Patent EA-004043-B1 (EA)
Title: 4-oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents
Inventor: TURNER STEVEN RONALD
IPC: A61K31/5377
Filed: 1999-12-22
Abstract: 1. A compound of formula I wherein R<1> is C1-7 alkyl, optionally substituted by hydroxy or NR<4>R<5>; R<2> is C1-7 alkyl substituted by hydroxy or NR<4>R<5>; R<3> is H, F or C1-7 alkoxy; R<4> and R<5> together with N are a 5- or 6-membered heterocyclic moiety having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in which sulfur may be substituted by one (1) or two (2) oxygen atoms; and a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein R<1> is C1-4 alkyl, optionally substituted by hydroxy; R<2> is C1-5 alkyl substituted by hydroxy or morpholine; and R<3> is H or F. 3. A compound of claim 1 which is (a) N-(4-chlorobenzyl)-6-(3-hydroxy-1,1-dimethylpropyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (b) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (c) N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (d) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (e) 1-(tert-butyl)-N (4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (f) N-(4-chlorobenzyl)-6-[(1,1-dioxo-1',4-thiazinan-4-yl)methyl]-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide; (g) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-[(1-oxo-1',4-thiazinan-4-yl)methyl]-1,4-dihydro-3-quinolinecarboxamide; or a pharmaceutically acceptable salt thereof. 4. A compound of claim 1, which is any of compounds (a), (b), (c), (d), (f) and (g) as defined in claim 3, or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1, which is any of compounds (b), (d), (f) and (g) as defined in claim 3, or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1, which is N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-i,4-dihydro-3-quinolinecarboxamide, or a pharmaceutically acceptable salt thereof. 7. A compound of claim 1 or claim 2, wherein R<3> is not F. 8. A compound of claim 1, which is N-(4-chlorobenzyl)-8-fluoro-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide, or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition which comprises a compound of any preceding claim and a pharmaceutically acceptable carrier. 10. Use of a compound of any of claims 1 to 8, for the manufacture of a medicament for the treatment of a herpesvirus infection. 11. Use according to claim 10, wherein the herpesvirus is herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes virus 6, human herpes virus 7 or human herpes virus 8. 12. Use according to claim 10, wherein the herpesvirus is human cytomegalovirus. 13. A compound useful as a synthetic intermediate in the preparation of the compound of claim 6, which is diethyl 2-{[methyl-4-(4-morpholinylmethyl)anilino]methylene}malonate. 14. A compound useful as a synthetic intermediate in the preparation of the compound of claim 6, which is ethyl 1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylate. 15. A compound useful as a synthetic intermediate in the preparation of the compound of claim 6, which is 1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid. 16. A process for the preparation of the compound of claim 6, comprising the steps of: a. heating a mixture of diethyl ethoxymethylenemalonate and N-(4-methylaminobenzyl)morpholine, to provide compound (a) of claim 13; b. adding a solution of the product of step a in toluene to a mixture of phosphorus pentoxide and methanesulfonic acid, to provide compound (b) of claim 14; c. converting the product of step b to compound (c) of claim 15; d. stirring the product of step c with carbonyldiimidazole and dimethylformamide; and e. reacting 4-chlorobenzylamine with the mixture of step d. 17. Use of a compound of formula I for use in treating infections from herpesviruses, which comprises administering to a patient in need thereof an effective amount of a compound of formula I as shown in claim 1. 18. The use of claim 17, wherein said herpesviruses is herpes simplex virus types 1, herpes simplex virus types 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes viruses 6, human herpes viruses 7 or human herpes viruses 8. 19. The use of claim 17, wherein said herpesviruses is herpes simplex virus types 1; herpes simplex virus types 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes viruses 7 or human herpes viruses 8. 20. The use of claim 17, wherein said herpesviruses is human cytomegalovirus. 21. The use of claim 17, wherein the effective amount of a compound of claim 1 is administered orally, parenterally or topically. 22. The use of claim 17, wherein the effective amount of a compound of claim 1 is in an amount of from about 0.1 to about 300 mg/kg of body weight. 23. The use of claim 17, wherein the effective amount of a compound of claim 1 is in an amount of from about 1 to about 30 mg/kg of body weight.