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Hepatitis C inhibitor tri-peptides |
| RE40525 |
Hepatitis C inhibitor tri-peptides
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| Patent Drawings: | |
| Inventor: |
Llinas-Brunet, et al. |
| Date Issued: |
September 30, 2008 |
| Application: |
11/241,899 |
| Filed: |
September 30, 2005 |
| Inventors: |
Llinas-Brunet; Montse (Laval, CA)
Bailey; Murray D. (Laval, CA)
Cameron; Dale R. (Vancouver, CA)
Faucher; Anne-Marie (St. Placide, CA)
Ghiro; Elise (Laval, CA)
Goudreau; Nathalie (S. Laurent, CA)
Halmos; Teddy (Laval, CA)
Poupart; Marc-Andre (Laval, CA)
Rancourt; Jean (Laval, CA)
Tsantrizos; Youla S. (St. Laurent, CA)
Wernic; Dominik M. (Kirkland, CA)
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| Assignee: |
Boehringer Ingelheim (Canada) Ltd. (Laval, CA) |
| Primary Examiner: |
Lambkin; Deborah C |
| Assistant Examiner: |
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| Attorney Or Agent: |
Morris; MichaelDevlin; Mary-Ellen M.Dow; David |
| U.S. Class: |
514/18; 514/312; 514/314; 514/339; 514/370; 514/425; 546/153; 546/159; 546/171; 546/175; 546/276.4; 548/517; 548/519; 548/523; 548/571 |
| Field Of Search: |
514/18; 514/312; 514/314; 514/339; 514/370; 514/425; 548/153; 548/159; 548/171; 548/175; 548/276.4; 548/517; 548/519; 548/523; 548/571 |
| International Class: |
A61K 38/00; A61K 31/40; A61K 31/47; C07D 215/16; C07D 405/00 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
196 00 034; 05 155827; WO 98 17679; WO 99 07733 |
| Other References: |
Gaucher et al: "Palladium (0) Catalyzed Tandem Alkylation and SN Cyclization of 1,4-Dichlorobut -2-ene by the N-(Diphenylmethylene)acetonitrile. A Stereoselective Synthesis of 1-Aminocyclo- propanecarboxylic Acids";Tetrahedron Letters, vol. 36, No. 17,pp. 2979-2982; 1995. cited by other.
Fliche, Et Al; "Enantioselective synthesis of (1R,2S) and (1S,2S) dehydrocoronamic acids", Synthetic Communications; vol. 24, No. 20, 1994, pp. 2873-2876. cited by other.
Chen, Et Al; "Chirally selective hydrolysis of D, L amino acid esters by alkaline protease"; J. Chem, Soc. Chem. Commun., vol. 20, 1986, pp. 1514-1516. cited by other.
Chen, Et Al; "Kinetic resolution of esters of amino acids in t-butanol containing 5% water catalyzed by a stable industrial alkaline protease"; Chirality, vol. 6, 1994, pp. 572-576. cited by other.
Linas-Brunet, M., Et Al; "Peptide-based inhibitors of the hepatitis C virus serine protease", Bioorganic & Medicinal Chemistry Letters, vol. 8, No. 13, pp. 1713-1718; 1998. cited by other.
Gershonov Et Al; "1-Aminocyclobutanecarboxylic acid derivates as novel structural elements in bioactive peptides; application to tuftsin analogs"; Journal of Medicinal Chemistry, vol. 39, No. 24, 1996, pp. 4833-4843. cited by other.
