Novel hypocholesterolemic compounds

Abstract

The present invention relates to novel hypocholesterolemic compounds of formula (I) useful in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels as well as to pharmaceutical compositions comprising said compounds alone or in combination with other active agents

1 - 17 . (canceled) 
   
   
       18 : A compound according to formula I 
     
       
         
         
             
             
         
       
     
     wherein
 P represents —N<, 
 x represents —CO—, —CS—, —CH 2 — or —NH—, 
 n represents 1, 
 R a  represents H, lower alkyl, —OR 3 , —O(CO)R 3 , —O(CO)OR 3 , —O(CO)NR 3 R 4 , —NR 3 R 4 , —NR 3 (CO)R 4 , —COOR 3 , —CONR 3 R 4 , —CH═CHCOOR 3 , —CF 3 , —CN, —NO 2 , SO 3 H, PO 3 H or halogen, wherein R 3  and R 4  represent H or lower alkyl, 
 R b  represents H, OH, —OSO 2 Me, —OSO 2 W wherein W represents optionally substituted aryl or heteroaryl, —OCO(CHOH) 2 COOR 5  wherein R 5  represents H or lower alky; or represents the formula -Sp 3 -R 6 ,
 wherein SP3 represents a covalent bond, —O—, —OCH 2 —, —OSO 2 CH 2 —, —OSO 2 —, —OSO 2 — (p) C 6 H 4 O— and R 6  represents one of carbohydrate structures A-D: 
 
 
     
       
         
         
             
             
         
       
       
         wherein 
         R 7 , R 8 , R 9 , R 11 , R 12 , R 13  and R 14  represent independently of each other H, lower allyl, aryl(lower alkyl), —CO-lower alkyl, —CO-aryl, —SO 3   −  or —PO 3   − , 
         R 10  represents —CH 2 OR 16  or —COOR 17 , and 
         R 15  represents —CH 2 OR 16 , —COOR 17 , —CH 2 NH 2 , —CH 2 OPO 3 — or —CH 2 OSO 3 —, wherein 
         R 16  and R 17  independently of each other represent H, lower alkyl, aryl(lower alkyl), —CO— lower alkyl, —CO-aryl, —SO 3   −  or —PO 3   − , 
       
       Z represents optionally substituted aryl or heteroaryl,
 Sp 1  represents a spacer unit, such as a straight-chain or branched lower alkyl group —(CH 2 ) p , wherein p is from 2-6, which is unsubstituted, mono or poly-substituted by —OH, —OR 18 , halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 19 , —NR 19 —CO—, —CO—NR 19 —, —CH═CH—, —C≡C— and wherein R 18  and R 19  represent a hydrogen atom or lower alkyl; 
 
       Sp 2  represents an optional spacer unit, such as a covalent bond or a straight-chain or branched lower alkyl group —(CH 2 ) q , wherein q is from 1-6, which is unsubstituted, mono or poly-substituted by —OH, —OR 20 , halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 21 —, NR 21 —CO—, —CO—NR 21 —, —CH═CH—, —C≡C— and wherein R 20  and R 21  represents a hydrogen atom or lower alkyl; 
       Y represents optionally substituted aryl or heteroaryl, 
     
     with the proviso, that if X═—CO— and Sp 2  represents a covalent bond, R b  may not represent H or OH and Sp 3  may not represent a covalent bond, —O— or —OCH 2 —. 
   
   
       19 : A compound according to  claim 18  having the formula IIa 
     
       
         
         
             
             
         
       
     
     wherein
 Ra represents H, lower alkyl, —OR 3 , —O(CO)R 3 , —O(CO)OR 3 , —O(CO)NR 3 R 4 , —NR 3 R 4 , —NR 3 (CO)R 4 , —COOR 3 , —CONR 3 R 4 , —CH═CHCOOR 3 , —CF 3 , —CN, —NO 2 , SO 3 H, PO 3 H or halogen, wherein R 3  and R 4  represent H or lower alkyl, 
 Rb represents H, OH, —OSO 2 Me, —OSO 2 W wherein W represents optionally substituted aryl or heteroaryl, —OCO(CHOH) 2 COOR 5  wherein R 5  represents H or lower alkyl; or represents the formula -Sp 3 -R 6 ,
 wherein Sp 3  represents a covalent bond, —O—, —OCH 2 —, —OSO 2 CH 2 —, —OSO 2 —, —OSO 2 — (p) C 6 H 4 O— and R 6  represents one of carbohydrate structures A-D: 
 
