New peptide derivatives

Abstract

The invention relates to new competitive inhibitors of trypsin-like serine proteases, their synthesis, pharmaceutical compositions containing the compounds as active ingredients, and the use of the compounds as thrombin inhibitors, anticoagulants and antiinflammatory inhibitors for prophylaxis and treatment of related diseases, according to the formula wherein A 1 represents a structural fragment of formulas A 2 represent a structural fragment of formulas B represents a structural fragment of formulas Further described is novel compounds, the new use of compounds and especially new structural fragment in synthesis of pharmaceutical compounds.

1 . A compound of the general formula  
       
         
           
           
               
               
           
         
         wherein:  
         A 1  represents a structural fragment of Formula IIa, IIb, IIc, IId or IIe;  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         k is an integer 0, 1, 2, 3 or 4;  
         m is an integer 1, 2, 3 or 4;  
         q is an integer 0, 1, 2, or 3;  
         R 1  represents H, an alkyl group having 1 to 4 carbon atoms, or R 11 ooc-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the position which is alpha to the carbonyl group, and the alpha substituent is a group R 17 —(CH 2 ) p —, wherein p is 0, 1 or 2 and R 17  is methyl, phenyl, OH, COOR 12 , CONHR 12 , where R 12  is H or an alkyl group having 1 to 4 carbon atoms, and R 11  is H or an alkyl group having 1 to 6 carbon atoms, or  
         R 1  represents Ph(4-COOR 12 )—CH 2 —, where R 12  is as defined above, or  
         R 1  represents R 13 —NH—CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted alpha to the carbonyl with an alkyl group having 1 to 4 carbon atoms and where R 13  is H or an alkyl group having 1 to 4 carbon atoms or —CH 2 COOR 2 , where R 12  is as defined above, or  
         R 1  represents R 12 OOC—CH 2 —OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted alpha to the carbonyl with an alkyl group having 1 to 4 carbon atoms and where R 12  is as defined above, or  
         R 1  represents R 14 SO 2 —, Ph(4-COOR 12 )—SO 2 ,— Ph(3-COOR 12 )—SO 2 —, Ph(2-COOR 12 )—SO 2 — where R 12  is as defined above and R 14  is an alkyl group having 1-4 carbon atoms, or  
         R 1  represents —CO—OR 15 , wherein R 15  is an alkyl group having 1-4 carbon atoms, or  
         R 1  represents —CO—OR 15 , where R 15  is as defined above, or  
         R 1  represent —CO—(CH 2 ) p —COOR 12 , where R 12  is as defined above and p is an interger 0, 1 or 2, or  
         R 1  represents —CH 2 PO(OR 16 ) 2 , —CH 2 SO 3 H or  
         —CH 2 -(5-(1H)-tetrazolyl) where R 16  is, individually at each occurrence, H, methyl or ethyl;  
         R 2  represents H or an alkyl group having 1 to 4 carbon atoms or R 21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and where R 21  is H or an alkyl group having 1 to 4 carbon atoms;  
         R 3  represents an alkyl group having 1-4 carbon atoms, and the alkyl group may or may not carry one or more fluorine atoms, or  
         R 3  represents a cyclopentyl, cyclohexyl- or a phenyl group which may or may not be substituted with an alkyl group having 1 to 4 carbon atoms, or  
         R 3  represents a phenyl group substituted with a OR 31  group, where R 31  is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, or  
         R 3  represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or  
         R 3  represent a cis- or trans-decalin group and k is 0, 1, or  
         R 3  represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may not be substituted with a OR 31  group,  
         where R 31  is as defined above and k is 0, 1, or  
         R 3  represents Si(Me) 3  or CH(R 32 ) 2 , wherein R 32  is a cyclohexyl- or a phenyl group;  
         R 4  represents H, an alkyl group having 1 to 4 carbon atoms, a cyclohexyl or a phenyl group;  
         A 2  represents a structural fragment of Formula IIIa, IIIb or IIIc  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         p is an interger 0, 1 or 2;  
         m is an integer 1, 2, 3 or 4;  
         Y represents a methylene group, or  
         Y represents an ethylene group and the resulting 5-membered ring may or may not carry one or two fluorine atoms, a hydroxy group or an oxo group in position 4, or may or may not be unsaturated, or  
         Y represents —CH 2 —O—, —CH 2 —S—, —CH 2 —SO—, with the heteroatom functionality in position 4, or  
         Y represents a n-propylene group and the resulting 6-membered ring may or may not carry in position 5 one fluorine atom, a hydroxy group or an oxo group, carry two fluorine atoms in one of positions 4 or 5 or be unsaturated in position 4 and 5, or carry in position 4 an alkyl group with 1 to 4 carbon atoms, or  
         Y represents —CH 2 —O—CH 2 —, —CH 2 —S—CH 2 —, —CH 2 —SO—CH 2 —, or  
         Y represent —CH 2 —CH 2 —CH 2 —CH 2 —;  
         R 3  is as defined above;  
         R 5  represents H or an alkyl group having 1 to 4 carbon atoms, or  
         R 5  represents —(CH 2 ) p —COOR 51 , where p is 0, 1 or 2 and  
         R 51  is H or an alkyl group having 1 to 4 carbon atoms;  
         n is an integer 0, 1, 2, 3 or 4;  
         B represents a structural fragment of Formula IVa, IVb, IVc or IVd  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         r is an interger 0 or 1;  
         X 1  represent CH 2  or NH or is absent;  
         X 2  represents CH 2 , NH or C═NH;  
         X 3  represents NH, C═NH, N—C(NH)—NH 2 , CH—C(NH)—NH 2 , CH—NH—C(NH)—NH 2  or CH—CH 2 —C(NH)—NH 2 ;  
         X 4  represents CH 2  or NH;  
         X 5  represents C(NH)—NH 2  or NH—C(NH)—NH 2 ;  
         X 6  represents CH or N;  
         R 6  is H or an alkyl group having 1-4 carbon atoms;  
         either the compound as such or stereoisomers thereof or in the form of a physiologically acceptable salt.  
       