Ogawa, Tomohisa Et Al; "2,3-Methanophenylalanine And.Alpha., .Beta.-Dehdrophenylalanine Derivatives As Chymotrypsin Inhibitor"; Pept. Chem. (1990), vol. 27; pp. 379-382. cited by other. |
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| Abstract: |
A racemate diastereoisomer and optical isomer of a compound of formula (I): ##STR00001## wherein B is H, a C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl; Het or (lower alkyl)-Het, all of which may be optionally substituted with C.sub.1-6 alkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C.sub.1-6 alkyl; amido; or (lower alkyl)amide; or B is an acyl derivative of formula R.sub.4--C(O)--; a carboxyl derivative of formula R.sub.4--O--C(O)--; an amide derivative of formula R.sub.4--N(R.sub.5)--C(O)--; a thioamide derivative of formula R.sub.4--N(R.sub.5)--C(S)--; or a sulfonyl of formula R.sub.4--SO.sub.2; R.sub.5 is H or C.sub.1-6 alkyl; and Y is H or C.sub.1-6 alkyl; R.sup.3 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, or C.sub.4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, amido, (lower alkyl)amido, C.sub.6 or C.sub.10 aryl, or C.sub.7-16 aralkyl; R.sub.2 is C.sub.2--R.sub.20, NH--R.sub.20, O--R.sub.20 or S--R.sub.20, wherein R.sub.20 is a saturated or unsaturated C.sub.3-7 cycloalkyl or C.sub.4-10 (alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R.sub.21, or R.sub.20 is a C.sub.6 or C.sub.10 aryl or C.sub.7-14 aralkyl optionally substituted, or R.sub.20 is Het or (lower alkyl)-Het, both optionally substituted, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C.sub.6 or C10 aryl, C.sub.7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted; and R.sup.1 is H; C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, all optionally substituted with halogen; or a pharmaceutically acceptable salt or ester thereof. |
| Claim: |
What is claimed is:
1. A racemate, diastereoisomer or optical isomer of a compound of formula (I): ##STR00319## wherein B is H, a C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl; Het or (loweralkyl)-Het, all of which optionally substituted with C.sub.1-6 alkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C.sub.1-6 alkyl; amido; or (loweralkyl)amide; or B is an acyl derivative of formula R.sub.4--C(O)--; a carboxyl derivative of formula R.sub.4--O--C(O)--; an amide derivative of formula R.sub.4--N(R.sub.5)--C(O)--; a thioamide derivative of formula R.sub.4--N(R.sub.5)--C(S)--; or asulfonyl derivative of formula R.sub.4--SO.sub.2 wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxyl, C.sub.1-6 alkoxy, amino optionally mono- or di-substituted with C.sub.1-6 alkyl, .Iadd.or.Iaddend.amido.[., or (lower alkyl) amide.]. ; .Iadd.and when B is R.sub.4--O--C(O)--; R.sub.4--N(R.sub.5)--C(O)--; R.sub.4--N(R.sub.5)--C(S)--; or R.sub.4--SO.sub.2, then R.sub.4 may additionally be selected from C.sub.1-10 alkyl substituted with(lower alkyl) amide;.Iaddend. (ii) C.sub.3-7 cycloalkyl, .Iadd.or .Iaddend.C.sub.3-7 cycloalkoxy, .[.or C.sub.4-10 alkylcycloalkyl,.]. all optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy)carbonyl, amino optionally mono- ordi-substituted with C.sub.1-6 alkyl, amido, or (lower alkyl) amide; .Iadd.or R.sub.4 is C.sub.4-10 alkylcycloalkyl, optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy)carbonyl, amino optionally mono- or di-substituted with C.sub.1-6 alkyl,or amido; and when B is R.sub.4--O--C(O)--; R.sub.4--N(R.sub.5)--C(O)--; R.sub.4--N(R.sub.5)--C(S)--; R.sub.4--SO.sub.2, then R.sub.4 may additionally be C.sub.4-10 alkylcycloalkyl substituted with (lower alkyl) amide;.Iaddend. (iii) aminooptionally mono- or di-substituted with C.sub.1-6 alkyl; amido; or (lower alkyl)amide; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono-or di-substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; R.sub.5 is H or C.sub.1-6alkyl; with the proviso that when B is a carboxyl derivative, an amide derivative or a thioamide derivative, R.sub.4 is not a cycloalkoxy; Y is H or C.sub.1-6 alkyl; R.sup.3 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, or C.sub.4-10 alkylcycloalkyl, alloptionally substituted with hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, amido, (lower alkyl)amido, C.sub.6 or C.sub.10 aryl, or C.sub.7-16 aralkyl; R.sub.2 is CH.sub.2--R.sub.20, NH--R.sub.20, O--R.sub.20 or S--R.sub.20, wherein R.sub.20 ispyridinyl, quinolyl, (lower alkyl)-pyridinyl or (lower alkyl)-quinolyl, each optionally mono-, di- or tri-substituted with R.sub.21, wherein each R.sub.21 is independently C.sub.1-6 alkyl; C.sub.1-6 alkoxy; lower thioalkyl; sulfonyl; NO.sub.2; OH; SH; halo; haloalkyl; amino optionally mono- or di-substituted with C.sub.1-6 alkyl, C.sub.6 or C.sub.10 aryl, C.sub.7-14 aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C.sub.1-6 alkyl, .[.C.sub.6 or C.sub.1-10 aryl,.]. .Iadd.C.sub.6 or C.sub.10 aryl, .Iaddend.C.sub.7-14 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C.sub.6 or C.sub.10 aryl, C.sub.7-14 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R.sub.22; whereinR.sub.22 is C.sub.1-6 alkyl; C.sub.3-7 cycloalkyl; C.sub.1-6 alkoxy; amino optionally mono- or di-substituted with C.sub.1-6 alkyl; sulfonyl; (lower alkyl)sulfonyl; NO.sub.2; OH; SH; halo; haloalkyl; carboxyl; amide; (lower alkyl)amide; orHet optionally substituted with C.sub.1-6 alkyl; R.sup.1 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 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 C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl,nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C.sub.1-6 alkyl; or B is Het or (lower alkyl)-Het, all optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl,halo, haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C.sub.1-6 alkyl.
