Patent GB-1523685-A (GB)
Title: Tripeptides
IPC: C07K5/097
Filed: 1976-07-27
Abstract: 1523685 Tripeptides AYERST MCKENNA & HARRISON Ltd 27 July 1976 [28 July 1975] 31222/76 Heading C3H [Also in Division C2] A peptide of Formula (I) wherein R<1> is hydrogen, lower alkyl (straightchain alkyl of 1 to 6 carbon atoms, or branched chain alkyl of 3 or 4 carbon atoms, with the exception of t-butyl) or NR<4>R<5> wherein R<4> and R<5> are lower alkyl, R<2> is hydrogen or lower alkyl; R<3> is amino, (lower alkyl)amino, di(lower alkyl)- amino or amino(lower alkyl)amino; Y is Gly or D-Ala with the proviso that, (i) when R<1> is NR<4>R<5>, then R<3> is (lower alkyl)amino, di- (lower alkyl)amino or amino(lower alkyl)amino; (ii) when R<1> is hydrogen and Y is Gly, then R<3> is amino(lower alkyl)amino or a pharmaceutically-acceptable acid addition salt thereof. The salts are preferably of acetic acid, lactic acid, succinic acid, benzoic acid, salicyclic acid, methane sulphonic acid, p-toluenesulphonic acid, pamoic acid, tannic acid, hydrochloric acid, sulphuric acid, phosphoric acid and carboxymethylcellulose. Peptides of Formula (II) wherein R<6> is an amino protecting group. R<7> is hydroxyl, lower alkoxy (of 1 to 6 carbon atoms) amino, (lower alkyl)amino, di(lower alkyl)amino or protected amino(lower alkyl)- amino; with the proviso that when R<7> is protected amino(lower alkyl)amino, R<6> may be hydrogen and with the further provisos that (i) when R<1> is NR<4>R<5>, R<7> is (lower alkyl)amino, di- (lower alkyl)amino, amino(lower alkyl)amino or protected amino(lower alkyl)amino, (ii) when R<1> is hydrogen and Y is Gly, then R<7> is amino(lower alkyl(amino or protected amino(lower alkyl)- amino. R<1> is preferably hydrogen, methyl, ethyl, isobutyl, dimethylamino, diethylamino, di-n-propylamino; R<2> is preferably hydrogen, methyl, isopropyl or isobutyl; R<3> is preferably amino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino or 4- aminobutylamino; R<6> is preferably t-butoxycarbonyl, benzyloxycarbonyl, benzyl, alpha,alpha-dimethyl - 3,4 - dimethoxybenzyloxycarbonyl or triphenylmethyl; R<7> is preferably methoxy, ethoxy, amino, methylamino, ethylamino, npropylamino, dimethylamino, diethylamino, 4-aminobutylamino or 4-(N-t-butoxycarbonyl)- butylamino. The peptides of formula may be prepared by deprotecting a compound of formula wherein R<8> is amino, (lower alkyl)amino, di- (lower alkyl)amino, amino(lower alkyl)amino or protected amino(lower alkyl)amino which may be prepared by a process which comprises acylating a compound of formula wherein R<9> is amino, (lower alkyl)amino, di- (lower alkyl)amino, protected amino(lower alkyl)amino, with an acid of formula or an acylating derivative thereof (defined), which may be prepared by hydrolysing an ester of formula which may be prepared by the sequential condensation of and The condensing agent is preferably N,N<1>- carbonyldiimidazole and R<8>, R<9> may be methylamino, ethylamino, dimethylamino, diethylamino, 4 - (N - t - butoxycarbonylamino)- butylamino. A preferred process for the preparation of a compound of Formula I wherein R<1> is CH3, R<2> is CH2CH(CH3)2, R<3> is NH2 and Y is D-Ala comprises: (i) reaction of an activated ester of benzyloxycarbonyl-L-(N-methyl)leucine with D-alanine methyl ester to yield benzyloxycarbonyl - L - (N - methyl(leucyl - D - alanine, methyl ester; (ii) hydrogenation of dipeptide (i) with hydrogen in the presence of a noble metal hydrogenation catalyst and isolation of L-(N- methyl)leucyl-D-alanine, methyl ester; (iii) reaction of dipeptide (ii) with an activated ester of benzyloxycarbonyl-L-proline and isolation of benzyloxycarbonyl - L - prolyl - L- (N - methyl)leucyl - D - alanine, methyl ester; (iv) reaction of tripeptide (iii) with ammonia and isolation of benzyloxycarbonyl-L-prolyl-L- (N - methyl)leucyl - D - alaninamide; (v) treatment of tripeptide (iv) with hydrogen in the presence of a noble metal hydrogenation catalyst and isolation of a peptide of Formula (I) wherein R<1> is CH3, R<2> is CH2CH(CH3)2R<3> is NH2 and Y is D-Ala. The compound of Formula (II) wherein R<1> is lower alkyl, or NR<4>R<5>, R<2> is hydrogen or lower alkyl, Y is Gly and R' is lower alkoxy may be prepared by a process which comprises the condensation of an enamine or hydrazone of formula with an amino acid of formula in the presence of an acetonitrile of formula and, optionally, hydrolysing the peptide of Formula (II) to obtain a peptide of Formula (II) wherein R' is hydroxyl. In the Examples, peptides prepared are; L-prolyl-L-(N-methyl)leucyl-glycinamide; L-prolyl-D-(N-methyl)leucyl-glycinamide; L-prolyl-(N-isobutyl)glycyl-glycinamide; L-prolyl-D-(N-dimethylamino)leucyl-glycine 4- amino-n-butylamide; L-prolyl-L-(N-dimethylamino)leucyl-glycine 4- amino-nbutylamide; L-prolyl-L-(N-methyl)leucyl-D-alanamide; L-prolyl-D-(N-methyl)leucyl-D-alanamide; L-prolyl-L-leucyl-glycine 4-amino-n-butylamide; L - prolyl - D - (N- dimethylamino)leucyl - glycinamide; L - prolyl - L - (N - dimethylamino)leucyl - glycinamide ; benzyloxycarbonyl - L-prolyl - DL - (N dimethyl - amino)leucyl-glycine, ethyl ester; t-butoxycarbonyl-L-prolyl-D-(N-methyl)leucylglycine, ethyl ester; t-butoxycarbonyl-L-prolyl-L-(N-methyl)leucylglycine, ethyl ester; t -butoxycarbonyl -L prolyl - L - (N -isobutyl)glycyl-glycine, ethyl ester; benzyloxycarbonyl - L - prolyl - D - (N - diethylamino)leucyl-glycinamide; benzyloxycarbonyl - L - prolyl - L - (N - diethylamino) leucyl-glycinamide; t - butoxycarbonyl - L - prolyl - D - (N - methyl) - leucyl-glycinamide; t - butoxycarbonyl - L - prolyl - L - (N - methyl) - leucyl-glycinamide; t - butoxycarbonyl - L - prolyl - (N - isobutyl)- glycyl-glycinamide; benzyloxycarbonyl - L - prolyl - DL - (N - dimethylamino)leucyl-glycine; benzyloxycarbonyl - L - prolyl - L - (N - dimethylamino)leucyl - glycine 4 - t - butoxycarbonylamino-n-butylamide; benzyloxycarbonyl - L - prolyl - D - (N - dimethylamino(leucyl - glycine 4 - t - butoxycarbonylamino-n-butylamide; benzyloxycarbonyl - L - prolyl - D - (N - methyl)- leucyl-D-alanine, methyl ester; benzyloxycarbonyl - L - prolyl - L - (N - methyl) - leucyl-D-alanine, methyl ester; benzyloxycarbonyl - L - prolyl - L - (N - methyl)- leucyl-D-alaninamide; benzyloxycarbonyl - L - prolyl - D - (N - methyl)- leucyl-D-alaninamide; benzyloxycarbonyl - L - prolyl - L - leucyl - glycine 4-t-butoxycarbonylamino-n-butylamide ; benzyloxycarbonyl - L - prolyl - DL - (N - diethylamino)alanyl-glycine, ethyl ester; benzyloxycarbonyl - L - prolyl - DL - (N - ethyl)- valyl-glycine, ethyl ester; L - prolyl - DL - (N - diethylamino)alanyl - glycine diethylamide; L - prolyl - DL - [N - di(n - propyl)amino]valylglycine, n-propylamide; L - prolyl - DL - (N - ethyl)valyl - glycine methylamide. Peptide intermediates isolated are: TRIPEPTIDES: Z-L-Pro-L-Leu-Gly-OH. DIPEPTIDES: Z and H - L - (N - CH3)Leu- Gly-OEt; H and Z-L-(N-CH3)Leu-D-Ala-OCH3. Pharmaceutical compositions, which may be used to treat central nervous system disorders in warm-blooded animals, comprises peptides of Formula (I) or the acid addition salts thereof, preferably in unit dosage form or in association with L-DOPA, in admixture with a pharmaceutically-acceptable carrier. Pharmaceutical compositions may also comprise peptides of Formula (II) in admixture with a pharmaceutically-acceptable carrier.