     
     
         2 . A compound of the general formula  
       
         
           
           
               
               
           
         
         wherein:  
         A 1  represents a structural fragment of Formula IIa, IIb, IIc, IId or IIe;  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         k is an integer 0, 1, 2, 3 or 4;  
         m is an integer 1, 2, 3 or 4;  
         q is an integer 0, 1, 2, or 3;  
         R 1  represents R 11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the position which is alpha to the carbonyl group, and the alpha substituent is a group R 17 —(CH 2 ) p —, wherein p is 0, 1 or 2 and R 17  is, COOR 12 , CONHR 12 , where R 12  is H, an alkyl group having 1 to 4 carbon atoms or a benzyl group, and R 11  is H or an alkyl group having 1 to 6 carbon atoms, or a benzyl group, or  
         R 1  represents Ph(4-COOR 12 )—CH 2 —, where R 12  is as defined above, or  
         R 1  represents R 13 —NH—CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted alpha to the carbonyl with an alkyl group having 1 to 4 carbon atoms and where R 13  is H or an alkyl group having 1 to 4 carbon atoms or —CH 2 COOR 12 , where R 12  is as defined above, or  
         R 1  represents R 12 ooc-CH 2 -ooc-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted alpha to the carbonyl with an alkyl group having 1 to 4 carbon atoms and where R 12  is as defined above, or  
         R 1  represents R 14 SO 2 —, Ph(4-COOR 12 )—SO 2 —, Ph(3-COOR 12 )—SO 2 —, Ph(2-COOR 12 )—SO 2 — where R 12  is as defined above and R 14  is an alkyl group having 1-4 carbon atoms, or  
         R 1  represents —CO—R 15 , wherein R 15  is an alkyl group having 1-4 carbon atoms, or  
         R 1  represents —CO—OR 15 , where R 5  is as defined above, or  
         R 1  represent —CO—(CH 2 ) p —COOR 12 , where R 12  is as defined above and p is an interger 0, 1 or 2, or  
         R 2  represents H or an alkyl group having 1 to 4 carbon atoms or R 21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and where R 21  is H or an alkyl group having 1 to 4 carbon atoms or a benzyl group;  
         R 3  represents an alkyl group having 1-4 carbon atoms, and the alkyl group may or may not carry one or more fluorine atoms, or  
         R 3  represents a cyclopentyl, cyclohexyl- or a phenyl group which may or may not be substituted with an alkyl group having 1 to 4 carbon atoms, or  
         R 3  represents a phenyl group substituted with a OR 31  group, where R 31  is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, or  
         R 3  represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or  
         R 3  represent a cis- or trans-decalin group and k is 0, 1, or  
         R 3  represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may not be substituted with a OR 31  group, where R 31  is as defined above and k is 0, 1, or  
         R 3  represents Si(Me) 3  or CH(R 32 ) 2 , wherein R 32  is a cyclohexyl- or a phenyl group;  
         R 4  represents H, an alkyl group having 1 to 4 carbon atoms, a cyclohexyl or a phenyl group;  
         A 2  represents a structural fragment of Formula IIIa, IIIb or IIIc  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         p is an interger 0, 1 or 2;  
         m is an integer 1, 2, 3 or 4;  
         Y represents a methylene group, or  
         Y represents an ethylene group and the resulting 5-membered ring may or may not carry one or two fluorine atoms, a hydroxy group or an oxo group in position 4, or may or may not be unsaturated, or  
         Y represents —CH 2 —O—, —CH 2 —S—, —CH 2 —SO—, with the heteroatom functionality in position 4 or  
         Y represents a n-propylene group and the resulting 6-membered ring may or may not carry in position 5 one fluorine atom, a hydroxy group or an oxo group, carry two fluorine atoms in one of positions 4 or 5 or be unsaturated in position 4 and 5, or carry in position 4 an alkyl group with 1 to 4 carbon atoms, or  
         Y represents —CH 2 —O—CH 2 —, —CH 2 —S—CH 2 —, —CH 2 —SO—CH 2 —, or  
         Y represent —CH 2 —CH 2 —CH 2 —CH 2 —;  
         R 3  is as defined above;  
         R 3  represents H or an alkyl group having 1 to 4 carbon atoms, or  
         R 5  represents —(CH 2 ) p —COOR 51 , where p is 0, 1 or 2 and R 51  is H or an alkyl group having 1 to 4 carbon atoms;  
         n is an integer 0, 1, 2, 3 or 4;  
         B represents a structural fragment of Formula IVa, IVb, IVc or IVd  
         
