Naphthyridine derivatives, processes for their preparation, their use and pharmaceutical compositions comprising them

Abstract

Naphthyridine compounds of the formula wherein the substituents are defined as in the specification which are vitronectin receptor antagonists and inhibitors of cell adhesion useful for treatment of illnesses based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-materix interaction processes. The compounds are particularly useful for inhibiting bone resorption by osteoclasts and are useful for treating osteoporosis.

1 . A compound selected from the group consisting of a compound of the formula  
       
         
           
           
               
               
           
         
       
       in which G  
       —(CR 1 R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 R 3 ) i —(CR 1 R 2 ) q —R 4    A is selected from the group consisting of a direct bond,    —C(O)NR 5 —, —NR 5 C(O)—, —C(O)—, —NR 5 —, —O—, —S—, —S(O)—,    —S(O) 2 —, (C 2 -C 4 )-alkynediyl, (C 2 -C 4 )-alkenediyl, and (C 5 -C 14 )-arylene where in the arylene residue one, two, three, four or five ring carbon atoms can be replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, or a divalent residue of a 3-membered to 7-membered saturated or unsaturated ring which can contain one or two ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen and which can be monosubstituted or disubstituted by a member selected from the group consisting of ═O, ═S and R 3 ;    B are individually selected from the group consisting of (C 1 -C 18 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl-, fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, nitro, hydroxycarbonyl-, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkoxycarbonyl-, (C 1 -C 6 )-alkylcarbonyl-, (C 5 -C 14 )-arylcarbonyl-, (C 1 -C 6 )-alkylamino-carbonyl-, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkoxy-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylcarbonyl-, (C 1 -C 6 )-alkanoylamino-, (C 1 -C 6 )-alkylsulfonylamino-, (C 5 -C 14 )-arylsulfonylamino-, (C 1 -C 6 )-alkylamino-, di-((C 1 -C 6 )-alkyl)amino-, (C 1 -C 6 )-alkylsulfonyl-, aminosulfonyl-, (C 5 -C 14 )-arylsulfonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylsulfonyl-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl;    X is selected from the group consisting of hydrogen, NR 6 R 6′ , fluorine, chlorine, bromine, —OR 6 , —SR 6 , hydroxy-(C 1 -C 6 )-alkyl-NH—, (hydroxy-(C 1 -C 6 )-alkyl) 2 N—, amino-(C 1 -C 6 )-alkyl-NH—, (amino-(C 1 -C 6 )-alkyl) 2 N—, hydroxy-(C 1 -C 6 )-alkyl-O—, hydroxy-(C 1 -C 6 )-alkyl-S— and —NH—C(O)—R 6 );    Y is selected from the group consisting of R 6 , fluorine, chlorine, bromine, cyano, —NR 6 R 6′ -, —OR 6 , —SR 6  and hydroxy-(C 1 -C 6 )-alkyl-NH—;    Z is N or                          R 1  and R 2  are individually selected from the group consisting of hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 10 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl-, R 6 —O—R 7 , R 6 —S(O) p —R 7 , R 6 S(O) 2 NHR 7 , R 6 OC(O)NHR 7  and R 6 R 6 N—R 7 ;    R 3  is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 18 )-alkyl, (C 2 ) to C 18 )-alkenyl, (C 2 ) to C 18 )alkenyl (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl-, R 6 -O—R 7 , R 6 R 6 N—R 7 , R 6 C(O)—O—R 7 , R 6 C(O)R 7 , R 6 OC(O)R 7 ), (R 6 N(R 6′ )C(O)OR 7 , R 6 S(O) p N(O)R 7 , R 6 OC(O)N(R 5 )R 7 , R 6 C(O)N(R 5 )R 7 , R 6 N(R 6′ )C(O)N(R)R 7  R 6 N(R 6′ )S(O) p N(R 5 )R 7 , R 6 S(O) p R 7 , R 6 SC(O)N(R 5 )R 7 , R 6 N(R 6′ )C(O)R 7  and R 6 N(R 6′ )S(O) p R 7 , where alkyl, cycloalkyl, aryl, and heteroaryl can be monosubstituted or polysubstituted by a member selected from the group consisting of R 6 , fluorine, chlorine, bromine, cyano, trifluoromethyl, R 6 R 6′ NR 7 , nitro, R 6 OC(O)R 7 , R 6 C(O)R 7 , R 6 N(R 6′ )C(O)R 7 , R 6 N(R 6′ )S(O) p R 7  and R 6 —O—R 7 , and where all R 3 s are independent of one another and can be identical or different;    R 4  is selected from the group consisting of —C(O)R 8 , —C(S)R 8 , —S(O) p R 8 , S(O) p R 8 , —P(O)R 8 R 8′  of and a 4-membered to 8-membered saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;    R 5  is selected from the group consisting of hydrogen, (C 1 -C 10 )-alkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 ) aryl and (C 5 -C 1-4 )aryl-(C 1 -C 8 )-alkyl;    R 6  and R 6′  are individually selected from the group consisting of hydrogen, (C 1 -C 18 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl and (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by individual substituents selected from the group group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, hydroxycarbonyl-, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkoxycarbonyl-, (C 1 -C 6 )-alkylcarbonyl-, (C 1 -C 6 )-alkylaminocarbonyl-, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkoxy-, (C 5 -C 14 )-arylcarbonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylcarbonyl-, (C 1 -C 6 )-alkanoylamino-, (C 5 -C 14 )-arylsulfonylamino-, (C 1 -C 6 )-alkylsulfonylamino-, (C 1 -C 6 )-alkylamino-, di-((C 1 -C 6 )-alkyl)amino-, (C 1 -C 6 )-alkylsulfonyl-, (C 1 -C 6 )-alkylaminosulfonyl-, (C 5 -C 14 )-arylaminosulfonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylaminosulfonyl, (C 5 -C 14 )-arylsulfonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylsulfonyl, (C 5 -C 14 )-aryl and (C 5 -C 14 -heteroaryl;    R 7  is (C 1 -C 4 )-alkanediyl or a direct bond, where all R 7  are independent of one another and can be identical or different;    R 8  and R 8′  are individually selected from the group consisting of hydroxy, (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 8 )-alkoxy-, NR 6 R 6′ , (di-((C 1 -C 8 )-alkyl)amino)carbonylmethyloxy-, (di-((C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl)amino)carbonylmethyloxy-, (C 5 -C 14 )-arylamino-, an amino acid, N-((C 1 -C 4 )-alkyl)piperidin-4-yloxy-, 2-methylsulfonylethoxy-, 1,3-thiazol-2-ylmethyloxy-, 3-pyridylmethyloxy-, 2-(di-((C 1 -C 4 )-alkyl)amino)-ethoxy and Q −  (CH 3 ) 3 N + —CH 2 —CH 2 —O— in which Q −  is a physiologically tolerable anion;    n is zero, one, two, three, four or five;    m is zero, one, two, three, four or five;    i is zero or one;    q is zero, one or two;    r is zero, one or two;    s is zero, one, two or three;    t is zero, one, two, three, four, five, six, seven or eight;    p is zero, one or two, where all numbers p are independent of one another and can be identical or different;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic physiologically tolerable salts;    where, instead of the purine structure shown in formula I, also a 3-deazapurine structure, a 7-deazapurine structure or a 7-deaza-8-azapurine structure can be present.    
     
