Patent EA-003398-B1 (EA)
Title: Drug complex with polymeric carrier
Inventor: SUSAKI HIROSHI
IPC: A61K47/48
Filed: 1999-05-21
Abstract: 1. A drug complex represented by the following formula: A-R-NH-Y-CH2-O-CO-Q wherein A is a carboxy(C1-C4) alkyldextran polyalcohol as a drug carrier; R is a spacer, wherein said spacer is an amino acid or an oligopeptide comprising 2 to 8 amino acids; Y is phenylene group which may be substituted by lower alkyl groups, cyclic C3-6 groups, halo(lower alkyl) groups, chloromethyl or trifluoromethyl groups, hydroxy(lower alkyl) groups, hydroxymethyl group, lower alkoxy groups, methoxy- and ethoxy- groups, lower alkenyl groups, vinyl group and allyl group, lower alkyl groups, propargyl group, hydroxy group, halogen atoms, any of fluorine, chlorine, bromine, iodine atoms, carboxy group, alkoxycarbonyl groups, methoxycarbonyl group, alkanoil groups, acetyl group, haloalkanoil groups, trifluoroacetyl group, aryl group, phenyl group, and naphthyl, aralkyl group, benzyl group, aryloxy group, phenoxy group, aralkyloxy groups, benzyloxy groups, aroyl groups, benzoyl group, heteroaryl groups, pyridyl group, quinolyl group, amino group, mono- or di-(lower alkyl) amino groups, carbamoil group, nitro group, cyano, lower alkyl sulphonyl groups, (lower alkyl) sulphonyl groups, thiol group, lower alkyl of thio group, and Q is a residue of a drug compound, wherein lower alkyl is C1-6 alkyl.. 2. The drug complex according to claim 1, wherein R is a spacer comprising peptide-bonded 2 to 8 amino acids. 3. The drug complex according to any one of claims 1 to 2, wherein Y is p-phenylene group, which may be substituted. 4. The drug complex according to any one of claims 1 to 2, wherein Y is unsubstituted p-phenylene group. 5. The drug complex according to claim 1, wherein dextran polyalcohol that constitutes the carboxy(C1-4)alkyldextran polyalcohol is dextran polyalcohol which is obtained by treating dextran under conditions that enable substantially complete polyalcoholization. 6. The drug complex according to claim 5, wherein the carboxy(C1-4)alkyldextran polyalcohol is carboxymethyldextran polyalcohol. 7. The drug complex according to any one of claims 1 to 6, wherein the drug compound is an antineoplastic agent or an anti-inflammatory agent. 8. The drug complex according to any one of claims 1 to 7, wherein the drug compound having an amino group is bound to A-R-NH-Y-CH2-O-CO- by means of the amino group. 9. The drug complex according to claim 8, wherein the drug compound is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10, 13(9H,15H)-dione. 10. The drug complex according to claim 9, wherein R is -Gly-Gly-Phe-Gly-. 11. The drug complex according to claim 9, wherein R is -Gly-Gly-Gly-Phe-. 12. A DDS compound represented by the following formula: A-R-NH-Y-CH2-O-CO-Q wherein A is a carboxy(C1-C4) alkyldextran polyalcohol as a drug carrier; R is a spacer, wherein said spacer is an amino acid or an oligopeptide comprising 2 to 8 amino acids; Y is phenylene group which may be substituted; by lower alkyl groups, cyclic C3-6-alkyl groups, halo(lower alkyl) groups, chloromethyl or trifluoromethyl groups, hydroxy(lower alkyl) groups, hydroxymethyl group, lower alkoxy groups, methoxy- and ethoxy- groups, lower alkenyl groups, vinyl group and allyl group, lower alkyl groups, propargyl group, hydroxy group, halogen atoms, any of fluorine, chlorine, bromine, iodine atoms, carboxy group, alkoxycarbonyl groups, methoxycarbonyl group, alkanoil groups, acetyl group, haloalkanoil groups, trifluoroacetyl group, aryl group, phenyl group, and naphthyl, aralkyl group, benzyl group, aryloxy group, phenoxy group, aralkyloxy groups, benzyloxy groups, aroyl groups, benzoyl group, heteroaryl groups, pyridyl group, quinolyl group, amino group, mono- or di-(lower alkyl) amino groups, carbamoil group, nitro group, cyano, lower alkyl sulphonyl groups, (lower alkyl) sulphonyl groups, thiol group, lower alkyl of thio group, and Q is a residue of a drug compound, wherein lower alkyl is C1-6 alkyl.. 