Patent GB-1333723-A (GB)
Title: Hypocalcaemic peptides and process for their manufacture
IPC: A61K38/00
Filed: 1970-09-16
Abstract: 1333723 Calcitonine-M derivatives CIBAGEIGY AG 16 Oct 1970 [22 Oct 1969 3 July 1970] 49248/70 Heading C2C Compounds (I), their salts, complexes, Nα- acyl and their desamino<SP>1</SP>-derivatives: H-Cys - Gly - Asn - Leu - Ser - Thr - Cys - XLeu - Gly - Thr - Tyr - Thr - Gln - Asp - Phe- Asn - Lys - Phe - His - Thr - Phe - Pro - Gln- Thr - Ala - Ile - Gly - Val - Gly - Ala - ProNH 2  (I) (where X is Met, Val, Nval, Leu, Ile, Nle, Abu and wherein at least one of the amino acids in positions 11, 12, 16, 17, 19, 20, 22 and 24 is replaced by another namely Thr<SP>11</SP> by Lys, Tyr<SP>12</SP> by Leu, Phe<SP>16</SP> by Leu, Asn<SP>17</SP> by His, Phe<SP>19</SP> by Leu, His<SP>20</SP> by Gln, Phe<SP>22</SP> by Tyr and Gln<SP>24</SP> by Arg) are prepared (a) by removing amino and/or carboxylic protecting groups from an appropriately protected dotriacontapeptide or (b) by oxidizing the corresponding linear dotriacontapeptide wherein the mercapto groups in the residues -Cysare free or protected by trityl groups. Starting materials and intermediates prepared are: Z- and H-Tyr(tBu)-ProOH, Z-Thr (tBu) - Tyr (tBu) ProOH, H-Gln-Thr (tBu)- Ala-Ile-Gly-Ome, Z-Thr (tBu)-Tyr (tBu)-Pro- Gln - Thr - (tBu) - Ala - lie - Gly OMe and OH and the unprotected octapeptide acetate salt, Z- and H - Asn - Lys (BOC) Phe - His - Thr (tBu)- Tyr (tBu) Pro - Gln - Thr (tBu) - Ala - Ile- Gly OH, Z - Thr (tBu) Tyr (tBu) - Thr (tBu)- Gln - Asp (OtBu) - Phe - Asn - Lys (BOC) - Phe- His - Thr (tBu) - Tyr (tBu) - Pro - Gln - Thr (tBu) - Ala - lie - Gly OH, Z- and H - Thr (tBu) - Tyr (tBu) - Thr (tBu) - Gln - Asp (OtBu)- Phe - Asn - Lys (BoC) - Phe - His - Thr (tBu)- Tyr (tBu) - Pro - Gln - Thr (tBu) - Ala - Ile - Gly- Val - Gly - Ala - Pro NH 2  and BoC-protected- Tyr<SP>22</SP> - calcitonine M. Z- and H-Asn-Leu-OMe, Z- and H - Asn - Leu OMe, BOC - Cys (Tri)- Gly - Asn - Leu OMe and -NHNH 2 , BOC and H - Met - Leu - Gly OMe, Tri- and H - Cys (Tri) - Met - Leu - Gly - OMe, H - Thr (tBu)- OMe, DPC - Ser (tBu) Thr (tBu) - OMe and -NHNH 2  DPC- and H-Ser (tBu) - Thr (tBu)- Cys (Tri) - Met - Leu - Gly - OMe and the free hexapeptide acid, BOC-Cys (Tri)-Gly-Asn-Leu- Ser (tBu) - Thr (tBu) Cys (Tri) - Met - Leu - Gly OH and the cyclic peptide (by oxidation), Z and