Method of treating contrast-induced nephropathy

Abstract

The present invention provides the use of a neutral endopeptidase inhibitor, in the manufacture of a medicament for the treatment, amelioration and/or prevention of contrast-induced nephropathy. The invention also relates to the use of a compound of Formula I: wherein R 1 , R 2 , R 3 , R 5 , X, A 3 , B 1 , s and n are defined herein, for the treatment, amelioration and/or prevention of contrast-induced nephropathy. The present invention further provides a combination of pharmacologically active agents for use in the treatment, amelioration and/or prevention of contrast-induced nephropathy.

1 . A method of preventing or ameliorating contrast-induced nephropathy in a subject in need thereof, comprising administering to the subject a neutral endopeptidase EC. 3.4. 24.11. inhibitor. 
     
     
         2 . The method of  claim 1  wherein the neutral endopeptidase inhibitor is selected from the group consisting of Candoxatril, Candoxatrilat, Dexecadotril, Ecadotril, Racecadotril, Sampatrilat, Fasidotril, Omapatrilat, Gemopatrilat, Daglutril, SCH-42495, SCH-32615, UK-447841, AVE-0848, PL-37 and (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester. 
     
     
         3 . The method of treating, preventing or ameliorating contrast-induced nephropathy in a subject in need thereof, according the  claim 1 , comprising administering to the subject a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is H, C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, —SH, —S—C 1-7 alkyl or NR b R c ; wherein alkyl is optionally substituted with C 6-10 -aryl, benzyloxy, hydroxy, C 3-7 cycloalkyl or C 1-6  alkoxy; 
         R 2  for each occurrence, is independently C 1-7 alkyl, halo, NO 2 , CN, C 1-7 alkanoylamino, C 3-7 cycloalkyl, hydroxy, C 1-7 alkoxy, haloC 1-7 alkyl, —NR b R c , C 6-10 aryl, heteroaryl or heterocyclyl; 
         R 3  is A 1 -C(O)X 1  or A 2 -R 4 ; 
         R 4  is C 6-10 aryl, C 3-7 cycloalkyl, or a heteroaryl, which can be monocyclic or bicyclic, each of which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC 1-7 alkyl, nitro, —NR b R c , —C(O)C 1-7 alkyl, C(O)—O—C 1-7 alkyl, C 1-7 alkoxy, halo, C 1-7 alkyl, halo-C 1-7 alkyl, C 2-7 alkenyl, C 6-10 aryl, heteroaryl, —NHSO 2 —C 1-7 alkyl, S(O) 2 —C 1-7 alkyl, C(O)—C 1-7 alkyl and benzyl; or R 4  is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC 1-7 alkyl, amino, C(O)—O—C 1-7 alkyl, C 1-7 alkoxy, halo, C 1-7 alkyl, halo-C 1-7 alkyl, C 6-10 aryl, heteroaryl, —NHSO 2 —C 1-7 alkyl and benzyl; 
         R 5  is H, halo, hydroxy, C 1-7 alkoxy, halo, C 1-7 alkyl or halo-C 1-7 alkyl; and 
         X and X 1  are independently OH, —O—C 1-7 alkyl, —NR b R c , —NHS(O) 2 —C 1-7 alkyl, —NHS(O) 2 -benzyl or —O—C 6-10 aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 6-10 aryl, heteroaryl, heterocyclyl, C(O)NH 2 , C(O)NH—C 1-6 alkyl, and C(O)N(C 1-6 alkyl) 2 ; 
         B 1  is —C(O)NR d — or —NR d C(O)—; 
         A 1  is a bond or a linear or branched C 1-7 alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 3-7 cycloalkyl, C 1-7 alkoxy, hydroxy and O-acetate; in which two geminal alkyl can optionally combine to form a C 3-7 cycloalkyl; or 
         A 1  is a linear or branched C 1-7 alkenylene; or 
         A 1  is a linear C 1-4  alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1  is optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-7 alkyl; in which R a  for each occurrence, is independently H, C 1-7 alkyl, —C(O)—O—C 1-7 alkyl or —CH 2 C(O)OH; or 
         A 1  is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halo, —NR b R c , —OCH 2 CO 2 H, and —OCH 2 C(O)NH 2 ; or 
         A 1  is a C 3-7 cycloalkyl or heterocyclyl; 
         A 1  is —C 1-4 alkylene-C 6-10 -aryl-, —C 1-4 alkylene-heteroaryl- or —C 1-4 alkylene-heterocyclyl-, wherein 
         A 1  may be in either direction; and 
         A 2  is a bond or a linear or branched C 1-7  alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-7 alkoxy, hydroxy, O-Acetate and C 3-7 cycloalkyl; 
         A 3  is CH 2 , O, NR e  or is absent; and when A 3  is O or NR e  then B 1  is C(O)NR d ; 
         R b  and R c  for each occurrence are independently H, C 6-10 aryl or C 1-7 alkyl; 
         R d  and R e  are independently H or C 1-7 alkyl; 
         Ring C is a phenyl or a monocyclic heteroaryl; 
         n is 0, 1, 2, 3, 4 or 5; 
         is 0, 1, 2, 3 or 4; and 
         when B 1  is C(O)NR d  and R 3  is A 2 -R 4 , then R d  and A 2 -R 4 , together with the nitrogen to which R d  and A 2 -R 4  are attached, form a 4- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halo, haloC 1-6 alkyl, C 1-6 alkoxy, hydroxy, CO 2 H and CO 2 C 1-6 alkyl;
 wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms unless otherwise specified, and 
 each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S. 
 
