Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament comprising them

• US 6,262,123 B1
• Filed: 09/17/1999
• Issued: 07/17/2001
• Est. Priority Date: 03/04/1996
• Status: Expired due to Fees

• Current Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Original Assignee: Aventis Pharma Deutschland GmbH (Sanofi )
• Inventors: Scholz, Wolfgang, Kleemann, Heinz-Werner, Brendel, Joachim, Weichert, Andreas, Lang, Hans Jochen, Schwark, Jan-Robert, Albus, Udo
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US09/398,196
• Time in Patent Office: 669 Days
• Field of Search: 514/614, 514/617, 514/618, 514/634, 514/307, 514/311, 514/357, 564/147, 564/162, 564/170, 564/176, 564/177, 546/145, 546/175, 546/329
• US Class Current: 514/617
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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 9/08 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

Abstract

Ortho-substituted benzoylguanidines of the formula I

in which R(1) to R(4) have the meanings given in the claims, are suitable, as antiarrhythmic pharmaceuticals having a cardioprotective component, for the prophylaxis and treatment of infarction and for the treatment of angina pectoris. They also inhibit, in a preventive manner, the pathophysiological processes associated with the genesis of ischemically induced damage, in particular associated with the triggering of ischemically induced cardiac arrhythmias.

Claims

1. An ortho-substituted benzoylguanidine of the formula I

in which:

R(1) is H, F, Cl, Br, I, CN, NO₂, alkyl, having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkoxy having 3, 4, 5, 6, 7 or 8 carbon atoms or X_a—

(CH₂)_b—

(CF₂)_c—

CF₃;

X is oxygen, S or NR(5),

a is zero or 1;

b is zero, 1 or 2;

c is zero, 1, 2or 3;

R (5) is H, alkyl having 1, 2, 3 or 4 carbon atoms or —

C_dH_2dR(⁶);

d is zero, 1, 2, 3 or 4;

R(6) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl, biphenylyl or naphthyl,

where the aromatic radicals phenyl, biphenylyl or naphthyl are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(7)R(8);

R(7) and R(8) are, independently, H or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R(1) is —

SR(10), —

OR(10) or —

CR(10)R(11)R(12);

R(10) is —

C_fH_2f-cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl ring, or phenyl,

where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino;

f is zero, 1 or 2;

R(11) and R(12) are, independently of each other, defined as R(10), or hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R(1) is phenyl, naphthyl, biphenylyl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, with the latter being linked by a C atom or an N atom of the ring, which are in each case unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(1) is —

SR(13),—

OR(13),—

NHR(13),—

NR(13)R(14),—

CHR(13)R(15), —

C[R(15)R(16)OH], —

C≡

CR(18), —

C[R(19)]═

CHR(18) or —

C[R(20)R(21)]_k—

(CO)—

[(CR(22)R(23)]_l—

R(24),

k is zero, 1, 2, 3 or 4;

l is zero, 1, 2, 3 or 4;

R(13) and R(14) are, identically or differently, —

(CH₂)_g—

(CHOH)_h—

(CH₂)_i—

(CHOH)_j—

R(17) or —

(CH₂)_g—

O—

(CH₂—

CH₂O)_h—

R(24);

R(17) is hydrogen or methyl,

g, h and i are, identically or differently, zero, 1, 2, 3 or 4;

is 1, 2, 3 or 4;

R(15) and R(16) are, identically or differently, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or are, together with the carbon atom carrying them, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;

R(18) is phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(25)R(26);

R(25) and R(26) are H or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R(18) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or substituted as phenyl;

or

R(18) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which is unsubstituted or substituted by 1-3 OH;

or

R(18) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;

R(19), R(20), R(21), R(22) and R(23) are, identically or differently, hydrogen or methyl;

R(24) is H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or —

C_mH_2m—

R(¹⁸);

m is 1, 2, 3 or 4;

one of the two substituents R(2) and R(3) is hydroxyl;

and

the other of the substituents R(2) and R(3) in each case is defined as R(1);

R(4) is alkyl having 1, 2, 3 or 4 carbon atoms;

alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CN, I or —

(CH₂)_n—

(CF₂)_o—

CF₃;

n is zero or 1;

o is zero or 1;

or a pharmaceutically tolerated salts thereof.

