Vitronectin receptor antagonists, their preparation and use

Abstract

The present invention relates to compounds of the formula I, A-B-D-E-F-G  (I) in which A, B, D, E, F and G have the meanings given in the patent claims, to their preparation and to their use as medicaments. The compounds of the invention are used as vitronectin receptor antagonists and as inhibitors of bone resorption.

1 . A compound of the formula I,  
       A-B-D-E-F-G (I)  
       in which: 
 A is  
                     
 is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system, which can contain from 1 to 4 heteroatoms from the group N, O and S and can optionally be substituted, once or more than once, by R 12 , R 13 , R 14  and R 15 ;  
 B is a direct linkage, (C 1 -C 8 )-alkanediyl, (C 5 -C 10 )-arylene, (C 3 -C 8 )-cycloalkylene, —C≡C—, —NR 2 —, —NR 2 C(O)—, —NR 2 —C(O)—NR 2 —, —NR 2 —C(S)—NR 2 —, —O—C(O)—, —NR 2 —S(O)—, —NR 2 —S(O) 2 —, —O—, —S— or —CR 2 ═CR 3 —, which can in each case be substituted, once or twice, by (C 1 -C 8 )-alkyl;  
 D is a direct linkage, (C 1 -C 8 )-alkanediyl, (C 5 -C 10 )-arylene, —O—, —NR 2 —, —CO—NR 2 —, —NR 2 —CO—, —NR 2 —C(O)—NR 2 —, —NR 2 —C(S)—NR 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 —NR 2 —, —S(O)—NR 2 —, —NR 2 —S(O)—, —NR 2 —S(O) 2 —, —S—, —CR 2 ═CR 3 — or —C≡C— which can in each case be substituted, once or twice, by (C 1 -C 8 )-alkyl, —CR 2 ═CR 3 — or (C 5 -C 6 )-aryl, with it not being possible for D to be —CO—NR 2 —, —C(O)O—, —S(O)—, —S(O) 2 —, —S(O)—NR 2 — or —S(O) 2 —NR 2 — when B is a direct linkage; 
 E is a template which is selected from the series of fibrinogen receptor antagonists;  
 F is defined like D,  
 G is  
                     
 R 2  and R 3  are, independently of each other, H, (C 1 -C 10 )-alkyl, which is optionally substituted, once or more than once, by fluorine, (C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 1 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl, R 8 OC(O)R 9 , R 8 R 8 NC(O)R 9  or R 8 C(O)R 9 ;  
 R 4 , R 5 , R 6  and R 7  are, independently of each other, H, fluorine, OH, (C 1 -C 8 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl, or R 8 OR 9 , R 8 SR 9 , R 8 CO 2 R 9 , ROC(O)R 9 , R 8 —, C 5 -C 14 )-aryl-R 9 , R 8 N(R 2 )R 9 , R 8 R 8 NR 9 , R 8 N(R 2 )C(O)OR 9 , R 8 S(O) n N(R 2 )R 9 , R 8 OC(O)N(R 2 )R 9 , R 8 C(O)N(R 2 )R 9 , R 8 N(R 2 )C(O)N(R 2 )R 9 , R 8 N(R 2 )S(O)N(R 2 )R 9 , R 8 S(O) n R 9 , R 8 SC(O)N(R 2 )R 9 , R 8 C(O)R 9 , R 8 N(R 2 )C(O)R 9  or R 8 N(R 2 )S(O) n R 9 ;  
 R 8  is H, (C 1 -C 8 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 14 )-aryl or (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;  
 R 9  is a direct linkage or (C 1 -C 8 )-alkanediyl; R 10  is C(O)R 11 , C(S)R 11 , S(O)R 11 , P(O)(R 11 ) n  or a four-membered to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S, such as tetrazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;  
 R 11  is OH, (C 1 -C 8 )-alkoxy, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkoxy, (C 5  C 14 )-aryloxy, (C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C 6 )-alkoxy, NH 2 , mono- or di-((C 1 -C 8 )-alkyl)-amino, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylamino, (C 1 -C 8 )-dialkylaminocarbonylmethyloxy (C 5 -C 14 )-aryl-(C 1 -C 8 )-dialkylaminocarbonylmethyloxy or (C 5 -C 14 )-arylamino or the radical of an L-amino acid or D-amino acid;  
 R 12 , R 13 , R 14  and R 15  are, independently of each other, H, (C 1 -C 10 )-alkyl which is optionally substituted, once or more than once, by fluorine, (C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl, H 2 N, R 8 ONR 9 , R 8 OR 9 , R 8 OC(O)R 9 , R 8 R 8 NR 9 , R 8 —(C 5 -C 14 )-aryl-R 9 , HO(C 1 -C 8 )-alkyl-N(R 2 )R 9 , R 8 N(R 2 )C(O)R 9 , R 8 C(O)N(R 2 )R 9 , R 8 C(O)R 9 , R 2 R 3 N—C(═NR 2 )—NR 2 , R 2 R 3 NC(═NR 2 ), ═O, or ═S; 
 where two adjacent substituents from R 12  to R 15  can also together be —OCH 2 O— or —OCH 2 CH 2 O—;  
 
