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Last Updated: October 16, 2019

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Claims for Patent: 6,207,858

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Summary for Patent: 6,207,858
Title: Regioselective synthesis of DTPA derivatives
Abstract:The present invention provides a process for high yield regioselective synthesis of DTPA derivatives that eliminates the need for ion exchange chromotographic separation of intermediates. Moreover, as this process yields a single regioisomer of the chelate, it provides for the regiospecific synthesis of desired chelates useful as radiolabeling agents.
Inventor(s): Chinn; Paul (Vista, CA), Gyorkos; Albert (Westminister, CO), LaBarre; Michael J. (San Diego, CA), Ruhl; Steve (San Diego, CA), Ryskamp; Thomas (Poway, CA)
Assignee: IDEC Pharmaceuticals Corporation (San Diego, CA)
Application Number:09/261,207
Patent Claims:1. A process for regioselective synthesis of a DTPA derivative suitable for chelating radioactive metals and coupling to immunoglobulins, the process comprising regioselectively coupling:

(a) a monoprotected diamine; and

(b) a compound comprising an amine and a moiety capable of effectively coupling the DTPA derivative to immunoglobulins or a compound comprising an amine and a moiety capable of being converted for effectively coupling the DTPA derivative to immunoglobulins;

thereby synthesizing a substantially isomerically pure DTPA derivative.

2. A process for preparing a DTPA derivative of formula (I) ##STR2##

wherein R.sub.1 and R.sub.2 are selected to provide a desired DTPA derivative, the process comprising:

(a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono protected diamine (B) to form compound (C);

(b) removing the amine protecting groups in (C) to form the TFA-salt (D);

(c) reducing (D) to form (E);

(d) penta-akylating (E) to form (F);

(e) removing the amine protecting groups in (F) to form the trifluoroacetic acid salt (G);

(f) reducing the nitro group in (G) to form the trifluoroacetic acid salt (H); and

(g) converting the amino group in (H) to form the DTPA derivative of formula (I).

3. The process of claim 2, wherein the compound of formula (I) is MX-DTPA.

4. The process of claim 2, wherein the compound of formula (I) is 1B3M-DTPA.

5. The process of claim 2, wherein the compound of formula (I) is CHx-DTPA.

6. The process of claim 2, wherein the nature of the DTPA derivative is controlled by selecting the diamine (B).

7. A process for preparing MX-DTPA comprising:

(a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono-N-tert-butoxycarbonyl protected diamine (B') to form N-(2-N-Tert-butoxycarbonyl-aminopropyl)-N-tert-butoxycarbonyl-p-nitropheny lalaninamide (C');

(b) removing the boc groups in (C') to form N-(2-Aminopropyl)-p-nitrophenylalaninamide TFA-salt (D');

(c) reducing (D') to form 2-Methyl-6-(p-nitrobenzyl)diethylenetriamine trihydrochloride (E');

(d) penta-alkylating (E') to form N,N,N',N",N"-Pentakis[(tert-butoxycarbonyl)methyl]-2-[(4-nitrophenyl)methy l]-6-methyldiethylenetriamine (F');

(e) removing the boc groups in (F') to form N,N,N',N",N"-Pentakis(carboxymethyl)-2-[(4-nitrophenyl)methyl]-6-methyldie thylenetriamine trifluoroacetic acid salt (G');

(f) reducing the nitro group in (G') to form N,N,N',N",N"-Pentakis(carboxymethyl)-2-[(4-aminophenyl)methyl]-6-methyldie thylenetriamine trifluoroacetic acid salt (H'); and

(g) converting the amino group in (H') to form 2-(p-Isothiocyanatobenzyl)-6-methyldiethylenetriamine-N,N,N',N",N"-pentaac etic acid (MX-DTPA).

8. The process of claim 7, wherein (a) comprises using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) as coupling reagent.

9. The process of claim 7, wherein (a) comprises using bis(2-oxo-3oxazolidinyl)phosphinic chloride (BOP--Cl) as coupling reagent.