           
             
             
                 
                 
             
           
         
         wherein:  
         r is an interger 0 or 1;  
         X 1  represent CH 2  or NH or is absent;  
         X 2  represents CH 2 , NH or C═NH;  
         X 3  represents NH, C═NH, N—C(NH)—NH 2 , CH—C(NH)—NH 2 , CH—NH—C(NH)—NH 2  or CH—CH 2 —C(NH)—NH 2 ;  
         X 4  represents CH 2  or NH;  
         X 5  represents C(NH)—NH 2  or NH—C(NH)—NH 2 ;  
         X 5  represents CH or N;  
         R 6  is H or an alkyl group having 1-4 carbon atoms;  
         D is Z or(Z) 2 ;  
         Z is a benzyloxy carbonyl group;  
         either the compound as such or stereoisomers thereof or in the form of a physiologically acceptable salt.  
       
     
     
         3 . A compound according to claims  1  wherein A 1  is a structural fragment of formula IIa or IIb.  
     
     
         4 . A compound according to  claim 1  wherein R 1  represents R 11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and R 11  is H.  
     
     
         5 . A compound according to  claim 1  wherein A 2  is a structural fragment of formula IIIa.  
     
     
         6 . A compound according to  claim 1  wherein A 2  is a structural fragment of formula IIIb.  
     
     
         7 . A compound according to  claim 1  wherein B is a structural fragment of formula IVa, wherein X 1 , X 2  and X 4  are CH 2 , X 3  is CH—C(NH)—NH 2 , r is 1 and n is 1.  
     
     
         8 . A compound according to  claim 1  wherein B is a structural fragment formula IVa, wherein X 1 , X 2  and X 4  are CH 2 , X 3  is N—C(NH)—NH 2 , r is 0 or 1 and n is 1 or 2.  
     
     
         9 . A compound according to  claim 1  wherein B is a structural fragment of formula IVb, wherein X 5  is C(NH)—NH 2  and R 6  is H and n is 1.  
     
     
         10 . A compound according to  claim 1  wherein B is a structural element of formula IVa, wherein X 1  and X 3  are NH, X 2  is C═NH, X 4  is CH 2 , r is 1 and n is 2.  
     
     
         11 . A compound according to  claim 1  wherein B is a structural element of formula IVa, wherein X 1  is absent, X 2  and X 4  are CH 2 , X 3  is N—C(NH)—NH 2 , r is 0 and n is 1 or 2.  
     
     
         12 . A compound according to claims  1  in which n is 1 or 2, A 1  is a structural fragment of formula IIa wherein k is 0 or 1, R 1  represents R 11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms, R 2  represents H, R 3  represents a cyclohexyl group, A 2 , represents a structural fragment of Formula IIIa wherein Y represents a methylene group, an ethylene group, or a n-propylene group and the resulting 6-membered ring may or may not carry in position 4 an alkyl group with 1 to 4 carbon atoms, R 5  represents H, B represents a structural fragment of formula IVa wherein X 1 , X 2  and X 4  are CH 2  and X 3  is CH—C(NH)—NH 2  or N—C(NH)—NH 2 , r is 0 or 1, or X 1  and X 3  is NH, X 2  is C═NH, X 4  is CH 2 , r is 1, or X 1  is absent, X 2  and X 4  are CH 2 , X 3  is N—C(NH)—NH 2 , r is 0.  
     
     
         13 . A compound according to claims  1  in which n is 1, A 1  is a structural fragment of formula IIa wherein k is 0 or 1, R 1  represents R 11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms, R 2  represents H, R 3  represents a cyclohexyl group, A 2  represents a structural fragment of Formula IIIa wherein Y represents a methylene group, an ethylene group, or a n-propylene group and the resulting 6-membered ring may or may not carry in position 4 an alkyl group with 1 to 4 carbon atoms, R 5  represents H, B represents a structural fragment of formula IVb wherein X 5  represents C(NH)—NH 2  and R 6  is H.  
     