 
 Y is NR 2 , O or S;  
 n is 1 or 2;  
 p and q are, independently of each other, 0 or 1;  
 in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts,  
 with compounds being excepted in which E 
 a) is a 6-membered aromatic ring system which can contain up to 4 N atoms and which can be substituted by from 1 to 4 identical or different arbitrary substituents, or  
 b) is 4-methyl-3-oxo-2,3,4,5-tetrahydro-1-H-1,4-benzodiazepine.  
 
 
     
     
         2 . A compound of the formula I as claimed in  claim 1 , in which: 
 A is the radical                          is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system which can contain from 1 to 4 heteroatoms from the group consisting of N, O and S and which can optionally be substituted, once or more than once, by R 12 , R 13 , R 14  and R 15 ;    B is a direct linkage, (C 1 -C 6 )-alkanediyl, (C 5 -C 8 )-arylene, (C 3 -C 8 )-cycloalkylene, —C≡C—, —NR 2 —, —NR 2 —C(O)—, —NR 2 —C(O)—NR 2 —, —NR 2 —S(O)—, —NR 2 —S(O) 2 —, —O— or —CR 2 ═CR 3 — which can in each case be substituted, once or twice, by (C 1 -C 6 )-alkyl;    D is a direct linkage, (C 1 -C 8 )-alkanediyl, (C 5 -C 8 )-arylene, —O—, —NR 2 —, —CO—NR 2 —, —NR 2 —CO—, —NR 2 —C(O)—NR 2 —, —OC(O)— —C(O)O—, —S(O) 2 —, —S(O) 2 —NR 2 —, —NR 2 —S(O) 2 —, —S—, —CR 2 ═CR 3 — or —C≡C— which can in each case be substituted, once or twice, by (C 1 -C 8 )-alkyl, —CR 2 ═CR 3 — or (C 5 -C 6 )-aryl, with it not being possible for D to be —CO—NR 2 —, —C(O)O—, —SO 2 — or —S(O) 2 —NR 2 — when B is a direct linkage;    F is defined like D;    G is                          R 2  and R 3  are, independently of each other, H, (C 1 -C 10 )-alkyl, which is optionally substituted, once or more than once, by fluorine, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, R 8 C(O)R 9 , R 8 R 8 NC(O)R 9  or R 8 C(O)R 9 ;    R 4 , R 5 , R 6  and R 7  are, independently of each other, H, fluorine, OH, (C 1 -C 8 )-alkyl, (C 5 -C 14 )cycloalkyl, (C 5 -C 14 )cycloalkyl-(C 1 -C 8 )-alkyl, or R 8 OR 9 , R 8 SR 9 , R 8 CO 2 R 9 , R 8 OC(O)R 9 , R 8 -(C 5 -C 14 )-aryl-R 9 , R 8 N(R 2 )R 9 , R 8 R 8 NR 9 , R 8 N(R 2 )C(O)OR 9 , R 8 S(O) n N(R 2 )R 9 , R 8 OC(O)N(R 2 )R 9 , R 8 C(O)N(R 2 )R 9 , R 8 N(R 2 )C(O)N(R 2 )R 9 , R 8 N(R 2 )S(O) n N(R 2 )R 9 , R 8 S(O) n R 9 , R 8 SC(O)N(R 2 )R 9 , R 8 C(O)R 9 , R 8 N(R 2 )C(O)R 9  or R 8 N(R 2 )S(O) n R 9 ;    R 8  is H, (C 1 -C 6 )-alkyl, (C 5 -C 14 )-cycloalkyl, (C 5 -C 14 )cycloalkyl-(C 1 -C 6 )-alkyl, (C 5 C 12 )-aryl or (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;    R 9  is a direct linkage or (C 1 -C 6 )-alkanediyl;    R 10  is C(O)R 11 , C(S)R 11 , S(O) n R 11 , P(O)(R 11 ) n  or a four-membered to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S;    R 11  is OH, (C 1 -C 6 )-alkoxy, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkoxy, (C 5 -C 12 )-aryloxy, (C 1 -C 6 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkylcarbonyloxy-(C 1 -C 6 )-alkoxy, NH 2 , mono-, or di(C 1 -C 6 )-alkyl)-amino, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkylamino, (C 1 -C 6 )-dialkylaminocarbonylmethyloxy;    R 12 , R 13 , R 14  and R 15  are, independently of each other, H, (C 1 -C 8 )-alkyl which is optionally substituted, once or more than once, by fluorine, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, H 2 N, R 8 ONR 9 , R 8 OR 9 , R 8 OC(O)R 9 , R 8 -(C 5 -C 12 )-aryl-R 9 , R 8 R 8 NR 9 , HO—(C 1 -C 8 )-alkyl-N(R 2 )R 9 , R 8 N(R 2 )C(O)R 9 , R 8 C(O)N(R 2 )R 9 , R 8 C(O)R 9 , R 2 R 3 N—C(═NR 2 ), R 2 R 3 N—C(═NR 2 )—NR 2 , ═O or ═S;    where two adjacent substituents from R 12  to R 15  can also together be —OCH 2 O—, —OCH 2 CH 2 O— or —OC(CH 3 ) 2 O—;    Y is NR 2 , or S;    n is 1 or 2;    p and q are, independently of each other, 0 or 1;    and E is as defined in  claim 1;     in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.    
     
