Pentafluorosulfanylbenzoylguanidines, process for their preparation, use as a medicament or diagnostic aid, and medicament comprising same

Abstract

Pentafluorosulfanylbenzoylguanidines of formula I wherein R1 to R4 have the meanings stated in the claims, are suitable, for example, as antiarrhythmic medicaments with a cardioprotective component for the prophylaxis of infarction and treatment of infarction and for the treatment of angina pectoris. They also inhibit preventively the pathophysiological processes associated with the development of ischemia-induced damage, especially in the triggering of ischemia-induced cardiac arrhythmias.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein R1 is 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 —(CH 2 ) n —(CF 2 ) o —CF 3  or —(SO m ) q —(CH 2 ) r —(CF 2 ) s —CF 3 ; 
 R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH 2 —CF 3 ;  
 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, Cl, Br, I, —CN, NR7R8, —O t —(CH 2 ) u —(CF 2 ) v —CF 3  or —(SO w ) x —(CH 2 ) y —(CF 2 ) z —CF 3 ;  
 R7 and R8 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or —CH 2 —CF 3 ;  
 w is zero, 1 or 2;  
 t, u, v, x, y and z are, independently of one another, zero or 1;  
 R3 is Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, —O a —(CH 2 ) b —(CF 2 ) c —CF 3 , —(SO d ) e —(CH 2 ) f —(CF 2 ) g —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 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 —CH 2 —CF 3 ;  
 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 —(CH 2 ) 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, —O j —(CH 2 ) k —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 j is zero or 1;  
 k is zero, 1, 2 or 3;  
 his zero, 1, 2, 3 or 4;  
 or R3 is —(CH 2 ) aa -heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O bb —(CH 2 ) cc —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 bb is zero or 1;  
 cc is zero or 1, 2 or 3;  
 aa is zero, 1, 2, 3 or 4;  
 R4 is hydrogen, F, Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR11R12, —O dd —(CH 2 ) ee —(CF 2 ) ff —CF 3 ; —(SO gg ) hh —(CH 2 ) jj —(CF 2 ) kk —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be substituted 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 —(CH 2 ) ll -phenyl or —O-phenyl, wherein the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O mm —(CH 2 ) nn —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 mm is zero or 1;  
 nn is zero, 1, 2 or 3;  
 ll is zero, 1, 2, 3 or 4;  
 or R4 is —(CH 2 ) oo -heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O pp —(CH 2 ) n —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 pp is zero or 1;  
 rr is zero, 1, 2 or 3; and  
 oo is zero, 1, 2, 3 or 4, and the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  wherein R1 is 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 —(CH 2 ) n —(CF 2 ) o —CF 3  or —(SO m ) q —(CH 2 ) r —(CF 2 ) s —CF 3 ; 
 R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or —CH 2 —CF 3 ;    m is zero, 1 or 2;    n, o, p, q, r and s are, independently of one another, zero or 1;    R2 is hydrogen or F;    R3 is Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, —O a —(CH 2 ) b —(CF 2 ) c —CF 3 , —(SO d ) e —(CH 2 ) f —(CF 2 ) g —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 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 —CH 2 —CF 3 ;    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-(CH 2 ) h -phenyl or —O-phenyl, wherein the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O j —(CH 2 ) k —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    j is zero or 1;    k is zero, 1, 2 or 3;    his zero, 1, 2, 3 or 4;    or R3 is —(CH 2 ) aa -heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O bb —(CH 2 ) cc —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    bb is zero or 1;    cc is zero, 1, 2 or 3;    aa zero, 1, 2, 3 or 4; and    R4 is hydrogen or F, and the pharmaceutically acceptable salts thereof.    
     
     
         3 . The compound of  claim 1  wherein R1 is 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—CH 2 —CF 3 , or —(SO m ) q —(CH 2 ) r —CF 3 ; 
 R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or —CH 2 —CF 3 ;    m is zero, 1 or 2;    q and r are, independently of one another, zero or 1;    R2 is hydrogen or F;    R3 is Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, —O—CH 2 —CF 3 , —(SO d ) e —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 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 —CH 2 —CF 3 ;    d is zero, 1 or 2;    e is zero or 1;    or R3 is phenyl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O j —(CH 2 ) k —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    zero or 1;    k is zero, 1, 2 or 3;    or R3 is heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O bb —(CH 2 ) cc —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    bb is zero or 1;    cc is zero, 1, 2 or 3; an    R4 is hydrogen or F, and the pharmaceutically acceptable salts thereof.    
     
