Piperazine compounds as inhibitors of MMP or TNF

Abstract

A compound of formula (I) wherein A is a sulfonyl or a carbonyl; R 1 is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; R 2 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R 3 is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substituted lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substituted amino; R 4 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R 5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and R 10 is a hydroxy or a protected hydroxy, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP-or TNFα-medicated diseases.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a sulfonyl or a carbonyl;  
 R 1  is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl;  
 R 2  is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;  
 R 3  is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substituted lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substituted amino:  
 R 4  is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;  
 R 5  is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and  
 R 1 0  is a hydroxy or a protected hydroxy, provided that when A-R 3  is methylsulfonyl, then R 1  is an aryl substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group, an optionally substituted heterocyclic group, an optionally substituted alkyl or an optionally substituted lower alkenyl, and the above-mentioned heterocyclic group is each selected from the group consisting of  
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,  
 saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,  
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to 5 nitrogen atoms,  
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,  
 saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,  
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,  
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,  
 saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,  
 unsaturated 3- to 8-membered heteromonocyclic group containing a sulfur atom,  
 unsaturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,  
 saturated 3- to 8-membered heteromonocyclic group containing an oxygen atom,  
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and  
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein 
 R 2  is a hydrogen or an optionally substituted lower alkyl, and    R 4  is a hydrogen or an optionally substituted lower alkyl,    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . The compound of  claim 2 , wherein 
 R 1  is an aryl optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group;    a heterocyclic group optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, heterocyclic group, haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl, cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl, hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower alkoxycarbonyl(lower)alkoxyaryl, lower alkylsulfonyloxyaryl, aryl substituted by halogen and hydroxy, aryl substituted by halogen and alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower alkyl-heterocyclic group and aryl-heterocyclic group;    a lower alkyl optionally substituted by halogen; or    a lower alkenyl optionally substituted by aryl;    the said heterocyclic group each being selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,    unsaturated 5- or 6membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, and    unsaturated 9- to 10-membered heterobicyclic group containing 1 or 2 oxygen atoms,    R 3  is a lower alkyl optionally substituted by a substituent selected from the group consisting of halogen, heterocyclic group, carbamoyl, lower alkylcarbamoyl, carboxy, protected carboxy, heterocyclic-carbonyl, di(lower)alkylamino, protected amino, arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfonylamino, heterocyclic-sulfonylamino, heterocyclic-thio, lower alkylheterocyclic-thio and heterocyclic-thio; a lower alkoxy; an aryloxy;    an aryl(lower)alkoxy; an optionally substituted lower alkenyl; an optionally substituted heterocyclic group; or a group of the formula:                          wherein R 8  and R 9  are the same or different and each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carbamoyl(lower)alkyl, hydroxy(lower)akyl, aryl, cyclo(lower)alkyl, heterocyclic-(lower)alkyl;    the said heterocyclic group each being selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,    saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atom and 1 to 3 nitrogen atoms,    saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atom and 1 to 3 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, and    unsaturated 9- or 10-membered heterobicyclic group containing 1 or 2 oxygen atoms,    or a pharmaceutically acceptable salt thereof.    
     
