Heterocyclyl-benzoylguanidines

• US 5,753,680 A
• Filed: 08/30/1995
• Issued: 05/19/1998
• Est. Priority Date: 08/31/1994
• Status: Expired due to Term

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Baumgarth, Manfred, Beier, Norbert, Gericke, Rolf, Dorsch, Dieter, Minck, Klaus-Otto
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US08/520,780
• Time in Patent Office: 993 Days
• Field of Search: 514/327, 514/255, 514/357, 514/394, 514/399, 514/406, 514/331, 514/427, 514/428, 514/429, 544/392, 546/221, 546/332, 548/336.1, 548/561, 548/583, 548/309.7, 548/377.1, 548/569, 549/491
• US Class Current: 514/331
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/68 attached in position 4
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• 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

Heterocyclyl-benzoylguanidines of the formula I ##STR1## in which R¹, R², R³ and Het have the meanings given herein, and physiologically unobjectionable salts thereof, display antiarrhythmic properties and act as inhibitors of the cellular Na⁺ /H⁺ antiporter.

Claims

1. Heterocyclylbenzoylguanidine of the formula I ##STR5## in which R¹ is A, CF₃, CHF, CHF₂, C₂ F₅, CN, NO₂, Hal, --C.tbd.CH or --X--R⁴,

R² is in each case independent of one another and are H, Hal, A, --X--R⁴, CN, NO₂, CF₃, CH₂ F, CHF₂, C₂ F₅, CH₂ CF₃, --SO_n --R⁶, --SO₂ NR⁴ R⁵, Ph or OPh,

R⁴ is H, A, cycloallyl of 5 to 7 carbon atoms, cycloalkylmethyl of 6 to 8 carbon atoms, CF₃, CH₂ F, CHF₂, CH₂ CF₃, Ph or --CH₂ --Ph,

R⁵ is H or A, or else

R⁴ and R⁵ together are alkylene of 4 to 5 carbon atoms, in which case one CH₂ group may also be replaced by O, S, NH, N--A or N--CH₂ --Ph,

R⁶ is A or Ph,

Het is imidazolyl, piperazinyl, piperidyl, pyrrolyl, pyridyl, oxodihydropyridyl, benzimidazolyl, pyrazolyl, furanyl and pyrrolidinyl,

A is alkyl of 1 to 6 carbon atoms,

X is O or S,

Ph is unsubstituted phenyl or phenyl which is mono-, di- or trisubstituted by A, OA, NR⁴ R⁵, F, Cl, Br, I or CF₃,

n is 1 or 2, and

Hal is F, Cl, Br or I.

3. Process for the preparation of heterocyclylbenzoylguanidine derivatives of the formula I according to claim 1 and of their salts, characterized in that a compound of the formula II ##STR6## in which R¹, R², R³ and Het have the meanings given above and

Q is Cl, Br, OA, O--CO--A, O--CO--Ph, OH or another reactive esterified OH group or leaving group which can easily be substituted nucleophilically,

is reacted with guanidine,

or in that a benzoylguanidine of the formula III ##STR7##

4. Pharmaceutical preparation, which comprises at least one compound of the general formula I according to claim 1 or one of it physiologically acceptable salts.

2. A compound selected from the group consisting of

(a) N-Diaminomethylene-2-ethyl-4-(1-imidazolyl)-5-methylsulfonylbenzamide;

(b) N-diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methylsulfonylbenzamide;

(c) N-diaminomethylene-2-methyl-4-(3-hydroxypiperidino)-5-methylsulfonylbenzamide;

(d) N-diaminomethylene-2-ethyl-4-(3-pyridyl)-5-methylsulfonylbenzamide;

(e) N-diaminomethylene-2-ethyl-4-(2-pyridyl)-5-methylsulfonylbenzamide;

(f) N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulfonylbenzamide;

and the physiologically acceptable salts thereof.