Amino acid derivatives

Claim 2

Compounds of the general formula wherein n stands for zero or 1; R¹ represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cyclo­alkylcarbonyl, aralkanoyl, aroyl, heterocyclyl­carbonyl, alkylsulphonyl, arylsulphonyl, monoaralkyl­carbamoyl, cinnamoyl or α-aralkoxycarbonylamino­alkanoyl and R² represents hydrogen or R¹ and R² together with the nitrogen atom to which they are attached represent a cyclic imide group of the formula in which P and Q together represent an aromatic system; R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkyl­sulphinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl or, when n stands for zero, R³ can also represent alkylthioalkyl or, when n stands for 1, R³ can also represent alkylsulphonylalkyl; R⁴ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R⁵ represents hydrogen and R⁶ represents hydroxy or R⁵ and R⁶ together represent oxo; R⁷ and R⁸ together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one -CH₂- group is replaced by -NH-, -N(alkoxycar­bonyl)-, -N(acyl)- or -S- or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R⁹ represents alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl. monoarylcarbamoyl or a group of the formula in which R¹⁰ and R¹¹ each represent alkyl; and pharmaceutically acceptable acid addition salts thereof.

Claim 3

Compounds according to claim 1, wherein n stands for zero, R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, carbamoylalkyl or alkoxycarbonylalkyl and R⁷ and R⁸ together represent a trimethylene or tetramethylene group in which one -CH₂- group can be replaced by -NH- or -S- or which can carry a fused cycloalkane, aromatic or heteroaromatic ring.

Claim 4

Compounds according to claim 1 or claim 2, wherein R¹ represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl or α-aralkoxycarbonylamino-­alkanoyl, preferably benzyloxycarbonyl, 2-naphthoyl, 1-hydroxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 2-quinolylcarbonyl or 3-quinolylcarbonyl, and R² represents hydrogen.

Claim 5

Compounds according to any one of claims 1 to 3, wherein R³ represents alkyl, cyanoalkyl, alkylthioalkyl or carbamoylalkyl, preferably cyanomethyl, methylthio­methyl or carbamoylmethyl.

Claim 6

Compounds according to any one of claims 1 to 4, wherein R⁴ represents aralkyl, preferably benzyl.

Claim 7

Compounds according to any one of claims 1 to 5, wherein R⁵ represents hydrogen and R⁶ represents hydroxy.

Claim 8

Compounds according to any one of claims 1 to 6, wherein -N(R⁷)-CH(R⁸)(R⁹) represents one of the following groups wherein R⁹ has the significance given in claim 1, R¹² represents hydrogen, hydroxy, alkoxycarbonyl­amino or acylamino, R¹³ represents hydrogen, alkoxycarbonyl or acyl, m stands for 1 or 2 and p stands for 1 or 2, preferably a group of formula (c) in which R¹² represents hydrogen and m stands for 2 or R¹² represents tert butoxycarbonylamino and m stands for 1, a group of formula (d) in which R¹³ represents tert.butoxycarbonyl, a group of formula (e) in which m stands for 1, a group of formula (f) in which m and p both stand for 1 or a group of formula (g), (i) or (j).

Claim 9

Compounds according to any one of claims 1 to 7, wherein R⁹ represents alkoxycarbonyl, monoalkylcarbamoyl or a group of formula (b) given in claim 1, preferably tert.butoxycarbonyl, isobutylcarbamoyl, tert.butyl­carbamoyl or a group of formula (b) given in claim 1 in which R¹⁰ represents sec.butyl and R¹¹ represents isobutyl.

Claim 10

Compounds according to any one of claims 1 to 8, wherein R¹ represents benzyloxycarbonyl, 2-naphthoyl, 1-hydroxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-benzyloxy-­2-naphthoyl, 2-quinolylcarbonyl or 3-quinolylcarbonyl and R² represents hydrogen, R³ represents cyanomethyl, methylthiomethyl or carbamoylmethyl, R⁴ represents benzyl, R⁵ represents hydrogen and R⁶ represents hydroxy and -N(R⁷)-CH(R⁸)(R⁹) represents a group of formula (c) given in claim 7, in which R¹² represents hydrogen and m stands for 2 or R¹² represents tert.­butoxycarbonylamino and m stands for 1, a group of formula (d) given in claim 7 in which R¹³ represents tert.­butoxycarbonyl, a group of formula (e) given in claim 7 in which m stands for 1, a group of formula (f) given in claim 7 in which m and p both stand for 1 or a group of formula (g), (i) or (j) given in claim 7 and R⁹ represents tert.butoxycarbonyl, isobutylcarbamoyl, tert.butylcarbamoyl or a group of formula (b) given in claim 1 in which R¹⁰ represents sec.butyl and R¹¹ represents isobutyl.

Claim 11

N²-[3(S)-[[N-(Benzyloxycarbonyl)-L-asparaginyl]­amino]-2(R or S)-hydroxy-4-phenylbutyl]-N¹-tert.butyl-L-­prolinamide or N²-[3(S)-[[N-(benzyloxycarbonyl)-­L-asparaginyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-­N¹-isobutyl-L-prolinamide.

