A racemate diastereoisomer and optical isomer of a compound of formula (I): ##STR00001##
wherein B is H, a C6 or C10 aryl, C7-16 aralkyl; Het or (lower alkyl)-Het, all of which may be optionally substituted with C1-6 alkyl; C1-6 alkoxy; C1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C1-6 alkyl; amido; or (lower alkyl)amide; or

Patent
   RE40525
Priority
Aug 10 1998
Filed
Sep 30 2005
Issued
Sep 30 2008
Expiry
Aug 05 2019
Assg.orig
Entity
Large
28
5
all paid
1. A racemate, diastereoisomer or optical isomer of a compound of formula (I): ##STR00319##
wherein B is H, a C6 or C10 aryl, C7-16 aralkyl; Het or (lower alkyl)-Het, all of which optionally substituted with C1-6 alkyl; C1-6 alkoxy; C1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C1-6 alkyl; amido; or (lower alkyl)amide;
or B is an acyl derivative of formula r4—C(O)—; a carboxyl derivative of formula r4—O—C(O)—; an amide derivative of formula r4—N(r5)—C(O)—; a thioamide derivative of formula r4—N(r5)—C(S)—; or a sulfonyl derivative of formula r4—SO2 wherein
r4 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxyl, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, or amido, or (lower alkyl) amide ; and when B is r4—O—C(O)—; r4—N(r5)—C(O)—; r4—N(r5)—C(S)—; or r4—SO2, then r4 may additionally be selected from C1-10 alkyl substituted with (lower alkyl) amide;
(ii) C3-7 cycloalkyl, or C3-7 cycloalkoxy, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyl) amide; or r4 is C4-10 alkylcycloalkyl, optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, or amido; and when B is r4—O—C(O)—; r4—N(r5)—C(O)—; r4—N(r5)—C(S)—; r4—SO2, then r4 may additionally be C4-10 alkylcycloalkyl substituted with (lower alkyl) amide;
(iii) amino optionally mono- or di-substituted with C1-6 alkyl; amido; or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
r5 is H or C1-6 alkyl; with the proviso that when B is a carboxyl derivative, an amide derivative or a thioamide derivative, r4 is not a cycloalkoxy;
Y is H or C1-6 alkyl;
r3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, amido, (lower alkyl)amido, C6 or C10 aryl, or C7-16 aralkyl;
r2 is CH2—R20, NH—R20, O—R20 or S—R20, wherein r20 is pyridinyl, quinolyl, (lower alkyl)-pyridinyl or (lower alkyl)-quinolyl, each optionally mono-, di- or tri-substituted with r21,
wherein each r21 is independently C1-6 alkyl; C1-6 alkoxy; lower thioalkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amino optionally mono- or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C1-6 alkyl, C6 or C1-10 aryl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with r22;
wherein r22 is C1-6 alkyl; C3-7 cycloalkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; (lower alkyl)sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide; (lower alkyl)amide; or Het optionally substituted with C1-6 alkyl;
r1 is H, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl, all optionally substituted with halogen;
or a pharmaceutically acceptable salt or ester thereof; wherein “Het” is defined as a five-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 C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl; or
B is Het or (lower alkyl)-Het, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl.
3. A compound of formula I according to claim 1, wherein B is r4—SO2 wherein r4 is preferably amido; (lower alkyl)amide; C6 or C10 aryl, C7-14 aralkyl or Het, all optionally substituted with C1-6 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) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy) carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl; or r4 is C4-10 alkylcycloalkyl optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally substituted with C1-6 alkyl;
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl.
5. A compound of formula I according to claim 1, wherein B is a carboxyl derivative of formula r4—O—C(O)—, wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(ii) C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyli, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl) amido.
6. A compound of formula I according to claim 1, wherein B is an amide derivative of formula r4—N(r5)—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl) amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 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 derivative of formula r4—NH—C(S)—; wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl or C1-6 alkoxy;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 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 C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-6 alkyl.
9. A compound of formula I according to claim 2, wherein B is Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 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) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy; or
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy) carbonyl, or
