SI8911201B - Amino acid derivatives - Google Patents

Claims (20)

A compound of the general formula, 4 1 1 I R — N C O CH R (°) R7T > R • CH2 — Nv R 19 8 in which n represents the number 0 or 1; R1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, monoaralkylcarbamoyl, cinamoyl or α-aralkoxycarbonyl-aminoalkanoyl, together with R and represents a hydrogen and R a cyclic imide group of formula O P ^ N— / (a) O in which P and Q together represent an aromatic system; R 1 represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylsulfinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl, or when n represents the number 0, R 1 represents alkylthioalkyl, or when n represents the number 1, R 1 may also represent alkyl; R 1 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R 1 represents hydrogen and R 6 represents hydroxy, or R 1 and R 6 together represent oxo; R7 and R8 together represent a trimethylene or tetramethylene group which may be substituted by hydroxy, alkoxycarbonylamino or acylamino, or in which one of the groups -CH2- is replaced by -NH-, -N (alkoxycarbonyl) -, -N (acyl) - or -S-, or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R 1 represents alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of formula 86 wherein R 10 and each independently represents alkyl; and pharmaceutically acceptable acid addition salts thereof. Compounds according to claim 1, wherein n denotes 0 (zero), represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, carbamoylalkyl or alkoxycarbonylalkyl, and and R 1 together represent a trimethylene or tetramethylene group in which is one; groups -CH2- replaced by -NH-, or -S-, or which may carry a fused cycloalkane, aromatic or heteroaromatic ring. Compounds according to claim 1 or 2, wherein R 1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl or α-aralkoxycarbonylaminoalkanoyl, preferably benzyloxycarbonyl, 2-naphthoyl -hydroxy-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 2-quinolylcarbonyl or 3-quinolylcarbonyl and R 1 represents hydrogen. Compounds according to any one of claims 1 to 3, wherein R 1 represents alkyl, cyanolakyl, alkylthioalkyl or carbamoylalkyl, preferably cyanomethyl, methylthiomethyl or carbamoylmethyl. Compounds according to any one of claims 1 to 4, in which R 1 represents aralkyl, preferably benzyl. Compounds according to any one of claims 1 to 5, wherein R 1 represents hydrogen and represents hydroxy. Compounds according to any one of claims 1 to 6, wherein -N (R 7) -CH (R 8) (r 9) represents one of the following groups 12 87 R R 9 / 'N \ / 9 \ N — R 13 / (c) (d) I9 N. (e) / \, / N. R (h) 9 I (i) 88 wherein the meaning given in claim 1, R.12 represents hydrogen, hydroxy, alkoxycarbonylamino or acylamino, R.13 represents hydrogen, alkoxycarbonyl or acyl, m denotes 1 or 2 and p denotes 1 or 2, preferably a group of formula (c) in which R 12 represents hydrogen and m represents 2, or represents tert-butoxycarbonylamino and m represents 1, a group of formula (d) in which R 1 represents tert-butoxycarbonyl, a group of formula (e) wherein m denotes 1, a group of formula (f) wherein m and p both denote 1, or a group of formula (g), (i) or (j). Compounds according to any one of claims 1 to 7, wherein R 1 represents alkoxycarbonyl, monoalkylcarbamoyl or a group of formula (b), as claimed in claim 1, preferably tert-butoxycarbonyl, isobutylcarbamoyl, tert-butylcarbamoyl or a group of formula ( b), claimed in claim 1, wherein R 10 represents sec-butyl and R 1 represents isobutyl. Compounds according to any one of claims 1 to 8, wherein R 1 represents benzyloxycarbonyl, 2-naphthoyl, 1-hydroxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 2-quinolylcarbonyl! or 3-quinolylcarbonyl and R 1 represents hydrogen, R 1 represents cyanomethyl, methylthiomethyl or carbamoylmethyl, R 