JPH083144A - Quinazoline and quinoline derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound, having actions as a potassium channel opener and useful as a vasodilator capable of manifesting strong vasodilator actions. CONSTITUTION:This compound is expressed by formula I [A and B are each N or CH; R1 and R2 are each H, a lower alkyl, a lower haloalkyl, a lower alkoxy, etc.; R3 is H, a (substituted) lower alkyl or a (substituted) aryl; R4 is a heterocyclic ring group, a carbamide, a carbothioamide, a cyanamide, etc.] and its pharmaceutically permissible salt, e.g. 2-ethyl-4-(1,2-dihydro-2- oxopyridyl)-6-nitroquinazoline. The compound of formula I is obtained by reacting a compound of formula II with a phosphorus halide, a phosphoryl halide or a thionyl halide, providing a compound of formula III (X is a halogen) and then reacting the resultant compound with a compound of the formula, R4H in the presence of a suitable base in an inert solvent at 0-150 deg.C.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel general formula (1) having a strong vasodilatory action as a potassium channel opener.

Embedded image (In the formula, A and B are the same or different and represent N or CH, and R ₁ and R ₂ are a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a halogen atom, a cyano group, A nitro group, a lower alkylsulfonyl group, a lower haloalkylsulfonyl group, an arylsulfonyl group, an acyl group, a carboxyl group, an ester group, an amide group, and R ₃ represents a hydrogen atom or an optionally substituted lower alkyl group, An aryl group which may have a substituent, R ₄ is a saturated or unsaturated heterocyclic group, a carboxamide group, a carbothioamide group, a cyanamide group, an amino group which may have a substituent, a lower alkoxy group ,
A cycloalkyloxy group, an aryloxy group or a heteroaryloxy group) or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art It has been conventionally known that quinazoline and quinoline derivatives are useful as medicines.

For example, Japanese Patent Publication No. 46-10543,
JP-A-46-4377, JP-A-47-2927, JP-A-47-4873, JP-A-48-72180, JP-A-49-69684, JP-A-49-72279, and JP-A-51-36469. , Ibid. 52-89682
Japanese Patent Publication No. 58-172379, Japanese Patent Application Laid-Open No. 2-16
No. 7277, No. 3-56469, No. 4-33
8378, U.S. Pat. Nos. 3,954,987, 4011323, etc. show that a series of quinazoline and quinoline derivatives have a vasodilatory action and a bronchodilatory action.

Further, as potassium channel openers, benzopyran compounds such as cromakalim have been known so far.

[0005]

However, none of the conventional quinazoline- and quinoline-based compounds show excellent activity as pharmaceuticals, and even in benzopyran-based compounds, the action of cromakalim as a potassium channel opener is still unsuccessful. Since it is not satisfactory, it has been desired to search for a compound having a stronger action.

[0006]

Means for Solving the Problems The present inventors have conducted extensive studies in order to search for a compound which has an action as a potassium channel opener and is an excellent vasodilator having a strong vasodilator action. The present invention has been completed by finding that the compound represented by the general formula (1) exhibits excellent activity.

In the compound of the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, specifically, a methyl group. , Ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-
Examples thereof include a butyl group.

The lower alkoxy group has 1 to 6 carbon atoms,
Preferably, it is a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group. Group, i-butoxy group, t-butoxy group and the like.

The lower haloalkyl group means a lower alkyl group in which one or more halogen atoms are substituted, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pentafluoroethyl group and a heptafluoropropyl group. To be

The lower haloalkoxy group means a lower alkoxy group in which one or more halogen atoms are substituted,
Preferred are fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, pentafluoroethoxy group, heptafluoropropoxy group and the like.

The halogen atom means a chlorine atom, a fluorine atom, a bromine atom, an iodine atom and the like.

The lower alkylsulfonyl group is, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t. -Butylsulfonyl group and the like can be mentioned.

The lower haloalkylsulfonyl group is a lower alkylsulfonyl group in which any hydrogen atom is substituted with one or more halogen atoms, and examples thereof include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group,
Examples thereof include trifluoromethylsulfonyl group.

Examples of the arylsulfonyl group include a phenylsulfonyl group, a naphthylsulfonyl group, a tolylsulfonyl group, a xylylsulfonyl group, a biphenylsulfonyl group and the like.

Examples of the acyl group include an acetyl group, a formyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a hexanoyl group, a benzoyl group and a benzyloxycarbonyl group, and an acetyl group is preferable.

As the ester group, for example, a lower alkyl ester group such as a methyl ester group, an ethyl ester group, a propyl ester group and a butyl ester group is preferably used.

In the definition of R _3, the lower alkyl which may have a substituent is, for example, a lower alkyl group which may be appropriately substituted with a halogen atom, an amino group, a nitro group, a cyano group or the like, Preferably a fluoromethyl group,
Examples thereof include trifluoromethyl group and aminomethyl group.

In the aryl group which may have a substituent, the aryl group is selected from aromatic hydrocarbon to hydrogen atom 1
Means a monovalent substituent except for phenyl group, tolyl group, xylyl group, biphenyl group, naphthyl group, anthryl group, phenanthryl group, etc., and any carbon atom on the ring is a halogen atom. , A lower alkyl group, a hydroxyl group, an alkoxy group, an amino group, a nitro group, a trifluoromethyl group, or the like.

As the saturated or unsaturated heterocyclic group, a nitrogen atom, an oxygen atom or a sulfur atom is used as a hetero atom.
It is a saturated or unsaturated 3- to 8-membered ring group contained in one or more rings, and may be condensed with one or more rings. Specifically, pyrrolidinyl group, piperidinyl group, pyridinyl group, quinolinyl group, imidazolinyl group, thiazolinyl group, oxazolinyl group, 2-oxopyrrolidin-1-yl group, 2-oxopiperidin-1-yl group, dihydro-
Examples thereof include a 2-oxopyridin-1-yl group, a 1-oxidepyridin-2-yl group, a pyrrolidine-2-oxy group, a piperidine-2-oxy group and a pyridine-2-oxy group.

The amino group which may have a substituent is
Lower alkyl group, aryl group, acyl group as a substituent,
An amino group which may have a lower alkoxy group and the like, for example, a methylamino group, an ethylamino group, a phenylamino group, a pyridylamino group, an acetylamino group, a benzoylamino group, a urea group, a methoxyamino group, an ethoxyamino group. , Benzyloxyamino group and the like.

The cycloalkyloxy group has 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, for example, cyclopropyloxy group, cyclobutyloxy group,
Examples thereof include a cyclopentyloxy group and a cyclohexyloxy group.

Examples of the aryloxy group include a phenyloxy group, a naphthyloxy group, a tolyloxy group, a xylyloxy group and a biphenyloxy group.