HAsp (OtBu) Leu OMe, Z and H-Gln-Asp (OtBu)-Leu OMe, Z and H-Thr (tBu)-Gln-Asp (OtBu) - Leu - OMe, Z and H - Leu - Thr (tBu)- Gln - Asp (OtBu) - Leu - OMe, Z - Thr (tBu)- Leu - Thr (tBu) - Gln - Asp (OtBu) - Leu OMe and -NHNH 2 , Z- and H - Lys (BOC) Leu- His - OMe, Z - Asn - Lys (BOC) Leu - His - OMe and -NHNH 2 , Z- and H-Asn-Lys (BOC) Leu- His - Thr (tBu) - Phe - Pro - Gln - Thr (tBu)-Ala- Ile - Gly OH, Z - Thr (tBu) - Leu - Thr (tBu)-Gln- Asp (OtBu) - Leu - Asn - Lys (BOC) - Leu - His- Thr (tBu) - Phe - Pro - Gln - Thr (tBu) - Ala-Ile- Gly OH. H - Val - Gly - Ala - Pro NH 2  Z- and H - Thr (tBu) - Leu - Thr (tBu) - Gln - Asp (OtBu) Leu - Asn - Lys (BOC) - Leu - His - Thr (tBu) - Phe - Pro - Gln - Thr (tBu) - Ala - Ile-Gly- Val-Gly-Ala-Pro NH 2  and BOC-Leu<SP>12,16,19</SP>-calcitonine - M, Z and H - Arg - Thr (tBu) - Ala- Ile - Gly - OH, Z - Thr (tBu) - Phe - Pro - Arg- Thr (tBu) - Ala - Ile - Gly OH, Z-Asn-Lys (BOC) Phe - His - Thr (tBu) - Phe - Pro - Arg - Thr (tBu)- Ala - Ile - Gly OH, Z - Lys (BOC) - Tyr (tBu)- Thr (tBu) - Gln - Asp (OtBu) - Phe - OMe and -NHNH 2 , Z - Lys (BOC) - Tyr (tBu) - Thr (tBu)- Gln - Asp (OtBu) - Phe - Asn - Lys (BOC) - Phe- His - Thr (tBu) - Phe - Pro - Arg - Thr (tBu)-Ala- Ile - Gly OH, Z and H - Lys (BOC) - Tyr (tBu)- Thr (tBu) - Gln - Asp (OtBu) - Phe - Asn - Lys (BOC) - Phe - His - Thr (tBu) - Phe - Pro - Arg- Thr (tBu) - Ala - Ile - Gly OH and BOC - Lys<SP>11</SP>- Arg<SP>24</SP> - calcitonine - M. Z - Lys (BOC) - Leu-OMe and -NHNH 2 , Z- and H-Lys (BOC)-Leu-Gln- OMe, Z - His - Lys (BOC) - Leu - Gln - OMe, HHis - Lys (BOC) - Leu - Gln - Thr (tBu) - Phe- Pro - Gln - Thr (tBu) - Ala - Ile - Gly OH, Z-Thr (tBu) - Tyr (tBu) - Thr (tBu) - Gln - Asp (OtBu)- Phe - His - Lys (BOC) - Leu - Gln - Thr (tBu)- Phe - Pro - Gln - Thr (tBu) - Ala - lie - Gly OH, Z- and H - Thr (tBu) - Tyr (tBu) - Thr (tBu)- Gln - Asp (OtBu) - Phe - His - Lys (BOC) - Leu- Gln - Thr (tBu) - Phe - Pro - Gln - Thr (tBu)-Ala- Ile - Gly - Val - Gly - Ala - Pro NH 2  and BOCHis<SP>17</SP> - Leu<SP>19</SP> - Gln<SP>20</SP> - calcitonine - M. Z and HLeu - Gly OMe, Z and H - Val - Leu - Gly OMe, TRI- and H-Cys (TRI)-Val-Leu-Gly OMe, DPC- and H-Ser (tBu)-Thr (tBu)-Cys (TRI)-Val- Leu - Gly - OMe, H - Ser (tBu) - Thr (tBu) - Cys (TRI) - Val - Leu - Gly - OH, BOC - Cys (TRI)- Gly - Asn - Leu - Ser (tBu) - Thr (tBu) - Cys (TRI) - Val - Leu - Gly