CA2551057A1 - Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same - Google Patents

Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same Download PDF

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CA2551057A1
CA2551057A1 CA002551057A CA2551057A CA2551057A1 CA 2551057 A1 CA2551057 A1 CA 2551057A1 CA 002551057 A CA002551057 A CA 002551057A CA 2551057 A CA2551057 A CA 2551057A CA 2551057 A1 CA2551057 A1 CA 2551057A1
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Heinz-Werner Kleemann
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Abstract

The invention relates to pentafluorosulfanyl benzoylguanidines of formula (I), in which R1 to R4 are defined as cited in the claims. Said substances are suitable for use as anti-arrhythmic medicaments comprising cardio-protective components for the prophylaxis and treatment of infarcts, in addition to the treatment of angina pectoris. They also preventatively inhibit the pathophysiological events that occur during ischaemically induced traumas, in particular during the triggering of ischaemically induced cardiac arrhythmia.

Claims (16)

1. A compound of the formula I

in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,
2, 3 or 4 carbon atoms, F, CI, Br, I, -CN, NR5R6, -O p-(CH2)n-(CF2)o-CF3 or -(SO m)q -(CH2)r(CF2)s-CF3;

R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or4 carbon atoms or-CH2-CF3;

m is zero, 1 or 2 n, o, p, q, r and s are, independently of one another, zero or 1;

R2 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, -CN, NR7R8, -O t-(CH2)u-(CF2)v-CF3 or -(SO w)x-(CH2)y(CF2)z-CF3;

R7 and R8 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;

w is zero, 1 or 2 t, u, v, x,y and z are, independently of one another, zero or 1;

R3 is CI, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -O a-(CH2)b-(CF2)c-CF3, -(SO d)e-(CH2)f-(CF2)g-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R9 and R10 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
a, b and c are, independently of one another, zero or 1;

d is zero, 1 or 2;

e is zero or 1;

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

g is zero or 1;

or R3 is -(CH2)h-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, CI, Br, I, -O j-(CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;

j is zero or 1;

k is zero, 1, 2 or 3;

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

or R3 is -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, CI, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;

bb is zero or 1;

cc is zero, 1, 2 or 3;

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

R4 is hydrogen, F, CI, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR11R12, -Odd-(CH2)ee-(CF2)ff-CF3; -(SOgg)hh-(CH2)jj-(CF2)kk-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

R11 and R12 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;

dd, ee and ff are, independently of one another, zero or 1;

gg is zero, 1 or 2;

hh is zero or 1;

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

kk is zero or 1;

or R4 is -(CH2)II-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, CI, Br, I, -Omm-(CH2)nn-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;

mm is zero or 1;

nn is zero, 1, 2 or 3;

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

or R4 is -(CH2)oo-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, CI, Br, I, -Opp-(CH2),T-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;

pp is zero or 1;
rr is zero, 1, 2 or 3;
oo is zero, 1, 2, 3 or 4;
and the pharmaceutically acceptable salts thereof.
2. A compound of the formula I as claimed in claim 1, in which the meanings are:
R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -O p-(CH2)n-(CF2)o-CF3 or -(SO m)q-(CH2)r(CF2)s-CF3;
R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
m zero, 1 or 2 n, o, p, q, r and s independently of one another zero or 1;
R2 hydrogen or F;
R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -O a-(CH2)b-(CF2)c-CF3, -(SO d)e-(CH2)f-(CF2)g-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R9 and R10 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
a, b and c independently of one another zero or 1;
d zero, 1 or 2;
e zero or 1;
f zero, 1, 2, 3 or 4;
g zero or 1;
or R3 -(CH2)h-phenyl or -O-phenyl, in which the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Oj-(CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
j zero or 1;
k zero, 1, 2 or 3;
h zero, 1, 2, 3 or 4;
or R3 -(CH2)aa-heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Obb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
bb zero or 1;
cc zero, 1, 2 or 3;
as zero, 1, 2, 3 or 4;
R4 hydrogen or F;
and the pharmaceutically acceptable salts thereof.
3. A compound of the formula I as claimed in claim 1 or 2, in which the meanings are.
R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, -CN, NR5R6, -O-CH2-CF3 or -(SO m)q-(CH2)r-CF3;
R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
m zero, 1 or 2 q and r independently of one another zero or 1;