     
         3 . A compound of the formula I as claimed in  claim 1  and/or  2 , in which: 
 A is one of the radicals  
                     
 B is a direct linkage, (C 1 -C 6 )-alkanediyl, (C 5 -C 6 )-arylene, (C 5 -C 6 )-cycloalkylene, —C≡C—, —NR 2 —, —NR 2 —C(O)—, —NR 2 —S(O) 2 —, —O— or —CR 2 ═CR 3 —, which can in each case be substituted, once or twice, by (C 1 -C 6 )-alkyl;  
 D is a direct linkage, (C 1 -C 6 )-alkanediyl, (C 5 -C 6 )-arylene, —O—, —NR 2 —, —NR 2 —C(O)—, —C(O)NR 2 —, —NR 2 —C(O)—NR 2 —, —OC(O)—, —S(O) 2 —NR 2 —, —NR 2 —S(O) 2 — or —CR 2 ═CR 3 — which can in each case be substituted, once or twice, by (C 1 C 6 )-alkyl, with it not being possible for D to be —C(O)NR 2 — or —S(O) 2 —NR 2 — when B is a direct linkage;  
 E a) is  
                     
  where R 1a , R 2a R 20a  R 21a  an R 22a  are:  
 R 1a  and R 2a  are, independently of each other, from one to three groups from the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxyl, mercapto or sulfonamido, or an optionally substituted radical from the group consisting of C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 3 -C 12 -alkynyl, C 3 -C 12 -cycloalkyl, C 6 -C 14 -aryl, C 6 -C 10 -aryl-C 1 -C 8 -alkyl, C 1 -C 12 -alkyloxy, C 6 -C 14 -aryloxy and C 1 -C 12 -acylamino, where the substituents are a radical from the group consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, C 1 -C 4 -alkoxy, phenyl and phenoxy;  
 R 20a  is hydrogen, halogen (fluorine, chlorine, bromine or iodine), C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, phenyl, benzyl or halogen-C 1 -C 4 -alkyl,  
 R 21a  and R 22a  are, independently of each other, 
 1. hydrogen  
 2. (C 1 -C 12 )-alkyl  
 3. (C 6 -C 14 )-aryl,  
 4. (C 3 -C 14 )-cycloalkyl,  
 5. (C 1 -C 12 )-alkyl-(C 6 -C 14 )-aryl,  
 6. (C 1 -C 12 )-alkyl-(C 3 -C 14 )-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of 
 halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C 1 -C 6 -alkyl; C 6 -C 14 -aryl; benzyl; C 3 -C 14 -cycloalkyl; COR 24a  or CONR 25 R 26 ; where  
 R 24a  is a radical from the group consisting of C 1 -C 8 -alkoxy; C 3 -C 12 -alkenoxy; C 6 -C 12 -aryloxy; di-C 1 -C 8 -alkylamino-C 1 -C 8 -alkoxy; acylamino-C 1 -C 8 -alkoxy; acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy; pivaloylethoxy; or C 6 -C 12 -aryl-C 1 -C 8 -alkoxy, where the aryl group can be optionally substituted by from one to three radicals selected from the group consisting of nitro, halogen, C 1 -C 4 -alkoxy, amino, hydroxyl, hydroxy-C 2 -C 8 -alkoxy or dihydroxy-C 3 -C 8 -alkoxy;  
 R 25  and R 26  are, independently of each other, hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -alkenyl, C 6 -C 14 -aryl or C 1 -C 6 -alkyl-C 6 -C 10 -aryl, or  
 R 25  and R 26  together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;  
 
