COMBINATION PREPARATIONS COMPRISING A QUINOXALINE AND A NUCLEOSIDE

PREPARATION D'UNE COMBINAISON RENFERMANT UNE QUINOXALINE ET UN NUCLEOSIDE

English Abstract

Combination preparations comprising a quinoxaline and a
nucleoside

A combination preparation comprising at least one
nucleoside and a compound of the formulae I and/or Ia


(I)

Image




Image
(Ia)

and physiologically acceptable salts thereof,
where the symbols X and n and the substituents R1-R5 have
the meanings mentioned, have an antiviral activity.

Claims

- 108 -
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A combination preparation comprising at least one
nucleoside and at least one compound of the formula
I and/or Ia,



Image
(I)




Image (Ia)


and physiologically acceptable salts and prodrugs
thereof, where, in formulae I and Ia,
n is zero,
one,
two,
three
or four,

the individual substituents R1 independently of one
another are
fluorine, chlorine, bromine, iodine, trifluoro-
methyl, trifluoromethoxy, hydroxyl, C1-C8-alkyl,
C5-C8-cycloalkyl, C1-C6-alkoxy, (C1-C6-alkoxy)-

(C1-C4-alkoxy), C1-C6-alkylthio, C1-C6-alkyl-
sulfinyl, C1-C6-alkylsulfonyl, nitro, amino,
azido, C1-C6-alkylamino, di(C1-C6-alkyl)amino,
piperidino, morpholino, 1-pyrrolidinyl,

- 109 -
4-methylpiperazinyl, thiomorpholino, imidazolyl,
triazolyl, tetrazolyl, C1-C6-acyl, C1-C6-acyloxy,
C1-C6-acylamino, cyano, carbamoyl, carboxyl,
(C1-C6-alkyl)oxycarbonyl, hydroxysulfonyl,
sulfamoyl

or

a phenyl, phenoxy, phenoxycarbonyl, phenylthio,
phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl,
phenylsulfonyloxy, anilinosulfonyl, phenyl-
sulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or
4-pyridyl radical which is substituted by up to
five radicals R6 which are independent of one
another,

where R6 can be

fluorine, chlorine, bromine, iodine, cyano, tri-
fluoromethyl, trifluoromethoxy, nitro, amino,
azido, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy,
C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkyl-
sulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino,
(C1-C6-alkyl)oxycarbonyl, phenyl, phenoxy, 2-, 3-
or 4-pyridyl,

R2 and R5 are identical or different and,
independently of one another, are

hydrogen, hydroxyl, C1-C6-alkoxy, aryloxy,
C1-C6-acyloxy, cyano, amino, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, arylamino, C1-C6-acylamino,
C1-C8-alkyl, optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;

- 110 -

C2-C8-alkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy, benzoyl-
oxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkyl-
thio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo,
thioxo, carboxyl and carbamoyl;

C3-C8-allenyl, optionally substituted by fluorine,
chlorine or hydroxyl,
C1-C4-alkoxy, oxo, phenyl;

C3-C8-alkynyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;

C3-C8-cycloalkyl,
optionally substituted by
fluorine, chlorine, .bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;

C3-C8-cycloalkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;


(C3-C8-cycloalkyl)-(C1-C4-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl,
phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

(C3-C8-cycloalkenyl)-(C1-C4-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;

C1-C6-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano,
amino, mercapto, hydroxyl, C1-C6-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenyl-
sulfonyl, oxo, thioxo, carboxyl or carbamoyl;

C2-C8-alkenylcarbonyl, optionally substituted by
fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

(C3-C8-cycloalkyl)carbonyl,optionallysubstituted
by fluorine, chlorine or hydroxyl, C1-C4-alkoxy,
oxo, phenyl;

(C5-C8-cycloalkenyl)carbonyl, optionally
substituted by fluorine, chlorine or hydroxyl,

- 112 -
C1-C4-alkoxy, oxo, phenyl;
(C3-C8-cycloalkyl)-(C1-C3-alkyl)carbonyl,
optionally substituted by fluorine, chlorine or
hydroxyl, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cycloalkenyl)-(C1-C3-alkyl)carbonyl,
optionally substituted by fluorine, chlorine or
hydroxyl, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkyloxycarbonyl, optionally substituted by
fluorine, chlorine, bromine, hydroxyl, C1-C4-
alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino,
C1-C4-alkylthio;

C2-C8-alkenyloxycarbonyl, optionally substituted
by fluorine, chlorine, hydroxyl, C1-C4-alkoxy,
oxo, phenyl;

C2-C8-alkynyloxycarbonyl, optionally substituted
by fluorine, chlorine, hydroxyl, C1-C4-alkoxy,
oxo, phenyl;

C1-C8-alkylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C2-C8-alkenylthiocarbonyl, optionally substituted
by fluorine, chlorine, hydroxyl, C1-C4-alkoxy,
oxo, phenyl;

C1-C8-alkylamino- and di(C1-C8-alkyl)aminocarbonyl,
in each case optionally substituted by fluorine,
chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl;

pyrrolidin-1-yl, morpholino-, piperidino-,
piperazinyl-, or 4-methylpiperazin-1-ylcarbonyl,
in each case optionally substituted by C1-C4-
alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo,
carboxyl, or phenyl;

- 113 -
C2-C8-alkenylamino- and di(C1-C6-alkenyl)amino-
carbonyl, in each case optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C1-C6-alkylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;
C1-C6-alkenylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

or aryl, arylcarbonyl, aryl(thiocarbonyl), (aryl-
thio)carbonyl, (arylthio)thiocarbonyl, aryloxy-
carbonyl, arylaminocarbonyl, (arylamino)thio-
carbonyl, arylalkylaminocarbonyl, arylsulfonyl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkyl-
carbonyl,arylalkenylcarbonyl,arylalkoxycarbonyl
or aryl(alkylthio)carbonyl, each of which is sub-
stituted by up to 5 radicals R6 which are indepen-
dent of one another, it being possible for the
alkyl radical to contain in each case 1 to
5 carbon atoms, and R6 being as defined above,

or heteroaryl, heteroarylalkyl, heteroaryl-
alkenyl, heteroarylalkylcarbonyl or heteroaryl-
alkenylcarbonyl, heteroaryloxycarbonyl, (hetero-
arylthio)carbonyl, heteroarylaminocarbonyl,
heteroarylalkyloxycarbonyl, heteroaryl-
(alkylthio)carbonyl or heteroarylalkylamino-
carbonyl, each of which is substituted by up to
three radicals R6 which are independent of one
another, it being possible for the alkyl radical
to contain in each case 1 to 3 carbon atoms,

R3 and R4 are identical or different and,
independently of one another, are hydrogen,
C1-C8-alkyl which is optionally substituted by
fluorine, chlorine, hydroxyl, amino, mercapto,

- 114 -
C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy,
C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-
amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-
alkylsulfinyl, carboxyl or carbamoyl;

C2-C8-alkenyl, optionally substituted by fluorine
or chlorine, hydroxyl, amino, mercapto, C1-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-
alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino,
C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkyl-
sulfinyl, carboxyl or carbamoyl;
C3-C8-cycloalkyl, optionally substituted by
fluorine, chlorine, hydroxyl, amino, mercapto,
C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy,
C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-
amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-
alkylsulfinyl, carboxyl or carbamoyl;

C3-C8-cycloalkenyl, optionally substituted by
fluorine or chlorine, hydroxyl, amino, mercapto,
C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy,
C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-
amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-
alkylsulfinyl, carboxyl or carbamoyl;

aryl, arylalkyl, heteroaryl or heteroarylalkyl,
each of which is substituted by up to five
radicals R5 which are independent of one another,
it being possible for the alkyl radical to
contain 1 to 3 carbon atoms in each case, and R5
being as defined above,

R3 and R4 or R3 and R5 can furthermore also be

part of a saturated or unsaturated carbo- or
heterocyclic ring which has 3 to 8 carbon atoms
and which can optionally be substituted by
fluorine, chlorine, hydroxyl, amino, C1-C6-alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-acyloxy,




- 115 -

benzoyloxy, C1-C6-alkoxy, oxo, thioxo, carboxyl,
carbamoyl or phenyl,

X is oxygen, sulfur, selenium or substituted
nitrogen N-R2, it being possible for R2 to have
the abovementioned meanings.

