl-1-phenethyl-7-azaindole mp 155-156 ° C PMR (CDCl ₃ ); 2.81 (3H, s), 3.22 (2H, t, J = 7), 4.61 (2H, t,
J = 7), 7.08 (2H, d, J = 7), 7.22-7.52 (8H, m), 8.10 (2H, d, J
= 7) IR (nujol); 2220, 1590, 1580 3-cyano-6-methyl-4-phenyl-1-phenethyl-7-azaindole mp 125-126 ° C PMR (CDCl ₃ ); 2.70 (3H, s) , 3.19 (2H, t, J = 7), 4.59 (2H, t, J
J = 7), 7.08-7.10 (3H, m), 7.23-7.35 (4H, m), 7.46-7.61
(5H, m) IR (nujol); 2220, 1580, 1570

Example-40 4-chloro-3-cyano-5-ethoxycarbonyl-1
-Phenethyl-7-azaindole 3-cyano-5-ethoxycarbonyl-4-hydroxy-1-phenethyl-7-azaindole (4.97 g)
Is added to POCl ₃ (large excess) and stirred at reflux for 18 hours. The solvent is distilled off, the residue is made basic with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. Purify on a silica column to give the title compound as a yellow solid, 3.38 g (64.6%) in the 10% ethyl acetate / chloroform outlet. PMR (CDCl ₃ ); 1.45 (3H, t, J = 7), 3.16 (2H, t, J = 7), 4.47 (2
H, q, J = 7), 4.58 (2H, t, J = 7), 7.01 (2H, dd, J = 2,8), 7.25-
7.29 (3H, m), 7.42 (1H, s), 8.90 (1H, s) MASS (EI); 356 (M + +3,20%), 354 (M + + 1,50%), 309, 2
50 (100%), 221, 91

Example 41 4-anilino-3-cyano-5-ethoxycarbonyl-
1-phenethyl-7-azaindole 4-chloro-3-cyano-5-ethoxycarbonyl-1
-Phenethyl-7-azaindole (0.9 g), aniline (1.0 g) in DMF was added to a solution of NaH (60% nujo).
1, 0.15 g) are added and the mixture is stirred under reflux for 5 hours. The solvent was evaporated, water was added to the residue, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and then evaporated. IPE was added to the residue and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate / hexane to give 0.44 g (42.3).
%) Of the title compound was obtained. _{mp 179~182 ℃ PMR (CDCl 3)} ; 1.44 (3H, t, J = 7), 3.16 (2H, t, J = 7), 4.41 (2
H, q, J = 7), 4.50 (2H, t, J = 7), 7.05 (2H, dd, J = 2,8), 7.11
(2H, d, J = 8), 7.16 (1H, s), 7.23-7.27 (4H, m), 7.36 (2H,
t, J = 8), 8.98 (1H, s), 10.24 (1H, brs) MASS (EI); 411 (M ^{+ +} 1,75%), 307, 261 (100%) IR (nujol); 3250, 2220 , 1680, 1600

Example 42 4-Benzylamino-3-cyano-5-ethoxycarbonyl-1-phenethyl-7-azaindole 4-chloro-3-cyano-5 in the same manner as in Example 41.
-Ethoxycarbonyl-1-phenethyl-7-azaindole (1.19 g) and benzylamine (1.57 g) gave 0.57 g (40.1%) of the title compound. _{mp 189~192 ℃ PMR (CDCl 3)} ; 1.37 (3H, t, J = 7), 3.15 (2H, t, J = 7), 4.33 (2
H, q, J = 7), 4.50 (2H, t, J = 7), 5.03 (2H, d, J = 5), 7.06 (2H,
dd, J = 2,8), 7.25-7.40 (9H, m), 8.89 (1H, s), 9.39 (1H, br
s) MASS (EI); 425 (M ⁺⁺ 1,75%), 378, 321, 91 (100%) IR (nujol); 3270, 2220, 1675

