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|Title:||Macrocyclic inhibitors of hepatitis C virus|
|Abstract:||Inhibitors of HCV replication of formula (I) ##STR00001## and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R.sup.1 is --OR.sup.7, --NH--SO.sub.2R.sup.8; R.sup.2 is hydrogen, and where X is C or CH, R.sup.2 may also be C.sub.1-6alkyl; R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl; R.sup.4 is aryl or Het; n is 3, 4, 5, or 6; R.sup.5 is halo, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, phenyl, or Het; R.sup.6 is C.sub.1-6alkoxy, or dimethylamino; R.sup.7 is hydrogen; aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, aryl or with Het; R.sup.8 is aryl; Het; C.sub.3-7cycloalkyl optionally substituted with C.sub.1-6alkyl; or C.sub.1-6alkyl optionally substituted with C.sub.3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.|
|Inventor(s):||Simmen; Kenneth Alan (Tervuren, BE), De Kock; Herman Augustinus (Arendonk, BE), Raboisson; Pierre Jean-Marie Bernard (Sterrebeek, BE), Nilsson; Karl Magnus (Huddinge, SE), Samuelsson; Bengt Bertil (Huddinge, SE), Rosenquist; .ANG.sa Annica Kristina (Huddinge, SE)|
|Assignee:||Tibotec Pharmaceuticals Ltd. (Eastgate, County Cork, IE) Medivar AB (Huddinge, SE)|
1. A compound of the formula: ##STR00194## or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable
salt of the stereochemically isomeric form.
2. A compound of the formula: ##STR00195## or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 in its pharmaceutically acceptable salt form.
4. The compound according to claim 3 wherein the pharmaceutically acceptable salt is an acid addition salt.
5. The compound according to claim 3 wherein the pharmaceutically acceptable salt is a base addition salt.
6. The compound according to claim 3 wherein the pharmaceutically acceptable salt is a hydrochloride acid addition salt.
7. The compound according to claim 3 wherein the pharmaceutically acceptable salt is a sodium addition salt.
8. The compound according to claim 2, which is stereochemically pure.
9. The compound according to claim 1 wherein the compound is a powder.
10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier therefore.
11. A method of inhibiting HCV replication in a warm-blooded animal comprising administering to said animal in need thereof a therapeutically effective amount of a compound according to claim 1.
12. The method according to claim 11 wherein the warm-blooded animal is human.
13. The method according to claim 11 wherein the compound has the formula ##STR00196## or a pharmaceutically acceptable salt thereof.
14. A process of preparing a compound of the formula ##STR00197## which comprises reacting under effective conditions a compound of formula 46 ##STR00198## and cyclopropylsulfonamide.
15. The process according to claim 14 wherein the process comprises (a) stirring at reflux under nitrogen for 2 hours, a solution of 560 mg (0.867 mmol) of compound no. 46 and 308 mg (1.90 mmol) of carbonyldiimidazole in 10 mL of dry tetrahydrofuran; (b) cooling the reaction mixture obtainable from step a) to room temperature and adding 400 mg (3.301 mmol) of cyclopropylsulfonamide and 286 mg of DBU (1.881 mmol); (c) heating the solution obtainable from step b) at 50.degree. C. for 15 hours; (d) cooling down the reaction mixture obtainable from step c) at room temperature and concentrating it under reduced pressure; (e) partitioning the residue obtainable from step d) between CH.sub.2Cl.sub.2 and HCl 1 N, washing the organic layer with brine, drying said organic layer with MgSO.sub.4, and evaporating said organic layer; (f) purifying the organic layer obtainable from step e) by flash chromatography (gradient of EtOAc (0 to 25%) in CH.sub.2Cl.sub.2) affording 314 mg of an off-white solid; and (g) washing the off-white solid obtainable from step f) with water and then with isopropyl ether, and drying said off-white solid in a vacuum oven.
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