2. A combination preparation as claimed in claim 1,
wherein the nucleoside is selected from the group
consisting of zidovudine, didanosine,
dideoxycytidine, lamivudine, stavudine, BW 935U83
and BW 1592U89.

3. A combination preparation as claimed in claim 1 or
2, which comprises zidovudine and S-4-isopropoxy-
carbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydro-
quinoxaline-2-(1H)-thione.

4. A pharmaceutical which comprises an effective amount
of a combination preparation as claimed in one or
more of claims 1-3, if appropriate in addition to
customary auxiliaries and/or excipients.

5. A combination preparation as claimed in one or more
of claims 1-3 for use as pharmaceutical.

6. A combination preparation as claimed in one or more
of claims 1-3 for the preparation of pharmaceuticals
for treating viral diseases.

7. A process for the preparation of a pharmaceutical,
which comprises bringing a combination preparation
as claimed in one or more of claims 1-3, if
appropriate together with customary auxiliaries
and/or excipients, into a suitable dosage form.

Description

21~76Q5

HOECHST AKTIENGESELLSCHAFT HOE 93/F 401 Dr. WN/wo

Description

Combination preparations comprising a quinoxaline and a
nucleoside

The present invention relates to combination preparations
comprising at least one quinozaline and at least one
nucleoside.
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 l-N-dialkyl-
aminoalkyl-3,4-dihydroquinoxalin-2(lH)-ones as spasmo-
lytic agents. A series of patent applications by the
Japanese company Sumitomo Chem. Co. Ltd. describe
4-N-aroyl-, arylacyl- and arylsulfonyl-3,4-dihydro-
quinoxalin-2(lH)-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(lH)-one-3-carboxamides are
contained in US Patent US 3,654,275 (4.4.72). They, too,
have an antiinflammatory act;on. In US Applications US
4,203,987 (21.5.79) and 4,032,639 (22.3.76), pyridinyl-
alkyltetrahydropyrazino[l,2-a]q~ OXA linone derivatives
are described by American Home Prod. Corp. as antihyper-
tensive 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(lH)-one-l-alkylcarboxylic acids as aldose reductase
inhibitors. However, an antiviral activity has not been
demonstrated to date.
A further document relating to quinoxalines is
EP 0 509 398, to which reference is expressly made at
this point.

-æ- 21 37605
Surprisingly, it has now been found that qllinnY~lines of
the formulae I and Ia
R 2
I




R n ~ ~// (I)

R 4
R S




and their tautomeric forms of the formula Ia


R~ R2
N R 3 (Ia)
R 4
R 5




and physiologically acceptable salts or prodrug~ thereof
in combinaton with at least one nucleoside 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 R1 indepe~P~tly of one
another are
fluorine, chlorine, bromine, iodine, trifluoromethyl,
trifluoromethoxy, hydroxyl, C1-CB-alkyl,
C5-C8-cycloalkyl, C1-C6-alkoxy, (Cl-C6-alkoxy)-(C1-C4-
alkoxy), C1-C6-alkylthio, C1-C6-alkylsulfinyl,
C1-C6-alkylsulfonyl, nitro, amino, azido, C1-C6-alkyl-

2137605
- 3 -
amino, di(C1-C6-alkyl)amino, piperidino, morpholino,
1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino,
imidazolyl, triazolyl, tetrazolyl, C1-C6-acyl,
C1-C6-acyloxy, C1-C6-acylamino, cyano, carbamoyl,
carboxyl, (C1-C6-alkyl)oxycarbonyl, hydroxysulfonyl,
sulfamoyl

or

a phenyl, phenoxy, phenoxycarbonyl, phenylthio,
phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl,
phenylsulfonyloxy, anilinosulfonyl, phenylsulfonyl-
amino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl
radical which is substituted by up to five radicals
R6 which are independent of one another,

where R6 can be

fluorine, chlorine, bromine, iodine, cyano, tri-
fluoromethyl, trifluoromethoxy, nitro, amino, azido,
Cl-C6-alkyl, C3-C8-cycloalkyl, Cl-C6-alkoxy,
Cl-C6-alkylthio, Cl-C6-alkylsulfinyl, Cl-C6-alkyl-
sulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino,
(C1-C6-alkyl)oxycarbonyl, phenyl, phenoxy, 2-, 3- or
4-pyridyl,

R2 and Rs are identical or different and, independently of
one another, are

hydrogen, hydroxyl, C1-C6-alkoxy, aryloxy,
C1-C6-acyloxy, cyano, amino, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, arylamino, C1-C6-acylamino,
C1-C8-alkyl, optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

21~7605
-- 4 --

C2-C8-alkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, Cl-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl and
carbamoyl;

C3-C8-allenyl, optionally substituted by fluorine,
chlorine or hydroxyl,
C1-C4-alkoxy, oxo, phenyl;
C3-C8-alkynyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

C3-C8-cycloalkyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-CB-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

C3-C8-cycloalkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

~137605
-- 5 --

(C3-C8-cycloalkyl)-(Cl-C4-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, Cl-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

(C3-C8-cycloalkenyl)-(Cl-C4-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

Cl-C6-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, C1-C6-alkyl-
sulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or
carbamoyl;

C2-C8-alkenylcarbonyl, optionally substituted by
fluorine, chlorine or hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

(C3-C8-cycloalkyl)carbonyl, optionally substituted by
fluorine, chlorine or hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

(C5-C8-cycloalkenyl)carbonyl, optionally substituted
by fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo,
phenyl;
(C3-C8-cycloalkyl)-(C1-C3-alkyl)carbonyl, optionally

2~7605

substituted by fluorine, chlorine or hydroxyl, C1-C4-
alkoxy, oxo, phenyl;

(C5-C6-cycloalkenyl)-(C1-C3-alkyl)carbonyl, optionally
substituted by fluorine, chlorine or hydroxyl, Cl-C4-
alkoxy, oxo, phenyl;

C1-C8-alkyloxycarbonyl, optionally substituted by
fluorine, chlorine, bromine, hydroxyl, C1-C4-alkox-~,
C1-C4-alkylamino, di(C1-C4-alkyl)amino,C1-C4-alkylthio;

C2-C8-alkenyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C2-C8-alkynyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C1-C8-alkylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C2-C8-alkenylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C1-C8-alkylamino- and di(C1-C8-alkyl)aminocarbonyl, in
each case optionally substituted by fluorine,
chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl;

pyrrolidin-l-yl, morpholino-, piperidino-, pipera-
zinyl-, or 4-methylpiperazin-1-ylcarbonyl, in each
case optionally substituted by C1-C4-alkyl,
C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo, carboxyl, or
phenyl;

C2-C8-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl,
in each case optionally substituted by fluorine,

2l3~6es

chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C1-C6-alkenylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

or aryl, arylcarbonyl, aryl(thiocarbonyl), (aryl-
thio)carbonyl, (arylthio)thiocarbonyl, aryloxy-
carbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl,
arylalkylaminocarbonyl, arylsulfonyl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkylcarbonyl,
arylalkenylcarbonyl, arylalkoxycarbonyl or
aryl(alkylthio)carbonyl, each of which is substituted
by up to five rA~;c~ls R6 which are independent of one
another, it being possible for the alkyl radical to
contain in each case 1 to 5 carbon atoms, and R6 being
as defined above,

or heteroaryl, heteroarylalkyl, heteroarylalkenyl,
heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl,
heteroaryloxycarbonyl, (heteroarylthio)carbonyl,
heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl,
h e t e r o a r y 1 ( a 1 k y 1 t h i o ) c a r b o n y 1 o r
heteroarylalkylaminocarbonyl, each of which is
substituted by up to three radicals R6 which are
independent of one another, it being possible for the
alkyl radical to contain in each case 1 to 3 carbon
atoms,

R3 and R4 are identical or different and, independently of
one another, are hydrogen, Cl-C8-alkyl which is
optionally substituted by fluorine, chlorine,
hydroxyl, amino, mercapto, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, Cl-C4-alkoxy, Cl-C4-alkylamino,
di(Cl-C4-alkyl)amino, Cl-C4-alkylthio, Cl-C4-alkyl-