Example-43 3-Cyano-5-ethoxycarbonyl-1-phenethyl-7-azaindole 3-carbamoyl-5-ethoxycarbonyl-1-phenethyl-7-azaindole 4-chloro-3-cyano-5 -Ethoxycarbonyl-1
-Phenethyl-7-azaindole (0.83 g) and powder Zn (1.05 g) were added to acetic acid, and the mixture was refluxed with stirring for 6 hours. The solvent was evaporated, saturated aqueous sodium hydrogen carbonate was added to the residue, extracted with chloroform, dried over anhydrous sodium sulfate, and then evaporated. Purify with a silica column and use 10% acetic acid ethyl ester / chloroform with 3-cyano-
5-Ethoxycarbonyl-1-phenethyl-7-azaindole (0.25 g, 33.1%) was obtained, and 3-carbamoyl-5-ethoxycarbonyl-1-phenethyl-7-azaindole (at the outlet of acetic acid ethyl ester). 0.36
g, 45.3%). 3-Cyano-5-ethoxycarbonyl-1-phenethyl-7-azaindole mp 105-106 ° C PMR (CDCl ₃ ); 1.45 (3H, t, J = 7), 3.18 (2H, t, J = 7), 4.45 (2
H, q, J = 7), 4.61 (2H, t, J = 7), 7.00-7.03 (2H, m), 7.10 (1
H, t, J = 7), 7.33-7.42 (3H, m), 8.72 (1H, d, J = 2), 9.11 (1H, d, J = 2) MASS (EI); 320 (M ⁺ +1, 90%), 275, 216 (100%), 187 3-carbamoyl-5-ethoxycarbonyl-1-phenethyl-7-azaindole mp 154-156 ° C PMR (CDCl ₃ ); 1.44 (3H, t, J = 7 ), 3.18 (2H, t, J = 7), 4.44 (2
H, q, J = 7), 4.59 (2H, t, J = 7), 5.63 (2H, brs), 7.06 (2H, d,
J = 8), 7.22-7.29 (3H, m), 7.52 (1H, s), 8.97 (1H, d, J = 2),
9.07 (1H, d, J = 2) MASS (EI); 338 (M ^{+ +} 1,40%), 292, 233 (100%) IR (nujol); 3400, 3200, 1710, 1640, 1615

Reference Example 2-Amino-3-cyano-1-phenethyl-pyrrole Phenethylamine (9.68 g) was added to a solution of sodium (2-cyano-2-cyanomethyl) -vinyl alcoholate (10.4 g) in water (25 ml). Then add acetic acid (25 ml) and heat at 110 ° C. for 15 minutes. After allowing to cool, the solvent was distilled off, and methanol and sodium methylate (28
% Methanol, 46 ml) was added and stirring was continued at room temperature overnight. The solvent is evaporated, water is added to the residue, extracted with chloroform, treated with activated carbon and purified with a silica column. At the outlet of 10% ethyl acetate / chloroform, 11.6 g (69.1%) of the title compound (oil) was obtained.

PMR (CDCl ₃ ); 2.61 (2H, brs), 2.97 (2H, t, J =
7), 4.05 (2H, t, J = 7), 5.63 (1H, d, J = 2), 6.76 (1H, d, J =
2), 7.01 (2H, d, J = 7), 7.23-7.31 (3H, m) IR (neat); 3400, 3330, 2220, 1630

H⁺, K⁺-ATPase inhibitory activity test H prepared from pig stomach⁺, K⁺-Use ATPase to
It measured like this. H ⁺, K⁺-ATPase diluted solution 100μ
l (50 μg of protein) 4 mM Magnesium chloride
10 mM Pipes-Tris containing 20 mM potassium chloride
(PH 6.2) Add to 40 μl of buffer and add 0.1% Na
Add 5 μl of a solution of gericin in ethanol. here
Add 5 μl of dimethyl sulfoxide and add 30 at 37 ° C.
Incubated for minutes. Then 4mM ATP binatori
450 μl of 10 mM Pipes-Tris buffer containing um
Start the reaction by adding, and after 30 minutes, 50% trichloroacetic acid
The reaction was stopped by adding 1 μl of acid. The play that resulted from this reaction
The amount of dephosphorized acid was determined by the method of D. Lebel, G. Poirier et al. (Anal. Bioch
800 nm according to em., 85, 86-89 (1978))
Color measurement and measure the absorbance reading at this time as C1.
To do. Separately, if potassium chloride is not added, perform the same measurement.
The reading of the absorbance at this time is designated as C2. Measuring inhibitory activity
Instead of dimethyl sulfoxide in the above reaction
Dimethyl sulfoxide containing 1-20 mg / ml concentration of inhibitor
Add 5 μl of sid solution and perform the same operation to remove potassium chloride.
Read the absorbance readings with and without um.
Let T1 and T2 respectively. The inhibition% (I) of the inhibitor is
It is calculated by the formula.

