Patent IE-41510-B1 (IE)
Title: Peptides having lh-rh/fsh-rh activity and proces for their manufacture
IPC: C07K5/103
Filed: 1975-08-08
Abstract: 1523623 Nona- and decapeptides HOECHST AG 11 Aug 1975 [9 Aug 1974] 33426/75 Heading C3H [Also in Division C2] A peptide of general Formula (I) H-(Pyr)Glu-His-Trp-Ser-Tyr-X-Leu-Arg-Pro-Y wherein X is D-Ser(Bu), D-Thr(Bu), D-Cys- (But), D-Asp(OBu), D-Glu(OBu), D-Orn(Boc) or D-Lys(Boc); Y is glycinamide, NH-cyclopropyl or NH alkyl wherein alkyl contains 1 to 3 carbon atoms, which groups Y may be substituted by one or more hydroxyl groups and/or fluorine atoms; and wherein the following substitutions of amino acid residues are optionally effected; Ser by Ala or Thr, Tyr by Phe, Leu by Ser(Bu), Cys(Bu), Asp(OBu), Glu(OBu), Orn(Boc) or Lys(Boc), Arg by Orn, Lys or Homoarg. Examples describe the preparation of H - (Pyr)Glu - His - Trp - Ser - Tyr - D - Ser(Bu)- Leu - Arg - Pro - NHEt; H - (Pyr)Glu - His - Trp - Ser - Tyr - D - Glu- (OBu) - Leu - Arg - Pro - NHEt; H - (Pyr)Glu- His - Trp - Ser - Tyr - D - Ser(But)- Arg-Pro-NHEt; H - (Pyr)Glu - His - Trp - Ser - Tyr - D - Lys(Boc)- Leu-Arg-Pro-Gly-NH2; H - (Pyr)Glu - His - Trp - Ser - Tyr - D - Ser (Bu)-Leu-Arg-Pro-NH.Cp (Cp = cyclopropyl). Comparative Examples describe: H - (Pyr)Glu - His - Trp - Ser - Tyr - D - Ser - Leu - Arg - Pro - NHEt; H - (Pyr)Glu - His - Trp-Ser- Tyr - D - Glu - Leu - Arg - Pro - NHEt; Peptide intermediates isolated are: OCTAPEPTIDE: H - Trp - Ser - Ter D - Lys- (Boc) -Leu-Arg-Pro-Gly-NH2; HEXAPEPTIDES: H - Ser - Tyr - D - Ser- (Bu) - Ser - - (Bu) - Arg - Pro - NHEt; H - Ser- Tyr - D - Ser(Bu) - Leu - Arg - Pro - NHEt; Z - Ser - Tyr(Bzl) - D - Ser(Bu) - Leu - Arg - Pro- NHEt; H - Ser - Tyr D - Glu(OBu) Leu - Arg- Pro - NHEt; Z - Ser - Tyr(Bzl) D - Glu(OBu)- Leu - Arg - Pro - NHEt; H - Ser - Tyr D - Ser- (Bu) - Leu - Arg - Pro - NHCp; Z - Ser - Tyr- (Bzl) - D - Ser(Bu) - Leu - Arg - Pro - NHCp. PENTAPEPTIDE: H - D - Lys(Boc) - Leu- Arg-Pro-Gly-NH2. TETRAPEPTIDES: Z and H - D - Ser(Bu)- Leu - Arg - Pro - NHEt and NHCp; Z and H - D - Glu(OBu) - Leu - Arg - Pro - NHEt; HD - Ser(Bu) - Ser(But) - Arg - Pro - NHEt; ZLeu - Arg(NO2) - Pro - Gly - NHMbh; H - Leu- Arg-Pro-Gly-NH2. TRIPEPTIDES: H - Leu - Arg - Pro - NHEt and NH.Cp; H-Ser(Bu)-Arg-Pro-NHEt. Dipeptide intermediates isolated are: Z - Arg(Z2) - Pro NHEt and NH.Cp; H - Arg- Pro-NHEt and NH.Cp; Z-Ser-Tyr(Bzl)-OH; Z and H-Pro-Gly-NH.Mbh; Z-Leu-Arg(NO2)-OH. Pharmaceutical preparations in a form for parenteral (intravenous, intramuscular, subcutaneous or intranasal) administration comprises peptides (I) in a admixture or conjunction with a pharmaceutically acceptable carrier and in a form for enteral (oral) administration comprise peptides (I) except wherein X is Lys(Boc) or Orn(Boc) and/or in which Leu is replaced by Lys(Boc) or Orn(Boc) in admixture or conjunction with a pharmaceutically acceptable carrier. The compounds (I) may be in unit dosage form and are used to aid contraception by the rhythm method, or to predetermine ovulation in a non-human female to facilitate conception. In the examples, pharmaceutical compositions are: (6) oral, peptide of Example 1, lactose, potato starch, gelatine, magnesium stearate, hydrated silica, talcum; (7) intranasal, peptide of Example 2, distilled water, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, benzyl alcohol, polyvinyl alcohol; (8) injection, peptide (I) wherein X is D-Lys(Boc), Y is NHEt, distilled water, phosphate buffer of pH 4À5, mannitol, sodium chloride, (9) injection, composition of Example 9, 4-hydroxybenzoic acid methyl ester.