3. A compound of formula I according to claim 1, wherein B is R.sub.4--SO.sub.2 wherein R.sub.4 is preferably amido; (lower alkyl)amide; C.sub.6 or C.sub.10 aryl, C.sub.7-14 aralkyl or Het, all optionally substituted with C.sub.1-6 alkyl.
4. A compound of formula I according to claim 1, wherein B is an acyl derivative of formula R.sub.4--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, hydroxy or C.sub.1-6 alkoxy, amido, .[.(loweralkyl)amide,.]. or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl .[.or C.sub.4-10 alkylcycloalkyl, both.]. optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy) carbonyl, amido, (loweralkyl)amide, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; .Iadd.or R.sub.4 is C.sub.4-10 alkylcycloalkyl optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, or amino optionally mono- or di-substitutedwith C.sub.1-6 alkyl;.Iaddend. (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally substituted with C.sub.1-6 alkyl; (v) Het or (loweralkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C.sub.1-6 alkyl.
5. A compound of formula I according to claim 1, wherein B is a carboxyl derivative of formula R.sub.4--O--C(O)--, wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxy,amino optionally mono- or di-substituted with C.sub.1-6 alkyl, amido or (lower alkyl)amide; (ii) C.sub.3-7 cycloalkyl, .Iadd.or .Iaddend.C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amino optionallymono- or di-substituted with C.sub.1-6 alkyl, amido or (lower alkyl)amide; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyli, .Iadd.all .Iaddend.optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl)amido, or amino optionallymono- or di-substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally mono- or di-substituted with C.sub.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.sub.4--N(R.sub.5)--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6alkoxy, amido, (lower alkyl) amido, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (loweralkyl)amido, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (iii) amino optionally mono- or di-substituted with C.sub.1-3 alkyl; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, optionally substituted with C.sub.1-6 alkyl,hydroxy, amido, (lower alkyl) amide, or amino optionally substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally substituted with C.sub.1-6 alkyl, amido or (loweralkyl)amide; and R.sub.5 is H or methyl.
7. A compound of formula I according to claim 1, wherein B is a thioamide derivative of formula R.sub.4--NH--C(S)--; wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl or C.sub.1-6 alkoxy; (ii)C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amino or amido.
8. A compound of formula I according to claim 2, wherein B is a C.sub.6 or C.sub.10 aryl optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl, amido,(lower alkyl) amide, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl.
9. A compound of formula I according to claim 2, wherein B is Het optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted withC.sub.1-6 alkyl.
10. A compound of formula I according to claim 4, wherein B is an acyl derivative of formula R.sub.4--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, hydroxy or C.sub.1-6 alkoxy; or (ii) C.sub.3-7cycloalkyl or C.sub.4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy) carbonyl, or (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy, or (v) Hetoptionally substituted with C.sub.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.sub.4--O--C (O)--, wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxy oramido, (lower alkyl) amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl, C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, aminooptionally mono- or di-substituted with C.sub.1-6 alkyl, or (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het,both optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, or amino optionally mono-substituted with C.sub.1-6 alkyl.
