Patent EA-003906-B1 (EA)
Title: Hepatitis c inhibitor tri-peptides
Inventor: LLINAS-BRUNET MONTSE
IPC: A61P31/14
Filed: 1999-08-09
Abstract: 1. A compound of formula (I) comprising racemates, diastereoisomers and optical isomers of wherein B is H, a C6- or C10aryl, C7-C16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C1-C6 alkyl; amido; or (lower alkyl)amide; or B is an acyl derivative of formula R4-C(O)-; a carboxyl of formula R4-O-C(O)-; an amide of formula R4-N(R5)-C(O)-; a thioamide of formula R4-N(R5)-C(S)-;or a sulfonyl of formula R4-SO2 wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, C1-C6 alkanoyl, hydroxy, C1-C6 alkoxy, amino optionally mono- or di-substituted with C1-C6 alkyl, amido, or (lower alkyl) amide; (II) C3-C7 cycloalkyl, C3-C7 cycloalkoxy, or C4-C10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C1-C6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-C6 alkyl, amido, or (lower alkyl) amide; (III) amino optionally mono- or di-substituted with C1-C6 alkyl; amido; or (lower alkyl)amide; (IV) C6- or C10aryl, C7-C16 aralkyl, all optionally substituted with C1-C6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or disubstituted with C1-C6 alkyl; or (V) Het or (lower alkyl)-Het, both optionally substituted with C1-C6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-C6 alkyl; R5 is H or C1-C6 alkyl; Y is H or C1-C6 alkyl; R3 is C1-C8 alkyl, C3-C7 cycloalkyl, or C4-C10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-C6 alkoxy, C1-C6 thioalkyl, amido, (lower alkyl)amido, C6 or C10 aryl, or C7-C16 aralkyl; R2 is CH2-R20, NH-R20, O-R20 or S-R20, wherein R20 is a saturated or unsaturated C3-C7 cycloalkyl or C4-C10 (alkylcycloalkyl), all of which being optionally mono-, di- or trisubstituted with R21, or R20 is a C6 or C10 aryl or C7-C14 aralkyl, all optionally mono-, di- or trisubstituted with R21, or R20 is Het or (lower alkyl)-Het, both optionally mono-, di- or trisubstituted with R21, wherein R21 is each independently C1-C6 alkyl; C1-C6 alkoxy; lower thioalkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amino optionally mono- or di-substituted with C1-C6 alkyl, C6 or C10 aryl, C7-C14 aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C1-C6 alkyl, C6 or C10 aryl, C7-C14 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-C14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R22; wherein R22 is C1-C6 alkyl; C3-C7 cycloalkyl; C1-C6 alkoxy; amino optionally mono- or di-substituted with C1-C6 alkyl; sulfonyl; (lower alkyl)sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide; (lower alkyl)amide; or Het optionally substituted with C1-C6 alkyl; R1 is H; C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl; wherein lower alkyl, alone, or in combination with other substituent, means acyclic substituted with linear or branched chain, containing from 1 to 6 carbon atoms; aminoaralkyl alone, or in combination with other substituent, means aminogroup, substituted with C7-C18 aralkyl group; (lower alkyl) amido alone, or in combination with other substituent, means amido, mono-substituted with C1-C6 alkyl carboxy(lower) alkyl alone, or in combination with other substituent, means carboxyl group (COOH), bonded through the lower alkyl group, defined above; Het is monovalent radical, formed by removing of hydrogen atom from five, six or seven-membered saturated or unsaturated (comprising aromatic) heterocycle, comprising from one to four heteroatoms selected from nitrogen, oxygen and sulfur; and (lower) alkyl Het bonded through the chain or branched alkyl group, where alkyl has overmentioned values, containing from 1 to 6 carbon atoms; or a pharmaceutically acceptable salt or ester thereof. 2. A compound of formula I according to claim 1, wherein B is a C6 or C10 aryl or C7-C16 aralkyl, all optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-C6 alkyl, amidogroup or (lower alkyl)amido; or B is Het or (lower alkyl)-Het, all optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxy; hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-C6 alkyl. 3. A compound of formula I according to claim 1, wherein B is R4-SO2 wherein R4 is C1-C6 alkyl; amido; (lower alkyl)amide; C6 or C10 aryl, C7-C14 aralkyl or Net, all optionally substituted with C1-C6 alkyl. 