Patent IE-41803-B1 (IE)
Title: Derivatives of histidyl-prolinamide
IPC: C07K5/097
Filed: 1975-10-01
Abstract: 1519636 Histidyl-prolinamide derivatives GRUNENTHAL GmbH 1 Oct 1975 [16 Oct 1974 21 June 1975] 40123/75 Heading C3H [Also in Division C2] Peptide derivatives of formula wherein R1, R2 are hydrogen, C1-3 alkyl or R1 and R2 represent an addition bond between the carbon atoms to which said radicals are attached:- R3 is hydrogen or C1-3 alkyl; Z is a divalent radical, which completes a fivemembered or six-membered ring, selected from wherein R4, R5 are H, C1-3 alkyl and pharmaceutically-acceptable acid salts thereof are claimed per se, and may be prepared by a process selected from the reaction of: (a) histidyl-prolinamide wherein the 1-(3)-position of the imidazole ring may be protected against acylation, or a derivative thereof obtained by the reaction of histidyl-prolinamide with a silylating agent derived from a trialkylsilanol or a dialkylsilanediol (wherein each radical of said silylating agents has 1 to 3 carbon atoms) with a carboxylic acid of the formulae wherein R1, R2, R2, Z are defined as above; Y is a group cleavable by hydrogenolysis in the presence of a condensation agent or with an acidhalide, anhydride, mixed anhydride, azide or activated ester of an acid of Formula II or IIa, and splitting off the group Y, the protecting group from the imidazole ring of the histidine residue and the silyl groups, if present; or (b) prolinamide with a compound of the formula wherein R1, R2, R3, Z are as above defined X is hydrogen or Y or a derivative of the compound of Formula III wherein the 1-(3)-position of the imidazole group is protected in the presence of a condensation agent, or with an acid halide, an anhydride, a mixed anhydride, an azide or an activated ester of a compound of Formula (III) and splitting off any protecting groups, if present; or (c) a compound of Formula IV wherein R1, R2, R3, X, Z are as above defined, W is hydroxy, acyloxy, p-nitrophenoxy, trichlorophenoxy, pentachlorophenoxy, pyridyloxy, pentafluorophenoxy, phenylmercapto, cyanomethyloxy, p-nitrophenylmercapto, the residue of N-hydroxysuccinimide of formula or a derivative of the compound of Formula IV in which the 1-(3)-position of the imidazole ring is protected, with ammonia or a compound which generates ammonia under the reaction conditions and splitting off any protective groups, if present; or (d) histidyl-prolinamide, wherein the 1-(3)-position of the imidazole group may be protected against acylation, with an acid of the formula wherein Hal is chlorine or bromine in the presence of a condensation agent, or with an acid halide, anhydride, mixed anhydride, azide or activated ester of an acid of Formula (V) and thereafter dehalogenating the intermediate by hydrogenolysis and effecting removal of the protective group, if present, to yield a compound of Formula (I) wherein R1, R2 form said additional bond, R3 is hydrogen and Z is and reacting, if desired, the compounds obtained with pharmaceutically-acceptable acids to form the corresponding salts. The protective group of (d) is preferably a group which is cleavable by hydrogenolysis in order to remove said group and the halogen atom coincidentally. Hydrogenolysis is preferably effected with a noble catalyst in the presence of an agent which binds the hydrogen halide released. In the Examples, the compounds prepared are: L - 2 - oxo - imidazolidine - 4 - carbonyl - L - histidyl - L - prolinamide hydrate; Orotyl - L - histidyl - L - prolinamide hydrate; Orotyl - L - histidyl - L - prolinamide hydrochloride; L - 5 - oxo - thiomorpholine - 3 - carbonyl - L - histidyl - L - prolinamide hydrate; 2 - oxo - imidazole - 4 - carbonyl - L - histidyl - L - prolinamide trihydrate; 5 - Oxo - 6 - DL - methyl - thiomorpholine - 3 - L - carbonyl - L - histidyl - L - prolinamide trihydrate; D - 5 - oxo - 2,2 - dimethyl - thiomorpholine - 3 - carbonyl - L - histidyl - L - prolinamide hydrate 5 - Methylorotyl - L - histidyl - L - prolinamide trihydrate; 5 - Ethylorotyl - L - histidyl - L - prolinamide hydrate; Orotyl - DL - histidyl - DL - prolinamide; Orotyl - L - histidyl - D - prolinamide; L - 2 - oxo - imidazolidine - 4 - carbonyl - L - histidyl - DL - prolinamide; 5 - Isopropylorotyl - histidyl - prolinamide; 2 - Oxo - 5,5 - dimethyl - imidazolidine - 4 - carbonyl - histidyl - prolinamide; 2 - Oxo - 4,5 - dimethyl - imidazolidine - 4 - carbonyl - histidyl - prolinamide; 2 - Oxo - 5 - ethyl - imidazolidine - 4 - carbonyl - histidyl - prolinamide; 2 - Oxo - 5 - methyl - 5 - ethyl - imidazolidine - 4 - carbonyl - histidyl - prolinamide; 5 - Oxo - 2,2,6 - trimethyl - thiomorpholine - 3 - carbonyl - histidyl - prolinamide; 5 - Oxo - 2,3,6 - trimethyl - thiomorpholine 3 - carbonyl - histidyl - prolinamide; 5 - Oxo - 6,6 - dimethyl - thiomorpholine - 3 - carbonyl - histidyl - prolinamide; 5 - Oxo - morpholine - 3 - carbonyl - histidyl - prolinamide; 5 - Oxo - 2,6 - dimethylmorpholine - 3 - carbonyl - histidyl - prolinamide. Intermediates isolated are:- N - benzyloxycarbonyl - L - 2 - oxo - imidazolidine - 4 - carbonyl - L - histidine; N - benzyloxycarbonyl - L - 2 - oxo - imidazolidine - 4 - carbonyl - L - histidyl L - prolinamide; 5 - Chloroerotyl - L - histidyl - L - prolinamide- 5 - Bromoorotyl L - histidyl - L - prolinamide. Pharmaceutical compositions, preferably for oral or parenteral administration, comprise compounds of Formula I, or the pharmaceutically-acceptable acid salts thereof.