     
         4 . The compound of  claim 1  wherein R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, F, Cl, NR5R6, —O—CH 2 —CF 3 , or —(SO m ) q —(CH 2 ) r —CF 3 ; 
 R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or —CH 2 —CF 3 ;    m is zero, 1 or 2;    q and r are, independently of one another, zero or 1;    R2 is hydrogen or F;    R3 is Cl, —CN, —SO 2 CH 3 , methoxy, ethoxy, NR9R10, —O—CH 2 —CF 3 , —(SO d ) e —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;    R9 and R10 are, independently of one another, hydrogen, methyl, ethyl or —CH 2 —CF 3 ;    d is zero, 1 or 2;    e is zero or 1;    or R3 is phenyl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, —O j —(CH 2 ) k —CF 3 , methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    j and k are, independently of one another, zero or 1;    or R3 is heteroaryl, which is unsubstituted or substituted by 1 or 2 radicals selected from the group consisting of F, Cl, —O bb —(CH 2 ) cc —CF 3 , methoxy, ethoxy, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;    bb and cc are, independently of one another, zero or 1; and    R4 is hydrogen or F, and the pharmaceutically acceptable salts thereof.    
     
     
         5 . The compound of  claim 1  selected from the group consisting of N-(5-methanesulfonyl-2-methyl-4-pentafluorosulfanylbenzoyl)guanidine, and the pharmaceutically acceptable salts thereof.  
     
     
         6 . A process for preparing a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein R1 is 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 —(CH 2 ) n —(CF 2 ) o —CF 3  or —(SO m ) q —(CH 2 ) r —(CF 2 ) s —CF 3 ; 
 R5 and R6 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH 2 —CF 3 ;  
 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, Cl, Br, I, —CN, NR7R8, —O t —(CH 2 ) u —(CF 2 ) v —CF 3  or —(SO w ) x —(CH 2 ) y —(CF 2 ) z —CF 3 ;  
 R7 and R8 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or —CH 2 —CF 3 ;  
 w is zero, 1 or 2;  
 t, u, v, x, y and z are, independently of one another, zero or 1;  
 R3 is Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR9R10, —O a —(CH 2 ) b —(CF 2 ) c —CF 3 , —(SO d ) e —(CH 2 ) f —(CF 2 ) g —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 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 —CH 2 —CF 3 ;  
 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 —(CH 2 ) 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, —O j —(CH 2 ) k —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 j is zero or 1;  
 k is zero, 1, 2 or 3;  
 his zero, 1, 2, 3 or 4;  
 or R3 is —(CH 2 ) aa -heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O bb —(CH 2 ) cc —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 bb is zero or 1;  
 cc is zero or 1, 2 or 3;  
 aa is zero, 1, 2, 3 or 4;  
 R4 is hydrogen, F, Cl, Br, I, —CN, —SO 2 CH 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, NR11R12, —O dd —(CH 2 ) ee —(CF 2 ) ff —CF 3 ; —(SO gg ) hh —(CH 2 ) jj —(CF 2 ) kk —CF 3 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be substituted by fluorine atoms;  
 R11 and R12 are, independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or —CH 2 —CF 3 ;  
 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 —(CH 2 ) ll -phenyl or —O-phenyl, wherein the phenyl radicals are unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O mm —(CH 2 ) nn —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 mm is zero or 1;  
 nn is zero, 1, 2 or 3;  
 ll is zero, 1, 2, 3 or 4;  
 or R4 is —(CH 2 ) oo -heteroaryl, which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of F, Cl, Br, I, —O pp —(CH 2 ) rr —CF 3 , alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms, and —SO 2 CH 3 ;  
 pp is zero or 1;  
 rr is zero, 1, 2 or 3; and  
 oo is zero, 1, 2, 3 or 4,  
 said process comprising the step of:  
 reacting a compound of formula II,  
                     
 wherein R1 to R4 are as previously defined, and L is a leaving group which can undergo nucleophilic substitution, with guanidine.  
 
     
     
         7 . The process of  claim 6  wherein L is an alkoxy group, a phenoxy group, a phenylthio group, a methylthio group, a 2-pyridylthio group, a nitrogen heterocycle, a hydroxide, or a halogen.  
     
     
         8 . The process of  claim 7  wherein L is a methoxy, 1-imidazolyl, hydroxy, or Cl.  
     
     
         9 . A medicament comprising the compound according to  claim 1 .  
     
     
         10 . A medicament comprising the compound according to  claim 3 .  
     
     
         11 . A medicament comprising the compound according to  claim 4 .  
     
     
         12 . A method for treating a patient experiencing one or more disorders in the course of which an increased activity of NEH is involved, the method comprising administering to the patient an efficacious amount of a compound of formula I, or an optionally stereoisomeric form thereof, or a physiologically tolerable salt of the foregoing, as claimed in  claim 1 .  
     