In the heteroaryloxy group, heteroaryl is a saturated or unsaturated 3- to 8-membered ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, for example, 2-oxopyrrolidine- 1-yl group, 2-oxopiperidin-1-yl group, dihydro-2
Examples include an -oxopyridin-1-yl group, a 1-oxidepyridin-2-yl group, a pyrrolidine-2-oxy group, a piperidine-2-oxy group and a pyridine-2-oxy group.

The compound represented by the general formula (1) of the present invention can be synthesized, for example, as follows.

First, the general formula (2)

Embedded image (In the formula, A, B, R ₁ , R ₂ and R ₃ have the same meanings as described above), the compound represented by the general formula (3) is reacted with phosphorus halide, phosphoryl halide or thionyl halide. )

[Chemical 4] (In the formula, X represents a halogen atom, A, B, R ₁ , R ₂
And R ₃ has the same meaning as described above).

The phosphorus halide used here is, for example, PCl ₃ , PCl ₅ , PBr ₃ or PBr _5.
Etc. PO as the halogenated phosphoryl
Examples include Cl ₃ and POBr ₃ . Examples of the thionyl halide include SOCl ₂ and SOBr ₂ .

Examples of the solvent used in this step include benzene, toluene, pyridine, quinoline, acetonitrile and the like. The reaction temperature is 20 to 150 ° C. and the reaction time is 1 to 24 hours.

Then, the compound represented by the general formula (3) is added to 0
In the presence of a suitable base in an inert solvent within the range of to 150 ° C, the compound of the general formula (4)

Embedded image A compound represented by the general formula (1) can be obtained by reacting with a compound represented by the formula (wherein R ₄ has the same meaning as described above).

The inert solvent used here is not particularly limited as long as it is inert during the reaction, but aprotic polar solvents such as diethyl ether, tetrahydrofuran, dimethylformamide and the like are preferably used.

Examples of the base include sodium hydride, potassium tert-butoxide, potassium hydroxide and the like.

The compound represented by the general formula (1) of the present invention also has the general formula (5)

[Chemical 6] (Wherein A, B, R ₁ , R ₂ and R ₃ have the same meanings as described above), using a suitable condensing agent,
Whether to react with an amine which may have a substituent or to thionate the obtained amide compound with Lawesson's reagent,
Alternatively, it can be produced by reacting the obtained thioamide compound with cyanamide.

Suitable condensing agents include N, N-carbonyldiimidazole, dicyclohexylcarbodiimide, 2,2-dipyridinedisulfide-triphenylphosphine and the like.

[0033]

【Example】

Example 1 2-Ethyl-4- (1,2-dihydro-2-oxopyrrole
Preparation of zir) -6-nitroquinazoline

1) A mixture of 7.7 g of anthranilic acid and 10 g of thiopropionamide was heated and stirred at 160 ° C. for 1 hour. After cooling, water was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and recrystallized from ethyl alcohol to obtain 5.6 g of 2-ethyl-4-hydroxyquinazoline.

H ¹ -NMR (CD ₃ OD-CDCl ₃ ,
δ) 1.42 (t, 3H, J = 7 Hz), 2.79
(Q, 2H, J = 7 Hz), 7.35-8.50 (m,
4H) MS: 174 (M ⁺ ) Melting point: 236-238 ° C

2) 20 ml of concentrated nitric acid in a mixture of 4.0 g of 2-ethyl-4-hydroxyquinazoline and 20 ml of concentrated sulfuric acid.
1 was added dropwise under ice cooling, and the mixture was further heated at 55 ° C. for 2.5 hours. After cooling to room temperature, ice water was added and the precipitated crystals were collected by filtration and recrystallized from ethyl alcohol to give 2-ethyl-4.
2.9 g of -hydroxy-6-nitroquinazoline was obtained.

H ¹ -NMR (DMSO-d6-CDCl
₃ , δ): 1.28 (t, 3H, J = 7 Hz), 2.6
8 (q, 2H, J = 7Hz), 7.73 (d, 1H, J
= 10 Hz), 8.48 (dd, 1H, J = 10H
z), 8.78 (d, 1H, J = 3 Hz) MS: 219 (M ⁺ ) Melting point: 280-283 ° C

3) 2-Ethyl-4-hydroxy-6-nitroquinazoline 1.9 g, benzene 20 ml, N, N-
2.1 g of dimethylaniline and 1.3 g of phosphorus oxychloride
The mixture was heated to reflux for 14.5 hours. After cooling to room temperature, the insoluble matter was filtered off, the reaction mixture was washed with water, aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent). Ethyl acetate: hexane =
1:10) to obtain 170 mg of 4-chloro-2-ethyl-6-nitroquinazoline.

H ¹ -NMR (CD ₃ OD-CDCl ₃ ,
δ): 1.47 (t, 3H, J = 7Hz), 3.14
(Q, 2H, J = 7 Hz), 8.10 (d, 1H, J =
9 Hz), 8.63 (dd, 1H, J = 9 Hz), 9.
08 (d, 1H, J = 3 Hz) MS: 237 (M ⁺ ) Melting point: 284 = 286 ° C.

4) Under a nitrogen atmosphere, a mixture of 82 mg of 2-hydroxypyridine and 3 ml of N, N-dimethylformamide was added with 33 mg of sodium hydride and 4-chloro-2-.
170 mg of ethyl-6-nitroquinazoline and N, N-
3 ml of dimethylformamide was added, and the mixture was stirred for 14.5 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methyl alcohol = 100: 1) to give 2-ethyl-4. −
40 mg of (1,2-dihydro-2-oxopyridyl) -6-nitroquinazoline was obtained.

H ¹ -NMR (CD ₃ OD-CDCl ₃ ,
δ): 1.48 (t, 3H, J = 7Hz), 3.20
(Q, 2H, J = 7 Hz), 6.23-6.82 (m,
2H), 7.38-7.71 (m, 2H), 8.00-
8.25 (m, 1H), 8.43-8.72 (m, 2
H) MS: 296 (M ⁺ ) Melting point: 221-223 ° C

[0042]

Example 2 4- (2-oxopyrrolidinyl) -2-isopropyloxy
Nazoline production

1) From 4.4 g of anthranilic acid and 6.6 g of thioisobutyric acid amide, 2.5 g of 4-hydroxy-2-isopropylquinazoline was obtained in the same manner as in Example 1-1).

H ¹ -NMR (DMSO-d6-CDCl
₃ , δ): 1.26 (d, 6H, J = 7Hz), 1.6
2-2.23 (m, 1H), 7.23-8.23 (m,
4H) MS: 188 (M ⁺ ) Melting point: 222-225 ° C

2) 1.8 g of 4-hydroxy-2-isopropylquinazoline, 2.4 g of N, N-dimethylaniline
Then, from 1.5 g of phosphorus oxychloride, 1.6 g of 4-chloro-6-nitro-2-isopropylquinazoline was obtained in the same manner as in Example 1-3).

H ¹ -NMR (CDCl ₃ , δ): 1.4
6 (d, 6H, J = 7 Hz), 3.09-3.62
(M, 1H), 7.43-8.38 (m, 4H) MS: 206 (M ⁺ ) Melting point: 71-72 ° C.

