Substituted benzenesulfonylureas and -thioureas-processes for their preparation and their use as pharmaceuticals

• US 20020058838A1
• Filed: 11/29/2001
• Published: 05/16/2002
• Est. Priority Date: 02/23/1993
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Kaiser, Joachim, Gogelein, Heinz, Mania, Dieter, Wettlaufer, David, Englert, Heinrich, Linz, Wolfgang, Hartung, Jens
• Granted Patent: US 6,506,937 B2
• Time in Patent Office: Days
• US Class Current: 564/23
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/58 having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 335/42 Sulfonylthioureas; Sulfonylisothioureas

Abstract

Benzenesulfonylureas and -thioureas of the formula I

where R(1) is H or (fluoro)methyl, R(2) is H, Hal or (fluoro) (mercapto)alk(oxy)yl, E is O or S; Y is —[CR(3)₂]_n—, where R(3)=H or alkyl and n=1-4, X is H, Hal or alkyl and Z is Hal, NO₃ or alk(yl)oxy, are described.

The compounds I are used for treatment of disturbances in cardiac rhythm and prevention of sudden cardiac death caused by arrhythmia, and can therefore be used an antiarrhythmics. They are particularly suitable for those cases where arrhythmias are a consequence of a narrowing of a coronary vessel, such as angina pectoris or acute cardiac infarction.

Claims

1. A substituted benzenesulfonylurea or -thiourea of the formula I

2. A compound of the formula I as claimed in claim 1, in which:

R(1) is hydrogen, methyl or trifluoromethyl,

R(2) is hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-mercaptoalkyl, (C₁-C₆)-fluoroalkyl, (C₁-C₆)-fluoroalkoxy or F, Cl, Br or I,

E is oxygen or sulfur,

Y is a hydrocarbon chain of the formula

—

[CR(3)₂]_n—

where R(3)=H or (C₁-C₂)-alkyl and n=1, 2, 3 or 4,

X is hydrogen, F, Cl or (C₁-C₄)-alkyl and

Z is nitro, F, Cl, (C₁-C₄) -alkyl or (C₁-C₄)-alkoxy.

3. A compound of the formula I as claimed in claim 1, in which:

R(1) is hydrogen or methyl, and

R(2) is hydrogen, fluorine or chlorine,

E is oxygen or sulfur,

Y is a hydrocarbon chain of the formula

—

[R(3)₂]_n—

where R(3) us or (C₁-C₂)-alkyl and n=1, 2, 3 or 4,

X is hydrogen, F, Cl or (C₁-C₄)-alkyl, and

Z is chlorine, fluorine, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy.

4. A compound of the formula I as claimed in claim 1, in which:

R(1) is hydrogen or methyl,

R(2) is (C₁-C₆)-fluoroalkyl, (C₁-C₆)-fluoroalkoxy or (C₁-C₆)-mercaptoalkyl,

E is oxygen or sulfur,

Y in a hydrocarbon radical of the formula;

—

[CR(3)₂]_n—

where R(3)=H or (C₁-C₂)-alkyl and n=1, 2, 3 or 4,

X in hydrogen, F, Cl or (C₁-C₄)-alkyl and

Z is chlorine, fluorine, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy.

5. A compound of the formula I as claimed in claim 1, in which:

R(1) is hydrogen or methyl,

R(2) is methoxy or methyl,

E is oxygen or sulfur,

Y is a substituted or unsubstituted hydrocarbon radical having two to three carbon atoms of the formula

—

[CR(3)₂]_n—

where R(3)=H or methyl and n=2 or 3,

X is hydrogen, F, Cl or (C₁-C₃) -alkyl and

Z is chlorine or fluorine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy.

6. A process for the preparation of a compound I an claimed in claim 1, which comprises

(a) reacting an aromatic sulfonamide of the formula II or salts thereof of the formula III

with an R(1)-substituted isocyanate of the formula IV

R(1)—

N=C=O 

 

IV

to give a substituted benzenesulfonylurea Ia, or

(b) preparing an unsubstituted benzenesulfonylurea Ia (R(1)=H)

by reaction of an aromatic benzenesulfonamide of the formula II or its salt III

with a trialkylsilyl isocyanate or silicon tetraisocyanate and hydrolysis of the primary silicon-substituted benzenesulfonylurea, or

(c) preparing a benzenesulfonylurea Ia

from an aromatic benzenesulfonamide II or its salt III from an R(1)-substituted trichloroacetamide of the formula V

in the presence of a base, or

d) reacting an aromatic sulfonamide of the formula II or salt thereof of the formula III

with an R(1)-substituted thioisocyanate of the formula VI

R(1)—

N═

C═

S 

 

VI

to give a substituted benzenesulfonylthiourea lb.

7. The use of a compound I an claimed in claim 1 for the preparation of a medicament for the treatment of disturbances in cardiac rhythm.

8. The use of a compound I an claimed in claim 1 for the preparation of a medicament for prevention of sudden cardiac death.

9. The use of a compound I an claimed in claim 1 for the preparation of a medicament for the treatment of ischemic conditions of the heart.

10. The use of a compound I as claimed in claim 1 for the preparation of a scientific tool for inhibition of ATP-sensitive potassium channels.

13. A medicine comprising an active amount of a compound of the formula I as claimed in claim 1.

11. The use of a compound I for the preparation of a medicament for the treatment of weakened cardiac force.

12. The use of a compound I for the preparation of a medicament for improving cardiac function following a heart transplant.