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, or (v) Het optionally substituted with C1-6 alkyl, hydroxy, amido or amino.
11. A compound of formula I according to claim 5, wherein B is a carboxyl derivative of formula r4—O—C (O)—, wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy or amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or
(iv) C6 or C10 aryl or C7-16 aralkyl, optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C1-6 alkyl.
12. A compound of formula I according to claim 6, wherein B is an amide derivative of formula r4—N(r5—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl, or
(iv) C6 or C10 aryl or C7-16 aralkyl, optionally substituted with C1-6 alkyl, hydroxy, amino or amido optionally substituted with C1-6 alkyl; or
(v) Het optionally substituted with C1-6 alkyl, hydroxy, amino or amido, and r5 is H.
13. A compound of formula I according to claim 7, wherein B is a thioamide derivative of formula r4—NH—C(S)—; wherein r4 is (i) C1-10 alkyl; or (ii) C3-7 cycloalkyl.
14. A compound of formula I according to claim 12, wherein B is an amide derivative of formula r4—NH—C (O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amino or amido.
15. A compound of formula I according to claim 1, wherein B is ##STR00320##
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 r3 is C1-8 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, acetamido, C6 or C10 aryl, or C7-16 aralkyl.
19. A compound of formula I according to claim 18, wherein r3 is the side chain of Tbg, Ile, Val, Chg or: ##STR00321##
20. A compound of formula I according to claim 19, wherein r3 is the side chain of Tbg, Chg or Val.
21. A compound of formula I according to claim 1, wherein r2 is S—R20 or O—R20 wherein r20 is a pyridinyl, quinolyl, —CH2-pyridinyl or —CH2-quinolyl, all optionally mono-, di- or tri-substituted with r21, wherein
r21 is C1-6 alkyl; C1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; NO2; OH; halo; trifluoromethyl; carboxyl; C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with r22, wherein r22 is C1-6 alkyl; C3-7 cycloalkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO2; OH; halo; trifluoromethyl; carboxyl or Het.
22. A compound of formula I according to claim 21, wherein r21 is C1-6 alkyl; C1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; C6 or C10 aryl, or Het, said aryl or Het being optionally substituted with r22, wherein r22 is C1-6 alkyl; C3-7 cycloalkyl; C1-6 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 r22 is C1-6 alkyl; C1-6 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 r22 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 r2 is ##STR00322##
26. A compound of formula I according to claim 21, wherein r2 is quinolinoxy unsubstituted, mono- or di-substituted with r21, as defined in claim 21.
27. A compound of formula I according to claim 26, wherein r2 is selected from the group consisting of: ##STR00323##
28. A compound of formula I according to claim 26, wherein r2 is: ##STR00324##
wherein r21A is C1-6 alkyl; C1-6 alkoxy; lower thioalkyl; halo; amino optionally mono-substituted with C1-6 alkyl; or C6, C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with r22 wherein r22 is C1-6 alkyl, C1-6 alkoxy, amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C1-6 alkyl, or Het; and
r21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl) amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
29. A compound of formula I according to claim 28, wherein r21A is C6, C10 aryl or Het, all optionally substituted with r22 as defined in claim 28.
30. A compound of formula I according to claim 29, wherein r21A is selected from the group consisting of: ##STR00325##
31. A compound of formula I according to claim 21, wherein r2 is: ##STR00326##
wherein r22A is C1-6 alkyl; C1-6 alkoxy; or halo; and r21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
32. A compound of formula I according to claim 28, wherein r2 is: ##STR00327##
wherein r22B is C1-6 alkyl, amino optionally mono-substituted with C1-6 alkyl, amido, or (lower alkyl)amide and r21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl) amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
33. A compound of formula I according to claim 31 or 32, wherein r21B is C1-6 alkoxy, or di(lower alkyl)amino.
34. A compound of formula I according to claim 31 or 32, wherein r21B is methoxy.
35. A compound of formula I according to claim 1, wherein r1 is H, C1-3 alkyl, C3-5 cycloalkyl, or C2-4 alkenyl, all optionally substituted with halo. ##STR00328##
36. A compound of formula I according to claim 35, wherein P1 is:
and r1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
37. A compound of formula I according to claim 36, wherein r1 is vinyl.
38. A compound of formula I according to claim 31, wherein r1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical: ##STR00329##
39. A compound of formula I according to claim 36, wherein r1 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical: ##STR00330##
