JPH11130750A - Novel derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel compound that is useful for treatment and prevention of central nervous system disorder as anxiety, depression, obsessive- compulsive neurosis and the like, withdrawal symptoms caused by drug abuse as cocaine, ethanol, nicotine or the like, schizophrenia or troubles relating to spinal trauma. SOLUTION: This novel compound is represented by formula I [R<1> is quinolyl, quinazolinyl and the like; R<2> is a group of the formula: -Y-R<3> (R<3> is phenyl or the like; Y is a lower alkylene) or its salts, typically 2,3- dihydro-1-[[3-[(isoquinoline-1-yl)aminomethyl]phenyl]carbamoyl]-indole. The compound of formula I is prepared by, for example, allowing a compound of formula II as 3-[(isoquinoline-1-yl)aminomethyl]aniline to react with a compound of formula III (X<1> is a halogen) as 4-nitrophenyl chloroformate in a solvent as N,N-dimethylformamide followed by reaction of the product with 2,3- dihydroindole.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel derivative and a salt thereof. In particular, 5-hydroxytryptoamine (5
The present invention relates to a novel derivative having pharmacological activity such as -HT) antagonism and a salt thereof.

The novel derivatives or salts thereof are useful in humans and animals, for example, in the central nervous system of anxiety, depression, obsessive-compulsive disorder, migraine, anorexia, Alzheimer's disease, sleep disorders, polyphagia, panic attacks, etc. CNS) disorders, cocaine,
5-HT for the treatment or prevention of withdrawal symptoms due to substance abuse such as ethanol, nicotine and benzodiazepine, schizophrenia or disorders related to spinal cord trauma and / or head disorders such as hydrocephalus. Useful as antagonism.

[0003]

BACKGROUND OF THE INVENTION 5-HT _2C receptors - derivatives having antagonistic activity International patent application (International Publication No. WO95 / 218
44) Described in WO 95/29177.

[0004]

DISCLOSURE OF THE INVENTION The novel derivatives of the present invention can be represented by the following general formula (I). Wherein R ¹ is a quinolyl group, a quinazolinyl group, an isoquinolyl group or a pyridyl group, and R ² is a group represented by the formula: —Y—R ³ (where R ³ is a phenyl group, cyclo (lower)
Alkyl group, an indolyl group, a lower alkyl in Dazo drill group or 2,3-dihydro-indolyl group, and Y is a bond, means a lower alkylene group or lower alkenylene group); or the formula: represented by -NH-R ⁴ Wherein R ⁴ represents a lower alkylindolyl group, a phenyl group optionally having a lower alkoxy group, or a phenyl (lower) alkyl group, and A represents a lower alkylene.

The target compound (I) of the present invention or a salt thereof can be produced by the following production method. Manufacturing method 1

Manufacturing method 2

Manufacturing method 3

Manufacturing method 4

Manufacturing method 5

Manufacturing method 6 (Wherein R ¹ , R ³ , R ⁴ , Y and A are the same as above, and X ¹ and X ² each represent halogen).

Further, the side chain of the target compound (I) obtained by the above production methods 1 to 6 can be changed within the scope of the compound of the present invention, as shown in the Examples below.

Compounds (I), (Ia), (Ib) and (I
c), (II), (IV), (V), (VI), (VI
Suitable salts of I), (VIII), (IX) and (XI) are the customary non-toxic pharmaceutically acceptable salts and include salts with bases or acid addition salts, for example inorganic bases Such as alkali metal salts (eg, sodium salt, potassium salt, cesium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts; salts with organic bases, eg, organic amines Salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salts (eg, hydrochloride, odor) Hydrochloride, hydroiodic acid, sulfate, phosphate, etc.); organic carboxylic acid addition salts or organic sulfonic acid addition salts (eg, formate, acetate, trif) Fluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p
Salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), and preferred examples thereof are acid addition salts.

In the above and following description of the present specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below.

"Lower" means, unless otherwise indicated, 1 to 6, preferably 1 to 4 carbon atoms.

Preferred "lower alkyl groups" include straight or branched chain alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl , Hexyl and the like, and among them, preferred are those having 1 to 4 carbon atoms, and particularly preferred is methyl.