3) 4-chloro-2-isopropylquinazoline (200 mg), sodium hydride (41 mg), 2-oxopyrrolidine (0.08 ml) and N, N-dimethylformamide (3 ml) were prepared in the same manner as in Example 1-4).
20 mg of-(2-oxopyrrolidinyl) -2-isopropylquinazoline was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.3
9 (d, 6H, J = 7Hz), 2.08-3.62
(M, 5H), 4.02-4.43 (m, 2H), 7.
32-8.16 (m, 4H) MS: 255 (M ⁺ ) Melting point: 68-69 ° C.

[0049]

Example 3 4- (2-oxopiperidinyl) -2-isopropylki
Nazoline production

4-chloro-2-isopropylquinazoline (500 mg), sodium hydride (111 mg), 2-oxopiperidine (0.27 ml) and N, N-dimethylformamide (18 ml) were used according to the same method as in Example 1-4) 4
70 mg of-(2-oxopiperidinyl) -2-isopropylquinazoline was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
1 (d, 6H, J = 7 Hz), 1.73-2.34
(M, 4H), 2.35-3.62 (m, 3H), 3.
68-4.08 (m, 2H), 7.29-8.10.
(M, 4H) MS: 269 (M ⁺ ).

[0052]

Example 4 2-t-butyl-N-methyl-6-nitroquinazoline-
Manufacturing of 4-carbamide

1) 2-t-Butyl-6-nitroquinazoline-4-carboxylic acid ethyl ester 5.5 g, concentrated sulfuric acid 1
A mixture of 5 ml and concentrated nitric acid 15 ml was heated with stirring at 50 ° C. for 3 hours. Ice water was added to the reaction mixture, and the precipitated crystals were collected by filtration to obtain 0.4 g of 2-t-butyl-6-nitroquinazoline-4-carboxylic acid having a decomposition point of 134 ° C.

H ¹ -NMR (CDCl ₃ , δ): 1.6
6 (s, 9H), 7.72 (d, 1H, J = 9Hz),
8.53 (dd, 1H, J = 2Hz and 9H
z), 8.68 (d, 1H, J = 2 Hz) MS: 275 (M ⁺ ).

2) A mixture of 0.4 g of 2-t-butyl-6-nitroquinazoline-4-carboxylic acid, 0.32 g of N, N-carbonyldiimidazole, 0.55 g of methylamine (methanol solution) and 15 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 12 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with aqueous sodium hydroxide solution, dried over potassium carbonate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of dichloromethane and hexane to give 2-
t-butyl-N-methyl-6-nitroquinazoline-4-
0.15 g of carboxamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
4 (s, 9H), 3.15 (d, 3H, J = 6Hz),
8.18 (d, 1H, J = 9 Hz), 7.90-8.6
0 (m, 1H), 8.66 (dd, 1H, J = 2Hz
and 9 Hz), 10.50 (d, 1H, J = 2H
z) MS: 288 (M ⁺ ) Melting point: 182-184 ° C

[0057]

Example 5 2-tert-Butyl-N-methyl-6-nitroquinazoline-
Preparation of 4-carbothioamide

A mixture of 0.43 g of 2-tert-butyl-N-methyl-6-nitroquinazoline-4-carboxamide, 0.68 g of Lawesson's reagent and 5 ml of benzene was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane), and recrystallized from a mixed solution of ethyl acetate and hexane to give 2-tert-butyl-N-methyl-.
6-Nitroquinazoline-4-carbothioamide 0.15
g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1,4
9 (s, 9H), 3.45 (d, 3H, J = 6Hz a
nd 3Hz), 8.03 (d, 1H, J = 9Hz),
8.50 (dd, 1H, J = 9Hz and 2H
z), 8.70-9.60 (m, 1H), 10.27
(D, 1H, J = 2 Hz) MS: 304 (M +) Melting point: 171-173 ° C

[0060]

Example 6 N- (2-Cyanoethyl) -2-tert-butyl-6-nit
Production of roquinazoline-4-carboxamide

2-tert-Butyl-6-nitroquinazoline-
0.2 g of 4-carboxylic acid, 0.2 cyanoethylamine.
074 g, N, N-carbonyldiimidazole 0.17
A mixture of g and tetrahydrofuran (10 ml) was stirred at room temperature for 41 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 3), and recrystallized from a mixed solution of ethyl acetate and hexane to give N-.
0.07 g of (2-cyanoethyl) -2-tert-butyl-6-nitroquinazoline-4-carbamide was obtained.

H ¹ = NMR (CDCl ₃ , δ):
1.56 (s, 9H), 2.87 (t, 2H, J = 6H
z), 3.89 (q, 2H, J = 6 Hz), 8.18
(D, 1H, J = 9 Hz), 8.50-9.00 (m,
1H), 8.68 (dd, 1H, J = 9Hz and
2Hz), 10.45 (d, 1H, J = 2Hz) MS: 327 (M +) Melting point: 148-151 ° C

[0063]

Example 7 2-tert-Butyl-N- (2-cyanoethyl) -6-nit
Production of roquinazoline-4-carbothioamide

2-tert-Butyl-N- (2-cyanoethyl) -6-nitroquinazoline-4-carboxamide 0.1
A mixture of 0 g, 0.13 g of Lawesson's reagent and 5 ml of 1,2-dichloroethane was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane) to give 2
-0.03 g of tert-butyl-N- (2-cyanoethyl) -6-nitroquinazoline-4-carbothioamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.
54 (s, 9H), 3.01 (t, 2H, J = 6H
z), 4.26 (q, 2H, J = 6Hz), 8.16
(D, 1H, J = 9 Hz), 8.61 (dd, 1H, J
= 9 Hz and 2 Hz), 9.40-9.70.
(M, 1H), 10.24 (d, 1H, J = 2Hz) MS: 343 (M +) Melting point: 136-138 ° C

[0066]

Example 8 N, 2-Dimethyl-6-nitroquinazoline-4-carbo
Amide production

1) From 6.0 g of anthranilic acid and 3.6 g of thioacetamide, 5.1 g of 4-hydroxy-2-methylquinazoline was prepared in the same manner as in Example 1-1).
I got

H ¹ -NMR (DMSO-d ₆ -CDCl
₃ , δ): 1.26 (d, 6H, J = 7Hz), 1.6
2-2.23 (m, 1 H), 7.23-8.23
(M, 4H) MS: 160 (M +) Melting point: 222-225 ° C

2) From 4-hydroxy-2-methylquinazoline (5.1 g), N, N-dimethylaniline (8.1 g) and phosphorus oxychloride (5.2 g), according to the same method as in Example 1-3), 4-chloro- 3.7 g of 2-methylquinazoline
I got

H ¹ -NMR (CDCl ₃ , δ): 1.
46 (d, 6H, J = 7 Hz), 3.09-3.62
(M, 1H), 7.43-8.38 (m, 4H) MS: 206 (M +) Melting point: 71-72 ° C.

