USRE42164EExpiredUtility
Hepatitis C inhibitor tri-peptides
Est. expiryAug 10, 2018(expired)· nominal 20-yr term from priority
Inventors:Montse Llinas-BrunetMurray D. BaileyDale R. CameronElise GhiroNathalie GoudreauMarc-Andre PoupartJean RancourtYoula S. TsantrizosAnne-Marie FaucherTeddy HalmosDominik M. Wernic
A61P 43/00A61P 31/16A61P 31/12A61P 31/14A61P 1/16C07K 5/081C07K 5/0812C07K 5/0808C07D 405/14C07D 401/12A61K 45/06C07D 409/14C07D 417/14C07D 403/12C12P 13/02C07K 5/0806C07D 403/14C12P 41/005C07D 207/16A61K 38/21C07K 5/08
69
PatentIndex Score
0
Cited by
29
References
96
Claims
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
exact text as granted — not AI-modified1. A racemate, diastereoisomer or optical isomer 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, or amido, or (lower alkyl) amide ; and when B is R 4 —O—C ( O ) —; R 4 —N ( R 5 ) —C ( O ) —; R 4 N ( R 5 ) —C ( S ) —; or R 4 —SO 2 , then R 4 may additionally be selected from C 1-10 alkyl substituted with ( lower alkyl ) amide;
(ii) C 3-7 cycloalkyl, or 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; or R 4 is C 4-10 alkylcycloalkyl, optionally substituted with hydroxy, carboxyl, ( C 1-6 alkoxy ) carbonyl, amino optionally mono - or di- substituted with C 1-6 alkyl, or amido; and when B is R 4 —O—C ( O ) —; R 4 —N ( R 5 ) —C ( O ) —; R 4 —N ( R 5 ) —C ( S ) —; or R 4 —SO 2 , then R 4 may additionally be C 4-10 alkylcycloalkyl substituted with ( 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 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, all optionally mono-, di- or tri-substituted with R 21 ,
or R 20 is Het or (lower alkyl)-Het, both optionally mono-, di- or tri-substituted with R 21 , provided that Het is not pyridinyl or quinolyl in these instances,
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 amido; (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 “Het” is defined as a five-, six-, or seven-membered saturated or unsaturated, aromatic or non-aromatic, 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; or C 4-10 alkylcycloalkyl, optionally substituted with hydroxy, carboxyl, ( C 1-6 alkoxy ) carbonyl, amino optionally mono - or di - substituted with C 1-6 alkyl, or amido;
(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, amino optionally mono- or di -substituted with C 1-6 alkyl, amido, or (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, or 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, or (C 1-6 alkoxy)carbonyl, or
(iv) C 6 or C 10 aryl or C 7-16 aralkyl, all both optionally substituted with C 1-6 alkyl, or 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, or amino optionally mono- or di-substituted with C 1-6 alkyl;
(ii) C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all both optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or 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 both optionally substituted with C 1-6 alkyl, hydroxy, 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, 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, or amino optionally mono- or di-substituted with C 1-6 alkyl;
(ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all both optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or 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, or amino optionally mono- or di-substituted with C 1-6 alkyl;
(ii) C 3-7 cycloalkyl or C 4-10 alkylcycloalkyl, all both optionally substituted with carboxyl, (C 1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; or
(iv) C 6 or C 10 aryl or C 7-16 aralkyl, both optionally substituted with C 1-6 alkyl, hydroxy, amino or amido.
15. A compound of formula I according to claim 1 , wherein B is Boc or
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, He Ile, 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 C 6 or C 10 aryl, C 7-16 C 7-14 aralkyl, Het or —CH 2 —Het, 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 mono- substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-16 C 7-14 aralkyl, Het or (lower alkyl)-Het; NO 2 ; OH; halo; trifluoromethyl; carboxyl; C 6 or C 10 aryl, C 7-16 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; mono- or di-(lower alkyl)amino; amido; (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 selected from the group consisting of:
26. A compound of formula I according to claim 21 , wherein R 2 is 1-naphthylmethoxy; 2-naphthylmethoxy; benzyloxy, 1-naphthyloxy; or 2-naphthyloxy; or 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 1-naphtylmethoxy; or quinolinoxy 1 - naphthylmethoxy unsubstituted, mono- or di-substituted with R 21 as defined in claim 26 .