12. A compound of formula I according to claim 6, wherein B is an amide derivative of formula R.sub.4--N(R.sub.5--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6alkoxy, amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide,amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (iii) amino optionally mono- or di-substituted with C.sub.1-3 alkyl, or (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, optionally substituted with C.sub.1-6 alkyl, hydroxy, amino oramido optionally substituted with C.sub.1-6 alkyl; or (v) Het optionally substituted with C.sub.1-6 alkyl, hydroxy, amino or amido, and R.sub.5 is H.
13. A compound of formula I according to claim 7, wherein B is a thioamide derivative of formula R.sub.4--NH--C(S)--; wherein R.sub.4 is (i) C.sub.1-10 alkyl; or (ii) C.sub.3-7 cycloalkyl.
14. A compound of formula I according to claim 12, wherein B is an amide derivative of formula R.sub.4--NH--C (O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxyamido, (lower alkyl) amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, aminooptionally mono- or di-substituted with C.sub.1-6 alkyl; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl optionally substituted with C.sub.1-6 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 R.sup.3 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, or C.sub.4-10 alkylcycloalkyl, all optionally substituted with hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, acetamido, C.sub.6 orC.sub.10 aryl, or C.sub.7-16 aralkyl.
19. A compound of formula I according to claim 18, wherein R.sup.3 is the side chain of Tbg, Ile, Val, Chg or: ##STR00321##
20. A compound of formula I according to claim 19, wherein R.sup.3 is the side chain of Tbg, Chg or Val.
21. A compound of formula I according to claim 1, wherein R.sup.2 is S--R.sub.20 or O--R.sub.20 wherein R.sub.20 is a pyridinyl, quinolyl, --CH.sub.2-pyridinyl or --CH.sub.2-quinolyl, all optionally mono-, di- or tri-substituted with R.sub.21,wherein R.sub.21 is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C.sub.1-6 alkyl, C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl, Het or (lower alkyl)-Het; NO.sub.2; OH; halo; trifluoromethyl; carboxyl; C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R.sub.22, wherein R.sub.22 is C.sub.1-6 alkyl; C.sub.3-7 cycloalkyl; C.sub.1-6 alkoxy; amino; mono- ordi-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO.sub.2; OH; halo; trifluoromethyl; carboxyl or Het.
22. A compound of formula I according to claim 21, wherein R.sub.21 is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; C.sub.6 or C.sub.10 aryl, or Het, said aryl or Het being optionally substituted withR.sub.22, wherein R.sub.22 is C.sub.1-6 alkyl; C.sub.3-7 cycloalkyl; C.sub.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.sub.22 is C.sub.1-6 alkyl; C.sub.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.sub.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.sup.2 is ##STR00322##
26. A compound of formula I according to claim 21, wherein R.sup.2 is quinolinoxy unsubstituted, mono- or di-substituted with R.sub.21, as defined in claim 21.
27. A compound of formula I according to claim 26, wherein R.sup.2 is selected from the group consisting of: ##STR00323##
28. A compound of formula I according to claim 26, wherein R.sup.2 is: ##STR00324## wherein R.sub.21A is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; lower thioalkyl; halo; amino optionally mono-substituted with C.sub.1-6 alkyl; or C.sub.6, C.sub.10aryl, C.sub.7-16 aralkyl, or Het, said aryl, aralkyl or Het optionally substituted with R.sub.22 wherein R.sub.22 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl, or Het; and R.sub.21B is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, di(lower alkyl) amino, (lower alkyl)amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl.
29. A compound of formula I according to claim 28, wherein R.sub.21A is C.sub.6, C.sub.10 aryl or Het, all optionally substituted with R.sub.22 as defined in claim 28.
30. A compound of formula I according to claim 29, wherein R.sub.21A is selected from the group consisting of: ##STR00325##
31. A compound of formula I according to claim 21, wherein R.sup.2 is: ##STR00326## wherein R.sub.22A is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; or halo; and R.sub.21B is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, di(lower alkyl)amino, (loweralkyl)amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl.
