Patent EA-003327-B1 (EA)
Title: Antiviral compounds
Inventor: SAHLBERG CHRISTER
IPC: C07D213/85
Filed: 1999-01-15
Abstract: 1. A compound of the formula I: wherein R<x> is cyano or bromo; R<1> is halo; R<2> is C1-C3 alkyl, R is hydrogen or a group of formula: wherein the X-containing ring is pyridyl, or phenyl. R<3> and R<4> independently from each other are selected from H, OH, amino, and substituted amino groups; n is independently 0, 1 or 2; p is 0 or 1; and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R<1> is fluoro. 3. A compound according to claim 1 wherein R<2> is ethyl. 4. A compound according to claim 1, comprising at least 60%, preferably at least 90 % 1S, 2S enantiomeric form. 5. A compound according to claim 1, wherein R<x> is cyano. 6. A compound according to claim 1, which represents compound of the formula II wherein X-containing ring, R<x>, R<1>, R<2>, R<3>, R<4>, n, and P are defined in claim 1, and pharmaceutically acceptable salts thereof. 7. A compound according to claim 6, wherein the X-containing ring is pyridyl. 8. A compound according to claim 7 wherein the X-containing ring is phenyl. 9. A compound according to claim 6 wherein the X-containing ring is pyrid-2-yl or preferably pyrid-3-yl. 10. A compound according to claim 6, wherein R<3> is -NH2, -NHCH3, -NHCH2CH3 or -N(CH3)2. 11. A compound according to claim 6 wherein R<3> is in the meta position relative to the carbonyl group especially where the X-containing ring is phenyl, or wherein R<3> is in the para position relative to the carbonyl group, especially where the X containing ring is a pyridyl. 12. A compound according to claim 6 wherein -(CH2)n and/or -(CH2)n- are absent, that is p and/or n are 0. 13. A compound according to claim 6, wherein R<x> is cyano. 14. A compound according to claim 6, wherein R<1> is fluoro. 15. A compound according to claim 6, wherein R<2> is ethyl. 16. A compound according to claim 6, comprising at least 60 %, preferably at least 90 % 1S, 2S enantiomeric form. 17. A compound according to claim 1 selected from 1. (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 2. (1R, 2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 3. (1S, 2S)-N-[cis-2-(6-fluoro, 2hydroxy, 3-propionylphenyl)-cyclopropyl]-N'-(s-bromopyrid-2-yl)-urea, and 4. (1R, 2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-N'-(5-brompyrid-2-yl)-urea and pharmaceutically acceptable salts thereof. 18. A compound according to claim 17 denoted (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1 selected from the group consisting of the following compounds: 1. (1S, 2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 2. (1S, 2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(s-cyanopyrid-2-yl)-urea, 3. (1S, 2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(s-cyanopyrid-2-yl)-urea, 4. (1S,2S)-N-{cis-2-[6-fluoro-3-propionyl-2-(6-methylaminopyrid-3-ylcarbonyloxy)phenyl] cyclopropyl}-N'-(5-cyanopyrid-2-yl)urea, 5. (1R, 2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 6. (1R, 2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 7. (1R, 2R)-N-[cis-2-(2-{3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-cyanopyrid-2-yl)-urea, 8. (1 R,2R)-N-{cis-2-[6-fluoro-3-propionyl-2-(6-methylaminopyrid-3-ylcarbonyloxy)phenyl] cyclopropyl}-N'-(5-cyanopyrid-2-yl)urea, 9. (1S, 2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 10. (1S, 2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 11. (1S, 2S)-N-[cis-2-(2-{3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 12. (1S,2S)-N- {cis-2-[6-fluoro-3-propionyl-2-(6-methylaminopyrid-3-ylcarbonyloxy)phenyl] cyclopropyl}-N'-(5-bromopyrid-2-yl)urea, 13. (1R, 2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 14. (1R, 2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 15. (1R, 2R)-N-(cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea, 16. (1R,2R)-N-{cis-2-[6-fluoro-3-propionyl-2-(6-methylaminopyrid-3-ylcarbonyloxy)phenyl] cyclopropyl}-N'-(5-bromopyrid-2-yl)urea, and pharmaceutically acceptable salts thereof. 20. A compound according to claim 19 denoted (1S,2S)-N-{cis-2-[6-fluoro-3-propionyl-2-(6-methylaminopyrid-3-ylcarbonyloxy)phenyl] cyclopropyl}N'-(5-cyanopyrid-2-yl)urea and its pharmaceutically acceptable salts. 21. A compound according to claim 19 denoted (1S, 2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-N'-(5-bromopyrid-2-yl)-urea and its pharmaceutically acceptable salts. 22. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 21 and a pharmaceutically acceptable carrier or diluent therefor. 23. A composition according to claim 22 further comprising one to three additional antiretroviral agents. 24. A composition according to claim 23 wherein the additional antiretroviral agent is selected from the group consisting of AZT, ddi, ddC, D4T, 3TC, adefovir, dipivoxil, abacavir, bis-POC-PMPA, foscarnet, hydroxyurea, efavirenz, trovirdine, nevirapine, delavirdine, PFA, H2G, ABT 606, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX 478), Mitsubishi MKC-442 and nelfinavir 25. A compound according to any one of claims 1 to 21 for use in therapy. 26. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for the treatment or prophylaxis of HIV. 27. A method for inhibiting or preventing HIV infection comprising administering an effective amount of a compound as defined in claim 1 or 6 to a subject in need thereof. 28. A method for the preparation of a compound of the Formula I wherein R is hydrogen, comprising the Curtius rearrangement of the azide acid of the following formula: PG is an hydroxy-protecting group, and R<1> and R have values indicated in claim 1 with the following coupling with a compound of the formula wherein R<x> has a values, indicated in claim 1 and removing of protecting group.