28. A compound of formula I according to claim 27 , wherein R 2 is selected from the group consisting of:
29. 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.
30. A compound of formula I according to claim 29 , wherein R 21A is C 6 , C 10 aryl or Het, all optionally substituted with R 22 as defined in claim 29 .
31. A compound of formula I according to claim 30 , wherein R 21A is selected from the group consisting of:
32. 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.
33. A compound of formula I according to claim 29 , wherein R 2 is:
wherein R 22B is C 1-6 alkyl, amino optionally mono-substituted with C 1-6 alkyl, amido, or (lower alkyl)amide; 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.
34. A compound of formula I according to claim 32 or 33 , wherein R 21B is C 1-6 alkoxy, or di(lower alkyl)amino.
35. A compound of formula I according to claim 32 or, 33 , wherein R 21B is methoxy.
36. A compound of formula I according to claim 1 , wherein R 1 is H, C 1-3 alky C 1-3 alkyl , C 3-5 cycloalkyl, or C 2-4 alkenyl, all optionally substituted with halo.
37. A compound of formula I according to claim 36 , wherein P1 is
and R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
38. A compound of formula I according to claim 37 , wherein R 1 is vinyl.
39. A compound of formula I according to claim 37 , wherein R 1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:
40. A compound of formula I according to claim 37 , wherein R 1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:
41. A compound of formula I according to claim 37 , wherein carbon 1 has the R configuration:
42. An optical isomer of a compound of formula I according to claim 41 , wherein said R 1 substituent and the carbonyl are in a syn orientation in the following absolute configuration:
43. A compound of formula I according to claim 42 , wherein R 1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.
44. A compound of formula I according to claim 42 , wherein R 1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.
45. 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, 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, (loweralkyl)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; or C 4-10 alkylcycloalkyl, optionally substituted with hydroxy, carboxyl, ( C 1-6 alkoxy ) carbonyl, amido 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 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 substituted with C 1-6 alkyl, amido, (lower alkyl)amide, or amino optionally mono- or di -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, or 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, all 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; or
(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, amino optionally mono- or di -substituted with C 1-6 alkyl, amido or (lower alkyl)amide; and
R 5 is H or methyl, or
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; or
(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 1-6 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 a C 6 or C 10 aryl, C 7-16 aralkyl, Het or —CH 2 -Het, all optionally mono-, di- or tri-substituted with R 21 , provided that Het is not pyridinyl or quinolyl in these instances, wherein
R 21 is C 1-6 alkyl; C 1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted mono- substituted with C 1-6 alkyl, C 6 or C 10 aryl, C 7-16 C 7-14 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 selected from the group consisting of:
or R 2 is 1-naphthylmethoxy; 2-naphthylmethoxy; benzyloxy; 1-naphthyloxy; or 2-naphthyloxy; or quinolinoxy unsubstituted, mono- or di-substituted with R 21 , as defined above; and
P 1 is:
P 1 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 oriented syn to the carbonyl at position 1, represented by the radical:
or a pharmaceutically acceptable salt or ester thereof.
46. A compound of formula I according to claim 45 , 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, or (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, or 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, 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)amide, or 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, oramino 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, 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)amide, or 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 tert- butylglycine ( Tbg ), He Ile, Val, Chg or:
R 2 is 1-naphtylmethoxy; or quinolinoxy 1 -aphthylmethoxy unsubstituted, mono- or di-substituted with R 21 as defined above, 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; 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;
P1 is:
R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
47. A compound of formula I according to claim 46 , 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, 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)amide, or amino optionally mono- or di-substituted with C 1-6 alkyl; or
(iv) C 6 or C 10 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, hydroxy, amino or amido;
R 3 is the side chain of Tbg, Chg or Val;
R 1 is:
wherein R 22A is C 1-6 alkyl; C 1-6 alkoxy; or halo; R 22B is C 1-6 alkyl, amino optionally mono-substituted with C 1-6 alkyl, amido, or (lower alkyl)amide; 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; and P1 is:
48. A compound according to claim 45 represented by the formula:
wherein B, R 3 , R 2 are as defined below:
Tab 1 Cpd # B R 3 R 2 101 Boc cHex —O—CH 2 -1-naphthyl; 102 cHex —O—CH 2 -1-naphthyl; 103 cHex —O—CH 2 -1-naphthyl; 104 cHex —O—CH 2 -1-naphthyl; 105 cHex —O—CH 2 -1-naphthyl; 106 Boc cHex 107 cHex —O—CH 2 -1-naphthyl; 108 Boc iPr 109 acetyl cHex 110 Boc i-Pr and 111 Boc t-Bu
!