     
         14 . A compound selected from 
 HOOC—CH 2 —(R)Cgl-Aze-Pab    HOOC—CH 2 —CH 2 —(R)Cgl-Aze-Pab    HOOC—CH 2 —(R)Cgl-Pro-Pab    HOOC—CH 2 —CH 2 —(R)Cgl-Pro-Pab    (HOOC—CH 2 ) 2 —(R)Cgl-Pro-Pab    H—(R)Cgl-Pic-Pab    HOOC—CH 2 —(R,S)CH(COOH)—(R)Cgl-Pic-Pab    H—(R)Cha-Aze-Pab    HOOC—CH 2 —(R)Cha-Aze-Pab    HOOC—CH 2 —(R,S)CH(COOH)—(R)Cha-Aze-Pab    HOOC—CH 2 —(RorS)CH(COOH)—(R)Cha-Aze-Pab/a    HOOC—CH 2 —(RorS)CH(COOH)—(R)Cha-Aze-Pab/b    HOOC—CH 2 —CH 2 —(R)Cha-Aze-Pab    HOOC—CH 2 —NH—CO—CH 2 —(R)Cha-Aze-Pab    H—(R)Cha-Pro-Pab    HOOC—CH 2 —(R)Cha-Pro-Pab    HOOC—CH 2 —(Me)(R)Cha-Pro-Pab    HOOC—CH 2 —CH 2 —(R)Cha-Pro-Pab    HOOC—CH 2 —CH 2 -(Me)(R)Cha-Pro-Pab    HOOC—CH 2 —(RorS)CH(COOH)—(R)Cha-Pro-Pab/a    HOOC—CH 2 —(RorS)CH(COOH)—(R)Cha-Pro-Pab/b    HOOC—CH 2 —NH—CO—CH 2 —(R)Cha-Pro-Pab    EtOOC—CH 2 —CH 2 —CH 2 —(R)Cha-Pro-Pab    Ph(4-COOH)—SO 2 —(R)Cha-Pro-Pab    H—(R)Cha-Pic-Pab    HOOC—CH 2 —(R)Cha-Pic-Pab    HOOC—CH 2 —(RorS)CH(COOH) (R)Cha-Pic-Pab/a    HOOC—CH 2 —(RorS)CH(COOH)—(R)Cha-Pic-Pab/b    HOOC—CH 2 —CH 2 —(R)Cha-Pic-Pab    HOOC—CO—(R)Cha-Pic-Pab    HOOC—CH 2 —CO—(R)Cha-Pic-Pab    Me-OOC—CH 2 —CO—(R)Cha-Pic-Pab    H 2 N—CO—CH 2 —(R)Cha-Pic-Pab    Boc-(R)Cha-Pic-Pab    Ac—(R)Cha-Pic-Pab    Me-SO 2 —(R)Cha-Pic-Pab    H—(R)Cha-(R,S)betaPic-Pab    HOOC—CH 2 —CH 2 —(R)Cha-(R,S)betaPic-Pab    HOOC—CH 2 —(R)Cha-Val-Pab    HOOC—CH 2 —CH 2 —(R)Cha-Val-Pab    H—(R)Hoc-Aze-Pab    HOOC—CH 2 —CH 2 —(R)Hoc-Aze-Pab    HOOC—CH 2 —(R,S)CH(COOH)—(R)Hoc-Pro-Pab    HOOC—CH 2 —(R)Hoc-Pic-Pab    (HOOC—CH 2 ) 2 —(R)Hoc-Pic-Pab    HOOC—CH 2 —(R)Pro (3-(S)Ph)-Pro-Pab    HOOC—CH 2 —CH 2 —(R)Pro (3-(S)Ph)-Pro-Pab    HOOC—CH 2 —CH 2 —-(R)Tic-Pro-Pab    HOOC—CH 2 —CH 2 —(R)Cgl-Aze-Pig    HOOC—CH 2 —(R)Cgl-Pro-Pig    H—(R)Cha-Aze-Pig    HOOC—CH 2 —(R)Cgl-Aze-Pac    H—(R)Cha-Pro-Pac    H—(R)Cgl-Ile-Pab    H—(R)Cgl-Aze-Pab    HOOC—(R,S)CH(Me)-(R)Cha-Pro-Pab    MeOOC—CH 2 —(R)Cgl-Aze-Pab    EtOOC—CH 2 —(R)Cgl-Aze-Pab      n BuOOC—CH 2 —(R)Cgl-Aze-Pab      n HexOOC—CH 2 —(R)Cgl-Aze-Pab    H—(R)Cgl-Pro-Pac    HOOC—CH 2 —(R)Cha-Pro-Pac    HOOC—CH 2 —CH 2 —(R)Cgl-Pro-Pac    HOOC—CH 2 —CH 2 —(R)Cha-Aze-Pac    HOOC—CH 2 —(R)Cha-Aze-Pig    HOOC—CH 2 —(R)Cha-Pro-Pig    HOOC—CH 2 —CH 2 —(R)Cha-Pro-Pig    (HOOC—CH 2 ) 2 —(R)Cgl-Pro-Pig    HOOC—CH 2 —CH 2  (HOOC—CH 2 )—(R)Cha-Pro-Pig    (HOOC—CH 2 )—(R)Cgl-Aze-(R,S)Itp    HOOC—CH 2 —(R)Cha-Aze-(R,S)Itp    H—(R)Cha-Pic-(R,S)Itp    HOOC—CH 2 —(R)Cha-Pic-(R,S)Itp    H—(R)Cgl-Pro-(R,S)Hig    HOOC—CH 2 —(R)Cgl-Pro-(R,S)Hig    H—(R)Cha-Pro-(R,S)Hig    H—(R)Cgl-Aze-Rig    HOOC—CH 2 —(R)Cgl-Aze-Rig    HOOC—CH 2 —(R)Cha-Pro-Rig    HOOC—CH 2 —CH 2 —(R)Cha-Aze-Rig    HOOC—CH 2 —(R)Cha-Pro-(S)Itp    H—(R)Cha-Pro-(R,S)Nig    H—(R)Cha-Pro-Mig    H—(R)Cha-Pro-Dig    H—(R)Cha-Aze-Dig    either as such or stereoisomer thereof or in the form of a physiologically acceptable salt.    
     