 7. Q 2 -L 3   1  where 
 Q 2  is hydrogen or Q 1 ; and  
 L 3  is a chemical bond, L 1  or L 2 ; 
 Q 1  is a substituted or unsubstituted, positively charged, nitrogen-containing radical,  
 L 1  is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene groups, alkyne groups, aryl groups or functional groups containing heteroatoms from the group consisting of N, O or S, and  
 L 2  is an optionally substituted, divalent radical;  
 
 
 
 and R 22b  is: 
 1. hydrogen  
 2. (C 1 -C 12 )-alkyl  
 3. (C 6 -C 14 )-aryl,  
 4. (C 3 -C 14 )-cycloalkyl,  
 5. (C 1 -C 12 )-alkyl-(C 6 -C 14 )-aryl,  
 6. (C 1 -C 12 )-alkyl-(C 3 -C 14 )-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of 
 halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C 1 -C 6 -alkyl; C 6 -C 14 -aryl; benzyl; C 3 -C 14 -cycloalkyl; COR 24a  or CONR 25 R 26 ; where  
 R 24a  is a radical from the group consisting of C 1 -C 8 -alkoxy; C 3 -C 12 -alkenoxy; C 6 -C 12 -aryloxy; di-C 1 -C 8 -alkylamino-C 1 -C 8 -alkoxy; acylamino-C 1 -C 8 -alkoxy; acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy; pivaloylethoxy; or C 6 -C 12 -aryl-C 1 -C 8 -alkoxy, where the aryl group can optionally be substituted by from one to three radicals selected from the group consisting of nitro, halogen, C 1 -C 4 -alkoxy, amino, hydroxyl, hydroxy-C 2 -C 8 -alkoxy or dihydroxy-C 3 -C 8 -alkoxy;  
 R 25  and R 26  are, independently of each other, hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -alkenyl, C 6 -C 14 -aryl or C 1 -C 6 -alkyl-C 6 -C 10 -aryl, or  
 R 25  and R 26  together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;  
 
 7. Q 2 -L 3 , where 
 Q 2  is hydrogen or Q 1 ; and  
 L 3  is a chemical bond, L 1  or L 2 ; 
 Q 1  is a substituted or unsubstituted, positively charged, nitrogen-containing radical,  
 L 1  is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene radicals, alkyne radicals, aryl radicals or functional groups containing heteroatoms from the group consisting of N, O or S, and  
 L 2  is an optionally substituted, divalent radical;  
 
 
 
 or b) is  
                     
 where R 1b  and R 2b  are:  
 R 1b  and R 2b  are, independently of each other, from one to three groups from the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxyl, mercapto or sulfonamido, or an optionally substituted radical from the group consisting of C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 3 -C 12 -alkynyl, C 3 -C 12 -Cycloalkyl, C 6 -C 14 -aryl-C 6 -C 10 -aryl-C 1 -C 8 -alkyl, C 1 -C 12 -alkyloxy, C 6 -C 14 -aryloxy and C 1 -C 12 -acylamino, where the substituents are a radical from the group consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, C 1 -C 4 -alkoxy, phenyl and phenoxy; and  
 R 25b  and R 26b  are, independently of each other, 
 hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -alkenyl, C 6 -C 14 -aryl or C 1 -C 6 -alkyl-C 6 -C 10 -aryl, or  
 
 R 25b  and R 26b  together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;  
 or c) is  
                     
 where  
 (R 2 ) p  is bonded to one or more carbon atoms of the 6-membered ring and is, independently of each other, a radical from the group consisting of H, alkyl, halogen-substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxyl, alkoxy, aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen, nitro and sulfo;  
 R is (C 1 -C 4 )-alkyl  
 p is an integer from 1 to 3,  
 or d) is  
                     
 where R 3  is hydrogen, (C 1 -C 6 )-alkyl or aryl-C 1 -C 6 -alkyl,  
 or e) is  
                     
  in which V is CR 7a  or N, and 
 D a  is CH 2 , CH 2 —CH 2 , CH 2 C(R 7a ) 2 CH 2  or  
                     
 
  in which x is CR 3a  or N  
  where R 3a  is CN, C(O)N(R 7a )R 8a ,  
                     
  in which V is CR 7a  or N, and 
 D a  is CH 2 , CH 2 —CH 2 , CH 2 C(R 7a ) 2 CH 2  or  
                     
 
  in which X is CR or N, in which 
 R 3a  is CN, C(O)N(R 7a )R 8a ,  
                     
 
  where Y 3  is O, or H 2 , and 
 R 7a  is hydrogen; C 1 -C 4 -alkyl which is optionally substituted by OH or (C 1 -C 4 )-alkoxy; C 2 -C 6 -alkenyl which is optionally substituted by (C 1 -C 4 )-alkoxy; or OH(C 1 -C 4 )-alkylaryl; or aryl which is optionally substituted by identical or different radicals from the group consisting of halogen, (C 1 -C 4 )-alkoxy, hydroxyl or (C 1 -C 4 )-alkyl,  
 R 8a  is hydrogen or C 1 -C 4 -alkyl,  
 n is an integer from 0 to 7, and  
 n′ is an integer from 0 to 3;  
 
