N-sulphonylated amino acid derivatives, method for the production and use thereof

Abstract

The present invention relates to N-sulfonylated amino acid derivatives, where an aryl radical is linked via the sulfonyl group N-terminally to the amino acid and a radical which comprises at least one imino group and at least one further basic group which represents an optionally modified amino, amidino or guanidino group is linked C-terminally via the carbonyl group. The invention likewise relates to processes for preparing these compounds and to their use, in particular as inhibitors of matriptase.

1 . A compound of the formula (I″), 
       
         
           
           
               
               
           
         
         or a salt of this compound, wherein
 optionally at least one of the methylene groups which are indexed with m or n in (I″) is substituted at least once by a hydroxyl, a halogen, a pseudohalogen, or a COOR 2 ′ group, and R 2 ′ is a linear, branched or cyclic alkyl group having 1 to 10 C atoms, and/or 
 optionally at least one of the C atoms of the methylene groups which are indexed with m or n in (I″) is replaced by S, N, or O, and/or 
 with retention of the imino group C-terminally linked to the sulfonylated amino acid, optionally at least one of the bonds forming the ring 
 
       
       
         
           
           
               
               
           
         
         
           in (I″) is a double bond, and wherein 
         
         (i) R 1  is an optionally partially hydrogenated aryl or heteroaryl group comprising at least one of the atoms O, N, or S having 5 to 20 C atoms, or a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, where R 1  is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched, or cyclic alkyl or alkyloxy or alkylthio group having 1 to 10 C atoms, which is optionally substituted at least once by a halogen, pseudohalogen, hydroxyl, amino, cyano, amidino, guanidine, or carboxyl group, where the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and where the linear, branched, or cyclic alkyl group having 1 to 10 C atoms optionally comprises at least one heteroatom selected from the group consisting of O, N, and S, and/or 
 at least one aryl or heteroaryl group having 5 to 20 C atoms, where this aryl or heteroaryl group is optionally substituted by
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms and/or 
 at least one COR 2 ′ and/or COOR 2 ′ group, where R 2 ′ is a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
 
  at least one halogen group, and/or 
  at least one pseudohalogen group, and/or
 at least one alkoxy group or one alkylthio group, where the alkyl radical has in each case 1 to 10 C atoms, and/or 
 
  at least one nitro group, and/or 
  at least one haloalkyl group having 1 to 10 C atoms, 
 and where the aryl or heteroaryl group is linked via an alkylene group having 1 to 3 C atoms or via an oxygen atom or a sulfur atom to the radical R 1 ; 
 at least one hydroxyl, amino, cyano, amidino, guanidino, carboxyl, or carboxyalkyl group, where the amino group is optionally acylated and/or where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms or is amidated, and 
 
 wherein said amidino is optionally substituted by a hydroxyl or a C 1 -C 6 -alkyloxycarbonyl group; 
 
         (ii) R 2  is an at least monosubstituted aryl group having 1 to 10 C atoms, where
 optionally at least one of these C atoms is replaced by S, N or O, 
 at least one substituent is a group according to R 4 , 
 R 2  is optionally additionally substituted by a hydroxyl, COR 2 ′ or COOR 2 ′ group, and R 2 ′ is a linear, branched or cyclic alkyl group having 1 to 10 C atoms; 
 
         (iii) R 3  is a radical of the following formula (II):
   A 1 -T-A 2 -R 4   (II)
 
 where
 A 1  is either absent or an alkylene group having 1 to 4 C atoms which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or 
  at least one linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
  at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or 
  at least one hydroxyl, cyano, alkyloxy or alkylthio having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
 T is either absent or one of the following groups: 
 
       
       
         
           
           
               
               
           
         
         
           
             where R 5  is hydrogen or an alkyl group having 1 to 10 C atoms or an alkylene group having 1 to 6 C atoms, which forms with A 2  a ring optionally comprising at least one heteroatom; 
           
           A 2  is a linear, branched, or cyclic alkylene group having 1 to 10 C atoms or an aryl-, heteroaryl-, or aralkylene group having 1 to 10 C atoms, optionally comprising at least one heteroatom selected from the group consisting of N, S, and O, which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms, 
 
  and/or
 at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or
 at least one hydroxyl, cyano, alkyloxy or alkylthio group having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
         
         (iv) R 4  is one of the following, optionally modified basic groups: 
       
       
         
           
           
               
               
           
         
         
           where t=0, 1; R 6  and R 7  are independently of one another hydrogen or an alkyl group having 1 to 6 C atoms or an alkylene group having 1 to 5 C atoms which forms a ring with A 2 , or are a hydroxyl, amino, alkylamino, acyl, or alkyloxycarbonyl group, where the alkylamino, acyl, and alkyloxycarbonyl groups have independently of one another 1 to 6 C atoms, and where R 8  is hydrogen, an alkyl group having 1 to 3 C atoms, a hydroxyl group, or a C 1 -C 6 -alkyloxycarbonyl group, or is an alkylene group having 1 to 3 C atoms which forms a ring with R 6 ; 
         
