Triterpene saponin analogues

Abstract

The present application relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, and intermediates thereto. The application also provides pharmaceutical compositions comprising compounds of the present invention and methods of using said compounds or compositions in the treatment of and immunization for infectious diseases.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
           is a single or double bond; 
         W is —CHO; 
         V is —OH; 
         Y is —O—; 
         wherein Z is a carbohydrate domain having the structure: 
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  is independently H or 
 
         
       
       
         
           
           
               
               
           
         
         
           
             R 2  is NHR 4 ; 
             R 3  is CH 2 OH; and 
             R 4  is -T-R z , —C(O)-T-R z , —NH-T-R z , —O-T-R z , —S-T-R z , —C(O)NH-T-R z , C(O)O-T-R z , C(O)S-T-R z , C(O)NH-T-O-T-R z , —O-T-R z , -T-O-T-R z , -T-S-T-R z , or 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
               X is —O—, —NR—, or T-R z ; 
               T is a covalent bond or a bivalent C 1-26  saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; 
               R z  is hydrogen, halogen, —OR, —OR x , —OR 1′ , —SR, NR 2 , —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
             
           
           R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; and 
           R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-6  aliphatic, or C 1-6  heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or:
 two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
 R 1′  is R x  or a carbohydrate domain having the structure: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
               each occurrence of a, b, and c is independently 0, 1, or 2; 
               d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; 
               R 0  is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
               each occurrence of R a , R b , R c , and R d  is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 
             
           
         
       
     
     
         2 . The compound according to  claim 1 , wherein R 4  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein the compound of Formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         5 . A method of synthesizing the compound according to  claim 1 , the method comprising:
 (a) providing a compound of Formula III:   
       
         
           
           
               
               
           
         
         
           wherein: 
              is a single or double bond; 
           Y′ is hydrogen, halogen, alkyl, aryl, OR, OR y , OH, NR 2 , NR 3 +, NHR, NH 2 , SR, or NROR; 
           W —CHO; 
           V —OH; 
           R y  is —OH, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; 
           each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12  aliphatic, or C 1-12  heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
           each occurrence of R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates; 
         
         (b) Treating said compound of Formula III under suitable conditions with a compound of formula V:
   LG-Z   (V)
 
 wherein: 
 Z is a carbohydrate domain having the structure: 
 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R 1  is independently H or 
         
       
       
         
           
           
               
               
           
         
         
           R 2  is NHR 4 ; 
           R 3  is CH 2 OH; and 
           R 4  is -T-R z , —C(O)-T-R z , —NH-T-R z , —O-T-R z , —S-T-R z , —C(O)NH-T-R z , C(O)O-T-R z , C(O)S-T-R z , C(O)NH-T-O-T-R z , —O-T-R z , -T-O-T-R z , -T-S-T-R z , or 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein:
 X is —O—, —NR—, or T-R z ; 
 T is a covalent bond or a bivalent C 1-26  saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; 
 R z  is hydrogen, halogen, —OR, —OR x , —OR 1′ , —SR, NR 2 , —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
 each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12  aliphatic, or C 1-12  heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
 each occurrence of R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates; 
 R 1′  is R x  or a carbohydrate domain having the structure: 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein: 
                each occurrence of a, b, and c is independently 0, 1, or 2; 
                d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; 
                R 0  is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
                each occurrence of R a , R b , R c , and R d  is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
             
           
         
         (c) to give a compound of Formula I as described herein. 
       
     
     
         6 . A method of synthesizing the compound according to  claim 1 , or an intermediate thereof, comprising the following steps:
 (a) providing a compound of Formula III:   
       
         
           
           
               
               
           
         
         
           wherein 
             is a single or double bond; 
           Y′ is hydrogen, halogen, alkyl, aryl, OR, OR y , OH, NR 2 , NR 3   + , NHR, NH 2 , SR, or NROR; 
           W —CHO; 
           V —OH; 
           R y  is —OH, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; 
           each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12  aliphatic, or C 1-12  heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
           each occurrence of R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates; 
         
