Patent GB-1459303-A (GB)
Title: Peptides and process for their manufacture
IPC: A61K38/00
Filed: 1974-03-26
Abstract: 1459303 Calcitonin derivatives CIBA-GEIGY AG 26 March 1974 [28 March 1973 14 Dec 1973] 13328/74 Heading C3H Peptides of Formula I wherein (i) X is Met, Val, Noa, Leu, Ile, Dab (Met and Val are preferred); (ii) Ala<SP>26</SP> is replaced by Asn and/or Ile<SP>27</SP> is replaced by Thr; (iii) optionally, one or more of the amino acids in the 11, 12, 16, 19, 22 and 24 positions is replaced by another amino acid the derivatives (especially the Nα-acyl and desamino<SP>1</SP> peptides), acid addition salts and complexes thereof are prepared by (1) removing blocking groups bound to free amino and/or carboxyl groups from a peptide of Formula (I); (2) oxidizing the linear peptide corresponding to (I), wherein the mercapto groups may be free or protected by trityl or acylamidomethyl groups, to the disulphide and converting the peptides obtained from (1) and (2) to the acid addition salts and complexes as desired. The preferred acids for salt formation are those which yield therapeutically acceptable compounds and may be inorganic or organic acids. Complexes, which prolong the activity of the peptides, may be made from inorganic (especially zinc phosphate, pyrophosphate and hydroxide) or organic compounds, including polyhydroxygelatin, carboxymethylcellulose, polysaccharides, polyglutamic acid and polyphoretine phosphate. Exemplified are Asn<SP>26</SP>-Thr<SP>27</SP>-Calcitonin M; Lys<SP>11</SP>-Leu<SP>12,16,19</SP>-Tyr<SP>22</SP>-Asn<SP>26</SP>-Thr<SP>27</SP>-Calcitonin M; Thr<SP>27</SP>-Calcitonin M; Leu<SP>12</SP>-Thr<SP>27</SP>-Calcitonin M; Leu<SP>12</SP>-Asn<SP>26</SP>-Thr<SP>27</SP>-Calcitonin M; Asn<SP>26</SP>-Calcitonin M; Desamino<SP>1</SP>-Asn<SP>26</SP>-Thr<SP>27</SP>-Calcitonin M; Desamino<SP>1</SP>-Val<SP>8</SP>-Lys<SP>11</SP>-Leu<SP>12</SP>-Tyr<SP>22</SP>-Asn<SP>26</SP>- Thr<SP>27</SP>-Calcitonin M; Desamino<SP>1</SP>-Lys<SP>11</SP>-Leu<SP>12,16,19</SP>-Tyr<SP>22</SP>-Asn<SP>26</SP>- Thr<SP>27</SP>-Calcitonin M. The following intermediates are isolated: Pro - NH 2 ; Bmp - Gly - Asn - Leu - Ser(tBu)- # Thr(tBu) - Cys - Met - Leu - Gly - Lys(Boc) - Leu- Thr(tBu) - Gln - Asp(OtBu) - Leu - Asn - Lys (Boc) - Leu - His - Thr(tBu) - Tyr(tBu) - Pro- Gln - Thr(tBu) - Asn - Thr(tBu) - Gly - Val - Gly- Ala-Pro-NH 2 ; DOCOSAPEPTIDES; 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) - Asn - Thr(tBu) - Gly - Val - Gly- Ala - Pro - NH 2 ; Z and H - Lys(Boc) - Leu- Thr(tBu) - Gln - Asp(OtBu) - Phe - Asn - Lys (Boc) - Phe - His - Thr(tBu) - Tyr(tBu) - Pro- Gln - Thr(tBu) - Asn - Thr(tBu) - Gly - Val - Gly- Ala - Pro - NH 2 ; Z and H - Lys(Boc) - Leu- Thr(tBu) - Gln - Asp(OtBu) - Phe - Asn - Lys (Boc) - Phe - His - Thr(tBu) - Phe - Pro - Gln- Thr(tBu) - Ala - Thr(tBu) - Gly - Val - Gly - Ala- Pro - NH 2 ; 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 - Thr(tBu) - Gly - Val - Gly - Ala- Pro - NH 2 ; Z and H - Thr(tBu) - Leu - Thr (tBu) - Gln - Asp(OtBu) - Phe - Asn - Lys(Boc)- Phe - His - Thr(tBu) - Phe - Pro - Gln - Thr(tBu)- Ala - Thr(tBu) - Gly - Val - Gly - Ala - Pro- NH 2 ; Z and H-Thr(tBu)-Leu-Thr(tBu)-Gln- Asp(OtBu) - Phe - Asn - Lys(Boc) - Phe - His- Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Asn- Thr(tBu) - Gly - Val - Gly - Ala - Pro - NH 2 ; 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) - Asn - Ile- Gly-Val-Gly-Ala-Pro-NH 2 ; HEXADECAPEPTIDES; Z and H-Asn- Lys(Boc) - Phe - His - Thr(tBu) - Phe - Pro - Gln- Thr(tBu) - Asn - Thr(tBu) - Gly - Val - Gly - Ala- Pro-NH 2 ; Z and H-Asn-Lys(Boc)-Phe-His- Thr(tBu) - Tyr(tBu) - Pro - Gln - Thr(tBu) - Asn- Thr(tBu) - Gly - Val - Gly - Ala - Pro - NH 2  and acetate; H and Z-Asn-Lys(Boc)-Leu-His- Thr(tBu) - Tyr(tBu) - Pro - Gln - Thr(tBu) - Asn- Thr(tBu) - Gly - Val - Gly - Ala - Pro - NH 2  and acetate; H and Z-Asn-Lys(Boc)-Phe-His- Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Ala- Thr(tBu) - Gly - Val - Gly - Ala - Pro - NH 2  and acetate; H and Z-Asn-Lys(Boc)-Phe-His- Thr(tBu) - Phe - Pro - Gln - Thr(tBu) - Asn - Ile- Gly-Val-Gly-Ala-Pro-NH 2 ; DODECAPEPTIDES; H and Z-Thr(tBu)- Phe - Pro - Gln - Thr(tBu) - Asn - Thr(tBu)- Gly - Val - Gly - Ala - Pro - NH 2 ; H and Z - Thr(tBu) - Tyr(tBu) - Pro - Gln - Thr(tBu)- Asn - Tyr(tBu) - Gly - Val - Gly - Ala - Pro - NH 2 ; Z - Asn - Lys(Boc) - Phe - His - Thr(tBu) - Phe- Pro - Gln - Thr(tBu) - Ala - Thr - Gly - OH; Z - Asn - Lys(Boc) - Phe - His - Thr(tBu) - Phe- Pro-Gln-Thr(tBu)-Asn-Ile-Gly-OH; NONAPEPTIDES; Z and H-Gln-Thr(tBu)- Asn-Thr(tBu)-Gly-Val-Gly-Ala-Pro-NH 2 ; OCTAPEPTIDES; H and Z-Thr(tBu)-Phe- Pro - Gln - Thr(tBu) - Ala - Thr(tBu) - Gly - OMe and OH; Z and H-Thr(tBu)-Phe-Pro-Gln- Thr(tBu)-Asn-Ile-Gly-OMe and OH; HEXAPEPTIDES; Z - Lys(Boc) - Leu - Thr (tBu) - Gly - Asp(OtBu) - Phe - OMe and NHNH 2 ; Z - Lys(Boc) - Leu - Thr(tBu) - Gln- Asp(OtBu) - Leu - OMe and NHNH 2 ; ZThr(tBu) - Lett - Thr(tBu) - Gln - Asp(OtBu)- Phe-OMe and NHNH 2 ; PENTAPEPTIDES; Z - Gln - Thr(tBu) - Asn- Thr(tBu) - Gly - OMe and OH; H and Z - Leu- Thr(tBu)-Gln-Asp(OtBu)-Phe-OMe; H-Leu-Thr- (tBu)-Gln-Asp(OtBu)-Leu-OMe; H and ZGln-Thr(tBu)-Ala-Thr(tBu)-Gly-OMe; H and Z-Gln-Thr(tBu)-Asn-Ile-Gly-OMe; TETRAPEPTIDES; Z and H-Thr(tBu)- Asn-Thr(tBu)-Gly-OMe; Z and H-Thr(tBu)- Ala-Thr(tBu)-Gly-OMe; Z and H-Thr(tBu)- Asn-Ile-Gly-OMe; TRIPEPTIDES; H and Z-Asn-Thr(tBu)- Gly - OMe; H and Z - Ala - Thr(tBu) - Gly- OMe; H and Z-Asn-Ile-Gly-OMe. The dipeptide intermediates isolated are H and Z-Thr(tBu)-Gly-OMe. Pharmaceutical compositions, useful as hypocalcaemic agents (for intravenous, intramuscular, subcutaneous or intranasal administration) comprise the peptides I and excipients which do not react with I. The compositions may be in the form of a lyophilisate or liquid (solutions, suspensions, emulsions or sprays) and may optionally contain other agents (preservatives, stabilizers, wetting agents). Reference has been directed by the Comptroller to Specification 1,287,125.