Preferred "lower alkylene groups" include 1
Linear or branched alkylene having from 6 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc., among which preferred are 1 to 4 carbon atoms Examples thereof include those having an atom, and particularly preferably methylene.

Preferred "lower alkenylene groups" include:
Linear or branched alkenylene having 2 to 6 carbon atoms, for example, vinylene, 1-propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 1-hexenylene and the like, among which preferable ones are mentioned. Includes those having 2 to 4 carbon atoms,
Particularly preferred is vinylene.

Preferred "cyclo (lower) alkyl" groups include cyclopropyl having 3 to 6 carbon atoms.
Examples thereof include cyclobutyl, cyclopentyl, and cyclohexyl, and more preferred is cyclopentyl.

Preferred examples of the "phenyl group optionally having a lower alkoxy group" include phenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl and isopropoxyphenyl, and particularly preferred is methoxyphenyl. Suitable "halogens" include fluorine, chlorine, bromine, iodine.

Preferred embodiments of R ¹ , R ² and A are as follows. R ¹ is a quinolyl group, a quinazolinyl group, an isoquinolyl group or a pyridyl group, and R ² is a group represented by the formula:
During Y-R ³ (wherein, R ³ is a phenyl group, cyclo (lower) alkyl; preferably cyclopentyl, indolyl group, a lower alkyl in Dazo Lil group; preferably methyl Inn Dazo drill or 2,3-dihydro-indolyl group , And Y are a bond, a lower alkylene group; preferably a methylene or lower alkenylene group; preferably vinylene) or a group represented by the formula: —NH—R ⁴ , wherein R ⁴ is a lower alkyl indolyl group; Preferably methyl indolyl,
A phenyl group optionally having a lower alkoxy group; preferably methoxyphenyl, or a phenyl (lower) alkyl group; preferably phenylmethyl) and A is a lower alkylene group; preferably methylene.

The production methods 1 to 6 of the objective compound (I) of the present invention are described in detail below.

Production Method 1 The desired compound (Ia) or a salt thereof can be obtained by reacting the compound (II) or a salt thereof with the compound (III), and then reacting with the compound (IV) or a salt thereof.

Compounds (Ia), (II) and (I
Suitable salts of V) include those exemplified for compound (I).

The reaction is usually carried out with water, methanol, ethanol.
, Propanol, diethyl ether, dioxane, tetrahydrofuran, N, N-dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine, triethylamine, benzene, etc., which do not adversely affect the reaction. In a solvent or a mixture thereof.

The reaction temperature is not particularly limited, but it is usually carried out under cooling, at room temperature or under heating.

Production Method 2 The desired compound (Ib) or a salt thereof is obtained by reacting the compound (V) or a salt thereof with the compound (VI) or a salt thereof to obtain a compound (VII) or a salt thereof.
It can be obtained by reacting with I) or a salt thereof.

Compounds (Ib), (II), (V) and (V
Suitable salts of I) and (VII) include those exemplified for compound (I). This reaction can be performed in the same manner as in Production Method 1 described above.

Production Method 3 The desired compound (Ib) or a salt thereof can be obtained by reacting the compound (II) or a salt thereof with the compound (VIII) or a salt thereof.

Compounds (Ib), (II) and (VI
Suitable salts of II) include those exemplified for compound (I). This reaction can be carried out in the same manner as in the first step of Production Method 1 described above.

Production Method 4 The desired compound (Ib) or a salt thereof can be obtained by reacting the compound (II) or a salt thereof with the compound (IX) or a salt thereof.

Compounds (Ib), (II) and (I
Suitable salts of X) include those exemplified for compound (I). This reaction is the first reaction of the aforementioned production method 1.
It can be performed in the same manner as the process.

Production Method 5 The desired compound (Ic) or a salt thereof can be obtained by reacting the compound (II) or a salt thereof with the compound (X) or a salt thereof.

Compounds (Ic), (II) and (X)
Suitable salts of are those exemplified for compound (I). This reaction can be carried out in the same manner as in the first step of Production Method 1 described above.

Production Method 6 The desired compound (Ic) or a salt thereof can be obtained by reacting the compound (II) or a salt thereof with the compound (XI) or a salt thereof.

Compounds (Ic), (II) and (X
Suitable salts of I) include those exemplified for compound (I).