32. A compound of formula I according to claim 28, wherein R.sup.2 is: ##STR00327## wherein R.sub.22B is C.sub.1-6 alkyl, amino optionally mono-substituted with C.sub.1-6 alkyl, amido, or (lower alkyl)amide and R.sub.21B is C.sub.1-6 alkyl,C.sub.1-6 alkoxy, amino, di(lower alkyl) amino, (lower alkyl)amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl.
33. A compound of formula I according to claim 31 or 32, wherein R.sub.21B is C.sub.1-6 alkoxy, or di(lower alkyl)amino.
34. A compound of formula I according to claim 31 or 32, wherein R.sub.21B is methoxy.
35. A compound of formula I according to claim 1, wherein R.sup.1 is H, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, or C.sub.2-4 alkenyl, all optionally substituted with halo. ##STR00328##
36. A compound of formula I according to claim 35, wherein P1 is: and R.sup.1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
37. A compound of formula I according to claim 36, wherein R.sup.1 is vinyl.
38. A compound of formula I according to claim 31, wherein R.sup.1 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 R.sup.1 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 R.sup.1 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 R.sup.1 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 R.sup.1 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 C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl,nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C.sub.1-6 alkyl; or Het or (lower alkyl)-Het, all optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl, halo,haloalkyl, nitro, cyano, cyanoalkyl, amido, (lower alkyl)amido, or amino optionally substituted with C.sub.1-6 alkyl, or B is R.sub.4--SO.sub.2 wherein R.sub.4 is preferably amido; (lower alkyl)amide; C.sub.6 or C.sub.10 aryl, C.sub.7-14 aralkyl orHet, all optionally substituted with C.sub.1-6 alkyl, or B is an acyl derivative of formula R.sub.4--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, hydroxy or C.sub.1-6 alkoxy, amido, (lower alkyl)amide, or aminooptionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, or amino optionally mono- ordi-substituted with C.sub.1-6 alkyl; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C.sub.1-6 alkyl; (v) Het or (loweralkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally substituted with C.sub.1-6 alkyl, amido, (lower alkyl)amide, or amino optionally substituted with C.sub.1-6 alkyl, or B is a carboxyl derivative of formulaR.sub.4--O--C(O)--, wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxy, amino optionally mono- or di-substituted with C.sub.1-6 alkyl, amido or (lower alkyl)amide; (ii) C.sub.3-7cycloalkyl, C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy) carbonyl, amino optionally mono- or di-substituted with C.sub.1-6 alkyl, amido or (lower alkyl)amide; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16aralkyl optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, (lower alkyl) amido, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, aminooptionally mono- or di-substituted with C.sub.1-6 alkyl, amido or (lower alkyl) amido, or B is an amide derivative of formula R.sub.4--N(R.sub.5)--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl,hydroxy, C.sub.1-6 alkoxy, amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy) carbonyl,amido, (lower alkyl)amido, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (iii) amino optionally mono- or di-substituted with C.sub.1-3 alkyl; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted withC.sub.1-6 alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally substituted with C.sub.1-6 alkyl,amido, (lower alkyl)amide; and R.sub.5 is preferably H or methyl, or B is thioamide derivative of formula R.sub.4--NH--C(S)--; wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl or C.sub.1-6 alkoxy; (ii)C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy) carbonyl, amino or amido; Y is H or methyl; R.sup.3 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, or C.sub.4-10 alkylcycloalkyl, all optionallysubstituted with hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, acetamido, C.sub.6 or C.sub.10 aryl, or C.sub.7-16 aralkyl; R.sup.2 is S--R.sub.20 or O--R.sub.20 wherein R.sub.20 is pyridinyl, quinolyl, --CH.sub.2-pyridinyl or --CH.sub.2-quinolyl, alloptionally mono-, di- or tri-substituted with R.sub.21, wherein R.sub.21 is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; lower thioalkyl; amino or amido optionally mono- or di-substituted with C.sub.1-6 alkyl, C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl, Hetor (lower alkyl)-Het; NO.sub.2; OH; halo; trifluoromethyl; carboxyl; C.sub.6 or C.sub.10 aryl, C.sub.7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R.sub.22, wherein R.sub.22 is C.sub.1-6 alkyl; C.sub.3-7cycloalkyl; C.sub.1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; sulfonylalkyl; NO.sub.2; OH; halo; trifluoromethyl; carboxyl or Het; or R.sup.2 is quinolinoxy unsubstituted, mono- or di-substituted with R.sub.21 asdefined above; and P1 is: ##STR00333## wherein R.sup.1 is H, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, or C.sub.2-4 alkenyl optionally substituted with halo, and said R.sup.1 at carbon 2 is orientated syn to the carbonyl at position 1, represented by theradical: ##STR00334## or a pharmaceutically acceptable salt or ester thereof.