     
         15 . A compound selected from 
 HOOC—CH 2 —(R)Cgl-Aze-Pab    HOOC—CH 2 —CH 2 —(R)Cha-Aze-Pab    HOOC—CH 2 —(R)Cha-Pro-Pab    HOOC—CH 2 —CH 2 —(R)Cha-Pro-Pab    HOOC—CH 2 —(R)Cha-Pic-Pab    HOOC—CH 2 —(R)Cgl-Pro-Pig    EtOOC—CH 2 —(R)Cgl-Aze-Pab    HOOC—CH 2 —(R)Cha-Pro-Pac    HOOC—CH 2 —(R)Cha-Pro-Pig    either as such or stereoisomer thereof or in the form of a physiologically acceptable salt.    
     
     
         16 . A compound selected from 
 BnOOC—CH 2 —(R)Cgl-Aze-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cgl-Aze-Pab(Z)    BnOOC—CH 2 —(R)Cgl-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cgl-Pro-Pab(Z)    (BnOOC—CH 2 ) 2 —(R)Cgl-Pro-Pab(Z)    BnOOC—CH 2 —(R,S)CH(COOBn)-(R)Cgl-Pic-Pab(Z)    BnOOC—CH 2 —(R)Cha-Aze-Pab(Z)    BnOOC—CH 2 —(R,S)CH(COOBn)-(R)Cha-Aze-Pab(Z)    BnOOC—CH 2 —(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/a    BnOOC—CH 2 —(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/b    BnOOC—CH 2 —CH 2 —(R)Cha-Aze-Pab(Z)    BnOOC—CH 2 —NH—CO—CH 2 —(R)Cha-Aze-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —(Me)(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 -(Me)(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —(R,S)CH(COOBn)-(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —NH—CO—CH 2 —(R)Cha-Pro-Pab(Z)    Ph(4-COOH)—SO 2  (R)Cha-Pro-Pab(Z)    Boc-(R)Cha-Pic-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pic-Pab(Z)    BnOOC—CH 2 —(R,S)CH(COOBn)-(R)Cha-Pic-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-Pic-Pab(Z)    EtOOC—CO—(R)Cha-Pic-Pab(Z)    MeOOC—CH 2 —CO—(R)Cha-Pic-Pab(Z)    H 2 N—CO—CH 2 —(R)Cha-Pic-Pab(Z)    Ac—(R)Cha-Pic-Pab(Z)    Me-SO 2 —(R)Cha-Pic-Pab(Z)    BnOOC—CH 2 —(R)Cha-Val-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-(R,S)Val-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Hoc-Aze-Pab(Z)    BnOOC—CH 2 —(R,S)CH(COOBn)-(R)Hoc-Pro-Pab(Z)    BnOOC—CH 2 —(R)Hoc-Pic-Pab(Z)    (BnOOC—CH 2 ) 2 —(R)Hoc-Pic-Pab(Z)    BnOOC—CH 2 —(R)Pro(3-(S)Ph)-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Pro(3-(S)Ph)-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Tic-Pro-Pab(Z)    BnOOC—CH 2 —CH 2 —(R)Cgl-Aze-Pig(Z) 2      BnOOC—CH 2 —(R)Cgl-Pro-Pig(Z) 2      BnOOC—CH 2 —(R)Cgl-Aze-Pac(Z)    BnOOC—(R,S)CH(Me)-(R)Cha-Pro-Pab(Z)    MeOOC—CH 2 —(R)Cgl-Aze-Pab(Z)    EtOOC—CH 2 —(R)Cgl-Aze-Pab(Z)      n BuOOC—CH 2  (R)Cgl-Aze-Pab(Z)      n HexOOC—CH 2 —(R)Cgl-Aze-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pac(Z)    BnOOC—CH 2 —CH 2 —(R)Cgl-Pro-Pac(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-Aze-Pac(Z)    BnOOC—CH 2 —(R)Cha-Aze-Pig(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pig(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-Pro-Pig(Z)    (BnOOC—CH 2 ) 2 —(R)Cgl-Pro-Pig(Z)    BnOOC—CH 2 —CH 2  (BnOOC—CH 2 )—(R)Cha-Pro-Pig(Z)    BnOOC—CH 2 —(R)Cha-Pic-(R,S)Itp(Z)    BnOOC—CH 2 —(R)Cgl-Pro-(R,S)Hig(Z)    BnOOC—CH 2 —(R)Cgl-Aze-Rig(Z)    BnOOC—CH 2 —(R)Cha-Pro-Rig(Z)    BnOOC—CH 2 —CH 2 —(R)Cha-Aze-Rig(Z)    either as such or stereoisomer thereof or in the form of a physiologically acceptable salt.    
     
