IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
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출원번호 |
US-0404152
(2003-04-02)
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등록번호 |
US-7399860
(2008-07-15)
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발명자
/ 주소 |
- Kumar,Anil M.
- Klein,J. Peter
- Bhatt,Rama
- Vawter,Edward
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
6 |
초록
The invention provides new processes for preparing polyglutamic acid-therapeutic agent conjugates for clinical development and pharmaceutical use, and polyglutamic acid-therapeutic agent conjugates prepared by these processes.
대표청구항
▼
What is claimed is: 1. A polyglutamic acid-camptothecin conjugate having the formula: wherein: PG is polyglutamic acid polymer; and camptothecin is selected from the group consisting of 20(S)-camptothecin, 20(S)-9-aminocamptothecin, 20(S)-9-nitrocamptothecin, 20(S)-7-ethyl-10-hydroxycamptothecin,
What is claimed is: 1. A polyglutamic acid-camptothecin conjugate having the formula: wherein: PG is polyglutamic acid polymer; and camptothecin is selected from the group consisting of 20(S)-camptothecin, 20(S)-9-aminocamptothecin, 20(S)-9-nitrocamptothecin, 20(S)-7-ethyl-10-hydroxycamptothecin, 9-dimethylaminomethyl-10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, and 7-methylpiperizinomethyl-10,11-ethylenedioxycamptothecin. 2. The conjugate of claim 1, wherein the weight % ratio of said camptothecin to said PG is about 1-60%. 3. The conjugate of claim 1, wherein the weight % ratio of said camptothecin to said PG is 10-45%. 4. The conjugate of claim 1, wherein said camptothecin is selected from 20(S)-camptothecin, 20(S)-9-aminocamptothecin, 20(S)-9-nitrocamptothecin, and 20(S)-7-ethyl-10-hydroxycamptothecin. 5. The conjugate of claim 4, wherein said camptothecin is 20(S)-camptothecin. 6. The conjugate of claim 5, wherein the weight % ratio of said 20(S)-camptothecin to said PG is 34%. 7. A method of preparing a polyglutamic acid-camptothecin conjugate having the formula: wherein: PG is polyglutamic acid polymer; and camptothecin is selected from the group consisting of 20(S)-camptothecin, 20(S)-9-aminocamptothecin, 20(S)-9-nitrocamptothecin, 20(S)-7-ethyl-10-hydroxycamptothecin, 9-dimethylaminomethyl-10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, and 7-methylpiperizinomethyl-10,11-ethylenedioxycamptothecin wherein said method comprises: (a) providing a polyglutamic acid polymer having a MW of about 20,000 to about 60,000 daltons, as determined by viscosity, and camptothecin for conjugation thereto; (b) attaching a glycine linker to the camptothecin, wherein the glycine linker consists of a single glycine residue; and (c) covalently linking said camptothecin to said polyglutamic acid polymer via the glycine linker under conditions sufficient to attach at least 5 molecules of the camptothecin per chain of polymer, thereby forming said polyglutamic acid-camptothecin conjugate. 8. The method of claim 7, wherein the weight % ratio of said camptothecin to said PG is 1-60%. 9. The method of claim 7, wherein the weight % ratio of said camptothecin or analog thereof to said PG is 10-45%. 10. The method of claim 7, wherein the weight % ratio of said camptothecin to said PG is 34%. 11. A pharmaceutical composition comprising the polyglutamic acid-camptothecin conjugate of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or diluent. 12. The pharmaceutical composition of claim 11, wherein said camptothecin is 20(S)-camptothecin. 13. The pharmaceutical composition of claim 12, wherein the weight % ratio of said 20(S)-camptothecin to said PG is 1-60%. 14. The pharmaceutical composition of claim 12, wherein the weight % ratio of said 20(S)-camptothecin to said PG is 10-45%. 15. The pharmaceutical composition of claim 12, wherein the weight % ratio of said 20(S)-camptothecin to said PG is 34%. 16. A conjugate comprising a polyglutamic acid polymer covalently bonded to a camptothecin molecule selected from the group consisting of 20(S)(+)-camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 7-ethyl-10-hydroxycamptothecin, 9-dimethylaminomethyl-10-hydroxycamptothecin and 7-methylpiperizinomethyl-10, 11-ethylenedioxy-camptothecin, wherein said polyglutamic acid is bonded to said camptothecin molecule by an indirect linkage consisting of one or more glycine residues. 17. The conjugate of claim 16, wherein said indirect linkage is via one glycine residue. 18. The conjugate of claim 16, wherein said camptothecin molecule is 20(S)(+)-camptothecin. 19. The conjugate of claim 18, wherein said conjugate is poly-1-glutamic acid-glycyl-20(S)(+)-camptothecin. 20. The conjugate of claim 16, wherein said conjugate comprises 1-60% by weight of said camptothecin. 21. The conjugate of claim 20, wherein said conjugate comprises 10-45% by weight of said camptothecin. 22. The conjugate of claim 21, wherein said conjugate is poly-L-glutamic acid-20-glycyl-20(S)camptothecin and wherein said conjugate comprises 34% by weight of said camptothecin molecule. 23. The conjugate of claim 16, wherein said polyglutamic acid polymer has a molecular weight from 20 kD to 60 kD as determined by viscosity. 24. A pharmaceutical composition comprising the conjugate of claim 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or diluent. 25. A process for preparing a conjugate according to claim 16, comprising: (a) providing the protonated form of a polyglutamic acid polymer and a camptothecin molecule selected from the group consisting of 20(S)(+)-camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 7-ethyl-10-hydroxycamptothecin, 9-dimethyl-aminomethyl-10-hydroxycamptothecin and 7-methylpiperizinomethyl-10,11-ethylenedioxy-camptothecin for conjugation thereto; and (b) covalently linking said camptothecin molecule to said polyglutamic acid polymer via a linker in an inert organic solvent to form a polyglutamic acid-camptothecin conjugate, wherein said linker consists of one or more glycine residues.
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