Hepatitis C inhibitor tri-peptides

{
  "publication_number": "US6410531B1",
  "country": "US",
  "kind": "B1",
  "title": "Hepatitis C inhibitor tri-peptides",
  "abstract": "Racemates, diastereoisomers and optical isomers of a compound of formula (I): wherein B is H, a C 6 or C 10 aryl, C 7-16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C 1-6 alkyl; amido; or (lower alkyl)amide; or B is an acyl derivative of formula R 4 - C(O) -; a carboxyl of formula R 4 - O - C(O) -; an amide of formula R 4 - N(R 5) - C(O) -; a thioamide of formula R 4 - N(R 5) - C(S) -; or a sulfonyl of formula R 4 - SO 2; R 5 is H or C 1-6 alkyl; and Y is H or C 1-6 alkyl; R 3 is C 1-8 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C 1-6 alkoxy, C 1-6 thioalkyl, amido, (lower alkyl)amido, C 6 or C 10 aryl, or C 7-16 aralkyl; R 2 is CH 2 - R 20, NH - R 20, O - R 20 or S - R 20, wherein R 20 is a saturated or unsaturated C 3-7 cycloalkyl or C 4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R 21, or R 20 is a C 6 or C 10 aryl or C 7-14 aralkyl optionally substituted, or R 20 is Het or (lower alkyl)-Het, both optionally substituted, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C 6 or C 10 aryl, C 7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted; and R 1 is H; C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, or C 2 6 alkynyl, all optionally substituted with halogen; or a pharmaceutically acceptable salt or ester thereof.",
  "claims": [
    "1. The racemates, diastereoisomers or optical isomers of a compound of formula (I): wherein B is H, a C 6 or C 10 aryl, C 7-16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C 1-6 alkyl; amido; or (lower alkyl)amide; or B is an acyl derivative of formula R 4 - C(O) -; a carboxyl derivative of formula R 4 - O - C(O) -; an amide derivative of formula R 4 - N(R 5) - C(O) -; a thioamide derivative of formula R 4 - N(R 5) - C(S) -; or a sulfonyl derivative of formula R 4 - SO 2 wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amino optionally mono-or di-substituted with C 1-6 alkyl, amido, or (lower alkyl) amide; (ii) C 3-7 cycloalkyl, C 3-7 cycloalkoxy, or C 4-10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C 1-6 alkoxy)carbonyl, amino optionally mono-or di-substituted with C 1-6 alkyl, amido, or (lower alkyl) amide; (iii) amino optionally mono- or di-substituted with C 1-6 alkyl; amido; or (lower alkyl)amide; (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono-or di-substituted with C 1-6 alkyl; R 5 is H or C 1-6 alkyl; with the proviso that when B is a carboxyl derivative, an amide derivative or a thioamide derivative, R 4 is not a cycloalkoxy; Y is H or C 1-6 alkyl; R 3 is C 1-8 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C 1-6 alkoxy, C 1-6 thioalkyl, amido, (lower alkyl)amido, C 6 or C 10 aryl, or C 7-16 aralkyl; R 2 is CH 2 - R 20, NH - R 20, O - R 20 or S - R 20, wherein R 20 is pyridinyl, quinolyl, (lower alkyl)-pyridinyl or (lower alkyl)-quinolyl, each optionally mono-, di- or tri-substituted with R 21, wherein each R 21 is independently C 1-6 alkyl; C 1-6 alkoxy; lower thioalkyl; sulfonyl; NO 2; OH; SH; halo; haloalkyl; amino optionally mono-or di-substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-14 aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-14 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C 6 or C 10 aryl, C 7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R 22; wherein R 22 is C 1-6 alkyl; C 3-7 cycloalkyl; C 1-6 alkoxy; amino optionally mono- or di-substituted with C 1-6 alkyl; sulfonyl; (lower alkyl)sulfonyl; NO 2; OH; SH; halo; haloalkyl; carboxyl; amide; (lower alkyl)amide; or Het optionally substituted with C 1-6 alkyl; R 1 is H; C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, all optionally substituted with halogen; or a pharmaceutically acceptable salt or ester thereof; wherein at least one “Het” group is present in the compound of formula (I) and “Het” is defined as a six- or seven-membered saturated or unsaturated aromatic or heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, wherein said heterocycle is optionally fused to a benzene ring.",
    "2. A compound of formula I according to claim 1, wherein B is a C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C 1-6 alkyl; or B is Het or (lower alkyl)-Het, all optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C 1-6 alkyl.",
    "3. A compound of formula I according to claim 1, wherein B is R 4 - SO 2 wherein R 4 is C 1-6 alkyl; amido; (lower alkyl)amide; C 6 or C 10 aryl, C 7-14 aralkyl or Het, all optionally substituted with C 1-6 alkyl.",
