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US 6,608,027 B1Granted
Macrocyclic peptides active against the hepatitis C virus
AssigneeBoehringer Ingelheim (Canada) Ltd.
InventorsYoula S. Tsantrizos, Dale R. Cameron, Anne-Marie Faucher, Elise Ghiro, Nathalie Goudreau, Teddy Halmos, Montse Llinas-Brunet
Life of this patent
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Abstract
The present invention covers macrocyclic compounds of formula I active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus. wherein W, R21, R22, R3, R4, D and A are as defined herein, or a pharmaceutically acceptable salts or ester thereof.
Claims145
A compound of formula (I):
- wherein
- W is CH or N,
- R21 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,
- wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;
- R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;
- said cycloalkyl, aryl or Het being substituted with R24,
- wherein R24 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH—C(O)—R25 or NH—C(O)—NH—R25, wherein each R25 is independently:
- H, C1-6 alkyl or C3-6 cycloalkyl;
- or R24 is NH—C(O)—OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl;
- R3 is hydroxy, NH2, or a group of formula —NH—R31, wherein R31 is C6 or 10 aryl, heteroaryl, —C(O)—R32, —C(O)—NHR32 or —C(O)—OR32,
- wherein R32 is C1-6 alkyl or C3-6 cycloalkyl;
- D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from:
- O, S, or N—R41, wherein
- R41 is H, C1-6 alkyl, C3-6 cycloalkyl or —C(O)—R42, wherein R42 is C1-6 alkyl, C3-6 cycloalkyl or C6 or 10 aryl;
- R4 is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of:
- C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio and C1-6 thioalkyl, and
- A is an amide of formula —C(O)—NH—R5, wherein R5 is selected from the group consisting of:
- C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl and C7-16 aralkyl;
- or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
16 more elements
A compound of formula:
- comprising a single stereoisomer at R1, wherein the optional double bond between 12 and 13, the position 13-R1 group bond stereochemistry and R22 are defined as follows:
- double bond between 12 and position 13 - R1 bond Cpd. # 13:
- stereochem:
- R22:
- 101 12,13-trans 1R, position 13 syn to phenyl;
- amide 102 none 1R, position 13 syn to phenyl;
- acid and none 1R position 13 syn to phenyl 103 amide.
4 more elements
A compound of formula:
- comprising a single stereoisomer at R1, wherein R3, R4, the optional 11, 12 or 13, 14 double bond position 14-R1 bond stereochemistry, R21 and R22 are defined as follows:
- position 14-R1 bond Cpd double stereo- # R3:
- R4:
- bond:
- chemistry:
- R21:
- R22:
- 202 NH-Boc H 11,12- 1R or 1S, H H;
- trans position 14 syn to acid 203 NH-acetyl H 11,12- 1R or 1S, H H;
- trans position 14 syn to acid 205 NH-Boc 11-OH none 1R or 1S, H H;
- 12-OH position 14 cis syn to acid 206 NH-Boc H 13,14- 1R, H H;
- cis position 14 syn to acid 207 NH-Boc H 13,14- 1R, OMe H;
- cis position 14 syn to acid 208 NH-Boc H 13,14- 1R, OMe phenyl;
- cis position 14 syn to acid 209 NH-C(O)- H 13,14- 1R, OMe phenyl;
- NH-tBu cis position 14 syn to acid 210 NH-Boc H 13,14- 1S, OMe phenyl;
- cis position 14 syn to acid 211 NH2 H 13,14- 1R, OMe phenyl;
- cis position 14 syn to acid 213 OH (one H 13,14- 1R, OMe H;
- isomer) cis position 14 syn to acid 214 NH-Boc 10-oxo 13,14- 1R, OMe phenyl;
- cis position 14 syn to acid 215 NH-Boc H none 1R, OMe phenyl;
- position 14 syn to acid 217 NH-Boc 10-OH 13,14- 1R, OMe phenyl;
- (mixt cis position 14 dia syn to acid stereo) 218 NH-Boc 10-oxo 13,14- 1R, OMe phenyl;
- cis position 14 syn to amide 219 NH-Ac H none 1R, OMe phenyl;
- position 14 syn to acid and 220 NH-Boc H 13,14- cis 1R, position 14 syn to amide OMe
20 more elements
A compound of formula:
- comprising a single stereoisomer at R1, wherein R3, D, D—R1 bond stereochemistry, R21 and R22 are defined as follows:
- D—R1 bond Cpd. # R3:
- —D—:
- stereochemistry:
- R21:
- R22:
- 301 NH—Boc 1R or 1S, D syn to acid H H;
- 302 NH—Boc 1R, D syn to amide OMe Ph;
- 303 NH—Boc 1R, D syn to amide OMe Ph;
- 304 NH—Boc 1R, D syn to acid OMe Ph;
- 305 HO 1R, D syn to acid OMe Ph;
- 306 NH—Boc 1R, D syn to amide OMe Ph;
- 307 NH—Boc 1R, D syn to acid OMe and 308 NH—Ac 1R, D syn to acid OMe OEt.
