Amino-substituted benzoylguanidines, process for their preparation, their use as a medicament and medicament containing them

• US 5,364,868 A
• Filed: 02/11/1993
• Issued: 11/15/1994
• Est. Priority Date: 02/15/1992
• Status: Expired due to Term

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Mania, Dieter, Scholz, Wolfgang, Lang, Hans-Jochen, Englert, Heinrich, Linz, Wolfgang, Albus, Udo
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US08/016,535
• Time in Patent Office: 642 Days
• Field of Search: 546/231, 548/567, 548/577, 564/237, 540/450, 540/470, 540/484, 540/544, 540/553, 540/575, 544/3, 544/53, 544/59, 544/63, 544/88, 544/169, 544/224, 544/238, 544/373, 514/183, 514/212, 514/218, 514/222.2, 514/226.8, 514/227.5, 514/228.8, 514/247, 514/255, 514/256, 514/331, 514/429, 514/634, 514/637
• US Class Current: 514/331
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

Amino-substituted benzoylguanidines, process for their preparation, their use as a medicament and medicament containing them

Benzoylguanidines of the formula I ##STR1## are described in which R(1) or R(2) is an amino group --NR(3)R(4), where R(3) and R(4) are H or (cyclo)alkyl or R(3) is phenyl-(CH₂)_p -- where p=0, 1, 2, 3 or 4, or phenyl, or R(3) and R(4) can also together be a methylene chain, and in which the other substituent R(1) or R(2) in each case is H, F, Cl, alkyl, alkoxy, CF₃, C_m F_2m+1 --CH₂ --, benzyl or phenoxy, and their pharmaceutically tolerable salts.

The compounds according to the invention have very good antiarrhythmic properties, as occur, for example, in the case of oxygen deficiency symptoms. The compounds are used as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment as well as for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the production of ischemically induced cardiac arrhythmias.

Claims

1. A benzoylguanidine of the formula I ##STR7## in which:

one of the two substituents R(1) or R(2) is --NR(3)R(4), where R(3) and R(4) together form a methylene chain (CH₂)_n, in which n is 4 or 5; and

the other substituent R(1) or R(2) is chlorine, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, or phenoxy, in which the phenyl radical is unsubstituted or substituted by one or two substituents selected from the group consisting of methyl, methoxy, fluorine or chlorine;

or its pharmaceutically tolerable salts.

2. A benzoylguanidine of the formula I as claimed in claim 1, in which the other substituent R(1) or R(2) is chlorine, C₁ -C₄ -alkoxy, or phenoxy, in which the phenyl radical is unsubstituted or substituted by one or two substituents selected from the group consisting of methyl, methoxy, fluorine or chlorine.

3. A benzoylguanidine of the formula I as claimed in claim 1, in which the other substituent R(1) or R(2) is chlorine or phenoxy, in which the phenyl radical is unsubstituted or substituted by one or two substituents selected from the group consisting of methyl, methoxy, fluorine or chlorine.

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

4-chloro-3-(1-pyrrolidino)benzoylguanidine, 4-methyl-3-(1-pyrrolidino)benzoylguanidine, 4-chloro-3-(1-piperidino)benzoylguanidine, 4-methyl-3-(1-piperidino)benzoylguanidine, 4-phenoxy-3-(1-pyrrolidino)benzoylguanidine and 4-(2-chlorophenoxy)-3-(1-pyrrolidino)benzoylguanidine or a pharmacologically tolerable salt thereof.

5. A method of treating arrhythmias comprising administering an effective amount for treating arrhythmias of a benzoylguanidine of formula I or its pharmaceutically tolerable salts as claimed in claim 1.

6. A method of prophylaxis or treatment of infarct in a mammal comprising administering an antiarrhythmic effective amount of a benzoylguanidine of formula I or its pharmaceutically tolerable salts as claimed in claim 1.

7. A method of treating angina pectoris in a mammal comprising administering an antiarrhythmic effective amount of a benzoylguanidine of formula I or its pharmaceutically tolerable salts as claimed in claim 1.