         (v) Q is N; 
         (vi) j=0, 1, or 2; 
         (vii) k=0, 1, 2, or 3; and 
         (viii) m and n are independently of one another=0, 1, 2, 3, 4, or 5, where m+n=3, 4, 5;
 and where the compound of formula (I″) is neither 
 
       
       
         
           
           
               
               
           
         
         
           with s=0, 1, 2, nor 
         
       
       
         
           
           
               
               
           
         
         
           with s=0, 1. 
         
       
     
     
         2 . The compound of  claim 1 , wherein T is present and T is one of the groups defined as in  claim 1 , it being possible for the amide and ester groups to be incorporated in both orientations. 
     
     
         3 . The compound of  claim 1 , wherein j=0 and R 1  is an at most disubstituted aryl radical. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of tert-butylphenyl, cyclohexylphenyl, 5,6,7,8-tetrahydronaphthyl, naphthyl, anthracyl, anthraquinoyl, anthrahydroquinoyl, pyridyloxyphenyl, phenyloxypyridyl, and pyridylalkylphenyl having a C 1 -C 3 -alkyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is an at least monosubstituted phenyl radical, thienyl radical, or pyridyl radical. 
     
     
         6 . The compound of  claim 1 , wherein k=1 and R 2  is a phenyl radical meta-substituted by an amidino group, and wherein the 3-amidinophenylalanine produced thereby has the L configuration. 
     
     
         7 . The compound of  claim 1 , wherein m=n=2. 
     
     
         8 . The compound of  claim 1 , wherein A 1  is absent and T is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein A 2  is a methylene, ethylene, or propylene group, and R 4  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein said compound has a structure according to: 
       
         
           
           
               
               
           
         
         wherein s is 1, 2, or 3. 
       
     
     
         11 . The compound of  claim 2 , wherein m=n=2, and R 3  is a guanidinooxyalkyl radical or an aryl or heteroaryl radical, wherein said aryl or heteroaryl radical is unsubstituted or substituted by at least one halogen, at least one methoxy radical, or at least one trifluoromethyl radical. 
     
     
         12 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt thereof, wherein Phe(3-Am) is 3-amidinophenylalanine. 
       
     
     
         13 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically suitable excipient. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said composition is in the form of a tablet, a coated tablet, a capsule, a pellet, a suppository, a solution, eye drops, nose drops, ear drops, a syrup, an emulsion or suspension, a pessary, a stick, an aerosol, a dusting powder, a paste, a cream, or an ointment. 
     
     
         15 . A compound of the formula (I″), 
       
         
           
           
               
               
           
         
         or a salt of this compound, wherein
 optionally at least one of the methylene groups which are indexed with m or n in (I″) is substituted at least once by a hydroxyl, a halogen, a pseudohalogen, or a COOR 2 ′ group, and R 2 ′ is a linear, branched or cyclic alkyl group having 1 to 10 C atoms, and/or 
 optionally at least one of the C atoms of the methylene groups which are indexed with m or n in (I″) is replaced by S, N, or O, and/or 
 with retention of the imino group C-terminally linked to the sulfonylated amino acid, optionally at least one of the bonds forming the ring 
 
       
       
         
           
           
               
               
           
         
         
           in (1″) is a double bond, and wherein 
         
         (i) R 1  is an optionally partially hydrogenated aryl or heteroaryl group comprising at least one of the atoms O, N, or S having 5 to 20 C atoms, or a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, where R I  is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched, or cyclic alkyl or alkyloxy or alkylthio group having 1 to 10 C atoms, which is optionally substituted at least once by a halogen, pseudohalogen, hydroxyl, amino, cyano, amidino, guanidine, or carboxyl group, where the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and where the linear, branched, or cyclic alkyl group having 1 to 10 C atoms optionally comprises at least one heteroatom selected from the group consisting of O, N, and S, and/or 
 at least one aryl or heteroaryl group having 5 to 20 C atoms, where this aryl or heteroaryl group is optionally substituted by
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms and/or 
 at least one COR 2 ′ and/or COOR 2 ′ group, where R 2 ′ is a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
 
 at least one halogen group, and/or 
 at least one pseudohalogen group, and/or
 at least one alkoxy group or one alkylthio group, where the alkyl radical has in each case 1 to 10 C atoms, and/or 
 
 at least one nitro group, and/or 
 at least one haloalkyl group having 1 to 10 C atoms, 
 