     
         17 . A compound selected from 
 BnOOC—CH 2 —(R)Cgl-Aze-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pic-Pab(Z)    BnOOC—CH 2 —(R)Cgl-Pro-Pig(Z) 2      EtOOC—CH 2 —(R)Cgl-Aze-Pab(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pac(Z)    BnOOC—CH 2 —(R)Cha-Pro-Pig(Z)    either as such or stereoisomer thereof or in the form of a physiologically acceptable salt.    
     
     
         18 . A compound selected from 
 H—(R)Pro-Phe-Pab    HOOC—CH 2 —(R)Pro-Phe-Pab    H—(R)Phe-Phe-Pab    HOOC—CH 2 —(R)Phe-Phe-Pab    HOOC—CO—(R)Phe-Phe-Pab    either as such or stereoisomer thereof or in the form of a physiologically acceptable salt.    
     
     
         19 . A compound selected from 
 Boc-(R)Pro-Phe-Pab(Z)    BnOOC—CH 2 —(R)Pro-Phe-Pab(Z)    Boc-(R)Phe-Phe-Pab(Z)    MeOOC—CO—(R)Phe-Phe-Pab(Z)    BnOOC—CH 2 —(R)Phe-Phe-Pab(Z)    either as such or steroisomer thereof or in the forms of a physiologically acceptable salt.    
     
     
         20 . A process for preparing a compound according to  claim 1 , which process comprises coupling of an N-terminally protected amino acid or dipeptide or amino acid, when an N-terminally amino acid is used a second amino acid is added afterwards using standard methods to a compound  
         H 2 N—(CH 2 ) n —X  wherein n is an integer 0, 1, 2, 3 or 4, X is B or B-D, where B is as defined in formula I and D is as defined in formula V as such or having the guanidino or amidino nitrogens either mono or diprotected with an amine protecting group such as a benzyloxy carbonyl- or tertbutyloxy carbonyl- or p-toluenesulphonyl group or X is a group transferable into B followed by removal of the protecting group(s) or deprotection of the N-terminal nitrogen followed by alkylation of the N-terminal nitrogen and if desired deprotection by known methods and if desired forming a physiologically acceptable salt, and in those cases where the reaction results in a mixture of stereoisomers, these are optionally separated by standard chromatographic or re-crystallisation techniques, and if desired a single stereoisomer is isolated.    
     
