PEPTIDES

摘要

1530182 Polypeptides AMERICAN HOME PRODUCTS CORP 18 March 1976 [21 March 1975 10 Dec 1975] 10900/76 Heading C3H Peptides of Formula (I) wherein n is an integer of 1 to 5; Trp represents D- or L-tryptophyl and other amino acids are of the L-configuration; and the non-toxic acid addition salts thereof. and the non-toxic acid addition salts thereof; wherein Trp represents either D- or L-tryptophyl, and all other amino acids are in the L- configuration; n is an integer of 1 to 5; R12 is hydrogen or a protecting group for the #-amino group of lysine; R3, R4, R5 are independently hydrogen or a protecting group for the alcoholic hydroxyl group of threonine and serine; R11 is hydrogen or anα-carboxyl protecting group; R10 is hydrogen or a protecting group for the amino function; with the proviso that at least one of R12, R3, R4, R6, R10 and R11 is other than hydrogen. Peptides of Formulae (III) or (J) wherein Trp represents D or L-tryptophyl and other chiral amino acids are of the L-configuration; R1, R2 are the same or different and represent a protecting group for the #-amino group of lysine; R3, R4, R5 independently are hydrogen or a protecting group for the hydroxyl group of threonine and serine; R9, R13 areα- carboxyl protecting groups; R8 is hydrogen or a side chain carboxyl protecting group which is removable under conditions that will not remove the R9 carboxyl protecting group; R7 is anα-amino protecting group which differs from said R1, R2 groups in that it is cleavable under conditions which will not cleave said R1 and R2 protecting groups. Peptides of the Formula (II) R-Lys(R1)-Asn- Phe - Phe - Trp - Lys(R2) - Thr(R3) - Phe - Thr- (R4) - Ser(R5) - R6 wherein Trp represents either D- or L-tryptophyl and other chiral amino acids are of the L-configuration; R is anα-amino protecting group that is cleaveable under conditions that will not cleave the R1 and R2 protecting groups; R1 and R2 are protecting groups for the #-amino group of lysine; R3, R4, R5 independently are hydrogen or protecting groups for the alcoholic hydroxyl group of threonine and serine; R6 is selected from OH, NHNH 2 , N 3 , OCH 3 and R1 R2, R12 are preferably selected from benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, substituted benzyloxycarbonyl wherein said substituted is selected from halo and nitro; R3, R4, R5 are preferably selected from acetyl, benzoyl, t-butyl, trityl, benzyl, 2,6-dichlorobenzyl, benzyloxycarbonyl; R7 is preferably t-butyloxycarbonyl; R9, R11, R13 are preferably benzyl, phenacyl, phthalimidomethyl, benzhydryl, 1,1,1-trichloroethyl, 4-picolyl,α-methylthioacetyl, 4-(methylthio)-phenyl, substituted benzyl wherein said substituent is selected from at least one of nitro, methyl and methoxy; R is preferably selected from formyl, trifluoroacetyl, phthalyl, p-toluenesulphonyl, benzenesulphonyl, p-nitrophenylsulphenyl, tritylsulphenyl, O-nitrophenoxyacetyl,γ-chlorobutyryl, benzyloxycarbonyl, substituted benzyloxycarbonyl, benzhydrylcarbonyl, 1- (p - diphenylyl) - 1 - methylethoxycarbonyl, t-butyloxycarbonyl,α,α- dimethyl-3,5-dimethoxybenzyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, alloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, triphenylmethyl, benzyl, trimethylsilane. In the examples, wherein Trp is either D- or L-tryptophyl, the cesium salt of Boc-Ser (Bzl)- OH is reacted with chloromethylated polystyrene resin followed by sequential coupling of Boc-Thr (Bzl)-OH, Boc-Phe-OH, Boc-Thr- (Bzl)-OH, Boc-Lys-(ClCBz)-OH, Boc-Trp-OH, Boc-Phe-OH, Boc-Phe-OH, Boc-Asn-ONP, Boc-Lys-(ClCBz)-OH, with N-deprotection after each coupling to yield Boc-Lys-(ClCBz)- Asn - Phe - Phe - Trp - Lys - (CICBz) - Thr - (Bzl) - Phe - Thr - (Bzl) - Ser(Bzl) - O - Resin which, on treatment with hydrazine, yields Boc - Lys - (ClCBz) - Asn - Phe - Phe - Trp - Lys - (ClCBz) - Thr(Bzl) - Phe - Thr(Bzl) - Ser - (Bzl) - NHNH 2 , which, on reaction with H-Glu- (OBu')-OBzl yields Boc - Lys - (ClCBz) - Asn - Phe - Phe - Trp - Lys(ClCBz) - Thr(Bzl) - Phe - Thr(Bzl) - Ser(Bzl) - Glu(OBut) - OBzl which is treated with trifluoroacetic acid to yield H - Lys(ClCBz) - Asn - Phe - Phe - Trp - Lys - (ClCBz) - Thr(Bzl) - Phe - Thr(Bzl) - Scr - (Bzl) - Glu - OBzl which is cyclized with 1 - hydroxybenzotriazole/dicyclohexylcarbodiimide to yield ClCBz - Lys(-) - Asn - Phe - Phe - Trp - Lys(ClCBz) - Thy(Bzl) - Phe - Thr(Bzl) - Ser(Bzl) - Glu(-) - OBzl - (cyclo 1 -α- lysyl toγ-glutamyl) which, on treatment with either (i) hydrogenation over palladium/carbon (LTrp) or (ii) hydrogen fluoride/anisole (D-Trp) yields Lys(-) - Asn - Phe - Phe - Trp - Lys - Thr - Phe - Thr - Ser - Glu(-) - OH(cyclo - 1-α-lysyl toγ-glutamyl). Pharmaceutical compositions comprise peptides I or a non-toxic acid addition salt thereof (preferably the hydrochloride, hydrobromide, sulphate, phosphates maleate, citrate, acetate, benzoate, succinate, malate or ascorbate), together with a pharmaceutically-acceptable carrier.