3) 3.7 g of 4-chloro-2-methylquinazoline, 3.14 g of silver carbonate, 0.47 g of palladium bis (triphenylphosphine) acetate, 20 m of ethanol
A mixture of 1 and 60 ml of N, N-dimethylformamide was heated and stirred at 60 ° C. for 8 hours under a carbon monoxide atmosphere. To the reaction mixture were added 1N aqueous sodium hydroxide solution and ethyl acetate, the insoluble matter was filtered off using Celite, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: hexane = 5: 1) to give 2-methylquinazoline. -4-carboxylic acid ethyl ester 0.80
g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
9 (t, 3H, J = 7Hz), 2.95 (s, 3H),
4.59 (q, 2H, J = 7Hz), 7.30-8.1
0 (m, 3H), 8.38 (dd, 1H, J = 8Hz
and 2 Hz) MS: 216 (M +)

4) 0.80 g of 2-methylquinazoline-4-carboxylic acid ethyl ester, 2 ml of nitric acid and 2 sulfuric acid
The mixture of ml was heated and stirred at 50 ° C. for 2 hours. Further, 30 ml of ethanol was added to the reaction mixture, and the mixture was heated under reflux for 14 hours. Ice water was added to the reaction mixture, which was neutralized with a 2N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent; dichloromethane:
Methanol = 100: 1), 2-methyl-6-nitroquinazoline-4-carboxylic acid ethyl ester 0.1
6 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
5 (t, 3H, J = 7Hz), 3,03 (s, 3H),
4.66 (q, 2H, J = 7Hz), 8.16 (d, 1
H, J = 9 Hz), 8.68 (dd, 1H, J = 9 Hz
and 3 Hz), 9.52 (d, 1H, J = 7H
z) MS: 261 (M +) melting point: 109-111 ° C.

5) 2-Methyl-6-nitroquinazoline-
A mixture of 0.80 g of 4-carboxylic acid ethyl ester, 0.2 ml of 40% methylamine methanol solution and 3 ml of dichloromethane was stirred at room temperature for 45 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 100: 1) to obtain 0.16 g of N, 2-dimethyl-6-nitroquinazoline-4-carbamide. It was

H ¹ -NMR (CDCl ₃ , δ): 2.9
6 (s, 3H), 3.13 (d, 3H, J = 5Hz),
8.10 (d, 1H, J = 9 Hz), 8.00-8.5
0 (m, 1H), 8.65 (dd, 1H, J = 9Hz
and 2 Hz), 10.55 (d, 1H, J = 2H
z) MS: 246 (M +) Melting point: 220-222 ° C

[0077]

Example 9 N, 2-Dimethyl-6-nitroquinazoline-4-carbo
Thioamide production

N, 2-Dimethyl-6-nitroquinazoline-4-carboxamide 0.12 g, Lawesson's reagent 0.11
According to the same manner as in Example 7, 16 g of N, 2-dimethyl-6-nitroquinazoline-4-carbothioamide was obtained from g and 1 ml of 1,2-dichloroethane.

H ¹ -NMR (CDCl ₃ , δ): 2.
94 (s, 3H), 3.47 (d, 3H, J = 5H
z), 8.08 (d, 1H, J = 9 Hz), 8.61
(Dd, 1H, J = 9 Hz and 2 Hz), 8.8
0-9.20 (m, 1H), 10.11 (d, 1H, J
= 2 Hz) MS: 262 (M +) Melting point: 176-178 ° C

[0080]

Example 10 2-Ethyl-N-methyl-6-nitroquinazoline-4-
Carbamide production

1) 4.5 g of 4-chloro-2-ethylquinazoline, 3.87 g of silver carbonate, 0.53 g of palladium bis (triphenylphosphine) acetate, 20 m of ethanol
1 and N, N-dimethylformamide (60 ml) were subjected to the same procedure as in Example 8-3) under a carbon monoxide atmosphere to obtain 0.70 g of 2-ethylquinazoline-4-carboxylic acid ethyl ester.

H ¹ -NMR (CDCl ₃ , δ): 1.4
8 (t, 3H, J = 7Hz), 1.50 (t, 3H, J
= 7 Hz), 3.22 (q, 2H, J = 7 Hz), 4.
61 (q, 2H, J = 7 Hz), 7.62 (t, 1H,
J = 8 Hz), 7.90 (t, 1H, J = 8 Hz),
8.04 (d, 1H, J = 8 Hz), 8.40 (d, 1
H, J = 8 Hz) MS: 230 (M +)

2) 0.70 g of 2-ethylquinazoline-4-carboxylic acid ethyl ester, 2 ml of nitric acid, 2 ml of sulfuric acid
And 40 ml of ethanol according to the same method as in Example 8-4), 2-ethyl-6-nitroquinazoline-4-
0.18 g of carboxylic acid ethyl ester was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.
50 (t, 3H, J = 7Hz), 1.55 (t, 3H,
J = 7 Hz), 3.28 (q, 2H, J = 7 Hz),
4.65 (q, 2H, J = 7Hz), 8.18 (d, 1
H, J = 9 Hz), 8.67 (dd, 1H, J = 9 Hz
and 3 Hz), 9.49 (d, 1H, J = 8 Hz
and 3 Hz) MS: 275 (M +) Melting point: 86-88 ° C

3) 2-Ethyl-6-nitroquinazoline-
2-Ethyl-N-methyl-6-nitroquinazoline-from a mixture of 0.17 g of 4-carboxylic acid ethyl ester, 0.2 ml of 40% methylamine methanol solution and 3 ml of dichloromethane according to the same method as in Example 8-5).
0.16 g of 4-carbamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
0 (t, 3H, J = 7Hz), 3.13 (d, 3H, J
= 5 Hz), 3.21 (q, 2H, J = 7 Hz), 8.
12 (d, 1H, J = 9 Hz), 8.10-8.50
(M, 1H), 8.65 (dd, 1H, J = 9Hz a
nd 3HZ), 10.48 (d, 1H, J = 3Hz) MS: 260 (M +) Melting point: 171-172 ° C.

