PROCESS FOR THE PREPARATION OF SOMATOSTATIN AND SOME DERIVATIVES THEREOF, SOME NEW DERIVATIVES OF SOMATOSTATIN AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

摘要

1486580 Hexa and heptapeptides AYERST MCKENNA & HARRISON Ltd 6 Dec 1974 [10 Dec 1973 1 Aug 1974] 50494/76 Divided out of 1486578 Heading C3H Peptides of formula wherein X is OH or O(lower(C 1 -C 4 )alkyl)αis Acm or Trt R 3 is hydrogen or Boc-NH- or an acylating derivative (defined) thereof, provided that, if R 3 is Boc-NH-, Lys may be replaced by D-Lys. The peptides may be prepared by a process which comprises: the reaction of the dipeptide with an activated ester of to yield the tripeptide which is treated under moderately acidic conditions (defined) to yield which is reacted with an activated ester of to yield the tetrapeptide which, on hydrogenation in the presence of a noble metal hydrogenation catalyst, yields which is reacted with an activated ester of wherein either 8 is hydrogen and 81 is Trt, or 8 and #1 together represent Chb, to yield which is reacted with an activated ester of (which is obtained by the reaction of H-Gly- O(lower alkyl) with an activated ester of CH 3 CH(R3)COOH, and hydrolysis of the resultant compound) to yield which, on reaction with hydrazine hydrate, yields which is reacted with an organic nitrite (preferably t-butyl nitrite or isoamyl nitrite) yields Peptides of the invention prepared are: Boc - Ala - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe-Phe-N 3 Boc - Ala - Gly - Cys(Trt) - D - Lys(Boc) - Asn- Phe-Phe-OCH3 Boc - Ala - Gly - Cys(Trt) - D - Lys(Boc) - Asn- Phe-Phe-NHNH 2 CH 3 CH 2 CO - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe-Phe-OCH 3 CH 3 CH 2 CO - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe-Phe-NHNH 2 CH 3 CH 2 CO - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe-Phe-N 3 . Peptides intermediates isolated are: PENTAPEPTIDES: Chb - Cys(Acm) - Lys- (Boc) - Asn - Phe - Phe - OCH 3 ; Trt and H - Cys- (Trt)-Lys(Boc)-Asn-Phe-Phe-OCH 3 ; H and Trt- Cys-D-Lys(Boc)-Asn-Phe-Phe-OCH 3 . TETRAPEPTIDES: Z and H-Lys(Boc)-Asn- Phe-Phe-OCH 3 ; Z and H-D-Lys(Boc)-Asn-Phe- Phe-OCH 3 . TRIPEPTIDES: Boc and H-Asn-Phe-Phe- OCH 3 . Dipeptide intermediates isolated are: Boc-Ala-Gly-OCH 3 , OH and OTcp; Boc and N-Phe-Phe-OCH 3 .