Quinoxalines, processes for their preparation and their use

Details Quinoxalines, processes for their preparation and their use Quinoxalines, processes for their preparation and their use

1995-04-07

2002-04-09

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S249000, C514S228200, C544S006000, C544S062000, C544S070000, C544S116000, C544S119000, C544S231000, C544S354000

Reexamination Certificate

active

06369057

ABSTRACT:

The present invention relates to quinoxalines, to processes for their preparation, and to their use.
Quinoxalines are a well-known class of compound (O. Hinsberg, J. Liebigs Ann. Chem. 237, 327 (1986)).
Quinoxaline derivatives have been described in the patent literature for use in various applications in medicine.
Austrian Patent 284,848 (19.12.67) mentions 1-N-dialkylaminoalkyl-3,4-dihydroquinoxalin-2(1H)-ones as spasmolytic agents. A series of patent applications by the Japanese company Sumitomo Chem. Co. Ltd. describe 4-N-aroyl-, arylacyl- and arylsulfonyl-3,4-dihydroquinoxalin-2(1H)-ones which have an antiinflammatory action (JA 17,137/69 (11.4.66), JA 17,136/69 (8.4.66), JA 7,008/422 (9.8.66), BE 706,623 (16.11.66)). 3,4-Dihydroquinoxalin-2(1H)-one-3-carboxamides are contained in U.S. Pat. No. 3,654,275 (4.4.72). They, too, have an antiinflammatory action. In U.S. Applications U.S. Pat. Nos. 4,203,987 (21.5.79) and 4,032,639 (22.3.76), pyridinyl-alkyltetrahydropyrazino[1,2-a]quinoxalinone derivatives are described by American Home Prod. Corp. as antihypertensive and antisecretory reagents. A European Patent Application by Pfizer Inc. (EP 266,102 A (30.10.86)) includes 4-N-benzenesulfonyl-3,4-dihydroquinoxalin-2(1H)-one-1-alkylcarboxylic acids as aldose reductase inhibitors. However, an antiviral activity has not been demonstrated to date.
Surprisingly, it has now been found that quinoxalines of the formulae I and Ia
and their tautomeric forms of the formula Ia
and physiologically acceptable salts or prodrugs thereof have an antiviral action, in particular against retroviruses, for example against the human immunodeficiency virus (HIV).
In the compounds of the formula I or Ia according to the invention,
1) n is
zero,
one,
two,
three
or four,
the individual substituents R
1
independently of one another are
fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C
1
-C
8
-alkyl, C
5
-C
8
-cycloalkyl, C
1
-C
6
-alkoxy, (C
1
-C
6
-alkoxy)-(C
1
-C
4
-alkoxy), C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl, C
1
-C
6
-alkylsulfonyl, nitro, amino, azido, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C
1
-C
6
-acyl, C
1
-C
6
-acyloxy, C
1
-C
6
-acylamino, cyano, carbamoyl, carboxyl, (C
1
-C
6
-alkyl)oxycarbonyl, hydroxysulfonyl, sulfamoyl or
a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five radicals R
6
which are independent of one another,
where R
6
can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C
1
-C
6
-alkyl, C
3
-C
8
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl, C
1
-C
6
-alkylsulfonyl, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, (C
1
-C
6
-alkyl)oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl,
R
2
is hydrogen, C
1
-C
6
-alkoxy, hydroxyl, picolyl, cyclopropyl or isopropenyloxycarbonyl and R
5
is
hydrogen, hydroxyl, C
1
-C
6
-alkoxy, aryloxy, C
1
-C
6
-acyloxy, cyano, amino, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, arylamino, C
1
-C
6
-acylamino, C
1
-C
8
-alkyl, optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
C
2
-C
8
-alkenyl,
optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl and carbamoyl;
C
3
-C
8
-allenyl, optionally substituted by fluorine, chlorine or hydroxyl,
C
1
-C
4
-alkoxy, oxo, phenyl;
C
3
-C
8
-alkynyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
C
3
-C
8
-cycloalkyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
C
3
-C
8
-cycloalkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
(C
3
-C
8
-cycloalkyl)-(C
1
-C
4
-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
(C
3
-C
8
-cycloalkenyl)-(C
1
-C
4
-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
C
1
-C
6
-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C
1
-C
6
-acyloxy, benzoyloxy, benzyloxy, phenoxy, C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, di(C
1
-C
6
-alkyl)amino, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;
C
2
-C
8
-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
(C
3
-C
8
-cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
(C
5
-C
8
-cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
(C
3
-C
8
-cycloalkyl)-(C
1
-C
3
-alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
(C
5
-C
6
-cycloalkenyl)-(C
1
-C
3
-alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
1
-C
8
-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylamino, di(C
1
-C
4
-alkyl)amino, C
1
-C
4
-alkylthio;
C
2
-C
8
-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
2
-C
8
-alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
1
-C
6
-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
2
-C
8
-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
1
-C
8
-alkylamino- and di(C
1
-C
8
-alkyl)aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
pyrrolidin-1-yl, morpholino, piperidino-, piperazinyl-, or 4-methylpiperazin-1-ylcarbonyl, in each case optionally substituted by C
1
-C
4
-alkyl, C
2
-C
6
-alkenyl, C
1
-C
4
-acyl, oxo, thioxo, carboxyl, or phenyl;
C
2
-C
8
-alkenylamino- and di(C
1
-C
6
-alkenyl)aminocarbonyl, in each case optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
1
-C
6
-alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxyl, C
1
-C
4
-alkoxy, oxo, phenyl;
C
1
-C
6
-alkenylsulfonyl

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