[0087]

Example 11 2-Ethyl-N-methyl-6-nitroquinazoline-4-
Production of carbothioamide

2-Ethyl-N-methyl-6-nitroquinazoline-4-carbamide 0.09 g, Lawesson's reagent 0.08 g and 1,2-dichloroethane 2 ml were prepared according to the same procedure as in Example 7 to prepare 2-ethyl-N. -Methyl-
6-Nitroquinazoline-4-carbothioamide 11 mg
I got

H ¹ -NMR (CDCl ₃ , δ): 1.4
8 (t, 3H, J = 7Hz), 3.18 (q, 2H, J
= 7 Hz), 3.47 (d, 3H, J = 5HZ), 8.
10 (d, 1H, J = 9 Hz), 8.60 (dd, 1
H, J = 9 Hz and 3 Hz), 8.70-9.2
0 (m, 1H), 10.12 (d, 1H, J = 3Hz) MS: 276 (M +) Melting point: 182-184 ° C

[0090]

Example 12 N-Methyl-6-nitro-2-isopropylquinazoline
-4-Production of carboxamide

1) 4-chloro-2-isopropylquinazoline 2.0 g, silver carbonate 1.41 g, bis (triphenylphosphine) palladium acetate 0.22 g, ethanol 1
From 0 ml and 30 ml of N, N-dimethylformamide, 1.2 g of 2-isopropylquinazoline-4-carboxylic acid ethyl ester was obtained in the same manner as in Example 8-3) under a carbon monoxide atmosphere.

MS: 244 (M +)

2) 1.2 g of 2-isopropylquinazoline-4-carboxylic acid ethyl ester, 2 ml of nitric acid, 2 sulfuric acid
According to the same manner as in Example 8-4), 0.08 g of ethyl 6-nitro-2-isopropylquinazoline-4-carboxylic acid ester was obtained from 40 ml of ethanol and 40 ml of ethanol.

MS: 289 (M +)

3) 6-Nitro-2-isopropylquinazoline-4-carboxylic acid ethyl ester 0.08 g, 40
A mixture of 0.1 ml of a methylamine methanol solution (0.1 ml) and dichloromethane (3 ml) was used to obtain 44 mg of N-methyl-6-nitro-2-isopropylquinazoline-4-carbamide by the same method as in Example 8-5).

H ¹ -NMR (CDCl ₃ , δ): 1.4
7 (d, 6H, J = 7Hz), 3.14 (d, 3H, J
= 5 Hz), 3.44 (tt, 1H, J = 5 Hz),
8.13 (d, 1H, J = 9Hz), 8.00-8.5
0 (m, 1H), 8.65 (dd, 1H, J = 9Hz
and 3 Hz), 10.49 (d, 1H, J = 3H
z) MS: 274 (M +) melting point: 148-150 ° C.

[0097]

Example 13 N-Methyl-6-nitro-2- (3-nitrophenyl)
Production of quinazoline-4-carboxamide

1) 4-hydroxy-2-phenylquinazoline 6.4 from 7.0 g of anthranilic acid and 7.7 g of thiobenzamide in the same manner as in Example 1-1).
7 g were obtained.

H ¹ -NMR (acetone-d ₆ ,
δ): 7.40-7.70 (m, 4H), 7.70-
7.90 (m, 2H), 8.20-8.40 (m, 3
H), 10.90-11.40 (m, 1H) MS: 222 (M +).

2) From 4-hydroxy-2-phenylquinazoline (2.2 g), N, N-dimethylaniline (2.5 g) and phosphorus oxychloride (1.6 g), follow the same procedure as in Example 1-3) to prepare 4-chloro- 2-phenylquinazoline 2.
01 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 7.5
0-7.60 (m, 3H), 7.67 (dt, 1H, J
= 7 Hz and 1 Hz), 7.94 (dt, 1H,
J = 8 Hz and 1 Hz), 8.10 (dd, 1
H, J = 8 Hz and 1 Hz), 8.25 (dd,
1 Hz, J = 8 Hz and 1 Hz), 8.50-
8.70 (m, 2H) MS: 240 (M +)

3) 0.73 g of 4-chloro-2-phenylquinazoline, 0.83 g of silver carbonate, 75 mg of palladium bis (triphenylphosphine) acetate, 5 ml of ethanol
Further, from 12 ml of N, N-dimethylformamide, 0.54 g of 2-phenylquinazoline-4-carboxylic acid ethyl ester was obtained in the same manner as in Example 8-3) in a carbon monoxide atmosphere.

H ¹ -NMR (CDCl ₃ , δ): 1.5
3 (t, 3H, J = 7Hz), 4.73 (q, 2H, J
= 7 Hz), 7.30-7.60 (m, 4H), 7.7
4 (dt, 1H, J = 7 Hz and 1 Hz), 7.
95 (dd, 1H, J = 8Hz and 1Hz),
8.11 (d, 1H, J = 8Hz), 8.50-8.6
0 (m, 2H) MS: 278 (M +)

4) 2-phenylquinazoline-4-carboxylic acid ethyl ester 0.39 g, nitric acid 2 ml, sulfuric acid 2 m
6-nitro-2- (3-nitrophenyl) quinazoline-4-carboxylic acid ethyl ester 0.1 from 1 and 30 ml of ethanol in the same manner as in Example 8-4).
2 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.6
1 (t, 3H, J = 7Hz), 4.71 (q, 2H, J
= 7 Hz), 7.75 (t, 1H, J = 8 Hz), 8.
31 (d, 1H, J = 9 Hz), 8.40 (dd, 1
H, J = 8 Hz and 1 Hz), 9.00 (d, 1
H, J = 8 Hz), 9.40-9.60 (m, 2H) MS: 368 (M +)

5) 6-Nitro-2- (3-nitrophenyl) quinazoline-4-carboxylic acid ethyl ester 0.1
0 g, 0.15 ml of 40% methylamine methanol solution
And 3 ml of dichloromethane and N-methyl-6-nitro-2- (3-nitrophenyl) quinazoline-4-carboxamide 0.09 according to the same method as in Example 8-5).
g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 3.2
3 (d, 3H, J = 5 Hz), 7.79 (t, 1H, J
= 8 Hz), 8.00-8.40 (m, 1H), 8.3
0 (d, 1H, J = 9Hz), 8.45 (ddd, 1
H, J = 8 Hz, 2 Hz and 1 Hz), 9.00
(D, 1H, J = 8 Hz), 9.45 (t, 1H, J =
2Hz), 10.50 (t, 1H, J = 2Hz) MS: 353 (M +) Melting point: 277-280 ° C

[0108]

Example 14 N-Methyl-6-nitro-2- (3-nitrophenyl)
Production of quinazoline-4-carbothioamide

N-methyl-6-nitro-2- (3-nitrophenyl) quinazoline-4-carboxamide 0.07
A mixture of g, 0.06 g of Lawesson's reagent and 2 ml of tetrahydrofuran was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane) to give 21 mg of N-methyl-6-nitro-2- (3-nitrophenyl) quinazoline-4-carbothioamide. It was

H ¹ -NMR (CDCl ₃ , δ): 3.5
6 (d, 3H, J = 5Hz), 7.75 (t, 1H, J
= 8 Hz), 8.26 (d, 1H, J = 9 Hz), 8.
67 (dd, 1H, J = 9 Hz and 2 Hz),
8.70-9.10 (m, 1H), 8.98 (d, 1)
H, J = 8 Hz), 9.00 (dt, 1H, J = 8H
z), 9.44 (s, 1H), 9.90 (d, 1H, J
= 2 Hz) MS: 369 (M +) Melting point: 226-229 ° C

[0111]

Example 15 2-tert-Butyl-6-cyano-N-methylquinazoline-
Preparation of 4-carbothioamide

1) 2-tert-Butylquinazoline-4-carboxylic acid ethyl ester 9.1 g, sulfuric acid 14 ml, nitric acid 5
According to the same method as in Example 8-4), 2.9 g of ethyl 2-tert-butyl-6-nitroquinazoline-4-carboxylic acid was obtained from 80 ml of ethanol and 80 ml of ethanol.