45. A compound of formula I according to claim 44, wherein B is a C.sub.6 or C.sub.10 aryl optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, cyano, cyanoalkyl,amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C.sub.1-6 alkyl; or B is Het optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, hydroxy, halo, amido, (lower alkyl)amide, or amino optionallymono- or di-substituted with C.sub.1-6 alkyl; or B is R.sub.4--SO.sub.2 wherein R.sub.4 is C.sub.6 or C.sub.10 aryl, a C.sub.7-14 aralkyl or Het all optionally substituted with C.sub.1-6 alkyl; amido, (lower alkyl)amide; B is an acyl derivative offormula R.sub.4--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, hydroxy or C.sub.1-6 alkoxy; or (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, both optionally substituted with hydroxy, carboxyl, (C.sub.1-6alkoxy)carbonyl; or (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy; or (v) Het optionally substituted with C.sub.1-6 alkyl, hydroxy, amido or amino; or B is a carboxyl derivative offormula R.sub.4--O--C(O)--, wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxy or amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii)C.sub.3-7 cycloalkyl, C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; or (iv) C.sub.6 or C.sub.10 aryl orC.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6 alkyl, hydroxy, amino optionally substituted with C.sub.1-6 alkyl; or (v) Het or (lower alkyl)-Het, both optionally substituted with C.sub.1-6 alkyl, hydroxy, amido, or amino optionallymono-substituted with C.sub.1-6 alkyl; or B is an amide derivative of formula R.sub.4--N(R.sub.5)--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl, hydroxy, C.sub.1-6 alkoxy, amido, (loweralkyl)amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy) carbonyl, amido, (lower alkyl)amide, amino optionally mono-or di-substituted with C.sub.1-6 alkyl; and R.sub.5 is H or methyl; or R.sub.4 is (iii) amino optionally mono- or di-substituted with C.sub.1-3 alkyl; or (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl, all optionally substituted with C.sub.1-6alkyl, hydroxy, amino or amido optionally substituted with C.sub.1-6 alkyl; or (v) Het optionally substituted with C.sub.1-6 alkyl, hydroxy, amino or amido; or B is a thioamide derivative of formula R.sub.4--NH--C(S)--; wherein RR.sub.4 is (i)C.sub.1-10 alkyl; or (ii) C.sub.3-7 cycloalkyl; or Y is H; R.sup.3 is the side chain or Tbg, Ile, Val, Chg or: ##STR00335## R.sup.2 is quinolinoxy unsubstituted, mono- or di-substituted with R.sub.21 as defined above, or R.sup.2 is: ##STR00336##wherein R.sub.21 is C.sub.1-6 alkyl; C.sub.1-6 alkoxy; C.sub.6, C.sub.10 aryl or Het; lower thioalkyl; halo; amino optionally mono-substituted with C.sub.1-6 alkyl; or C.sub.6, C.sub.10 aryl, C.sub.7-16 aralkyl or Het, optionally substituted withR.sub.22 wherein R.sub.22 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl, or Het; and R.sub.21B is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino, di(lower alkyl)amino, (loweralkyl)amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl; P1 is: ##STR00337## R.sup.1 is ethyl, vinyl, cyclopropyl, 1 or 2-bromoethyl or 1 or 2-bromovinyl.