Claim 12

N²-[3(S)-[[N-(Benzyloxycarbonyl)-L-asparaginyl]­amino]-2(R or S)-hydroxy-4-phenylbutyl]-N¹-tert.butyl-L-­prolinamide or N²-[3(S)-[[N-(benzyloxycarbonyl)-­L-asparaginyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-­N¹-isobutyl-L-prolinamide.

Claim 13

A compound according to claim 1, selected from: N²-[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, 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-prolin­amide N²-oxide, 1-[3(S)-[[N-(benzyloxycarbonyl)-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, N²-[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(S)-[[N-(3-hydroxy-2-naphthoyl)-­L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-­piperidinecarboxamide, trans-2-[3(S)-[[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.

Claim 14

N-tert.Butyl 1-[2(R)-hydroxy-4-phenyl-3(S)-[[N-­(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-2(S)-­piperidinecarboxamide.

Claim 15

N-tert.Butyl 1-[2(R)-hydroxy-4-phenyl-3(S)-[[N-­(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-2(S)-­piperidinecarboxamide.

Claim 16

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.

Claim 17

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.

Claim 18

N-tert.Butyl-1,2,3,4-tetrahydro-2 [2(R)-hydroxy-4-­phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]­butyl]pyrido[3,4-b]indole-1(R or S)-carboxamide.

Claim 19

N-tert.Butyl-1,2,3,4-tetrahydro-2 [2(R)-hydroxy-4-­phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]­butyl]pyrido[3,4-b]indole-1(R or S)-carboxamide.

Claim 20

Compounds of the general formula wherein R represents hydrogen or the group R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, alkylsulphinylalkyl, carbamoylalkyl or alkoxy­carbonylalkyl; R⁴ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R⁵ represents hydrogen and R⁶ represents hydroxy or R⁵ and R⁶ together represent oxo; R⁷ and R⁸ together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonyl­amino or acylamino or in which one -CH₂- group is replaced by -NH-, -N(alkoxycarbonyl)-, -N(acyl)- or -S- or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R⁹ represents alkoxy­carbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula in which R¹⁰ and R¹¹ each represent alkyl.

Claim 21

Compounds of the general formula wherein R represents hydrogen or the group R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, alkylsulphinylalkyl, carbamoylalkyl or alkoxy­carbonylalkyl; R⁴ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R⁵ represents hydrogen and R⁶ represents hydroxy or R⁵ and R⁶ together represent oxo; R⁷ and R⁸ together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonyl­amino or acylamino or in which one -CH₂- group is replaced by -NH-, -N(alkoxycarbonyl)-, -N(acyl)- or -S- or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R⁹ represents alkoxy­carbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula in which R¹⁰ and R¹¹ each represent alkyl.

Claim 22

Compounds of the general formula wherein n stands for zero or 1; R¹ represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cyclo­alkylcarbonyl, aralkanoyl, aroyl, heterocyclyl­carbonyl, alkylsulphonyl, arylsulphonyl, monoaralkyl­carbamoyl, cinnamoyl or α-aralkoxycarbonylamino-­alkanoyl and R² represents hydrogen or R¹ and R² together with the nitrogen atom to which they are attached represent a cyclic imide group of the formula in which P and Q together represent an aromatic system; R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkyl­sulphinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl or, when n stands for zero, R³ can also represent alkylthioalkyl or, when n stands for 1, R³ can also represent alkylsulphonylalkyl; R⁴ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R⁵ represents hydrogen and R⁶ represents hydroxy or R⁵ and R⁶ together represent oxo; R 7′ and R 8′ together represent a trimethylene or tetramethylene group which is substituted by amino; and R⁹ represents alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula in which R¹⁰ and R¹¹ each represent alkyl.

Claim 23

Compounds of the general formula wherein n stands for zero or 1; R¹ represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cyclo­alkylcarbonyl, aralkanoyl, aroyl, heterocyclyl­carbonyl, alkylsulphonyl, arylsulphonyl, monoaralkyl­carbamoyl, cinnamoyl or α-aralkoxycarbonylamino-­alkanoyl and R² represents hydrogen or R¹ and R² together with the nitrogen atom to which they are attached represent a cyclic imide group of the formula in which P and Q together represent an aromatic system; R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkyl­sulphinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl or, when n stands for zero, R³ can also represent alkylthioalkyl or, when n stands for 1, R³ can also represent alkylsulphonylalkyl; R⁴ represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R⁵ represents hydrogen and R⁶ represents hydroxy or R⁵ and R⁶ together represent oxo; R 7′ and R 8′ together represent a trimethylene or tetramethylene group which is substituted by amino; and R⁹ represents alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula in which R¹⁰ and R¹¹ each represent alkyl.

Claim 24

Amino acid derivatives according to any one of claims 1 to 14 for use as therapeutically active substances.

Claim 25

Amino acid derivatives according to any one of claims 1 to 14 for use in the treatment or prophylaxis of viral infections.