- 8 _ 21376~
æulfonyl, C1-C4-alkylsulfinyl, carboxyl or carbamoyl;

C2-C8-alkenyl, optionally substituted by fluorine or
chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio,
C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;

C3-C8-cycloalkyl, optionally substituted by fluorine,
chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio,
C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;

C3-C8-cycloalkenyl, optionally substituted by fluorine
or chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino,di(Cl-C4-alkyl)amino,C1-C4-alkylthio,C1-C4-
alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;

aryl, arylalkyl, heteroaryl or heteroarylalkyl, each
of which is æubætituted by up to five rA~;c~ls R6 which
are independent of one another, it being poæsible for
the alkyl radical to contain 1 to 3 carbon atoms in
each case, and R6 being as defined above,

R3 and R4 or R3 and Rs can furthermore also be

part of a saturated or unæaturated carbo- or hetero-
cyclic ring which haæ 3 to 8 carbon atomæ and which
can optionally be æubætituted by fluorine, chlorine,
hydroxyl, amino, C1-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C1-C6-acyloxy, benzoyloxy, C1-C6-alkoxy,
oxo, thioxo, carboxyl, carbamoyl or phenyl,

X iæ oxygen, æulfur, æelenium or æubætituted nitrogen

2137~05
g

N-R2, it being possible for R2 to have the above-
mentioned meanings.

In a preferred group of componn~s of the formula I or Ia,

2) n is zero,
one,
two
or three,

the individual substituents R1 indepe~e~tly of one
another are

fluorine, chlorine, bromine, trifluoromethyl, tri-
fluoromethoxy, hydroxyl, Cl-C4-alkyl, C5-C6-cycloalkyl,
Cl-C4-alkoxy, ( Cl-C4-alkoxy ) - ( Cl-C4-alkoxy ), Cl-C4-
alkylthio, Cl-C4-alkylsulfinyl, C1-C4-alkylsulfonyl,
nitro, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino,
piperidino, morpholino, 1-pyrrolidinyl,
4-methylpiperazinyl, thiomorpholino, imidazolyl,
C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano,
carbamoyl, carboxyl, (C1-C4-alkyl)oxycarbonyl,
hydroxysulfonyl or sulfamoyl

or

a phenyl, phenoxy, phenoxycarbonyl, phenylthio,
phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl,
phenylsulfonyloxy, anilinosulfonyl, phenylsulfonyl-
amino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl
radical which is substituted by up to two radicals R6
which are independent of one another,

where R6 can be

fluorine, chlorine, bromine, cyano, trifluoromethyl,
nitro, amino, C1-C4-alkyl, C3-C7-cycloalkyl, C1-C4-
alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfinyl, C1-C4-
alkylsulfonyl, Cl-C4-alkylamino, di(Cl-C4-alkyl)amino,

2~376Q~
-- 10 --
(C1-C4-alkyl)oxycarbonyl, phenyl or phenoxy,

R2 is hydrogen and R5 is

hydrogen, hydroxyl, cyano, amino,
Cl-C6-alkyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C2-C8-alkenyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;
C3-C8-allenyl,

C3-C8-alkynyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C3-C8-cyc loalkyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, ~;no,
mercapto, hydroxyl, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C3-C8-cycloalkenyl,

-11- 2~37~5
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, Cl-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, Cl-C4-alkyle~ino,
di(Cl-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

(C3-C8-cycloalkyl)-(Cl-C2-alkyl)
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, ~ino~
mercapto, hydroxyl, Cl-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, Cl-C4-alkoxy, Cl-C4-alkylamino,
di(Cl-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

(C3-C8-cycloalkenyl)-(Cl-C2-alkyl),
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, Cl-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, Cl-C4-alkoxy, Cl-C4-alkylamino,
di(Cl-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

Cl-C6-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, Cl-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, Cl-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C2-C6-alkenylcarbonyl, optionally substituted by
fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

(C3-C6-cycloalkyl)carbonyl, optionally substituted by
fluorine, chlorine or hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

- 12 - 213~5
(C5-C6-cycloalkenyl)carbonyl, optionally ~ubstituted
by fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

(C3-C6-cycloalkyl)-(Cl-C2-alkyl)carbonyl, optionally
subætituted by fluorine, chlorine or hydroxyl, C1-C4-
alkoxy, oxo, phenyl;

(C5-C6-cycloalkenyl)-(Cl-C2-alkyl)carbonyl, optionally
substituted by fluorine, chlorine or hydroxyl, Cl-C4-
alkoxy, oxo, phenyl;

Cl-C6-alkyloxycarbonyl, optionally substituted by
fluorine, chlorine, bromine, hydroxyl, Cl-C4-alkoxy,
Cl-C4-alkylamino, di(Cl-C4-alkyl)amino, Cl-C4-alkylthio;

C2-C6-alkenyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

C2-C6-alkynyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

Cl-C6-alkylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

C2-C6-alkenylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy, oxo,
phenyl;

Cl-C6-alkylamino- and di(Cl-C6-alkyl)aminocarbonyl, in
each case optionally substituted by fluorine,
chlorine, hydroxyl, Cl-C4-alkoxy, oxo, phenyl;

pyrrolidin-l-yl, morpholino-, piperidino-, pipera-
zinyl-, or 4-methylpiperazin-1-ylcarbonyl;

- 13 - ~1'376~

C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl,
in each case optionally substituted by fluorine,
chlorine, hydroxyl, C1-C4-alkoxy, oxo, phenyl;

C1-C4-alkylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

C1-C4-alkenylsulfonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo,
phenyl;

or aryl, arylcarbonyl, aryl(thiocarbonyl), (aryl-
thio)carbonyl, (arylthio)thiocarbonyl, aryloxy-
carbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl,
arylalkylaminocarbonyl, arylsulfonyl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkylcarbonyl,
arylalkenylcarbonyl, aryl(alkylthio)carbonyl or
arylalkoxycarbonyl, each of which i8 substituted by up
to three radicals R6 which are independent of one
another, it being possible for the alkyl rA~;c~l to
contain in each case 1 to 5 carbon atoms and R6 being
as defined above,

or 1- or 2-naphthylmethyl,.2-, 3- or 4-picolyl, 2- or
3-furylmethyl, 2- or 3-thienylmethyl, 2- or
3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or
3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or
3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2-
or 3-furylmethyloxycarbonyl, 2- or 3-thienylmethyl-
oxycarbonyl, each of which is substituted by up to two
radicals R6 which are independent of one another,
and

R3 and R4 are identical or different and independently of
one another are

hydrogen,
Cl-C6-alkyl,

~13~605
- 14 -
optionally substituted by fluorine, chlorine,
hydroxyl, amino, mercapto, C1-C4-acyloxy, benzoyloxy,
benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, C1-C4-alkylthio, C1-C4-alkyl-
sulfonyl, C1-C4-alkylsulfinyl, carboxyl or carbamoyl;

C2-C~-alkenyl, optionally substituted by fluorine or
chlorine, hydroxyl, amino, mercapto, Cl-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio,
C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;
C3-C~-cycloalkyl, optionally substituted by fluorine,
chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino, di(C1-C4-alkyl)amino, Cl-C4-alkylthio,
Cl-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;

C3-C~-cycloalkenyl, optionally substituted by fluorine
or chlorine, hydroxyl, amino, mercapto, C1-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-
alkylamino,di(C1-C4-alkyl)amino,C1-C4-alkylthio,C1-C4-
alkylsulfonyl, C1-C4-alkylsulfinyl, carboxyl or
carbamoyl;
aryl, arylalkyl, heteroaryl or heteroarylalkyl, each
of which is substituted by up to three radicals R6
which are independent of one another, it being
possible for the alkyl rA~;~Al to contain in each case
1 to 3 carbon atoms and R6 being as defined above,

R3 and R4 can furthermore also be

part of a saturated or unsaturated carbo- or hetero-
cyclic ring which has 3 to 7 carbon atoms and which
can optionally be substituted by fluorine, chlorine,
hydroxyl, amino, C1-C4-alkyl, C2-C4-alkenyl,
C2-C4-alkynyl, C1-C4-acyloxy, benzoyloxy, C1-C4-alkoxy,
oxo, thioxo, caxboxyl, carbamoyl or phenyl, and

21~6Q5
- 15 -

X is oxygen, sulfur or selenium.

