Amine-containing lipids and uses thereof

Abstract

Nitrogen-containing lipids prepared from the conjugate addition of amines to acrylates, acrylamides, or other carbon-carbon double bonds conjugated to electron-withdrawing groups are described. Methods of preparing these lipids from commercially available starting materials are also provided. These amine-containing lipids or salts forms of these lipids are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems. Given the amino moiety of these lipids, they are particularly suited for the delivery of polynucleotides. Complexes or nanoparticles containing the inventive lipid and polynucleotide have been prepared. The inventive lipids may also be used to in preparing microparticle for drug delivery. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein V is selected from the group consisting of C═O, C═S, S═O, and SO 2 ;
 R 1  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 2  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N 3 ; —N(R B ) 2 ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; —OC(═O)OR B ; —OC(═O)R B ; —OC(═O)N(R B ) 2 ; —NR B C(═O)OR B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 wherein R 1  and R 2  may be taken together to form a cyclic structure; 
 R 3  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N 3 ; —N(R C ) 2 ; —NHC(═O)R C ; —NR C C(═O)N(R C ) 2 ; —OC(═O)OR C ; —OC(═O)R C ; —OC(═O)N(R C ) 2 ; —NR C C(═O)OR C ; or —C(R C ) 3 ; wherein each occurrence of R C  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 each occurrence of R 5  is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
 each occurrence of R 6  is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
 with the proviso that when all occurrences of R 5  and R 6  are hydrogen, V is C═O, R 1  is —OR A , R 2  is —OR B , and R 1  and R 2  are the same, then R 3  is not —CH 2 CH 2 OR C ′, wherein R C ′ is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, decyl, methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, (2-methoxyethoxy)methyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, tetrahydrofurfuryl, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, methoxyacetyl, ethoxyacetyl, acetoxyacetyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-oxopropyl, 2-oxobutyl, 2-oxocyclopentyl, 2-oxo-3-tetrahydrofuranyl, 2-oxo-3-tetrahydropyranyl, methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl; and 
 with the proviso that when all occurrences of R 5  and R 6  are hydrogen, V is C═O, R 1  is —OR A , wherein R A  is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; R 2  is —OR B , wherein R B  is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; and R 1  and R 2  are the same, the R 3  is not —CH 2 CH 2 OR C ″, wherein R C ″ is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; 
 
       and salts thereof. 
     
     
         2 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein V is selected from the group consisting of C═O, C═S, S═O, and SO 2 ;
 R 1  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 2  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N 3 ; —N(R B ) 2 ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; —OC(═O)OR B ; —OC(═O)R B ; —OC(═O)N(R B ) 2 ; —NR B C(═O)OR B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 wherein R 1  and R 2  may be taken together to form a cyclic structure; 
 R 3  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N 3 ; —N(R C ) 2 ; —NHC(═O)R C ; —NR C C(═O)N(R C ) 2 ; —OC(═O)OR C ; —OC(═O)R C ; —OC(═O)N(R C ) 2 ; —NR C C(═O)OR C ; or —C(R C ) 3 ; wherein each occurrence of R C  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 each occurrence of R 5  is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
 each occurrence of R 6  is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
 R 7  is hydrogen or C 1 -C 6  aliphatic; and 
 X is an anion; 
 with the proviso that when all occurrences of R 5  and R 6  are hydrogen, V is C═O, R 1  is —OR A , R 2  is —OR B , and R 1  and R 2  are the same, then R 3  is not —CH 2 CH 2 OR C ′, wherein R C ′ is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, decyl, methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, (2-methoxyethoxy)methyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl, tetrahydrofurfuryl, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, methoxyacetyl, ethoxyacetyl, acetoxyacetyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-oxopropyl, 2-oxobutyl, 2-oxocyclopentyl, 2-oxo-3-tetrahydrofuranyl, 2-oxo-3-tetrahydropyranyl, methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl; and 
 with the proviso that when all occurrences of R 5  and R 6  are hydrogen, V is C═O, R 1  is —OR A , wherein R A  is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; R 2  is —OR B , wherein R B  is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; and R 1  and R 2  are the same, the R 3  is not —CH 2 CH 2 OR C ″, wherein R C ″ is a straight-chain, branched or cyclic alkyl group of 1 to 20 carbon atoms which may contain an ether, carbonyl, or carbonyloxy group; 
 
       and salts thereof. 
     
     
         3 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein each occurrence of R 5  and R 6  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       are the same. 
     
     
         9 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       are the same and are different than R 3 . 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       are independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       are independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         15 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 3 ′ is C 1-6 alkyl, hydroxyl, thiol; C 1-6 alkoxy; amino, C 1-6 alkylamino, diC 1-6 alkylamino; carbocyclic moiety; heterocyclic moiety; aryl; or heteroaryl moiety; 
 n is an integer between 5 and 20, inclusive; and 
 m is an integer between 1 and 10, inclusive; and pharmaceutically acceptable salts thereof. 
 
     
     
         21 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein V is C═O. 
     
     
         29 . The compound of  claim 28  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is —OR A ; and R 2  is —OR B . 
     
     
         30 . (canceled) 
     
     
         31 . The compound of  claim 29 , wherein R A  and R B  are C 6 -C 30  straight chain alkyl groups. 
     
     
         32 - 50 . (canceled) 
     
     
         51 . The compound of  claim 28  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is —N(R A ) 2 ; and R 2  is —N(R B ) 2 . 
     
     
         52 . The compound of  claim 28  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is —NHR A ; and R 2  is —NHR B . 
     
     
         53 - 82 . (canceled) 
     
     
         83 . A composition prepared by the method of reacting an amine of one of the formula (1-117): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       with an acrylate or acrylamide of formula: 
       
         
           
           
               
               
           
         
       
     
     
         84 - 95 . (canceled) 
     
     
         96 . A microparticle, liposome, or micelle comprising a compound of  claim 1  and an agent to be delivered. 
     
     
         97 - 108 . (canceled) 
     
     
         109 . A pharmaceutical composition comprising a compound of  claim 1  and pharmaceutical agent. 
     
     
         110 - 111 . (canceled) 
     
     
         112 . A method of preparing a compound of  claim 1 , the method comprising steps of:
 reacting one or more equivalents of a compound of formula:   
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
 R 5  is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
 with an amine of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N 3 ; —N(R C ) 2 ; —NHC(═O)R C ; —NR C C(═O)N(R C ) 2 ; —OC(═O)OR C ; —OC(═O)R C ; —OC(═O)N(R C ) 2 ; —NR C C(═O)OR C ; or —C(R C ) 3 ; wherein each occurrence of R C  is independently a hydrogen; a protecting group; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; an acyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
 to form a compound of formula: 
 
       
         
           
           
               
               
           
         
       
     
     
         113 - 131 . (canceled)