In the present reaction, when the compound (XI) is used in the form of a free acid or a salt thereof, the reaction is preferably carried out in the presence of a conventional condensing agent. N'-dicyclohexylcarbodiimide; N-
Cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-di-ethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide;N-ethyl-N'- (3-di-methylaminopropyl) carbodiimide; N, N'-carbonylbis-
(2-methylimidazole); pentamethyleneketene-
N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; lower alkyl haloformate {eg, ethyl chloroformate, isopropyl chloroformate and the like}; triphenylphosphine; 2-ethyl-
7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; benzotriazol-1-yl-oxy-tris- (dimethylamino) phosphonium Hexafluorophosphate; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; by reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. So-called Vilsmeier reagent prepared; and the like.

This reaction is usually carried out with water, methanol, ethanol, propanol, dimethyl ether, dioxane,
Tetrahydrofuran, N, N-dimethylformamide,
The reaction is carried out in a conventional solvent or a mixture thereof which does not adversely influence the reaction, such as acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine, triethylamine, benzene and the like.

The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling, at room temperature, or under heating.

The target compound (I) of the present invention can be isolated and purified by a conventional method such as extraction, precipitation, fractionation, crystallization, recrystallization, chromatography and the like.

The target compound (I) thus obtained can be converted into its salt by a conventional method.

The target compound (I) and its salts include solvates [eg clathrate compounds (eg hydrates)].

The compound (I) of the present invention exhibits pharmacological activity such as 5-HT antagonism, especially 5HT _2C antagonism, and therefore, anxiety, depression, obsessive-compulsive disorder, migraine, anorexia Central nervous system (CNS) disorders such as Alzheimer's disease, sleep disorders, binge eating, panic attacks, withdrawal symptoms due to substance abuse such as cocaine, ethanol, nicotine, and benzazepine, schizophrenia, or spinal cord It is useful as a 5-HT antagonism for the treatment or prevention of trauma-related disorders and / or head diseases such as hydrocephalus.

In order to show the usefulness of the target compound (I),
The pharmacological activities of representative compounds of the present invention are shown below.

(1) Test method [^Three H] -mesrazine binding 5-HT of test compound_2CThe affinity for the binding site
In the prefrontal cortex of the rat^ThreeH] -mesurazine
Can be determined by evaluating the substitutability with
You. This method is similar to 1984, by Pazos et al.
The method has been done.

The membrane suspension (500 μl) was mixed with [ ³ H] -mesrazine (1 nM) in a Tris-HCl buffer solution containing 4 mM calcium chloride and 0.1% ascorbic acid (pH 7.4) at 37 ° C. For 30 minutes. Non-specific binding is measured in the presence of mianserin (1 μM). 30n
Used to Supiroperon the M prevents the binding of 5-HT _2A sites. 100 μl of test compound (10 ⁻⁵ M)
Are added one by one. The total volume is 1000 μl. The culture was terminated by rapid filtration using a Brandel Cell Harvester, and the radioactivity was measured by a detector.

(2) Test compound (a) 2,3-dihydro-1- [3-[(isoquinolin-1-yl) aminomethyl] phenylcarbamoyl] indole (b) N- [3-[(isoquinoline -1-yl) aminomethyl] phenyl] -N '-(1-methylindole-
5-yl) urea (c) N- [3-[(pyridin-2-yl) aminomethyl] phenyl] -N '-(1-methylindole-5-
Yl) urea (d) N- [3-[(isoquinolin-1-yl) aminomethyl] phenyl] -phenylacetamide

(3) Test results

For the purpose of therapeutic or prophylactic administration, the desired compound (I) of the present invention and a salt thereof are an organic or inorganic solid or liquid excipient suitable for oral, parenteral and external administration. The compound can be used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient by mixing with a pharmaceutically acceptable carrier such as. Pharmaceutical preparations include solid forms such as tablets, dragees, granules and capsules, or liquid forms such as suspensions, syrups, emulsions and lemonades.

If necessary, an auxiliary agent,
Stabilizers, wetting agents or other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, co-
Starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol and the like.

