Patent GB-1287601-A (GB)
Title: Peptides and process for their manufacture
Inventor: RITTEL W
IPC: C07K14/585
Filed: 1969-08-25
Abstract: 1287601 Calcitonin derivatives CIBA GEIGY AG 25 Aug 1969 [23 Aug 1968 27 Aug 1968 30 Aug 1968 10 Oct 1968 19 Nov 1968] 42272/69 Heading C2C Compounds (I) Met - Leu - Gly - Thr - Tyr - Thr - Gln - Asp- Phe - Asn - Lys - Phe - His - Thr - Phe - Pro- Gln . Thr - Ala - Ile - Gly - Val - Gly - Ala - Pro- NH 2  (I) (wherein R is H or a free or acylated amino group and the corresponding compounds in which independently of one another, one or more asparagine and glutamine residues are replaced by the aspartic or glutamic acid residues, respectively, end the aspartic acid residus is replaced by an asparagine residue), their dimers and acid addition salts and complexes of these compounds are prepared by (1) splitting off a protective group from a compound (I) or a dimer in which at least one amino or one carboxyl group is protected by such a group or (2) oxidizing the mercapto group which may be free or protected by trityl groups, to a disulphide bridge, in a compound (II) CH 2 SH R CH - CO - Gly - Asn - Leu - Ser - Thr- Cys - Met - Leu - Gly - Thr - Tyr - Thr - Gln- Asp . Phe - Asn - Lys - Phe - His - Thr - Phe- Pro - Gln - Thr - Ala - Ile - Gly - Val - Gly - Ala- ProNH 2  (II) or an analogue thereof or (3) condensing a compound of Formula (III) or (IV) (wherein the side chain amino group is optionally protected and in which A is 1 to 21 of the amino acid residue which follows Cys<SP>7</SP> and R is H or an acylated amino group, with the remaining sequence of the peptide, this sequence having an optionally protected side chain amino group and whose C-terminal amino acid is L- protine) and if desired converting a resulting free compound into an acid addition salt or complex thereof. The free acid dotricosopeptide derived from calcitonin M (the amide) is also disclosed together with its preparation. The following compounds are prepared as starting materials and intermediates: Z-Asn-Leu- OMe, H - Asn - Leu - OMe, Z - and H - Gly. Asn - Leu - OMe, BOC - Cys(TRI) - Gly - Asn- Leu - OMe and - NHNH 2 ; BOC - and HMet - Leu - GlyOMe, TRI - and H - Cys(TRI )- Met - Leu - GlyOMe, H - Cys(TRI) - Met - Leu- GlyOH, HThr(tBu)OMe, DPC - Ser(tBu) - Thr- (tBu) - OMe and NHNH 2 , DPC - Ser(tBu)Thr- (tBu) - Cys(TRI) - Met - Leu - Gly - OMe and - OH, H - Ser(tBu) - Thr(tBu) - Cys(TRI) - Met- Leu - Gly OH, BOC - Cys(TRI ) - Gly - Asn - Leu- Ser - (tBu) - Thr(tBu) - Cys(TRI) - Met - Leu- Thr(tBu) - Cys - Met - Leu - Gly - OH, Z - and H - Asp(OtBu) - PheOMe, Z - and H - Gln- Asp(OtBu) - Phe - OMe, Z - and H - Thr(tBu)- Gln - Asp(OtBu)PheOMe, Z - and H - Tyr(tBu)- Thr(tBu) - Gln - Asp(OtBu) - PheOMe and -NHNH 2 , Z - Lys(BOC) - Phe - OMe and NHNH 2 , Z - and H - Lys - (BOC) - Phe - His- OMe, Z - Asn - Lys(BOC) - Phe - His - OMe and - NHNH 2 , Z - Thr(tBu) - Phe - ProOH, Z- and H - Ile - Gly - OMe, Z - and H - Ala - Ile- Gly - OMe, Z - and H - Thr(tBu) - Ala - lie - Gly- OMe, H - Thr(tBu) - Ala - Ile - GlyOH, Z - and H - Gln . Thr(tBu) - Ala - lie - GlyOH, Z - and H - Thr(tBu) - Phe - Pro - Gin - Thr(tBu) - Ala- Ile - GlyOH, Z - and H - Asn - Lys(BOC) - Phe- His - Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Ala- Ile - GlyOH, Z - Thr(tBu) - Tyr(tBu) - Thr(tBu)- Gln - Asp(OtBu) - Phe - Asn - Lys(BOC) - Phe- His - Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Ala- Ile - GlyOH, Z - Ala - ProNH 2 , Z - and HGly - Ala - ProNH 2 , Z - and H - Val - Gly - Ala- ProNH 2 , and Z - and H - Thr(tBu) - Tyr(tBu)- Thr(tBu) - Gln - Asp(OtBu) - Phe - Asn- Lys(BOC) - Phe - His - Thr(tBu) - Phe - Pro- Gln - Thr(tBu) - Ala-Ile - Gly - Val - Gly- Ala - Pro - NH 2 , Z and H - Gln - Asn- Phe - OMe Z - and H - Thr - (tBu)- Gln - Asn - Phe - OMe, Z - and H - Tyr- (tBu) - Thr(tBu) - Gin - Asn - Phe - OMe, ZThr(tBu) - Tyr(tBu) - Thr(tBu) - Gln - Asn - Phe- OMe - and NHNH 2 , Z - Thr(tBu) - Tyr(tBu)- Thr(tBu) - Gln - Asn - Phe - Asn - Lys(BOC)- Phe - His - Thr(tBu) - Phe - Pro - Gln - Thr(tBu)- Ala - Ile - Gly - OH and Z and H - Thr(tBu)- Tyr(tBu) - Thr(tBu) - Gin - Asn - Phe - Asn - Phe- Asn - Lys(BOC) - Phe - His - Thr(tBu) - Phe- Pro - Gln - Thr(tBu) - Ala - Ile - Gly - Val - Gly- Ala - Pro - NH 2 . H - and DPC - Ser(tBu) - Thr- (tBu) - Cys(TRI) - OH, Z - Thr(tBu) - Tyr(tBu)- Thr(tBu) - Gln - Asp(OtBu) - Phe - OMe and - NHNH2, H - Phe - Pro - OH, Z - Thr(tBu) - Phe- Pro - OH, Z - Gln - Thr(tBu) Ala - Ile - Gly OMe, H - Gln - Thr(tBu) - Ala - Ile-Gly OMe, H - and Z - Gln - Aso - PheOMe, Z - and H - Thr(tBu)- Gln - Asn - PheOMe, Z - and H - Tyr(tBu)- Thr(tBu) - Gln - Asn - Phe - OMe, Z - Thr(tBu)- Tyr(tBu) - Thr(tBu) - Gln - Asn - Phe - OMe, - NHNH 2 , Z - Thr(tBu) - Tyr(tBu) - Thr(tBu). Gln - Asn - Phe - Asn - Lys(BOC) - Phe - His- Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Ala - Ile- Gly - OH, H - and Z - Thr(tBu) - Tyr(tBu)- Thr(tBu) - Gin - Asn - Phe - Asn - Lys(BOC)- Phe - His - Thr(tBu) - Phe - Pro - Gln - Thr(tBu)- Ala - Ile - Gly - Val - Gly - Ala - ProNH 2 . H - and TRI - Cys(TRI ) - Gly - Asn - LeuOMe. Ac- Cys(TRI ) - Gly - Asn - Leu - OMe and - NHNH 2 . Ac - Cys(TRI) - Gly - Asn - Leu - Ser(tBu) - Thr- Gly - Asn - Leu - Ser(tBu) - Thr(tBu)Cys - Met. Leu - GlyOH, Bmp(TRI)OH, Bmp(TRI )Gly. Asn - LeuOMe and - NHNH 2 . Bmp(TRI)- Gly - Asn - Leu - Ser(tBu) - Thr(tBu) - Cys(TRI )- Ser(tBu) - Thr(tBu)Cys - Met - Leu - GlyOH. HPro - OtBu, Z - and H - Ala - Pro - OtBu, Z - and H - Gly - Ala - Pro - OtBu, Z - and HVal - Gly - Ala - Pro - OtBu, H - Thr(tBu) - Tyr- (tBu) - Thr(tBu) - Gln - Asp(OtBu) - Phe - Asn- Lys(BOC) - Phe - His - Thr(tBu) - Phe - Pro- Gly - Asn - Leu - Ser(tBu) - Thr(tBu) - Gys - Met- Leu Gly - Thr(tBu) - Tyr(tBu) - Thr(tBu) - Gln- Asp(OtBu) - Phe - Asn - Lys(BOC) - Phe - His- Thr(tBu) - Phe - Pro - Gin - Thr(tBu) - Ala - Ile- GlyOH. BOC - Ser - Thr - OBzl, H - Ser - Thr- OBzl, BOC and H - Leu - Ser - Thr - OBzl, BOC - and H - Asn - Leu - Ser - ThrOBzl, BOCGly - Asn - Leu - Ser - Thr - OBzl, and OH, BOC - Gly - Asn - Leu - Ser - Thr - Cys(Bzl]- NHNHZ, H - Cys - Asn - Leu - Ser - Thr - Cys- (Bzl) - NHNHZ, BOC - Cys(Bzl) - Gly - Asn- Leu - Ser - Thr - Cys(Bzl) - NHNHZ. BOCCys - Gly - Asn - Leu - Ser - Thr - CysNHNH 2 . Cys - NHNH 2 , H - Leu - GlyOtt, BOC - Met- Leu - GlyOtt and OH, H - Met - Leu - Gly - OH, BOC - Cys - Gly - Asn - Leu - Ser - Thr - Cys- Met - Leu - GlyOH. Palmitic acid (Pal) - and lauric acid (Lau) para-nitrophenyl esters, Pal- and Lau - Cys(TRI) - Oly - Asn - Leu - OMe and -NHNH 2 , Pal- and Lau-Cys(TRI)-Gly-Asn- Leu - Ser(tBu) - Thr(tBu) - Cys(TRI ) - Met - Leu- Leu - Ser(tBu) - Thr(tBu) - Cys - Met - Leu - Gly- OH. BOC - Cys(TRI) - Gly - Asa - Leu - Ser. (tBu) - Thr(tBu) - Cys(TRI) - Met - Leu - Gly- Thr(tBu) - Tyr(tBu) - Thr(tBu) - Gln - Asp- (OtBu) - Phe - Asn - Lys(BOC) - Phe - His - Thr- (tBu) - Phe - Pro - Gln - Thr(tBu} - Ala - Ile - Gly- Asn - Leu - Ser(tBu) - Thr(tBu) - Cys - Met - Leu- Gly - Thr(tBu) - Tyr(tBu) - Thr(tBu) - Gln - Asp- (OtBu) - Phe - Asn - Lys(BOC) - Phe - His - Thr- (tBu) - Phe - Pro - Gln - Thr(tBu) - Ala - Ile - Gly- OH. Calcitonin. M and Asn<SP>15</SP>-calcitonin M where any free NH 2  is blocked by BOC, OH by tBu and COOH by COOtBu and N<SP>α</SP>-acetyl, palmitoyl and lauryl-calcitonin M similarly blocked. Pharmaceutical compositions in forms suitable for oral or parenteral administration and useful as hypocalcaemic agents contain peptides (I).