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

R(1) is H, F, Cl, Br, I, CN, NO2, alkyl, having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkoxy having 3, 4, 5, 6, 7 or 8 carbon atoms or X_a—

(CF₂)_c—

CF₃;

X is oxygen;

a is zero or 1;

c is zero, 1, 2 or 3;

or

R(1) is —

SR(10) or —

OR(10);

R(10) is —

C_fH_2f-cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl ring, or phenyl, where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino;

f is zero or 1;

or

R(1) is phenyl, naphthyl, biphenylyl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, with the latter being linked via a C atom or N atom of the ring, which are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(1) is —

SR(13), —

OR(13), —

NHR(13), —

NR(13)R(14),—

C≡

CR(18) or —

C[(R(19)]═

CHR(18);

R(13) and R(14) are, identically of differently, —

(CH₂)_g—

(CHOH)_h—

(CH₂)_i—

(CHOH)_j—

R(17) or —

(CH₂)_g—

O—

(CH₂-CH₂O)_h—

R(24);

R(17) is hydrogen or methyl, g, h and i are, identically or differently, zero, 1 or 2;

is 1 or 2;

R(18) is phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(25)R(26);

R(25) and R(26) are H or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R(18) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or substituted as phenyl;

or

R(18) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which is unsubstituted or substituted by 1-3 OH;

or

R(18) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;

R(19) is hydrogen or methyl;

one of the substituents R(2) and R(3) is hydroxyl;

and

the other of the substituents R(2) and R(3) in each case is defined as R(1);

R(4) is alkyl having 1 or 2 carbon atoms, methoxy, F, Cl, Br, CN or —

(CH₂)_n—

(CF₂)_o—

CF₃;

n is zero or 1;

o is zero or 1.

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

R(1) is H, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, cycloalkoxy having 5 or 6 carbon atoms or —

X_a—

(CF₂)_c—

CF₃;

X is oxygen;

a is zero or 1;

c is zero or 1;

or

R(1) is —

SR(10) or —

OR(10);

R(10) is cycloalkyl having 4, 5 or 6 carbon atoms, or phenyl, where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino;

or

R(1) is quinolyl, isoquinolyl or pyridyl, which are linked via a C atom or N atom of the ring;

and which are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(1) is phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(1) is —

C≡

CR(18);

R(18) is phenyl or cycloalkyl having five or 6 carbon atoms;

one of the two substituents R(2) and R(3) is hydroxyl;

and the other of the substituents R(2) and R(3) in each case is defined as R(1);

R(4) is methyl, methoxy, F, Cl or CF₃;

and the pharmaceutically tolerated salts thereof.

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

R(1) is H, F, Cl, an alkyl having 1, 2, 3 or 4 carbon atoms, an alkoxy having 1, 2, 3 or 4 carbon atoms, a cylcoalkyl having 5 or 6 carbon atoms, a cycloalkoxy having 5 or 6 carbon atoms or CF₃;

one of the substituents R(2) and R(3) is hydroxyl, and the other of the substituents R(2) and R(3) in each case is defined as R(1); and

R(4) is methyl, methoxy, F, Cl or CF₃.

5. A compound according to claim 1 which is 2-chloro-4-hydroxybenzoylguanidine or a pharmaceutically tolerable salt thereof.

6. A compound according to claim 1 which is 2-chloro-4-hydroxy-5-iodobenzoylguanidine or a pharmaceutically tolerable salt thereof.

7. A compound according to claim 1 which is 2-chloro-4-hydroxy-3,5-diiodobenzoylguanidine or a pharmaceutically tolerable salt thereof.

8. A compound according to claim 1 which is 2-chloro-4-hydroxy-3,5-diiodobenzoylguanidine or a pharmaceutically tolerable salt thereof.

9. A compound according to claim 1 which is 4-hydroxy-5-trifluoromethylbenzoylguanidine or a pharmaceutically tolerable salt thereof.

10. A compound according to claim 1 which is 4-hydroxy-2-methyl-5-trifluoromethylbenzoylguanidine or a pharmaceutically tolerable salt thereof.

11. A method of treating or preventing diseases which are brought about by ischemic conditions in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

12. A method of treating or preventing cardiac infarction in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

13. A method of treating or preventing angina pectoris in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

14. A method of treating or preventing ischemic conditions of the heart in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

15. A method of treating or preventing ischemic conditions of the peripheral and central nervous system and stroke in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

16. A method of treating or preventing ischemic conditions of peripheral organs and limbs in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

17. A method of treating shock conditions in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

18. A method of preparing a patient for a surgical operation or an organ transplantation comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

19. A method of preparing a medicament for the preservation and storage of transplants for surgical procedures comprising administering to the transplant a therapeutically effective amount of a compound according to claim 1.

20. A method of treating diseases in which cell proliferation constitutes a primary or secondary cause in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.

21. The method according to claim 20, wherein the diseases in which cell proliferation constitutes a primary or secondary cause are atherosclerosis, complications of diabetes, cancerous diseases, fibrotic diseases, or prostate hyperplasia.

22. The method according to claim 21, wherein said fibrotic diseases are pulmonary fibrosis, hepatic fibrosis or renal fibrosis.

23. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in admixture with a physiologically acceptable carrier.