     
         21 . A process according to  claim 20  for preparing a compound as defined above, which process comprises: 
 a) (Method Ia) Coupling of an N-terminally protected dipeptide, selected from A 1  and A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n is as defined in Formula 1, W 1  is an N-terminal amino protecting group such as tert-butyloxy carbonyl and benzyloxy carbonyl and Q 1  is —C(NH)—NH 2 , —C(NW 2 )—NH—W 2 , —C(NH)—NH—W 2 , —NH—C(NH)—NH 2 , —NH—C(NH)—NH—W 2 , —N(W 2 )—C(NH)—NH—W 2  or —NH—C(NW 2 )—NH—W 2 , where W 2  is an amine protecting group such as tert-butyloxy carbonyl or benzyloxy carbonyl, or Q 1  is —CN, —CO—NH 2  or —CS—NH 2  where the group is subsequently transferred into a amidino group or Q 1  is NH 2  or NH—W 2 , where W 2  is as defined above, where the amino group is subsequently transferred into a guanidino group (giving Q 1 =—NH—C(NH)—NH 2 ), after deprotection of the W 2 -group when Q 1  is —NH—W 2  (W 2  in this case must be orthogonal to W 1 ), by methods known in the art.    b) (Method Ib) Coupling of an N-terminally protected amino acid, selected from A 2  in Formulas I or V and prepared by using standard peptide coupling, shown in the formula                          wherein n, W 1- , and Q 1  are as defined above followed by deprotection of the W 1 -group and coupling with the N-terminal amino acid, in a protected form, leading to the protected peptide described in Method Ia above,    c) (Method IIa) Coupling of an N-terminally protected dipeptide, selected from A 1  and A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n is as defined in Formula i, W 1  is an N-terminal amino protecting group such as tert. butyloxy carbonyl and benzyloxy carbonyl and Q 1  is —C(NH)—NH 2 , —C(W 2 )—NH—W 2 , —C(NH)—NH—W 2 , —NH—C(NH)—NH 2 , —NH—C(NH)—NH—W 2 , —N (W 2 )—C(NH)—NH—W 2  or —NH—C(NW 2 )—NH—W 2 , where W 2  is an amine protecting group such as tert. butyloxy carbonyl or benzyloxy carbonyl, or Q 1  is —CN, —CO—NH 2  or CS—NH 2 , where the group is subsequently transferred into a amidino group or Q 1  is NH 2  or NH—W 2 , where W 2  is as defined above, where the amino group is subsequently transferred into a guanidino group (giving Q 1 =—NH—C(NH)—NH 2 ), after deprotection of the W 2 -group when Q 1  is —NH—W 2  (W 2  in this case must be orthogonal to W 1 ), by methods known in the art.    d) (Method IIb) Coupling of an N-terminally protected amino acid, selected from A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n, W 1  and Q 1  are as defined above followed by deprotection of the W 1 -group and coupling with the N-terminal amino acid, in a protected form, leading to the protected peptide described in Method IIa above,    e) (Method IIIa) Coupling of an N-terminally protected dipeptide, selected from A 1  and A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n is as defined in Formula I and r is 0 or 1 when X 1 , X 2  and X 4  are CH 2  or r is 0 when X 2  and X 4  are CH 2  and X 1  is abscent, W 1  is an N-terminal amino protecting group such as tert-butyloxy carbonyl and benzyloxy carbonyl and Q 2  is —C(NH)—NH 2 , —C(NW 2 )—NH—W 2 , or —C(NH)—NH—W 2 , where W 2  is an amine protecting group such as tert-butyloxy carbonyl or benzyloxy carbonyl, or O 2  is equal to W 2  where the amino group, after deprotection of the W 2  group (W 2  in this case must be orthogonal to W 1 ), is subsequently transferred into a guanidino group using a unprotected, N-protected or N,N′-diprotected guanidation reagent by methods known in the art,    f) (Method IIIb) Coupling of an N-terminally protected amino acid, selected from A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n, r, X 1 , X 2  and X 4 , W 1 , and Q 2  are as defined above followed by deprotection of the W 1 -group and coupling with the N-terminal amino acid, in a protected form, leading to the protected peptide described in Method IIIa above,    g) (Method IVa) Coupling of an N-terminally protected dipeptide, selected from A 1  and A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n is as defined in Formula I, W 1  is an N-terminal amino protecting group such as tert-butyloxy carbonyl or benzyloxy carbonyl and W 3  is H or an amino protecting group such as aryl sulfonyl, benzyloxy carbonyl or tert-butyloxy carbonyl.    h) (Method IVb) Coupling of an N-terminally protected amino acid, selected from A 2  in Formulas I or V by using standard peptide coupling, shown in the formula                          wherein n, W 1 , and W 3  are as defined above followed by deprotection of the W 1 -group and coupling with the N-terminal amino acid, in a protected form, leading to the protected peptide described in Method IVa,    the final compounds can be made in any of the following ways, depending on the nature of the Q 1 - or Q 2 -groups used: Removal of the protecting group(s) (when Q 1 =—C(NH)—NH 2 , —C(NW 2 )—NH—W 2 , —C(NH)—NH—W 2 , —NH—C(NH)—NH 2 , —NH—C(NH)—NH—W 2 , —N(W 2 )—C(NH)—NH—W 2  or —NH—C(NW 2 )—NHW 2 ), or a selective deprotection of the W 1 -group (e.g when Q 1  or Q 2 =—C(NW 2 )—NH—W 2 , —C(NH)—NH—W 2 , —NH—C(NH)—NH—W 2 , —N (W 2 )—C(NH)—NH—W 2  or —NH—C(NW 2 )—NH—W 2  (W 2  in this case must be orthogonal to W 1 ) followed by alkylation of the N-terminal nitrogen and if desired deprotection.    
     
     
         22 . A compound according to  claim 1  for use in therapy.  
     
     
         23 . A compound according to  claim 1  for use as an anticoagulant or antithrombotic agent.  
     
     
         24 . A compound according to  claim 1  for use as an anti-inflammatory agent.  
     
     
         25 . A pharmaceutical preparation comprising an effective amount of a compound as outlined in  claim 1  in conjunction with one or more pharmaceutical carriers.  
     
     
         26 . A pharmaceutical preparation comprising an effective amount of a compound as outlined in  claim 1  in conjunction with one or more pharmaceutical carriers for use as an anticoagulant or antithrombotic agent.  
     