OH, the corresponding cyclic peptide by oxidation and BOG-Val<SP>8</SP>-Tyr<SP>22</SP>- calcitonine - M). BOC - Val<SP>s</SP> - Leu<SP>12,16,19</SP>-calcitonine - M. BOC - desamino<SP>1</SP> - Leu<SP>12,16,19</SP>-calcitonine M. BOC - desamino<SP>1</SP> - Tyr<SP>22</SP>-calcitonine- M. Bmp (TRI) - Gly - Asn - Leu - Ser (tBu)- Thr (tBu) - Cys (TRI) - Val - Leu - Gly OH the corresponding cyclic peptide by oxidation and BOC - desamino<SP>1</SP> - Val<SP>8</SP> - Leu<SP>12,16,19</SP> - calcitonine - M. Z - Asn - Lys (BOC) - Leu- His - Thr (tBu) - Tyr (tBu) - Pro - Gln- Thr (tBu) - Ala - Ile - Gly OH, Z- and HAsn - Lys (BOC) - Leu - His - Thr (tBu) - Tyr (tBu) - Pro - Gln - Thr (tBu) - Ala - Ile - Gly - Val- Gly - Ala - Pro NH 2 , Z- and H - Thr (tBu)-Leu- Thr (tBu) - Gln - Asp (OtBu) - Leu - Asn - Lys (BOC) - Leu - His - Thr (tBu) - Tyr (tBu) - Pro- Gln - Thr (tBu) - Ala - lie - Gly - Val - Gly - Ala- Pro NH 2  and BOC - Leu<SP>12,16,19</SP>-Tyr<SP>22</SP>-calcitonine- M, BOC - Val<SP>s</SP>-Leu<SP>12,16,19</SP>-Tyr<SP>22</SP>-calcitonine-M. BOC - desamino<SP>1</SP>-Val<SP>8</SP>-Leu<SP>12,16,19</SP> - Tyr<SP>22</SP> - calcitonine - M. H - Thr (tBu) - Gln - Asp (OtBu)-Phe- OMe, Z - Leu - Thr (tBu) - Gln - Asp (OtBu)-Phe OMe, Z - Thr (tBu) - Leu - Thr (tBu) - Gln-Asp (OtBu) - Phe - OMe and NHNH 2 , Z- and HAsn - Lys (BOC) - Phe - His - Thr (tBu) - Phe- Pro - Gln - Thr (tBu) - Ala - lie - Gly - Val - Gly- Ala - Pro - NH 2 , H - Thr (tBu) - Leu - 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  and BOCLeu<SP>12</SP>-calcitonine - M. Z- and H - Asp (OtBu)- Leu - OMe, Z- and H - Gln - Asp (OtBu) - Leu OMe, Z- and H - Thr (tBu) - Gln - Asp (OtBu)- Leu - OMe, Z - Tyr (tBu) - Thr (tBu) - Gln-Asp (OtBu) - Leu - OMe, Z - Thr (tBu) - Tyr (tBu)- Thr (tBu)- Gln - Asp (OtBu) - Leu - OMe and- -NHNH 2 , Z- and H-Thr (tBu)-Tyr (tBu)-Thr (tBu) - Gln - Asp (OtBu) - Leu - Asn - Lys (BOC)- Phe - His - Thr (tBu) - Phe - Pro - Gln - Thr (tBu)- Ala - lie - Gly - Val - Gly - Ala - Pro NH 2  and BOC - Leu<SP>16</SP>-calcitonine - M. Z- and H-Asn- Lys (BOC) - Leu - His - Thr (tBu) - Phe - Pro- Gln - Thr (tBu) - Ala - Ile - Gly - Val - Gly - Ala- Pro NH 2 , Z- and H-Thr (tBu)-Tyr (tBu)-Thr (tBu) - Gln - Asp (OtBu) - Phe - Asn - Lys (BOC)- Leu - His - Thr (tBu) - Phe - Pro - Gln - Thr (tBu)- Ala - Ile - Gly - Val - Gly - Ala - Pro NH 2  and BOC-Leu<SP>19</SP>-calcitonine-M.