I = [(C1-C2)-(T1-T2)] × 1
00 / (C1-C2)

[Table 1]

[0075] The components are uniformly mixed to obtain a powder for direct compression. This is molded into a tablet having a diameter of 6 mm and a weight of 100 mg with a rotary tableting machine.

Formulation Example 2 Granules (1 package) Compound of example 10 10 mg lactose 90 mg corn starch 50 mg crystalline cellulose 50 mg B.I. After uniformly mixing the components of hydroxypropyl cellulose 10 mg ethanol 9 mg A, the solution B is added and kneaded, and the mixture is sized by extrusion granulation and then dried in a dryer at 50 ° C. The dried granules have a particle size of 297 μm to 1460 μm
Granules are prepared by sieving. 200 per packet
Set to mg.

Formulation Example 3 Syrup Compound of Example 10 1.000 g White sugar 30.000 g D-sorbitol 70 W / V% 25,000 g Ethyl paraoxybenzoate 0.030 g Propyl paraoxybenzoate 0.015 g Flavor 0.20 g Glycerin 0.150 g 96% ethanol 0.500 g Distilled water Appropriate amount 100 ml Sucrose, D-sorbitol, methyl paraoxybenzoate
Propyl paraoxybenzoate and the above active ingredients are dissolved in 60 g of warm water. After cooling, a solution of flavoring agent dissolved in glycerin and ethanol is added. Then water is added to the mixture to bring it to 100 ml.

[0078] Sodium chloride and the active ingredient are dissolved by adding distilled water to make the total volume 1.0 ml.

[0079] Glycerin is added to the active ingredient and dissolved. Polyethylene glycol 4000 is added thereto, heated and dissolved, and then poured into a suppository mold and cooled and solidified to produce 1.5 g of a suppository.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Masanori Sugita 50 No. 16 Sanko-cho, Sakado-shi, Saitama Prefecture (72) Inventor Koichi Katsuyama 1-27 Hinode-cho, Sakado-shi, Saitama Room 501 Hinode Mansion (72) Inventor Suzuki Chikako 2-23-22 Yamamuro, Fujimi-shi, Saitama (72) Inventor Koichi Nakamaru 2-24-47 Sekizawa, Fujimi-shi, Saitama

Claims (5)