4. A compound of formula I according to claim 1, wherein B is an acyl derivative of formula R4-C(O)- wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, hydroxy or C1-C6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-C6 alkyl; (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-C6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-C6 alkyl; (IV) C6 or C10 aryl, C7-C16 aralkyl, all optionally substituted with C1-C6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-C6 alkyl; (V) Het or (lower alkyl)-Het, both optionally substituted with C1-C6 alkyl, hydroxy, amino optionally substituted with C1-C6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C1-C6 alkyl. 5. A compound of formula I according to claim 1, wherein B is a carboxyl of formula R4-O-C(O)-, wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, C1-C6 alkanoyl, hydroxy, C1-C6 alkoxy, amino optionally mono- or di-substituted with C1-C6 alkyl, amido or (lower alkyl)amide; (II) C3-C7 cycloalkyl, C4-C10alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-C6 alkyl, amido or (lower alkyl)amide; (IV) C6 or C10 aryl or C7-C16 aralkyl optionally substituted with C1-C6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-C6 alkyl; or (V) Het or (lower alkyl)-Het, both optionally substituted with C1-C6 alkyl, hydroxy, amino optionally mono- or di-substituted with C1-C6 alkyl, amido or (lower alkyl)amido. 6. A compound of formula I according to claim 1, wherein B is an amide of formula R4-N(R5)-C(O)- wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, C1-C6 alkanoyl, hydroxy, C1-C6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-C6 alkyl; (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-C6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-C6 alkyl; (III) amino optionally mono- or di-substituted with C1-C3 alkyl; (IV) C6 or C10 aryl or C7-C16 aralkyl, all optionally substituted with C1-C6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-C6 alkyl; or (V) Het or (lower alkyl)-Het, both optionally substituted with C1-C6 alkyl, hydroxy, amino optionally substituted with C1-C6 alkyl, amido or (lower alkyl)amide; and R5 is H or methyl. 7. A compound of formula I according to claim 1, wherein B is a thioamide of formula R4-NH-C(S)-; wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, C1-C6 alkanoyl or C1-C6 alkoxy; (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-C6 alkoxy)carbonyl, amino or amido. 8. A compound of formula I according to claim 2, wherein B is a C6 or C10 aryl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-C6 alkyl. 9. A compound of formula I according to claim 2, wherein r B is Het optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-C6 alkyl. 10. A compound of formula I according to claim 4, wherein B is an acyl derivative of formula R4-C(O)- wherein R4 is (I) C1-C10 alkyl optionally substituted with carboxyl, hydroxy or C1-C6 alkoxy; or (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-C6 alkoxy)carbonyl, or (IV) C6 or C10 aryl or C7-C16 aralkyl, all optionally substituted with C1-C6alkyl, hydroxy, or (V) Het optionally substituted with C1-C6alkyl, hydroxy, amido or amino. 11. A compound of formula I according to claim 5, wherein B is a carboxyl of formula R4-O-C(O)-, wherein R4 is (I) C1-C10alkyl optionally substituted with carboxyl, C1-C6alkanoyl, hydroxy, C1-C6alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-C6alkyl; (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-C6alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-C6alkyl, or (IV) C6 or C10 aryl or C7-C16 aralkyl, all optionally substituted with C1-C6alkyl, hydroxy, amino optionally substituted with C1-C6alkyl; or (V) Het or (lower alkyl)-Het, both optionally substituted with C1-C6alkyl, hydroxy, amido, or amino optionally mono-substituted with C1-C6alkyl. 12. A compound of formula I according to claim 6, wherein B is an amide of formula R4-N(R5)-C(O)- wherein R4 is (I) C1-C10alkyl optionally substituted with carboxyl, C1-C6alkanoyl, hydroxy, C1-C6alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-C6alkyl; (II) C3-C7 cycloalkyl or C4-C10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-C6alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-C6alkyl; (III) amino optionall