The dose of Compound (I) may be increased or decreased depending on the age and condition of the patient, the type of disease or condition, and the type of Compound (I) to be applied. Generally, from 0.01 mg to about 500 mg or more per day will be administered to the patient. For the treatment of disease, the compound of interest (I) of the present invention has an average single dose of about 0.05 mg, 0.1 m
g, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 5 mg
Used as 0 mg and 100 mg.

Now, the present invention will be described in further detail with reference to Examples.

Example 1 To a solution of 3-[(isoquinolin-1-yl) aminomethyl] aniline in N, N-dimethylformamide and pyridine was added 4-nitrophenylchloroformate at 5 ° C, and the mixture was cooled to 5 ° C. For 30 minutes and at room temperature for 30 minutes. 2,3-Dihydroindole and triethylamine are added to the reaction mixture. The mixture is stirred for 24 hours at room temperature, the mixture is poured into ice-water and after 30 minutes the precipitate formed is collected by filtration, washed with water, dissolved with methylene chloride, washed with brine and dried over magnesium sulfate. . The solvent is distilled off, and the residue is purified by silica gel chromatography to obtain 2,3-dihydro-1-[[3-[(isoquinolin-1-yl) aminomethyl] phenyl] carbamoyl] indole. m. p. 174-176 ° C IR (nujol): 3460, 1675 cm ^-1 NMR (DMSO-d ₆ , δ): 3.14 (2H, t,
J = 8.5 Hz), 4.09 (2H, t, J = 8.5)
Hz), 4.74 (2H, t, J = 5.7 Hz), 6.
84-6.90 (2H, m), 7.03-7.24 (4
H, m), 7.40-7.73 (5H, m), 7.8.
0-7.85 (2H, m), 7.99 (1H, t, J =
5.6 Hz), 8.32 (1H, d, J = 8.3H)
z), 8.46 (1H, s) Mass: 395 (M + 1)

Example 2 5-amino-1-methylindole (438 mg), te
Trahydrofuran (10 ml), and carbonyldiyl
Stir the mixture of midazole (0.54 g) for 2 hours at room temperature
I do. 3-[(isoquinolin-1-yl) is added to the reaction mixture.
Aminomethyl] aniline (0.57 g) is added. mixture
Stir the material overnight (〜16 hours) at room temperature. Solvent distilled off
And partition the residue between methylene chloride and brine. Profit
From the suspension obtained, the precipitate formed was collected by filtration,
After drying at 40 ° C. under reduced pressure, N- [3-[(isoquinoline
-1-yl) aminomethyl] phenyl] -N '-(1-
Methylindol-5-yl) urea is obtained. m. p. 225-227 ° C IR (nujol): 1635 cm^-1 NMR (DMSO-d ₆, Δ): 3.74 (3H,
s), 4.73 (2H, d, J = 5.8 Hz), 6.3.
2 (1H, d, J = 3.0 Hz), 6.88-6.97
(2H, m), 7.25 (1H, d, J = 3.0H
z), 7.07-7.73 (9H, m), 7.83 (1
H, d, J = 5.8 Hz), 8.03 (1H, m),
8.30-8.40 (2H, m), 8.54 (1H,
s) Mass: 422 (M + 1)

Example 3 The following compounds were obtained in the same manner as in Example 2. N- [3-[(pyridin-2-yl) aminomethyl] f
Enyl] -N '-(1-methylindole-5-yl)
Urea m. p. 182-184 ° C IR (nujol): 1630cm^-1  NMR (DMSO-d ₆, Δ): 3.75 (3H,
s), 4.43 (2H, d, J = 6.0 Hz), 6.
33 (1H, d, J = 3.0 Hz), 6.43-6.5
2 (2H, m), 6.88-7.39 (9H, m),
7.67 (1H, d, J = 1.7 Hz), 7.95
(1H, d, J = 3.8 Hz), 8.37 (1H,
s), 8.54 (1H, s) Mass: 372 (M + 1)