1 represents benzyl, R 1 represents hydrogen and R 1 represents hydroxy, and -N (R 7) -CH (R 8) (R 9) represents a group of formula (c) according to claim 7, wherein R 12 represents hydrogen and m represents 2, or R 12 represents tert-butoxycarbonylamino and m represents 1, a group of formula (d), as claimed in claim 7, wherein R 13 represents tert-butoxycarbonyl , a group of formula (e) given in claim 7, in which m represents 1, a group of formula (f) shown in claim 7, in which m and p represent 1, or a group of formulas (g), (i) or (j) mentioned in claim 7, and R 1 represents tert-butoxycarbonyl, isobutylcarbamoyl, tert-butylcarbamoyl, or a group of formula (b), as claimed in claim 1, in which R 10 represents sec-butyl and R 1. represents isobutyl. 10. N2- [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2 (R or S) -hydroxy-4-phenylbutyl] -N1-tert-butyl-L-prolinamide or N 1 - [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2 (R or S) -hydroxy-4-phenylbutyl] -N1-isobutyl-L-prolinamide. Compounds according to claim 1, selected from the group consisting of: N 2 - [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2 (R) -hydroxy-4-phenylbutyl] -N1-tert-butyl-4 (R) -thiazolidinecarboxamide, N-tert-butyl-1- [2 (R) -hydroxy-3 (S) - [[N- (2-naphthoyl) -L -asparaginyl] amino] -4-phenylbutyl] -2 (S) -piperidinecarboxamide, 89 1- [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2- (R) -hydroxy- 4-Phenylbutyl] -N-tert-butyl-octahydro- (3aS, 6aS) -cyclopenta [b] pyrrole-2 (S) -carboxamide, 1- [3 (S) - [[N- (benzyloxycarbonyl) -L -asparaginyl] amino] -2- (R) -hydroxy-4-phenylbutyl] -N-tert-butyl-2 (S) -piperidinecarboxamide, 2- [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2- (R) -hydroxy-4-phenylbutyl] -N-tert-butyl-1,2,3,4-tetrahydropyrido [3,4-b] indole-1-carboxamide, N-tert-butyl-3- [2 (R) -hydroxy-3 (S) - [[N- (2-naphthoyl) -L-asparaginyl] amino] -4-phenylbutyl] -4 (R) -thiazolidinecarboxamide , N1-tert-butyl-N2- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] -L-pronynamide N 2 - oxide, 1- [3 (S) - [[N- (ben zyloxycarbonyl) -3-cyano-L-alanyl] amino] -2- (R) -hydroxy-4-phenylbutyl-N-tert-butyl-2 (S) -piperidinecarboxamide, 1- [3 (S) - [[ N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2 (R) -hydroxy-4-phenylbutyl] -4- (tert-butoxycarbonyl) -N-tert-butyl-2- (R or S) -piperazinecarboxamide , 1- [3 (S) - [[N- (benzyloxycarbonyl) -3-cyano-L-alanyl] amino] -2- (R) -hydroxy-4-phenylbutyl] -4- (tert-butoxycarbonyl) - N-tert-butyl-2 (R or S) -piperazinecarboxamide, N, N- [3 (S) - [[N- (benzyloxycarbonyl) -L-asparaginyl] amino] -2- (R) -hydroxy-4- phenylbutyl] -4 (R) - (tert-butoxyformamido) -N1-tert-butyl-L-prolinamide, 1- [3 (S) - [[N- (3-benzyloxy-2-naphthoyl) -L- asparaginyl] amino] -2- (R) -hydroxy-4-phenylbutyl] -N- (tert-butyl-2 (S) -piperidinecarboxamide, N-tert-butyl-1- [2 (R) - hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] -2-piperidinecarboxamide 1-oxide, N-tert-butyl-1- [3 ) - [[N- (3-hydroxy-2-naphthoyl) -L-asparaginyl] amino] -2 (R) -hydroxy-4-phenylbutyl] -2 (S) -piperidinecarboxamide, trans-2- [3 ) - [[N-benzyloxycarbonyl) -L -asparaginyl] amino] -2- (R) -hydroxy-4-phenylbutyl] -N-tert-butyl-decahydro- (4aR, 8aS) -isoquinoline-3 (S) -carboxamide, 4- (tert-butoxycarbonyl) ) -N-tert-butyl-1- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] '2 (R or S) piperazinecarboxamide, N-tert-butyl-1- [2 (R) -hydroxy-3 (S) - [[N- (1-hydroxy-2-naphthoyl) -L-asparaginyl] amino] -4- phenylbutyl] -2 (S) -piperidinecarboxamide, trans-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) - L-asparaginyl] amino] butyl] - (4aR, 8aS) -isoquinoline-3 (S) -carboxamide and N-tert-butyl-1- [2 (R) -hydroxy-4-phenyl-3 (S) - [N- (2-quinolylcarbonyl) -L-cysteinyl] amino] butyl] -2 (S) -piperidinecarboxamide. 