40. A compound of formula I according to claim 36, wherein carbon 1 has the r configuration: ##STR00331##
41. An optical isomer of a compound of formula I according to claim 40, wherein said r1 substituent and the carbonyl are in a syn orientation in the following absolute configuration: ##STR00332##
42. A compound of formula I according to claim 41 wherein r1 is ethyl, hence the asymmetric carbon atoms at positions 1 and 2 have the r,R configuration.
43. A compound of formula I according to claim 41, wherein r1 is vinyl, hence the asymmetric carbon atoms at positions 1 and 2 have the r,S configuration.
44. A compound of formula I according to claim 1, wherein
B is a C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl; or Het or (lower alkyl)-Het, all optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C1-6 alkyl, or
B is r4—SO2 wherein r4 is preferably amido; (lower alkyl)amide; C6 or C10 aryl, C7-14 aralkyl or Het, all optionally substituted with C1-6 alkyl, or
B is an acyl derivative of formula r4—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl;
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl, or
B is a carboxyl derivative of formula r4—O—C(O)—, wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy) carbonyl, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl) amido, or amino optionally mono- or di-substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido or (lower alkyl) amido, or
B is an amide derivative of formula r4—N(r5)—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy) carbonyl, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C1-6 alkyl;
(iii) amino optionally mono- or di-substituted with C1-3 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, amido, (lower alkyl)amide; and
r5 is preferably H or methyl, or
B is thioamide derivative of formula r4—NH—C(S)—; wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl or C1-6 alkoxy;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy) carbonyl, amino or amido;
Y is H or methyl;
r3 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C1-6 alkoxy, C1-6 thioalkyl, acetamido, C6 or C10 aryl, or C7-16 aralkyl;
r2 is S—R20 or O—R20 wherein r20 is pyridinyl, quinolyl, —CH2-pyridinyl or —CH2-quinolyl, all optionally mono-, di- or tri-substituted with r21, wherein
r21 is C1-6 alkyl; C1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; NO2; OH; halo; trifluoromethyl; carboxyl; C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with r22, wherein
r22 is C1-6 alkyl; C3-7 cycloalkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO2; OH; halo; trifluoromethyl; carboxyl or Het;
or r2 is quinolinoxy unsubstituted, mono- or di-substituted with r21 as defined above; and
P1 is: ##STR00333##
wherein r1 is H, C1-3 alkyl, C3-5 cycloalkyl, or C2-4 alkenyl optionally substituted with halo, and said r1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by the radical: ##STR00334##
or a pharmaceutically acceptable salt or ester thereof.
45. A compound of formula I according to claim 44, wherein B is a C6 or C10 aryl optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl; or B is Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl; or
B is r4—SO2 wherein r4 is C6 or C10 aryl, a C7-14 aralkyl or Het all optionally substituted with C1-6 alkyl; amido, (lower alkyl)amide; B is an acyl derivative of formula r4—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, hydroxy or C1-6 alkoxy; or
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C1-6 alkoxy)carbonyl; or
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy; or
(v) Het optionally substituted with C1-6 alkyl, hydroxy, amido or amino;
or B is a carboxyl derivative of formula r4—O—C(O)—, wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl; or
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C1-6 alkyl;
or B is an amide derivative of formula r4—N(r5)—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy) carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl; and r5 is H or methyl; or
r4 is (iii) amino optionally mono- or di-substituted with C1-3 alkyl; or
(iv) C6 or C10 aryl or C7-16 aralkyl, all optionally substituted with C1-6 alkyl, hydroxy, amino or amido optionally substituted with C1-6 alkyl; or
(v) Het optionally substituted with C1-6 alkyl, hydroxy, amino or amido; or
B is a thioamide derivative of formula r4—NH—C(S)—; wherein RR4 is
(i) C1-10 alkyl; or (ii) C3-7 cycloalkyl; or
Y is H;
r3 is the side chain or Tbg, Ile, Val, Chg or: ##STR00335##
r2 is quinolinoxy unsubstituted, mono- or di-substituted with r21 as defined above, or r2 is: ##STR00336##
wherein r21 is C1-6 alkyl; C1-6 alkoxy; C6, C10 aryl or Het; lower thioalkyl; halo; amino optionally mono-substituted with C1-6 alkyl; or C6, C10 aryl, C7-16 aralkyl or Het, optionally substituted with r22 wherein r22 is C1-6 alkyl, C1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl, or Het; and r21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl)amide, NO2, OH, halo, trifluoromethyl, or carboxyl;