     
         2 . A compound of  claim 1 , wherein G is  
       —(CR 1 R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 —R 3 ) i —(CR 1 R 3 ) i —(CR 1 R 2 ) q —R 4    A is selected from the group consisting of a direct bond,    —C(O)NR 5 —, —NR 5 C(O)—, —C(O)—, —NR 5 —, —O—, —S—, —S(O)—, —S(O) 2 —, (C 2 -C 4 )-alkynediyl, (C 2 -C 4 )— alkenediyl, (C 5 -C 14 )-arylene where in the arylene residue one, two, three, four or five ring carbon atoms can be replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and a divalent residue of a 3-membered to 7-membered saturated or unsaturated ring which can contain one or two ring heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen and which can be monosubstituted or disubstituted by a member selected from the group consisting of ═O, ═S and R 3 ;    B is selected from the group consisting of (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )heteroaryl-(C 1 -C 8 )-alkyl-, fluorine, chlorine, bromine, hydroxy, cyano, trifluoro-methyl, nitro, hydroxycarbonyl-, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkylcarbonyl-, (C 5 -C 14 )-arylcarbonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylcarbonyl-(C 1 -C 6 )-alkylaminocarbonyl-, (C 1 -C 6 )-alkanoylamino-, (C 1 -C 6 )-alkylsulfonylamino-, (C 5 -C 14 )-aryl-sulfonylamino-, (C 5 -C 14 )-alkylamino-, di-((C 1 -C 6 )-alkyl)amino-, (C 1 -C 6 )-alkylsulfonyl-, (C 5 -C 14 )-arylsulfonyl-, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkylsulfonyl-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl, where all Bs are independent of one another and can be identical or different;    X is selected from the group consisting of hydrogen, NH 2 , —NH—C(O)—R 6  and OH;    Y is hydrogen;    Z is N;    R 1  and R 2  are independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 10 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl-, R 6 —O—R 7 , R 6 S(O) 2 NHR 7 , R 6 OC(O)NHR 7  and R 6 R 6′ N—R 7 ;    R 3  is selected from the group consisting of hydrogen, fluorine, chlorine, cyano, nitro, (C 1 -C 18 )-alkyl, (C 2 -C 18 )-alkenyl, (C 2 -C 18 )-alkynyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl-, R 6 —O—R 7 , R 6 R 6′ N—R 7 , R 6 C(O)—O—R 7 , R 6 C(O)R 7 , R 6 ,N(R 6′ )C(O)OR 7 , R 6 ,S(O) p N(R 5 )R 7 , R 6 OC(O)N(R 5 )R 7 , R 6 C(O)N(R 5 )R 7 , R 6 N(R 6′ )C(O)N(R 5 )R 7 , R 6 N(R 6′ )S(O) p N(R 5 )R 7 , R 6 S(O)R 7 , R 6 SC(O)N(R 5 )R 7 , R 6 N(R 6 )C(O)R 7  R 6 N(R 6 )S(O) p R 7 , where alkyl, cycloalkyl, aryl and heteroaryl can be monosubstituted or polysubstituted by a member selected from the group consisting of R 6 , fluorine, chlorine, bromine, cyano, trifluoromethyl, R 6 R 6 NR 7 , nitro, R 6 OC(O)R 7 , R 6 C(O)R 7 , R 6 N(R 6′ )C(O)R 1 R 6 N(R 6′ )S(O) p R 7  and R 6 —O—R 7 , and where all R 3  are independent of one another and can be identical or different;    R 4  is —C(O)R 8  or —P(O)R 8 R 8′ ;    R 5  is selected from the group consisting of hydrogen, (C 1 -C 10 )-alkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl- of and (C 5 -C 14 -aryl-(C 1 -C 8 )-alkyl-, where all R 5  are independent of one another and can be identical or different;    R 6  and R 6′  are individually selected from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 -aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl and (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by individual substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, hydroxycarbonyl-, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy-, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 5 -C 14 )-arylcarbonyl-, (C 5 -C 14 )-aryl-(C 1 -C 6 )-alkylcarbonyl-, (C 1 -C 6 )-alkanoylamino-, (C 5 -C 14 )-arylsulfonylamino-, (C 1 -C 6 )-alkylsulfonylamino-, (C 1 -C 6 )-alkylamino-, di((C 1 -C 6 )-alkyl)amino-, (C 1 -C 6 )-alkylsulfonyl-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl, and where all R 6  and R 6′  are independent of one another and can be identical or different;    R 7  is (C 1 -C 4 )-alkanediyl or a direct bond, where all R 7  are independent of one another and can be identical or different;    R 8  and R 8′  are individually selected from the group consisting of (C 1 -C 8 )-alkoxy, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkoxy-, (C 1 -C 8 )-alkylcarbonyloxy-(C 1 -C 4 )-alkoxy- and NR 6 R 6′  where all R 8  and R 8′  are independent of one another and can be identical or different;    n is zero, one, two, three, four or five;    m is zero, one, two, three, four or five;    i is zero or one;    q is zero, one or two;    r is zero, one or two;    s is zero, one, two or three;    t is zero, one, two, three, four, five, six, seven or eight;    p is zero, one or two, where all numbers p are independent of one another and can be identical or different;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic, physiologically tolerable salts.    
     
