Compounds for treatment of lipoprotein metabolism disorders

Abstract

The present disclosure relates to use of heparin analogues as inhibitors of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) for the treatment of lipoprotein metabolism disorders.

1 - 109 . (canceled) 
     
     
         110 . A method for treating a disorder of lipoprotein metabolism in a subject, said method comprising obtaining a level of low-density lipoprotein-C (LDL-C) in a subject and wherein, if the level of LDL-C is above 3.3 mmol/L or above 2.6 mmol/L if the subject is at risk of heart disease, then administering to the subject a composition comprising a compound having the structure of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, 
         wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkylsulfonyl, substituted alkylsulfonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, ester, amide, acyl, substituted acyl, amino, substituted amino, thioalkyl, substituted thioalkyl, aryl, heteroaryl, substituted aryl, hydrogen, and halogen; 
 each R 2  is independently selected from the group consisting of —OSO 3   − , —OH, —NH 2 , —NHSO 3   − , —NHOCH 3  and —OPO 3   2− ; 
 each R 3  is independently selected from the group consisting of —OSO 3   − , —OH and —OPO 3   2− ; 
 each R 4  is independently selected from the group consisting of —OSO 3   − , —OH, —OPO 3   2−  and —H; 
 each R 5  is independently selected from the group consisting of —CH 2 OSO 3   − , —CH 2 OH, —COO −  and —CH 2 OPO 3   2− ; 
 n is an integer equal to, or greater than 1. 
 
       
     
     
         111 . The method according to  claim 110 , wherein the compound of formula (I) is selected from the group consisting of:
 A) a compound of formula (XII):   
       
         
           
           
               
               
           
         
         
           wherein R 10  is —O—R 1 ; 
         
         B) a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 6  is selected from the group consisting of —OSO 3   − , —OH, —NH 2 , —NHSO 3   − , —NHOCH 3  and —OPO 3   2− ; 
 R 7  is selected from the group consisting of —OSO 3   − , —OH and —OPO 3   2− ; and 
 R 8  is selected from the group consisting of —CH 2 OSO 3   − , —CH 2 OH, —COO −  and —CH 2 OPO 3   2− ; 
 
         
         C) a compound of formula (XXIII): 
       
       
         
           
           
               
               
           
         
         
           wherein R 8  is —PO 3   2− , and R 9  is individually —SO 3   −  or —H; 
         
         D) a compound of formula (XXIV): 
       
       
         
           
           
               
               
           
         
         
           wherein p is an is an integer, equal to or greater than 1, and R 9  is individually —SO 3   −  or —H; 
         
         E) a compound of formula (XXV): 
       
       
         
           
           
               
               
           
         
         
           wherein R 9  is individually —SO 3   −  or —H; 
         
         F) a compound of formula (XXVI): 
       
       
         
           
           
               
               
           
         
         
           wherein 
           q is an integer, equal to or greater than 1; 
           R 9  is individually —SO 3   −  or —H; and 
           R 10  is —O—R 1  or comprises or consists of a group of formula (XXI) or formula (XXII): 
         
       
       
         
           
           
               
               
           
         
         G) a compound of formula (XXVII): 
       
       
         
           
           
               
               
           
         
         
           wherein (XXVII) 
           R 9  is individually —SO 3   −  or —H; and 
           R 10  consists of a group of formula (XXI) or formula (XXII): 
         
       
       
         
           
           
               
               
           
         
         H) a compound of formula (XXVIII): 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 9  is individually —SO 3   −  or —H; and 
           R 10  is —O—R 1  or comprises or consists of a group of formula (XXI) or formula (XXII): 
         
       
       
         
           
           
               
               
           
         
         I) a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
       
     
     
         112 . The method according to  claim 110 , wherein R 1  comprises or consists of a group selected from:
 A) A group of formula (XI):   
       
         
           
           
               
               
           
         
         B) A group of formula (II): 
       
       
         
           
           
               
               
           
         
         
           wherein:
 X is CH 2  or SO 2    
 m is an integer independently equal to, or greater than 1; 
 
         
         C) a group of formula (XV): 
       
       
         
           
           
               
               
           
         
         
           wherein s is an integer, equal to or greater than 1; 
         
         D) a group of formula (XVI); 
       
       
         
           
           
               
               
           
         
         E) a group of formula (XVII); 
       
       
         
           
           
               
               
           
         
         F) a group of formula (XVIII); 
       
       
         
           
           
               
               
           
         
         G) a group of formula (XIX); 
       
       
         
           
           
               
               
           
         
         H) a group of formula (XX); 
       
       
         
           
           
               
               
           
         
         I) a group of formula (XXIX); 
       
       
         
           
           
               
               
           
         
         J) a group of formula (XXX); 
       
       
         
           
           
               
               
           
         
         K) a group of formula (XXXI); 
       
       
         
           
           
               
               
           
         
         L) -PEG 2000 -OMe; and 
         M) -PEG 5000 -OMe. 
       
     
     
         113 . The method according to  claim 110 , wherein n is an integer of 3 to 10. 
     
     
         114 . The method according to  claim 110 , wherein R 2  is —OSO 3   − , R 3  is —OSO 3   − , R 4  is —OSO 3   − , and/or R 5  is —CH 2 OSO 3   − . 
     