In a yet more preferred qroup of compounds of the formula
I or Ia,

3) n is zero,
one
or two,

the individual substituents Rl independently of one
another are

fluorine, chlorine, bromine, trifluoromethyl,
hydroxyl, C1-C4-alkyl, Cl-C4-alkoxy, (C1-C4-alkoxy)-
(Cl-C4-alkoxy), Cl-C4-alkylthio, nitro, amino, Cl-C4-
alkylamino, di(Cl-C4-alkyl)amino, piperidino, morpho-
lino, 1-pyrrolidinyl, 4-methylpiperazinyl, Cl-C4-acyl,
Cl-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl,
carboxyl, (C1-C4-alkyl)oxycarbonyl, hydroxysulfonyl or
sulfamoyl,

or

a phenyl, phenoxy, phenylthio, phenylsulfonyl,
phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or
4-pyridyl radical which is substituted by up to two
radicals R6 which are independent of one another,

where R6 can be
fluorine, chlorine, bromine, cyano, trifluoromethyl,
nitro, amino, C1-C4-alkyl, Cl-C4-alkoxy, (Cl-C4-
alkyl)oxycarbonyl, phenyl or phenoxy,

R2 is hydrogen and R5 is

Cl-C6-alkyl,
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-acyloxy, benzoyl-


21~7605
- 16 -
oxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C2-C6-alkenyl,
optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-acyloxy, benzoyl-
oxy, benzyloxy, phenoxy, Cl-C4-alkoxy, C1-C4-alkylamino,
di(C1-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C3-C8-allenyl,

C3-C8-alkynyl,
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-acyloxy, benzoyl-
oxy, benzyloxy, phenoxy, Cl-C4-alkoxy, Cl-C4-alkylamino,
di(Cl-C4-alkyl)amino, Cl-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

C3-C8-cycloalkyl,
optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkyl, Cl-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, Cl-C4-alkoxy,
Cl-C4-alkylamino, di(Cl-C4-alkyl)amino, Cl-C4-alkylthio,
oxo, thioxo, carboxyl or carbamoyl;

C3-C8-cycloalkenyl,
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkyl, C1-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, Cl-C4-alkoxy,
Cl-C4-alkylamino, di(Cl-C4-alkyl)amino, Cl-C4-alkylthio,
oxo, thioxo, carboxyl or carbamoyl;

(C3-C6-cycloalkyl)-(Cl-C2-alkyl),
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkyl, C1-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy,
Cl-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio,

21376Q~

oxo, thioxo, carboxyl or carbamoyl;

(C3-C6-cycloalkenyl)-(Cl-C2-alkyl),
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkyl, Cl-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy,
C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio,
oxo, thioxo, carboxyl or carbamoyl;

Cl-C6-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkyl, C1-C4-
acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy,
C1-C4-alkylamino, C1-C4-alkenylamino, di(C1-C4-
alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino,
4-methylpiperazin-1-yl, C1-C4-alkylthio, oxo, thioxo,
carboxyl or carbamoyl;

Cz-C6-alkenylcarbonyl, optionally substituted by
fluorine, chlorine or hydroxyl;

(C3-C6-cycloalkyl)carbonyl,

(C5-C6-cycloalkenyl)carbonyl,

(C3-C6-cycloalkyl)-(C1-C2-alkyl)carbonyl,

(C5-C6-cycloalkenyl)-(C1-C2-alkyl)carbonyl,
C1-C6-alkyloxycarbonyl, optionally substituted by
fluorine, chlorine, bromine, hydroxyl, C1-C4-alkoxy,
C1-C4-alkylamino, di(C1-C4-alkyl)amino or C1-C4-alkyl-
thio;

C2-C6-alkenyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy;

C2-C6-alkynyloxycarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, C1-C4-alkoxy;

21'~376~5
- 18 -
Cl-C6-alkylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy;

C2-C6-alkenylthiocarbonyl, optionally substituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy;

Cl-C6-alkylamino- and di(C1-C6-alkyl)aminocarbonyl, in
each case optionally substituted by fluorine,
chlorine, hydroxyl, Cl-C4-alkoxy;

pyrrolidin-l-yl, morpholino-, piperidino-, pipera-
zinyl-, or 4-methylpiperazin-1-ylcarbonyl;

C2-C6-alkenylamino- and di(Cl-C6-alkenyl)aminocarbonyl,
in each case optionally substituted by fluorine,
chlorine, hydroxyl, Cl-C4-alkoxy;

Cl-C4-alkylsulfonyl, optionally ~ubstituted by
fluorine, chlorine, hydroxyl, Cl-C4-alkoxy;

Cl-C4-alkenylsulfonyl;

or aryl, arylcarbonyl, (arylthio)carbonyl, aryloxy-
carbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl,
arylsulfonyl, arylalkylaminocarbonyl, arylalkyl,
arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or
aryl(alkylthio)carbonyl, each of which is substituted
by up to two radicals R6 which are independent of one
another, it being possible for the alkyl radical to
contain in each case 1 to 3 carbon atoms, and R6 being
as defined above,

or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or
3-furylmethyl, 2- or 3-thienylmethyl, 2- or
3-pyrrolylmethyl,

2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl,
2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-,
3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxy-

2137605
-- 19 --
carbonyl or 2- or 3-thienylmethyloxycarbonyl, each of
which is substituted by up to two radicals R6 which are
independent of one another,

and
R3 and R4 are identical or different and indepç~ently of
one another are hydrogen, C1-C4-alkyl, optionally
substituted by fluorine, chlorine, hydroxyl, amino,
mercapto, C1-C4-acyloxy, benzoyloxy, phenoxy, C1-C4-
alkoxy, Cl-C4-alkylamino, di(Cl-C4-alkyl)amino, C1-C4-
alkylthio, Cl-C4-alkylsulfonyl, Cl-C4-alkylsulfinyl,
carboxyl or carbamoyl;

C2-C6-alkenyl, optionally substituted by fluorine or
chlorine;

C3-C6-cycloalkyl, optionally substituted by fluorine,
chlorine, hydroxyl, amino, mercapto, Cl-C4-acyloxy,
benzoyloxy, benzyloxy, phenoxy, Cl-C4-alkoxy, Cl-C4-
alkylamino, di(Cl-C4-alkyl)amino, Cl-C4-alkylthio,
Cl-C4-alkylsulfonyl, Cl-C4-alkylsulfinyl, carboxyl or
carbamoyl;

C3-C8-cycloalkenyl, optionally substituted by fluorine
or chlorine;

aryl, benzyl, heteroaryl or heteroarylmethyl, each of
which is substituted by up to two radicals R6 which are
independent of one another,

R3 and R4 can furthermore also be

part of a saturated or unsaturated carbo- or hetero-
cyclic ring which has 3 to 6 carbon atoms and which
can optionally be substituted by fluorine, chlorine,
hydroxyl, amino, Cl-C4-acyloxy, benzoyloxy, Cl-C4-
alkoxy, oxo, thioxo, carboxyl or carbamoyl, and

X is oxygen or sulfur.

