IE40930B1 - Decapeptides - Google Patents

Abstract

1458685 Decapeptides AMERICAN HOME PRODUCTS CORP 25 Sept 1974 [3 Oct 1973 21 Nov 1973] 41612/74 Heading C3H Peptides of Formula (I) wherein X is Ala or Leu, and the non-toxic salts thereof (hydrocholoride, hydrobromide, sulphate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate or ascorbate). Derivatives of (I) of Formula (II) wherein N<SP>9</SP> represents side chain nitrogen atoms of Arg, R is NH 2 , OH, O-(lower)alkyl ("lower" being C 1-6 ), O-benzyl, R<SP>1</SP> is a protecting group for the N<SP>8</SP>, N<SP>#</SP>, N<SP>#1</SP> atoms of Arg, and is nitro, tosyl, benzyloxycarbonyl or adamantyloxycarbonyl (if R<SP>1</SP> is nitro or tosyl, protection is on either the N<SP>#</SP> or N<SP>#1</SP> and, if R<SP>1</SP> is benzyloxycarbonyl or adamantyloxycarbonyl, protection is on N<SP>#</SP> and either N<SP>#</SP> or N<SP>#1</SP>); R<SP>2</SP> is a protecting group for the phenolic hydroxyl of Tyr and is acetyl, tosyl, benzoyl, t-butyl, tetrahydropyranyl, trityl, benzyl, 2,4-dichlorobenzyl or benzyloxycarbonyl; R<SP>3</SP> is a protecting group for the alcoholic hydroxyl of Ser and is one specified for R<SP>2</SP>; R<SP>4</SP> is an aminoprotecting group or hydrogen; wherein R<SP>1</SP>, R<SP>2</SP> or R<SP>3</SP> may also be hydrogen, with the proviso that at least one of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is a protecting group and the non-toxic salts thereof. Derivatives of (II) of Formula (III) wherein R<SP>5</SP> is R<SP>4</SP>-(Pry)Glu, an α-aminoprotecting group or hydrogen; and A represents one of Preferred resins are benzhydrilamine, chloromethylated or hydroxymethyl styrene resins. The peptides may be prepared by Merrifield synthesis, to yield (III), followed by either (i) a one step cleavage and deprotection to yield (I) or (ii) cleavage to yield (II) followed by deprotection. Step (i) may be effected with hydrogen fluoride using benzhydrilamine resin, and step (ii) ammonolysis using a chloromethylated or hydroxymethyl resin. In the examples, the following peptides were prepared: H-(Pyr)Glu-D-Phe-Trp- Ser(Bzl) - Tyr(Bzl) - D - Ala - Leu- Arg(NO 2 ) - Pro - Gly benzhydrilamine resin; H - (Pyr)Glu - D - Phe - Trp - Ser- Tyr - D - Ala - Leu - Arg - Pro - Gly- NH 2 and acetate; H-(Pyr)Glu-D-Phe- Trp - Ser(Bzl) - Tyr(Bzl) - D - Leu- Leu - Arg(NO 2 ) - Pro - Gly benzhydrilamine resin; H - (Pyr)Glu - D - Phe - Trp- Ser - Tyr - D - Leu - Leu - Arg - Pro- Gly.NH 2 and acetate. Pharmaceutical compositions, for the inhibition of ovulation in female mammals, comprises a peptide of Formula (I) or a non-toxic salt thereof and a pharmaceutically acceptable carrier, said composition may be in unit dosage form. [GB1458685A]