Patent GB-1243035-A (GB)
Title: New hypocalcaemic peptides and processes for their manufacture
IPC: C07K1/06
Filed: 1968-11-05
Abstract: 1,243,035. Thyrocalcitons. CIBA GEIGY A.G. 5 Nov., 1968 [9 Nov., 1967; 6 Feb., 1968; 29 April, 1968; 4 May, 1968; 10 May, 1968; 21 May; 1968], No. 52391/68. Heading C2C. Compounds of the formula HCys - Ser - Asn - Leu - Ser - Thr - Cys - Val- Leu - Ala - Tyr - Try - Arg - Asn - Leu - Asn- Asn - Phe - His - .Arg - Phe - Ser - Gly - Met- Gly - Phe - Gly - Pro - Glu - Thr - Pro - OH and the corresponding compound where one or more asparaginine residues are replaced by aspartic acid residues and/or the glutamic acid residue by the glutamine residue and/or methionine residue by the valine, norvaline, leucine, isoleucine or norsleucine residue, and their salts derivatives (including esters, amides, N-acyl derivatives desamino<SP>1</SP>-peptides and Met<SP>25</SP>-sulphoxides) and complexes, are prepared in a per se conventional manner for forming polypeptides from amino acids or smaller peptide units. N-acylated peptides include N-acetyl, N- phenylthiocarbamoyl- and N-pyroglutamylpeptides and complexes are those formed with zinc phosphate, pyrophosphate, or hydroxide, gelatine, polyphloretine phosphate or polyglutamic acid. Pharmaceutical compositions containing the compounds of the invention in forms suitable for enteral and parenteral administration. The compounds are hypocalcaemic agents and compositions may contain other drugs. The following starting materials and intermediates are prepared: H-Thr(tBu)-OMe, DPC- - Ser (tBu) - Thr[tBu) - OMe, Z - Val - Leu - OMe, DPC - Ser(tBu) - Thr(tBu)NHNH 2  H - Val- Leu - OMe, HCl, TR1 - and H - Cys(TR1)- Val - Leu - OMe, DPC - Ser(tBu) - Thr(tBu)- Cys(TR1)- Val - Leu - OMe and -OH - H - Ser (tBu) - Thr(tBu) - Cys(TR1) - Val - Leu - OH, Z - Asn - Leu - OMe, H - Asn - Leu - OMe, Z and H - Ser(tBu) - Asn - Leu - OMe, BOC - Cys (TR1) - Ser(tBu) - Asn - Leu - OMe and -NHNH 2 , BOC - Cys(TR1) - Ser(tBu) - Asn- Leu - Ser(tBu) - Thr(tBu) - -Cys(TR1) - Val - Leu- OH, BOC- # Cys-Ser-(tBu)-Asn-Leu-Ser(tBu)-Thr(tBu)Cys- Val - Leu OH, H - and Z - Tyr(tBu)-Try- OMe, H - and Z - Ala - Tyr(tBu) - Try - OMe, DPC - Ser(tBu) - Ala - Tyr(tBu)Try - OMe and -NHNH 2  Z - and H - Asn - Phe - NHNHBOC, Z - and H - Asn - Asn - Phe - NHNHBOC Z- and H Asn - Asn - Phe NHNHBOC, Z - and H - Leu- Asn - Asn - Phe - NHNH - BOC, Z - and H - "Asn - Leu - Asn - Asn, Phe- NHNHBOC, Z - Arg - Asn - Leu - Asn, - Asn- Phe - NHNHBOC, HCl and - NHNH 2 HCl, Z - Phe - Ser(tBu) - OMe and - NHNH 2  Z and H - Phe - Ser(tBu) - GlyOMe, Z - and HArg - Phe - Ser(tBu) - Sly - OMe, HBr, Z   -   and H - His - Arg - Phe - Ser(tBu) - Gly - OMe, HHis Arg Phe - Ser(tBu) - GlyOH, HOAc, Z- and H - Arg - Asn - Leu - Asn - Asn - Phe - His- Arg - Phe - Ser(tBu) - GlyOH, HOAc, DPCSer(tBu) - Ala - Tyr(tBu) - Try - Arg - Asn - Leu- Asn - Asn - Phe - His - Arg - Phe - Ser(tBu) - -Gly- OH, Z - Sly - Phe - Gly - Pro - OtBu and - OHZ - and H - Thr(tBu) - ProNH 2 , Z - and HGlu(OtBu)Thr(tBu) - ProNH 2 , Z - and H - Gly, Phe - Sly - Pro - Glu(OtBu) - Thr(tBu) - ProNH 2 - DPC - and H - Met - Gly - Phe - Gly - Pro- Glu(OtBu) - Thr(tBu) - ProNH 2 , DPC - Ser (tBu) - Ala - Tyr(tBu) - Try - Arg - Asn - Leu, Asn - Asn - Phe - His - Arg - Phe - Ser(tBu-) Gly - OH ditosylate DPC - and H - Ser(tBu)- Ala - Tyr(tBu) - Try - Arg - Asn - Leu - Asn- Asn - Phe - His - Arg - Phe - Ser(tBu) - Gly- Met - Gly - Phe - Gly - Pro - Glu(OtBu) - Thr (tBu)ProNH 2 , BOCCys-Ser(tBu)-Asn-Leu-Ser.(tBu)-Thr(tBu)Cys Val - Leu - Ser(tBu) - Ala - Tyr(tBu) - Try- Arg- Asn - Leu - Ash - Asn - Phe - His - Arg - Phe- Ser(tBu) - Gly - Met - Gly - Phe - Gly - Pro- Glu(OtBu) - Thr(tBu) - ProNH 2  and BOC- # Cys-Ser (tBu) -Asn-Leu-Ser (tBu) - Thr (tBu) - Cys - Val - Leu - Ser(tBu) - Ala - Tyr(tBu) - Try- Arg - Asn - Leu - Ash - Asn - Phe - His - Arg- Phe - Ser(tBu) - GlyOH; BOC and H - Val- Leu - OBzl, BOC - and H - Cys(Bzl) - Val- Leu - OBzl, BOC - and H - Ser - Thr - OBzl, BOC - and H - Asn - Leu - NHNHZ, BOCSer - Ash - Leu - NHNHZ and - NHNH 2 , BOC - Ser - Ash - Leu - Ser - Thr - OBzl and - OH, H - Ser - Asn. Leu - Ser , ,; Thr OH, BOC - Cys(Bzl) - Ser - Asn - Lent - Ser - Thr OH, BOC - Cys(Bzl) - Ser - Asn - Leu - Ser - Thr- Cys(Bzl) - Val - Leu OH, BOC - Cys - Ser- Asn - Leu - Ser - Thr - Cys - Val - Left OH, BOCI I Cys-Ser-Asn-Leu-Ser-Thr-Cys Val - Left OH and BOGCys-Ser-Asn-Leu-Ser-Thr-Cys Val - Leu - Ser(tBu) - Ala - Tyr(tBu) - Try - Arg- Asn Len - Asn - Asn - Phe - His - Arg - Phe- Ser(tBu) - Gly - Met - Gly - Phe - ,- Gly - Pro- Glu(OtBu), Thr(tBu)ProNH 2 ; N - acetyl- # Cys  Ser Asn - Leu - Ser - Thr - Cys - Val- Leu - OH, H - Ser - Ala - Tyr - Try - Arg - Asn- Leu - Asn - Asn - Phe - His - Arg - Phe - Ser- Oly Met - Gly - Phe - Gly - Pro - Olu - Thr- ProNH 2  diacetate; Z- and HThr(tBu) -Pro- OtBu; Z - and H - Glu(OtBu) - Thr(tBu)- Pro(OtBu), Z - and H - Gly - Phe - Gly - Pro- Glu(OtBu) - Thr(tBu) - Pro OtBu, DPC - and H - Met - Gly - Phe - Gly - Pro - Glu(OtBu)- Thr(tBu) - Pro OtBu; and BOC- # Cys-Ser(tBn)-Asn-Leu-Ser(tBn)-Thr-(tBu)-Cys- Val - Leu - Ser(tBu) - Ala - Tyr(tBu) - Try Arg- Asn - Leu - Asn - Asn - Phe - His - Arg - Phe - Ser(tBu) - Gly - Met - Gly - Phe - Gly - Pro - Olu(OtBu) - Thr(tBu) -Pro -OtBu.