Patent GB-1486578-A (GB)
Title: Process for preparing somatostatin and derivatives thereo
IPC: A61K38/00
Filed: 1974-12-06
Abstract: 1486578 Somatostatin derivatives AYERST MCKENNA & HARRISON Ltd 6 Dec 1974 [10 Dec 1973 1 Aug 1974] 52779/74 Heading C3H [Also in Division C2] A process for the preparation of a peptide of formula or in which R<SP>1</SP> is H or NH 2  and R<SP>2</SP> is H or CO 2 H comprises treating a corresponding compound of formula  or wherein R<SP>3</SP> is H or BOC-NH; R<SP>2</SP> is H or CO 2 H; α and # are either both hydrogen or independently represent Acm or Trt; γ,γ<SP>1</SP>,γ<SP>2</SP> are either all H or all But; to remove the protecting groups, and, optionally converting the compound to a pharmaceutically acceptable salt; wherein one of the Lys residues may be replaced by D-Lys. The preferred conditions to remove the protecting groups are anhydrous trifluoroacetic or 2-12N hydrochloric acid. Compound II may be obtained by removal of protecting groups α,# from II(a) (preferably with a mercuric or silver salt) followed by oxidation (preferably by hydrogen sulphide, iodine, oxygen, 1,2-diiodoethane or sodium or potassium ferricyanide), or by one-step conversion using iodine (preferably in a C 1-4  alkanol) or thiocyanogen. Compound (I) may be prepared by oxidation of compound (Ia). The peptides are claimed per se. Cyclic peptides prepared are Linear peptides prepared are: Boc - Ala - Gly - Cys(Acm) - Lys(Boc) - Asn- Phe - Phe - Trp - Lys(Boc) - Thr - Phe - Thr- Ser - Cys(Acm) - OH; Boc - Ala - Gly - Cys(Trt)- Lys(Boc) - Asn - Phe - Phe - Trp - Lys(Boc)- Thr - Phe - Thr - Ser - Cys(Trt) - OH; Boc - Ala- Gly - Cys(Acm) - Lys(Boc) - Asn - Phe - Phe- Trp - Lys(BOC) - Thr(But) - Phe - Thr(But)- Ser(But) - Cys(Acm - OH; Boc - Ala - Gly - Cys- (Trt) - Lys(Boc) - Asn - Phe - Phe - Trp - Lys- (Boc) - Thr(But) - Phe - Thr(But) - Ser(But)- Cys(Trt) - OH; H - Ala - Gly - Cys - Lys - Asn- Phe - Phe - Trp - Lys - Thr - Phe - Thr - Ser- Cys - OH; CH 3 CH 2 CO - Gly - Cys(Trt) - Lys- (Boc) - Asn - Phe - Phe - Trp - Lys(Boc) - Thr- (But) - Phe - Thr(But) - Ser(But) - Cys(Trt)- OH; Boc - Ala - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe - Phe - Trp - Lys(Boc) - Thr(But) - Phe- Thr(But) - Ser(But) - NHCH 2 CH 2 S - Trt; CH 3 CH 2 CO - Gly - Cys(Trt) - Lys(Boc) - Asn- Phe - Phe - Trp - Lys(Boc) - Thr(But) - Phe- Thr(But) - Ser(But) - NHCH 2 CH 2 S - Trt; Boc- Ala - Gly - Cys(Trt) - D - Lys(Boc) - Asn - Phe- Phe - Trp - Lys(Boc) - Thr(But) - Phe - Thr- (But) - Ser(But) - Cys(Trt) - OH; Boc - Ala- Gly - Cys(Trt) - Lys(Boc) - Asn - Phe - Phe - DLys(Boc) - Thr(But) - Phe - Thr(But) - Ser(But)- Cys(Trt)-OH. Peptide intermediates isolated are: HEPTAPEPTIDES: Boc - Ala - Gly - Cys- (Acm) - Lys(Boc) - Asn - Phe - Phe - OCH3 and NHNH 2 ; Boc - Ala - Gly - Cys(Trt) - Lys(Boc)- Asn - Phe - Phe - OCH 3  and NHNH 2 ; H and Ddz - Trp - Lys(Boc) - Thr - Phe - Thr - Ser - Cys- (Acm) - OH; H and Ddz - Trp - Lys(Boc) - Thr- Phe - Thr - Ser - Cys(Trt) - OH; H and Ddz- Trp - Lys(Boc) - Thr(But) - Phe - Thr(But) - Ser- (But) - Cys(Acm) - OH; H and Ddz - Trp- Lys(Boc) - Thr(But) - Phe - Thr(But) - Ser(But)- Cys(Trt) - OH; Boc - Ala - Gly - Cys(Trt) - DLys(Boc) - Asn - Phe - Phe - OCH 3  and NHNH 2 ; H and Ddz - Trp - D - Lys(Boc) - Thr But)- Phe - Thr(But) - Ser(But) - Cys(Trt) - OH. HEXAPEPTIDES: Ddz - Trp - Lys(Boc) - Thr- Phe - Thr - Ser - OCH 3  and NHNH 2 ; Ddz- Trp - Lys(Boc) - Thr(But) - Phe - Thr(But) - Ser- (But) - OCH 3  and NHNH 2 ; CH 3 CH 2 CO - Gly- Cys(Trt) - Lys(Boc) - Asn - Phe - Phe - OCH 3  and NHNH 2 ; Ddz and H - Trp - Lys(Boc)- Thr(But) - Phe - Thr(But) - Ser(But) - NHCH 2 - CH 2 S - Trt; Ddz - Trp - D - Lys(Boc) - Thr(But)- Phe-Thr(But)-Ser(But)-OCH 3  and NHNH 2 . PENTAPEPTIDES: H and Chb - Cys(Acm)- Lys(Boc) - Asn - Phe - Phe - OCH 3 ; H and Trt- Cys(Trt) - Lys(Boc) - Asn - Phe - Phe - OCH 3 ; H and Z - Lys(Boc) - Thr - Phe - Thr - Ser - OCH 3 ; Z - Lys(Boc) - Thr(But) - Phe - Thr(But) - Ser- (But) - OCH 3 ; H and Trt - Cys(Trt) - D - Lys- (Boc) - Asn - Phe - Phe - OCH 3 ; Z - D - Lys(Boc)- Thr(But)-Phe-Thr(But)-Ser(But)-OCH 3 . TETRAPEPTIDES: Z and H - Lys(Boc)- Asn - Phe - Phe - OCH 3 ; Z and H - Thr - Phe- Thr - Ser - OCH 3 ; Z and H - Thr(But) - Phe- Thr(But) - Ser(But) - OCH 3 ; Z - D - Lys(Boc)- Phe-Phe-OCH 3 . TRIPEPTIDES: Boc and H - Asn - Phe - Phe- OCH 3 ; Z and H - Phe - Thr - Ser - OCH 3 ; z and H-Phe-Thr(But)-Ser(But)-OCH 3 . Dipeptide intermediates isolated are Boc-Ala- Gly-OCH 3 , OH and OTcp; Boc and H-Phe- Phe-OCH 3 ; Z and H-Thr-Ser-OCH 3 ; Z and H-Thr(But)-Ser(But)-OCH 3 . Pharmaceutical compositions comprise peptides I or Ia, optionally in unit dosage form, together with a pharmaceutically-acceptable carrier or diluent.