Patent GB-1461437-A (GB)
Title: Peptides and process for preparing them
IPC: C07K1/113
Filed: 1974-05-09
Abstract: 1461437 Angiotensis (II) derivatives HOECHST AG 9 May 1974 [9 May 1973] 20528/74 Heading C3H [Also in Division C2] Peptides (I) of formula X - Arg - Val - Tyr - Ile - His - Pro - Phegly - OH where X=aliphatic carboxylic acid residue of up to five carbon atoms, optionally substituted by one or more -CO 2 H, -CONH 2 , -NH 2 , -NHCH 3  or carbobenzoxyamino groups; or a phthalic acid radical Phegly-OH is L-C- phenylglycyl may be prepared by condensing a peptide H - Arg - Val - Tyr(tBu) - Ile - His - Pro- Phegly-OtBu with a carboxylic acid in which any free amino and/or carboxyl groups are protected by a group removable by hydrogenolysis or proton solvolysis and, if two carboxyl groups are present, they may be in the form of an intramolecular anhydride, and subsequently eliminating some, or all, of the protective groups by hydrogenolysis and/or proton solvolysis. Carboxylic acids of the formula X-OH specified are asparagine, isoasparagine, aspartic acid, sarcosine, #-alanine, glutamic acid, glutamine, N-methylglutamine, isoglutamine, N - methylasparagine, and the N - carbobenzoxy derivatives thereof; succinic acid, glutaric acid and the #-amides thereof. Zinc complexes of (I) are prepared by adding an excess of a solution of a zinc salt (chloride or sulphate) to an aqueous solution of (I) in the optional presence of a phosphate and precipitating the complex as the basic hydroxide or phosphate on pH adjustment to weakly alkaline. Gelatine complexes are prepared by reacting a partially-degraded cross-linked (with hexamethlene diisocyanate) gelatine with (I). A gelatine/polyphloretin phosphate/(I) complex is prepared by the reaction of aqueous solutions of gelatine, polyphloretin phosphate and (I) in any order. The following compounds are exemplified H.Asn - Arg - Val - Tyr - Ile - His - Pro - Phegly- OH; H.Asp - Arg - Val - Tyr - Ile - His - Pro- Phegly - OH; H.Asp(Arg - Val - Tyr - Ile - His- Pro - Phegly - OH) - OH; H.Sar - Arg - Val- Tyr - Ile - His - Pro - Phegly - OH; H.# - Ala- Arg - Val - Tyr - Ile - His - Pro - Phegly - OH; Glutaroyl - Arg - Val - Tyr - Ile - His - Pro- Phegly - OH; Phthaloyl - Arg - Val - Tyr - Ile- His - Pro - Phegly - OH; Succinamidyl - Arg- Val - Tyr - Ile - His - Pro - Phegly - OH. The following intermediates are isolated: OCTAPEPTIDES : Z - Asn - Arg - Val - Tyr- Ile - His - Pro - Phegly - OH; Z - Asn - Arg - Val- Tyr(OtBu) - Ile - His - Pro - Phegly - OtBu; Z - Asp(OtBu) - Arg - Val - Tyr(tBu) - Ile - His- Pro - Phegly - OtBu; Z - Asp - Arg - Val - Tyr- Ile - His - Pro - Phegly - OH; Z - Asp(Arg - Val- Tyr(tBu) - Ile - His - Pro - Phegly - OtBu)- oBzl; H - Asp(Arg - Val - Tyr(tBu) - Ile - His- Pro - Phegly - OtBu) - OH; Boc - Sar - Arg- Val - Tyr(tBu) - Ile - His - Pro - Phegly - OtBu. HEPTAPEPTIDES: Boc - # - Ala - Arg - Val- Tyr(tBu) - Ile - His - Pro - Phegly - OtBu; Glutaroyl - Arg - Val - Tyr(tBu) - Ile - His- Pro - Phegly - OtBu; Phthaloyl - Arg - Val - Tyr- (tBu) - Ile - His - Pro - Phegly - OtBu; Succinamidyl - Arg - Val - Tyr(tBu) - Ile - His - Pro- Phegly - OtBu. HEXAPEPTIDES: Z - Val - Tyr(tBu) - Ile His - Pro - Phegly - OtBu; H - Val - Tyr(tBu)- Ile - His - Pro - Phegly - OtBu.CH 3 COOH. TRIPEPTIDES: Z - His - Pro - Phegly- OtBu; H - His - Pro - Phegly - OtBu; Z - Val- Tyr(tBu) - Ile - OCH 3 ; Z - Val - Tyr(tBu) - Ile- OH. The following dipeptides are isolated: ZPro - Phegly - OtBu; H - Pro - Phegly - OtBu; Z - Tyr(tBu) - Ile - OCH 3 ; H - Tyr(tBu) - Ile- OCH 3 . Pharmaceutical compositions, which are used for the differential diagnosis of hypertonia and for treatment of renin-angiotension induced forms of hypertonia, comprise (I) or the complexes of (I) and a pharmaceutically acceptable carrier (optionally including a preserving agent) in the form of aqueous solutions or lyophilized products.