Patent GB-1259870-A (GB)
Title: Polypeptides
Inventor: GUTTMANN STEPHAN
IPC: C07K1/113
Filed: 1969-03-31
Abstract: 1,259,870. Peptides. SANDOZ Ltd. 31 March, 1969 [16 April, 1968 (4); 18 Oct., 1968 (2); 25 Oct., 1968 (2); 6 Nov., 1968 (2)], No. 16822/69. Heading C2C. Compounds (I) of the formula S S CH 2  X-CH-CO-Ser - Asn - Leu - Ser - Thr - Cys- Val - Leu - Ser - Ala - Tyr - Trp - Arg - Asn- Leu - Asn - Asn - Phe - His - Arg - Phe - Ser- Gly - Y - Gly - Phe - Gly - Pro - Glu - Thr- Pro.NH 2 , where X is H, NH 2 RCONH or R<SP>2</SP>OCONH; R is alkyl or optionally substituted aryl or aralkyl ; R<SP>1</SP> is alkyl, alkenyl or optionally substituted aryl or optionally substituted aralkyl and Y is Met or Nle are prepared by (a) removing the protective groups from an appropriately N-protected peptide to give (I X=NH 2 ) or (b) converting a compound (II) #S S #CH 2 # #X<SP>1</SP>-CO-Ser - Asn - Leu - Ser - Thr - Cys-# Val-Leu-X<SP>11</SP>, where X<SP>1</SP> is H, RCONH or R<SP>1</SP>OCONH, and X<SP>11</SP> is NHNH 2  into its azide and condensing this with a compound (III): H - Ser - Ala - Tyr - Trp - Arg - Asn - Leu - Asn- Asn - Phe - His - Arg - Phe - Ser - Gly - Y - Gly- Phe - Gly - Pro - Glu - Thr - ProNH 2  to give (I X = H, RCONH or R<SP>2</SP>OCONH) or (c) condensing an active ester of (II) with (III).  The following starting materials and intermediates are prepared: R<SP>11</SP> - Cys - Ser - Asn - Leu - Ser - Thr - Cys - Val- Leu - OSu where R<SP>11</SP> is BOC, Piv (pivaloyl) or EOC; Z - Thr - ProNH 2 , H - Thr - ProNH 2 , Z - Glu(OTB) - Thr - ProNH 2 , H - Glu(OTB)- Thr - Pro - NH 2 , Z - Phe - Gly - Pro - Glu(OTB)- Thr - Pro - NH 2  and H - Phe - Gly - Pro- Glu(OTB) - Thr - ProNH 2 ; H - Met - Gly OEt, HCl, BOC - Ser - Gly - OEt and its hydrazide, BOC - Ser - Gly - Met - Gly - OEt and its free acid, Z - Arg(NO 2 ) - Phe - OMe, H - Arg(NO 2 )- Phe - OMe, Z - His(Z) - Arg(NO 2 ) - PheOMe, H - His - Arg - Phe - OMe, 4HCl. Trit His (Trit) - Arg - Phe - OMe, HCl, and its hydrazide; H - Ser - Gly - Met - Gly - Phe - Gly - Pro - Glu - Thr - Pro - NH 2 HCl and its BOC protected-Glu-(OTB) derivative, HHis(Trit) - Arg - Phe - Ser - Gly - Met- Gly - Phe - Gly - Pro - Glu - Thr - Pro- NH 2  and its N - trityl derivative; BOCPheNHNHZ, BOC - Asn - Phe - NHNHZ, BOC - Asn - Asn - Phe - NHNHZ, BOCLeu - Asn - Asn - Phe - NHNHZ, BOC - Asn- Leu - Asn - Asn - Phe - NHNHZ, and its N- unprotected derivative; BOC - Ser - Ala - Tyr- Trp - Arg - NHNH 2 , BOG - Tyr - Trp - Arg(NO 2 ) OMe, BOC - Als - Tyr - Trp - Arg(NO 2 ) - OMe, BOC - Ser - Ala - Tyr - Trp - Arg(NO 2 ) - OMe and BOC - Ser - Ala - Tyr - Trp - Arg - NHNH 2 ; BOG - Ser - Ala - Tyr - Trp - Arg - Asn - Leu- Asn - Asn - Phe - NHNH - Z and BOC - Ser- Ala - Tyr - Trp - Arg - Asn - Leu - Asn - Asn- Phe - NHNH 2 ; a compound (III, Y=Met.) and its BOC - N<SP>im</SP> - trityl derivative; H - Cys- (Bzl) - Val - Leu - OMe, HBr, H - Thr - Cys- (Bzl) - Val - Leu - OMe and its Z-derivative; H - Asn - Leu - Ser - Ome, HCl - H - Ser - Asn- Leu - Ser - OMe, HCl and BOC - Cys(Bzl)- Ser - Asn - Leu - Ser - NHNH 2 ; BOC - Cys(Bzl)- Ser - Asn - Leu - Ser - Thr - Cys(Bzl) - Val - Leu- OMe, and its hydrazide, compound (II, X<SP>1</SP>= BOC - NH-, X<SP>11</SP>=NHNH 2 ); H - Thr - Cys- (Bzl) - Val - Leu - OH, BOC - Cys(Bzl) - Ser- Asn - Len - Ser - Thr - Cys(Bzl) - Val - Leu - OH, BOC - Cys - Ser - Asn - Leu - Ser - Thr - Cys- Val - Leu - OH and a compound (II, X<SP>1</SP>= BOC - NH, X<SP>11</SP>=OH), Z - Nle - Gly - OH, HNle - Gly - OH, Z - Gly - Nle - Gly - OH, and Z - Ser - Gly - Nle - Gly - OH; Z - Ser - Gly- Nle - Gly - Phe - Gly - Pro - Glu(OTB) - Thr- Pro - NH 2  and the N-unprotected peptide, Trit- His(Trit) - Arg - Phe - Ser - Gly - Met - Gly - Phe- Gly - Pro - Glu - Thr - Pro - NH 2  and the N- unprotected peptide; compounds BOC-(III, Y=  Nle) and (III, Y=Nle); a compound (II, X<SP>1</SP>= pivaloylamino, X<SP>11</SP>=OH) and pivalic acid pnitrophenyl ester; a compound (II, X<SP>1</SP> = EOC-NH and X<SP>11</SP>=OH) and carbonic acid p-nitrophenyl ethyl ester; H - Asn - Leu - Ser - OMe, BOC - Ser- Asn - Leu - Ser - OMe and the N - unprotected peptide, BzlMCP - Ser - Asn - Leu - Ser - OMe and its hydrazide; BzlMCP - Ser - Asn- Leu - Ser - Thr - Cys(Bzl) - Val - Leu - OMe, its hydrazide and a compound (II, X<SP>1</SP>=H, X<SP>11</SP>= NHNH 2 ).