     
         3 . A compound of  claim 1  wherein  
       —(CR 1 R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 —R 3 ) i —(CR 1 R 2 ) q R 4    A is selected from the group consisting of a direct bond, —C(O)NR 5 —, —NR 5 C(O)—, —C(O)—, —NR 5 — and (C 5 -C 14 )-arylene where in the arylene, one or two ring carbon atoms can be replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur;    B is selected from the group consisting of (C 1 -C 6 )-alkyl, chlorine, hydroxy, cyano, trifluoromethyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylcarbonyl-, (C 1 -C 6 )-alkanoylamino-, (C 1 -C 6 )-alkylamino of and di((C 1 -C 6 )-alkyl)amino-, where all Bs are independent of one another and can be identical or different;    X is hydrogen;    Y is hydrogen;    Z is N;    R 1  and R 2  are individually selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl, R 6 S(O) 2 NHR 7  and R 6 OC(O)NHR 7 ;    R 3  is selected from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 2  to C 18 )-alkenyl (C 2 -C 18 )-alkynyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 6 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 6 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-(C 1 -C 6 )-alkyl-, R 6 R 6′ N—R 7 , R 6 S(O) 2 N(R 5 )R 7 , R 6 OC(O)N(R 5 )R 7  and R 6 C(O)N(R 5 )R 7 , where alkyl, cycloalkyl, aryl, and heteroaryl can be monosubstituted or polysubstituted by a member selected from the group consisting of R 6 , fluorine, chlorine, trifluoromethyl, R 6 C(O)R 7  and R 6 —O—R 7 ;    R 4  is —C(O)R 8 ;    R 5  is hydrogen or (C 1 -C 4 )-alkyl, where all R 5 s are independent of one another and can be identical or different;    R 6  and R 6′  are individually selected from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl and (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by members selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy-, (C 1 -C 6 )-alkylamino-, di-((C 1 -C 6 )-alkyl)amino-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl, and where all R 6 s and R 6′ s are independent of one another and can be identical or different;    R 7  is (C 1 -C 2 )-alkanediyl or a direct bond, where all R 7 s are independent of one another and can be identical or different;    R 8  is hydroxy or (C 1 -C 6 )-alkoxy;    n is zero, one, two, three, four or five;    m is zero or one;    i is zero or one;    q is zero or one;    r is zero or one;    s is zero, one or two;    t is zero, one, two, three or four;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic physiologically tolerable salts.    
     