Example 4 3-[(quinazolin-4-yl) aminomethyl] aniline (125 mg), 4-nitrophenyl-N- (1-methylindole-5-yl) carbamate, (187 m
g) and N, N-dimethylformamide (2.5 m
To the solution of l) is added triethylamine (98 μl) at room temperature. The mixture was stirred for 20 hours and the mixture was washed with water (40 m
1), the precipitate formed is collected by filtration, washed with water, recrystallized from 95% ethanol and treated with N- [3-
[(Quinazolin-4-yl) aminomethyl] phenyl]
-N '-(1-methylindol-5-yl) urea is obtained. m. p. 238-40 ° C IR (KBr) 3390, 1691 cm ^-1 NMR (DMSO-d ₆ , δ) 3.74 (3H, s)
4.77 (2H, d, J = 5.8 Hz), 6.32 (1
H, d, J = 3.0 Hz), 6.94 (1H, d, J)
= 7.5 Hz), 7.09-7.43 (6H, m),
7.59 (1H, m), 7.65-7.79 (3H,
m), 8.34 (1H, d, J = 8.0 Hz), 8.4
6 (1H, s), 8.53 (1H, s) 8.74 (1
H, s), 8.88 (1H, t, J = 〜5 Hz) Mass: 423 (M + 1)

Example 5 The following compounds were obtained in the same manner as in Example 4. N- [3-[(quinolin-2-yl) aminomethyl] f
Enyl] -N '-(1-methylindol-5-yl)
Urea m. p. 124-128 ° C IR (KBr) 3298, 1614 cm^-1  NMR (DMSO-d₆, Δ): 3.75 (3H,
s), 4.62 (2H, d, J = 5.8 Hz), 6.3.
3 (1H, d, J = 3.1 Hz), 6.84 (1H,
d, J = 8.9 Hz), 6.98 (1H, d, J = 7.
5Hz), 7.1-7.67 (12H, m), 7.8
7 (1H, d, J = 8.8 Hz), 8.36 (1H,
s), 8.54 (1H, s) Mass: 422 (M + 1)

Example 6 3-[(isoquinolin-1-yl) aminomethyl] ani
Phosphorus (51 mg), Phenyl isocyanate (24 μl)
And a solution of tetrahydrofuran (1 ml) at room temperature
Stir for 8 hours. After evaporation of the solvent, the residue is
Purification by column chromatography, methylene chloride and
Eluted with a mixed solution of
After recrystallization, N- [3-[(isoquinolin-1-yl) a
[Minomethyl] phenyl] -N'-phenylurea is obtained. m. p. 221-222 ° C IR (nujol): 1640 cm^-1  NMR (DMSO-d₆, Δ): 4.23 (2H, d,
J = 5.8 Hz), 6.88-6.98 (3H, m)
7.15-7.44 (10H, m), 7.83 (1H,
d, J = 5.8 Hz), 8.00 (1H, t, J = 5.
8 Hz), 8.32 (1H, d, J = 8.1 Hz),
8.54 (1H, s), 8.59 (1H, s) Mass: 369 (M + 1)

Example 7 The following compounds were obtained in the same manner as in Example 6. N- [3-[(isoquinolin-1-yl) aminomethyl] phenyl] -N'-benzylurea m. p. 198-200 ° C IR (nujol): 1625 cm ^-1 NMR (DMSO-d ₆ , δ): 4.26 (2H, d,
J = 5.9 Hz), 4.70 (2H, d, J = 5.8)
Hz), 6.50 (1H, t, J = 〜6), 6.87
−6.92 (2H, m), 7.13 (1H, t, J =
7.7 Hz), 7.71-7.36 (7H, m), 7.
40-7.33 (3H, m), 7.81 (1H, d,
J = 5.8 Hz), 7.96 (1 H, t, J = 〜6 H)
z), 8.30 (1H, d, J = 8.3 Hz), 8.4
9 (1H, s) Mass: 383 (M + 1)

