Lipophilic drug derivatives for use in liposomes
First Claim
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1. A pharmaceutical compound for use in liposome and micellar formulations, said compound being a member selected from the group consisting of compounds of formula I and compounds of formula II:
- ##STR21## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical, --NR1 R2, --OCOR3, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;
wherein,R1 and R2 are each members independently selected from the group consisting of H and lower alkyl; and
R3 is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals;
X1 and X2 are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group;
Y1 and Y2 are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH2)p CO2 --, --O--, ═
NNHCO--, --CO-- and --CO(CH2)p CONH--, wherein p is an integer of from 0 to 8;
Z1 and Z2 are each independently a therapeutic agent; and
m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1; and
with the further provisos that when m is 0, X1 is not a linking group, and when n is 0 that X2 is not a linking group.
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Abstract
The present invention provides novel lipophilic drug derivatives which are capable of being formulated in liposomes or micelles. These drug derivatives are known therapeutic agents which are covalently attached to a fatty acid chain of a phospholipid, glyceride, ceramide or 1,2-diacyloxypropane-3-amine. The linkage between the therapeutic agent and the lipid is one which can be cleaved in vivo, allowing the therapeutic agent to be separated from the micellar or liposomal formulation.
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Citations
19 Claims
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1. A pharmaceutical compound for use in liposome and micellar formulations, said compound being a member selected from the group consisting of compounds of formula I and compounds of formula II:
- ##STR21## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical, --NR1 R2, --OCOR3, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;
wherein, R1 and R2 are each members independently selected from the group consisting of H and lower alkyl; and R3 is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals; X1 and X2 are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group; Y1 and Y2 are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH2)p CO2 --, --O--, ═
NNHCO--, --CO-- and --CO(CH2)p CONH--, wherein p is an integer of from 0 to 8;Z1 and Z2 are each independently a therapeutic agent; and m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1; and
with the further provisos that when m is 0, X1 is not a linking group, and when n is 0 that X2 is not a linking group. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
- ##STR21## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical, --NR1 R2, --OCOR3, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;
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11. A pharmaceutical composition comprising a compound selected from the group consisting of compounds of formula I and compounds of formula II:
- ##STR22## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinsitol radical, --NR1 R2, --OCOR3, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;
wherein, R1 and R2 are each members independently selected from the group consisting of H and lower alkyl; and R3 is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals; X1 and X2 are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group; Y1 and Y2 are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH2)p CO2 --, --O--, ═
NNHCO--, --CO-- and --CO(CH2)p CONH--, wherein p is an integer of from 0 to 8;Z1 and Z2 are each independently a therapeutic agent; and m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1, and with the further provisos that when m is 0 that X1 is not a linking group, and when n is 0 that X2 is not a linking group, in a micellar formulation. - View Dependent Claims (12, 13, 14)
- ##STR22## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinsitol radical, --NR1 R2, --OCOR3, --OH, --O--glucose, --O--galactose and --O--oligosaccharide;
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15. A pharmaceutical composition comprising a compound selected from the group consisting of compounds of formula I and compounds of formula II:
- ##STR23## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical and --NR1 R2, --OCOR3, hydrogen, --O--glucose, --O--galactose and --O--oligosaccharide;
wherein, R1 and R2 are each members independently selected from the group consisting of H and lower alkyl; and R3 is a member selected from the group consisting of alkyl radicals and unsaturated alkyl radicals; X1 and X2 are each members independently selected from the group consisting of alkyl, unsaturated alkyl, alkyl linking group, and unsaturated alkyl linking group; Y1 and Y2 are each members independently selected from the group consisting of --S--, --NH--, --NHCO--, --CO(CH2)p CO2 --, --O--, ═
NNHCO--, --CO-- and --CO(CH2)p CONH--, wherein p is an integer of from 0 to 8;Z1 and Z2 are each independently a therapeutic agent; and m and n are each independently an integer of from 0 to 1, with the proviso that n+m is at least 1, and with the further provisos that when m is 0 that X1 is not a linking group, and when n is 0 that X2 is not a linking group, in a liposomal formulation. - View Dependent Claims (16, 17, 18, 19)
- ##STR23## wherein, A is a member selected from the group consisting of a serine radical, an ethanolamine radical, a choline radical, a phosphocholine radical, a phosphoserine radical, a phosphoethanolamine radical, a glycerol radical, a phosphoglycerol radical, an inositol radical, a phosphoinositol radical and --NR1 R2, --OCOR3, hydrogen, --O--glucose, --O--galactose and --O--oligosaccharide;
Specification