JPH02184673A - Sulfonamide compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [ring A is pyridine ring, 2-oxypyridine ring or 4-alkyl substituent thereof; R<1> is H or lower alkyl; Z is -NR<2>R<3> (R<2> and R<3> are R<1>, (substituted) phenylalkyl, N-alkylpyrrolidinylalkyl, piperidinyl, etc.), formula II (R<4> and R<5> are R<1>, (substituted) phenylalkyl or forms heterocyclic ring together with adjacent N; n is 1-4)] or acid addition salt thereof. EXAMPLE:4-[Bis(4-fluorophenyl)methyl]-1-(8-methoxyquinoline-5-sulfonyl) piperazine. USE:A medicine. The compound expressed by formula I exhibits excellent calmodulin antagonism, coronary blood flow-increasing action, vasodepressor, etc. and is used as preventive and remedy for circulatory disease such as vasodilator, angina pectoris or hypotensive agent. PREPARATION:A compound expressed by formula III is reacted with a com pound expressed by the formula ZH in a solvent in the presence of a deacidification agent such as triethylamine to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel and pharmaceutically useful sulfonamide compound or an acid addition salt thereof.

[Conventional technology]

JP-A-57-156463, JP-A No. 57-200366
No. 5B-121278, No. 58121279,
No. 60-81168, No. 61-152658, No. 6
No. 3-211267 discloses an isoquinoline sulfonic acid amide compound that can be used as a vasodilator, cerebral circulation improver, or other pharmaceutical agent.

[Problem to be solved by the invention]

An object of the present invention is to provide a novel sulfonic acid amide compound or an acid addition salt thereof, which has excellent calmodulin antagonism, coronary blood flow increasing, and blood pressure lowering effects, and is useful as a therapeutic agent for cardiovascular diseases. shall be.

[Failure to solve the problem]

The present invention relates to the general formula lower alkyl, phenylalkyl, substituted phenylalkyl, N-alkylpyrrolidinylalkyl, piperidyl,
It represents N-substituted piperidyl, pyridyl or pyridylalkyl, or represents a group which together with the adjacent nitrogen atom forms a heterocycle. ) or -NH(CHt), lNR'R'
Here, R4R8 are the same or different and represent hydrogen, lower alkyl, phenylalkyl or substituted phenylalkyl, or a group forming a heterocycle with the adjacent nitrogen atom. n represents an integer of 1 to 4. ) is shown. ] The present invention relates to a sulfonamide compound represented by: or an acid addition salt thereof.

(In the formula, term 8 is a pyridine ring or a 2-oxopyridine ring or a 4-alkyl substituted product thereof, R' is hydrogen or lower alkyl, and Z is -NR"R" (herein, Rz,
Rs are the same or different and hydrogen; in the above definition, the pyridine ring or 2-oxopyridine ring or its 4-alkyl substituent in ring A is fused with a benzene ring to form a quinoline ring, 1,2-dihydro-2- Oxoquinoline ring, 1,2,3.4-tetrahydro-2-oxoquinoline ring or its 4-alkyl or 4,4-dialkyl (here, alkyl is methyl, ethyl, propyl, isopropyl, etc., but methyl is preferred) means a substituted product.

Lower alkyl in R", R3, R' and R5 means methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc. Phenyl alkyl in R2R3, R4, R5 means hensyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, etc., substituted phenylalkyl in R2R3 means halogen (chlorine, bromine, fluorine, etc.), lower alkyl (same as above), lower alkoxy (methoxy, ethoxy, propoxy, etc.) on the benzene ring. Isopropoxy, butoxy, tertiary
phenylalkyl having 1 to 3 substituents such as (butoxy, etc.) or trifluoromethyl. R",
What is N-alkylpyrrolidinylalkyl in Ri?
1-methyl-2=pyrrolidinylmethyl, 1-ethyl-2
-pyrrolidinylmethyl, 2-(1-ethyl-2-pyrrolidinyl)ethyl, etc., piperidyl refers to 4-piperidyl, N-substituted piperidyl refers to lower alkyl substituents, etc.
Phenylalkyl, substituted phenylalkyl (these are
(same as above), preferably 1-methyl-4-
Piperidyl, 1-ethyl 4-piperidyl, 1-benzyl-4-piperidyl, 1-(2-phenylethyl)-4
-piperidyl, 1-(3-phenylpropyl)piperidyl, etc.; pyridyl refers to 2-pyridyl, 3-pyridyl,
4-pyridyl and pyridylalkyl include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(
2-pyridyl)ethyl, 2-(3-pyridyl)ethyl,
2-(4-pyridyl)ethyl, etc. Rt, R
A heterocycle formed with adjacent nitrogen atoms in s and R', R% refers to a ring atom such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, 1-homopiperazinyl, morpholino, thiomorpholino, etc. that further includes nitrogen,
A 5- to 7-membered ring which may contain oxygen or sulfur, or its lower alkyl, phenylalkyl, substituted phenylalkyl (these are the same as above), hydroxyalkyl (hydroxymethyl, 2-hydroxyethyl, etc.), acyl (acetyl , propionyl, butyryl, pivaloyl, benzoyl, etc.), phenyl, substituted phenyl [substituents include 1 to 3 halogens, lower alkyl, lower alkoxy (
These are the same as above), trifluoromethyl, and hydroxyl group. ], benzhydryl, substituted benzhydryl (W substituents include 1 to 3 halogen, lower alkyl, lower alkoxy (these are the same as above), and trifluoromethyl).