     
         4 . A compound of  claim 1  wherein G  
       —(CR 1 R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 R 3 ) i —(CR 1 R 2 ) q —R 4    A is a direct bond;    B is (C 1 -C 6 )-alkyl or hydroxy, where all Bs are independent of one another and can be identical or different;    X is hydrogen;    Y is hydrogen;    Z is N;    R 1  and R 2  are individually selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl, R 6 S(O) 2 NHR 7  and R 6 OC(O)NHR 7 ;    R 3  is selected from the group from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 2 -C 12 )-alkenyl, (C 5 -C 14 )-alkynyl (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 6 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 6 )-alkyl-, (C 5 -C 14 )-heteroaryl, (C 5 -C 14 )-heteroaryl-C 1 -C 6 )-alkyl-, R 6 R 6′ N—R 7 , R 6 S(O) 2 N(R 5 )R 7 , R 6 OC(O)N(R 5 )R 7  and R 6 C(O)N(R 5 )R 7 , where alkyl, cycloalkyl, aryl and heteroaryl can be monosubstituted or polysubstituted by at least one member selected from the group consisting of R 6 , fluorine, chlorine, trifluoromethyl, R 6 C(O)R 7  and R 6 —O—R 7 ;    R 4  is —C(O)R 8 ;    R 5  is hydrogen or (C 1 -C 4 )-alkyl;    R 6  and R 6′  are individually selected from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl or (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by at least one substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino, di((C 1 -C 6 )-alkyl)amino-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl, and where all R 6 s and R 6′ s are independent of one another and can be identical or different;    R 7  is a direct bond;    R 8  is hydroxy or (C 1 -C 4 )-alkoxy;    n is zero, one or two;    m is zero or one;    i is zero or one;    q is zero or one;    r is zero or one;    s is zero, one or two;    t is zero;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic, physiologically tolerable salts.    
     