R2 hydrogen or F;
R3 Cl, Br, I, -CN, -SO2CH3, alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, -O-CH2-CF3, -(SO d)e-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R9 and R10 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
d zero, 1 or 2;
a zero or 1;
or R3 phenyl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -Oj-(CH2)k-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
j zero or 1;
k zero, 1, 2 or 3;
or R3 heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, -O bb-(CH2)cc-CF3, alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
bb zero or 1;
cc zero, 1, 2 or 3;
R4 hydrogen or F;
and the pharmaceutically acceptable salts thereof.
4. A compound of the formula I as claimed in one or more of claims 1, 2 and 3, in which the meanings are:

R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, -O-CH2-CF3 or -(SO m)q-(CH2)r-CF3;
R5 and R6 independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -CH2-CF3;
m zero, 1 or 2 q and r independently of one another zero or 1;
R2 hydrogen or F;
R3 Cl, -CN, -S02CH3, methoxy, ethoxy, NR9R10, -O-CH2-CF3, -(SO d)e-CF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, in which 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;
R9 and R10 independently of one another hydrogen, methyl, ethyl or -CH2-CF3;
d zero, 1 or 2;
a zero or 1;
or R3 phenyl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, CI, -Oj-(CH2)k-CF3, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
j and k independently of one another zero or 1;
or R3 heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, CI, -Obb-(CH2)cc-CF3, methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms and -SO2CH3;
bb and cc independently of one another zero or 1;
R4 hydrogen or F;
and the pharmaceutically acceptable salts thereof.
5. A compound of the formula I as claimed in any of claims 1 to 4 and selected from: N-(5-methanesulfonyl-2-methyl-4-pentafluorosulfanyl-benzoyl)guanidine, and the pharmaceutically acceptable salts thereof.
6. A process for preparing a compound of the formula I as claimed in one or more of claims 1, 2, 3, 4 and 5 and/or the pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula II, in which R1 to R4 have the meaning stated in claims 1 to 4 and L is a leaving group which can undergo nucleophilic substitution, with guanidine.
7. A compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5 for use as medicament.
8. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5 for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, for the treatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis of states of shock, of diseases in which cellular proliferation represents a primary or secondary cause, of cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from overexcitability of the CNS, epilepsy or centrally induced convulsions, of disorders of the central nervous system, especially of anxiety states, depressions or psychoses, for the treatment or prophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) or late damage from diabetes, of thromboses, of disorders resulting from endothelial dysfunction, of intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive heart failure, of acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry, and for use for surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for use in bypass operations, for use in resuscitation after a cardiac arrest, for preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.
9. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5 in combination with other medicaments or active ingredients for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, for the treatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis of states of shock, of diseases in which cellular proliferation represents a primary or secondary cause, of cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from overexcitability of the CNS, epilepsy or centrally induced convulsions, of disorders of the central nervous system, especially of anxiety states, depressions or psychoses, for the treatment or prophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) or late damage from diabetes, of thromboses, of disorders resulting from endothelial dysfunction, of intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive heart failure, of acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry, and for use for surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for use in bypass operations, for use in resuscitation after a cardiac arrest, for preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.
10. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in claim 9 in combination with cardiotoxic and cytotoxic medicaments or active ingredients for producing a medicament with reduced cardiotoxic and cytotoxic properties.
11. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events.
12. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment of life-threatening cardiac ventricular fibrillation.
13. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment or prophylaxis of metastasis.
14. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 8 and/or 9 for producing a medicament for the treatment or prophylaxis of fibrotic disorders of the heart, of heart failure or of congestive heart failure.
15. A medicine for human, veterinary and/or phytoprotective use comprising an effective amount of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5, together with pharmaceutically acceptable carriers and additives.
16. A medicine for human, veterinary and/or phytoprotective use comprising an effective amount of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in one or more of claims 1 to 5, together with pharmaceutically acceptable carriers and additives in combination with other pharmacological active ingredients or medicaments.
CA2551057A 2003-11-13 2004-11-03 Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same Expired - Fee Related CA2551057C (en)

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DE10353202A DE10353202A1 (en) 2003-11-13 2003-11-13 Pentafluorsulfuranyl-benzoylguanidine, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them
PCT/EP2004/012393 WO2005047239A1 (en) 2003-11-13 2004-11-03 Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same

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JP2014505052A (en) * 2011-01-06 2014-02-27 ベータ ファルマ カナダ インコーポレーテッド New urea for cancer treatment and prevention

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US9682931B2 (en) 2013-11-01 2017-06-20 Ube Industries, Ltd. Aryloyl(oxy or amino)pentafluorosulfanylbenzene compound, pharmaceutically acceptable salt thereof, and prodrugs thereof

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EP1685096A1 (en) 2006-08-02
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HRP20070364T3 (en) 2008-01-31
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DE10353202A1 (en) 2005-06-16
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