Acid addition salts of the compound of general formula (1) of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, maleate, fumarate, citrate, Examples include organic acids such as succinate, tartrate, methanesulfonate, and P-toluenesulfonate. Further, hydrates are also included in the present invention. When an asymmetric carbon is present in the compound of general formula (1), the present invention includes all optical isomers based thereon and mixtures thereof.

The compound of the general formula (1) of the present invention is, for example, a compound represented by the general formula (in which each symbol has the same meaning as above) and a compound represented by the general formula % formula % (1) (wherein Z is the above-mentioned ) can be produced by reacting with a compound represented by water or a suitable solvent (methanol, ethanol, isopropyl alcohol, ) L/, methylene chloride, dichloroethane, chloroform, ethyl acetate, dioxane, acetonitrile, benzene, toluene, acetone, dimethylformamide, etc.) or any mixed solvent thereof. The reaction temperature is also not particularly limited, and is usually carried out at a temperature ranging from O''C to the boiling point temperature of the solvent.
The reaction may be carried out in the presence of an organic base such as N-dimethylaniline or an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.).

The compound of general formula (I) of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and chromatography alone or in combination.

The compound of general formula (1) of the present invention is an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or maleic acid, fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid,
The above-mentioned acid addition salt can be obtained by treatment with p-)luenesulfonic acid or the like in a conventional manner.

When the compound of the present invention is used as a medicine, a carrier,
It can be mixed with excipients, diluents, solubilizing agents, etc. and safely administered to patients in the form of tablets, powders, granules, capsules, injections, etc. The dosage is usually 1 to 50 per day for adults.
It is about 0 ■.

[Action and effect of the invention]

The compounds of the present invention exhibit excellent calmodulin antagonistic effects, coronary blood flow increasing effects, antihypertensive effects, etc., and are vasodilators,
It is useful as a preventive and therapeutic agent for circulatory system diseases, such as a cerebral circulation improving agent, an angina treatment agent, and a blood pressure lowering agent.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 3.7 g of 1-[bis(4-fluorophenyl)methylcopiperazine and 2.4 g of triethylamine were dissolved in 50 tl+ of chloroform, and 8-methoxy-
Add 3.0 g of 5-quinolinesulfonyl chloride.

After stirring at room temperature for 2 hours, the mixture is refluxed for 3 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. When ethanol is added to the residual aroma to crystallize it and recrystallized from a mixed solvent of methanol and chloroform, 4-[bis(4-fluorophenyl)methyl)-1-(8-methoxy 3.8 g of quinoline-5-sulfonyl)piperazine are obtained.

Example 2 4.9 g of l-((4-10 lophenyl)phenylmethylcopiperazine and 3.0 g of triethylamine were dissolved in chloroform 70, and 8-methoxy-5
- Add 4.0 g of quinolinesulfonyl chloride. After stirring at room temperature for 2 hours, the mixture is refluxed for 3.5 hours. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. After washing the residual fragrance with methanol, recrystallization from acetonitrile produces white crystals with a melting point of 206-208°.
C 4-((4-chlorophenyl)phenylmethyl]-
2.8 g of 1-(8-methoxy-5-quinolinesulfonyl)piperazine are obtained.