     
         4 . The compound of  claim 3 , wherein 
 R 1  is a heterocyclic group selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, each of which is optionally substituted by a substituent selected from the group consisting of halogen; phenyl; halophenyl; hydroxyphenyl; lower alkoxyphenyl; lower alkylphenyl; nitrophenyl; biphenylyl; phenoxyphenyl; trihalo(lower) alkyphenyl; cyano(lower)alkoxyphenyl; cyanophenyl; cyano(lower)alkylphenyl; lower alkanoyloxyphenyl; lower alkanoyloxy(lower)alkylphenyl; di(lower)alkylaminosulfonylphenyl; hydroxy(lower)alkylphenyl; lower alkoxycarbonylphenyl; lower alkoxycarbonyl(lower)alkoxyphenyl; lower alkylsulfonyloxyphenyl; phenyl substituted by halogen and hydroxy; phenyl substituted by halogen and lower alkanoyloxy; phenyl substituted by halogen and lower alkoxy; heterocyclic group selected from the group consisting of unsaturated 9- or 10 membered heterobicyclic group containing 1 or 2 oxygen atoms,    unsaturated 5- or 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms,    unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms and    unsaturated 5- or 6membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms;    and a lower alkyl- or (phenyl-)heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms;    R 2  is a hydrogen,    R 3  is a lower alkyl; a halo(lower)alkyl; a heterocyclic(lower)alkyl, said heterocyclic group being selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms and saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a carbamoyl(lower)alkyl; a lower alkylcarbamoyl(lower)alkyl; a carboxy(lower)alkyl; a phenyl(lower)alkoxycarbonyl(lower)alkyl; a heterocyclic-carbonyl(lower)alkyl, said heterocyclic group being saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a di(lower)alkylamino(lower)alkyl; a phenyl(lower)alkoxycarbonylamino(lower)alkyl; a lower alkoxycarbonylamino(lower)alkyl; a benzoylamino(lower)alkyl; a heterocyclic carbonylamino(lower)alkyl, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a lower alkanoylamino(lower)alkyl; a lower alkylsulfonylamino(lower)alkyl; a di(lower)alkylaminosulfonylamino(lower)alkyl; a heterocyclic-sulfonylamino(lower)alkyl, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a heterocyclic-thio(lower)alkyl, said heterocyclic group being selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 9- or 10-membered heterobicyclic group containing 1 to 5 nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; a lower alkylheterocyclic-thio(lower)alkyl, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a heterocyclic-thio(lower)alkyl, said heterocyclic group being unsaturated 9- or 10-membered heterobicyclic group containing 1 to 5 nitrogen atoms; a lower alkoxy; a phenyloxy; a fluorenyl(lower)alkoxy; a heterocyclic(lower)alkenyl, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a heterocyclic group, said heterocyclic group being selected from the group consisting of unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, which is optionally substituted by heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a mono- or di(lower)alkylamino; a carboxy(lower)alkylamino; a lower alkoxycarbonyl(lower)alkylamino; an N-(lower)alkyl-N-(lower)alkoxycarbonylamino; a carbamoyl(lower)alkylamino; a hydroxyamino(lower)alkyl; a phenylamino; or a cyclo(lower)alkylamino;    R 4  is a hydrogen,    R 5  is a hydrogen, and    R 1 0  is a hydroxy, a lower alkoxy, a phenyl(lower)alkoxy, a fluorenyl(lower)alkoxy or a tetrahydropyranyloxy, or a pharmaceutically acceptable salt thereof.    
     