2) A mixture of 2.8 g of 2-tert-butyl-6-nitroquinazoline-4-carboxylic acid ethyl ester, 0.3 g of 10% palladium carbon and 100 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 30 minutes. . After removing the catalyst by filtration, the reaction mixture was concentrated under reduced pressure to obtain 2.6 g of 6-amino-2-tert-butylquinazoline-4-carboxylic acid ethyl ester.

3) 2.6 g of 6-amino-2-tert-butylquinazoline-4-carboxylic acid ethyl ester, 0.68 g of sodium nitrite, 1.60 g of potassium iodide, 0.91 g of sulfuric acid, 30 ml of water and 10 ml of dichloromethane.
The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with dichloromethane, the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent). Ethyl acetate: hexane = 10: 1), 2-tert-butyl-6
-0.95 g of iodoquinazoline-4-carboxylic acid ethyl ester was obtained.

H ¹ NMR (CDCl ₃ , δ): 1.51
(T, 3H, J = 7Hz), 1.52 (s, 9H),
4.58 (q, 2H, J = 7Hz), 7.72 (d, 1
H, J = 9 Hz), 8.10 (dd, 1H, J = 9 Hz
and 2 Hz), 8.77 (d, 1H, J = 2H)
z) MS: 384 (M +)

4) 0.43 g of 2-tert-butyl-6-iodoquinazoline-4-carboxylic acid ethyl ester, 0.30 g of hydrocyanic acid No. 1 steel and N, N-dimethylformamide 1
0 ml of the mixture was heated and stirred at 150 ° C. for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was filtered off with Celite, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent; dichloromethane), 2- Tert-butyl-6
0.12 g of -cyanoquinazoline-4-carboxylic acid ethyl ester was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
5 (t, 3H, J = 7Hz), 1.46 (s, 9H),
4.55 (q, 2H, J = 7Hz), 7.70-8.2
0 (m, 2H), 8.70-8.90 (m, 1H) MS: 283 (M +)

5) 2-tert-Butyl-6-cyanoquinazoline-4-carboxylic acid ethyl ester 0.12 g, 40%
A mixture of 0.2 ml of methylamine methanol solution and 5 ml of ethanol was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give 2-tert-butyl-6-cyano-N-
0.12 g of methylquinazoline-4-carbamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
2 (s, 9H), 3.15 (d, 3H, J = 6Hz),
7.70-8.50 (m, 3H), 8.90-10.1
0 (m, 1H) MS: 268 (M +)

6) 2-tert-Butyl-6-cyano-N-methylquinazoline-4-carbamide 0.12 g, Lawesson's reagent 0.20 g and 1,2-dichloroethane 5 ml.
According to the same method as in Example 7 from the mixture of above, 0.08 g of 2-tert-butyl-6-cyano-N-methylquinazoline-4-carbothioamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
0 (s, 9H), 3.46 (d, 3H, J = 5Hz),
7.95 (dd, 1H, J = 9Hz and 2H
z), 8.07 (d, 1H, J = 9 Hz), 8.90-
9.20 (m, 1H), 9.70 (d, 1H, J = 2H
z) MS: 284 (M +) melting point: 188-189 ° C.

[0122]

Example 16 2-tert-Butyl-6-trifluoromethyl-N-methyl
Production of quinazoline-4-carbothioamide

1) 2-tert-Butyl-6-iodoquinazoline-4-carboxylic acid ethyl ester 0.50 g, potassium trifluoroacetate 0.42 g, cupric acid cuprous 0.53
A mixture of g, 5 ml of toluene and 20 ml of N, N-dimethylformamide was heated and stirred at 150 ° C. for 6 hours. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was filtered off with Celite, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; dichloromethane: hexane = 1: 3). Attached to
2-tert-butyl-6-trifluoromethylquinazoline-
0.12 g of 4-carboxylic acid ethyl ester was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
0 (t, 3H, J = 7Hz), 1.52 (s, 9H),
4.61 (q, 2H, J = 7Hz), 7.70-8.3
0 (m, 2H), 8.60-8.90 (m, 1H) MS: 326 (M +).

2) 2-tert-Butyl-6-trifluoromethylquinazoline-4-carboxylic acid ethyl ester 0.1
A mixture of 2 g, 40% methylamine methanol solution 0.2 ml and methanol 2 ml was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give 2-tert-butyl-6-
0.10 g of trifluoromethyl-N-methylquinazoline-4-carbamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
1 (s, 9H), 3.12 (d, 3H, J = 6Hz),
7.70-8.60 (m, 3H), 8.80-10.0
0 (m, 1H) MS: 311 (M +)

3) 2-tert-Butyl-6-trifluoromethyl-N-methylquinazoline-4-carboxamide 0.1
A mixture of 0 g, Lawson's reagent 0.17 g and 1,2-dichloroethane 5 ml was subjected to the same procedure as in Example 7 to give 2-tert-butyl-6-trifluoromethyl-N-methylquinazoline-4-carbothioamide 0.07 g. Got

H ¹ -NMR (CDCl ₃ , δ): 1.5
1 (s, 9H), 3.47 (d, 3H, J = 5Hz),
7.99 (dd, 1H, J = 9Hz and 2H
z), 8.11 (d, 1H, J = 9 Hz), 8.90-
9.20 (m, 1H), 9.59 (d, 1H, J = 2H
z) MS: 327 (M +) melting point: 119-120 ° C.

[0129]

Example 17 2-tert-Butyl-N-methyl-6-nitroquinoline-4
- preparation of carboxamide 1) 4-bromo-2-tert-butyl-6-nitroquinoline 2.15 g, potassium acetate 2.80 g, bis (triphenylphosphine) palladium acetate 75 mg, potassium iodide 1.15g and N, N -Dimethylformamide 3
0 ml of the mixture was heated at 130 ° C. under a carbon monoxide atmosphere for 2
The mixture was heated and stirred for an hour. A 2N aqueous hydrochloric acid solution and ethyl acetate were added to the reaction mixture, the insoluble matter was filtered off using Celite, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform: methanol: acetic acid = 500: 5:
1) to 2-tert-butyl-6-nitroquinoline-4-
0.12 g of carboxylic acid was obtained.