20 ~ 76Q5

In a yet again preferred group of compounds of the
formula I or Ia,

4) n is zero,
one
or two,

the individual substituents R1 indepe~e~tly of one
another are

fluorine, chlorine, bromine, trifluoromethyl,
hydroxyl, Cl-C4-alkyl, C1-C4-alkoxy, (C1-C4-alkoxy)-
(C1-C2-alkoxy), C1-C4-alkylthio, nitro, amino, C1-C4-
alkylamino, di(C1-C4-alkyl)amino, piperidino, morpho-
lino, 1-pyrrolidinyl, 4-methylpiperazinyl, C1-C4-acyl,
C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl,
carboxyl, (C1-C4-alkyl)oxycarbonyl, hydroxysulfonyl or
sulfamoyl

or

a phenyl, phenoxy, phenylthio, phenylsulfonyl,
phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or
4-pyridyl radical, each of which is substituted by up
to two radicals R6 which are independent of one
another,

where R6 can be

fluorine, chlorine, bromine, cyano, trifluoromethyl,
nitro, amino, C1-C4-alkyl, C1-C4-alkoxy, (C1-C4-
alkyl)oxycarbonyl, phenyl or phenoxy,

R2 is hydrogen and R5 i8

Cl-C6-alkyl,
optionally substituted by C1-C4-alkoxy or C1-C4-
alkylthio;

- 21 - 2137 6Q5

C2-C6-alkenyl,
optionally substituted by oxo;

C3-C6-allenyl;

C3-C8-alkynyl, in particular 2-butynyl;

C3-C6-cycloalkyl;

Cs-C6-cycloalkenyl;

(C3-C6-cycloalkyl)-(Cl-C2-alkyl), in particular
cyclopropylmethyl, optionally substituted by Cl-C4-
alkyl;

(C3-C6-cycloalkenyl)-~Cl-C2-alkyl), in particular
cyclohexenylmethyl;

Cl-C6-alkylcarbonyl,
optionally substituted by
fluorine, chlorine, hydroxyl, benzyloxy, phç~oxy,
Cl-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkenylamino,
di(C1-C4-alkyl)amino, l-pyrrolidinyl, piperidino,
morpholino, 4-methylpiperazin-1-yl or C1-C4-alkylthio;

C2-C6-alkenylcarbonyl;

C1-C6-alkyloxycarbonyl, optionally substituted by
fluorine, chlorine, bromine, hydroxyl, C1-C4-alkoxy,
C1-C4-alkylamino, di(C1-C4-alkyl)amino or Cl-C4-alkyl-
thio;

C2-C6-alkenyloxycarbonyl, in particular vinyloxy-
carbonyl, allyloxycarbonyl, isopropenyloxycarbonyl,
butenyloxycarbonyl or pentenyloxycarbonyl;

C2-C6-alkynyloxycarbonyl, in particular propynyloxy-
carbonyl or butynyloxycarbonyl;

- 22 - ~137 605

Cl-C6-alkylthiocarbonyl;

C2-C6-alkenylthiocarbonyl, in particular allylthio-
carbonyl;

Cl-C6-alkylamino- and di(C1-C6-alkyl)aminocarbonyl;

pyrrolidin-1-yl, morpholino-, piperidino-, pipera-
zinyl-, or 4-methylpiperazin-1-ylcarbonyl;

C2-C6-alkenylamino- and di(Cl-C6-alkenyl)aminocarbonyl;

Cl-C4-alkylsulfonyl;

Cl-C4-alkenylsulfonyl;

or aryl which is substituted by up to two radicals R6
which are independent of one another, in particular
phenyl, arylcarbonyl, in particular benzoyl,
(arylthio)carbonyl, aryloxycarbonyl, arylamino-
carbonyl, (arylamino)thiocarbonyl, arylalkylamino-
carbonyl, arylsulfonyl, arylalkyl, in particular
benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl,
arylalkoxycarbonyl or aryl(alkylthio)carbonyl, it
being possible for the alkyl radical to contain in
each case 1 to 3 carbon atoms and R6 being as defined
above,
or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or
3-furylmethyl, 2- or 3-thienylmethyl, 2- or
3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or
3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or
3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2-
or 3-furylmethyloxycarbonyl, or 2- or 3-thienyl-
methyloxycarbonyl, each of which is substituted by up
to two radicals R6 which are independent of one
another,

and

2137~05
- 23 -

R3 and R4 are identical or different and independently of
one another are

hydrogen,
Cl-C4-alkyl,
optionally substituted by hydroxyl, mercapto, Cl-C4-
alkoxy, C1-C4-alkylthio, Cl-C4-alkylsulfonyl, C1-C4-
alkylsulfinyl, carboxyl or carbamoyl;

C2-C6-alkenyl,

aryl, benzyl, thienyl or thienylmethyl, each of which
is substituted by up to two radicals R6 which are
independent of one another, R6 being as defined above,

R3 and R4 can also be

part of a saturated or unsaturated carbo- or hetero-
cyclic ring which has 3 to 6 carbon atoms and can
optionally be substituted by oxo or thioxo, and

X is oxygen or sulfur.

Compounds of the formula I or Ia as defined above wherein
the substituents mentioned have the following meanings
are very particularly important:
n is zero or
one,

the individual substituents Rl independently of one
another are

fluorine, chlorine, bromine, Cl-C2-alkyl, Cl-C2-alkoxy,
C2-C4-acyl or cyano,

R2 is hydrogen and R5 is

C2-C6-alkenyl,

- - 24 - 2137~0~

C3-C8-alkynyl, in particular 2-butynyl;

(C3-C6-cycloalkyl)-(C1-C2-alkyl), in particular
cyclopropylmethyl, optionally substituted by Cl-C4-
alkyl;

(C3-C6-cycloalkenyl)-(C1-C2-alkyl), in particular
cyclohexenylmethyl;

C2-C6-alkylcarbonyl,

C2-C6-alkenylcarbonyl;

C1-C6-alkyloxycarbonyl;

C2-C6-alkenyloxycarbonyl, in particular vinyloxy-
carbonyl, allyloxycarbonyl, isopropenyloxycarbonyl,
butenyloxycarbonyl or pentenyloxycarbonyl;

C2-C6-alkynyloxycarbonyl, in particular propynyloxy-
carbonyl or butynyloxycarbonyl;

C2-C6-alkenylthiocarbonyl, in particular allylthio-
carbonyl;

C1-C4-alkylsulfonyl;
C1-C4-alkenylsulfonyl;

or arylalkyl, in particular benzyl or arylalkenyl,
which is substituted by up to two rA~;cAls R6 which
are independent of one another, it being possible for
the alkyl radical to contain in each case 1 to 3
carbon atoms and for the alkenyl radical to contain
2-3 carbon atoms,

or 1-naphthylmethyl, 2- or 3-picolyl, 2-furylmethyl
or 2- or 3-thienylmethyl, each of which is substituted
by up to two rA~; rA 1 s R6 which are independent of one

- 25 - 2137605
another,

where R6 is

fluorine, chlorine, bromine, cyano, C1-C2-alkyl or
Cl-C2-alkoxy,

and

R3 and R4 are identical or different and indepe~ently of
one another are

hydrogen,
Cl-C4-alkyl,
optionally substituted by hydroxyl, mercapto, C~-C4-
alkoxy, C1-C2-alkylthio, and

X is oxygen or sulfur.

The alkyl groups in the above definitions can be
straight-chain or branched. Unless otherwise defined,
they preferably contain 1-8, particularly preferably 1-6,
in particular 1-4, carbon atoms. Examples are the methyl,
ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,
2-methylpropyl and 1,1-dimethylethyl group, and similar
groups.

The alkenyl groups mentioned in the above definitions can
be straight-chain or branched and contain 1 to 3 double
bonds. Unless otherwise defined, these groups preferably
contain 2-8, in particular 2-6, carbon atoms. Examples
are the 2-propenyl, 1-methylethenyl, 2-butenyl,
3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl,
2,3-dimethyl-2-butenyl, 3,3-dichloro-2-propenyl and
pentadienyl groups and similar groups.

The alkynyl groups mentioned in the above definitions can
be straight-chain or branched and contain 1 to 3 triple
bonds. Unless otherwise defined, they contain preferably

21'37~Q5
- 26 -
2-8, particularly preferably 3-6, carbon atoms. Examples
are the 2-propynyl and 3-butynyl group and similar
groups.

Unless otherwise defined, the cycloalkyl and cycloalkenyl
groups mentioned in the above definitions contain pre-
ferably 3-8, particularly preferably 4-6, carbon atoms.
Examples are the cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl or cyclohexenyl group.

The acyl groups mentioned in the above definitions can be
aliphatic, cycloaliphatic or aromatic. Unless otherwise
defined, they preferably contain 1-8, particularly
preferably 2-7, carbon atoms. Examples of acyl groups are
the formyl, acetyl, chloroacetyl, trifluoroacetyl,
hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl,
cyclohexanoyl or benzoyl group.