Example 3 N-(3-aminopropyl)morpholine and 1°2.3.
4-Tetrahydro-8-methoxy-4methyl-2-oxo-5-quinolinesulfonyl chloride was reacted and treated in the same manner as in the previous example to form a fumarate salt with a melting point of 164 to 166°C. N-(3-morpholinopropyl)1.2,3.4-tetrahydro-8-methoxy4-methyl-2-oxo-5-quinolinesulfonic acid amide fumarate is obtained.

Example 4 By reacting and treating 1-methylpiperazine and 8-methoxy-5-quinolinesulfonyl chloride in the same manner as in the above example, 1-
(8-Methoxy-5-quinolinesulfonyl)-4-methylpiperazine is obtained.

Example 5 Using l-(2-methoxyphenyl)piperazine and 8methoxy-5-quinolinesulfonyl chloride, the reaction and treatment were carried out in the same manner as in the above example.
4-(2-methoxyphenyl)-1-(8-methoxy-5-quinolinesulfonyl)piperazine at 0°C is obtained.

Example 6 Using l-(3-chlorophenyl)piperazine and 8=methoxy-5-quinolinesulfonyl chloride, the melting point was 170 to 170 by reacting and treating in the same manner as in the above example.
4-(3-chlorophenyl)-1-(8-
Methoxy-5-quinolinesulfonyl)piperazine is obtained.

Example 7 Using l-(2-hydroxyethyl)piperazine 8-methoxy-5-quinolinesulfonyl chloride, the melting point was 109 by reacting and treating in the same manner as in the above example.
~112'C 4-(2-hydroxyethyl)-1-(
8-Methoxy-5-quinolinesulfonyl)piperazine is obtained.

Example 8 Using homopiperazine and 8-methoxy-5-quinolinesulfonyl chloride, 1-(8-
Methoxy-5-quinolinesulfonyl)homopiperazine is obtained.

Example 9 Using 4-benzylpiperidine and 8-methoxy-5quinolinesulfonyl chloride, 4-benzyl-1-(8-methoxy-5 -quinolinesulfonyl)piperidine is obtained.

Example 10 Using 1-ethyl-2-aminomethylpyrrolidine and 8-methoxy-5-quinolinesulfonyl chloride, the melting point was 164 by reacting and treating in the same manner as in the above example.
N-(1-ethyl-2-pyrrolidinylmethyl)-8-methoxy-5-quinolinesulfonic acid amide at ~166°C is obtained.

Example 11 By reacting and treating in the same manner as in the above example using 1-(2-phenylethyl)-4-aminopiperidine and 8-methoxy-5-quinolinesulfonyl chloride,
N-(1-(2-phenylethyl)-4-piperidylco-8-methoxy-5-quinolinesulfonic acid amide with a melting point of 164-167"C is obtained.

Example 12 Using 4-aminopyridine and 8-methoxy-5-quinolinesulfonyl chloride, a reaction was carried out in the same manner as in the above example.
By processing, melting point 280-282'C (decomposition)
N-(4-pyridyl)-8-methoxy-5-quinolinesulfonic acid amide is obtained.

Example 13 1.3-Propanediamine and 8-methoxy-5-quinolinesulfonyl chloride were reacted and treated in the same manner as in the above example to form a hydrobromide salt, with a melting point of 2.
N-(3-aminopropyl)-8-methoxy-5-quinolinesulfonic acid amide hydrobromide at 29-231°C (decomposition) is obtained.

Example 14 N-(3-aminopropyl)morpholine and 8-methoxy-5-quinolinesulfonyl chloride were reacted and treated in the same manner as in the above example to achieve a melting point of 132-
N-(3-morpholinopropyl)-8-methoxy-5-quinolinesulfonic acid amide at 135°C is obtained.

Example 15 By reacting and treating 1-(3-aminopropyl)-4-phenylpiperidine and 8-methoxy-5-quinolinesulfonyl chloride in the same manner as in the above example, a product with a melting point of 131 to 134°C was obtained. N-(3-(4-phenylpiperidino)propyl]-8-methoxy5-quinolinesulfonic acid amide is obtained.

Example 16 3-diethylaminopropylamine and 8-methoxy-5
-Using quinoline sulfonyl chloride, the melting point was 117 to 12 by treating and treating in the same manner as in the above example.
N-(3-diethylaminopropyl)-8-methoxy-5-quinolinesulfonic acid amide at 0°C is obtained.