H ¹ -NMR (acetone-d ₆ ,
δ): 1.53 (s, 9H), 8.24 (d, 1H, J
= 9 Hz), 8.37 (s, 1H), 8.49 (dd,
1H, J = 9 Hz and 3 Hz, 9.83 (d,
1H, J = 3Hz) MS: 274 (M +)

2) 0.23 g of 2-tert-butyl-6-nitroquinoline-4-carboxylic acid, 0.20 g of N, N'-carbonyldiimidazole, 0.2 ml of 40% methylamine methanol solution and 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 0.15 g of 2-tert-butyl-N-methyl-6-nitroquinoline-4-carboxamide.

H ¹ -NMR (CDCl ₃ , δ): 1.4
4 (s, 9H), 3.42 (d, 3H, J = 6Hz),
7.52 (s, 1H), 7.40-8.10 (m, 1
H), 8.08 (d, 1H, J = 9 Hz), 8.35
(Dd, 1H, J = 9 Hz and 3 Hz), 8.96
(D, 1H, J = 3 Hz) MS: 287 (M +) Melting point: 191-193 ° C

[0133]

Example 18 2-Tert-butyl-N-methyl-6-nitroquinoline-4
-Preparation of carbothioamide 2-tert-butyl-N-methyl-6-nitroquinoline-4
2-tert-Butyl-N-methyl-6 following the same procedure as in Example 7 from a mixture of 0.10 g of carboxamide, 0.09 g of Lawesson's reagent and 2 ml of 1,2-dichloroethane.
0.10 g of -nitroquinoline-4-carbothioamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.5
1 (s, 9H), 3.47 (d, 3H, J = 5Hz),
7.99 (dd, 1H, J = 9Hz and 2H
z), 8.11 (d, 1H, J = 9 Hz), 8.90-
9.20 (m, 1H), 9.59 (d, 1H, J = 2H
z) MS: 303 (M +) Melting point: 228-230 ° C

[0135]

Example 19 2-tert-Butyl-N- (2-cyanoethyl) -6-nit
Preparation of roquinoline-4-carboxamide 2-tert-butyl-6-nitroquinoline-4-carboxylic acid 0.85 g, N, N' -carbonididiimidazole .
Example 17-2) from a mixture of 55 g, 2-cyanoethylamine 0.24 g and tetrahydrofuran 10 ml.
2-tert-Butyl-N- (2-cyanoethyl) -6-nitroquinoline-4-carboxamide 0.
65 g were obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
0 (s, 9H), 2.84 (t, 2H, J = 6Hz),
3.79 (q, 2H, J = 6Hz), 7.67 (s, 1
H), 7.70-7.90 (m, 1H), 7.96.
(D, 1H, J = 9 Hz), 8.19 (dd, 1H, J
= 9 Hz and 3 Hz), 8.96 (d, 1H, J
= 3 Hz) MS: 326 (M +) Melting point: 145-147 ° C

[0137]

Example 20 2-tert-Butyl-N- (2-cyanoethyl) -6-nit
Preparation of roquinoline-4-carbothioamide Carried out from a mixture of 0.14 g of 2-tert-butyl-N- (2-cyanoethyl) -6- nitroquinoline-4-carboxamide , 0.11 g of Lawesson's reagent and 3 ml of 1,2-dichloroethane. Following a procedure similar to Example 7, 2-tert-butyl-N- (2-cyanoethyl) -6-nitroquinoline-4
-0.12 g of carbothioamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
4 (s, 9H), 2.93 (t, 2H, J = 6Hz),
4.10 (q, 2H, J = 6Hz), 7.47 (s, 1
H), 7.96 (d, 1H, J = 9 Hz), 8.15
(Dd, 1H, J = 9 Hz and 3 Hz), 8.2
0-8.70 (m, 1H), 8.80 (d, 1H, J =
3 Hz) MS: 343 (M +) Melting point: 155-157 ° C

[0139]

Example 21 2-tert-Butyl-6-cyano-N- (2-cyanoethyl
1) Preparation of quinoline-4-carboxamide 1) 2-tert-butyl-N- (2-cyanoethyl) -6-
Nitroquinoline-4-carbamide 0.43 g, 10%
A mixture of 0.10 g of palladium carbon and 50 ml of methanol was stirred under a hydrogen atmosphere at room temperature for 20 minutes. After removing the catalyst by filtration, the reaction mixture was concentrated under reduced pressure, and to the resulting residue were added 0.19 g of sulfuric acid, 0.12 g of sodium nitrite, 0.34 g of potassium iodide, 20 ml of water and 10 ml of dichloromethane, and the mixture was stirred at room temperature for 2 hours. It was stirred. A 2N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate =).
1: 1), 2-tert-butyl-N- (2-cyanoethyl) -6-iodoquinoline-4-carboxamide 0.4.
3 g were obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
4 (s, 9H), 3.42 (d, 3H, J = 6Hz),
7.52 (s, 1H), 7.40-8.10 (m, 1
H), 8.08 (d, 1H, J = 9 Hz), 8.35
(Dd, IH, J = 9 Hz and 3 Hz), 8.96
(D, 1H, J = 3Hz) MS: 407 (M +)

2) 2-tert-Butyl-N- (2-cyanoethyl) -6-iodoquinoline-4-carboxamide 0.1
A mixture of 4 g, cuprous cyanide 36 mg and N, N-dimethylformamide 5 ml was heated with stirring at 140 ° C. for 3 hours. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was filtered off using Celite, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. 10 organic layers
% Aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1). 0.08 g of 6-cyano-2-tert-butyl-N- (2-cyanoethyl) quinoline-4-carbamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
7 (s, 9H), 2.85 (t, 2H, J = 6Hz),
3.80 (q, 2H, J = 6Hz), 6.80-7.0
0 (m, 1H), 7.69 (s, 1H), 7.80 (d
d, 1H, J = 9 Hz and 3 Hz), 8.14
(D, 1H, J = 9 Hz), 8.64 (d, 1H, J =
3 Hz) MS: 306 (M +) Melting point: 181-183 ° C

[0143]

Example 22 2-tert-Butyl-6-cyano-N- (2-cyanoethyl
1) Preparation of quinoline-4-carbothioamide Carried out from a mixture of 6-cyano-2-tert-butyl-N- (2-cyanoethyl) quinoline-4-carboxamide 0.06 g, Lawesson's reagent 50 mg and 1,2-dichloroethane 2 ml. Following a procedure similar to that of Example 7, 6-cyano-2
-Tert-butyl-N- (2-cyanoethyl) quinoline-4
-0.06 g of carbothioamide was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
6 (s, 9H), 3.04 (t, 2H, J = 6Hz),
4.18 (q, 2H, J = 6Hz), 7.58 (s, 1
H), 7.66 (dd, 1H, J = 9 Hz and 3
Hz), 8.10 (d, 1H, J = 9 Hz), 8.49
(D, 1H, J = 3 Hz), 8.50-8.70 (m,
1H) MS: 322 (M +) melting point: 178-180 ° C.

