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Title:HIV replication inhibiting pyrimidines
Abstract: This invention concerns HIV replication inhibitors of formula ##STR00001## the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a.sup.1=a.sup.2-a.sup.3=a.sup.4- and -b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R.sup.1 is hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; substituted C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy; substituted C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl; R.sup.2 is hydroxy, halo, optionally substituted C.sub.1-6alkyl, C.sub.3-7cycloalkyl, optionally substituted C.sub.2-6alkenyl, optionally substituted 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 a 5-membered heterocycle; X.sub.1 is --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4alkanediyl, --CHOH--, --S--, --S(.dbd.O).sub.p--, --X.sub.2--C.sub.1-4alkanediyl- or --C.sub.1-4alkanediyl-X.sub.2--; R.sup.3 is NHR.sup.13; NR.sup.13R.sup.14; --C(.dbd.O)--NHR.sup.13; --C(.dbd.O)--NR.sup.13R.sup.14; --C(.dbd.O)--R.sup.15; --CH.dbd.N--NH--C(.dbd.O)--R.sup.16; substituted C.sub.1-6alkyl; optionally substituted C.sub.1-6alkyloxyC.sub.1-6alkyl; substituted C.sub.2-6alkenyl; substituted C.sub.2-6alkynyl; C.sub.1-6alkyl substituted with hydroxy and a second substituent; --C(.dbd.N--O--R.sup.8)--C.sub.1-4alkyl; R.sup.7; or --X.sub.3--R.sup.7; R.sup.4 is halo, hydroxy, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyl, formyl, amino, mono- or di(C.sub.1-4alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.
Inventor(s): Guillemont; Jerome Emile Georges (Ande, FR), Janssen; Paul Adriaan Jan (N/A), Palandjian; Patrice (Louviers, FR), de Jonge; Marc Rene (Leidschendam, NL), Koymans; Lucien Maria Henricus (Retie, BE), Vinkers; Hendrik Maarten (Antwerpen, BE), Daeyaert; Frederik Frans Desire (Beerse, BE), Heeres; Jan (Vosselaar, BE), Van Aken; Koen Jeanne Alfons (Kortrijk, BE), Lewi; Paulus Joannes (N/A)
Assignee: JANSSEN PHARMACEUTICA NV (Beerse, BE)
Filing Date:Aug 05, 2014
Application Number:14/451,761
Claims:1. A combination containing (a) a compound of formula (I) ##STR00255## an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of formula: --CH.dbd.CH--CH.dbd.CH-- (a-1); -b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents a bivalent radical of formula: --CH.dbd.CH--CH.dbd.CH-- (b-1); n is 0, 1, 2, 3, 4, or 5; m is 1, 2, 3, or 4; R.sup.l is selected from the group consisting of: hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is substituted with a member selected from the group consisting of: formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, and C.sub.1-6alkylcarbonyloxy; and C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl, wherein said C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl is substituted with C.sub.1-6alkyloxycarbonyl; each R.sup.2 independently is selected from the group consisting of: 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.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, 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 and a radical of formula ##STR00256## wherein each A.sub.1 independently is N, CH or CR.sup.6; and A.sub.2 is NH, O, S or NR.sup.6; X.sub.1 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4alkanediyl, --CHOH--, --S--, --S(.dbd.O).sub.p--, --X.sub.2--C.sub.1-4alkanediyl- and --C.sub.1-4alkanediyl-X.sub.2--; X.sub.2 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --CHOH--, --S--, and --S(.dbd.O).sub.p--; R.sup.3 is R.sup.7; X.sub.3 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --S--, --S(.dbd.O).sub.p--, --X.sub.2--C.sub.1-4alkanediyl-, --C.sub.1-4alkanediyl-X.sub.2a--, --C.sub.1-4alkanediyl-X.sub.2b--C.sub.1-4alkanediyl, and --C(.dbd.N--OR.sup.8)--C.sub.1-4alkanediyl-; with X.sub.2a being selected from the group consisting of: --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --S--, and --S(.dbd.O).sub.p--; and with X.sub.2b being selected from the group consisting of: --NH--NH--, --N.dbd.N--, --C(.dbd.O)--, --S--, and --S(.dbd.O).sub.p--; R.sup.4 is selected from the group consisting of: halo, hydroxy, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyl, formyl, amino, mono- or di(C.sub.1-4alkyl)amino and R.sup.7; R.sup.5 is selected from the group consisting of: hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is substituted with a member selected from the group consisting of: formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; and C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl, wherein said C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl is substituted with C.sub.1-6alkyloxycarbonyl; R.sup.6 is C.sub.1-4alkyl, amino, mono- or di(C.sub.1-4alkyl)amino or polyhaloC.sub.1-4alkyl; R.sup.7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, --CH(.dbd.N--O--R.sup.8), R.sup.7a, --X.sub.3--R.sup.7a and R.sup.7a--C.sub.1-4alkyl; R.sup.7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, and --CH(.dbd.N--O--R.sup.8); R.sup.8 is selected from the group consisting of: hydrogen, C.sub.1-4alkyl, aryl and arylC.sub.1-4alkyl; p is 1 or 2; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, R.sup.7 and --X.sub.3--R.sup.7; and (b) another antiretroviral compound.

