Patent GB-1520830-A (GB)
Title: Peptide carbazates
IPC: C07K5/08
Filed: 1976-12-16
Abstract: 1520830 Azapeptides MERCK & CO Inc 16 Dec 1976 [23 Dec 1975] 52634/76 Heading C3H [Also in Division C2] A compound of the Formula (I) B-P4-P3-P2-NH-NR1-CO-0-CH(R2)-COR3 wherein B is C1-C5 alkanoyl, t-butoxycarbonyl, carbobenzyloxy, P4 is alanyl or prolyl, P, is alanyl, P2 is prolyl or leucyl, R1 is C1-C5 alkyl, R2 is methyl, benzyl, 4-aminobutyl, R3 is hydroxy, C1-C5 alkoxy, amino, (C1-C5 alkyl)amino, di(C1-C5alkyl)amino, benzylamino, phenylamino, hydrazino, univalent hydrocarbon-substituted hydrazino, benzyloxy, halogen-substituted benzyloxy or ZÀCH(R4)-COR5 wherein R4 is methyl or benzyl; R5 is hydroxy, C1-C5alkyl, amino, (C1-C5alkyl)amino, di- (C1-C5alkyl)amino, benzylamino, phenylamino, hydrazino, benzyloxy or halogensubstituted benzyloxy; Z is -NH- or -O-; may be prepared by a process which comprises the reaction of a compound of the formula wherein X is OH, halogen, p-nitrophenoxy, O-P2-P3-P4-B or -OOOC1-C5 alkyl with a compound of formula Compounds prepared are.-Acetylprolylalanylprolyl - 2 - azaalanyl - DL - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - DL- lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lactic acid benzyl ester; acetylalanylalanylprolyl-2-azaalanyl-L-lactic acid piodobenzyl ester; acetylalanylalanylprolyl-2- azaalanyl-N-benzyl-L-lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - laothydrazide; acetylalanylalanylprolyl - 2 - azaalanyl - N- phenyl - L - lactamide; acetylprolylalanylprolyl-2-azavalyl-DL-lactamide; acetylalanylalanylprolyl - 2 - azavalyl - L - lactic acid benzyl ester; acetylalanylalanylprolyl - 2 - azavalyl- DL - lactamide; acetylalanylalanylprolyl - 2- azavalyl - L - lactic acid p - iodobenzyl ester; acetylalanylalanylprolyl - 2 - azavalyl - N- benzyl - L - lactamide; acetylalanylalanylprolyl- 2 - azavalyl - N - methyl - L - lactamide; acetylalanylalanylprolyl - 2 - azavalyl - L - lacthydrazide; acetylalanylalanylprolyl - 2 - azavalyl - N- phenyl - L - lactamide; acetylprolylalanylprolyl - 2 - azaalanyl - DL - alpha - (4 - aminobutyl)- glycolamide; acetylalanylalanylprolyl - 2 - azaalanyl - DL - alpha - (4 - aminobutyl)glycolamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - alpha- (4-aminobutyl)glycolic acid benzyl ester; acetylalanylalanylprolyl - 2 - azaalanyl - L - alpha - (4- aminobutyl)glycolic acid p-iodobenzyl ester; acetylalanylalanylprolyl - 2 - azaalanyl - N- benzyl-L-alpha-(4-aminobutyl)glycolamide; acetylalanylalanylprolyl - 2 - azaalanyl - N - methyl- L - alpha - (4 - aminobutyl)glycolamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - alpha - (4 - aminobutyl)glycolhydrazide; acetylalanylalanylprolyl - 2 - azaalanyl - N - phenyl - L - alpha - (4 - aminobutyl)glycolamide; acetylprolylalanylprolyl - 2- azavalyl - DL - alpha - (4 - aminobutyl)glycolamide; acetylalanylalanylprolyl - 2 - azavalyl - DL - alpha- (4 - aminobutyl)glycolamide; acetylalanylalanylprolyl - 2 - azavalyl - L - alpha - (4 - aminobutyl)glycolic acid benzyl ester; acetylalanylalanylprolyl - 2 - azavalyl - L - alpha - (4 - aminobutyl)glycolic acid p-iodobenzyl ester; acetylalanylalanylprolyl - 2 - azavalyl - N - benzyl- L - alpha - (4 - aminobutyl)glycolamide; acetylalanylalanylprolyl-2-azavalyl-N-methyl-L-alpha-(4-aminobutyl)glycolamide; acetylalanylalanylprolyl-2- azavalyl - L - alpha - (4 - aminobutyl)glycolhydrazide; acetylalanylalanylprolyl - 2 - azavalyl - N- phenyl - L - alpha - (4 - aminobutyl)glycolamide; acetylprolyl - alanyprolyl - 2-azaalanyl - L- lactic acid ethyl ester; acetylalanylalanylprolyl - 2 - azaalanyl - L - lactic acid ethyl ester; acetylprolylalanylprolyl-2-azaalanyl-DL -lactic acid ethyl ester; acetylalanylalanylleucyl - 2 azaalanyl - DL - lactic acid ethyl ester; acetylalanylalanylprolyl - 2 - azaalanyl-L- 3-phenylactic acid ethyl ester; acetylprolylalanylleucyl- 2 - azaalanyl - DL lactic acid ethyl ester; acetylalanylalanylprolyl - 2 - azaalanyl- L - lactic acid; acetylalanylalanylprolyl-2-azaalanyl - L - lactylphenylalanine ethyl ester; acetylalanylalanylprolyl - 2 - azaalanyl - N- methyl - L - lactamide; acetylprolylalanylprolyl - 2 - azaalanyllactyllactic acid ethyl ester; acetylalanylalanylprolyl - 2 - azavalyl - L - lactic acid ethyl ester; 5 - amino - 1 - ethoxycarbonylpentylacetylprolylalanylprolyl - 2 - azaalaninate hydrochloride. Intermediates isolated are: N-t-butoxycarbonylalanylleuoine benzyl ester; alanylleucinebenzyl ester hydrochloride; acetylalanylalanylleucine benzyl ester; acetylalanylalanylleucine; acetylprolylalanylleucine benzyl ester; acetylprolylalanylleucine; acetylprolylalanylprolyl-2- azaalanine 5 - benzyloxycarbonylamino - 1- ethoxycarbonyl pentyl ester. Pharmaceutical compositions which may be used to treat pancreatitis comprise peptide of Formula (I) and a non-toxic pharmaceuticallyacceptable carrier and, if B, P4, P3, P2 and R1 are defined as above whilst R2 is methyl and R3 is amino, hydrazino; benzylamino, phenylamino- or methylamino, the pharmaceutical compositions may be used to treat emphysema and and rheumatoid arthritis. Exemplified pharmaceutical compositions are: (I) a compound selected from: acetylalanylalanylprolyl - 2 - azaalanyl - DL - lacthydrazide; acetylalanylalanylprolyl - 2 - azaalanyl - DL- lactamide; acetylprolylalanylprolyl - 2 - azaalanyl - DL - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lactic acid benzyl ester; acetylalanylalanylprolyl - 2 - azaalanyl- L-lactic acid p-iodobenzyl ester; acetylalanylalanylprolyl - 2 - azaalanyl - N - benzyl - L - lactamide ; acetylalanylalanylprolyl - 2 - azaalanyl- N-methyl-L-lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lacthydrazide; acetyl alanylalanylprolyl - 2 - azaalanyl - N - phenyl- L-lactamide; plus (A) sodium chloride, NaOH or HCl to pH 5-6, water and, optionally, benzyl alcohol, methylparaben, propylparaben or buffering agents (citric acid, sodium phosphate) (B) mannitol, NaOH or HCl to pH 5-6, water and, optionally, phenylmercuric acetate. (II) a compound selected from: acetylalanylalanylprolyl - 2 - azaalanyl - DL- lacthydrazide; acetylprolylalanylprolyl - 2 - azaalanyl - DL- lactamide; acetylalanylalanylprolyl - 2 - azaalanyl DL - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lactic acid benzyl acid; acetylalanylalanylprolyl - 2 - azaalanyl- L-lactic acid p-iodobenzyl acid; acetylalanylalanylprolyl - 2 - azaalanyl - N - benzyl - L - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl- N - methyl - L - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lactamide; acetylalanylalanylprolyl - 2 - azaalanyl - L - lacthydrazide; plus (A) "Freon"; (B) "Freon"/ anhydrous ethanol; (C) lactose; (D) HCl or NaOH to pH 5-6/water. The compositions may be administered by the parenteral route and/or may be in the form of a tablet, capsule, troche, powder, soft gelatin capsule, syrup, liquid solution, liquid suspension, liquid emulsion, suppository, gel, lotion or aerosol spray. [The word "FREON" is a registered Trade Mark].