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1. (CA2290646) TRITERPENE SAPONIN ANALOGS HAVING ADJUVANT AND IMMUNOSTIMULATORY ACTIVITY
注意: このテキストは、OCR 処理によってテキスト化されたものです。法的な用途には PDF 版をご利用ください。
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. ~A triterpene saponin-lipophile conjugate, comprising
a nonacylated or desacylated triterpene saponin that includes a 3-glucuronic acid residue; and
a lipophilic moiety;
wherein said saponin and said lipophilic moiety are covalently attached to one
another, either directly or through a linker group, and wherein said direct attachment or attachment to said linker occurs through a covalent bond between the carboxyl carbon of said 3-glucuronic acid residue, and a suitable functional group on the lipophilic residue or linker group.
2. ~The saponin-lipophile conjugate of claim 1, wherein said triterpene saponin (a) has a triterpene aglycone core structure with branched sugar chains attached to positions 3 and 28, and an aldehyde group linked or attached to position 4; and (b) is either originally non-acylated, or requires removal of an acyl or acyloil group that is bound to a saccharide at the 28-position of the triterpene aglycone.
3. ~The saponin-lipophile conjugate of claim 1, wherein said triterpene saponin has a quillaic acid or gypsogenin core structure.
4. ~The saponin-lipophile conjugate of claim 1, wherein said desacylsaponin or
nonacylated saponin is selected from the group consisting of Quillaja desacylsaponin, S. jenisseensis desacylsaponin, Gypsophila saponin, Saponaria saponin, Acanthophyllum saponin and lucyoside P saponin.
5. ~The saponin-lipophile conjugate of claim 1, wherein said lipophilic moiety
comprises one or more residues of a fatty acid, terpenoid, aliphatic amine, aliphatic
alcohol, aliphatic mercaptan, mono- or poly- C2-C4 alkyleneoxy derivative of a fatty acid, mono- or poly- C2-C4 alkyleneoxy derivative of a fatty alcohol, glycosyl-fatty acid, glycolipid, phospholipid or a mono-, or di-acylglycerol.
6. The saponin-lipophile conjugate of claim 5, wherein said lipophilic moiety comprises the residues of one or more C6-C24 fatty acid.
7. The saponin-lipophile conjugate of claim 6, wherein said lipophilic moiety is the residue of a C14-C2A fatty acid.
8. The saponin-lipophile conjugate of claim 6, wherein said fatty acid is selected from the group consisting of lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, palmitoleic, oleic, linoleic, linolenic and arachidonic acid.
9. The saponin-lipophile conjugate of claim 5, wherein said lipophilic moiety comprises the residues of one or more aliphatic amines, aliphatic alcohols, or aliphatic mercaptans.
10. The saponin-lipophile conjugate of claim 9, wherein said aliphatic amines,
aliphatic alcohols or aliphatic mercaptans have from 6 to 20 carbon atoms.
11. The saponin-lipophile conjugate of claim 10, wherein said lipophilic moiety is the residue of nonylamine or dodecylamine.
12. The saponin-lipophile conjugate of claim 5, wherein said lipophilic moiety is the residue of a terpenoid.
13. The saponin-lipophile conjugate of claim 12, wherein said lipophilic moiety is the residue of retinal A.
14. The saponin-lipophile conjugate of claim 5, wherein said lipophilic moiety
comprises the residues of one or more phosphoglycerides, mono-acylglycerols or diacylglycerols.
15. The saponin-lipophile conjugate of claim 5, wherein said lipophilic moiety is the residue of an glycosyl-fatty acid or a glycolipid.
16. The saponin-lipophile conjugate of claim 15, wherein said lipophilic moiety is the residue of glucosamine-ricinoleic acid.
17. The saponin-lipophile conjugate of claim 1, wherein said nonacylated or desacylated triterpene saponin is directly attached to said lipophilic moiety via a covalent bond between the 3-glucuronic acid residue of the triterpene saponin and a reactive functional group of the lipophilic residue.
18. The saponin-lipophile conjugate of claim 1, wherein said nonacylated or desacylated triterpene saponin is attached to said lipophilic residue via a bifunctional linker having a first functional group that forms a bond between the 3glucuronic acid residue of the triterpene saponin and a second functional group that forms a bond with a reactive functional group of the lipophilic residue.
19. The saponin-lipophile conjugate of claim 1, wherein said linking group is selected from the group consisting of -NH-CH2-CH2-NH-, -NH-CH(COOH)-CH2-NH-, -NH-CH2-CH(COOH)-NH-, -NH-CH2-CH2-CH2-NH-, -O-(CH2)1-NH-, -S-(CH2), -NH-, -S- (CH2)r-C(O)-, -NH-CH2-C(O)-, -O-CH2-CH2-O-CH2-CH2-O-, -NH-NH-C(O)-CH2-, -NH-C(CH3)2-C(O)-, and -NH-NH-C(O)-(CH2)r-C(O)-NH-N=, where r, in each instance, is from 2-5.
20. ~The saponin-lipophile conjugate of claim 1, wherein said conjugate is represented by Formula II:
or a pharmaceutically acceptable salt thereof; wherein
R1 is glucose or hydrogen; R 2 is apiose or xylose; X is S, 0, NH or a linking group; and R3 is a lipophilic moiety.
21. ~The saponin-lipophile conjugate of claim 1, wherein said conjugate is represented by Formula III:
or a pharmaceutically acceptable salt thereof; wherein
X is S, O, NH or a linking group; and
R3 is a lipophilic moiety.