10 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, R4, X9, and the optional 11,12 double bond are defined as follows:
- 11, 12 double Cpd # R4:
- X9:
- bond:
- 401 H CH2 trans;
- 402 H CH2 cis;
- 403 H O trans;
- 404 O trans;
- 405 O trans;
- 406 H O none;
- 407 O none;
- 408 O none;
- 409 O cis;
- 410 S trans;
- 411 S cis;
- and 8-(Me)2 9-S Cis. 412
13 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, X10, X11, and X12 are defined as follows:
- Cpd # X10:
- X11:
- X12:
- 501 CH2 O CH2;
- 502 CH2 CH2 CH2;
- 503 CH2 CH2 NH;
- 504 CH2 CH2 N(Me);
- 505 CH2 CH2 N(CO)Me;
- 506 CH2 CH2 N(CO)Ph;
- 507 NH CH2 CH2;
- and N(CO)Me CH2 CH2 508.
9 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, R21 and R22 are defined as follows:
- Cpd # R21:
- R22:
- 601 N(Me)2 602 OH (CF3);
- and 603 OMe
2 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, R4, X9, X10, X11, the optional 13,14 double bond and R22 are defined as follows:
- X9;
- X10;
- 13,14 double Cpd # R4:
- and X11:
- bond:
- R22:
- 701 H X9 = CH2 Cis phenyl;
- X10 = CH2 X11 = O 702 H CH2 (All) Cis 703 H CH2 (All) None 704 H CH2 (All) Cis 705 H CH2 (All) Cis 707 H CH2 (All) Cis 708 H CH2 (All) Cis 709 H CH2 (All) None 710 H CH2 (All) None 711 H CH2 (All) None 712 H CH2 (All) Cis —OEt;
- 713 H CH2 (All) None 714 H CH2 (All) None —OEt;
- 715 H CH2 (All) Cis 716 H CH2 (All) Cis 717 H CH2 (All) Cis 718 H CH2 (All) Cis 719 H CH2 (All) Cis 720 H CH2 (All) None 721 H CH2 (All) None 722 H CH2 (All) Cis 723 H CH2 (All) None 724 H CH2 (All) None 725 H CH2 (All) Cis 726 H CH2 (All) Cis 727 H CH2 (All) Cis —CH2—OMe;
- 728 H CH2 (All) Cis Me;
- 729 H CH2 (All) Cis 730 H CH2 (All) None 731 H CH2 (All) Cis 732 H CH2 (All) Cis 733 H CH2 (All) Cis 734 H CH2 (All) Cis 735 H CH2 (All) Cis 736 H CH2 (All) Cis 737 H CH2 (All) Cis 738 H CH2 (All) Cis 739 10-(R) Me CH2 (All) none Ph;
- 740 10-(S) Me CH2 (All) none Ph;
- and 741 H CH2 (All) Cis
12 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, said 13,14 double bond is cis, R32, R4 and R22 are defined as follows:
- Cpd # R32:
- R4:
- R22:
- 801 H 803 n-Pr H OEt;
- 804 H 805 H 806 H OEt;
- 807 H OEt;
- 808 H OEt;
- 809 H 810 H 811 H 812 H 813 H OEt;
- 814 H 815 H 816 H 817 H 818 H 819 H 820 H 821 H 822 H 823 H and 824 10-(R) Me OEt.
7 more elements
A compound of formula:
- wherein the position 14-R1 bond is syn to acid, R32, R4 and R22 are defined as follows:
- Cpd # R32:
- R4:
- R22:
- 901 H OEt;
- 902 H 903 H 904 H 905 H 906 H 907 H 908 H 909 H 910 H 911 H 912 H 913 H 914 H 915 H and 916 10 (R) Me OEt.
3 more elements
A compound of formula:
- wherein said position 14-R1 bond is syn to acid, said 13,14 double bond is cis, R32, R4 and R22 are defined as follows:
- Cpd # R32:
- R4:
- R22:
- 825 H 826 H 827 H and 828 H
2 more elements
Dependencies are inferred from the claim text.