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Last Updated: March 28, 2024

Claims for Patent: 5,981,791


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Summary for Patent: 5,981,791
Title: High purity N-(4-[N,N-bis(2-iodoethyl)amino]phenoscycarbonyl)-L-glutamic acid
Abstract:A new salt of a prodrug useful in antibody directed enzyme prodrug therapy (ADEPT) is disclosed. A hydrogen iodide salt of the prodrug N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid is prepared which can be obtained in crystalline form. Preparation of the crystalline form of the prodrug enables preparation of the prodrug in highly pure form.
Inventor(s): Heaton; David William (Macclesfield, GB), Dines; Susan (Macclesfield, GB), Dowell; Robert Ian (Macclesfield, GB)
Assignee: Zeneca Limited (London, GB)
Application Number:08/860,880
Patent Claims:1. A hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid.

2. A hydrogen iodide salt according to claim 1 in substantially pure form.

3. A hydrogen iodide salt according to any one of claims 1-2 in crystalline form.

4. A hydrogen iodide salt according to claim 3 in which the crystalline form has a melting point of 142-145.degree. C.

5. A hydrogen iodide salt according to claim 3 in which the crystalline form has an X-ray powder diffraction spectrum substantially as shown in FIG. 3.

6. A pharmaceutical composition comprising a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in substantially pure form and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition according to claim 6 in dry form.

8. A pharmaceutical composition according to claim 7 in which the excipient is a buffer.

9. A pharmaceutical composition according to claim 8 in which the buffer is sodium bicarbonate.

10. A two component pharmaceutical composition comprising a first component which is a pharmaceutical composition as defined in any one of claims 6-9 and a second component which is a sterile diluent for reconstitution of the first component.

11. A process of making a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in which the process comprises deprotecting a compound of Formula 1 ##STR1## wherein Pr1 and Pr2 represent protecting groups in the presence of HI to produce a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid.

12. A process according to claim 11 in which Pr1 and Pr2 are tertiarybutyl ester groups.

13. A process according to claim 11 in which Pr1 and Pr2 are trimethylsilyl protecting groups.

14. A process of making a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid comprising deprotecting in 2 stages a compound of Formula 1 ##STR2## wherein Pr.sup.1 and Pr.sup.2 represent protecting groups, said process comprising:

Pr.sup.1 and Pr.sup.2 firstly being tertiarybutyl ester groups, and replacing said tertiarybutyl ester groups by second protecting groups which are trimethylsilyl groups; and

removing the second protecting groups in the presence of HI to produce a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid.

15. A process of making a pharmaceutical composition comprising N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in which the process comprises dissolving a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in a buffer suitable for intravenous administration.

16. The process according to claim 15 in which the buffer is sodium bicarbonate.

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