P1 is: ##STR00337##
r1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
46. A compound of formula I according to claims claim 45, wherein
B is an amide derivative of formula r4—NH—C(O)— wherein r4 is
(i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C1-6 alkoxy) carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C1-6 alkyl;
(iv) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, amino or amido;
r3 is the side chain of Tbg, Chg or Val;
r2 is: ##STR00338##
wherein r22A is C1-6 alkyl, C1-6 alkoxy; r22B is C1-6 alkyl, amino optionally mono-substituted with C1-6 alkyl, or (lower alkyl)amide; and r21B is C1-6 alkyl, C1-6 alkoxy, amino, di(lower alkyl)amino, (lower alkyl) amide, NO2, OH, halo, trifluoromethyl, or carboxyl;
and P1 is: ##STR00339##
47. A compound according to claim 44 represented by the formula: ##STR00340##
wherein B, r3, r2 are as defined below:
Tab 1
Cpd # B r3 r2
106 Boc cHex ##STR00341##
108 Boc iPr ##STR00342##
109 acetyl cHex ##STR00343##
110 Boc i-Pr ##STR00344##
and 111 Boc t-Bu ##STR00345##
!
48. compound #111 according to claim 47.
49. A compound according to claim 44 represented by the formula: ##STR00346##
wherein B, r3, r2, R1 are defined below:
Table
2 r1
Cpd anti to
# B r3 r2 carboxy
203 Boc t-Bu ##STR00347## vinyl 1R, 2R.
!
50. compound #203 according to claim 48.
51. A compound according to claim 44 represented by the formula: ##STR00348##
wherein B, r3, r2, r1 are as defined below:
r1
Table 3 syn to
Cpd # B r3 r2 carboxyl
304 Boc cHex ##STR00349## ethyl;
306 Boc cHex ##STR00350## vinyl;
307 Boc cHex ##STR00351## vinyl;
310 Boc cHex ##STR00352## vinyl;
311 Boc cHex ##STR00353## vinyl;
312 Boc cHex ##STR00354## vinyl;
313 Boc cHex ##STR00355## vinyl;
314 Boc cHex ##STR00356## vinyl;
315 Boc cHex ##STR00357## vinyl;
316 Acetyl cHex ##STR00358## vinyl;
317 Boc cHex ##STR00359## vinyl;
318 CF3—C(O)— i-Pr ##STR00360## vinyl;
322 Boc t-Bu ##STR00361## vinyl;
323 Boc t-Bu ##STR00362## ##STR00363##
325 Boc t-Bu ##STR00364## ##STR00365##
327 ##STR00366## t-Bu ##STR00367## vinyl;
328 Boc t-Bu ##STR00368## vinyl;
331 ##STR00369## t-Bu ##STR00370## vinyl;
332 Boc t-Bu ##STR00371## ethyl;
333 ##STR00372## t-Bu ##STR00373## vinyl;
and 334 ##STR00374## t-Bu ##STR00375## vinyl.
!
52. A compound according to claim 51, selected from the group consisting of compound #, 307, 314, 325, 327, 331, 332, 333, and 334.
53. A compound according to claim 44 represented by the formula: ##STR00376##
wherein B, r3, r2 and r1 are as defined below:
Table 4
Cpd # B r3 r2 r1
401 Boc i-Pr ##STR00377## H;
402 Boc t-Bu ##STR00378## H;
403 Boc t-Bu ##STR00379## H;
404 Boc t-Bu ##STR00380## 3-(═CH2);
405 Boc t-Bu ##STR00381## 2-vinyl;
and 406 Boc t-Bu ##STR00382## 2-Et.
!
54. A compound according to claim 53, selected from the group consisting of compound #: 403, 405, and 406.
55. A compound according to claim 44 represented by the formula:
Table 5
Cpd # r3
501 t-Bu;
502 H;
503 ##STR00383##
504 ##STR00384##
505 ##STR00385##
506 ##STR00386##
507 ##STR00387##
508 ##STR00388##
509 ##STR00389##
510 ##STR00390##
and 511 ##STR00391##
!
wherein r3 is as defined below: ##STR00392##
56. A compound according to claim 55, selected from the group consisting of compound #: 501, 509, and 510.
57. A compound according to claim 45 represented by the formula: ##STR00393##
wherein r3, R21A, r21B are as defined below:
Table 6
Cpd # r3 r21A r21B
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 iPr 7-Cl;
608 CH2-iPr 7-Cl;
610 t-Bu Cl —;
611 t-Bu Ph 7-N(Me)2;
613 t-Bu ##STR00394## —;
614 t-Bu ##STR00395## —;
615 t-Bu 7-N(Me)2;
616 t-Bu ##STR00396## —;
618 t-Bu ##STR00397## —;
619 t-Bu ##STR00398## —;
621 t-Bu ##STR00399## —;
622 t-Bu ##STR00400## —;
623 t-Bu MeO— —;
624 t-Bu (Me)2N— —;
625 t-Bu Ph 7-S(Me);
626 t-Bu Ph 7-Br;
627 t-Bu Ph 7-F;
628 t-Bu ##STR00401## 7-N(Me)2;
629 t-Bu ##STR00402## 7-N(Me)2;
and 630 t-Bu ##STR00403## 7-N(Et)2;
!
58. A compound according to claim 57, selected from the group consisting of compound #: 606, 607, 610, 611, 615, 616, 621, 622, 625, 626, 627, 628, 629, and 630.
59. A compound according to claim 45 represented by the formula: ##STR00404##
wherein r3 and r21A are as defined below:
Table 7
Cpd # r3 r21A
701 t-Bu ##STR00405##
702 t-Bu ##STR00406##
703 t-Bu ##STR00407##
704 t-Bu ##STR00408##
706 t-Bu ##STR00409##
707 t-Bu ##STR00410##
708 t-Bu Ph—N(Me)—
709 t-Bu ##STR00411##
710 t-Bu HOOC—
711 t-Bu ##STR00412##
712 t-Bu (Me)2N—
713 t-Bu ##STR00413##
714 t-Bu ##STR00414##
717 t-Bu ##STR00415##
718 t-Bu NH2
719 t-Bu ##STR00416##
720 t-Bu ##STR00417##
722 t-Bu ##STR00418##
723 t-Bu ##STR00419##
726 t-Bu i-Pr
728 t-Bu ##STR00420##
730 t-Bu ##STR00421##
731 t-Bu ##STR00422##
732 t-Bu ##STR00423##
733 t-Bu ##STR00424##
734 t-Bu ##STR00425##
735 t-Bu ##STR00426##
736 t-Bu t-Bu;