    "4. A compound of formula I according to claim 1, wherein B is an acyl derivative of formula R 4 - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, hydroxy or C 1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C 1-6 alkyl; (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl; (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl.",
    "5. A compound of formula I according to claim 1, wherein B is a carboxyl derivative of formula R 4 - O - C(O) -, wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amino optionally mono-or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amide; (ii) C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amide; (iv) C 6 or C 10 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono-or di-substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally mono-or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amido.",
    "6. A compound of formula I according to claim 1, wherein B is an amide derivative of formula R 4 - N(R 5) - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C 1-6 alkyl; (iii) amino optionally mono- or di-substituted with C 1-3 alkyl; (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl, amido or (lower alkyl)amide; and R 5 is H or methyl.",
    "7. A compound of formula I according to claim 1, wherein B is a thioamide derivative of formula R 4 - NH - C(S) -; wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl or C 1-6 alkoxy; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amino or amido.",
    "8. A compound of formula I according to claim 2, wherein B is a C 6 or C 10 aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl.",
    "9. A compound of formula I according to claim 2, wherein B is Het optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl.",
    "10. A compound of formula I according to claim 4, wherein B is an acyl derivative of formula R 4 - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, hydroxy or C 1-6 alkoxy; or (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C 1-6 alkoxy)carbonyl, or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, or (v) Het optionally substituted with C 1-6 alkyl, hydroxy, amido or amino.",
    "11. A compound of formula I according to claim 5, wherein B is a carboxyl derivative of formula R 4 - O - C(O) -, wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl, or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C 1-6 alkyl.",
    "12. A compound of formula I according to claim 6, wherein B is an amide derivative of formula R 4 - N(R 5) - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (iii) amino optionally mono- or di-substituted with C 1-3 alkyl, or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amino or amido optionally substituted with C 1-6 alkyl; or (v) Het optionally substituted with C 1-6 alkyl, hydroxy, amino or amido, and R 5 is H.",
    "13. A compound of formula I according to claim 7, wherein B is a thioamide derivative of formula R 4 - NH - C(S) -; wherein R 4 is (i) C 1-10 alkyl; or (ii) C 3-7 cycloalkyl.",
    "14. A compound of formula I according to claim 12, wherein B is an amide derivative of formula R 4 - NH - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (iv) C 6 or C 10 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, hydroxy, amino or amido.",
    "15. A compound of formula I according to claim 1, wherein B is",
    "16. A compound of formula I according to claim 1, wherein Y is H or methyl.",
    "17. A compound of formula I according to claim 16, wherein Y is H.",
    "18. A compound of formula I according to claim 1, wherein R 3 is C 1-8 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C 1-6 alkoxy, C 1-6 thioalkyl, acetamido, C 6 or C 10 aryl, or C 7-16 aralkyl.",
    "19. A compound of formula I according to claim 18, wherein R 3 is the side chain of Tbg, IIe, Val, Chg or:",
    "20. A compound of formula I according to claim 19, wherein R 3 is the side chain of Tbg, Chg or Val.",
    "21. A compound of formula I according to claim 1, wherein R 2 is S - R 20 or O - R 20 wherein R 20 is a pyridinyl, quinolyl, - CH 2 -pyridinyl or - CH 2 -quinolyl, all optionally mono-, di-or tri-substituted with R 21, wherein R 21 is C 1-6 alkyl; C 1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-16 aralkyl, Het or (lower alkyl)-Het; NO 2; OH; halo; trifluoromethyl; carboxyl; C 6 or C 10 aryl, C 7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R 22, wherein R 22 is C 1-6 alkyl; C 3-7 cycloalkyl; C 1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO 2; OH; halo; trifluoromethyl; carboxyl or Het.",
    "22. A compound of formula I according to claim 21, wherein R 21 is C 1-6 alkyl; C 1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; C 6 or C 10 aryl, or Het, said aryl or Het being optionally substituted with R 22, wherein R 22 is C 1-6 alkyl; C 3-7 cycloalkyl; C 1-6 alkoxy; amino; mono- or di(lower alkyl)amino; amido; (lower alkyl)amide; halo; trifluoromethyl or Het.",
