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Claims for Patent: 5,500,413

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Claims for Patent: 5,500,413

Title: Process for manufacture of 1-deamino-8-D-arginine vasopressin
Abstract:A process for the manufacture of 1-deamino-8-D-arginine vasopressin (DDAVP) comprising, condensing a preparation of Mpa(R.sup.1)-Tyr-Phe-Gln-Asn-Cys(R.sup.2)-Pro-OH (SEQ ID NO: 1), where R.sup.1 and R.sup.2 are sulfhydryl-protecting groups, with the dipeptide (R.sup.3)-D-Arg(HCl)-Gly-NH.sub.2, where R.sup.3 is an acid-sensitive amino-protecting group, to form Mpa(R.sup.1)-Tyr-Phe-Gln-Asn-Cys(R.sup.2)-Pro-D-Arg(HCl)-Gly-NH.sub.2 (SEQ ID NO: 1), which is oxidized with iodine in a protic solvent. The reaction mixture containing the oxidized product can be purified by ion exchange chromatography on a cation exchange resin equilibrated with acid. Also disclosed is high-purity DDAVP obtained by this process and its use for treating diurea.
Inventor(s): Larsson; Krister (Malmo, SE), Mellbrand; Thomas (Malmo, SE), Mornstam; Birgitta (Malmo, SE), Roschester; Jan (Lund, SE), Skoldback; Jan-Ake (Malmo, SE)
Assignee: Ferring AB (Malmo, SE)
Application Number:08/084,847
Patent Claims: 1. A method for synthesis of 1-deamino-8-D-arginine vasopressin, comprising the steps of:

a) preparing the heptapeptide: Mpa(R.sup.1)-Tyr-Phe-Gln-Asn-Cys(R.sup.2)-Pro-OH (SEQ ID NO:1), where R.sup.1 and R.sup.2 are sulfhydryl-protecting groups;

b) condensing the heptapeptide from step (a) with the dipeptide: (R.sup.3)-D-Arg(HCl)-Gly-NH.sub.2, where R.sup.3 is an acid-sensitive, amino-protecting group;

c) forming the nonapeptide: Mpa(R.sup.1)-Tyr-Phe-Gln-Asn-Cys(R.sup.2)-Pro-D-Arg(HCl)-Gly-NH.sub.2 (SEQ ID NO: 1); and

d) oxidizing the nonapeptide from step (c) with iodine in a protic solvent.

2. The method of claim 1, wherein said sulfhydryl-protecting radicals R.sup.1 and R.sup.2 can be identical or can be, independent of the other, selected from the group consisting of acetamidomethyl, tert-butyl, tert-butylsulfenyl, p-methylbenzyl, p-methoxybenzyl, 2-(3-nitropyridine sulfenyl), ethylcarbamoyl, triphenylmethyl, and 9-fluorenylmethyl.

3. The method of claim 2, wherein said sulfhydryl-protecting radicals R.sup.1 and R.sup.2 are both acetamidomethyl.

4. The method of claim 1, wherein said amino-protecting group R.sup.3 is N-tert-butyloxy.

5. The method of claim 1, wherein said heptapeptide of step (a) is prepared with a process, comprising:

condensing the tripeptide: Mpa(R.sup.1)-Tyr-Phe-X, where X is a reactive moiety taking the place of the --OH, in the --COOH of Phe, with the tetrapeptide: R.sup.3 -Gln-Asn-Cys(R.sup.2)-Pro-OH.

6. The method according to claim 5, wherein said reactive moiety X is selected from the group consisting of alkoxy, aryloxy and azido.

7. The method according to claim 6, wherein the alkoxy is succinimidoxy.

8. The method according to claim 6, wherein the aryloxy is p-nitrophenyloxy.

9. The method according to claim 1, wherein said oxidation with iodine of step (d) is carried out at pH below 5.0.

10. The method according to claim 9, wherein said oxidation with iodine is carried out at a pH between 1.5-4.3.

11. The method according to claim 1, wherein the reaction mixture containing said oxidized nonapeptide from step (d) is purified by ion exchange chromatography on a cation exchange resin equilibrated with an acid.

12. A method for treating diurea in humans comprising the administration of a therapeutic amount of said 1-deamino-8-D-arginine vasopressin (DDAVP) prepared according to the method of claim 1.

13. A compound prepared according to the method of claim 1 containing the following structure: ##STR2##

14. A therapeutic for treating diurea in humans comprising the compound according to claim 13.

15. A method for treating diurea in humans comprising the administration of a therapeutic amount of the compound according to claim 13.
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