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Details for Patent: 8,530,655

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Details for Patent: 8,530,655

Title:HIV replication inhibiting pyrimidines
Abstract: This invention concerns the use of compounds of formula ##STR00001## the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- forms a phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl with the attached vinyl group; n is 0 to 4; and where possible 5; R.sup.1 is hydrogen, aryl, formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, substituted C.sub.1-6alkyl, or substituted C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl; each R.sup.2 independently is hydroxy, halo, optionally substituted C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkylamino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, --S(.dbd.O).sub.pR.sup.6, --NH--S(.dbd.O).sub.pR.sup.6, --C(.dbd.O)R.sup.6, --NHC(.dbd.O)H, --C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.6, --C(.dbd.NH)R.sup.6 or a 5-membered heterocyclic ring; p is 1 or 2; L is optionally substituted C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl or C.sub.3-7cycloalkyl; or L is --X--R.sup.3 wherein R.sup.3 is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; X is --NR.sup.1--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --CHOH--, --S--, --S(.dbd.O)-- or --S(.dbd.O).sub.2--; Q is hydrogen, C.sub.1-6alkyl, halo, polyhalo-C.sub.1-6alkyl or an optionally substituted amino group; Y represents hydroxy, halo, C.sub.3-7cycloalkyl, optionally substituted C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, --S(.dbd.O).sub.pR.sup.6, --NH--S(.dbd.O).sub.pR.sup.6, --C(.dbd.O)R.sup.6, --NHC(.dbd.O)H, --C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.6, --C(.dbd.NH)R.sup.6 or aryl; aryl is optionally substituted phenyl; Het is an optionally substituted heterocyclic radical; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
Inventor(s): De Corte; Bart (Southampton, PA), de Jonge; Marc Rene (Hontenissestraat, NL), Heeres; Jan (Vosselaar, BE), Ho; Chih Yung (Lansdale, PA), Janssen; Paul Adriaan Jan (Vosselaar, BE), Kavash; Robert W. (Glenside, PA), Koymans; Lucien Maria Henricus (Retie, BE), Kukla; Michael Joseph (Maple Glen, PA), Ludovici; Donald William (Quakertown, PA), Van Aken; Koen Jeanne Alfons (Kuurne, BE), Andries; Koenraad Jozef Lodewijk Marcel (Beerse, BE)
Assignee: Janssen Pharmaceutica NV (Beerse, BE)
Filing Date:Jul 06, 2011
Application Number:13/177,188
Claims:1. A compound having the formula ##STR00032## a N-oxide, an addition salt, or a stereochemically isomeric form thereof, wherein -b.sup.1=b.sup.2-C(R.sup.2a)=b.sup.3-b.sup.4= represents a bivalent radical of formula --N.dbd.CH--C(R.sup.2a).dbd.CH--CH.dbd. (b-2); --CH.dbd.N--C(R.sup.2a).dbd.CH--CH.dbd. (b-3); --N.dbd.CH--C(R.sup.2a).dbd.N--CH.dbd. (b-4); --N.dbd.CH--C(R.sup.2a).dbd.CH--N.dbd. (b-5); --CH.dbd.N--C(R.sup.2a).dbd.N--CH.dbd. (b-6); --N.dbd.N--C(R.sup.2a).dbd.CH--CH.dbd. (b-7); q is 0, 1, 2 or 3; R.sup.1 is hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkyl substituted with formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy; C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl substituted with C.sub.1-6alkyloxycarbonyl; R.sup.2a is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl, C.sub.1-6alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl, C.sub.2-6alkenyl substituted with cyano, or C.sub.2-6alkynyl substituted with cyano; each R.sup.2 independently is hydroxy, halo, C.sub.1-6alkyl optionally substituted with cyano or --C(.dbd.O)R.sup.6, C.sub.3-7cycloalkyl, C.sub.2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C.sub.2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, --S(.dbd.O).sub.pR.sup.6, --NH--S(.dbd.O).sub.pR.sup.6, --C(.dbd.O)R.sup.6, --NHC(.dbd.O)H, --C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.6, --C(.dbd.NH)R.sup.6 or a radical of formula ##STR00033## wherein each A independently is N, CH or CR.sup.6; B is NH, O, S or NR.sup.6; p is 1 or 2; and R.sup.6 is methyl, amino, mono- or dimethylamino or polyhalomethyl; L is C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from C.sub.3-7cycloalkyl, indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C.sub.1-6alkylcarbonyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R.sup.2; or L is --X--R.sup.3 wherein R.sup.3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R.sup.2; and X is --NR.sup.1--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --CHOH--, --S--, --S(.dbd.O)-- or --S(.dbd.O).sub.2--; Q represents hydrogen, C.sub.1-6alkyl, halo, polyhaloC.sub.1-6alkyl or --NR.sup.4R.sup.5; and R.sup.4 and R.sup.5 are each independently selected from hydrogen, hydroxy, C.sub.1-12alkyl, C.sub.1-12alkyloxy, C.sub.1-12alkylcarbonyl, C.sub.1-12alkyloxycarbonyl, aryl, amino, mono- or di(C.sub.1-12alkyl)amino, mono- or di(C.sub.1-12alkyl)aminocarbonyl wherein each of the aforementioned C.sub.1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyloxy, carboxyl, C.sub.1-6alkyloxycarbonyl, cyano, amino, imino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, --S(.dbd.O).sub.pR.sup.6, --NH--S(.dbd.O).sub.pR.sup.6, --C(.dbd.O)R.sup.6, --NHC(.dbd.O)H, --C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.6, --C(.dbd.NH)R.sup.6, aryl and Het; or R.sup.4 and R.sup.5 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C.sub.1-12alkyl)aminoC.sub.1-4-alkylidene; Y represents hydroxy, halo, C.sub.3-7cycloalkyl, C.sub.2-6alkenyl optionally substituted with one or more halogen atoms, C.sub.2-6alkynyl optionally substituted with one or more halogen atoms, C.sub.1-6alkyl substituted with cyano or --C(.dbd.O)R.sup.6, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, --S(.dbd.O).sub.pR.sup.6, --NH--S(.dbd.O).sub.pR.sup.6, --C(.dbd.O)R.sup.6, --NHC(.dbd.O)H, --C(.dbd.O)NHNH.sub.2, --NHC(.dbd.O)R.sup.6, --C(.dbd.NH)R.sup.6 or aryl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, cyano, nitro, polyhaloC.sub.1-6alkyl and polyhaloC.sub.1-6alkyloxy; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy.