 or f) is  
                     
 where:  
 X′ is an oxygen, sulfur or nitrogen atom or an —NR 2b -group, where  
 R 2b  is a hydrogen atom, a straight-chain or branched alkyl group having from 1 to 15 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having in each case from 3 to 10 carbon atoms, where the double bond or triple bond cannot connect directly to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl group having from 2 to 6 carbon atoms which is substituted, from the 1 position to the nitrogen atom of the —NR 2b  group onwards, by an R 3b O, (R 3b ) 2 N—, R 4b CO—NR 3b —, alkylsulfonyl-NR 3b —, arylsulfonyl-NR 3b —, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R 5b  group, or an alkyl group having from 1 to 6 carbon atoms which is substituted by one or two aryl groups, R 6b OCO; (R 3b ) 2 NCO—, R 5b —CO—, R 3b O—CO-alkylene-NR 3 —CO—, (R 3b ) 2 N—CO-alkylene-NR 3b  or R 5b CO-alkylene-NR 3b —CO— group, in which R 3b  and R 5b  are defined as indicated below and R 6b  is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,  
 Y′ is an NO-group, a nitrogen atom or a methine group which is optionally substituted by an alkyl group,  
 Z 1 , Z 2 , Z 3  and Z 4 , which can be identical or different, are methine groups, carbon atoms, imino groups or nitrogen atoms, where at least one of the radicals Z 1  to Z 4  has to contain a carbon atom, and one or two methine groups which are adjacent to a nitrogen atom can in each case be replaced by carbonyl groups,  
 Z 5  and Z 6  are in each case a carbon atom, or else one of the radicals Z 5  or Z is a nitrogen atom and the other of the radicals Z 5  or Z 6  is a carbon atom,  
 R 3b  is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,  
 R 4b  is a hydrogen atom, an alkyl or alkoxy group having in each case from 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6 carbon atoms in the alkyl moiety, and  
 R 5b  is an azetidino, pyrrolidino, hexamethylenimino or heptamethylenimino group or a piperidino group in which the methylene group in the 4 position can be replaced by an oxygen atom, by a sulfenyl, sulfinyl or sulfonyl group, or by an imino group which is substituted by an R 3 , R 4 CO—, alkylsulfonyl or arylsulfonyl group, where R 3  and R 4  are defined as mentioned above;  
 F is a direct linkage, (C 1 -C 6 ), alkanediyl, —O—, O—NR 2 —, —NR 2 —CO—, —NR 2 —C(O)—NR 2 —, —OC(O)—, —C(O)O—, —CO—, —S(O) 2 —, —S(O) 2 —NR 2 —, —NR 2 —S(O) 2 —, —CR 2 ═CR 3 —, —C≡C— which can in each case be substituted, once or twice, by (C 1 -C 6 )-alkyl;  
 G is  
                     