Example 17 Using 1-(2-aminoethyl)-4-bis(4-fluorophenyl)methylbiperazine and 8-methoxy-5-quinolinesulfonyl chloride, the reaction and treatment were carried out in the same manner as in the above example to obtain the fumarate salt. By setting the melting point 1
N-(2-(4-bis(4-fluorophenyl)methyl-1-pyrrolidinylmethyl)-8- at 58-161 °C
Methoxy-5-quinolinesulfonic acid amide fumarate is obtained.

Example 18 Using 1-(3-aminopropyl)-4-diphenylmethylbiperazine and 8-methoxy-5-quinolinesulfonyl chloride, the melting point was 187 to 190 by reacting and treating in the same manner as in the above example. ``C (decomposition)-(3-
(4-diphenylmethyl-1-piperazinyl), propyl]-8-methoxy5-quinolinesulfonic acid amide is obtained.

Example 19 Homopiperazine and 1.2,3.・4-tetrahydro-8
-Methoxy-4-methyl-2-oxo-5-quinolinesulfonyl chloride was reacted and treated in the same manner as in the above example to obtain a fumarate salt with a melting point of 202
1-(1,2,3,4-tetrahydro-
8-methoxy-4-methyl-2-oxo-5-quinolinesulfonyl) homopiperazine fumarate is obtained.

Example 20 The above procedure using 4-amino-1-(2-phenylethyl), veridine and 1,2,3,4-tetrahydro-8-methoxy-4-methyl-2-oxo-5-quinolinesulfonyl chloride By reacting and treating in the same manner as in Examples, N-(1-(2-phenylethyl)-4-piperidyl)-1,2,3,4-tetrahydro-8-methoxy- with a melting point of 163 to 166°C was obtained. 4-methyl-2-oxo-5
-Quinoline sulfonic acid amide is obtained.

Example 21 In the same manner as in the above example, using 4-amino-1-(3-phenylpropyl)piperidine and 1,2-dihydro-8-methoxy-4methyl-2-oxo-5-quinolinesulfonyl chloride. By reaction and treatment, N-(1-(3-phenylpropyl)-4-piperidyl)-1,2-dihydro-8-methoxy-4-methyl-2-oxo-5 with a melting point of 174-176°C -Quinoline sulfonic acid amide is obtained.

Example 22 4-amino-1-(3-(4-chlorophenyl)propylcopiperidine and 1,2-dihydro-8-methoxy-4
~ Using methyl-2-oxo-5-quinolinesulfonyl chloride, by reacting and treating in the same manner as in the above example, N-[1-(3-(
4-chlorophenyl)propyl]-4-piperidyl)-
1,2dihydro-8-methoxy-4-methyl-2-oxo-5-quinolinesulfonic acid amide is obtained.

Example 23 Using 3-aminomethylpyridine and 1,2,3,4-tetrahydro-8-methoxy-4-methyl-2-oxo-5-quinolinesulfonyl chloride, the reaction and treatment were carried out in the same manner as in the above example. , N-(3-pyridylmethyl)- with a melting point of 163 to 165°C by making it a fumarate salt.
1,2,,3,4tetrahydro-8-methoxy-4-methyl-2-oxo-5-quinolinesulfonic acid amide fumarate is obtained.

Example 24 2-diethylaminoethylamine and 1.2,3°4-tetrahydro-8-methoxy-4-methyl-2-oxo-
Using 5-quinolinesulfonyl chloride, the melting point was 164 to 1 by reacting and treating in the same manner as in the above example.
N-(2-diethylaminoethyl)-1,2, at 66°C
3,4-tetrahydro-8-methoxy-4-methyl-2
-Oxo-5-quinolinesulfonic acid amide is obtained.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, ring A is a pyridine ring or 2-oxopyridine ring or its 4-alkyl substituted product, R^1 is hydrogen or lower alkyl, Z is -NR^2R^3 (here, R
^2 and R^3 are the same or different and represent hydrogen, lower alkyl, phenylalkyl, substituted phenylalkyl, N-alkylpyrrolidinylalkyl, piperidyl, N-substituted piperidyl, pyridyl or pyridylalkyl, or adjacent nitrogen atoms Indicates a group that forms a heterocycle with the following. )
or -NH(CH_2)_nNR^4R^5 (where R^4 and R^5 are the same or different and represent hydrogen, lower alkyl, phenylalkyl or substituted phenylalkyl, or together with the adjacent nitrogen atom, a heterocycle (n is an integer of 1 to 4). ] A sulfonamide compound or an acid addition salt thereof.