22. ~The saponin-lipophile conjugate of claim 1, wherein said conjugate is represented by Formula IV:
or a pharmaceutically acceptable salt thereof; wherein
X is S, O, NH or a linking group; and
R3 is a lipophilic moiety.
23. The saponin-lipophile conjugate of claims 20-22, wherein X is a linking group, and said linking group is a bifunctional molecule.
24. The saponin-lipophile conjugate of claims 20-22, wherein X is NH.
25. The saponin-lipophile conjugate of claims 20-22, wherein X is O.
26. The saponin-lipophile conjugate of claims 20-22, wherein X is S.
27. The saponin-lipophile conjugate of claims 20-22, wherein R3 is a lipophilic moiety selected from the group consisting of fatty acid, terpenoid, aliphatic amine, aliphatic alcohol, polyethylene glycol, glycosyl-fatty acid, glycolipid, phospholipid, mono-acylglycerol and di-acylglycerol.
28. The saponin-lipophile conjugate of any of claims 20-22, wherein the combination of -X-R3 is a residue of a compound selected from the group consisting of fatty acid, terpenoid, aliphatic amine, aliphatic alcohol, aliphatic mercaptan, polyethylene glycol, glycosyl-fatty acid, glycolipid, phospholipid, mono-acylglycerol and diacylglycerol.
29. The saponin-lipophile conjugate of any of claims 20-22, wherein the combination of -X-R3 is a residue of a compound selected from the group consisting of fatty acid,
terpenoid, aliphatic amine, aliphatic alcohol, aliphatic mercaptan, mono- or poly-C2-C4 alkyleneoxy derivative of a fatty acid, mono- or poly-C2-C4 alkyleneoxy derivative of a fatty alcohol, glycosyl-fatty acid, glycolipid, phospholipid, and mono- or diacylglycerol.
30. The saponin-lipophile conjugate of claim 23 or 27, wherein X is S, O, NH or a linking group selected from the group consisting of -NH-CH2-CH2-NH-, -NH-CH(COOH)-CH2-NH-, -NH-CH2-CH(COOH)-NH-, -NH-CH2-CH2-CH2-NH-, -O-(CH2)r-NH-, -S-(CH2)r-NH-, -S-(CH2)r-C(O)-, -NH-CH2-C(O)-, -O-CH2-CH2-O-CH2-CH2-O-, -NH-NH-C(O)-CH2-, -NH-C(CH3)2-C(O)-, and -NH-NH-C(O)-(CH2)r-C(O)-NH-N=, where r, in each instance, is from 2-5.
31. The saponin-lipophile conjugate of claim 4, wherein said nonacylated or desacylated triterpene saponin is Quillaja desacylsaponin.
32. The saponin-lipophile conjugate of claim 31, wherein said lipophilic moiety comprises one or more residues of a fatty acid, terpenoid, aliphatic amine, aliphatic alcohol, aliphatic mercaptan, mono- or poly- C2-C4 alkyleneoxy derivative of a fatty acid, mono- or poly- C2-C4 alkyleneoxy derivative of a fatty alcohol, glycosyl-fatty acid, glycolipid, phospholipid and a mono-, or di-acylglycerol.
33. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety comprises a residue of one or more C6-C24 fatty acids.
34. The saponin-lipophile conjugate of claim 33, wherein said lipophilic moiety is a residue of a C14-C24 fatty acid.
35. The saponin-lipophile conjugate of claim 33, wherein said fatty acid is selected from the group consisting of lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, palmitoleic, oleic, linoleic, linolenic and arachidonic acid.
36. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety comprises a residue of one or more aliphatic amines, aliphatic alcohols, or aliphatic mercaptans.
37. The saponin-lipophile conjugate of claim 36, wherein said aliphatic amines, aliphatic alcohols or aliphatic mercaptans have from 6 to 20 carbon atoms.
38. The saponin-lipophile conjugate of claim 37, wherein X is NH, and R3 is nonyl or dodecyl.
39. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety is the residue of a terpenoid.
40. The saponin-lipophile conjugate of claim 39, wherein said lipophilic moiety is the residue of retinal A.
41. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety comprises the residues of one or more phosphoglycerides, mono-acylglycerols or diacylglycerols.
42. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety is the residue of an glycosyl-fatty acid or a glycolipid.
43. The saponin-lipophile conjugate of claim 32, wherein said lipophilic moiety is the residue of glucosamine-ricinoleic acid.
44. A pharmaceutical composition, comprising
one or more saponin-lipophile conjugates of any of claims 1-43, and a pharmaceutically acceptable carrier or diluent.
45. The pharmaceutical composition of claim 44, further comprising an antigen.
46. A vaccine, comprising:
(a) one or more saponin-lipophile conjugates of any of claims 1-43; (b) an immunologically effective amount of an antigen; and
(c) a pharmaceutically acceptable carrier or diluent.
47. The use of a saponin-lipophile conjugate as claimed in any of claims 1-43 in the preparation of a medicament for the enhancement of an immune response in an animal.
48. The use of a saponin-lipophile conjugate as claimed in any of claims 1-43 in the preparation of a medicament for potentiating an immune response to an antigen in an animal.
49. The use of a saponin-lipophile conjugate as claimed in any of claims 1-43 in the preparation of a vaccine.