and t-Bu cHex
737.
!
60. A compound according to claim 59, selected from the group consisting of compound #: 701, 702, 703, 704, 706, 707, 708, 709, 711 to 714, 717 to 720, 722, 723, 726, 728, and 730 to 737.
61. A compound according to claim 44 represented by the formula: ##STR00427##
wherein B, r3, and r22 are as defined below:
Table 8
Cpd # B r3 r22
801 ##STR00428## t-Bu —;
802 ##STR00429## t-Bu —;
803 ##STR00430## t-Bu —;
804 ##STR00431## t-Bu —;
805 Ac t-Bu —;
806 ##STR00432## t-Bu —;
807 ##STR00433## t-Bu —;
808 ##STR00434## t-Bu —;
809 ##STR00435## i-Pr —;
810 ##STR00436## t-Bu —;
811 Boc t-Bu 4-Cl;
812 ##STR00437## t-Bu —;
813 ##STR00438## t-Bu —;
814 Boc t-Bu 2-Cl;
815 Boc t-Bu 3-Cl;
816 ##STR00439## t-Bu —;
817 ##STR00440## t-Bu —;
818 ##STR00441## t-Bu —;
819 ##STR00442## i-Pr —;
820 ##STR00443## i-Pr —;
821 ##STR00444## i-Pr —;
822 ##STR00445## i-Pr —;
823 Boc t-Bu 2-OMe;
824 Boc t-Bu 3-OMe;
825 Boc t-Bu 4-OMe;
826 ##STR00446## i-Pr —;
827 ##STR00447## t-Bu —;
828 ##STR00448## i-Pr —;
829 ##STR00449## t-Bu —;
830 ##STR00450## t-Bu —;
831 ##STR00451## t-Bu —;
832 ##STR00452## t-Bu —;
833 ##STR00453## t-Bu —;
834 ##STR00454## i-Pr —;
835 ##STR00455## t-Bu —;
836 ##STR00456## i-Pr —;
837 ##STR00457## i-Pr —;
838 ##STR00458## i-Pr —;
839 ##STR00459## i-Pr —;
840 ##STR00460## i-Pr —;
841 Boc t-Bu 2-Me;
842 Boc t-Bu 3-Me;
843 Boc t-Bu 4-Me;
844 ##STR00461## t-Bu 4-OMe;
845 ##STR00462## i-Pr —;
846 ##STR00463## i-Pr —;
847 Boc cHex —;
848 Boc ##STR00464## —;
849 Boc ##STR00465## —;
850 Boc ##STR00466## —;
851 Boc ##STR00467## —;
852 Boc ##STR00468## —;
853 Boc ##STR00469## —;
854 ##STR00470## i-Pr —;
855 ##STR00471## i-Pr —;
856 ##STR00472## i-Pr —;
857 ##STR00473## t-Bu —;
858 ##STR00474## t-Bu —;
859 ##STR00475## i-Pr —;
860 ##STR00476## i-Pr —;
861 ##STR00477## i-Pr —;
862 ##STR00478## i-Pr —;
863 ##STR00479## i-Pr —;
864 ##STR00480## i-Pr —;
865 ##STR00481## t-Bu —;
866 ##STR00482## t-Bu —;
867 ##STR00483## t-Bu —;
868 ##STR00484## t-Bu —;
869 ##STR00485## t-Bu —;
870 ##STR00486## t-Bu —;
871 ##STR00487## t-Bu —;
872 ##STR00488## t-Bu —;
and 873 ##STR00489## t-Bu —.
!
62. A compound according to claim 61, selected from the group consisting of compound #:801 to 825, 827 to 858, and 860 to 873.
63. A compound according to claim 44 represented by the formula: ##STR00490##
wherein B is as defined below:
Table 9
Cpd # B
901 Boc
902 ##STR00491##
903 ##STR00492##
904 ##STR00493##
905 ##STR00494##
906 ##STR00495##
907 ##STR00496##
908 ##STR00497##
909 ##STR00498##
910 ##STR00499##
911 ##STR00500##
912 ##STR00501##
913 ##STR00502##
914 ##STR00503##
915 ##STR00504##
916 ##STR00505##
!
64. A compound according to claim 44 represented by the formula: ##STR00506##
wherein B—N(Y)—, r3, and r2 are as defined below:
Table 10 Cpd # B—N(Y)— r3 r2
1001 Ph—N(Me)— i-Pr ##STR00507##
1002 Boc-NH— t-Bu ##STR00508##
and 1003 ##STR00509## i-Pr ##STR00510##
!
65. 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.
66. A method of treating a hepatitis C viral infection in a mammal comprises 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.
67. A method of treating a hepatitis C viral infection in a mammal comprises administering to the mammal an anti-hepatitis C virally effective amount of the composition according to claim 66.
68. A method of inhibiting the replication of hepatitis C virus comprises 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.
69. A method of treating a hepatitis C viral infection in a mammal comprises 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.
70. A method according to claim 69, wherein said other anti-HCV agent is selected from the group consisting of: α- or β-interferon, ribavirin and amantadine.
71. A method according to claim 69, wherein said other anti-HCV agent comprises an inhibitor of other targets in the HCV life cycle, selected from: helicase, polymerase, metalloprotease or IRES.
72. 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: ##STR00511##
 wherein r1 is C1-6 alkyl, cycloalkyl or C2-6 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.
73. 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: ##STR00512##
 wherein r1 is C1-6 alkyl, cycloalkyl or C2-6 alkenyl, all optionally substituted with halogen, and CPG is a carboxyl protecting group.
74. 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: ##STR00513##
wherein CPG is a carboxyl protecting group.
75. A process according to claim 72, 73 or 74 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.
76. A 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.
77. 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.
78. 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.
79. A compound of formula (I) according to claim 1, wherein each Het group is independently selected from the group consisting of pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1,4-dioxane, indole, or any of the following heterocycles: ##STR00514##

