Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-02-05
2004-08-10
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06774235
ABSTRACT:
The present invention is concerned with trisubstituted 1,3,5-triazine 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.
Substituted 1,3,5-triazines are disclosed in the prior art.
For instance, Zerkowski et al. in Chem. Mater. (1994), 6(8), 1250-1257 discloses 4-[[4-amino-6-[(4-iodophenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile and is used in the study of the crystal structure of H-bonded complexes. U.S. Pat. No. 2,671,810 discloses 4-cyano-anilino substituted 1,3,5-triazines useful as plasticizers, surface-active agents and as parfume ingredients. Brit. 701,789 discloses a process for preparing 4-cyano-anilino substituted 1,3,5-triazines.
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;
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 or trihalomethyloxy;
L is —X—R
5
or —X—Alk—R
6
; wherein
R
5
and R
6
each independently are indanyl, indolyl or phenyl; each of said indanyl, indolyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, hydroxy, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl; and
X is —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, pyridinyl, 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 for 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 a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
A particular embodiment of the present invention relates to compounds of formula
wherein
the variables R
1
, R
2
, R
3
and L are as defined in formula (D; and
A′ is CH or N;
R
4
′ is cyano, aminocarbonyl, nitro or trifluoromethyl;
with the proviso that
when R
4′
is cyano, R
3
is hydrogen, L is —X—R
5
wherein X is NH and R
5
is 4-cyanophenyl or 4-iodophenyl, then NR
1
R
2
is other than NH
2
, NH[CH
2
CH
2
N(C
2
H
5
)
2
], N(C
2
H
5
)
2
, NHCH
3
, NHC
2
H
5
or NH(4-cyano-phenyl);
when R
4′
is trifluoromethyl, R
3
is hydrogen, L is —X—R
5
wherein X is NH and R
5
is 4-trifluoromethylphenyl, then NR
1
R
2
is other than NH
2
or N[(CH
2
)
6
CH
3
]
2
;
when R
4′
is nitro, R
3
is hydrogen or methyl, L is —X—R
5
wherein X is NH or N—CH
3
and R
5
is 4-fluorophenyl, 2,6-dimethylphenyl, 4-methylphenyl or 4-nitrophenyl, then NR
1
R
2
is other than NHaryl, NCH
3
aryl, N(aryl)
2
, NH
2
, NH[CH
2
CH
2
N(C
2
H
5
)
2
], NH[CH
2
CH
2
N(CH
3
)
2
], NH[CH
2
C(═O)OC
2
H
5
], NH[CH
2
C(═O)OH] or N(C
2
H
5
)
2
;
when R
4′
is nitro, R
3
is hydrogen, L is —X—R
5
wherein X is S(O)
2
or S and R
5
is phenyl or 4-chlorophenyl, then R
1
and R
2
are other than aryl or C
1-12
alkyl substituted with one or more carboxyl groups;
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof.
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
1-12
alkyl as a group or part of a 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 geminal 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.
When R
5
is optionally substituted indanyl or indolyl, it is preferably attached to the remainder of the molecule via the fused phenyl ring. For instance, R
5
is suitably 4-, 5-, 6- or 7-indolyl.
As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom.
When any variable (e.g. aryl, R
3
, R
4
etc.) occurs more than one time in any constituent, each definition is independent.
Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms. For instance, R
4
can be attached to any available carbon atom of the phenyl or pyridyl ring.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (F) ar
Daeyaert Frederik Frans Desire
De Corte Bart
De Jonge Marc Rene
Heeres Jan
Ho Chih Yung
Janssen Pharmaceutica N.V.
Shah Mukund J.
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