 R 2  and R 3  are, independently of each other, H, (C 1 -C 6 )-alkyl which is optionally substituted, once or more than once, by fluorine, (C 5 -C 6 )Cycloalkyl, (C 5 -C 6 )-cycloalkyl-(C 1 -C 4 )-alkyl, (C 5 -C 10 )-aryl, (C 5 -C 10 )-aryl-(C 1 -C 4 )-alkyl, R 8 OC(O)R 9 , R 8 R 8 NC(O)R 9  or R 8 C(O)R 9 ;  
 R 4 , R 5 , R 6  and R 7  are, independently of each other, H, fluorine, OH, (C 1 -C 6 )-alkyl, (C 5 -C 14 )-cycloalkyl, (C 5 -C 14 )-cycloalkyl-(C 1 -C 6 )-alkyl, or R 8 OR 9 , R 8 CO 2 R 9 , R 8 OC(O)R 9 , R 8 —(C 5 -C 10 )-aryl-R 9 , R 8 NHR 9 , R 8 R 8 NR 9 , R 8 NHC(O)OR 9 , R 8 S(O) n NHR 9 , R 8 OC(O)NHR 9 , R 8 C(O)NHR 9 , R 8 C(O)R 9 , R 8 NHC(O)NHR 9 , R 8 NHS(O) n NHR 9 , R 8 NHC(O)R 9  or R 8 NHS(O) n R 9 , where at least one radical from the group R 4 , R 5 , R 8  and R 7  is a lipophilic radical;  
 R 8  is H, (C 1 -C 6 )-alkyl, (C 5 -C 14 )-cycloalkyl, (C 5 -C 14 )-cycloalkyl-(C 1 -C 4 )-alkyl, (C 5 -C 10 )-aryl or (C 5 -C 10 )-aryl-(C 1 -C 4 )-alkyl, where the alkyl radicals can be substituted by from 1 to 6 fluorine atoms;  
 R 9  is a direct linkage or (C 1 -C 6 )-alkanediyl;  
 R 10  is C(O)R 11 ;  
 R 11  is OH, (C 1 -C 6 )-alkoxy, (C 5 -C 10 )-aryl-(C 1 -C 6 )-alkoxy, (C 5 -C 10 )-aryloxy, (C 1 -C 6 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, (C 5 -C 10 )-aryl-(C 1 -C 4 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, NH 2  or mono- or di(C 1 -C 6 )-alkyl)-amino;  
 R 12  is H, (C 1 -C 6 )-alkyl which is optionally substituted, once or more than once, by fluorine, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-cycloalkyl-(C 1 -C 4 )-alkyl, (C 5 -C 10 )-aryl, (C 5 -C 10 )-aryl-(C 1 -C 4 )-alkyl, H 2 N, R 8 OR 9 , R 8 OC(O)R 9 , R 8 -(C 5 -C 10 )-aryl-R 9 , R 8 R 8 NR 9 , R 8 NHC(O)R 9 , R 8 C(O)NHR 9 , H 2 N—C(═NH)—, H 2 N—C(═NH)—NH— or ═O; 
 where two adjacent substituents R 12  can together also be —OCH 2 O— or —OCH 2 CH 2 O—;  
 
 Y is NR 2 , O or S;  
 n is 1 or 2; and  
 p and q are, independently of each other, 0 or 1;  
 in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.  
 
     
     
         4 . A compound of the formula I as claimed in one or more of  claims 1  to  3 , in which: 
 A is one of the radicals  
                     
 B is a direct linkage, (C 1 -C 4 )-alkanediyl, phenylene, pyridindiyl, thiophenediyl, furandiyl, cyclohexylene, cyclopentylene, —C═C— or CR 2 ═CR 3 — which can in each case be substituted, once or twice, by (C 1 -C 4 )-alkyl;  
 D is a direct linkage, (C 1 -C 4 )-alkanediyl or phenylene, —O, —NR 2 —, —NR 2 —C(O)—, —C(O)—NR 2 , —NR 2 —S(O) 2 , —NR 2 —C(O)—NR 2 — or —CR 2 ═CR 3 — which can in each case be substituted, once or twice, by (C 1 -C 4 )-alkyl, with it not being possible for D to be —C(O)—NR 2 — when B is a direct linkage;  
 E a) is  
                     
  where R 1a , R 20a , R 21a , R 22a  and R 22b  are in this case:  
 R 1a  is, independently of each other, from one to three groups from the series consisting of hydrogen and halogen (fluorine, chlorine, bromine or iodine);  
 R 20a  is hydrogen;  
 R 21a  and R 22a  are, independently of each other, 
 1. hydrogen,  
 2. (C 1 -C 6 )-alkyl,  
 3. (C 6 -C 12 )-aryl,  
 4. (C 6 -C 12 )-cycloalkyl,  
 5. (C 1 -C 6 )-alkyl-(C 6 -C 12 )-aryl,  
 6. (C 1 -C 6 )-alkyl-(C 6 -C 12 )-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide, (C 1 -C 6 )-alkyl, (C 6 -C 12 )-aryl, benzyl or (C 6 -C 12 )-cycloalkyl;  
 
 R 22b  is 1 hydrogen, 
 2. (C 1 -C 12 )-alkyl,  
 3. (C 6 -C 14 )-aryl,  
 4. (C 3 -C 14 )-cycloalkyl,  
 5. (C 1 -C 12 )-alkyl-(C 6 -C 14 )-aryl,  
 6. (C 1 -C 12 )-alkyl-(C 3 -C 14 )cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of 
 halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C 1 -C 6 -alkyl; C 6 -C 14 -aryl; benzyl; C 3 -C 14 -cycloalkyl; COR 24a  or CONR 25 R 26 ; where  
 R 24a  is a radical from the group consisting of C 1 -C 8 -alkoxy; C 3 -C 12 -alkenoxy; C 6 -C 12 -aryloxy; di-C 1 -C 8 -alkylamino-C 1 -C 8 -alkoxy; acylamino-C 1 -C 8 -alkoxy; acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy; pivaloylethoxy; or C 6 -C 12 -aryl-C 1 -C 8 -alkoxy, where the aryl group can be optionally substituted by from one to three radicals selected from the group consisting of nitro, halogen, C 1 -C 4 -alkoxy, amino, hydroxyl, hydroxy-C 2 -C 8 -alkoxy and dihydroxy-C 3 -C 8 -alkoxy;  
 R 25  and R 26  are, independently of each other, hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -alkenyl, C 6 -C 14 -aryl or C 1 -C 6 -alkyl-C 6 -C 10 -aryl, or  
 R 25  and R 26  together form-a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;  
 