The present application claims benefit to U.S. Provisional Applications No. 60/095,931, filed on Aug. 10, 1998, and Ser. No. 60/132,386, filed on May 4, 1999.

The 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 ana intermediates for the synthesis of these peptide analogs.

Hepatitis 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 15 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.

The 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. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulins treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.

Various clinical studies have been conducted with the goal of identifying pharmaceutical agents capable of effectively treating HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone an in combination with other anti-viral agents. Such studies have shown that a substantial number of the participants do not respond to these therapies, and of those that do respond favorably, a large proportion were found to relapse after termination of treatment.

Until recently, interferon (IFN) was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Recently, interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone. However, the side effects caused by IFN are not alleviated with this combination therapy.

Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.

HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one, as yet poorly characterized, cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (henceforth referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV.

A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus. In this vein, patent application WO 97/06804 describes the (−) enantiomer of the nucleoside analogue cytosine-1,3-oxathiolane (also known as 3TC) as active against HCV. This compound, although reported as safe in previous clinical trials against HIV and HBV, has yet to be clinically proven active against HCV and its mechanism of action against the virus has yet to be reported. Intense efforts to discover compounds which inhibit the NS3 protease or RNA helicase of HCV have led to the following disclosures:

Several studies have reported compounds inhibitory to other serine proteases, such as human leukocyte elastase. One family of these compounds is reported in WO 95/33764 (Hoechst Marion Roussel, 1995). The peptides disclosed in this application are morpholinylcarbonyl-benzoyl-peptide analogues that are structurally different from the peptides of the present invention.

Steinkühler et al. and Ingallinella et al. have published on NS4A-4B product inhibition (Biochemistry (1998), 37, 8899-8905 and 8906-8914). However, the peptides and peptide analogues presented do not include nor do they lead to the design of the peptides of the present invention.