    "23. A compound of formula I according to claim 22, wherein R 22 is C 1-6 alkyl; C 1-6 alkoxy; halo; amino optionally mono- or di-substituted with lower alkyl; amido; (lower alkyl)amide; or Het.",
    "24. A compound of formula I according to claim 23, wherein R 22 is methyl; ethyl; isopropyl; tert-butyl; methoxy; chloro; amino optionally mono- or di-substituted with lower alkyl; amido, (lower alkyl)amide; or (lower alkyl) 2-thiazole.",
    "25. A compound of formula I according to claim 21, wherein R 2 is",
    "26. A compound of formula I according to claim 21, wherein R 2 is quinolinoxy unsubstituted, mono- or di-substituted with R 21 as defined in claim 21.",
    "27. A compound of formula I according to claim 26, wherein R 2 is selected from the group consisting of:",
    "28. A compound of formula I according to claim 26, wherein R 2 is: wherein R 21A is C 1-6 alkyl; C 1-6 alkoxy; lower thioalkyl; halo; amino optionally mono-substituted with C 1-6 alkyl; or C 6, C 10 aryl, C 7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with R 22 wherein R 22 is C 1-6 alkyl, C 1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl, or Het; and R 21B is C 1-6 alkyl, C 1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO 2, OH, halo, trifluoromethyl, or carboxyl.",
    "29. A compound of formula I according to claim 28, wherein R 21A is C 6, C 10 aryl or Het, all optionally substituted with R 22 as defined in claim 28.",
    "30. A compound of formula I according to claim 21, wherein R 2 is: wherein R 22A is C 1-6 alkyl; C 1-6 alkoxy; or halo; and R 21B is C 1-6 alkyl, C 1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO 2, OH, halo, trifluoromethyl, or carboxyl.",
    "31. A compound of formula I according to claim 30, wherein R 21B is C 1-6 alkoxy, or di(lower alkyl)amino.",
    "32. A compound of formula I according to claim 30, wherein R 21B is methoxy.",
    "33. A compound of formula I according to claim 1, wherein R 1 is H, C 1-3 alkyl, C 3-5 cycloalkyl, or C 2-4 alkenyl, all optionally substituted with halo.",
    "34. A compound of formula I according to claim 33, wherein P1 is: and R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.",
    "35. A compound of formula I according to claim 34, wherein R 1 is vinyl.",
    "36. A compound of formula I according to claim 34, wherein R 1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:",
    "37. A compound of formula I according to claim 34, wherein R 1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:",
    "38. A compound of formula I according to claim 34, wherein carbon 1 has the R configuration:",
    "39. An optical isomer of a compound of formula I according to claim 38, wherein said R 1 substituent and the carbonyl in a syn orientation in the following absolute configuration:",
    "40. A compound of formula I according to claim 39, wherein R 1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.",
    "41. A compound of formula I according to claim 39, wherein R 1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.",
    "42. A compound of formula I according to claim 1, wherein B is a C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C 1-6 alkyl; or Het or (lower alkyl)-Het, all optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C 1-6 alkyl,. or B is R 4 - SO 2 wherein R 4 is preferably amido; (lower alkyl)amide; C 6 or C 10 aryl, C 7-14 aralkyl or Het, all optionally substituted with C 1-6 alkyl, or B is an acyl derivative of formula R 4 - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, hydroxy or C 1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl; (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl, or B is a carboxyl derivative of formula R 4 - O - C(O) -, wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amino optionally mono- or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amide; (ii) C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amide; (iv) C 6 or C 10 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C 1-6 alkyl, amido or (lower alkyl)amido, or B is an amide derivative of formula R 4 - N(R 5) - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C 1-6 alkyl; (iii) amino optionally mono- or di-substituted with C 1-3 alkyl; (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl, amido or (lower alkyl)amide; and R 5 is H or methyl, or B is thioamide derivative of formula R 4 - NH - C(S) -; wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl or C 1-6 alkoxy; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amino or amido; Y is H or methyl; R 3 is C 1-8 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C 