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US 2004/0171572 A1Published application
Complex cationic lipids having quaternary nitrogens therein
AssigneeVical Incorporated
InventorCarl J. Wheeler
Life of this patent
Estimating the term…
Abstract
Cationic lipids having a derivatized quaternary ammonium head group that provide improved cell targeting ability and enhanced transfective efficacy for introducing molecules into cells are provided.
Claims63
A compound of the formula
- 63
- wherein
- R1 and R2 are independently H, linear or branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0 to 4.
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- R5 has the structure
- 64
- wherein Z is selected from the group consisting of O, S, NR1, NH, Se, and CR7R8;
- R6 is selected from the group consisting of absent, H, R1, R2, R3 and R4;
- n is 1 to 6;
- m is 1 to 10;
- Y is a pharmaceutically acceptable anion;
- and
- R7 and R8 independently or in combination are H or alkyl groups as defined for R1 and R2;
- wherein if Z is O, n is 1, and m is 3, then R6 is selected from the group defined for R3 and R4 and wherein R1 and R2 are not both H.
11 more elements
A compound of the formula
- 65
- wherein
- R1 and R2 are independently H, linear or branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- wherein R5 has the structure
- 66
- wherein
- R6, or R6 together with R7, is selected from the group defined for R1, R2, R3 and R4 and optionally further comprises a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono, di- or polysaccharide, or other bioactive or pharmaceutical agent;
- R8 is absent, or is H or an alkyl group selected from the group consisting of R1, R2, R3 and R4 and wherein R8 may be joined to R6 or R7 so as to form a ring;
- W is O, NR10, NH, S, or Se;
- R10 is an alkyl group as defined for R1 and R2;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion;
- wherein R1 and R2 are not both H.
13 more elements
A compound of the formula
- 67
- wherein
- R1 and R2 are independently H, linear or branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms k is 0-4;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- wherein R5 is —O—R6 such that R5—O—R6 comprises an ether linkage, wherein R6 is selected from the group consisting of amino acids, peptides, polypeptides, proteins, nucleic acids, nucleotides, polynucleotides, monosaccharides, disaccharides, polysaccharides, bioactive agents, pharmaceutical agents, and linear or branched, unsubstituted or substituted C1-23 heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion;
- and
- wherein R1 and R2 are not both H.
8 more elements
A compound having the structure
- 68
- wherein R1 and R2 are independently H, linear or branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- wherein R5 is selected from the group defined for R3 and R4 and optionally further comprises a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, monosaccharide, disaccharide or polysaccharide, or other bioactive or pharmaceutical agent;
- and
- Z is NH, or S;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion;
- wherein R1 and R2 are not both H, and
- wherein if Z is NH and n is 1 and m is 2 to 6, and R1 and R2 separately or together are C1-C23 alkyl or C(O)—C1-C23, and R3 and R4 separately or together are H or unbranched alkyl C1-C6, then R5 is not —(CH2)zNH2 where z is 2-6;
- or —(CH2)3—NH—(CH2)4—NH2;
- or —NH—(CH2)3—NH—(CH2)4—NH(CH2)3—NH2, C(O)-fluorescein, or
- 69
- where p is 2-5, Z is H or other groups attached by amide or alkyl amino groups.
13 more elements
A compound having the structure:
- 70
- wherein
- R1 and R2 are independently H, linear, branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene, or heteroalkyl groups having from 0 to 6 sites of unsaturation, or cyclic or aryl groups, said cyclic or aryl groups containing up to five heteroatoms, wherein the substituent groups are selected from the group consisting of —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein k is 0 to 4, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms;
- R3 and R4 are independently linear, branched, unsubstituted or substituted C1-23 alkyl, acyl, alkene, or heteroalkyl groups having from 0 to 6 sites of unsaturation, or cyclic or aryl groups, said cyclic or aryl groups containing up to five heteroatoms, wherein the substituent groups are selected from the group consisting of —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein k is 0 to 4, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0 to 4;
- R5 is absent, H or an alkyl group as defined for R1 and R2;
- R5 through R10 independently or in combination are absent, or are H or alkyl groups as defined for R1 and R2 and, optionally, further comprise a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono-, di- or polysaccharide, or other bioactive or pharmaceutical agent;
- G is absent, O, N, S or Se;
- Z is O, N, S, or Se;
- A is O, N, S, Se, or C;
- n is 1-6;
- m is 1-10;
- Y is a pharmaceuticallyacceptable anion;
- wherein if G is N and Z is O, then A is not C;
- wherein if G is O and Z is O then A is not C;
- wherein if G is absent, Z is O, A is O, R6 and R7 are absent, n is 1, and m is 3, then R8 is not absent or H;
- wherein R1 and R2 are not both H;
- and wherein if G is NH and n is 1 and m is 2 to 6, and R1 and R2 separately or together are C1-C23 alkyl or alkenyl or C(O)—C1-C23 alkyl or alkenyl, and R3 and R4 separately or together are H or unbranched alkyl C1-C6, and Z is O then A is not fluorescein, or
- 71
- where p is 2-5, Z is H or other groups attached by amide or alkyl amino groups.