 7. Q 2 -L 3  where 
 Q 2  is hydrogen or Q 1 ; and  
 L 3  is a chemical bond or L 1 ; 
 Q 1  is an amino, amidino, aminoalkylenimino, iminoalkylenamino or guanidino group, preferably an amidino group;  
 L 1  is C 6 -C 14 -aryl-C 2 -C 4 -alkynylene; C 6 -C 14 -aryl-C 1 -C 3 -alkylene; C 6 -C 14 -aryl-C 1 -C 3 -alkyloxyene or —R 14c —CO—NR 6c R 15c , where  
 R 6c  is hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl or halogen-C 1 -C 4 -alkyl;  
 R 14c  is a chemical bond, C 1 -C 8 -alkylene, C 3 -C 7 -cycloalkylene, C 2 -C 5 -alkenylene, C 3 -C 5 -alkynylene, C 6 -C 10 -arylene, C 1 -C 3 -alkyl-C 6 -C 12 -arylene, C 1 -C 2 -alkyl-C 6 -C 10 -aryl-C 1 -C 2 -alkylene, C 6 -C 10 -aryl-C 1 -C 2 -alkylene or C 6 -C 10 -aryloxy-C 1 -C 2 -alkylene, and  
 R 15c  is a chemical bond, C 1 -C 4 -alkylene, C 2 -C 4 -alkenylene, C 2 -C 4 -alkynylene, C 6 -C 10 -arylene or C 1 -C 3 -alkyl-C 6 -C 12 -arylene;  
 
 
 
 or b) is  
                     
  where R 1b , R 2b , R 25b  and R 26b  are in this case:  
 R 1b  and R 2b  are, independently of each other, from one to three groups from the series consisting of hydrogen and halogen (fluorine, chlorine, bromine or iodine); and  
 R 25b  and R 26b  are, independently of each other, 
 hydrogen, C 1 -C 10 -alkyl, C 3 -C 10 -alkenyl, C 6 -C 14 -aryl or C 1 -C 6 -alkyl-C 6 -C 10 -aryl, or  
 R 25b  and R 26b  together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;  
 
 or c) is  
                     
 or d) is  
                     
 or e) is  
                     
  where Y 3 , V and D a  are defined as described above;  
 or f) is  
                     
 where:  
 X′ is an oxygen, sulfur or nitrogen atom or an —NR 2b -group, where 
 R 2b  is a hydrogen atom, a straight-chain or branched alkyl group having from 1 to 15 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having in each case from 3 to 10 carbon atoms, where the double bond or triple bond cannot connect directly to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl group having from 2 to 6 carbon atoms which is substituted, from the β position to the nitrogen atom of the —NR 2b — group onward, by an R 3b O—, (R 3b ) 2 N—, R 4b CO—NR 3b , alkylsulfonyl-NR 3b , arylsulfonyl-NR 3b , alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R 5b  group, or an alkyl group, having from 1 to 6 carbon atoms which is substituted by one or two aryl groups, R 6b OCO—, (R 3b ) 2 NCO—, R 5b —CO—, R 3b O—CO-alkylene-NR 3b —CO—, (R 3b ) 2 N—CO-alkylene-NR 3b —CO— or R 5b CO-alkylene-NR 3b —CO— group, in which R 3b  and R 5b  are defined as indicated below and R 6b  is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,  
 
 Y′ is an NO-group, a nitrogen atom or a methine group which is optionally substituted by an alkyl group,  
 Z 1 , Z 2 , Z 3  and Z 4 , which can be identical or different, are methine groups, carbon atoms, imino groups or nitrogen atoms, where at least one of the radicals Z 1  to Z 4  has to contain a carbon atom, and one or two methine groups which are adjacent to a nitrogen atom can in each case be replaced by carbonyl groups,  
 Z 5  and Z 6  are in each case a carbon atom, or else one of the radicals Z 5  or Z 6  is a nitrogen atom and the other of the radicals Z 5  or Z 6  is a carbon atom,  
 R 3b  is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,  
 R 4b  is a hydrogen atom, an alkyl or alkoxy group having in each case from 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6 carbon atoms in the alkyl moiety, and  
 R 5b  is an azetidino, pyrrolidino, hexamethylenimino or heptamethylenimino group or a piperidino group in which the methylene group in the 4 position can be replaced by an oxygen atom, by a sulfenyl, sulfinyl or sulfonyl group, or by an imino group which is substituted by an R 3b , R 4b CO—, alkylsulfonyl or arylsulfonyl group, where R 3b  and R 4b  are defined as mentioned above,  
 F is a direct linkage, (C 1 -C 6 )-alkanediyl, —O—, —CO—NR 2 —, —NR 2 —CO—, —NR 2 —C(O)—NR 2 , —S(O) 2 —NR 2 , —NR 2 —S(O) 2 —, —CR 2 ═CR 3 —, or —C≡C— which can in each case be substituted, once or twice, by (C 1 -C 4 )-alkyl;,  
 G is  
                     