 and where the aryl or heteroaryl group is linked via an alkylene group having 1 to 3 C atoms or via an oxygen atom or a sulfur atom to the radical R 1 ; 
 at least one hydroxyl, amino, cyano, amidino, guanidino, carboxyl, or carboxyalkyl group, where the amino group is optionally acylated and/or where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms or is amidated, and 
 
          wherein said amidino is optionally substituted by a hydroxyl or a C 1 -C 6 -alkyloxycarbonyl group; 
         (ii) R 2  is an at least monosubstituted aryl group having 1 to 10 C atoms, where
 optionally at least one of these C atoms is replaced by S, N or O, 
 at least one substituent is a group according to R 4 ,
 R 2  is optionally additionally substituted by a hydroxyl, COR 2 ′ or COOR 2 ′ group, and R 2 ′ is a linear, branched or cyclic alkyl group having 1 to 10 C atoms; 
 
 
         (iii) R 3  is a radical of the following formula (II):
   A 1 -T-A 2 -R 4   (II)
 
 where
 A 1  is either absent or an alkylene group having 1 to 4 C atoms which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or 
  at least one linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
  at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or
 at least one hydroxyl, cyano, alkyloxy or alkylthio having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
 T is either absent or one of the following groups: 
 
       
       
         
           
           
               
               
           
         
         
           
             where R 5  is hydrogen or an alkyl group having 1 to 10 C atoms or an alkylene group having 1 to 6 C atoms, which forms with A 2  a ring optionally comprising at least one heteroatom; 
           
            A 2  is a linear, branched, or cyclic alkylene group having 1 to 10 C atoms or an aryl-, heteroaryl-, or aralkylene group having 1 to 10 C atoms, optionally comprising at least one heteroatom selected from the group consisting of N, S, and O, which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms, 
 
  and/or
 at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or
 at least one hydroxyl, cyano, alkyloxy or alkylthio group having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
         
         (iv) R 4  is one of the following, optionally modified basic groups: 
       
       
         
           
           
               
               
           
         
         
           where t=0, 1; R 6  and R 7  are independently of one another hydrogen or an alkyl group having 1 to 6 C atoms or an alkylene group having 1 to 5 C atoms which forms a ring with A 2 , or are a hydroxyl, amino, alkylamino, acyl, or alkyloxycarbonyl group, where the alkylamino, acyl, and alkyloxycarbonyl groups have independently of one another 1 to 6 C atoms, and where R 8  is hydrogen, an alkyl group having 1 to 3 C atoms, a hydroxyl group, or a C 1 -C 6 -alkyloxycarbonyl group, or is an alkylene group having 1 to 3 C atoms which forms a ring with R 6 ; 
         
         (v) Q is a CH group; 
         (vi) j=0, 1, or 2; 
         (vii) k=0, 1, 2, or 3; and 
         (viii) m=n=1. 
       
     
     
         16 . The compound of  claim 15 , wherein R 1  is naphthyl. 
     
     
         17 . The compound of  claim 15 , wherein R 2  is an at least monosubstituted phenyl radical. 
     
     
         18 . The compound of  claim 15 , wherein k=1 and R 2  is a phenyl radical meta-substituted by an amidino group, and wherein the 3-amidinophenylalanine produced thereby has the L configuration. 
     
     
         19 . The compound of  claim 15 , wherein said compound is 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein Phe(3-Am) is 3-amidinophenylalanine. 
       
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 15  and a pharmaceutically suitable excipient. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein said composition is in the form of a tablet, a coated tablet, a capsule, a pellet, a suppository, a solution, eye drops, nose drops, ear drops, a syrup, an emulsion or suspension, a pessary, a stick, an aerosol, a dusting powder, a paste, a cream, or an ointment. 
     
     
         22 . A compound having a structure according to the following formula, 
       
         
           
           
               
               
           
         
         or a salt of this compound, wherein
 Phe(3-Am) is 3-amidinophenylalanine and Gly is glycine, 
 optionally at least one of the methylene groups which are indexed with m or n is substituted at least once by a hydroxyl, a halogen, a pseudohalogen, or a COOR 2 ′ group, and R 2 ′ is a linear, branched or cyclic alkyl group having 1 to 10 C atoms, and/or 
 optionally at least one of the C atoms of the methylene groups which are indexed with m or n in (I″) is replaced by S, N, or O, and/or 
 with retention of the imino group C-terminally linked to the sulfonylated amino acid, optionally at least one of the bonds forming the ring 
 
       
       
         
           
           
               
               
           