49. Compound #111 according to claim 48 .
50. A compound according to claim 45 represented by the formula:
wherein B, R 3 , R 2 , R 1 are as defined below:
Table 2 R 1 Cpd # B R 3 R 2 anti to carboxy 201 Boc cyclohexyl —O—CH 2 -1-naphthyl ethyl (one isomer); 202 Boc cyclohexyl —O—CH 2 -1-naphthyl ethyl (other isomer); and 203 Boc t-Bu vinyl 1R, 2R .
!
51. Compound #203 according to claim 49 .
52. A compound according to claim 45 represented by the formula:
wherein B, R 3 , R 2 and R 1 are as defined below:
Table 3 R 1 Cpd # B R 3 R 2 syn to carboxyl 301 Boc cHex —O—CH 2 -1-naphthyl ethyl; 302 iPr —O—CH 2 -1-naphthyl ethyl; 303 cHex —O—CH 2 -1-naphthyl ethyl; 304 Boc cHex ethyl; 305 Boc cHex —O—CH 2 -1-naphthyl vinyl; 306 Boc cHex vinyl; 307 Boc cHex vinyl; 308 Boc cHex vinyl; 309 Boc cHex vinyl; 310 Boc cHex vinyl; 311 Boc cHex vinyl; 312 Boc cHex vinyl; 313 Boc cHex vinyl; 314 Boc cHex vinyl; 315 Boc cHex vinyl; 316 Acetyl cHex vinyl; 317 Boc cHex vinyl; 318 CF 3 —C(O)— i-Pr vinyl; 319 cHex vinyl; 320 cHex vinyl; 321 Boc t-Bu vinyl; 322 Boc t-Bu vinyl; 323 Boc t-Bu 324 Boc t-Bu vinyl; 325 Boc t-Bu 326 Boc t-Bu vinyl; 327 t-Bu Vinyl; 328 Boc t-Bu vinyl; 329 Boc t-Bu vinyl; 330 Boc t-Bu vinyl; 331 t-Bu Vinyl; 332 Boc t-Bu ethyl; 333 t-Bu vinyl; and 334 t-Bu vinyl .
!
53. A compound according to claim 52 , selected from the group consisting of compound #307, 314, 317, 319, 321, 324, 325, and 326, 327, 329, 331, 332, 333, and 334 .
54. A compound according to claim 45 represented by the formula:
wherein B, R 3 , R 2 and R 1 are as defined below:
Table 4 Cpd # B R 3 R 2 R 1 401 Boc i-Pr H; 402 Boc t-Bu H; 403 Boc t-Bu H; 404 Boc t-Bu 3-(═CH 2 ); 405 Boc t-Bu 2-vinyl; and 406 Boc t-Bu 2-Et.
!
55. A compound according to claim 54 , selected from the group consisting of compound #:403, 405, and 406.
56. A compound according to claim 45 represented by the formula:
wherein R 3 is as defined below:
Table 5 Cpd # R 3 501 t-Bu; 502 H; 503 504 505 506 507 508 509 510 and 511
!
57. A compound according to claim 56 , selected from the group consisting of compound #: 501, 509, and 510.
58. A compound according to claim 46 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 601 i-Pr Ph 7-OMe; 602 t-Bu Ph 8-OMe, 7-OMe; 603 i-Pr Ph 7-ethyl; 604 t-Bu — 7-OMe; 605 t-Bu Ph 7-O-iPr; 606 t-Bu — 7-Cl; 607 i-Pr — 7-Cl; 608 CH 2 -iPr — 7-Cl; 609 t-Bu —; 610 t-Bu Cl —; 611 t-Bu Ph 7-N(Me) 2 ; 612 t-Bu —; 613 t-Bu —; 614 t-Bu —; 615 t-Bu — 7-N(Me) 2 ; 616 t-Bu —; 617 t-Bu —; 618 t-Bu —; 619 t-Bu —; 620 t-Bu —; 621 t-Bu —; 622 t-Bu —; 623 t-Bu MeO— —; 624 t-Bu (Me 2 )N— —; 625 t-Bu Ph 7-S(Me); 626 t-Bu Ph 7-Br; 627 t-Bu Ph 7-F; 628 t-Bu 7-N(Me) 2 ; 629 t-Bu 7-N(Me) 2 ; and 630 t-Bu 7-N(Et) 2 ;
!
