Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-09-26
2002-04-30
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S206000, C544S211000
Reexamination Certificate
active
06380194
ABSTRACT:
The present invention is concerned with novel compounds of formula (I) having HIV replication inhibiting properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Compounds structurally related to the present novel compounds are disclosed in the prior art. DE-2,121,694, published on Nov. 25, 1971, discloses a number of s-triazines useful as anti-inflammatory, tranquillising, antiviral, antispasmodic, hypo-glycaemic, diuretic, and vasodilating agents, and for modifying adreno-cortico hormone secretion. DE-2,226,474, published on Feb. 22, 1973, discloses diamino- 1,3,5-triazine derivatives with hormone secretion-increasing activity, and anti-inflammatory effect. Substituted triazines having diuretic activity were published in Guioca,
Ann. Pharm. Fr.,
31:283 -292 (1973). A number of 2,4-diamino-triazines were prepared in Kelarev V.I. et al.,
Khim. GeterotsikL. Soedin.,
1392-1397 (1987) and Kelarev V.I. et al.,
Khim. Geterotsikl. Soedin.,
1395-1399 (1992). The preparation of 2-amino-4-benzyl-6-o-toluidino-s-triazine was described in Yuki Y. et al.,
Kobunshi Kagaku,
26: 141-147 (1969). The use of aralkylguanamines, in particular 2-amino-4-anilino-6-benzyl-s-triazine, for the manufacture of resins is disclosed in U.S. Pat. No. 2,817,614, granted Dec. 24, 1957.
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 compounds of formula
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R
1
and R
2
are each independently selected from hydrogen; hydroxy; amino; C
1-6
alkyl; C
1-6
alkyloxy; C
1-6
alkylcarbonyl; C
1-6
alkyloxycarbonyl; Ar
1
; mono- or di(C
1-6
alkyl)amino; mono- or di(C
1-6
alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C
1-6
alkyl substituted with one or two substituents each independently selected from amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC
1-6
alkyloxy, carboxyl, mono- or di(C
1-6
alkyl)amino, C
1-6
alkyloxycarbonyl and thienyl; or
R
1
and R
2
taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C
1-6
alkyl)aminoC
1-4
alkylidene;
R
3
is hydrogen, Ar
1
, C
1-6
alkylcarbonyl, C
1-6
alkyl, C
1-6
alkyloxycarbonyl, C
1-6
alkyl substituted with C
1-6
alkyloxycarbonyl; and
R
4
, R
5
, R
6
, R
7
and R
8
are each independently selected from hydrogen, hydroxy, halo, C
1-6
alkyl, C
1-6
alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy;
L is C
1-10
alkyl; C
3-10
alkenyl; C
3-10
alkynyl; C
3-7
cycloalkyl; or
L is C
1-10
alkyl substituted with one or two substituents independently selected from C
3-7
cycloalkyl; indolyl or indolyl substituted with one, two, three or four substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C
1-6
alkylcarbonyl; 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, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C
1-6
alkylcarbonyl; and,
Ar
1
is phenyl, or phenyl substituted with one, two or three substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, cyano, nitro or trifluoromethyl; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
This invention also concerns novel compounds of formula
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the substituents are as defined under formula (I); with the proviso that compounds (a) to (o) are not included.
Co.
No.
Alk
R
1
/R
2
R
3
R
4
R
5
R
6
R
7
R
8
a
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
H
CH
3
H
H
H
H
b
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
H
H
H
NO
2
H
H
c
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
C
6
H
5
H
H
H
H
H
d
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
H
NO
2
H
CH
3
H
H
e
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
H
H
H
NH
2
H
H
f
4-(2-methylpropyl)phenylmethyl
H/H
H
H
CF
3
H
H
H
g
1-(4-(2-methylpropyl)phenyl)ethyl
H/H
H
H
H
Cl
H
H
h
4-(2-methylpropyl)phenylmethyl
H/H
H
H
H
H
H
H
i
3,4-dimethoxyphenylmethyl
H/H
H
H
H
H
H
H
j
2,3-dimethoxyphenylmethyl
H/H
H
H
H
H
H
H
k
3,4-diethoxyphenylmethyl
H/H
H
H
H
H
H
H
l
2-(3,5-(1,1-dimethylethyl)-4-
H/H
H
H
H
H
H
H
hydroxy-phenyl)ethyl
m
2-(3,5-(1,1-dimethylethyl)-4-
H/H
H
H
t-Bu
OH
t-Bu
H
hydroxy-phenyl)ethyl
n
phenylmethyl
H/H
H
CH
3
H
H
H
H
o
phenylmethyl
H/H
H
H
H
H
H
H
The proviso is intended to exclude compounds (a) to (f) disclosed in DE-2,121,694 and DE-2,226,474; compound (g) disclosed in DE-2,226,474; compounds (h) to (k) disclosed in Guioca,
Ann. Pharm. Fr.,
31:283-292 (1973); compounds (l) disclosed in Kelarev V.I. et al.,
Khim. Geterotsikl. Soedin.,
1392-1397 (1987); compound (m) disclosed in Kelarev V.I. et al.,
Khim. Geterotsikl. Soedin.,
1395-1399 (1992); compound (n) disclosed in Yuki Y. et al.,
Kobunshi Kagaku,
26: 141-147 (1969); and compound (o) disclosed in U.S. Pat. No. 2,817,614.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C
1-2
alkyl includes methyl and ethyl; C
1-3
alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, for example, methyl, ethyl, propyl and the like; C
1-4
alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-3
alkyl as well as the higher homologues thereof containing 4 carbon atoms such as, for example, butyl and the like; C
1-6
alkyl encompasses the straight and branched chained saturated hydro-carbon 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
3-6
alkyl defines straight and branched chained saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as, for example, propyl, butyl, pentyl, hexyl and the like; C
2-6
alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
3-6
alkyl as well as ethyl; C
1-10
alkyl 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
1-4
alkylidene defines bivalent straight and branched chained hydro-carbons having from 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C
3-7
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C
3-10
alkenyl 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 triazine ring is preferably an aliphatic carbon atom; C
3-10
loalkynyl defines straight and branch chained hydrocarbon radicals containing one triple bond and having from 3 to 10 carbon atoms such as, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; C
1-6
alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove
Heeres Jan
Janssen Paul A. J.
Kukla Michael Joseph
Ludovici Donald W.
Moereels Henri E. L.
Appollina Mary A.
Ford John M.
Janssen Pharmaceutica N.V.
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