The aryl groups mentioned in the above definitions are
preferably aromatic groups having 6-14 carbon atoms, in
particular 6-10 carbon atoms, for example phenyl or
naphthyl.

Suitable hetero atoms in the abovementioned heterocyclic
rings or heteroaryl groups are, in particular, oxygen,
sulfur and nitrogen, where, in the case of a nitrogen-
contA; n ing ring which is saturated in this position, a
structure N-Z is present in which Z is H or R5 with the
individual above-described definitions.

Unless otherwise defined, the heterocyclic rings pre-
ferably have 1-13 carbon atoms and 1-6 hetero atoms, in
particular 3-9 carbon atoms and 1-4 hetero atoms.

Suitable radicals for the heteroaryl groups mentioned in
the above definitions are, for example, heteroaromatic
radicals such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-
or 4-pyridyl, pyrimidyl, indolyl, quinolyl or iso-
quinolyl.

- 27 - 21 37605

Examples of the aralkyl groups mentioned in the above
definitions are benzyl, phenylethyl, naphthylmethyl or
styryl.

The abovementioned substituents Rl to R5 are preferably
trisubstituted, particularly preferably disubstituted, in
particular monosubstituted, by the particular substi-
tuents mentioned.

In the case of the particular definitions of composite
substituents (such as, for example, arylalkoxycarbonyl),
the ranges which have been described above as being
preferred for the individual substituents are also
preferred.

Depending on the various substituents, compounds of the
formulae I and Ia can have several asymmetric carbon
atoms. The invention therefore relates both to the pure
stereoisomers and to mixtures thereof such as, for
example, the corresponding racemate.
The pure stereoisomers of the compounds of the formulae
I and Ia can be prepared directly by known methods or
analogously to known methods, or they can be resolved
later.

A variety of nucleosides can be employed according to the
invention, with zidovudine (AZT), ~ nosine (DDI),
dideoxycytidine (DDC) and lamivudine (3-TC0), stavudine
(D4T), BW 935U83 and BW 159U89 being particularly
important, especially zidovudine. The nucleosides
mentioned can be prepared by generally known processes
(cf. Merck Index, 11th Edition Rahway, N.J. 1989, Drugs
45 (4), 488 et seq., 45 (5), 637 et seq., 1993, Gruds 44
(4), 656 et seq., 1992, Clin. Pharmacol. Ther. 55, No. 2,
198, 1994, Antiviral-Chem. Chemother, 2, No. 3, 125-32,
1991, Antiviral-Rest. 23, Suppl. 1, 67, 1994, Abstracts
of the 34th JCAAC, Orlando 4.-7. 10.94).

- 28 - 2~ 3 160~
The compounds of the formulae I and Ia can be prepared by
known methods or modifications thereof (see, for example,
Rodd's Chemistry of Carbon Compounds, S. Coffey, M. F.
Ansell (Editor); Elsevier, Amsterdam, 1989; Vol. IV Part
IJ, p. 301-311. Heterocyclic Compounds. R. C. Elderfield
(Editor); Wiley, New York, 1957; Vol. 6, p. 491-495).
The preparation of compounds of the formulae I and Ia as
explained in 1) - 4) above is effected, for example,
A) for preparing compounds of the formula I where X is
oxygen and the radicals Rl, R2, R3, R4 and R5 are as
defined under 1) - 4), by reacting a compound of the
formula II
H
I




R 1 ~ ~ (II)

R 4
H




with the definitions mentioned under 1) - 4) applying to
Rl, R3 and R4, with a compound of the formula III

R-Z (III)

where R has the meanings for R5 and R2 which have been
mentioned above under 1) - 4) with the exception of
hydrogen, hydroxyl, Cl-C6-alkoxy, aryloxy, Cl-C6-acyloxy,
amino, Cl-C6-alkylamino, di(Cl-C6-alkyl)amino, arylamino
and Cl-C6-acylamino, and Z i8 a leaving group,
or by
B) preparing compounds of the formula I where X is sulfur
and R1, RZ, R3, R4 and R5 are as defined under 1) - 4) by
reacting a compound of the formula I where X is oxygen
and the definitions mentioned under 1) - 4) apply to R1,
RZ, R3, R4 and R5, with a sulfurizing reagent,
or by
C) preparing compounds of the formula Ia where X and the
radicals R1 to R5 are as defined under 1) - 4), by
reacting a compound of the formula IV

- 29 - 2 1'37 ~0~
H
I




N ~ (IV)
I R4
RS




or


~R 3 (IVa)
R 4
R S




where the definitions mentioned under 1) - 4) apply to
R1, R3, R4 and R5, with a compound of the formula III

R2_Z (III)

where the definitions described under 1) - 4) for formula
I and Ia apply to R2, with the exception of hydrogen,
hydroxyl, C1-C6-alkoxy, aryloxy, C1-C6-acyloxy, amino,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, arylamino or
C1-C6-acylamino, and Z iæ a leaving group,
or by
D) preparing compounds of the formula I where X is oxygen
and the radicals R1 to R5 are as defined under 1) - 4) by
cyclizing a compound of the formula V
R 2




~ NH
R n~ ~/ C O - Y V

~\N/
R 4
R S




where R1 to R5 are as defined under 1) - 4) and Y iæ
hydroxyl, C1-C4-alkoxy, optionally halogenated
C1-C4-acyloxy, chlorine, bromine or iodine,

~ 30 - 2 137 6 ~5
or by
E) preparing compounds of the formula I where X is
oxygen, R4 and R5 are hydrogen and the definitions men-
tioned under 1) - 4) apply to R1 to R3, from the quinoxa-
linones of the formula XI
R2
I




R n ~ N ~ X XI

~" ~ R3

where R1 to R3 are as defined under 1) - 4), by addition
of hydrogen on the C=N bond,
or by
F) preparing compounds of the formula I where X is oxygen
and R1 to R5 are as defined under 1) - 4), from compounds
of the formula VI


~N H
R n ~ VI
N H
R 5




where R1, RZ and R5 are as defined under 1) - 4), by
reacting them with chloroform or bromoform and a carbonyl
compound of the formula XIII

R3-Co-R4 (XIII)

where R3 and R4 are as defined under 1) - 4), or with
~-(trihalomethyl)alkanols of the formula XIV

Hal3C-C(OH)-R3R4 (XIV)

where Hal is Cl, Br or I,

- 31 ~ 2~3~605

in which R3 and R4 are as defined under 1) - 4),
or by
G) preparing compounds of the formula I where X i8 oxygen
and R1, R2, R3, R4 and R5 are as defined under 1) - 4), by
reacting a compound of the formula I where X is oxygen
and the definitions mentioned under 1) - 4) apply to R1,
R2, R5 and to R3 and R4, with the exception that at least
one of the radicals R3 or R4 is hydrogen, with an alkylat-
ing reagent of the formula XV

R'-Z (XV)

where R' has the meanings mentioned above for R3 and R4
with the exception of hydrogen and Z is a leaving group,
or by
H) preparing compounds of the formula I where X i8
oxygen, R1, R2, R3 and R4 are as defined under 1) - 4) and
R5 is C1-C8-alkyl, optionally substituted by fluorine,
chlorine, bromine, iodine, hydroxyl, C1-C6-acyloxy,
benzoyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
di(C1-C6-alkyl)amino, C1-C6-alkylthio, cyano, carboxyl,
carbamoyl, C3-C8-alkenyl, optionally substituted by
fluorine, chlorine, bromine, iodine, hydroxyl,
C1-C6-acyloxy, benzoyloxy, phenoxy, Cl-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkylthio,
cyano, carboxyl or carbamoyl, C3-C8-alkynyl, optionally
substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkylthio,
cyano, carboxyl or carbamoyl, C4-C8-cycloalkyl, optionally
substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy,
C1-C6-alkoxy, C1-C6-alk~lamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, cyano, carboxyl or carbamoyl, C5_CB_CYC10-
alkenyl, optionally substituted by fluorine, chlorine,
bromine, iodine, hydroxyl, C1-C6-acyloxy, benzoyloxy,
phenoxy, C1-C6-alkoxy, C1-C6-alkylamino,
C1-C6-dialkylamino, C1-C6-alkylthio, cyano, carboxyl or