     
         5 . A compound of  claim 1  wherein G  
       —(CR 1 R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 R 3 ) i —(CR 1 R 2 ) q —R 4    A is a direct bond;    X is hydrogen;    Y is hydrogen;    Z is N;    R 1  and R 2  are hydrogen or (C 1 -C 2 )-alkyl, where all R 1 s and R 2 s are independent of one another and can be identical or different;    R 3  is selected from the group consisting of R 6 R 6′ N—R 7 , R 6 S(O) 2 N(R 5 )R 7  and R 6 C(O)N(R 5 )R 7 ;    R 4  is —C(O)R 8 ;    R 5  is hydrogen or (C 1 -C 2 )-alkyl;    R 6  and R 6′  are individually selected from the group consisting of hydrogen, (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl and (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by at least one substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino-, di-((C 1 -C 6 )-alkyl)amino-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl, and where the R 6 s and R 6′ s are independent of one another and can be identical or different;    R 7  is a direct bond;    R 8  is hydroxy or (C 1 -C 4 )-alkoxy;    n is zero, one or two;    m is zero or one;    i is zero or one;    q is zero or one;    r is zero;    s is zero;    t is zero;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic, physiologically tolerable salts.    
     
     
         6 . A compound of  claim 1  wherein G is  
       —(CR 1 —R 2 ) n -A-(CR 1 R 2 ) m —(CR 1 —R 3 ) i —(CR 1 R 2 ) q —R 4    A is a direct bond;    X is hydrogen;    Y is hydrogen;    Z is N;    R 1  and R 2  are hydrogen;    R 3  is R 6 S(O) 2 N(R 5 )R 7  or R 6 OC(O)N(R 5 )R 7 ;    R 4  is —C(O)R 8 ;    R 5  is hydrogen;    R 6  is selected from the group consisting of (C 1 -C 12 )-alkyl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-aryl, (C 5 -C 14 )-aryl-(C 1 -C 8 )-alkyl-, (C 5 -C 14 )-heteroaryl and (C 5 -C 14 )-heteroaryl-(C 1 -C 8 )-alkyl- where aryl, heteroaryl, cycloalkyl and alkyl can be substituted one, two or three times by at least one substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylamino, di-((C 1 -C 6 )-alkyl)amino-, (C 5 -C 14 )-aryl and (C 5 -C 14 )-heteroaryl;    R 7  is a direct bond;    R 8  is hydroxy or (C 1 -C 4 )-alkoxy;    n is one;    m is zero;    i is one;    q is zero;    r is zero;    s is zero;    t is zero;    in all their stereoisomeric forms and mixtures thereof in all ratios, and their non-toxic, physiologically tolerable salts.    
     
     
         7 . A process for the preparation of a compound of  claim 1  comprising reacting a compound of the formula VI  
       
         
           
           
               
               
           
         
       
       with a compound of the of formula VIIa or of formula VIIb  
       
         
           
           
               
               
           
         
       
       wherein L 1  is a leaving group and B, G, X, Y, r, s and t are defined as in  claim 1  but wherein functional groups can also be present in the form of precursor groups or in protected form.  
     
     
         8 . A pharmaceutical composition, comprising an amount of a compound of  claim 1  sufficient to act as a vitronectin receptor antagonist and a pharmaceutically acceptable carrier.  
     
     
         9 - 10 . (cancelled)