       
     
     
         4 . The method of preventing or ameliorating contrast-induced nephropathy in a subject in need thereof, according to  claim 3 , comprising administering to the subject a therapeutically effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1-7 alkyl; 
         for each occurrence, R 2  is independently C 1-7 alkyl, NO 2 , CN, halo, C 3-7 cycloalkyl, hydroxy, C 1-7 alkoxy, halo-C 1-7 alkyl, NR b R c , C 6-10 aryl, heteroaryl or heterocyclyl; wherein R b  and R c  for each occurrence, are independently H or C 1-7 alkyl; 
         R 3  is A 1 C(O)X 1  or A 2 -R 4 ; 
         R 4  is C 6-10 aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from hydroxy, hydroxy-C 1-7 alkyl, NR b R c , nitro, C 1-7 alkoxy, halo, C 1-7 alkyl, halo-C 1-7 alkyl, C 2-7 alkenyl, C 6-10 aryl, heteroaryl, —C(O)C 1-7 alkyl, —NHS(O) 2- C 1-7 alkyl, —SO 2 C 1-7 alkyl and benzyl; 
         R 5  is H, halo, hydroxy, C 1-7 alkoxy, halo, C 1-7 alkyl or halo-C 1-7 alkyl; and 
         X and X 1  are independently OH, —O—C 1-7 alkyl, —NR b R c , —NHS(O) 2 —C 1-7 alkyl, —NHS(O) 2 -benzyl or —O—C 6-10 aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, —C(O)NH 2 , —C(O)NH—C 1-6 alkyl, and —C(O)N(C 1-6 alkyl) 2 ; 
         A 1  is a bond or a linear C 1-4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, C 1-7  alkyl and C 3-7 cycloalkyl; in which two geminal alkyl can optionally combine to form a C 3-7 cycloalkyl; or 
         A 1  is a linear or branched C 2-6 alkenylene; or 
         A 1  is a linear C 1-4  alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1  is optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-7 alkyl; in which R a  for each occurrence, is independently H, C 1-7 alkyl or CH 2 C(O)OH; or 
         A 1  is a C 3-7 cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halo, NR b R c , OCH 2 CO 2 H, and OCH 2 C(O)NH 2 ; or 
         A 1  is —C 1-4 alkylene-C 6-10 -aryl-, —C 1-4 alkylene-heteroaryl- or —C 1-4 alkylene-heterocyclyl-, wherein 
         A 1  may be in either direction; and 
         A 2  is a bond or a linear or branched C 1-7 alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-7 alkoxy, hydroxy, O-Acetate and C 3-7 cycloakyl; 
         n is 0, 1, 2, 3, 4 or 5;
 wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and 
 each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S. 
 
       
     
     
         5 . The method of  claim 4  wherein the compounds has the Formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4; R 2a  is halo; W 1 , W 2 , W 3  and W 4  are independently N or CR f , in which each R f  is independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halo, NR b R c , OCH 2 CO 2 H and OCH 2 C(O)NH 2 ; R b  and R c  for each occurrence, are independently H or C 1-7 alkyl; and Y 1 , Y 2  and Y 3  are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring, and each Y 4  is independently N, S, O or CH. 
       