One advantage of the present invention is that it provides tripeptides that are inhibitory to the NS3 protease of the hepatitis C virus.

A further advantage of one aspect of the present invention resides in the fact that these peptides specifically inhibit the NS3 protease and do not show significant inhibitory activity at concentrations up to 300 μM against other serine proteases such as human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B (Cat B).

A further advantage of the present invention is that it provides small peptides of low molecular weight that may be capable of penetrating cell membranes and may be active in cell culture and in vivo with good pharmacokinetic profile.

Included in the scope of the invention are racemates, diastereoisomers and optical isomers of a compound of formula (I): ##STR00002##

Included within the scope of this invention is a pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula 1, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.

An important aspect of the invention involves 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 1, or a therapeutically acceptable salt or ester thereof or a composition as described above.

Another important aspect involves 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 1, or a therapeutically acceptable salt or ester thereof or a composition as described above.

Still another aspect involves 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 1, or a therapeutically acceptable salt or ester thereof. According to one embodiment, the pharmaceutical compositions of this invention comprise an additional immunomodulatory agent. Examples of additional immunomodulatory agents include but are not limited to, α-, β-, and δ-interferons.

Definitions

As used herein, the following definitions apply unless otherwise noted: With reference to the instances where (R) or (S) is used to designate the configuration of a substituent, e.g. R1 of the compound of formula 1, the designation is done in the context of the compound and not in the context of the substituent alone.

The natural amino acids, with exception of glycine, contain a chiral carbon atom. Unless otherwise specifically indicated, the compounds containing natural amino acids with the L-configuration are preferred. However, applicants contemplate that when specified, some amino acids of the formula I can be of either D- or L-configuration or can be mixtures of D- and L-isomers, including racemic mixtures. The designation “P1, P2 and P3” as used herein refer to the position of the amino acid residues starting from the C-terminus end of the peptide analogues and extending towards the N-terminus [i.e. P1 refers to position 1 from the C-terminus, P2: second position from the C-terminus, etc.) (see Berger A. & Schechter I., Transactions of the Royal Society London series (1970), B257, 249-264].

The abbreviations for the α-amino acids used in this application are set forth in

TABLE A
Amino Acid Symbol
1-aminocyclopropyl-carboxylic acid Acca
Alanine Ala
Aspartic acid Asp
Cysteine Cys
Cyclohexylglycine Chg
(also named: 2-amino-2-cyclohexylacetic acid)
Glutamic acid Glu
Isoleucine Ile
Leucine Leu
Phenylalanine Phe
Proline Pro
Valine Val
tert-Butylglycine Tbg

As used herein the term “1-aminocyclopropyl-carboxylic acid” (Acca) refers to a compound of formula: ##STR00003##

As used herein the term “tert-butylglycine” (Acca) refers to a compound of formula: ##STR00004##

The term “residue” with reference to an amino acid or amino acid derivative means a radical derived from the corresponding α-amino acid by eliminating the hydroxyl of the carboxy group and one hydrogen of the α-amino group. For instance, the terms Gin, Ala, Gly, lie, Arg, Asp, Phe, Ser, Leu, Cys, Asn, Sar and Tyr represent the “residues” of L-glutamine, L-alanine, glycine, L-isoleucine, L-arginine, L-aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively.

The term “side chain” with reference to an amino acid or amino acid residue means a group attached to the α-carbon atom of the α-amino acid. For example, the R-group side chain for glycine is hydrogen, for alanine it is methyl, for valine it is isopropyl. For the specific R-groups or side chains of the α-amino acids reference is made to A. L. Lehninger's text on Biochemistry (see chapter 4).

The term “halo” as used herein means a halogen substituent selected from bromo, chloro, fluoro or iodo.

The term “C1-6 alkyl” or “(lower)alkyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing from 1 to six carbon atoms and includes, for example, methyl, ethyl, propyl, butyl, tert-butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.

The term “C3-7 cycloalkyl” as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. This term also includes “spiro”-cyclic group such as spiro-cyclopropyl or spiro-cyclobutyl: ##STR00005##

The term “unsaturated cycloalkyl” includes, for example, cyclohexenyl: ##STR00006##

The term “C4-10 (alkylcycloalkyl) as used herein means a cycloalkyl radical containing from three to seven carbon atoms linked to an alkyl radical, the linked radicals containing up to ten carbon atoms; for example, cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl or cycloheptylethyl.

The term “C2-10 alkenyl” as used herein, either alone or in combination with another radical, means an alkyl radical as defined above containing from 2 to 10 carbon atoms, and further containing at least one double bond. For example alkenyl includes allyl and vinyl.