         (b) reacting the compound of Formula III with a compound of Formula X: 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R H  is a halogen; 
           R 2  is hydrogen, N 3 , NH 2 , halogen, OH, OR, OC(O)R 4 , OC(O)OR 4 , OC(O)NHR 4 , OC(O)NRR 4 , OC(O)SR 4 , NHC(O)R 4 , NRC(O)R 4 , NHC(O)OR 4 , NHC(O)NHR 4 , NHC(O)NRR 4 , NHR 4 , N(R 4 ) 2 , NHR 4 , NRR 4 , N 3 , or an optionally substituted group selected from C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
           R 4  is -T-R z , —C(O)-T-R z , —NH-T-R z , —O-T-R z , —S-T-R z , —C(O)NH-T-R z , C(O)O-T-R z , C(O)S-T-R z , C(O)NH-T-O-T-R z , —O-T-R z , -T-O-T-R z , -T-S-T-R z , or 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
             X is —O—, —NR—, or T-R z ; 
             T is a covalent bond or a bivalent C 1-26  saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; 
             R z  is hydrogen, halogen, —OR, —OR x , —OR 1′ , —SR, NR 2 , —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
             each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C 1-12  aliphatic, or C 1-12  heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
             each occurrence of R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, and carbonates; 
             R 1′  is R x  or a carbohydrate domain having the structure: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
               each occurrence of a, b, and c is independently 0, 1, or 2; 
               d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; 
               R 0  is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
               each occurrence of R a , R b , R c , and R d  is independently hydrogen, halogen, OH, OR, OR x , NR 2 , NHCOR, or an optionally substituted group selected from acyl, C 1-10  aliphatic, C 1-6  heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, 
             
           
         
         oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 
       
     
     
         7 . The method according to  claim 6 , wherein the compound of Formula X is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 6 , further comprising:
 (c) reacting the product of step (b) or a compound obtained after modifying the product of step (b) with R 4 —OH.   
     
     
         9 . The method according to  claim 8 , wherein R 4 —OH is HO—C(O)—(CH 2 ) 10 —C(O)—OR x , wherein R x  is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates. 
     
     
         10 . The method according to  claim 9 , wherein R x  is H. 
     
     
         11 . The method according to  claim 9 , wherein R x  is Bn. 
     
     
         12 . A method of synthesizing the compound according to  claim 1 , or an intermediate thereof, comprising at least one of the following steps: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising the compound according to  claim 1  and an immunologically effective amount of an antigen associated with a bacteria or virus causing a disease selected from the group consisting of Hepatitis B, pneumococcus, diphtheria, tetanus, pertussis, or Lyme disease including the closely related spirochetes of the genus  Borrelia  such as,  B. burgdorferi, B. garinii, B. afzelli , and  B. japonica.    
     
     
         14 . A pharmaceutical composition comprising the compound according to  claim 2  and an immunologically effective amount of an antigen associated with a bacteria or virus causing a disease selected from the group consisting of Hepatitis B, pneumococcus, diphtheria, tetanus, pertussis, or Lyme disease including the closely related spirochetes of the genus  Borrelia  such as,  B. burgdorferi, B. garinii, B. afzelli , and  B. japonica.    
     
     
         15 . A pharmaceutical composition comprising the compound according to  claim 3  and an immunologically effective amount of an antigen associated with a bacteria or virus causing a disease selected from the group consisting of Hepatitis B, pneumococcus, diphtheria, tetanus, pertussis, or Lyme disease including the closely related spirochetes of the genus  Borrelia  such as,  B. burgdorferi, B. garinii, B. afzelli , and  B. japonica.    
     
     
         16 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with Hepatitis B virus. 
     
     
         17 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with pneumococcus bacterium. 
     
     
         18 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with  Corynebacterium diphtheria  bacterium. 
     
     
         19 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with  Clostridium tetani  bacterium. 
     
     
         20 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with  Bordetella pertussis  bacterium. 
     
     
         21 . A pharmaceutical composition comprising the compound according to  claim 4  and an immunologically effective amount of an antigen associated with a bacterium causing Lyme disease or a spirochete of the genus  Borrelia  selected from the group consisting of  B. burgdorferi, B. garinii, B. afzelli , and  B. japonica.    
     
     
         22 . A method for obtaining the compound according to  claim 1  comprising:
 providing the compound according to  claim 1  and a second substance, and 
 subsequently purifying the compound of  claim 1  by removing at least a portion of the second substance. 
 
     
     
         23 . A method for obtaining the compound according to  claim 2  comprising:
 providing the compound according to  claim 2  and a second substance, and 
 subsequently purifying the compound of  claim 2  by removing at least a portion of the second substance. 
 
     
     
         24 . A method for obtaining the compound according to  claim 3  comprising:
 providing the compound according to  claim 3  and a second substance, and 
 subsequently purifying the compound of  claim 3  by removing at least a portion of the second substance. 
 
     
     
         25 . A method for obtaining the compound according to  claim 4  comprising:
 providing the compound according to  claim 4  and a second substance, and 
 subsequently purifying the compound of  claim 4  by removing at least a portion of the second substance.