16 more elements
A compound having the structure:
- 72
- wherein R1 and R2 are independently H, linear or branched, unsubstituted or substituted C1-23 alkyl, acyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0 to 4;
- R3 is a linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl group having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0 to 4;
- X1 and X2 are independently selected from the group consisting of NR4R5 and OR4, wherein R4 and R5 are selected from the group consisting of R1 as defined above, amino acids, peptides, polypeptides, proteins, nucleic acids, nucleotides, polynucleotides, monosaccharides, disaccharides, polysaccharide, other bioactive agents and other pharmaceutical agents;
- n is 1 to 8;
- m is 1 to 8;
- wherein R1 and R2 are not both H.
4 more elements
A compound of the formula:
- 73
- wherein
- R1 and R2 are saturated or unsaturated C10-C18 alkyl groups;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- R5 has the structure
- 74
- R7 and R8 are independently selected from the group defined for R1, R2, R3 and R4 and optionally further comprise a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono-, di- or polysaccharide, or other bioactive or pharmaceutical agent;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion.
8 more elements
A compound of the formula:
- 75
- wherein
- R1 and R2 are saturated or unsaturated C10-C18 alkyl groups;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- R5 has the structure
- 76
- Z is C;
- R7, R8 and R9 are independently selected from the group defined for R1, R2, R3 and R4 and optionally further comprise a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono-di- or polysaccharide, or other bioactive or pharmaceutical agent;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion.
9 more elements
A compound of the formula
- 77
- wherein
- R1 and R2 are saturated or unsaturated C10-C18 alkyl groups;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- wherein R5 has the structure
- 78
- wherein
- R6 or R6 together with R7 are selected from the group defined for R1, R2, R3 and R4 and optionally further comprises a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono, di- or polysaccharide, or other bioactive or pharmaceutical agent;
- W is O, NR8, NH, S, or Se;
- R8 is an alkyl group as defined for R1 and R2;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion.
11 more elements
A compound of the formula
- 79
- wherein
- R1 and R2 are saturated or unsaturated C10-C18 alkyl groups;
- R3 and R4 are independently linear or branched, unsubstituted or substituted C1-23 alkyl, alkylene or heteroalkyl groups having from 0 to 6 sites of unsaturation, cyclic and aryl groups, said groups comprising from 0 to 5 heteroatoms wherein said heteroatoms are not the first atoms in said groups, wherein the substituent groups are selected from —O—(CH2)k—CH3, —S—(CH2)k—CH3, X—(CH2)k—, wherein X is a halide, and —N((CH2)k—CH3)2, wherein the alkyl groups of said substituents comprise from 0 to 2 heteroatoms and k is 0-4;
- wherein R5 has the structure
- 80
- wherein R6, or R6 together with R7, is selected from the group defined for R1, R2, R3 and R4 and optionally further comprises a chemically linked amino acid, peptide, polypeptide, protein, nucleic acid, nucleotide, polynucleotide, mono, di- or polysaccharide, or other bioactive or pharmaceutical agent;
- W is O, NR8, NH, S, or Se;
- R8 is an alkyl group as defined for R1 and R2;
- n is 1 to 6;
- m is 1 to 10;
- and
- Y is a pharmaceutically acceptable anion.
10 more elements
The method of claim 62, wherein said cells are in an assay selected from the group consisting of murine lung transfection, murine intraperitoneal tumor, murine intramuscular and porcine or rabbit intraarterial.
Dependencies are inferred from the claim text.