90 12. N-tert-butyl-1- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] -2 (S ) -piperidinecarboxamide. 13. N-tert-butyl-octahydro-1- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] - ( 3aS, 6aS) -cyclopenta [b] pyrrole-2 (S) -carboxamide. 14. N-tert-butyl-1,2,3,4-tetrahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolyl-carbonyl) - L-asparaginyl] amino] butyl] pyrido [3,4-b] indole-1 (R or S) -carboxamide. 15. Compounds of general formula R R A R CH 5 R 8 in which R represents hydrogen or a CO group CH 2 R 2 represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, alkylsulfinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl; R 1 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R 1 represents hydrogen and R 1 represents hydroxy, or R 1 and R 2 together represent oxo; R 1 and R 2 together represent a trimethylene or tetramethylene group which may be substituted by hydroxy, alkoxycarbonylamino or acylamino, or in which one of the groups -CH 2 - may be replaced by -NH-, -N (alkoxycarbonyl) -, N ) - or -S-, or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R 1 represents alkoxycarbonyl, monoalkylcarbamoyl, mono-aralkylcarbamoyl, monoarylcarbamoyl or a group of formula NH / -CO. Δ C 1 CH NH 3, 11 (b); R 10 VI 91 wherein each of R 10 and represents alkyl. Compounds of general formula VI. XCH NH .C ψη R7 ', CH_-N R2 \ ca / 19 8 R in which n represents the number 0 or 1; R 1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, monoaralkylcarbamoyl, cinnamoyl or α-aralkoxycarbonyl-aminoalkanoyl, and R 1 represents an atom and R 1 represents bound, represent a cyclic imide group of formula O (a) N-PIQO in which P and Q together represent an aromatic system; R 1 represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylsulfinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl, or when n represents the number 0, R 1 may also represent alkylthioalkyl, or when n represents the number 1, R 1 may also represent represents alkylsulfonylalkyl; R 1 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R 1 represents hydrogen and R 6 represents hydroxy or R 1 and R 6 together represent oxo; R 1 and R 2 together represent a trimethylene or tetramethylene group which may be substituted by amino; and R 1 represents alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of formula -co / N N R R 10 NH-R 11 (b) 92 wherein each of R 10 and R 1 represents alkyl. Amino acid derivatives according to any one of claims 1 to 14 for use as therapeutically active substances. Amino acid derivatives according to any one of claims 1 to 14 for use in the treatment or prophylaxis of viral infections. Process for the production of a compound according to any one of claims 1 to 14, characterized in that it comprises (a) for the preparation of compounds of formula I in which n represents 0, a compound of general formula H2N I I in which they have R ^, r5? r6; r7? r8 and r9 as claimed in claim 1 react with an acid of the general formula R 1 R 1 -N CH-, 3 COOH III in which R 1, R 2 and R 2 have the meaning stated in claim 1, or with a reactive derivative thereof, or 93 (b) for the preparation of a compound of formula I in which n represents 0, represents hydrogen and represents hydroxy, reduce a compound of formula I in which n represents 0, and R 3 and R 2 together represent oxo, or (c) for the preparation of a compound of formula I wherein n denotes 0 and R * represents alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, cinamoyl or α-aralkoxycarbonylaminoalkanoyl, and R2 represents hydrogen, or R1 and R2 together with the atom , representing a cyclic imide group of formula (a) as claimed in claim 1, a compound of general formula in which R 3, R 4, R 5, R 6, R 7, R 8 and R 6 have the meaning shown in claim 1, react with an agent which gives the group alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, cinamoyl or α-aralkoxycarbonyl aminoalkanoyl, or with an agent forming a cyclic imide group of formula (a) as claimed in claim 1, or (d) for the preparation of a compound of formula I in which n represents 0 and R 3 represents monoaralkylcarbamoyl and R 2 represents hydrogen, a compound with the above formula IV is reacted with a compound of general formula R 1 '-N = C = 0 V in which R 1 represents aralkyl, or (e) to prepare a compound of formula I in which R 3 represents alkylsulfinylalkyl and n represents 0, oxidize the compound of formula I in which R3 represents alkylthioalkyl and n represents 0, or 94 (f) for the preparation of a compound of formula I in which n represents 1 is oxidized to a compound of formula I in which n represents 0, or (g) for the preparation compounds of formula I in which n denotes 1 and represents a flavor N-heterocyclylcarbonyl N-oxide group, and represents hydrogen, oxidize a compound of formula I in which n represents 1 and R1 represents an aromatic N-heterocyclylcarbonyl group and R1 represents hydrogen, or (h) to prepare a compound of formula I , wherein n represents 1 and R 1 represents alkylsulfonylalkyl, oxidizing a compound of formula I in which n represents 1 and R 1 represents alkylsulfinylalkyl, or (i) to prepare a compound of formula I in which R 1 represents carboxy-substituted aroyl, hydroxy -substituted aroyl or hydrocinnamoyl, and R 1 represents hydrogen, catalytically hydrogenated a compound of formula I in which R 1 represents benzyloxycarbonyl-substituted aroyl, benzyloxy-substituted aroyl or cinamoyl and R 1 represents hydrogen, or (j) for the preparation of a compound of formula I , wherein R 1 represents imidazol-4-yl and / or R 1 represents hydroxy-substituted aryl or hydroxy-substituted aralkyl and / or R 1 and R 8 together represent a trimethylene or tetramethylene group in which one group -CH2- replaced by -NH-, is treated with a compound of formula I in which R 1 represents 1- (benzyloxycarbonyl) -imidazol-4-yl and / or R 1 represents tert-butoxy-substituted aryl or tert- butoxy-substituted aralkyl and / or R 1 and R 8 together represent a trimethylene or tetramethylene group in which one -CH 2 - group is replaced by an -N (tert-butoxycarbonyl) - group, with a strong acid, or (k) for the preparation of a compound of formula I, in which R 1 and R 8 together represent an acylamino-substituted trimethylene or tetramethylene group, or in which one -CH 2 - group is replaced by -N (acyl) -, a compound of general formula H 2 R 4 is acylated CH NH / C »/ Ch2 C '°» n R7-1' 'CH' R9 R 8 'VI 95 in which n, R1, R2, R3, R4, R5, R6 and R9 have the meaning given in claim 1 and R2 and R 1 together represent a group of trimethylene or tetramethylene substituted with amino or in which one group -CH 2 - is replaced by -NH-, and / or (l) if desired, separate the mixture of diastereoisomeric racemates to diast ereoisomeric racemates or optically pure diastereoisomers and / or (m) if desired, separating the mixture of diastereoisomers into optically pure diastereoisomers and / or (n) if desired, converting the obtained compounds of formula I into pharmaceutically acceptable acid addition salts. Process according to Claim 19, characterized in that the compounds of the formula I in which n represents 0, R 3 represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, carbamoylalkyl or alkoxycarbonylalkyl and R 2 and R 2 together represent a group trimethylene or tetramethylene, in which one group -CH2- may be replaced by -NH- or -S-, or which may bear a fused cycloalkane, aromatic or heteroaromatic ring, and their pharmaceutically acceptable acid addition salts are prepared on the basis of embodiments (a), (b), (c), (d) and / or (n) of the procedure. For: F.HOFFMANN-LA ROCHE AG 4 VRELI J A G 4.