13. The DDS compound according to claim 12, wherein the drug compound is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-(9H,15H)-dione. 14. The DDS compound according to claim 13, wherein R is -Gly-Gly-Phe-Gly-. 15. The DDS compound according to claim 13, wherein R is -Gly-Gly-Gly-Phe-. 16. A compound represented by the following formula: R'-NH-Y-CH2-O-CO-Q wherein R' is a group which comprises one amino acid or peptide-bonded 2 to 8 amino acids and whose N-terminal is protected or not protected; Y is phenylene group which may be substituted; by lower alkyl groups, cyclic C3-6-alkyl groups, halo(lower alkyl) groups, chloromethyl or trifluoromethyl groups, hydroxy(lower alkyl) groups, hydroxymethyl group, lower alkoxy groups, methoxy- and ethoxy- groups, lower alkenyl groups, vinyl group and allyl group, lower alkyl groups, propargyl group, hydroxy group, halogen atoms, any of fluorine, chlorine, bromine, iodine atoms, carboxy group, alkoxycarbonyl groups, methoxycarbonyl group, alkanoil groups, acetyl group, haloalkanoil groups, trifluoroacetyl group, aryl group, phenyl group, and naphthyl, aralkyl group, benzyl group, aryloxy group, phenoxy group, aralkyloxy groups, benzyloxy groups, aroyl groups, benzoyl group, heteroaryl groups, pyridyl group, quinolyl group, amino group, mono- or di-(lower alkyl) amino groups, carbamoil group, nitro group, cyano, lower alkyl sulphonyl groups, (lower alkyl) sulphonyl groups, thiol group, lower alkyl of thio group, and Q is a residue of a drug compound, wherein lower alkyl is C1-6 alkyl; and Q is a residue of a drug compound. 17 The compound according to claim 18, wherein Y is unsubstituted p-phenylene group, R' is a group represented by H-Gly-Gly-Phe-Gly-, and the drug compound is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-(9H,15H)-dione. 18. The compound according to claim 16, wherein Y is unsubstituted p-phenylene group, R' is a group represented by H-Gly-Gly-Gly-Phe-, and the drug compound is (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-(9H,15H)-dione. 19. A compound represented by the following formula: A-R-NH-Y-CH2-O-CO-X wherein A is a polymer as a drug carrier; R is a spacer, wherein said spacer is an amino acid or an oligopeptide comprising 2 to 8 amino acids; Y is phenylene group which may be substituted; by lower alkyl groups, cyclic C3-6-alkyl groups, halo (lower alkyl) groups, chloromethyl or trifluoromethyl groups, hydroxy(lower alkyl) groups, hydroxymethyl group, lower alkoxy groups, methoxy- and ethoxy- groups, lower alkenyl groups, vinyl group and allyl group, lower alkyl groups, propargyl group, hydroxy group, halogen atoms, any of fluorine, chlorine, bromine, iodine atoms, carboxy group, alkoxycarbonyl groups, methoxycarbonyl group, alkanoil groups, acetyl group, haloalkanoil groups, trifluoroacetyl group, aryl group, phenyl group, and naphthyl, aralkyl group, benzyl group, aryloxy group, phenoxy group, aralkyloxy groups, benzyloxy groups, aroyl groups, benzoyl group, heteroaryl groups, pyridyl group, quinolyl group, amino group, mono- or di-(lower alkyl) amino groups, carbamoil group, nitro group, cyano, lower alkyl sulphonyl groups, (lower alkyl) sulphonyl groups, thiol group, lower alkyl of thio group, and Q is a residue of a drug compound, wherein lower alkyl is C1-6 alkyl, and X is selected from the group comprising hydroxyl group, -O-M wherein M is a protective group for carboxyl group, or an eliminating group. 20. The compound according to any one of claims 16 to 19 for use in the manufacture of the drug complex according to any one of claims 1 to 9.