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) ##STR00257## an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of a formula: --CH.dbd.CH--CH.dbd.CH-- (a-1); -b.sup.1=b.sup.2-b.sup.3=b.sup.4- represents a bivalent radical of a formula: --CH.dbd.CH--CH.dbd.CH--(b-1); n is 0, 1, 2, 3, or 5; m is 1, 2, 3, or 4; R.sup.1 is selected from the group consisting of: hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is substituted with a member selected from the group consisting of: formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl, and C.sub.1-6alkylcarbonyloxy; and C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl wherein said C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl is substituted with C.sub.1-6alkyloxycarbonyl; each R.sup.2 independently is selected from the group consisting of: 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.1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.sub.1-6alkyl)amino, polyhalomethyl, 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 and a radical of formula ##STR00258## wherein each A.sub.1 independently is N, CH or CR.sup.6; and A.sub.2 is NH, O, S or NR.sup.6; X.sub.1 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, C.sub.1-4alkanediyl, --CHOH--, --S--, --S(.dbd.O).sub.p--, --X.sub.2--C.sub.1-4alkanediyl- and --C.sub.1-4alkanediyl-X.sub.2--; X.sub.2 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --CHOH--, --S--, and --S(.dbd.O).sub.p--; R.sup.3 is R.sup.7; X.sub.3 is selected from the group consisting of: --NR.sup.5--, --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --S--, --S(.dbd.O).sub.p--, --X.sub.2--C.sub.1-4alkanediyl-, --C.sub.1-4alkanediyl-X.sub.2a--, --C.sub.1-4alkanediyl-X.sub.2b--C.sub.1-4alkanediyl, and --C(.dbd.N--OR.sup.8)--C.sub.1-4alkanediyl-; with X.sub.2a being selected from the group consisting of: --NH--NH--, --N.dbd.N--, --O--, --C(.dbd.O)--, --S--, and --S(.dbd.O).sub.p--; and with X.sub.2b being selected from the group consisting of: --NH--NH--, --N.dbd.N--, --C(.dbd.O)--, --S--, and --S(.dbd.O).sub.p--; R.sup.4 is selected from the group consisting of: halo, hydroxy, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyl, formyl, amino, mono- or di(C.sub.1-4alkyl)amino and R.sup.7; R.sup.5 is selected from the group consisting of: hydrogen; aryl; formyl; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is substituted with a member selected from the group consisting of: formyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; and C.sub.1-6alkyloxyC.sub.1-6alkylcarbonyl substituted with C.sub.1-6alkyloxycarbonyl; R.sup.6 is C.sub.1-4alkyl, amino, mono- or di(C.sub.1-4alkyl)amino or polyhaloC.sub.1-4alkyl; R.sup.7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, --CH(.dbd.N--O--R.sup.8), R.sup.7a, --X.sub.3--R.sup.7a and R.sup.7a--C.sub.1-4alkyl; R.sup.7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, formyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, and --CH(.dbd.N--O--R.sup.8); R.sup.8 is selected from the group consisting of: hydrogen, C.sub.1-4alkyl, aryl and arylC.sub.1-4alkyl; p is 1 or 2; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C.sub.1-6alkyl, hydroxyC.sub.1-6 alkyl, aminoC.sub.1-6alkyl, mono or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylthio, cyano, nitro, polyhaloC.sub.1-6alkyl, polyhaloC.sub.1-6alkyloxy, aminocarbonyl, R.sup.7 or --X.sub.3--R.sup.7; and (b) another antiretroviral compound.

3. A combination containing (a) a compound of formula (I''') ##STR00259## an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, m and X.sub.1 are as defined in claim 1; n' is 0, 1, 2, 3 or 4; R.sup.2' is selected from the group consisting of: halo, C.sub.1-6alkyl, trihalomethyl, cyano, aminocarbonyl, and C.sub.1-6alkyl substituted with cyano or aminocarbonyl; and (b) another antiretroviral compound.

4. The combination as claimed in claim 3 wherein R.sup.2' is cyano, aminocarbonyl or C.sub.1-6alkyl substituted with cyano or aminocarbonyl.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I''') ##STR00260## an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, m and X.sub.1 are as defined in claim 2; n' is 0, 1, 2, 3 or 4; R.sup.2' is a member selected from the group consisting of: halo, C.sub.1-6alkyl, trihalomethyl, cyano, aminocarbonyl, and C.sub.1-6alkyl substituted with cyano or aminocarbonyl; and (b) another antiretroviral compound.

6. The composition as claimed in claim 5 wherein R.sup.2' is cyano, aminocarbonyl or C.sub.1-6alkyl, wherein said C.sub.1-6alkyl is substituted with cyano or aminocarbonyl.

7. The combination as claimed in claim 1, comprising (a) a compound and an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, selected from the group consisting of: ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## and (b) another antiretroviral compound.

8. The composition as claimed in claim 1, comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound and an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, selected from the group consisting of: ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## and (b) another antiretroviral compound.
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