Claim 26

A process for the manufacture of a compound in accordance with any one of claims 1 to 14, which process comprises (a) for the manufacture of a compound of formula I in which n stands for zero, reacting a compound of the general formula wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ have the significance given in claim 1, with an acid of the general formula wherein R¹, R² and R³ have the significance given in claim 1, or a reactive derivative thereof, or (b) for the manufacture of a compound of formula I in which n stands for zero, R⁵ represents hydrogen and R⁶ represents hydroxy, reducing a compound of formula I in which n stands for zero and R⁵ and R⁶ together represent oxo, or (c) for the manufacture of a compound of formula I in which n stands for zero and R¹ represents alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclyl­carbonyl, alkylsulphonyl, arylsulphonyl, cinnamoyl or α-­ aralkoxycarbonylaminoalkanoyl and R² represents hydrogen or R¹ and R² together with the nitrogen atom to which they are attached represent a cyclic imide group of formula (a) given in claim 1, reacting a compound of the general formula wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ have the significance given in claim 1, with an agent yielding an alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulphonyl, arylsulphonyl, cinnamoyl or α-aralkoxycarbonylamino-­alkanoyl group or with an agent forming a cyclic imide group of formula (a) given in claim 1, or (d) for the manufacture of a compound of formula I in which n stands for zero and R¹ represents monoaralkyl­carbamoyl and R² represents hydrogen, reacting a compound of formula IV given earlier in this claim with a compound of the general formula R 1′ -N=C=O      V wherein R 1′ represents aralkyl, or (e) for the manufacture of a compound of formula I in which R³ represents alkylsulphinylalkyl and n stands for zero, oxidizing a compound of formula I in which R³ represents alkylthioalkyl and n stands for zero, or (f) for the manufacture of a compound of formula I in which n stands for 1, oxidizing a compound of formula I in which n stands for zero, or (g) for the manufacture of a compound of formula I in which n stands for 1 and R¹ represents an aromatic N-heterocyclylcarbonyl N-oxide group and R² represents hydrogen, oxidizing a compound of formula I in which n stands for 1 and R¹ represents an aromatic N-hetero­cyclylcarbonyl group and R² represents hydrogen, or (h) for the manufacture of a compound of formula I in which n stands for 1 and R³ represents alkylsulphonyl­alkyl, oxidizing a compound of formula I in which n stands for 1 and R³ represents alkylsulphinylalkyl, or (i) for the manufacture of a compound of formula I in which R¹ represents carboxy-substituted aroyl, hydroxy-­substituted aroyl or hydrocinnamoyl and R² represents hydrogen, catalytically hydrogenating a compound of formula I in which R¹ represents benzyloxycarbonyl-­substituted aroyl, benzyloxy-substituted aroyl or cinnamoyl and R² represents hydrogen, or (j) for the manufacture of a compound of formula I in which R³ represents imidazol-4-yl and/or R⁴ represents hydroxy-substituted aryl or hydroxy-substituted aralkyl and/or R⁷ and R⁸ together represent a trimethylene or tetramethylene group in which one -CH₂- group is replaced by -NH-, treating a compound of formula I in which R³ represents 1-(benzyloxycarbonyl)-imidazol-4-yl and/or R⁴ represents tert.butoxy-substituted aryl or tert.butoxy-substituted aralkyl and/or R⁷ and R⁸ together represent a trimethylene or tetramethylene group in which one -CH₂- group is replaced by -N(tert.butoxy­ carbonyl)- with a strong acid, or (k) for the manufacture of a compound of formula I in which R⁷ and R⁸ together represent a trimethylene or tetramethylene group which is substituted by acylamino or in which one -CH₂- group is replaced by -N(acyl)-, acylating a compound of the general formula wherein n, R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ have the significance given in claim 1 and R 7′ and R 8′ together represent a trimethylene or tetra­methylene group which is substituted by amino or in which one -CH₂- group is replaced by -NH-, and/or (l) if desired, separating a mixture of diastereoisomeric racemates into the diastereoisomeric racemates or optically pure diastereoisomers, and/or (m) if desired, separating a mixture of diastereoisomers into the optically pure diastereoisomers, and/or (n) if desired, converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.

Claim 27

A process according to claim 19 wherein compounds of formula I wherein n stands for zero, R³ represents alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkylthioalkyl, carbamoylalkyl or alkoxy­carbonylalkyl and R⁷ and R⁸ together represent a trimethylene or tetramethylene group in which one -CH₂- group can be replaced by -NH- or -S- or which can carry a fused cycloalkane, aromatic or heteroaromatic ring and their pharmaceutically acceptable acid addition salts are manufactured according to embodiments (a), (b), (c), (d) and/or (n).

Claim 28

A medicament containing an amino acid derivative according to any one of claims 1 to 14 and a therapeutically inert excipient.

Claim 29

A medicament for the treatment or prophylaxis of viral infections, containing an amino acid derivative according to any one of claims 1 to 14 and a therapeutically inert excipient.

Claim 30

The use of an amino acid derivative according to any one of claims 1 to 14 in the control or prevention of illnesses.

Claim 31

The use of an amino acid derivative according to any one of claims 1 to 14 in the treatment or prophylaxis of viral infections.

Claim 32

The use of an amino acid derivative according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prophylaxis of viral infections.