     
         5 . The compound of  claim 4 , wherein 
 R 1  is a thienyl substituted by a substituent selected from the group consisting of halogen, phenyl, halophenyl, hydroxyphenyl, lower alkoxyphenyl, lower alkylphenyl, nitrophenyl, biphenylyl, phenoxyphenyl, trihalo(lower)alkylphenyl, cyano(lower)alkoxyphenyl, cyanophenyl, cyano(lower)alkylphenyl, lower alkanoyloxyphenyl, lower alkanoyloxy (lower) alkylphenyl, di(lower) alkylaminosulfonylphenyl, hydroxy (lower) alkylphenyl, lower alkoxycarbonylphenyl, lower alkoxycarbonyl (lower) alkoxyphenyl, lower alkylsulfonyloxyphenyl, phenyl substituted by halogen and hydroxy, phenyl substituted by halogen and lower alkanoyloxy, phenyl substituted by halogen and lower alkoxy, thiazolyl, oxazolyl, pyridyl, benzodihydrofuranyl, benzodioxolenyl, lower alkyloxadiazolyl and phenyloxadiazolyl; a thiazolyl substituted by phenyl or a thiadiazolyl substituted by phenyl;    R 3  is a lower alkyl, a halo(lower)alkyl, a morpholinyl(lower)alkyl, a piperidinyl( lower)alkyl, a pyridyl(lower)alkyl, a carbamoyl(lower)alkyl, a lower alkylcarbamoyl(lower)alkyl, a carboxy(lower)alkyl, a phenyl(lower)alkoxycarbonyl(lower)alkyl, a morpholinylcarbonyl(lower)alkyl, a di(lower)alkylamimno(lower)alkyl, a phenyl(lower)alkoxycarbonylamino(lower)alkyl, a lower alkoxycarbonylamino(lower)alkyl, a benzoylamino(lower)alkyl, a pyridyl-carbonylamino(lower)alkyl, a lower alkanoylamino(lower)alkyl, a lower alkylsulfonylamino(lower)alkyl, a di(lower)alkylaminosulfonylamino(lower)alkyl, a pyridyl-sulfonylamino(lower)alkyl, a triazolylthio(lower)alkyl, an imidazolylthio(lower)alkyl, a thiazolylthio(lower)alkyl, a benzimidazolylthio(lower)alkyl, a lower alkyltriazolylthio(lower)alkyl, a lower alkoxy, a fluorenyl(lower)alkoxy, a phenoxy, a pyridyl(lower)alkenyl, a pyridyl, a piperidinyl, a thienyl substituted by oxazolyl, a mono- (or di-) (lower)alkylamino, a carboxy(lower)alkylamino, a lower alkoxycarbonyl(lower)alkylamino, an N-(lower)alkyl-N-(lower)alkoxycarbonyl(lower)alkylamino, a carbamoyl(lower)alkylamino, a hydroxy(lower)alkylamino, a phenylamino or a cyclo(lower)alkylamino, and    R 1 0  is a hydroxy,    or a pharmaceutically acceptable salt thereof.    
     
     
         6 . The compound of  claim 5 , wherein 
 R 1  is a thienyl, a halothienyl, a phenylthienyl, a halophenylthienyl, a hydroxyphenylthienyl, a lower alkoxyphenylthienyl, a lower alkylphenylthienyl, a nitrophenylthienyl, a biphenylylthienyl, a phenoxyphenylthienyl, a trihalo(lower)alkylphenylthienyl, a cyano(lower)alkoxyphenylthienyl, a cyanophenylthienyl, a cyano(lower)alkylphenylthienyl, a lower alkanoyloxyphenylthienyl, a lower alkanoyloxy(lower)alkylphenylthienyl, a di(lower)alkylaminosulfonylphenylthienyl, a hydroxy(lower)alkylphenylthienyl, a lower alkoxycarbonylphenylthienyl, a lower alkoxycarbonyl(lower)alkoxyphenylthienyl, a lower alkylsulfonyloxyphenylthienyl, a phenylthienyl wherein the phenyl group being substituted by halogen and hydroxy, a phenylthienyl wherein the phenyl group being substituted by halogen and lower alkanoyloxy, or a phenylthienyl wherein the phenyl group being substituted by halogen and lower alkoxy,    or a pharmaceutically acceptable salt thereof.    
     
     
         7 . A process for the preparation of the piperazine compound of  claim 1  or a salt thereof, which comprises, 
 (1) reacting a compound of the formula (II):  
                     