59. A compound according to claim 58 , selected from the group consisting of compound #: 601, 602, 603, 604, 605, 606, 607, 610, 611, 612, 615, 616, 617, 620, 621, 622, 625, 626, 627, 628, 629, and 630.
60. A compound according to claim 46 represented by the formula:
wherein R 3 and R 21A are as defined below:
Table 7 Cpd # R 3 R 21A 701 t-Bu 702 t-Bu 703 t-Bu 704 t-Bu 705 t-Bu 706 t-Bu 707 t-Bu 708 t-Bu Ph-N(Me)—; 709 t-Bu 710 t-Bu HOOC—; 711 t-Bu 712 t-Bu (Me) 2 N; 713 t-Bu 714 t-Bu 715 t-Bu 716 t-Bu 717 t-Bu 718 t-Bu NH 2 ; 719 t-Bu 720 t-Bu 721 t-Bu 722 t-Bu 723 t-Bu 724 t-Bu 725 t-Bu 726 t-Bu i-Pr; 727 t-Bu 728 t-Bu 729 t-Bu 730 t-Bu 731 t-Bu 732 t-Bu 733 t-Bu 734 t-Bu 735 t-Bu 736 t-Bu t-Bu; and 737 t-Bu CHex.
!
61. A compound according to claim 60 , selected from the group consisting of compound #: 701, 702, 703, 704, 705, 706, 707, 708, 709, and 711 to 737.
62. A compound according to claim 45 represented by the formula:
Table 8 Cpd # B R 3 R 22 801 t-Bu —; 802 t-Bu —; 803 t-Bu —; 804 t-Bu —; 805 Ac t-Bu —; 806 t-Bu —; 807 t-Bu —; 808 t-Bu —; 809 i-Pr —; 810 t-Bu —; 811 Boc t-Bu 4-Cl; 812 t-Bu —; 813 t-Bu —; 814 Boc t-Bu 2-Cl; 815 Boc t-Bu 3-Cl; 816 t-Bu —; 817 t-Bu —; 818 t-Bu —; 819 i-Pr —; 820 i-Pr —; 821 i-Pr —; 822 i-Pr —; 823 Boc t-Bu 2-OMe; 824 Boc t-Bu 3-OMe; 825 Boc t-Bu 4-OMe; 826 i-Pr —; 827 t-Bu —; 828 i-Pr —; 829 t-Bu —; 830 t-Bu —; 831 t-Bu —; 832 t-Bu —; 833 t-Bu —; 834 i-Pr —; 835 t-Bu —; 836 i-Pr —; 837 i-Pr —; 838 i-Pr —; 839 i-Pr —; 840 i-Pr —; 841 Boc t-Bu 2-Me; 842 Boc t-Bu 3-Me; 843 Boc t-Bu 4-Me; 844 t-Bu 4-OMe; 845 i-Pr —; 846 i-Pr —; 847 Boc cHex —; 848 Boc —; 849 Boc —; 850 Boc —; 851 Boc —; 852 Boc —; 853 Boc —; 854 i-Pr —; 855 i-Pr —; 856 i-Pr —; 857 t-Bu —; 858 t-Bu —; 859 i-Pr —; 860 i-Pr —; 861 i-Pr —; 862 i-Pr —; 863 i-Pr —; 864 i-Pr —; 865 t-Bu —; 866 t-Bu —; 867 t-Bu —; 868 t-Bu —; 869 t-Bu —; 870 t-Bu —; 871 t-Bu —; 872 t-Bu —; and 873 t-Bu —.
!
wherein B, R 3 , and R 22 are as defined below:
63. A compound according to claim 62 , selected from the group consisting of compound #: 801 to 825, 827 to 858, and 860 to 873.
64. A compound according to claim 45 represented by the formula:
wherein B is as defined below:
Table 9 Cpd # B 901 Boc; 902 903 904 905 906 907 908 909 910 911 912 913 914 915 and 916
!