     
         13 . A method for the treatment or prophylaxis of one or more conditions, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in  claim 1 , wherein the condition or conditions are chosen from acute or chronic damage, disorders, or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, arrhythmias, life-threatening cardiac ventricular fibrillation, myocardial infarction, angina pectoris, ischemic states of the heart, ischemic states of the peripheral and central nervous system, stroke, ischemic states of peripheral organs and tissues, states of shock, diseases in which cellular proliferation represents a primary or secondary cause, cancer, metastasis, prostate hypertrophy, prostate hyperplasia, atherosclerosis, disturbances of lipid metabolism, high blood pressure, essential hypertension, disorders of the central nervous system (CNS), disorders resulting from overexcitability of the CNS, epilepsy, centrally induced convulsions, disorders of the central nervous system, anxiety states, depressions, psychoses, non-insulin-dependent diabetes mellitus (NIDDM), late damage from diabetes, thromboses, disorders resulting from endothelial dysfunction, intermittent claudication, fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels, fibrotic disorders of the heart, heart failure, congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, malaria, and coccidiosis in poultry.  
     
     
         14 . A method for the protection of an organ during a surgical operation, organ transplantation, or bypass operation, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in  claim 1 .  
     
     
         15 . A method for the preservation or storage of an organ to be transplanted, comprising storing said organ in a solution comprising an effective amount of at least one compound as claimed in  claim 1 .  
     
     
         16 . A method for treating a patient having a cardiac arrest comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1 .  
     
     
         17 . A method for the preventing age-related tissue change in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1 .  
     
     
         18 . A method for the treatment or reduction of the cardiotoxic effects in thyrotoxicosis in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1 .  
     
     
         19 . A method for diagnosing a condition in which the activity of the Na + /H +  exchanger (NHE) increases above normal cellular levels, comprising measuring the NHE activity by using a compound of  claim 1 , and then determining whether the measured NHE activity is above normal cellular levels.  
     
     
         20 . A method for the treatment or prophylaxis of one or more conditions, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient, wherein the condition or conditions are chosen from acute or chronic damage, disorders, or indirect sequelae of organs and tissues caused by ischemic or reperfusion events, arrhythmias, life-threatening cardiac ventricular fibrillation, myocardial infarction, angina pectoris, ischemic states of the heart, ischemic states of the peripheral and central nervous system or of stroke, ischemic states of peripheral organs and tissues, states of shock, diseases in which cellular proliferation represents a primary or secondary cause, cancer, metastasis, prostate hypertrophy, prostate hyperplasia, atherosclerosis, disturbances of lipid metabolism, high blood pressure, essential hypertension, disorders of the central nervous system, disorders resulting from overexcitability of the CNS, epilepsy, centrally induced convulsions, disorders of the central nervous system, anxiety states, depressions, psychoses, non-insulin-dependent diabetes mellitus (NIDDM), late damage from diabetes, thromboses, disorders resulting from endothelial dysfunction, intermittent claudication, fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels, fibrotic disorders of the heart, heart failure, congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, malaria, and coccidiosis in poultry.  
     
     
         21 . A method for the protection of an organ during a surgical operation, organ transplantation, or bypass operation, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient.  
     
     
         22 . A method for the preservation or storage of an organ to be transplanted, comprising storing said organ in a solution comprising an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient.  
     
     
         23 . A method for the resuscitation after a cardiac arrest of a patient in need thereof, comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient.  
     
     
         24 . A method for the preventing age-related tissue change in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient.  
     
     
         25 . A method for the treatment or reduction of the cardiotoxic effects in thyrotoxicosis in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound as claimed in  claim 1  and at least one additional active ingredient.  
     
     
         26 . A method as claimed in  claim 13  for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events.  
     
     
         27 . A method as claimed in  claim 20  for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events.  
     
     
         28 . A method as claimed in  claim 13  for the treatment of life-threatening cardiac ventricular fibrillation.  
     
     
         29 . A method as claimed in  claim 20  for the treatment of life-threatening cardiac ventricular fibrillation.  
     
     
         30 . A method as claimed in  claim 13  for the treatment or prophylaxis of metastasis.  
     
     
         31 . A method as claimed in  claim 20  for the treatment or prophylaxis of metastasis.  
     
     
         32 . A method as claimed in  claim 13  for the treatment or prophylaxis of fibrotic disorders of the heart, of heart failure or of congestive heart failure.  
     
     
         33 . A method as claimed in  claim 20  for the treatment or prophylaxis of fibrotic disorders of the heart, of heart failure or of congestive heart failure.