     
     
         6 . The method of preventing or ameliorating contrast-induced nephropathy in a subject in need thereof, according to  claim 3 , comprising administering to the subject a therapeutically effective amount of a compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is H, C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, —SH, —S—C 1-7 alkyl or NR b R c ; 
         R 2  for each occurrence, is independently C 1-7 alkyl, halo, NO 2 , CN, C 1-7 alkanoylamino, C 3-7 cycloalkyl, hydroxy, C 1-7 alkoxy, —NR b R c , C 6-10 aryl, heteroaryl or heterocyclyl; wherein R b  and R c  for each occurrence are independently H or C 1-7 alkyl; 
         R 3  is A 1 -C(O)X 1  or A 2 -R 4 ; 
         R 4  is C 6-10 aryl or a heteroaryl, which can be monocyclic or bicyclic, and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxyC 1-7 alkyl, nitro, —NR b R c , —C(O)C 1-7 alkyl, C 1-7 alkoxy, halo, C 1-7 alkyl, C 2-7 alkenyl, C 6-10 aryl, heteroaryl, —NHSO 2 —C 1-7 alkyl and benzyl; or R 4  is a heterocyclyl which can be optionally substituted with one or more substituents independently selected from the group consisting of oxo, hydroxy, hydroxyC 1-7 alkyl, amino, C(O)—O—C 1-7 alkyl, C 1-7 alkoxy, halo, C 1-7 alkyl, halo-C 1-7 alkyl, C 6-10 aryl, heteroaryl, —NHSO 2 —C 1-7 alkyl and benzyl; 
         R 5  is H, halo, hydroxy, C 1-7 alkoxy, halo, C 1-7 alkyl or halo-C 1-7 alkyl; and 
         X and X 1  are independently OH, —O—C 1-7 alkyl, —NR b R c , —NHS(O) 2 —C 1-7 alkyl, —NHS(O) 2 -benzyl or —O—C 6-10 aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 6-10 aryl, heteroaryl, heterocyclyl, C(O)NH 2 , C(O)NH—C 1-6 alkyl, and C(O)N(C 1-6 alkyl) 2 ; 
         B 1  is —C(O)NH— or —NHC(O)—; 
         A 1  is a bond or a linear or branched C 1-7 alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 3-7 cycloalkyl, C 1-7 alkoxy, hydroxy and O-acetate; in which two geminal alkyl can optionally combine to form a C 3-7 cycloalkyl; or 
         A 1  is a linear or branched C 1-7 alkenylene; or 
         A 1  is a linear C 1-4  alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1  is optionally substituted with one or more substituents independently selected from the group consisting of halo and C 1-7 alkyl; in which R a  for each occurrence, is independently H, C 1-7 alkyl, —C(O)—O—C 1-7 alkyl or —CH 2 C(O)OH; or 
         A 1  is a phenyl or a heteroaryl; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halo, —NR b R c , —OCH 2 CO 2 H, and —OCH 2 C(O)NH 2 ; or 
         A 1  is a C 3-7 cycloalkyl; 
         A 1  is —C 1-4 alkylene-C 6-10 -aryl-, —C 1-4 alkylene-heteroaryl- or —C 1-4 alkylene-heterocyclyl-, wherein 
         A 1  may be in either direction; and 
         A 2  is a bond or a linear or branched C 1-7  alkylene; which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-7 alkoxy, hydroxy, O-Acetate and C 3-7 cycloalkyl; 
         n is 0, 1, 2, 3, 4 or 5;
 wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and 
 each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S. 
 
       
     
     
         7 . The method of  claim 6  wherein the compound of the following Formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4; R 2a  is halo; W 1 , W 2 , W 3  and W 4  are independently N or CR f , in which each R f  is independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, halo-C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halo, NR b R c , OCH 2 CO 2 H and OCH 2 C(O)NH 2 ; R b  and R c  for each occurrence are independently H or C 1-7 alkyl; and Y 1 , Y 2  and Y 3  are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring, and each Y 4  is independently N, S, O or CH. 
       
