Patent EA-004765-B1 (EA)
Title: Hepatitis c inhibitor peptides
Inventor: LLINAS-BRUNET MONTSE
IPC: H01Q21/06
Filed: 1999-08-09
Abstract: 1. Racemates, diastereoisomers and optical isomers of formula (I): wherein a is 0 or l; b is 0 or 1; Y is H or C, 6alkyl; B is H, an acyl derivative of formula R7-C (O)- or a sulfonyl of formula R7-SO2 wherein R7 is C1-10alkyl optionally substituted with carboxyl, C1-6alkanoyloxy or C1-6alkoxy; C6 or C10 aryl or C7-16aralkyl optionally substituted with C1-6alkyl, hydroxy, or amino optionally substituted with C1-6alkyl; or Het optionally substituted with C1-6alkyl, hydroxy, amino optionally substituted with C1-6alkyl, or amido optionally substituted with C1-6alkyl; R6, when present, is C1-6alkyl substituted with carboxyl; R5, when present, is C1-6alkyl optionally substituted with carboxyl; R4 is C1-10alkyl, C3-7cycloalkyl or C4-10(alkylcycloalkyl); R3 is C1-10alkyl, C3-7cycloalkyl or C4-10(alkylcycloalkyl); R2 is CH2-R20 or O-R20, wherein R20 is a saturated or unsaturated C3-7cycloalkyl or C4-10(alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R21, or R20 is a C6 or C10 aryl or C7-16aralkyl optionally mono-, di- or tri-substituted with R21, or R20 is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R21, wherein each R21 is independently C1-6alkyl, C1-6alkoxy, halo, haloalkyl, amido, optionally mono substituted with C1-6alkyl, C6 or C10aryl, C7-16aralkyl, Het or (lower alkyl)-Het, C6 or C10aryl, or Het, said aryl or Het being optionally substituted with R22, wherein R22 is C1-6alkyl; R1 is C1-6alkyl or C2-6alkenyl optionally substituted with halogen; and W is hydroxy or a N-substituted amino; or a pharmaceutically acceptable salt or ester thereof. 2. The compound according to claim 1, wherein, when B is H or an acyl derivative of formula R7C (O)-, wherein R7 is C1-6alkyl, C1-6alkoxy, amido optionally substituted with C1-6alkyl or Het, C6 or C10 aryl, C7-16aralkyl or Het all optionally substituted with C1-6alkyl or hydroxy. 3. The compound according to claim 2, wherein R7 is C1-6alkyl or Het. 4. The compound according to claim 3, wherein said Het is selected from the group consisting of: 5. The compound according to claim 2, wherein B is selected from the group consisting of: H, acetyl, 6. The compound according to claim 5, wherein B is acetyl. 7. The compound according to claim 1, wherein B is R7-SO2 and R7 is C6 or C10 aryl, a C7-16aralkyl or Het, all optionally substituted with C1-6alkyl. 8. The compound according to claim 1, wherein R6 when present, is the side chain of Asp or Glu. 9. The compound according to claim 8, wherein R6, when present, is the side chain of Asp. 10. The compound according to claim 1, wherein a is 0 and then R6 is absent. 11. The compound according to claim 1, wherein R5, when present, is the side chain of an amino acid selected from the group consisting of: D-Asp, L-Asp, D-Glu, L-Glu, D-Val, L-Val, D-tert-butylglycine (Tbg), and L-Tbg. 12. The compound according to claim 11, wherein R5, when present, is the side chain of D-Asp, D-Val, or D-Glu. 13. The compound according to claim 12, wherein R5, when present, is the side chain of D-Glu. 14. The compound according to claim 1, wherein a is 0 and b is 0, and then both R6 and R5 are absent. 15. The compound according to claim 1, wherein R4 is the side chain of an amino acid selected from the group consisting of: Val, cyclohexylglycine (Chg), Tbg, Ile or Leu. 16. The compound according to claim 15, wherein R4 is the side chain of Chg or Ile. 17. The compound according to claim 16, wherein R4 is the side chain of Chg. 18. The compound according to claim 1, wherein Y is H, or Me. 19. The compound according to claim 18, wherein Y is H. 20. The compound according to claim 1, wherein R3 is the side chain of an amino acid selected from the group consisting of: Ile, Chg, Val or Tbg. 21. The compound according to claim 20, wherein R3 is the side chain of Val, Chg or Tbg. 22. The compound according to claim 21, wherein R3 is the side chain of Val or Tbg. 23. The compound according to claim 1, wherein R2 is S-R20, wherein R20 is C6 or C10aryl, C7-16aralkyl, Het or -CH2-Het, all optionally mono-, di- or tri substituted with R21, wherein R21 is C1-6alkyl, C1-6alkoxy, amido optionally mono-substituted with C1-6alkyl, C6 or C10 aryl, C7-16aralkyl, Het or (lower alkyl)-Het, halo; trifluoromethyl, C6 or C10aryl or Het, said aryl aralkyl or Het being optionally substituted with R22, wherein R22 is C1-6alkyl. 24. The compound according to claim 23, wherein R21 is C1-6alkyl, C1-6alkoxy-, (lower alkyl) amide, C6- or C10aryl, or Het. 25. The compound according to claim 23, wherein R2 is 1-naphthylmethoxy; 2-naphthylmethoxy-, benzyloxy-, 1-naphthyloxy-, 2-naphtyloxy-, or quinolinoxy, unsubstituted, mono- or di-substituted with R2, wherein R2, is as defined in claim 23. 26. The compound according to claim 23, wherein R2 is 1-naphtylmethoxy-, or quinolinoxy unsubstituted, mono- or di-substituted with R2, wherein R21 is as defined in claim 23. 