1-6 alkoxy, C 1-6 thioalkyl, acetamido, C 6 or C 10 aryl, or C 7-16 aralkyl; R 2 is S - R 20 or O - R 20 wherein R 20 is pyridinyl, quinolyl, - CH 2 -pyridinyl or - CH 2 -quinolyl, all optionally mono-, di- or tri-substituted with R 21, wherein R 21 is C 1-6 alkyl; C 1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-16 aralkyl, Het or (lower alkyl)-Het; NO 2; OH; halo; trifluoromethyl; carboxyl; C 6 or C 10 aryl, C 7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R 22, wherein R 22 is C 1-6 alkyl; C 3-7 cycloalkyl; C 1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO 2; OH; halo; trifluoromethyl; carboxyl or Het; or R 2 is or R 2 is quinolinoxy unsubstituted, mono- or di-substituted with R 2 as defined above; and P1 is: wherein R 1 is H, C 1-3 alkyl, C 3-5 cycloalkyl, or C 2-4 alkenyl optionally substituted with halo, and said R 1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical: wherein at least one “Het” group is present in the compound of formula (I) and “Het” is as defined in claim 1; or a pharmaceutically acceptable salt or ester thereof.",
    "43. A compound of formula I according to claim 42, wherein B is a C 6 or C 10 aryl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; or B is Het optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; or B is R 4 - SO 2 wherein R 4 is C 6 or C 10 aryl, a C 7-14 aralkyl or Het all optionally substituted with C 1-6 alkyl; amido, (lower alkyl)amide; or B is an acyl derivative of formula R 4 - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, hydroxy or C 1-6 alkoxy; or (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C 1-6 alkoxy)carbonyl; or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy; or (v) Het optionally substituted with C 1-6 alkyl, hydroxy, amido or amino; or B is a carboxyl derivative of formula R 4 - O - C(O) -, wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amino optionally substituted with C 1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C 1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C 1-6 alkyl; or B is an amide derivative of formula R 4 - N(R 5) - C(O) - wherein R 4 is (i) C 1-10 alkyl optionally substituted with carboxyl, C 1-6 alkanoyl, hydroxy, C 1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; (ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl; and R 5 is H or methyl; or R 4 is (iii) amino optionally mono- or di-substituted with C 1-3 alkyl; or (iv) C 6 or C 10 aryl or C 7-16 aralkyl, all optionally substituted with C 1-6 alkyl, hydroxy, amino or amido optionally substituted with C 1-6 alkyl; or (v) Het optionally substituted with C 1-6 alkyl, hydroxy, amino or amido; or B is a thioamide derivative of formula R 4 - NH - C(S) -; wherein R 4 is: (i) C 1-10 alkyl; or (ii) C 3-7 cycloalkyl; or Y is H; R 3 is the side chain of Tbg, IIe, Val, Chg or: R 2 is quinolinoxy unsubstituted, mono- or di-substituted with R 21 as defined in claim 42, or R 2 is: wherein R 21A is C 1-6 alkyl; C 1-6 alkoxy; C 6, C 10 aryl or Het; lower thioalkyl; halo; amino optionally mono-substituted with C 1-6 alkyl; or C 6, C 10 aryl, C 7-16 aralkyl or Het, optionally substituted with R 22 wherein R 22 is C 1-6 alkyl, C 1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C 1-6 alkyl, or Het; R 21B is C 1-6 alkyl, C 1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO 2, OH, halo, trifluoromethyl, or carboxyl; P1 is: and R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.",
    "44. A compound according to claim 42 represented by the formula: wherein B, R 3, R 2, R 1 are as defined below: R 1 syn to Table 3 car- Cpd # B R 3 R 2 boxyl 329 Boc t-Bu vinyl",
    "45. A compound according to claim 42 represented by the formula: wherein R 3, R 21A and R 21B are as defined below: Table 6 Cpd # R 3 R 21A R 21B 609 t-Bu -; 612 t-Bu -; 617 t-Bu -; and 620 t-Bu -.",
    "46. A compound according to claim 45, selected from the group consisting of compound #612, 617, and 620.",
    "47. A compound according to claim 42 represented by the formula: wherein R 3 and R 21A are as defined below: Table 7 Cmpd # R 3 R 21A 705 t-Bu; 715 t-Bu; 716 t-Bu; 721 t-Bu; 724 t-Bu; 725 t-Bu; 727 t-Bu; and 729 t-Bu;",
    "48. A compound according to claim 47, which is compound #715.",
    "49. A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "50. A method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.",
    "51. A method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the composition according to claim 49.",
    "52. A method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.",
    "53. A method of treating a hepatitis C viral infection in a mammal by administering thereto an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof with another anti-HCV agent.",
