POLYPEPTIDE

摘要

1523812 Polypeptides IMPERIAL CHEMICAL INDUSTRIES Ltd 18 March 1977 [8 April 1976 21 May 1976 27 May 1976 14 July 1976 28 Oct 1976 (2)] 14362/76 21063/76 22055/76 29298/76 44837/76 and 44838/76 Heading C3H [Also in Division C2] A polypeptide of the formula wherein R<1> is hydrogen or an alkyl radical of 1 to 6 carbon atoms. R<2> is hydrogen, or a radical which is selected from (i) alkanoyl of 1 to 3 carbon atoms; (ii) alkoxycarbonyl of 2 to 6 carbon atoms; (iii) an amino acid residue, which is H-Arg, H-Gly, H-Glu, H-Asp, H-Phe, H-#-Ala, H-Lys, H-D-Lys wherein H-Lys and H-D-Lys may be substituted on the #-amino group by alkoxycarbonyl of 2 to 6 carbon atoms; (iv) a peptide residue of 2 to 6 amino acid residues, which residues are independently selected from Gly, Lys, Pro, Phe, Gln, Glu, Leu, D-Lys, Arg, Asp; wherein Lys, Arg are optionally alternatively bonded via the #-amino or #-guanidino moieties thereof respectively; and wherein Asp and Glu are optionally alternatively bonded via the #-carboxy or gamma-carboxy moieties thereof respectively; (v) alkyl of 1 to 6 carbon atoms; B is D-Ser, D-Thr which are optionally substituted on the #-hydroxyl thereof by alkyl of 1 to 6 carbon atoms, or B is D-Ala, D-Leu, D-Asp, D-Lys, D-Trp, D-Met, #-Ala, Azala; E is Gly, Azgly which are optionally substituted on the alpha-amino by alkyl of 1 to 6 carbon atoms; or E is #-Ala optionally substituted on the #-amino by alkyl of 1 to 6 carbon atoms; F is Phe, hexahydroPhe, Azphe, hexahydro- Azphe which residues may be substituted on the alpha-amino by alkyl of 1 to 6 carbon atoms; G is Leu, D-Leu, Met, D-Met, Nle, D-Nle, Ile, D-Ile which residues may be substituted on the alpha-amino by alkyl of 1 to 6 carbon atoms; or G is Pro, Azleu, Azpro; K is selected from (i) OH, NH2; (ii) OR<3> wherein R<3> is alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms; aminoalkyl of up to 6 carbon atoms; alkylaminoalkyl of 2 to 10 carbon atoms wherein the nitrogen atom of aminoalkyl and alkylaminoalkyl may be substituted by benzyloxycarbonyl; phenyl; a radical of formula wherein R<4> is alkanoyl of 1 to 20 carbon atoms; (iii) NHR<5> wherein R<5> is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; (iv) NR<6>R<7>, wherein R<6>, R' are alkyl of 1 to 6 carbon atoms, or R<6> and R<7>, taken together with the nitrogen atom, form a 5-membered or 6- membered ring which may include one other hetero atom; (v) NHCH2CH2OR<4>; (vi) hydroxyalkylamino