Patent EA-000584-B1 (EA)
Title: Conjugates of a compound containing sulfhydryl group and fatty acid derivatives, method of obtaining conjugates, intermediate compounds for obtaining thereof, methods of increasing absorption and prolonged blood and tissue retention of the compound by mammalian cells containing sulfhydryl group
Inventor: EKRAMI HOSSEIN M
IPC: A61K47/48
Filed: 1996-01-25
Abstract: 1. A compound of general formula VI   in which P is selected from the sulfhydryl group consisting of peptides, proteins and oligonucleotides; R<1> is hydrogen, lower alkyl or aryl; R<2> is a lipid-containing moiety comprising a lipid group; and R<3> is -OH, a lipid-containing moiety comprising a lipid group or an ammo acid chain comprising one or 2 amino acids and terminating in -CO2H or -COR<2>. 2. A compound according to Claim 1, wherein R<1> is hydrogen, R<2> is a lipid group and R<3> is -OH. 3. A compound according to Claim 1, wherein R<1> is hydrogen, R<2> is -CH2CH2CH(NH2)C02H or -CH2CH2CH(NHCO-lipid)CO-lipid and R<3> is -NHCH2CO2H or -NHCH2CO-lipid in which at least one of R<2> and R<3> comprises a lipid group. 4. A compound according to Claim 1, wherein said lipid group is a hydrophobic substituent comprising about 4 to about 26 carbon atoms. 5. A compound according to Claim 4, wherein said lipid group is a hydrophobic substituent comprising about 5 to about 19 carbon atoms. 6. A method for increasing absorption of a compound containing sulfhydryl-group selected from the group consisting of peptides, proteins and oligonucleotides into mammalian cells, said method comprising: forming from the sulfhydryl-containing compound a compound of general formula VI   in which P is a moiety derived from the sulfhydryl-group containing compound selected from the group consisting of peptides, proteins and oligonucleotides; R<1> is hydrogen, lower alkyl or aryl; R<2> is a lipid-containing moiety; and R<3> is -OH, a lipid-containing moiety or an amino acid chain comprising one or 2 ammo acids and terminating in -CO2H or -COR<2>; and administering the compound of general formula VI to the cells. 7. A method according to Claim 6, wherein R<1> is hydrogen, R<2> is a lipid group and R<3> is -OH. 8. A method according to Claim 6, wherein R<1> is hydrogen, R<2> is - -CH2CH2C(NH2)CO2H or CH2CH2CH(NHCO-lipid)CO-lipid and R<3> is-NHCH2CO2H or -NHC2CO-lipid in which at least one of R<2> and R<3> comprises a lipid group. 9. A method for prolonging blood and tissue retention of a compound containing sulfhydryl-group selected from the group consisting of peptides, proteins and oligonucleotides into mammalian cells, said method comprising: forming from the sulfhydryl-containing compound a compound of general formula VI   in which P is a lipid compound containing sulfhydryl group and selected from the group consisting of peptides, proteins and oligonucleotides; R<1> is hydrogen, lower alkyl or aryl; R<2> is a lipid-containing moiety; and R<3> is -OH, a lipid-containing moiety or an amino acid chain comprising one or 2 ammo acids and terminating in -CO2H or -COR<2>; and administering the compound of general formula VI to the cells. 10. A method according to Claim 9, wherein R<1> is hydrogen, R<2> is a lipid group and R<3> is -OH. 11. A method according to Claim 9, wherein R<1> is hydrogen, R<2> is -CH2CH2CH(NH2)C02H or -CH2CH2CH(NHCO-lipid)CO-lipid and R<3>is-NHCH2CO2H or -NHC2CO-lipid in which at least one of R<2> and R<3> comprises a lipid group. 12. A compound of general formula V A - S - S - CH2 - CR<1>(CNHCOR<2>)C(=O)R<3> V in which A is an aromatic activating residue; R<1> is hydrogen, lower alkyl or aryl; R<2> is a lipid-containing moiety comprising a lipid group; and R<3> is -OH, a lipid-containing moiety comprising a lipid group or an ammo acid chain comprising one or 2 amino acids and terminating in -CO2H or -COR<2>. 13. A compound according to Claim 12, wherein A is 2-pyridyl or 4-nitrophenyl. 14. A compound according to Claim 12, wherein R<1> is hydrogen, R<2> is a lipid group and R<3> is -OH. 15. A compound according to Claim 12, wherein R<1> is hydrogen, R<2> is -CH2CH2CH(NH2)CO2H or -CH2CH2CH(NHCO-lipid)CO-lipid and R<3> is -NHCH2CO2H or -NHC2CO-lipid in which at least one of R<2> and R<3> comprises a lipid group. l6. A method for a forming a compound of general formula VI, comprising: reacting a compound of general formula PSH, in which P is selected from the group consisting of peptides, proteins and oligonucleotides, with a compound of general formula V A - S - S - CH2 - CR<1>(HCOR<2>)C(=O)R<3 >V in which A is an aromatic activating residue; R<1> is hydrogen, lower alkyl or aryl; R<2> is a lipid-containing moiety comprising a lipid group; and R<3> is -OH, a lipid-containing moiety comprising a lipid group or an ammo acid chain comprising one or 2 ammo acids and terminating in -CO2H. or -COR<2>. 17. A method according to Claim 16, wherein A is 2-pyridyl or 4-nitrophenyl. 18. A method according to Claim 16, wherein R<1> is hydrogen, R<2> is a lipid group and R<3> is -OH. 19. A method according to Claim 16, wherein R' is hydrogen, R<2> is -CH2CH2CH(NH2)CO2H or-CH2CH2CH(NHCO-lipid)CO-lipid and R<3> is -NHCH2CO2H or -NHCH2CO-lipid in which at least one of R<2> and R<3> comprises a lipid group. 20. A compound of general formula III A - S - S - CH; - CR<1>(NH2)C (=O)R<3> in which R<3> is -OH or an amino acid chain comprising one or two amino acids and terminating in -CO2H.; A is an aromatic activating residue; and R<1> is hydrogen, lower alkyl or aryl. 21. A compound according to Claim 20, wherein R<1> is hydrogen and R<3>' is -OH. 22. A compound according to Claim 20, wherein R<1> is hydrogen and R<3> is -NHCH2 CO2H.