 
     
       
         
         
             
             
         
       
       
         wherein 
         R 7 , R 8 , R 9 , R 11 , R 12 , R 13  and R 14  represent independently of each other H, lower alkyl, alyl(lower allyl), —CO-lower allyl, —CO-aryl, —SO 3   −  or —PO 3   − , 
         R10 represents-CH 2 OR 16  or —COOR 17 , and 
         R15 represents —CH 2 OR 16 , —COOR 17 , —CH 2 NH 2 , —CH 2 OPO 3 — or —CH 2 OSO 3 —, wherein 
         R 16  and R 17  independently of each other represent H, lower allyl, aryl(lower alkyl), —CO-lower alkyl, —CO-aryl, —SO 3   −  or —PO 3   − , 
       
       Z represents optionally substituted aryl or heteroaryl, 
       Sp 1  represents a spacer unit, such as a straight-chain or branched lower alkyl group —(CH 2 )—, wherein p is from 2-6, which is unsubstituted, mono or poly-substituted by —OH, —OR18, halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 19 —, —NR 19 —CO—, —CO—NR 19 —, —CH═CH—, —C≡C— and wherein R 18  and R 19  represent a hydrogen atom or lower alkyl; 
       Sp 2  represents an optional spacer unit, such as a covalent bond or a straight-chain or branched lower alkyl group —(CH 2 ) q —, wherein q is from 1-6, which is unsubstituted, mono or poly-substituted by —OH, —OR 20 , halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 21 —, —NR 21 —CO—, —CO—NR 21 —, —CH═CH—, —C≡C— and wherein R 20  and R 21  represents a hydrogen atom or lower alkyl; 
       Y represents optionally substituted aryl or heteroaryl, 
     
     with the proviso, that if Sp 2  represents a covalent bond R b  may not represent H or OH and Sp 3  may not represent a covalent bond, —O— or —OCH 2 —. 
   
   
       20 : A compound according to  claim 19  wherein R a  is in the meta-position and R b  is in the para-position. 
   
   
       21 : A compound according to  claim 19  wherein R a  is H, straight-chain or branched C(1-8)allyl, —OR 3 , —NR 3 R 4 , —COOR 3 , —CONR 3 R 4  or halogen, wherein R 3  and R 4  represent independently of each other H or straight-chain or branched C(1-8)allyl. 
   
   
       22 : A compound according to  claim 19  wherein R b  is H, OH, —OSO 2 Me, —OSO 2 Ph; or the formula -Sp 3 -R 6 , wherein Sp 3  preferably represents a covalent bond, —O—, —OCH 2 — or —OSO 2 CH 2 — and R 6  represents one of carbohydrate structures A-D, preferably carbohydrate structures A, B or D. 
   
   
       23 : A compound according to  claim 19  wherein Sp 1  represents a straight-chain or branched —(CH 2 ) m — group, which is unsubstituted, mono or poly-substituted by —OH, —OR 18 , halogen or cyano group, wherein R 18  represents hydrogen or straight-chain or branched C(1-8)allyl and m is 1 to 3. 
   
   
       24 : A compound according to  claim 19  wherein Y represents an optionally substituted phenyl group. 
   
   
       25 : A compound according to  claim 19  wherein Z represents an optionally substituted phenyl group. 
   
   
       26 : A compound according to  claim 18  having the formula IIc 
     
       
         
         
             
             
         
       
     
     wherein
 R a  represents H, lower alkyl, —OR 3 , —O(CO)R 3 , —O(CO)OR 3 , —O(CO)NR 3 R 4 , —NR 3 R 4 , —NR 3 (CO)R 4 , —COOR 3 , —CONR 3 R 4 , —CH═CHCOOR 3 , —CF 3 , —CN, —NO 2 , SO 3 H, PO 3 H or halogen,
 wherein R 3  and R 4  represent H or lower alkyl, 
 