The term “C1-6 alkanoyl” as used herein, either alone or in combination with another radical, means straight or branched 1-oxoalkyl radicals containing one to six carbon atoms and includes formyl, acetyl, 1-oxopropyl(propionyl), 2-methyl-1-oxopropyl, 1-oxohexyl and the like.

The term “C3-7 alkoxy” as used herein, either alone or in combination with another radical, means the radical —O(C1-6 alkyl) wherein alkyl is as defined above containing up to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter radical is known commonly as tert-butoxy.

The term “C3-7 cycloalkoxy” as used herein, either alone or in combination with another radical, means a C3-7 cycloalkyl group linked to an oxygen atom, such as, for example: ##STR00007##

The term “C6 or C10 aryl” as used herein, either alone or in combination with another radical, means either an aromatic monocyclic group containing 6 carbon atoms or an aromatic bicyclic group containing 10 carbon atoms. For example, aryl includes phenyl, 1-naphthyl or 2-naphthyl.

The term “C7-16 aralkyl” as used herein, either alone or in combination with another radical, means a C6 or C10 aryl as defined above linked to an alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. C7-16 aralkyl includes for example benzyl, butylphenyl, and 1-naphthylmethyl.

The term “amino aralkyl” as used herein, either alone or in combination with another radical, means an amino group substituted with a C7-16 aralkyl group, such as, for example, the amino aralkyl: ##STR00008##

The term “(lower alkyl)amide” as used herein, either alone or in combination with another radical, means an amide mono-substituted with a C1-6 alkyl, such as: ##STR00009##

The term “carboxy(lower)alkyl” as used herein, either alone or in combination with another radical, means a carboxyl group (COOH) linked through a (lower)alkyl group as defined above and includes for example butyric acid.

The term “heterocycle” or “Het” as used herein, either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Furthermore, “Het” as used herein, means a heterocycle as defined above fused to one or more other cycle, be it a heterocycle or any other cycle. Examples of suitable heterocycles include: pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, thiazolo[4,5-b]-pyridine, quinoline, or indole, or the following heterocycles: ##STR00010##

The term “(lower alkyl)-Het” as used herein, means a heterocyclic radical as defined above linked through a chain or branched alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. Examples of (lower alkyl)-Het include: ##STR00011##

The term “pharmaceutically acceptable ester” as used herein, either alone or in combination with another substituent, means esters of the compound of formula I in which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, is replaced by an alkoxycarbonyl function: ##STR00012##
in which the R moiety of the ester is selected from alkyl (e.g. methyl, ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl); alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl); aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl), optionally substituted with halogen, C1-4 alkyl or C1-4 alkoxy. Other suitable prodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected in a mammal and transformed into the acid form of the compound of formula I.

With regard to the esters described above, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.

In particular the esters may be a C1-6 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C1-6 alkyl, C1-6 alkoxy, nitro or trifluoromethyl.

The term “pharmaceutically acceptable salt” as used herein includes those derived from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na+, K+, and Ca++ salts are also contemplated to be within the scope of the invention (also see Pharmaceutical salts, Birge, S. M. Et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein by reference).

Preferred Embodiments

Included within the scope of this invention are compounds of formula I wherein

Alternatively, B is preferably R4—SO2 wherein R4 is preferably C1-6 alkyl; amido; (lower alkyl)amide; C6 or C10 aryl, C7-14 aralkyl or Het, all optionally substituted with C1-6 alkyl.

Alternatively, B is preferably an acyl derivative of formula R4—C(O)— wherein R4 is preferably

Alternatively, B is preferably a carboxyl of formula R4—O—C(O)—, wherein R4 is preferably

Alternatively, B is preferably an amide of formula R4—N (R5)—C(O)— wherein R4 is preferably

Alternatively, B is a preferably thioamide of formula R4—NH—C(S)—; wherein R4 is preferably

More preferably, B is a C6 or C10 aryl optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl, such that B is for example: ##STR00013##
or B is more preferably Het optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C1-6 alkyl, such that B is for example: ##STR00014##

Alternatively, B is more preferably R4—SO2 wherein R4 is preferably C6 or C10 aryl, a C7-14 aralkyl or Het all optionally substituted with C1-6 alkyl; amido, (lower alkyl) amide, such that B is, for example: ##STR00015##

Alternatively, B is more preferably an acyl derivative of formula R4—C(O)— wherein R4 is preferably

Alternatively, B is more preferably a carboxyl of formula R4—O—C(O)—, wherein R4 is preferably