of 1 to 6 carbon atoms; (vii) (alkylamino)alkylamino of 2 to 10 carbon atoms or (dialkylamino)akylamino of 3 to 10 carbon atoms; (viii) Gly-OR<8>, D-Thr-OR<8>, Thr-OR<8>, D-Ala- OR<8>, Ala-OR<8> wherein R<8> is hydrogen, alkyl of 1 to 6 carbon atoms or a radical of Formula II, III or IV; (ix) alkyl of 1 to 6 carbon atoms; or G and K, taken together, represent the D-configuration or L-configuration of a radical of formula; wherein n is an integer of 1 to 4; or a radical of formula and the pharmaceutically-acceptable acid addition salts thereof if the polypeptide (I) contains a basic function, and the pharmaceutically-acceptable base addition salts thereof, if the polypeptide (I) contains an acidic function. R<1> is preferably methyl; R<2> may be acetyl, # D-Lys(Boc), Lys(Boc), H-Glu-Gly-OH H-Lys, H - Phe- H - Lys, H - Gly - Gly - Gly- H - Lys, H - Asp- H - Lys, H - Lys H - Lys, H - Gly- # Gly, H-Leu-Leu-Leu, H-Arg-Pro-Lys, H-Pro- Gln-Gln, H-Gly-Gly-Gly, H-Arg-Pro-Lys-Pro- Gln-Gln, H-Gly-Gly-Gly-Gly-Gly, methyl; B may be D-Ser(Bu); K may be methoxy, tbutoxy, isopentyloxy, allyloxy, 2-hydroxyethoxy, 2 - aminoethoxy, (2 - methylamino)- ethoxy, 2 - (N - phenoxycarbonylamino)ethoxy, 2 - (N - methyl - N - phenoxycarbonylamino)- ethoxy, phenoxy, 1,3-diacetoxyprop-2-yloxy, 2,3 - diacetoxypropoxy, 1,3 - dihexanoyloxyprop - 2 - yloxy, 2 - acetoxyethoxy, 2,3 - dipalmitoyloxypropoxy, 2 - palmitoylethoxy, ethylamino, cyclohexylamino, diethylamino, pyrrolidino, morpholino, 2 - hydroxyethylamino, 2 - (methylamino)ethylamino, methyl, Gly - OMe, Thr - OH, 2 - (dimethylamino)ethylamino, D - Thr - OH, Ala - OMe, D - Ala - OMe. Peptides (I) may be prepared by a process selected from: (i) deprotection of a protected peptide which peptide corresponds to Formula (I); (ii) in peptides (I) in which K is other than hydroxy, or, wherein K is Gly-OR<8>, D-Thr-OR<8>, Thr-OR<8>, D-Ala-OR<8> or Ala-OR<8>, R<8> is other than H, and in peptides (I) in which G and K, taken together, represent radicals of Formula V, VI and VII; the reaction of a carboxylic acid of formulae R<1>R<2>-Tyr-B-E-F-G-OH or R<1>R<2>-Tyr-B-E-F-OH or an activated derivative thereof, with an alcohol or amine, so as to produce a peptide of the Formula (I) Polypeptides of Formula (I) prepared are: TETRAPEPTIDE PENTAPEPTIDES H - MeTyr - D - Ala - Gly - Phe - Leu - OMe ; H - Tyr - D - Ala - Azgly - Phe - Azleu - NH2; H - Tyr - D - Ala - Gly - Phe - Leu - OCH2CH2NH2; H - Tyr - D - Ala - Gly - Phe - Leu - OCH2CH2NHMe; H-Tyr-D-Ala-Gly-Phe-Leu-NH2; HTyr - D - Ala - Gly - Phe - Nle - OMe; H - Tyr- D - Ala - Gly - Phe(6H) - Leu - OH; H - Tyr - DAsp - Gly - Phe - Leu - OMe; H - Tyr - Azala- Gly - Phe - Leu - OMe; H - Tyr - D - Leu - Gly- Phe - Leu - OMe; H - Tyr - D - Ser - Gly - Azphe- Leu - OMe; H - Tyr - D - Ser - Gly - Phe - Leu- OCH2CH2OAC; H - Tyr - D - Ser - Gly - Phe- Leu - OCH2CH2OCOC15H31; H - Tyr - D - Ser- Gly - Phe - Leu - OCH2CH2OH; H - Tyr - DSer - Gly - Phe - Leu - OCH2CH(OAc)CH2OAc; H - Tyr - D - Ser - Gly - Phe - Leu - OCH2CH- (OCOC15H31(CH2OCOC15H31; H - Tyr - D - Ser- Gly - Phe - Leu - OCH(CH2OAc)2; H - Tyr - DSer - Gly - Phe - Leu - OCH(CH2OCOC5H11)2; H - Tyr - D - Ser - Gly - Phe - Leu - OBu; HTyr - D - Thr - Gly - Phe - Leu - OMe; H - Tyr- # - Ala - Gly - Phe - OMe; H - MeTyr - D - Ser- Gly - Phe - Leu - OMe; H - MeTyr - D - Ser(Bu)- Gly - Phe - Leu - OMe; H - Tyr - D - Ala - Gly- Phe - Azleu - NH2; H - Tyr - D - Ala - Gly - Phe- Leu - OMe; H - Tyr - D - Ala - Gly - Phe - Met- OMe; H - Tyr - D - Ala - Gly - Phe - Pro - NHEt; H-Tyr-D-Lys-Gly-Phe-Leu-OMe; HTyr - D - Met - Gly - Phe - Leu - OMe; H - Tyr- D - Ser - Gly - Phe - Azleu - NH2; H - Tyr - DSer - Gly - Phe - Leu - OMe; H - Tyr - D - Ser- Gly - Phe - Met - OMe; H - Tyr - D - Ala - Gly- Phe - Leu - OH; H - Tyr - D - Ala - Gly - Phe- Leu-OCH2CH2OH; H-Tyr-D-Ala-Gly-Phe-Leu- OCH2CH2NHZ; H - Tyr - D - Ala - Gly - Phe- Leu - OCH2CH2NMeZ; H - Tyr - D - Ala - Gly- Phe - Leu - OCH2CH = CH2; H - Tyr - D - Ala- Gly - Phe - Leu - OPh; H - Tyr - D - Ala - Gly- Phe - Leu - NHCH2CH2OH; H - Tyr - D - Ala- Gly - Phe - Leu - NHCH2CH2NHMe; H - Tyr - DAla - Gly - Phe - DL - OMe; H - Tyr - D - Ser- Gly - Phe - Azpro - NHEt; H - Tyr - D - Ser - Gly- Phe - Leu - OCH2CH2CHMe2; H - Tyr - D - Ser- Gly - Phe - Pro - NHEt; H - Tyr - D - Ser - Gly- Phe(6H) - Leu - OH; H - MeTyr - D - Ser - Gly- Phe(6H)-Leu-OH; Ac-Tyr-D-Ala-Gly-Phe-Leu- OH; H - MeTyr - D - Ala - Gly - Phe - Leu - NH2; H-Tyr-D-Ala-Gly-Phe-Leu-NHEt. HEXAPEPTIDES: H - # - Ala - Tyr - D - Ala- Gly - Phe - Leu - OMe; H - Asp - Tyr - D - Ala- Gly - Phe - Leu - OMe; H - Lys - MeTyr- D - Ser- Gly - Phe - Leu - OMe; H - Gly - Tyr - D - Ala- Gly - Phe - Leu - OMe; H - Lys - Tyr - D - Ala- Gly - Phe - Azleu NH2; H - D - Lys - Tyr - DAla - Gly - Phe - Leu -OMe; H - Lys - Tyr - Azala- Gly - Phe - Leu - OMe; H - Lys - Tyr - D - Ala- Gly - Phe - Met - OMe; H - Tyr - D - Ala - Gly- Phe-Leu-D Ala - OMe; H Tyr - D - -Ala- Gly- Phe - Leu - Ala - OMe; H - Tyr - D - Ala - Gly- Phe - Leu - Gly - OMe; H - Tyr - DAla - Gly- Phe-Leu-D-Thr-OH. HEPTAPEPTIDES: H - Gly - Gly - - Tyr D- # Ala - Gly - Phe - Leu - OMe; H - Asp- H - Lys- Tyr - D - Ala - Gly - Phe - Leu - OMe; H- # Lys- H - Lys - Tyr - D - Ala - Gly - Phe - Leu- # OMe; H - Phe- H - Lys Tyr - D - Ala - Gly- Phe-Leu-OMe. OCTAPEPTIDES: H - Arg - Pro - Lys - Tyr- D - Ala - Gly - Phe - Leu - OMe; H - Gly - Gly- Gly - Tyr - D - Ala - Gly - Phe - Leu - OMe; HGly - Gly - Gly - Tyr - D - Ser - Gly - Phe(6H)- Leu - OMe; H - Leu - Leu - Leu - Tyr - D - Ala- Gly - Phe - Leu - OMe; H - Pro - Gln - - Gln Tyr- D - Ala - Gly - Phe - Leu- OMe; H - Glu - Gly - OH # # H - Lys - Tyr - D - Ala - Gly - Phe - Leu - OMe; H - Gly - Gly - Gly - MeTyr - D - Ser - Gly - Phe- Leu-OMe. NONAPEPTIDES: H - Asp - Gly - Gly - Gly- Tyr - D - Ala - Gly - Phe - Leu - OMe; H - Lys- Gly - Gly - Gly - Tyr - D - Ala - Gly - Phe - Leu- OMe; H - Gly - Gly - Gly- H - Lys - Tyr - D - Ala- Gly-Phe-Leu-OMe. UNDECAPEPTIDES: H - Arg - Pro - Lys- Pro - Gln - Gln - Tyr - D - Ala - Gly - Phe - Leu- OMe; H - Gly - GIy - GIy - Gly - Gly - Gly - Tyr- D-Ala-Gly-Phe-Leu-OMe. Peptides intermediates isolated are: DIPEPTIDES: H - Azphe - Leu - OMe.HCl; H and Z - - Gln Gln - NHNHBoc; H - Phe- Azleu - NH2; H - Phe - Nle - OMe; Z - Phe - Nle- OMe; Boc - - Phe - Azleu - NH2; H - Pro - Lys (Z)- OMe.HCl; Boc-Pro-Lys(Z)-OMe. TRIPEPTIDES: H and Z - D - Ala - Gly- Phe - OMe; Z - Arg(Z2) - Pro - Lys(Z) - OH and OMe; H - Azgly - Phe Azleu - NH2.HCl; ZAzgly - Phe - Azleu - NH2; H - Gly - Azphe - Leu- OME.HCI; H Gly - Phe - Nle - OMe.TosOH; Z - Gly - Phe - Nle - OMe; Boc - Gly - Azphe - Leu- OMe; Boc - Gly - Gly - Gly - OH, ONa, OMe, OBzl; H - Gly - Phe - Leu - OMe; Z - Pro Gln- Gln - NHNHBoc; Z and H - D - Ser(Bu) - Gly- Phe - OMe; H - D - Ser(Bu) - Gly - Phe(6H)- OMe; Z-Tyr(Bzl)-Azala-Gly-NHNH2 TRIPEPTIDES: H - D - Ala - Gly - Phe - Leu- OMe.HCl; H - D - Asp Gly - Phe - Leu OMe; Z-D-Ala-Gly-Phe-Leu-OMe; Z-D-Asp(OBzl)- Gly-Phe-Leu-OMe; H - D - Leu - Gly - Phe- Leu - OME.TFA; Boc D - Leu Gly - Phe - Leu- OMe; Z and H - D - Lys(Boc) Gly - Phe - Leu- OMe; H - D - Met Gly - Phe - Leu - OMe.HCl; Boc - D - Met - Gly - Phe - Leu - OMe; Z and H - D - Ser (But - Gly - Phe - Leu - OMe ; Z and H-D-Thr-Gly-Phe-Leu-OMe; H-D-Trp- Gly - Phe - Leu - OMe.TFA; Boc - D - Trp - Gly- Phe - Leu - OMe; H - D - Ala - Azgly - Phe- Azleu - NH2.HCl; H - D - Ala - Gly - Phe - Nle- OMe.TosOH; H - D - Ala G