 R b  represents H, OH, —OSO 2 Me, —OSO 2 W wherein W represents optionally substituted aryl or heteroaryl, —OCO(CHOH) 2 COOR 5  wherein R 5  represents H or lower alkyl; or represents the formula
   -Sp 3 -R 6 , 
 wherein SP3 represents a covalent bond, —O—, —OCH 2 —, —OSO 2 CH 2 —, —OSO 2 —, —OSO 2 — (p) C 6 H 4 O— and R 6  represents one of carbohydrate structures A-D: 
 
 
     
       
         
         
             
             
         
       
       
         wherein 
         R 7 , R 8 , R 9 , R 11 , R 12 , R 13  and R 14  represent independently of each other H, lower alkyl, aryl(lower allyl), —CO-lower alkyl, —CO-aryl, —SO 3   −  or —PO 3   − , 
         R 10  represents —CH 2 OR 16  or —COOR 17 , and 
         R 15  represents —CH 2 OR 16 , —COOR 17 , —CH 2 NH 2 , —CH 2 OPO 3  or —CH 2 OSO 3   − , wherein R 16  and R 17  independently of each other represent H, lower alkyl, aryl(lower alkyl), —CO— lower alkyl, —CO-alyl, —SO 3   −  or —PO 3   − , 
       
       Z represents optionally substituted aryl or heteroaryl, 
       Sp 1  represents a spacer unit, such as a straight-chain or branched lower alkyl group —(CH 2 ) p —, wherein p is from 2-6, which is unsubstituted, mono or poly-substituted by —OH, —OR 18 , halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 19 —, —NR 19 —CO—, —CO—NR 19 —, —CH═CH—, —C≡C— and 
       wherein
 R 18  and R 19  represent a hydrogen atom or lower allyl; 
 
       Sp 2  represents an optional spacer unit, such as a covalent bond or a straight-chain or branched lower alkyl group —(CH 2 ) q —, wherein q is from 1-6, which is unsubstituted, mono or poly-substituted by —OH, —OR 20 , halogen or cyano group, wherein one or more —CH 2 — groups may independently be replaced by —O—, —CO—, —CO—O—, —O—CO—, —NR 21 —, —NR 21 —CO—, —CO—NR 21 —, —CH═CH—, —C≡C— and wherein R 20  and R 21  represents a hydrogen atom or lower alkyl; 
       Y represents optionally substituted aryl or heteroaryl. 
     
   
   
       27 : A compound according to  claim 26  wherein R a  is in the meta-position and R b  is in the para-position. 
   
   
       28 : A compound according to  claim 26  wherein R a  is H, straight-chain or branched C(1-8)alkyl, —OR 3 , —NR 3 R 4 , —COOR 3 , —CONR 3 R 4  or halogen, wherein R 3  and R 4  represent independently of each other H or straight-chain or branched C(1-8)alkyl. 
   
   
       29 : A compound according to  claim 26  wherein R b  is H, OH, —OSO 2 Me, —OSO 2 Ph; or the formula -Sp 3 -R 6 , wherein Sp 3  preferably represents a covalent bond, —O—, —OCH 2 — or —OSO 2 CH 2 — and R r  represents one of carbohydrate structures A-D, preferably carbohydrate structures A, B or D. 
   
   
       30 : A compound according to  claim 26  wherein S p1  represents a straight-chain or branched —(CH 2 ) m  group, which is unsubstituted, mono or poly-substituted by —OH, —OR 18 , halogen or cyano group, wherein R 18  represents hydrogen or straight-chain or branched C(1-8) alkyl and m is 1 to 3. 
   
   
       31 : A compound according to  claim 26  wherein Y represents an optionally substituted phenyl group. 
   
   
       32 : A compound according to  claim 26  wherein Z represents an optionally substituted phenyl group. 
   
   
       33 : A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 18  with a pharmaceutically acceptable carrier. 
   
   
       34 : A pharmaceutical composition according to  claim 33  for the treatment of artheriosclerosis or for the reduction of cholesterol levels. 
   
   
       35 : A kit comprising a pharmaceutical composition according to  claim 33  for use in the treatment of artheriosclerosis or for the reduction of cholesterol levels. 
   
   
       36 : A method for the treatment of artheriosclerosis or for the reduction of cholesterol levels comprising administering to a subject in need of such treatment an effective amount of a compound according to  claim 18 .