[0145]

Example 23 2-tert-Butyl-N- (2-cyanoethyl) -6-pen
Preparation of tafluoroethylquinoline-4-carboxamide 1) 2-tert-butyl-6-nitroquinoline-4-carboxylic acid 0.50 g, sulfuric acid 1 ml and ethanol 50 ml
The mixture was heated and stirred at 70 ° C. for 15 hours. A 2N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.53 g of ethyl 2-tert-butyl-6-nitroquinoline-4-carboxylic acid ester.

H ¹ -NMR (CDCl ₃ , δ): 1.5
2 (s, 9H), 1.56 (t, 3H, J = 7Hz),
4.59 (q, 2H, J = 7Hz), 8.13 (d, 1
H, J = 9 Hz), 8.20 (s, 1H), 8.34
(Dd, 1H, J = 9 Hz and 3 Hz), 9.6
3 (d, 1H, J = 3Hz) MS: 302 (M +)

2) A mixture of 2-tert-butyl-6-nitroquinoline-4-carboxylic acid ethyl ester 0.58 g, 10% palladium on carbon 0.2 g and ethanol 150 ml was prepared in the same manner as in Example 15-2). , 6-amino-2-tert-butylquinoline-4-carboxylic acid ethyl ester 0.42 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
1 (s, 9H), 1.40 (t, 3H, J = 7Hz),
3.60-4.10 (m, 2H), 4.34 (q, 2
H, J = 7 Hz), 6.92 (dd, 1H, J = 9 Hz
and 3 Hz), 7.70-7.90 (m, 3H) MS: 272 (M +).

3) 0.38 g of 6-amino-2-tert-butylquinoline-4-carboxylic acid ethyl ester, sulfuric acid 0.
15 g, sodium nitrite 0.11 g, potassium iodide 0.28 g, water 14 ml and dichloromethane 10 ml
Was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 10: 1).
-0.18 g of tert-butyl-6-iodoquinoline-4-carboxylic acid ethyl ester was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
6 (s, 9H), 1.48 (t, 3H, J = 7Hz),
4.49 (q, 2H, J = 7Hz), 7.40-8.1
0 (m, 3H), 9.02 (d, 1H, J = 3Hz) MS: 383 (M +)

4) 0.18 g of ethyl 2-tert-butyl-6-iodoquinoline-4-carboxylic acid, 0.20 g of cuprous cyanide, 0.20 g of potassium pentafluoropropionate, 2 ml of toluene and N, N-. According to the same method as in Example 16-1) from a mixture of 10 ml of dimethylformamide, 2-tert-butyl-6-pentafluoroethylquinoline-4-carboxylic acid ethyl ester 0.0
6 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
4 (s, 9H), 1.44 (t, 3H, J = 7Hz),
4.42 (q, 2H, J = 7Hz), 7.30-8.2
0 (m, 3H), 8.80-9.00 (m, 1H) MS: 375 (M +)

5) 2-tert-Butyl-6-pentafluoroethylquinoline-4-carboxylic acid ethyl ester 0.0
6 g, potassium hydroxide 0.1 g and ethanol 3 ml
The mixture was stirred at room temperature for 2 hours. Water and concentrated hydrochloric acid were added to the reaction mixture. The precipitated crystals are filtered and N, N '
-Carbonyldiimidazole 0.04 g, 2-cyanoethylamine 0.03 g and tetrahydrofuran 3 ml
And the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.15 g of 2-tert-butyl-N- (2-cyanoethyl) -6-pentafluoroethylquinoline-4-carbamide.

H ¹ -NMR (CDCl ₃ , δ): 1.4
7 (s, 9H), 2.84 (t, 2H, J = 6Hz),
3.81 (q, 2H, J = 6Hz), 6.60-6.8
0 (m, 1H), 7.68 (s, 1H), 7.87 (d
d, 1H, J = 9 Hz and 3 Hz), 8.22
(D, 1H, J = 9 Hz), 8.50 (d, 1H, J =
3 Hz) MS: 399 (M +) melting point: 164-166 ° C

[0155]

Example 24 2-tert-Butyl-N- (2-cyanoethyl) -6-pen
Preparation of tafluoroethylquinoline-4-carbothioamide
Concrete 2 tertiary butyl-N-(2-cyanoethyl) -6-pentafluoroethyl-4-carbamide 0.02
g, 25 mg of Lawesson's reagent and 2 ml of 1,2-dichloroethane according to the same procedure as in Example 7.
-Tert-butyl-N- (2-cyanoethyl) -6-pentafluoroethylquinoline-4-carbothioamide 0.0
2 g was obtained.

H ¹ -NMR (CDCl ₃ , δ): 1.4
7 (s, 9H), 3.01 (t, 2H, J = 6Hz),
4.20 (q, 2H, J = 6Hz), 7.54 (s, 1
H), 7.84 (dd, 1H, J = 9 Hz and 3
Hz), 7.90-8.20 (m, 1H), 8.20
(D, IH, J = 9 Hz), 8.34 (d, 1H, J =
3 Hz) MS: 415 (M +) Melting point: 137-139 ° C

[0157]

[Test Example] Test method using isolated rat aorta Male Sprague Dawley rat (450 g-
The thoracic aorta was taken out from 600 g) and used as a 2 mm wide annular sample. This sample is Krebs-Henselei
The suspension was suspended under a tension of 2 g in a 2 ml organ bath containing the t solution, and 95% oxygen and 5% carbon dioxide gas were bubbled through the suspension. The contraction response of the sample was recorded isometrically with an FD pickup. After equilibration for 1-1.5 hours, 30 mM potassium chloride is added to contract the tissue, and the activity of the compound that relaxes the sustained contraction by potassium chloride is suppressed by 50% with respect to the maximum relaxing action of the compound. Concentration (EC ₅₀ )
It was evaluated by determining. The results are shown in Table 1.

[0158]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 211/57 8517-4H 211/58 211/59 211/60 255/49 317/16 317/26 317/44 C07D 215/50 401/04 235 403/04 207 // A61K 31/47 ABS 31/505 ABR

Claims (5)

[Claims] 1. A compound represented by the general formula (1): (In the formula, A and B are the same or different and represent N or CH, and R ₁ and R ₂ are a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a halogen atom, a cyano group, A nitro group, a lower alkylsulfonyl group, a lower haloalkylsulfonyl group, an arylsulfonyl group, an acyl group, a carboxyl group, an ester group, an amide group, and R ₃ represents a hydrogen atom or an optionally substituted lower alkyl group, An aryl group which may have a substituent, R ₄ is a saturated or unsaturated heterocyclic group, a carboxamide group, a carbothioamide group, a cyanamide group, an amino group which may have a substituent, a lower alkoxy group ,
A compound represented by a cycloalkyloxy group, an aryloxy group or a heteroaryloxy group) and a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein A and B are N, and a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein A is N and B is CH, and a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, wherein A and B are CH, and a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1 or 2, wherein R ₃ is a lower alkyl group, and a pharmaceutically acceptable salt thereof.