10. The process of claim 7, wherein the mono-boc protected diamine (B') is obtained by a process comprising (i) treating a lactonitrile with ammonium hydroxide to form .alpha.-aminonitrile (2); (ii) treating (2) with hydrochloric acid to form the amine hydrochloride salt (3); (iii) protecting the amine with di-tert-butyl dicarbonate to form the boc protected derivative (4); (iv) reducing the nitrile using Raney nickel with a saturated solution of ethanol under two atmospheres of hydrogen to form the mono-boc protected diamine (B').

11. The process of claim 7, wherein the mono-boc protected diamine (B') was obtained by a process comprising (i) alkylating the Schiff Base (5) under phase transfer conditions to form a mono-alkylated product (6); (ii) deprotecting (6) with 1N hydrochloric acid followed by protecting with di-tert-butyl dicarbonate to form the boc protected amine (4); and (iii) reducing (4) with Raney nickel to form the mono-boc protected diamine (B').

12. The process of claim 7, wherein removing the boc groups in (C') to form (D') is performed using trifluoroacetic acid in dichloromethane.

13. The process of claim 7, wherein the step of reducing (D') comprises treating (D') with borane-tetrahydrofuran complex, followed by treatment with hydrogen chloride to form the triamine hydrochloride salt (E').

14. The process of claim 7, wherein Penta-alkylation of intermediate (E') is performed using acetonitrile and potassium carbonate.

15. The process of claim 7, wherein Penta-alkylation of intermediate (E') is performed using bromo-tert-butylacetate in dimethylformamide and sodium carbonate.

16. The process of claim 7, wherein (F') is purified using column chromatography on silica gel.

17. The process of claim 7, wherein deprotecting the carboxylic acids in (F') to form the penta-acetic acid derivative (G') is performed using trifluoroacetic acid.

18. The process of claim 7, wherein reducing the nitro group in (G') to form (H') is performed using palladium on carbon under two atmospheres of hydrogen in water.

19. The process of claim 7, wherein the step of converting (H') into MX-DTPA comprises using thiophosgene to convert the amine group in (H') to the isothiocyanate functionality in MX-DTPA.

20. The process of claim 14, wherein the step of converting (H') into MX-DTPA comprises: (i) adding thiophosgene to a biphasic mixture containing the penta-acetic acid derivative (H') in chloroform and water; (ii) rapidly stirring the mixture for two hours; (iii) removing the solvent under reduced pressure to form a residue; (iv) purifying the residue on reverse phase silica; and (v) eluting with 25% acetonitrile in water containing 1% acetic acid.

21. The process of claim 19, wherein converting (H') into MX-DTPA comprises using dichloromethane and triethylamine.

22. The process of claim 19, wherein converting (H') into MX-DTPA comprises using acetonitrile and sodium bicarbonate or sodium carbonate.

23. An MX-DTPA composition produced according to the method of claim 7.

24. An improved method of producing an antibody chelator, wherein the improvement comprises linking MX-DTPA produced according to claim 7 to an antibody.

25. A substantially isomerically pure MX-DTPA composition.

26. A method of producing a radiolabeled MX-DTPA, comprising combining the MX-DTPA composition of claim 25 with a radiolabel.

27. A process for preparing CHx-DTPA comprising:

(a) coupling N-tert-butoxycarbonyl-p-nitro-L-phenylalanine (A) and mono protected diamine (B") to form compound (C");

(b) removing the amine protecting groups in (C") to form the TFA-salt (D");

(c) reducing (D") to form (E");

(d) penta-alkylating (E") to form (F");

(e) removing the amine protecting groups in (F") to form the trifluoroacetic acid salt (G");

(f) reducing the nitro group in (G") to form the trifluoroacetic acid salt (H"); and

(g) converting the amino group in (H") to form the CHx-DTPA.

28. The process of claim 27, wherein the mono protected diamine (B") is in the sys form.

29. The process of claim 27, wherein the mono protected diamine (B") is in the trans form.

Details for Patent 6,207,858

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Spectrum Pharms ZEVALIN ibritumomab tiuxetan INJECTABLE; INJECTION 125019 001 2002-02-19   See Pricing IDEC Pharmaceuticals Corporation (San Diego, CA) 2036-04-30 RX Orphan company
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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