    "54. A method according to claim 53, wherein said other anti-HCV agent is selected from the group consisting of: α-or β-interferon, ribavirin and amantadine.",
    "55. A method according to claim 53, wherein said other anti-HCV agent comprises an inhibitor of other targets in the HCV life cycle, selected from: helicase, polymerase, metalloprotease or IRES.",
    "56. A process for the preparation of a peptide analog of formula (I) according to claim 1 wherein P1 is a substituted aminocyclopropyl carboxylic acid residue, comprising the step of: coupling a peptide selected from the group consisting of: APG-P3-P2; or APG-P2; with a P1 intermediate of formula: wherein R 1 is C 1-6 alkyl, cycloalkyl or C 2-6 alkenyl, all optionally substituted with halogen, CPG is a carboxyl protecting group and APG is an amino protecting group and P3 and P2 are as defined above.",
    "57. A process for the preparation of: a peptide analog of formula (I) according to claim 1, this process comprising the step of: coupling a suitably protected amino acid, peptide or peptide fragment with a P1 intermediate of formula: wherein R 1 is C 1-6 alkyl, cycloalkyl or C 2-6 alkenyl, all optionally substituted with halogen, and CPG is a carboxyl protecting group.",
    "58. A process for the preparation of: a peptide analog of formula (I) according to claim 1, this process comprising the step of: coupling a suitably protected amino acid, peptide or peptide fragment with a P1 intermediate of formula: wherein CPG is a carboxyl protecting group.",
    "59. The process according to claim 56, 57 or 58 wherein said carboxyl protecting group (CPG) is selected from the group consisting of: alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.",
    "60. Method of preparing a composition for treating a hepatitis C viral infection in a mammal comprising combining an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "61. Method of preparing a composition for inhibiting the replication of hepatitis C virus comprising combining a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "62. Method of preparing a composition for treating a hepatitis C viral infection in a mammal comprising combining an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, and an interferon with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "63. A compound of formula (I) according to claim 1, wherein each Het group is independently selected from the group consisting of diazepine, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, or quinoline."
  ],
  "description_excerpt": "This application is a divisional of U.S. application Ser. No. 09/368,866, filed on Aug. 5, 1999, U.S. Pat. No. 6,323,180 which claims the benefit of U.S. Provisional Application No. 60/095,931, filed Aug. 10, 1998, and U.S. Provisional Application No. 60/132,386, filed May 4, 1999.\n\nThe present invention relates to compounds, process for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection. The present invention also provides processes and intermediates for the synthesis of these peptide analogs.\n\nHepatitis C virus (HCV) is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 150 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.\n\nThe mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established.",
  "cpc": [
    "C12P 13/02",
    "A61K 38/21",
    "A61K 45/06",
    "A61P 1/16",
    "A61P 31/12",
    "A61P 31/14",
    "A61P 31/16",
    "A61P 43/00",
    "C07D 207/16",
    "C07D 401/12",
    "C07D 403/12",
    "C07D 403/14",
    "C07D 405/14",
    "C07D 409/14",
    "C07D 417/14",
    "C07K 5/08",
    "C07K 5/0806",
    "C07K 5/0808",
    "C07K 5/081",
    "C07K 5/0812",
    "C12P 41/005"
  ],
  "ipc": [
    "A61K 31/13",
    "A61K 31/7056",
    "A61K 38/00",
    "A61K 38/06",
    "A61K 38/21",
    "A61P 1/16",
    "A61P 31/12",
    "A61P 31/14",
    "C07C 229/48",
    "C07K 1/06",
    "C07K 5/08",
    "C07K 5/083",
    "C07K 5/087",
    "C12N 15/09",
    "C12N 9/50",
    "C12N 9/99",
    "C12P 21/02",
    "C12P 41/00"
  ],
  "assignees": [
    "Boehringer Ingelheim Canada Ltd"
  ],
  "inventors": [
    "Montse Llinas-Brunet",
    "Murray D. Bailey",
    "Dale R. Cameron",
    "Elise Ghiro",
    "Nathalie Goudreau",
    "Marc-Andre Poupart",
    "Jean Rancourt",
    "Youla S. Tsantrizos",
    "Anne-Marie Faucher",
    "Teddy Halmos",
    "Dominik M. Wernic"
  ],
  "filing_date": "2001-05-04",
  "publication_date": "2002-06-25",
  "grant_date": "2002-06-25",
  "priority_date": "1998-08-10",
  "application_number": "US-84905701-A",
  "family_id": "26790767",
  "cited_by_count": 220,
  "citations": [
    "DE19600034A1",
    "WO1998017679A1",
    "WO1999007733A2",
    "US6277830B1"
  ]
}