     
     
         8 . The method of  claim 7  wherein the compound is of Formula III-F or III-G, wherein A 1  is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 8 , wherein R 1  is H, p is 0; X and X 1  are independently OH or —O—C 1-7 alkyl, R 2a  is chloro; or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of preventing or ameliorating contrast-induced nephropathy in a subject in need thereof, according to  claim 3 , comprising administering to the subject a therapeutically effective amount of a compound of Formula IV: 
       
         
           
           
               
               
           
         
         wherein: 
         X is OH, —O—C 1-7 alkyl, —NR b R c , —NHS(O) 2 —C 1-7 alkyl or —NHS(O) 2 -benzyl; wherein R b  and R c  for each occurrence are independently H or C 1-7 alkyl; 
         R 1  is H, C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, —SH, —S—C 1-7 alkyl or NR b R c ; wherein alkyl is optionally substituted with C 6-10 -aryl, benzyloxy, hydroxy or C 1-6  alkoxy; 
         for each occurrence, R 2  is independently C 1-5 -alkoxy, hydroxy, halo, C 1-6 -alkyl, cyano or trifluoromethyl; 
         A 3  is O or NR e ; 
         R d  and R e  are independently H or C 1-6  alkyl; 
         A 2  is a bond or C 1-3 alkylene chain; 
         R 4  is a 5- or 6-membered heteroaryl, C 6-10 -aryl or C 3-7 -cycloalkyl, wherein each heteroaryl, aryl or cycloalkyl are optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halo, haloC 1-6 alkyl, C 1-6 alkoxy, hydroxy, CO 2 H and CO 2 C 1-6 alkyl; 
         R 5  for each occurrence is independently halo, hydroxy, C 1-7 alkoxy, halo, C 1-7 alkyl or halo-C 1-7 alkyl; or 
         R d , A 2 -R 4 , together with the nitrogen to which R d  and A 2 -R 4  are attached, form a 4- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halo, haloC 1-6 alkyl, C 1-6 alkoxy, hydroxy, CO 2 H and CO 2 C 1-6 alkyl; and 
         n is 0 or an integer from 1 to 5; 
         s is 0 or an integer from 1 to 4; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 10  wherein the compound is of Formula IV-A: 
       
         
           
           
               
               
           
         
         Wherein: 
         X represent OH or O—C 1-6 -alkyl; 
         R 1  is H, C 1-6  alkyl or C 6-10 -aryl-C 1-6  alkyl; 
         for each occurrence, R 2  is independently C 1-6 -alkoxy, hydroxy, halo, C 1-6 -alkyl, cyano or trifluoromethyl; 
         R d  and R e  are independently H or C 1-6  alkyl; 
         A 2  is a bond or C 1-3 alkylene chain; 
         R 4  is a 5- or 6-membered heteroaryl, C 6-10 -aryl or C 3-7 -cycloalkyl, wherein each heteroaryl, aryl or cycloalkyl are optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halo, halo-C 1-6 alkyl, C 1-6 alkoxy, hydroxy, CO 2 H and CO 2 C 1-6 alkyl; 
         R 5  for each occurrence is independently halo, hydroxy, C 1-7 alkoxy, halo, C 1-7 alkyl or halo-C 1-7 alkyl; or 
         R d , A 2 -R 4 , together with the nitrogen to which R d  and A 2 -R 4  are attached, form a 4- to 7-membered heterocyclyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halo, haloC 1-6 alkyl, C 1-6 alkoxy, hydroxy, CO 2 H and CO 2 C 1-6 alkyl; and 
         n is 0 or an integer from 1 to 5; 
         s is 0 or an integer from 1 to 4; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of  claim 10  wherein the compound is of Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4 and R 2a  is halo. 
       
     
     
         13 - 24 . (canceled) 
     
     
         25 . The method of ameliorating or preventing contrast-induced nephropathy in a subject, according to  claim 1 , further comprising at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. 
     
     
         26 . The method of  claim 25  wherein the other therapeutic agent is selected from adenosine-receptor antagonist, a calcium channel blocker, an anti-apoptotic agent, an antioxidant, a MAP kinase inhibitor, a prostacyclin or prostacyclin analogue, endothelin antagonist, an ion chelator and a dopamine receptor agonist, or a pharmaceutically acceptable salt thereof. 
     
     
         27 - 28 . (canceled)