Example 8 To a solution of 3-[(isoquinolin-1-yl) aminomethyl] aniline (100 mg), pyridine (65 μl) and methylene chloride (2 ml) is added at 5 ° C. phenylacetyl chloride (58 μl). The solution is stirred for 30 minutes and a saturated aqueous sodium bicarbonate solution is added. The mixture was diluted with ethyl acetate, the organic layer was separated, and brine (twice)
, Dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography, eluted with a mixed solution of methylene chloride and methanol, recrystallized from 95% ethanol to give N- [3-
[(Isoquinolin-1-yl) aminomethyl] phenyl] phenylacetamide (36 mg) is obtained. m. p. 181-183 ° C IR (nujol): 3400, 1665 cm ^-1 NMR (DMSO-d ₆ , δ): 3.58 (2H,
s), 4.71 (2H, d, J = 5.8 Hz), 6.8.
9 (1H, d, J = 5.8 Hz), 7.03 (1H,
d, J = 7.7 Hz), 7.16-7.35 (6H,
m), 7.45-7.54 (3H, m), 7.59-
7.73 (2H, m), 7.80 (1H, d, J =
5.8 Hz), 7.98 (1 H, t, J = 〜6 Hz),
8.30 (1H, d, J = 8.0 Hz), 10.08
(1H, s) Mass: 368 (M + 1)

Example 9 The following compounds were obtained in the same manner as in Example 8. N- [3-[(isoquinolin-1-yl) aminomethyl
L] phenyl] benzamide m. p. 98-103 ° C IR (Nujol): 3400, 1655 cm^-1 NMR (DMSO-d ₆, Δ): 4.76 (2H, d,
J = 5.7 Hz) 6.89 (1H, d, J = 5.8H)
z), 7.11 (1H, d, J = 7.6 Hz), 7.2
7 (1H, dd, J = 7.7 and 7.7 Hz), 7.
46-7.76 (11H, m), 8.02 (1H, t,
J = 〜5 Hz), 8.33 (1H, d, J = 8.1H)
z), 10.21 (1H, s) Mass: 354 (M + 1)

Example 10 3-[(isoquinolin-1-yl) aminomethyl] ani
Phosphorus (50 mg), 1-methyl-1H-indazole-
3-carboxylic acid (35 mg) and 1-hydroxyben
N, N-dimethylform
Mix the mixture in amide (5 ml) with WSCD (water-soluble carbodi
Imide, 1- (3-dimethylaminopropyl) -3-e
(Carboxyimide hydrochloride) (38 mg) at 0 ° C.
I can. The reaction mixture was stirred overnight at room temperature and saturated sodium bicarbonate
Pour into aqueous thorium solution. Extract the mixture with ethyl acetate
And dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.
You. The residue was purified by silica gel column chromatography.
Purify and elute with hexane-ethyl acetate (3: 2)
Triturate with isopropyl ether and add N- [3-[(
Nolin-1-yl) aminomethyl] phenyl] -1-me
Cyl-1H-indazole-3-carboxamide (50
mg). m. p 173-175 ° C IR (Nujol) 3350, 1655 cm^-1  NMR (DMSO-d₆, Δ) 4.18 (3H, s)
4.77 (2H, d, J = 5.8 Hz) 6.90 (1
H, d, J = 5.8 Hz), 7.08-7.12 (1
H, m), 7.22-7.35 (2H, m), 7.46.
−7.56 (2H, m), 7.60-7.85 (5H,
m) 7.92 (1H, s), 8.02 (1H, t, J =
5.8 Hz), 8.20 (1 H, d, J = 8.1 H)
z), 8.34 (1H, d, J = 8.1 Hz) Mass: 408 (M + 1)⁺

Example 11 3-[(isoquinolin-1-yl) aminomethyl] aniline (100 mg), trans-cinnamic acid (59 m)
g), WSCD (water-soluble carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
Hydrochloride) (92 mg), and methylene chloride (2 ml)
Is stirred at room temperature for 4 hours, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is purified by silica gel column chromatography and eluted from a mixed liquid of methylene chloride and methanol to obtain N- [3-[(isoquinolin-1-yl) aminomethyl] phenyl] cinnamic acid amide. m. p. 216-218 ° C IR (nujol): 3360, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 4.76 (2H, d,
J = 5.8 Hz), 6.80 (1H, d, J = 15.7)
Hz), 6.90 (1H, d, J = 5.6 Hz), 7.
26 (1H, dd, J = 7.7 and 7.7 Hz),
7.40-7.74 (12H, m), 7.82 (1H,
d, J = 5.8 Hz), 8.04 (1H, t, J = 5.
9Hz), 8.32 (1H, d, J = 8.1 Hz),
10.14 (1H, s) Mass: 380 (M + 1)