         
         
           in (I″) is a double bond, and wherein 
         
         (i) R 1  is an optionally partially hydrogenated aryl or heteroaryl group comprising at least one of the atoms O, N, or S having 5 to 20 C atoms, or a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, where R 1  is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched, or cyclic alkyl or alkyloxy or alkylthio group having 1 to 10 C atoms, which is optionally substituted at least once by a halogen, pseudohalogen, hydroxyl, amino, cyano, amidino, guanidine, or carboxyl group, where the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and where the linear, branched, or cyclic alkyl group having 1 to 10 C atoms optionally comprises at least one heteroatom selected from the group consisting of O, N, and S, and/or 
 at least one aryl or heteroaryl group having 5 to 20 C atoms, where this aryl or heteroaryl group is optionally substituted by
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms and/or 
 at least one COR 2 ′ and/or COOR 2 ′ group, where R 2 ′ is a linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
 
 at least one halogen group, and/or 
 at least one pseudohalogen group, and/or
 at least one alkoxy group or one alkylthio group, where the alkyl radical has in each case 1 to 10 C atoms, and/or 
 
 at least one nitro group, and/or 
 at least one haloalkyl group having 1 to 10 C atoms, 
 
 and where the aryl or heteroaryl group is linked via an alkylene group having 1 to 3 C atoms or via an oxygen atom or a sulfur atom to the radical R 1 ; 
 at least one hydroxyl, amino, cyano, amidino, guanidino, carboxyl, or carboxyalkyl group, where the amino group is optionally acylated and/or where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl group having 1 to 10 C atoms or is amidated, and 
 
          wherein said amidino is optionally substituted by a hydroxyl or a C 1 -C 6 -alkyloxycarbonyl group; 
         (ii) R 3  is a radical of the following formula (II):
   A 1 -T-A 2 -R 4   (II)
 
 where
 A 1  is either absent or an alkylene group having 1 to 4 C atoms which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or 
  at least one linear, branched, or cyclic alkyl group having 1 to 10 C atoms, and/or 
  at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or 
  at least one hydroxyl, cyano, alkyloxy or alkylthio having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
 T is either absent or one of the following groups: 
 
       
       
         
           
           
               
               
           
         
         
           
             where R 5  is hydrogen or an alkyl group having 1 to 10 C atoms or an alkylene group having 1 to 6 C atoms, which forms with A 2  a ring optionally comprising at least one heteroatom; 
           
           A 2  is a linear, branched, or cyclic alkylene group having 1 to 10 C atoms or an aryl-, heteroaryl-, or aralkylene group having 1 to 10 C atoms, optionally comprising at least one heteroatom selected from the group consisting of N, S, and O, which is optionally substituted by
 at least one halogen and/or pseudohalogen group, and/or
 at least one linear, branched or cyclic alkyl group having 1 to 10 C atoms, 
 
  and/or
 at least one aryl or one aralkyl group having 5 to 10 C atoms, and/or 
 
 at least one cycloalkyl group having 3 to 10 C atoms, and/or
 at least one hydroxyl, cyano, alkyloxy or alkylthio group having 1 to 10 C atoms, carboxyl or carboxyalkyl group, where the alkyl group of the carboxyalkyl group has 1 to 10 C atoms, and/or the carboxyl group is optionally esterified with a linear, branched, or cyclic alkyl radical having 1 to 10 C atoms, or is amidated; 
 
 
         
         (iii) R 4  is one of the following, optionally modified basic groups: 
       
       
         
           
           
               
               
           
         
         
           where t=0, 1; R 6  and R 7  are independently of one another hydrogen or an alkyl group having 1 to 6 C atoms or an alkylene group having 1 to 5 C atoms which forms a ring with A 2 , or are a hydroxyl, amino, alkylamino, acyl, or alkyloxycarbonyl group, where the alkylamino, acyl, and alkyloxycarbonyl groups have independently of one another 1 to 6 C atoms, and where R 8  is hydrogen, an alkyl group having 1 to 3 C atoms, a hydroxyl group, or a C 1 -C 6 -alkyloxycarbonyl group, or is an alkylene group having 1 to 3 C atoms which forms a ring with R 6 ; 
         
         (iv) Q is N or CH; 
         (v) j=0, 1, or 2; and 
         (vi) m and n are independently of one another=0, 1, 2, 3, 4, or 5, where m+n=3, 4, 5. 
       
     
     
         23 . The compound of  claim 22 , wherein k=1 and R 2  is a phenyl radical meta-substituted by an amidino group, and wherein the 3-amidinophenylalanine produced thereby has the L configuration. 
     
     
         24 . The compound of  claim 22 , wherein R 1  is naphthyl or anthracyl. 
     
     
         25 . The compound of  claim 22 , wherein m=n=2. 
     
     
         26 . The compound of  claim 22 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         27 . A pharmaceutical composition comprising the compound of  claim 22  and a pharmaceutically suitable excipient. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said composition is in the form of a tablet, a coated tablet, a capsule, a pellet, a suppository, a solution, eye drops, nose drops, ear drops, a syrup, an emulsion or suspension, a pessary, a stick, an aerosol, a dusting powder, a paste, a cream, or an ointment.