     
         115 . The method according to  claim 110 , wherein the compound of formula (I) is compound (X): 
       
         
           
           
               
               
           
         
       
     
     
         116 . The method according to  claim 110 , wherein compound of formula (I) is Heparin I or Heparin VII: 
       
         
           
           
               
               
           
         
       
     
     
         117 . The method according to  claim 111 , wherein the compound of formula (I) is selected from the group consisting of:
 A) A compound of formula (XXIV) wherein p is 2 and R 1  is of formula (XX):   
       
         
           
           
               
               
           
         
         B) A compound of formula (XXIV) wherein p is 2 and R 1  is of formula (XVII): 
       
       
         
           
           
               
               
           
         
         C) A compound of formula (XXIV) wherein p is 2 and R 1  is formula (XVIII): 
       
       
         
           
           
               
               
           
         
         D) A compound of formula (XXIV) wherein p is 3 and R 1  is formula (XVII); 
         E) A compound of formula (XXIV) wherein p is 0 and R 1  is formula (XVII); 
         F) A compound of formula (XXIV) wherein p is 1 and R 1  is formula (XVII); 
         G) A compound of formula (XXIV) wherein p is 1 and R 1  is formula (XIX); 
         H) A compound of formula (XXIV) wherein p is 3 and R 1  is formula (XX); and 
         I) A compound of formula (XXIV) wherein p is 3 and R 1  is formula (XXIX): 
       
       
         
           
           
               
               
           
         
       
     
     
         118 . The method according to  claim 111 , wherein the compound of formula (I) is compound is:
 A) A compound of formula (XXV) wherein R 1  is formula (XVII):   
       
         
           
           
               
               
           
         
       
       or
 B) A compound of formula (XXV) wherein R 1  is formula (XIX): 
 
       
         
           
           
               
               
           
         
       
     
     
         119 . The method according to  claim 111 , wherein the compound of formula (I) is selected from the group consisting of:
 A) A compound of formula (XXVI), wherein q is 2 and R 10  is —O-formula (XVII):   
       
         
           
           
               
               
           
         
         B) A compound of formula (XXVI), wherein q is 2 and R 10  is formula (XXI); 
         C) A compound of formula (XXVI), wherein q is 1 and R 10  is formula (XVII); 
         D) A compound of formula (XXVI), wherein q is 2 and R 10  is —O-formula (XXII); 
         E) A compound of formula (XXVI), wherein q is 1 and R 10  is —O-formula (XVII); 
         F) A compound of formula (XXVI), wherein q is 2 and R 10  is —O-formula (XVIII): 
       
       
         
           
           
               
               
           
         
         G) A compound of formula (XXVI), wherein q is 1 and R 10  is —O-formula (XVIII); 
         H) A compound of formula (XXVI), wherein q is 0 and R 10  is —O-formula (XVII); and 
         I) A compound of formula (XXVI), wherein q is 0 and R 10  is —O-formula (XXI). 
       
     
     
         120 . The method according to  claim 111 , wherein the compound is of formula (XXVII) and R 10  is formula (XVII). 
     
     
         121 . The method according to  claim 111 , wherein the compound is
 A) A compound of formula (XXVIII), wherein
 R 10  is —O-formula (XVII), 
 R 11  is H, and 
 R 12  is OR 9 ; or 
   B) A compound of formula (XXVIII), wherein
 R 10  is formula (XXI), 
 R 11  is OR 9 , and 
 R 12  is H. 
   
     
     
         122 . The method according to  claim 110 , wherein the compound is conjugated to an albumin binding moiety, a bile acid and/or a dendritic structure of the formula: 
       
         
           
           
               
               
           
         
         wherein the compound is conjugated as R. 
       
     
     
         123 . The method according to  claim 110 , wherein said compound binds to one or more amino acids selected from the group consisting of R93, R96, R97, R104, R105, K136, H139, R165 and R167 of PCSK9 (SEQ ID NO: 1). 
     
     
         124 . The method according to  claim 110 , wherein the LDL-C is above 3.3 mmol/kg or above 2.5 mmol/kg if the subject is at risk of heart disease due to a disorder of lipoprotein metabolism selected from the group consisting of diabetes, obesity, metabolic syndrome, xanthoma, hypercholesterolemia, familial hypercholesterolemia, dyslipidemia, hyperlipidemia, sitosterolemia, hypertension, angina, acute coronary syndrome, vascular inflammation and sepsis. 
     
     
         125 . The method according to  claim 110 , wherein n is an integer of 3 to 10, and R 1  comprises a group with a formula selected from:
 A) Formula (XI):   
       
         
           
           
               
               
           
         
         or 
         B) Formula (II): 
       
       
         
           
           
               
               
           
         
       
     
     
         126 . A pharmaceutical composition comprising:
 A) a compound having the general structure of formula (I):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkylsulfonyl, substituted alkylsulfonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, ester, amide, acyl, substituted acyl, amino, substituted amino, thioalkyl, substituted thioalkyl, aryl, heteroaryl, substituted aryl, hydrogen, and halogen; 
 each R 2  is independently selected from the group consisting of —OSO 3   − , —OH, —NH 2 , —NHSO 3   − , —NHOCH 3  and —OPO 3   2− ; 
 each R 3  is independently selected from the group consisting of —OSO 3   − , —OH and —OPO 3   2− ; 
 each R 4  is independently selected from the group consisting of —OSO 3   − , —OH, —OPO 3   2−  and —H; 
 each R 5  is independently selected from the group consisting of —CH 2 OSO 3   − , —CH 2 OH, —COO −  and —CH 2 OPO 3   2− ; 
 n is an integer equal to, or greater than 1; and 
 
         B) at least one of:
 an antibody inhibiting binding of PCSK9 to LDLR; 
 a statin; 
 cholestyramine; 
 ezetimibe. 
 
       
     
     
         127 . The method according to  claim 126 , wherein the antibody is selected from the group consisting of lodelcizumab, ralpancizumab, alirocumab, evolocumab and bococizumab. 
     
     
         128 . A method for reducing plasma lipoprotein levels in a subject in need thereof, said method comprising the step of administering to said subject a composition as defined in  claim 110 .