Example 12 The following mixture was obtained in the same manner as in Example 11. N- [3-[(isoquinolin-1-yl) aminomethyl] phenyl] indol-2-yl) acetamide m. p. 94-96 ° C IR (nujol): 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 3.76 (2H,
s), 4.73 (2H, d, J = 5.7 Hz), 6.2.
3 (1H, s), 6.87-7.16 (4H, m),
7.22 (1H, t, J = 7.7 Hz), 7.31 (1
H, d, J = 7.8 Hz), 7.39-7.73 (6
H, m), 8.81 (1H, d, J = 5.8 Hz),
8.00 (1H, t, J = 〜5 Hz), 8.31 (1
H, d, J = 8.2 Hz), 10.11 (1H, s),
10.97 (1H, brs) Mass: 407 (M + 1)

Example 13 The following compounds were obtained in the same manner as in Example 11. N- [3-[(isoquinolin-1-yl) aminomethyl] phenyl] cyclopentanecarboxamide m. p. 168-169 ° C IR (nujol): 3360, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.40-1.90
(8H m) 2.73 (1H, quintuple, J = 〜7H
5. z), 4.71 (2H, d, J = 5.8 Hz);
89 (1H, d, J = 5.7 Hz), 7.01 (1H,
d, J = 7.6 Hz), 7.19 (1H, dd, J =
7.6 and 7.6 Hz), 7.43-7.59 (3
H, m), 7.63 (1H, dd, J = 〜7 and ７7
Hz), 7.69 (1H, dd, J = 〜7 and ７7)
Hz), 7.81 (1H, d, J = 5.8 Hz), 7.
99 (1H, t, J = 5.6 Hz), 8.31 (1H,
d, J = 7.9 Hz), 9.78 (1H, brs) Mass: 346 (M + 1)

Example 14 3-[(isoquinolin-1-yl) aminomethyl] aniline (125 mg), 2-methoxyphenyl isocyanate (66 μl) and tetrahydrofuran (1 ml)
Is stirred at room temperature for 24 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
Elution with a mixed solution of methylene chloride and methanol, 95%
Recrystallization from ethanol gives N- [3- (isoquinolin-1-yl) aminomethyl] phenyl-N '-(2-methoxyphenyl) urea. m. p. 160-161 ° C IR (KBr): 3348, 1691 cm ^-1 NMR (DMSO-d ₆ , δ): 3.84 (3H,
s), 4.74 (2H, d, J = 5.8 Hz), 6.8
3-7.01 (5H, m), 7.20 (1H, dd, J
= 7.7, 7.7 Hz), 7.30 (1H, brs),
7.40-7.55 (2H, m), 7.64 (1H, d
d, J = 7.7 Hz), 7.70 (1H, dd, J =
7.7 Hz), 7.82 (1H, d, J = 5.8H)
z), 8.00 (1H, t, J = 5.6 Hz), 8.1
1 (1H, dd, J = 7.2 Hz), 8.16 (1H,
s), 8.32 (1H, d, J = 8.3 Hz), 9.2
2 (1H, s) Mass: 399 (M + 1)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/47 AAN A61K 31/47 AAN ABJ ABJ ACJ ACJ ADR ADR ADR AEN AEN 31/505 AAE 31/505 AAE C07D 215/38 C07D 215 / 38 217/22 217/22 239/84 239/84 401/12 209 401/12 209 403/12 209 403/12 209 231 231 (72) Inventor Yuka Noda 5-8-D73- 203 (72) Inventor Masayuki Kato 6-16-12, Goryo Oedayamacho, Nishikyo-ku, Kyoto-shi, Kyoto

Claims (1)

[Claims] 1. The general formula: Wherein R ¹ is a quinolyl group, a quinazolinyl group, an isoquinolyl group or a pyridyl group, and R ² is a group represented by the formula: —Y—R ³ (where R ³ is a phenyl group, cyclo (lower)
Alkyl group, an indolyl group, a lower alkyl in Dazo drill group or 2,3-dihydro-indolyl group, and Y is a bond, means a lower alkylene group or lower alkenylene group); or the formula: represented by -NH-R ⁴ Wherein R ⁴ represents a lower alkyl indolyl group, a phenyl group optionally having a lower alkoxy group, or a phenyl (lower) alkyl group, and A represents a lower alkylene; salt.