 R 2  and R 3  are, independently of each other, H, (C 1 -C 4 )-alkyl, trifluoromethyl, pentafluoroethyl, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkyl-(C 1 -C 4 )-alkyl, phenyl or benzyl;  
 R 4  is (C 10 -C 14 )-cycloalkyl, (C 10 -C 14 )-cycloalkyl-(C 1 -C 4 )-alkyl, or R 16 OR 9 , R 16 NHR 9 , R 16 NHC(O)OR 9 , R 16 S(O) n NHR 9 , R 16 OC(O)NHR 9 , R 16 C(O)NHR 9 , R 16 C(O)R 9 , R 16 NHC(O)R 9  or R 16 NHS(O) n R 9 ;  
 R 5  is H, (C 1 -C 6 )-alkyl, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkyl-(C 1 -C 4 )-alkyl, trifluoromethyl, pentafluoroethyl, phenyl or benzyl;  
 R 8  is H, (C 1 -C 4 )-alkyl, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkyl-(C 1 -C 2 )-alkyl, phenyl, benzyl, trifluoromethyl or pentafluoroethyl;  
 R 9  is a direct linkage or (C 1 -C 4 )-alkanediyl;  
 R 10  is C(O)R 11 ;  
 R 11  is OH, (C 1 -C 6 )-alkoxy, phenoxy, benzyloxy, (C 1 -C 4 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy, NH 2  or mono- or di(C 1 -C 6 )-alkyl)amino;  
 R 12  is H, (C 1 -C 4 )-alkyl, trifluoromethyl, pentafluoroethyl, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkyl-(C 1 -C 2 )-alkyl, (C 5 -C 6 )-aryl, (C 5 -C 6 )-aryl-(C 1 -C 2 )-alkyl, H 2 N, R 8 R 8 NR 9 , R 8 NHC(O)R 9 , H 2 N—C(═NH) or H 2 N—C(═NH)—NH—; where two adjacent substituents R 12  can also be —OCH 2 O— or —OCH 2 CH 2 O—;  
 R 16  is (C 10 -C 14 )-cycloalkyl or (C 10 -C 14 )-cycloalkyl-(C 1 -C 4 )-alkyl which can optionally be substituted, once or twice, by (C 1 -C 4 )-alkyl, trifluoromethyl, phenyl, benzyl, (C 1 -C 4 )-alkoxy, phenoxy, benzyloxy, ═O or mono- or di(C 1 -C 4 )-alkyl)-amino, where the cycloalkyl radicals are preferably 1-adamantyl or 2-adamantyl, which can be substituted as described above;  
 n is 1 or 2; and  
 q is 0 or 1;  
 in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.  
 
     
     
         5 . A compound of the formula I as claimed in one or more of  claims 1  to  4 , in which the distance between R 10  and the first N atom in A is from 12 to 13 covalent bonds along the shortest route between these atoms, in all its stereoisomeric forms and mixtures thereof in all proportions, and its physiologically tolerated salts.  
     
     
         6 . A process for preparing a compound of the formula I as claimed in one or more of  claims 1  to  5 , which comprises linking, by means of fragment condensation, two or more fragments which can be derived retrosynthetically from the formula I.  
     
     
         7 . A compound of the formula I as claimed in one or more of  claims 1  to  5 , and/or its physiologically tolerated salts, for use as a pharmaceutical.  
     
     
         8 . A compound of the formula I as claimed in one or more of  claims 1  to  5 , and/or its physiologically tolerated salts, for use as an inhibitor of bone resorption by osteoclasts, as an inhibitor of tumor growth or tumor metastasis, as an inflammation inhibitor, for the treatment or prophylaxis of cardiovascular diseases, for the treatment or prophylaxis of neuropathies or retinopathies, or as a vitronectin receptor antagonist for the treatment or prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes.  
     
     
         9 . A pharmaceutical preparation, comprising at least one compound of the formula I as claimed in one or more of  claims 1  to  5 , and/or its physiologically tolerated salts, in addition to pharmaceutically unobjectionable carrier and auxiliary substances.