     
         27 . A pharmaceutical preparation comprising an effective amount of a compound as outlined in  claim 1  in conjunction with one or more pharmaceutical carriers for use as an anti-inflamanatory agent.  
     
     
         28 . Use of compound according to  claim 1  as an active ingredient for manufacture of a pharmaceutical preparation for inhibition of thrombin in a human or animal organism.  
     
     
         29 . Use of compound according to  claim 1  as an active ingredient for manufacture of a pharmaceutical preparation for inhibition of kininogenases in a human or animal organism.  
     
     
         30 . A method for obtaining inhibition of thrombin in a human or animal organism in need of such inhibition, comprising administering to said organism an inhibitory effective amount of a compound claimed in  claim 1 .  
     
     
         31 . A method for obtaining inhibition of kininogenases in a human or animal organism in need of such inhibition, comprising administering to said organism an inhibitory effective amount of a compound claimed in  claim 1 .  
     
     
         32 . Use of a compound of the formula:  
       
         
           
           
               
               
           
         
         either as such or having the amidino group either mono- or diprotected at the nitrogens with a protective group, or in the form of a salt, as a starting material in synthesis of a peptidic serine protease inhibitor, and in particular in synthesis of a peptidic thrombin inhibitor or a peptidic kininogenases inhibitor.  
       
     
     
         33 . A structural fragment of the formula  
       
         
           
           
               
               
           
         
         as a structural element in a pharmaceutically active compound, especially a peptidic compound.  
       
     
     
         34 . A compound 4-aminomethyl-1-(N-benzyloxycarbonylamidino) benzene either as such, in the form of a salt or having a protection with a benzyloxycarbonyl group at the other nitrogen.  
     
     
         35 . Use of a compound of the formula:  
       
         
           
           
               
               
           
         
         either as such or having the amidino group either mono- or diprotected at the nitrogens with a protective group, or in the form of a salt, as a starting material in synthesis of a thrombin inhibitor, and in particular in synthesis of a peptidic thrombin inhibitor.  
       
     
     
         36 . A structural fragment of the formula  
       
         
           
           
               
               
           
         
         as a structural element in a thrombin inhibitor, especially a peptidic thrombin inhibitor.  
       
     
     
         37 . A compound 4-aminomethyl-1-(N-benzyloxy-carbonylamidino) cyclohexane either as such, in the form of a salt or having a protection with a benzyloxycarbonyl group at the other nitrogen.  
     
     
         38 . A compound of the formula:  
       
         
           
           
               
               
           
         
         either as such or having the amidino group either mono- or diprotected at the nitrogens with a protective group, or in the form of a salt.  
       
     
     
         39 . Use of a compound as described in  claim 38 , as a starting material in the synthesis of a serine protease inhibitor.  
     
     
         40 . A structural fragment of the formula  
       
         
           
           
               
               
           
         
         as a structural element in a thrombin inhibitor, especially a peptidic thrombin inhibitor.  
       
     
     
         41 . A compound of the formula:  
       
         
           
           
               
               
           
         
         either as such or having the amidino group either mono- or diprotected at the nitrogen with a protective group, or in the form of a salt.  
       
     
     
         42 . Use of a compound as described in  claim 41 , as a starting material in the synthesis of a serine protease inhibitor.  
     
     
         43 . A structural fragment of the formula  
       
         
           
           
               
               
           
         
         as a structural element in a thrombin inhibitor, especially a peptidic thrombin inhibitor.  
       
     
     
         44 . A compound 4-aminoethyl-1-benzyloxy-carbonylamidino piperidine either as such, in the form of a salt or having a protection with a benzyloxycarbonyl group at the other nitrogen.  
     
     
         45 . A compound of the formula:  
       
         
           
           
               
               
           
         
         where n is 1 or 2 and s is 0 or 1,  
         either as such or having the amidino group either mono- or diprotected at the nitrogens with a protective group, or in the form of a salt.  
       
     
     
         46 . Use of a compound as described in  claim 45 , as a starting material in the synthesis of a serine preotease inhibitor.  
     
     
         47 . A structural fragment of the formula  
       
         
           
           
               
               
           
         
         where n is 1 or 2 and s is 0 or 1,  
         as a structural element in a thrombin inhibitor, especially a peptidic thrombin inhibitor.  
       
     
     
         48 . A compound which is (3RS)-1-(N-benzyloxycarbonyl-amidino)-3-aminomethylpyrrolidine, (3RS)-1-(N-benzyl-oxycarbonylamidino)-3-aminoethyl pyrrolidine, 3-amino-methyl-1-(N-benzyloxycarbonyl-amidno)azetidine, 3-aminoethyl-1-(N-benzyloxycarbonyl-amidino)azetidine or either as such, in the form of a salt or having a protection with a benzyloxycarbonyl group at the other nitrogen.