65. A compound according to claim 45 represented by the formula:
wherein B, X, R 3 , z and R 21B are as defined below:
Table 10 Cpd # B—X— R 3 Z R 21B 1001 Ph-N(Me)— i-Pr O H; 1002 Boc-NH— t-Bu S OMe; and 1003 i-Pr O —.
!
66. 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 therof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.
67. A method of treating a hepatitis C viral infection in a mammal comprising 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.
68. A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the composition according to claim 66 .
69. A method of inhibiting the replication of hepatitis C virus comprising 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.
70. A method of treating a hepatitis C viral infection in a mammal comprising 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.
71. A method according to claim 70 , wherein said other anti-HCV agent is selected from the group consisting of: α- or β-interferon, ribavirin and amantadine.
72. A method according to claim 70 , wherein said other anti-HCV agent comprises an inhibitor or other targets in the HCV life cycle, selected from: helicase, polymerase, metalloprotease or IRES.
73. A process for the preparation of a peptide analog compound of formula (I) according to claim 1 wherein P1 is a substituted aminocyclopropyl carboxylic acid residue as shown for the P 1 part of formula (I), comprising the step of:
coupling a peptide selected from the group consisting of: APG-P3-P 2; or and 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.
74. A process for the preparation of: a peptide analog compound 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.
75. A process for the preparation of: a peptide analog compound 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.
76. A process according to claim 73 , 74 or 75 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.
77. 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.
78. 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.
79. 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.
80. A compound of the formula:
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;
R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl;
APG is an amino protecting group selected from: 1) acyl groups, 2) aromatic carbamate groups, 3) aliphatic carbamate groups, 4) cyclic alkyl carbamate groups, 5) alkyl groups, 6) trialkylsilyl, and 7) thiol containing groups; and
CPG is a carboxyl protecting group selected from: alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.
81. The compound according to claim 80 , wherein said carboxyl protecting group is selected from: methyl, trimethylsilylethyl, t-butyl, benzyl, substituted benzyl, trichloroethyl and phenacyl esters.
82. The compound according to claim 80 , wherein said amino protecting group is selected from: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, as benzyloxycarbonyl, substituted benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilyl, phenylthiocarbonyl and dithiasuccinoyl.
83. The compound according to claim 80 , wherein said amino protecting group is selected from: tert-butyloxycarbonyl and 9-fluorenylmethyloxycarbonyl.
84. A compound of formula I according to claim 80 , wherein R 21A is C 6 , C 10 aryl or Het, all optionally substituted with R 22 as defined in claim 80 .
85. A compound of formula I according to claimwherein claim 80 , wherein R 21A is selected from the group consisting of:
86. A compound of the formula:
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;
R 1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl;
APG is an amino protecting group selected from: 1) acyl groups, 2) aromatic carbamate groups, 3) aliphatic carbamate groups, 4) cyclic alkyl carbamate groups, 5) alkyl groups, 6) trialkylsilyl, and 7) thiol containing groups; and
CPG is a carboxyl protecting group selected from: alkyl esters, aralkyl esters, and esters being cleavable by mild base treatment or mild reductive means.
87. A compound of formula I according to claim 80 , wherein R 2 is:
wherein R 22B is C 1-6 alkyl, amino optionally mono-substituted with C 1-6 alky, amido, or (lower alkyl)amide; 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.
88. A compound of formula I according to claim 86 or 87 , wherein R 21B is C 1-6 alkoxy, or di(lower alkyl)amino.
89. A compound of formula I according to claim 86 or 87 , wherein R 21B is methoxy.
90. A compound of formula I according to claim 80 , wherein R 1 is vinyl.
91. A compound of formula I according to claim 80 , wherein R 1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical:
92. A compound of formula I according to claim 80 , wherein R 1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical:
93. A compound of formula I according to claim 80 , wherein carbon 1 has the R configuration:
94. An optical isomer of a compound of formula I according to claim 93 , wherein said R 1 substituent and the carbonyl are in a syn orientation in the following absolute configuration:
95. A compound of formula I according to claim 94 , wherein R 1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.
96. A compound of formula I according to claim 94 , wherein R 1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the R,S configuration.Cited by (0)
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