 wherein A, R 2 , R 3 , R 4  and R 5  are each as defined in  claim 1  and R 1 0 a  is a protected hydroxy, or a salt thereof, with a compound of the formula (III): 
 R 1 —SO 2 -X   (III)  
 wherein R 1  is as defined in  claim 1  and X is a leaving group, to give a compound of the formula (IV):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof,  
 (2) subjecting a compound of the formula (IV):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula (V):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4  and R 5  are each as defined above, or a salt thereof,  
 (3) reacting a compound of the formula (VI):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4  and R 5  are each as defined above, or a salt thereof, with a compound of the formula (VII): 
 H 2 N—R 1 0 a    (VII)  
 wherein R 1 0 a  is as defined above, or a salt thereof, to give a compound of the formula (IV):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof,  
 (4) reacting a compound of the formula (VIII):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above and R 3 a  is an alkyl substituted by halogen, or a salt thereof, with a compound of the formula (IX): 
 H—R 1 1    (IX)  
 wherein R 1 1  is a di(lower)alkylamino, an N-containing heterocyclic group or an optionally substituted heterocyclic-thio, or a salt thereof, to give a compound of the formula (X):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above and R 3 b  is a di(lower) alkylamino (lower)alkyl, an N-containing heterocyclic(lower)alkyl or an optionally substituted heterocyclic-thio(lower)alkyl, or a salt thereof,  
 (5) subjecting a compound of the formula (XI):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above and R 3 c  is a protected carboxy(lower)alkyl or a protected carboxy(lower)alkylamimno, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula (XII):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above, and R 3 d  is a carboxy(lower)alkyl or a carboxy(lower)alkylamino, or a salt thereof,  
 (6) subjecting a compound of the formula (XII):  
                     
 wherein A, R 1 , R 2 , R 3 d  , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof, to amidation reaction, to give a compound of the formula (XIII):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above, and R 3 e  is an N-containing heterocyclic-carbonyl(lower)alkyl, an optionally substituted amino-carbonyl(lower)alkyl or an optionally substituted amino-carbonyl(lower)alkylamino, or a salt thereof,  
 (7) reacting a compound of the formula (XIV):  
                     
 wherein R 1 , R 2 , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof, with a compound of the formula (XV): 
 R 3 -A-X   (XV)  
 wherein R 3 , A and X are each as defined above, or a salt thereof, to give a compound of formula (IV):  
                     
 wherein A, R 1 , R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof,  
 (8) reacting a compound of the formula (XVI):  
                     
 wherein A, R 1 , R 2 , R 4 , R 5 , R 1 0 a  and X are each as defined above, or a salt thereof, with a compound of the formula (XVII): 
 H 2 N—R 3 f    (XVII)  
 wherein R 3 f  is a hydroxy(lower)alkyl, or a salt thereof, to give a compound of the formula (XVIII):  
                     
 wherein A, R 1 , R 2 , R 3 f , R 4 , R 5  and R 1 0 a  are each as defined above, or a salt thereof,  
 (9) subjecting a compound of the formula (XIX):  
                     
 wherein A, R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, and R 1 a  is a heterocyclic group having a substituent which is aryl substituted by acyloxy, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula (XX):  
                     
 wherein A, R 2 , R 3 , R 4  and R 5  are each as defined above, and R 1 b  is a heterocyclic group having a substituent which is aryl substituted by hydroxy, or a salt thereof, or  
 (10) subjecting a compound of the formula (XXI):  
                     
 wherein A, R 2 , R 3 , R 4 , R 5  and R 1 0 a  are each as defined above, and R 1 c  is a heterocyclic group having a substituent which is aryl substituted by cyanoalkyloxy, or a salt thereof, to solvolysis, to give a compound of the formula (XXII):  
                     
 wherein A, R 2 , R 3 , R 4  and R 5  are each as defined above, and R 1 d  is a heterocyclic group having a substituent which is aryl substituted by alkoxycarbonylalkyloxy, or a salt thereof.  
 
     
     
         8 . A pharmaceutical composition which comprises the compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.  
     
     
         9 . A process for preparing a pharmaceutical composition which comprises admixing the compound of  claim 1  or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or excipient.  
     
     
         10 . Use of the compound of  claim 1  or a pharmaceutically acceptable salt thereof as a medicament.  
     
     
         11 . Use of the compound of  claim 1  or a pharmaceutically acceptable salt thereof as an inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor α (TNFα).  
     
     
         12 . Use of the compound of  claim 1  or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating and/or preventing MMP- or TNFα-mediated diseases.  
     
     
         13 . A method for treating and/or preventing MMP- or TNFα-mediated diseases which comprises administering the compound of  claim 1  or a pharmaceutically acceptable salt thereof to a human being or an animal.