- 21'37~
- 32 -
carbamoyl, (Cl-C6-alkoxy)-(Cl-C6-alkyl),
di(Cl-C6-alkylamino)-(Cl-C6-alkyl) or (C3-C6-cycloalkyl)-
alkyl, (C6-C8-cycloalkenyl)alkyl, or arylalkyl, naphthyl-
alkyl or heteroarylalkyl, each of which i8 substituted by
up to five r~ic~l 8 R6 which are indep~n~e~t of one
another, it being possible for the alkyl radical to
contain in each case 1 to 3 carbon atoms,
by reductive alkylation of a compound of the formula I
where R5 is hydrogen and X is oxygen and the definitions
mentioned under 1) - 4) apply to Rl, R2, R3 and R4, with a
carbonyl compound of the formula XVI,

R"-C(=O)-R"' (XVI)

where R" and R"' are identical or different and indepen-
dently of one another are hydrogen, Cl-C7-alkyl, optional-
ly substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy, Cl-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkylthio,
cyano, carboxyl or carbamoyl, C3-C7-alkenyl, optionally
substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, Cl-C6-alkylthio,
cyano, carboxyl or carbamoyl, C3-C7-alkynyl, optionally
substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy, C1-C6-alkoxy,
C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkylthio,
cyano, carboxyl or carbamoyl, C4-C8-cycloalkyl, optionally
substituted by fluorine, chlorine, bromine, iodine,
hydroxyl, C1-C6-acyloxy, benzoyloxy, phenoxy,
C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)amino,
C1-C6-alkylthio, cyano, carboxyl or carbamoyl,
C6-cycloalkenyl, optionally substituted by fluorine,
chlorine, bromine, iodine, hydroxyl, Cl-C6-acyloxy,
benzoyloxy, phenoxy, Cl-C6-alkoxy, Cl-C6-alkylamino,
di(Cl-C6-alkyl)amino, Cl-C6-alkylthio, cyano, carboxyl or
carbamoyl, (cl-c6-alkoxy)-(cl-c5-alkyl)~
[di(C1-C6-alkyl)amino]-(Cl-C5-alkyl) or (C4-C6-cycloalkyl)-
alkyl, (C6-cycloAlke~yl)alkyl, orarylalkyl, naphthylalkyl

33 ~137~
.
or heteroarylalkyl, each of which is substituted by up to
five radicals R6 which are independent of one another, it
being possible for the alkyl radical to contain in each
case O to 2 carbon atoms,
and where R" and R"' can be linked to each other to form
a 4- to 8-membered ring,
or
I) preparing compounds of the formula I where X is oxygen
and Rl, RZ, R3 and R4 are as defined under 1) - 4) and R5
is Cl-C8-alkyloxycarbonyl, Cl-C8-alkylthiocarbonyl,
C2-C8-alkenyloxycarbonyl, C2-C8-alkenylthiocarbonyl,
C2-C8-alkynyloxycarbonyl, Cl-C6-alkylaminocarbonyl,
C3-C6-alkenylaminocarbonyl, di(Cl-C6-alkyl)aminocarbonyl,
pyrrolidin-l-yl, morpholino-, piperidino-, piperazinyl-,
4-methylpiperazin-1-ylcarbonyl, optionally substituted by
fluorine, chlorine, bromine, iodine, cyano, amino,
mercapto, hydroxyl, C1-C6-acyloxy, benzoyloxy, benzyloxy,
phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-
amino, Cl-C6-alkylthio, Cl-C6-alkylsulfonyl, phenylsul-
fonyl, oxo, thioxo, carboxyl or carbamoyl;or aryloxycarbonyl, arylthio(carbonyl), arylaminocar-
bonyl, heteroaryloxycarbonyl, heteroarylthiocarbonyl,
heteroarylaminocarbonyl, arylalkyloxycarbonyl, (aryl-
alkylthio)carbonyl, arylalkylaminocarbonyl, heteroalkyl-
oxycarbonyl, (heteroalkylthio)carbonyl or heteroalkyl-
aminocarbonyl, each of which is substituted by up to five
radicals R6 which are independent of one another, it being
possible for the alkyl radical to contain in each case
1 to 3 carbon atoms, by reacting a compound of the
formula XVII

~ 34 ~ 21'3~ 605




R n~ ~ R3 XVII


( CH2 ) n


where the definitions mentioned under 1) - 4) apply to
R1, R2, R3 and R4, n is 0, 1, 2 or 3, X is oxygen and U is
a leaving group, with a compound of the formula XVIII

Nu-H (X~nl)

where Nu is C1-CB-alkoxy, C2-C8-alkenyloxy, C2-C8-alkynyl-
oxy, Cl-C8-alkylthio, C2-C8-alkenylthio, C~-C8-alkylamino-
and di(C1-C8-alkyl)amino, C2-C8-alkenylamino- and
di(C1-C6-alkyl)amino, optionally substituted by fluorine,
chlorine, bromine, hydroxyl, C1-C4-alkoxy, C1-C4-alkyl-
amino, di(C1-C4-alkyl)amino, C~-C4-alkylthio,
pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-
or 4-methylpiperazin-1-ylcarbonyl, optionally substituted
by Cl-C4-alkyl, C2-C6-alkenyl, Cl-C4-acyl, oxo, thioxo,
carboxyl or phenyl, or aryloxy, arylthio, arylamino,
arylalkyloxy, arylalkylthio, arylalkylamino, heteroaryl-
oxy, heteroarylthio, heteroarylamino, heteroarylalkyloxy,
heteroarylalkylthio or heteroarylalkylamino, each of
which is substituted by up to five radicals R6 (R6 is as
defined at the outset) which are independent of one
another, it being possible for the alkyl r~icAl to
contain in each case 1 to 3 carbon atoms.

The abovementioned method A preferably proceeds under the
following conditionæ:

The substituent Z in formula III is a suitable leaving

~ - - 35 ~ 7 6 QS

group such as, for example, chlorine, bromine or iodine,
a suitable radical of sulfuric acid, an aliphatic or
aromatic sulfonate, or optionally halogenated acyloxy.

The reaction is expediently carried out in an inert
solvent. Suitable solvents are, for example, aromatic
hydrocarbons such as toluene or xylene, lower alcohols
such as methanol, ethanol or 1-butanol, ethers such as
tetrahydrofuran or glycol dimethyl ether, dipolar aprotic
solvents such as N,N-dimethylformamide, N-methyl-2-~ylLo
lidone, acetonitrile, nitrobenzene, dimethyl sulfoxide,
or mixtures of theRe solvents. Two-phase systems with
aqueous solutions of bases in the presence of a phase
transfer catalyst ~uch as, for example, benzyltriethylam-
monium chloride, are also possible.

The presence of a suitable base, for example of an alkali
metal carbonate, alkali metal hydrogen carbonate,
alkaline earth metal carbonate or alkaline earth metal
hydrogen carbonate such as sodium carbonate, calcium
carbonate or sodium bicarbonate, of an alkali metal
hydroxide or alkaline earth metal hydroxide such as
potassium hydroxide or barium hydroxide, an alcoholate
such as sodium ethanolate or potassium tert.-butylate, an
organolithium compound such as butyllithium or lithium-
diisopropylamine, an alkali metal hydride or alkaline
earth metal hydride such as sodium hydride or calcium
hydride, an alkali metal fluoride such as potassium
fluoride, or an organic base such as triethylamine or
pyridine for scavenging the acid which i8 liberated
during the reaction, may be expedient.

In some cases, the addition of an iodide, for example
potassium iodide, is expedient. The reaction is generally
carried out at temperatures between -10 and 160C,
preferably at room temperature.

To carry out this reaction, any nucleophilic substituents
such as, for example, hydroxyl, mercapto or amino groups,

- 36 - ~1~7~Q~
with the exception of the 1- and/or 4-position in com-
pounds of the formula II or III, must, before the
reaction is carried out, be derivatized in a suitable
manner or provided with conventional protective groups
such as, for example, acetyl or benzyl, which can then be
eliminated.

