Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-27
2002-08-27
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S321000, C544S320000, C544S323000, C514S274000, C514S275000
Reexamination Certificate
active
06440986
ABSTRACT:
The present invention is concerned with pyrimidine derivatives having HIV replication inhibiting properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
Compounds structurally related to the present compounds are disclosed in the prior art.
JP-2,052,360, JP-2,308,248. JP-9,080,676 and JP-9,068,784 disclose a number of trisubstituted pyrimidines useful in photographic material. JP-8,199,163 discloses trisubstituted pyrimidines useful in an organic electroluminescent device. JP-2,300,264 and GB-1,477,349 disclose pyrimidinetriamines for their use in the dye industry.
J. Indian Chem. Soc. (1975), 52(8), 774-775 discloses the synthesis of some bis(arylamino)pyrimidines. J. Heterocycl. Chem. (1973), 10(2), 167-171 discloses the condensation of various aminopyrimidines with picryl halides. J. Org. Chem. (1961), 26, 4433-4440 discloses several triaminopyrimidines as intermediates in the synthesis of triazolo[4,5-d]pyrimidines.
WO 91/18887 discloses diaminopyrimidines as gastric acid secretion inhibitors.
Unexpectedly, it has now been found that the compounds of formula (I) effectively inhibit the replication of the Human Immunodeficiency Virus (HIV) and consequently may be useful for the treatment of individuals infected by HIV.
The present invention concerns the use of the compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
A is CH, CR
4
or N,
n is 0, 1, 2, 3 or 4:
Q is hydrogen or —NR
1
R
2
;
R
1
and R
2
are each independently selected from hydrogen, hydroxy, C
1-12
alkyl, C
1-12
alkyloxy, C
1-12
alkylcarbonyl, C
1-12
alkyloxycarbonyl, aryl, amino, mono- or di(C
1-12
alkyl)amino, mono- or di(C
1-12
alkyl)aminocarbonyl wherein each of the aforementioned C
1-12
alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, carboxyl, C
1-6
alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C
1-6
alkyl)amino, aryl and Het; or
R
1
and R
2
taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C
1-12
alkyl)aminoC
1-4
alkylidene;
R
3
is hydrogen, aryl, C
1-6
alkylcarbonyl, C
1-6
alkyl, C
1-6
alkyloxycarbonyl, C
1-6
alkyl substituted with C
1-6
alkyloxycarbonyl; and
each R
4
independently is hydroxy, halo, C
1-6
alkyl, C
1-6
alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C
1-6
alkyl substituted with cyano or aminocarbonyl;
R
5
is hydrogen or C
1-4
alkyl;
L is C
1-10
alkyl, C
3-10
alkenyl, C
3-10
alkynyl, C
3-7
cycloalkyl, or C
1-10
alkyl substituted with one or two substituents independently selected from C
3-7
cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or where possible five substituents each independently selected from halo, hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, cyano, aminocarbonyl, C
1-6
alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C
1-6
alkylcarbonyl; or
L is —X
1
—R
6
or —X
2
—Alk—R
7
wherein
R
6
and R
7
each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl; and
X
1
and X
2
are each independently —NR
3
—, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)
2
—;
Alk is C
1-4
alkanediyl;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, cyano, nitro and trifluoromethyl;
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, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy;
for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
The present invention also relates to a method of treating warm-blooded animals suffering from HIV (Human Immunodeficiency Virus) infection. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or any subgroup thereof, a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
This invention also concerns compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein L, Q, R
3
, R
4
, R
5
and A are as defined under formula (I), and
R
4′
is halo, C
1-6
alkyl, cyano, aminocarbonyl, nitro, trihalomethyl, trihalomethyloxy, or
C
1-6
alkyl substituted with cyano or aminocarbonyl;
n′ is 0, 1, 2 or 3;
with the proviso that Q and L are other than anilino, 2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino, 3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino, 2-(C
1-6
alkyl)-anilino, 4-(C
1-6
alkyl)-anilino, 3-chloro-anilino, 4-bromo-anilino, 4-nitro-anilino, and 4-chloro-anilino.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C
1-4
alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and the like; C
1-6
alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-4
alkyl as well as the higher homologues thereof containing 5 or 6 carbon atoms such as, for example pentyl or hexyl; C
1-10
alkyl as a group or part of a group group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-6
alkyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl or decyl; C
1-12
alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-10
alkyl as well as the higher homologues thereof containing 11 or 12 carbon atoms such as, for example, undecyl, dodecyl and the like; C
1-4
alkylidene as a group or part of a group defines bivalent straight and branched chained hydrocarbons having from 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C
1-4
alkanediyl as a group or part of a group encompasses those radicals defined under C
1-4
alkylidene as well as other bivalent straight and branched chained hydrocarbons having from 1 to 4 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C
3-7
cycloalkyl as a group or part of a group is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C
3-10
alkenyl as a group or part of a group defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached to the pyrimidine ring is preferably an aliphatic carbon atom; C
3-10
alkynyl as a group or part of a group defines straight and br
Andries Koenraad Jozef Lodewijk Marcel
De Corte Bart
De Jonge Marc Rene
Heeres Jan
Ho Chih Yung
Appollina Mary A.
Janssen Pharmaceutica N.V.
Liu Hong
Shah Mukund J.
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