2. A compound as claimed in claim 1 wherein R.sup.1 is hydrogen, aryl, formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyl substituted with formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl.

3. A compound as claimed in claim 1 wherein L is --X--R.sup.3 wherein R.sup.3 is 2,4,6-trisubstituted phenyl.

4. A compound as claimed in claim 1 wherein Y is cyano, --C(.dbd.O)NH.sub.2 or a halogen.

5. A compound as claimed in claim 1 wherein Q is hydrogen or NR.sup.4R.sup.5.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1.

7. A process for preparing a compound as claimed in claim 1, comprising a) reacting an intermediate of formula (II) with an amino derivative of formula (III) under solvent-free conditions or in a reaction-inert solvent under a reaction-inert atmosphere ##STR00034## wherein W.sup.1 is a suitable leaving group and L, Y, Q, R.sup.1, R.sup.2, R.sup.1a, q and -b.sup.1=b.sup.2-C(R.sup.2a)=b.sup.3-b.sup.4= are as defined in claim 1; b) reacting an intermediate of formula (IV) with an intermediate of formula (V) under solvent-free conditions or in an appropriate solvent under a reaction-inert atmosphere ##STR00035## wherein W.sup.2 is a suitable leaving group and Y, Q, R.sup.1, R.sup.2, R.sup.2a, R.sup.3, q and -b.sup.1=b.sup.2-C(R.sup.2a)=b.sup.3-b.sup.4= are as defined in claim 1; c) reacting an intermediate of formula (IV) with an intermediate of formula (VI) in an appropriate solvent under a reaction-inert atmosphere in the presence of a suitable base ##STR00036## wherein W.sup.2 is a suitable leaving group and Y, Q, R.sup.1, R.sup.2, R.sup.2a, R.sup.3, q and -b.sup.1=b.sup.2-C(R.sup.2a)=b.sup.3-b.sup.4= are as defined in claim 1; or optionally converting compounds of formula (I-a) into each other following art-known transformation reactions; and further, if desired, converting the compounds of formula (I-a), into an acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and optionally preparing stereochemically isomeric forms thereof.

8. The combination of a compound as defined in claim 1 and another antiretroviral compound.

9. A product containing (a) a compound as defined in claim 1 and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound as defined in claim 1 and (b) another antiretroviral compound.
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