27. The compound according to claim 26, wherein R2 is wherein R21A is amido optionally substituted with C1-6alkyl, C6 or C10 aryl, C7-16aralkyl or Het, C6- or C10 aryl or Het, R21B is C1-6alkyl, C1-6alkoxy, (lower alkyl) amide, halo or trifluoromethyl. 28. The compound according to claim 27, wherein R21A is C6- or C10aryl or Het. 29. The compound according to claim 27, wherein R21B is C1-6alkoxy. 30. The compound according to claim 29, wherein R21B is methoxy. 31. The compound according to claim 1, wherein the asymmetric carbon at position 1 has the R configuration, represented by the following absolute configurations: wherein R1 is as defined in claim 1. 32. The compound according to claim 31, wherein the R1 substituent on P1 is oriented syn to the carbonyl group as represented by the following absolute configuration: wherein R1 is methyl, ethyl, propyl, vinyl, all of which optionally substituted with halo. 33. The compound according to claim 32, wherein R1 is ethyl, vinyl or bromovinyl. 34. The compound according to claim 33, wherein R1 is vinyl. 35. The compound according to claim 1, wherein W is hydroxy or di (lower alkyl)amino- or aralkyl amino, or a pharmaceutically acceptable salt or ester thereof. 36. The compound according to claim 33, wherein W is hydroxy or N(R13a)R13b, wherein R13a and R13b are independently H, aryl or C1-6alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutically acceptable salt thereof. 37. The compound according to claim 36, wherein W is -OH, -NH-benzyl or -NH-CH(Me)Ph. 38. The compound according to claim 37, wherein W is -OH or -NH-(S)CH(Me)-phenyl. 39. The compound according to claim 38, wherein when W is an ester, said ester is selected from the group consisting of C1-6alkoxy, phenoxy, or aryl(C1-6alkoxy). 40. The compound according to claim 39, wherein said ester is methoxy, ethoxy, phenoxy, benzyloxy, or PhCH(Me)-O-. 41. The compound of formula I according to claim 1, wherein B is H, lower alkyl-C(O)- or Het-C(O)-, R6, when present, is the side chain of Asp or Glu, R5, when present, is the side chain of D- or L-Asp, Glu, Val, or Tbg, Y is H or methyl, R4 is the side chain of Val, Chg, Tbg, Ile or Leu, R3 is hydrogen or the side chain of Ile, Chg, Val, or Tbg, R2 is 1-naphthylmethoxy, 2-naphthylmethoxy, O-Bn, P1 is a cyclopropyl ring system of formula wherein R1 is ethyl, vinyl or bromovinyl, and W is hydroxy or N (R13a) R13b wherein R13a and R13b are independently H, aryl or C1-6alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutically acceptable salt or ester thereof. 42. The compound of formula I according to claim 1, wherein B is H, acetyl or Het-C(O)-, R6, when present, is the side chain of Asp, R5, when present, is the side chain of D-Asp, D-Glu or D-Val, Y is H, R4 is the side chain of Chg or Lle, R3 is the side chain of Val, Chg or Tbg, R2 is 1-naphthylmethoxy, benzyloxy, 4-quinolinoxy, or P1 is a cyclopropyl ring system of formula wherein R1 is Et or CH=CH2 or CH=CHBr; and W is hydroxy or NH-(S)-CHMePh, or a pharmaceutically acceptable salt thereof. 43. The compound of formula I according to claim 1, wherein B is acetyl, R6, when present, is the side chain of Asp, R5, when present, is the side chain of D-Glu, Y is H, R4 is the side chain of Chg, R3 is the side chain of Val or Tbg, R2 is W is hydroxy, or a pharmaceutically acceptable salt or ester thereof. 44. The compound according to claim 41 represented by formula: wherein B, P6, P5, P4, P3, R2, and R, are as defined below: 45. The compound according to claim 41 represented by formula: wherein P6, P5, P4, P3, R2, and R1 are as defined below: 46. The compound according to claim 41 represented by formula: wherein B, P6, P5, P4, P3, R2, R1 and W are as defined below: 47. The compound according to claim 41 represented by formula: wherein B, Y, P4, P3, R2 and R1 are as defined below: 48. The compound according to claim 41 represented by formula: wherein B, and R20, are as defined below: 49. A hexapeptide of formula I according to claim 44, selected from the group consisting of compound #: 108; 116; 117; and 120. 50. A hexapeptide of formula I according to claim 45, selected from the group consisting of compound #: 212; 222; 236; and 238. 51. A hexapeptide of formula I according to claim 46, selected from the group consisting of compound #: 301 and 302. 52. A tetrapeptide of formula I according to claim 44 selected from the group consisting of compound #: 122; and 123. 53. A tetrapeptide of formula I according to claim 45 selected from the group consisting of compound #: 202; 203; 205; 206; 207; 208; 209; 210; 211; 214; 215; 216; 218; 219; 220; 221; 223; 224; 225; 226; 228; 229; 230; 231; 232; 233; 234; 235. 54. A tetrapeptide of formula I according to claim, 47 selected from the group consisting of compound #: 401. 55. A tetrapeptide of formula I according to claim, or 48, selected from the group consisting of compound #: 501; 502; 503; 504; 505; 506; 507; 508; 509; 510; and 511. 56. A method of inhibiting the replication of hepatitis C virus by exposing the