[Claims] 1. The following formula (I): [In the formula, R represents phenyl, C ₁ -C ₄ alkyl-substituted phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, halogen-substituted or nitro-substituted phenyl, indolyl or pyridyl, and R ₁ and R ₂ are independently of each other. , Hydrogen, C ₁ -C ₄ alkyl, phenyl, C ₁ -C ₄ alkoxy substituted phenyl, aralkyl, nitrile, carbamyl group or R
₁ and R ₂ together form a ring to form-(CH ₂ ) ₄ -or R ₃ , R ₄ and R ₅ independently of each other are hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxycarbonyl, NHR ₆ (R ₆ represents phenyl or aralkyl). Or phenyl, X is CH ₂ CH ₂ , COO, COCH ₂ , CH ₂ CO, C
ONH, COCH ₂ O, COOCH ₂ , or CH ₂ CH
Represents an (OH) group, provided that -X-R is CH ₂ CH ₂ Ph and R ₃ , R ₄ and R ₅ are hydrogen, or are only hydrogen and alkyl]. 7-Azaindole derivatives and their adducts with pharmaceutically acceptable acids. 2. The following formula (II):[In the formula, R₁And R₂Independently of one another, hydrogen, C₁~ C_Four
Alkyl, phenyl, C ₁~ C_FourAlkoxy substituted phenyl
Or represents a aralkyl, aralkyl, nitrile, carbamyl group,
Or R₁And R₂Together to form a ring-(C
H₂)_Four-OrRepresents R₃, R_FourAnd R_FiveIndependently of each other, hydrogen, hydroxy
Shi, C₁~ C_FourAlkyl, C₁~ C_FourAlkyl oxycarbo
Nil, NHR₆(R₆Represents phenyl or aralkyl
Or a compound represented by phenyl]
The following formula (III) ZXR [In formula, R is phenyl, C₁~ C_FourAlkyl substituted phenyl
Le, C₁~ C_FourAlkoxy-substituted phenyl, halogen-substituted
Or nitro-substituted phenyl, indolyl, pyridyl
X is CH₂CH₂, COO, COCH₂, CH₂CO, C
ONH, COCH₂O, COOCH₂, Or CH₂CH
Represents an (OH) group, Z represents halogen, mesyloxy, tosyloxy, hydro
Xy, or R-X-O, where R and X are as defined above.
The compound of
Formula (I) of(In the formula, R₁~ R_Five, X and R are as defined above.
Provided that -X-R is CH₂CH₂Ph and R₃, R_FourAnd R_FiveIs hydrogen or only hydrogen and alkyl
7-azaindole inducement represented by
Method of manufacturing conductor. 3. The following formula (IV): (In the formula, R represents phenyl, C ₁ -C ₄ alkyl-substituted phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, halogen-substituted or nitro-substituted phenyl, indolyl or pyridyl, R ₁ and R ₂ independently of each other, Represents hydrogen, C ₁ -C ₄ alkyl, phenyl, C ₁ -C ₄ alkoxy substituted phenyl, aralkyl, nitrile, carbamyl group, or R
₁ and R ₂ together form a ring to form-(CH ₂ ) ₄ -or Is represented by the following formula (V): [Wherein R ₃ ′, R ₄ and R ₅ ′ are independently of each other hydrogen, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxycarbonyl, NHR ₆ ( R ₆
Represents phenyl or aralkyl) or represents phenyl], or R ₃ ′ in formula V,
When R ₅ ′ is hydrogen or C ₁ -C ₄ alkyl, it is reacted with its ketal and acetal to give the following formula (VI): (In the formula, R and R _{1 to} R ₅ are as defined above. Provided that R is Ph and R ₃ , R ₄ and R ₅ are hydrogen, or are only hydrogen and alkyl. Except) and a method for producing a 7-azaindole derivative. 4. The following formula (VII): (In the formula, R represents phenyl, C ₁ -C ₄ alkyl-substituted phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, halogen-substituted or nitro-substituted phenyl, indolyl or pyridyl, R ₁ and R ₂ independently of each other, Represents hydrogen, C ₁ -C ₄ alkyl, phenyl, C ₁ -C ₄ alkoxy substituted phenyl, aralkyl, nitrile, carbamyl group, or R
₁ and R ₂ together form a ring to form-(CH ₂ ) ₄ -or Of the compound represented by the formula (VIII) is chlorinated and reduced or aminated to form a compound of the following formula (VIII): [Wherein R, R ₁ and R ₂ are as defined above, and Y
Is hydrogen or a substituted amino group (NHR ₆ ) (R ₆ is phenyl, aralkyl)]. 5. The following formula (I): [In the formula, R represents phenyl, C ₁ -C ₄ alkyl-substituted phenyl, C ₁ -C ₄ alkoxy-substituted phenyl, halogen-substituted or nitro-substituted phenyl, indolyl or pyridyl, and R ₁ and R ₂ independently of each other, Represents hydrogen, C ₁ -C ₄ alkyl, phenyl, C ₁ -C ₄ alkoxy substituted phenyl, aralkyl, nitrile, carbamyl group, or R
₁ and R ₂ together form a ring to form-(CH ₂ ) ₄ -or R ₃ , R ₄ and R ₅ independently of one another are hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxycarbonyl, NHR ₆ (R ₆ represents phenyl or aralkyl) or Represents phenyl, X is CH ₂ CH ₂ , COO, COCH ₂ , CH ₂ CO, C
ONH, COCH ₂ O, COOCH ₂ , or CH ₂ CH
(OH) represents a group, however, represented by a -X-R is CH ₂ CH ₂ Ph, or R _3, R ₄ and R ₅ are hydrogen, except when only hydrogen and alkyl) An anti-ulcer drug containing a 7-azaindole derivative or an addition salt thereof with a pharmacologically acceptable acid as an active ingredient.