46. A compound of formula I according to .[.claims.]. .Iadd.claim .Iaddend.45, wherein B is an amide derivative of formula R.sub.4--NH--C(O)-- wherein R.sub.4 is (i) C.sub.1-10 alkyl optionally substituted with carboxyl, C.sub.1-6 alkanoyl,hydroxy, C.sub.1-6 alkoxy.Iadd., .Iaddend.amido, (lower alkyl) amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (ii) C.sub.3-7 cycloalkyl or C.sub.4-10 alkylcycloalkyl, all optionally substituted with carboxyl, (C.sub.1-6 alkoxy)carbonyl, amido, (lower alkyl)amide, amino optionally mono- or di-substituted with C.sub.1-6 alkyl; (iv) C.sub.6 or C.sub.10 aryl or C.sub.7-16 aralkyl optionally substituted with C.sub.1-6 alkyl, hydroxy, amino or amido; R.sup.3 is the side chain ofTbg, Chg or Val; R.sup.2 is: ##STR00338## wherein R.sub.22A is C.sub.1-6 alkyl, C.sub.1-6 alkoxy; R.sub.22B is C.sub.1-6 alkyl, amino optionally mono-substituted with C.sub.1-6 alkyl, or (lower alkyl)amide; and R.sub.21B is C.sub.1-6 alkyl, C.sub.1-6alkoxy, amino, di(lower alkyl)amino, (lower alkyl) amide, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl; .Iadd.and P1 is: .Iaddend. ##STR00339##
47. A compound according to claim 44 represented by the formula: ##STR00340## wherein B, R.sub.3, R.sub.2 are as defined below: TABLE-US-00012 Tab 1 Cpd # B R.sup.3 R.sup.2 106 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, R.sup.3, R.sup.2, R1 are defined below: TABLE-US-00013 Table 2 R.sub.1 Cpd anti to # B R.sup.3 R.sup.2 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, R.sup.3, R.sup.2, R.sup.1 are as defined below: TABLE-US-00014 R.sub.1 Table 3 syn to Cpd # B R.sub.3 R.sub.2 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 CF.sub.3--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, R.sup.3, R.sup.2 and R.sup.1 are as defined below: TABLE-US-00015 Table 4 Cpd # B R.sup.3 R.sup.2 R.sup.1 401 Boc i-Pr ##STR00377## H; 402 Boc t-Bu##STR00378## H; 403 Boc t-Bu ##STR00379## H; 404 Boc t-Bu ##STR00380## 3-(.dbd.CH.sub.2); 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-US-00016 Table 5 Cpd # R.sub.3 501 t-Bu; 502 H; 503 ##STR00383## 504 ##STR00384## 505 ##STR00385## 506 ##STR00386## 507 ##STR00387## 508 ##STR00388## 509 ##STR00389## 510##STR00390## and 511 ##STR00391##
! wherein R.sub.3 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 R.sub.3, R21A, R.sub.21B are as defined below: TABLE-US-00017 Table 6 Cpd # R.sub.3 R.sub.21A R.sub.21B 601 i-Pr Ph 7-OMe; 602 t-Bu Ph 8-OMe, 7-OMe; 603i-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 CH.sub.2-iPr -- 7-Cl; 610 t-Bu Cl --; 611 t-Bu Ph 7-N(Me).sub.2; 613 t-Bu ##STR00394## --; 614 t-Bu ##STR00395## --; 615 t-Bu -- 7-N(Me).sub.2; 616t-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).sub.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).sub.2; 629 t-Bu ##STR00402## 7-N(Me).sub.2; and 630 t-Bu ##STR00403## 7-N(Et).sub.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 R.sub.3 and R.sub.21A are as defined below: TABLE-US-00018 Table 7 Cpd # R.sub.3 R.sub.21A 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).sub.2N-- 713 t-Bu ##STR00413## 714 t-Bu ##STR00414## 717 t-Bu ##STR00415## 718 t-Bu NH.sub.2719 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, R.sub.3, and R.sub.22 are as defined below: TABLE-US-00019 Table 8 Cpd # B R.sub.3 R.sub.22 801 ##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-US-00020 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)--, R.sup.3, and R.sup.2 are as defined below: TABLE-US-00021 Table 10 Cpd # B--N(Y)-- R.sup.3 R.sup.2 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 acceptablecarrier 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 orester 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 esterthereof.
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 acceptablesalt 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: .alpha.- or .beta.-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 R.sup.1 is C.sub.1-6 alkyl, cycloalkyl or C.sub.2-6 alkenyl, all optionally substituted with halogen, CPG is a carboxyl protecting group and APG is an amino protecting groupand 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 R.sup.1 is C.sub.1-6 alkyl, cycloalkyl or C.sub.2-6 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 acceptablesalt 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 acceptablesalt 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 atherapeutically 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## |
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