The sulfurizing reagent which i8 preferably used for the
reaction as described above under B) is
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane
2,4-disulfide (Lawesson's reagent), bis(tricyclohexyltin)
sulfide, bis(tri-n-butyltin) sulfide, bis(triphenyltin)
sulfide, bis(trimethylsilyl) sulfide or phosphorus
pentasulfide.
The reaction is carried out expediently in an organic
solvent or in a solvent mixture, at room temperature or
above, preferably at the boiling point of the reaction
mixture, and, if possible, under anhydrous conditions.
Suitable substances are, for example, carbon disulfide,
toluene, xylene, pyridine and 1,2-dichloroethane. If the
tin sulfides or silyl sulfides which have been mentioned
are used, it is advisable to carry out the sulfurization
reaction in the presence of a Lewis acid, such as boron
trichloride.

In the presence of other carbonyl groups in a compound of
the formula I, for example in a compound where X is
oxygen and one or more radicals Rl to R6 are acyl, the
carbonyl is to be protected by known methods prior to the
sulfurization reaction by a suitable protective group,
for example by acetalization; subsequent elimination of
the protective groups results in the desired compound.

For the reaction described above under C, the substituent
Z i8 a suitable leaving group, preferably chlorine,
bromine or iodine, a suitable radical of sulfuric acid,
an aliphatic or aromatic sulfonate, or optionally halo-
genated acyloxy.
The reaction conditions for this reaction correspond to

~t'37~Q~
- - 37 -
those of method A.

The cyclization described under D) is effected in a
suitable solvent such as methanol, ethanol, N,N-dimethyl-
formamide or N-methylpyrrolidone, in the presence of a
base; suitable bases are A 1 kA 1 i metal carbonates, A 1 kA 1;
metal hydrogen carbonates, alkaline earth metal car-
bonates or alkaline earth metal hydrogen carbonates such
as sodium carbonate, calcium carbonate or sodium bicar-
bonate, alkali metal hydroxides or alkaline earth metal
hydroxides such as potassium hydroxide or barium
hydroxide, alcoholates such as sodium ethanolate or
potassium tert.-butylate, organolithium compounds such as
butyllithium or lithium diisopropylamine, Al kAl; metal
hydrides or alkaline earth metal hydrides such as sodium
hydride or calcium hydride, or an organic base such as
triethylamine or pyridine - the latter substances can
also be used as solvents, or organic or mineral acids
such as glacial acetic acid, trifluoroacetic acid,
hydrochloric acid or phosphoric acid. The reaction is
preferably carried out at temperatures between 20 and
120C, particularly preferably at room temperature.

The compounds of the formula V, where R1 to R5 and Y are
as defined under 1) - 5), can be obtained from compounds
of the formula VI



~N H
Rln I VI
~/\N H
R 5




where R1, R2 and R5 are as defined under 1) - 4), by
alkylation with a compound of the formula VII

21'~7~Q5
- - 38 -

co-r
~ R3 VII
R4




where R3, R4 and Y are as defined under 1) - 5) and Z is
as defined under A). The reaction conditions for this
alkylation correspond to those given in method A.
Simultaneous cyclization to give the dihydroquinoxaline
of the formula I takes place under suitable conditions.

Compounds of the formula V in which Rl, R3 to R5 and Y are
as defined under 1) - 5) and R2 is hydrogen can also be
prepared from compoundæ of the formula VIII


Rl ~ N ~ (VIII)
I R4
R5




where Rl, R3 to R5 and Y are as defined under 1) - 5) by
reducing the nitro group by known processes to the amino
group.
Simultaneous cyclization to give the dihydroquinoxaline
of the formula I takes place under suitable conditions,
for example by carrying out the reduction in the presence
of an acid.
The reduction is carried out by stAn~rd methods (see,
for example, Methoden der Organischen Chemie tMethods in
Organic Chemistry] (Houben-Weyl), E. Muller (Editor);
G. Thieme Verlag, Stuttgart, 1957; Vol. XI/1,
p. 360-490), for example using tin(II) chloride in
glacial acetic acid, TiCl3 in hydrochloric acid, or by
catalytic hydrogenation, the choice of reagent being
determined by the chemical stability of the various
substituents Rl and R3 to R5; if, for example, one of the
radicals is alkenyl, the first method will be selected to
obtain the double bond.

~ 39 ~ 21'37&Q5

The phenylenediamines of the formula VI which are re-
quired as starting materials for the synthe6es described
are known from the literature or commercially available
or can be synthesized by methods known from the litera-
ture.

N-ortho-nitrophenylamino acid derivatives of the formula
VIII, where R1n and R3 to R5 are as defined under 1) - 4)
and Y is oR7, where R7 is hydrogen, Cl-C6-alkyl, optionally
in each case for example halogen-substituted phenyl,
benzyl or 9-fluorenylmethyl, can be obtained for example
by amination of ortho-halonitro aromatic substances of
the formula IX
~ N02
R 1 nt-- l l IX
~\w

where R1 is as defined under 1) - 4) and W is fluorine,
chlorine, bromine or iodine, with amino acids or their
esters of the formula X
C O O R 7
~R 3
HN R4 X
R 5




where R3, R4, R5 and R7 are as defined under 1) - 5). The
reaction can be carried out in the presence of an
inorganic or organic auxiliary base such as, for example,
sodium carbonate, potassium carbonate, sodium hydroxide
or triethylamine. It is advantageous to use an inert
solvent at temperatures between 0 and 150C, preferably
at reflux temperature. Suitable solvents are open-chain
or cyclic ethers, for example tetrahydrofuran or glycol
dimethyl ether, aromatic hydrocarbons, for example
toluene or chlorobenzene, alcohols, for example ethanol,
isopropanol or glycol monomethyl ether, dipolar aprotic
solvents, for example N,N-dimethylformamide,
N-methyl-2-pyrrolidone or 1,3-dimethyl-tetrahydro-


- 40 - 213~60~
2(lH)-pyrimidinone.

The N-ortho-nitrophenylamino acids of the formula VIII
where Y is hydroxyl can, if desired or necessary, be
converted by well-known stAn~Ard methods into the acid
derivatives of the formula VIII where Y is hydroxyl,
C1-C4-alkoxy, optionally halogenated Cl-C4-acyloxy,
chlorine, bromine or iodine.

Ortho-halonitroaromatic compounds of the formula IX and
amino acids of the formula X are known from the litera-
ture and commercially available or can be prepared bymethods known from the literature.

The reaction described above under E) is preferably
effected by means of catalytic hydrogenation (using
hydrogen) or hydrosilylation (using alkylsilanes, for
example diphenylsilane) in the presence of a hydrogena-
tion catalyst, for example Raney nickel or palladium-on-
charcoal, at a hydrogen pressure of 1 to 5 bar, or by
means of a reducing agent from the class of the complex
metal hydrides such aæ sodium borohydride or sodium
cyanoborohydride, or using metals, or metal salts, and
acid such as, for example, zinc/glacial acetic acid or
SnCl2/HCl. It is advantageous to carry out the reaction
in an inert solvent such as lower alcohols, for example
methanol or isopropanol, ethers such as tetrahydrofuran
or glycol dimethyl ether, dipolar aprotic solvents such
as N,N-dimethylformamide, aromatic hydrocarbons such as
toluene or xylene, or mixtures of these solvents, at
temperatures between -20 and 100C, preferably at room
temperature.

If a chiral hydrogenation catalyst, for example
di-~-chloro-bis[(cycloocta-lc,5c-diene)-rhodium(I)]/(+)
or (-)-4,5-bis-(diphenylphosphinomethyl)-2,2-dimethyl-
1,3-dioxolane, or a chiral complex metal hydride, for
examplesodiumtris-(N-benzyloxycarbonyl-L-prolinoyloxy)-
borohydride, are used in the above-described reaction,

~1'37605
- 41 -
the individual enantiomers can be prepared selectively.

If, in compounds of the formula XI, substituents are
present which can be hydrogenated or reduced under the
above-described conditions, for example oxo, it is neces-
sary to use an intermediate of the formula XI withsubstituents which are not attacked, but which can be
derivatized to give the group required, for example
hydroxyl. The substituents can also be provided with a
customary protective group, for example an acetal protec-
tive group, which can then be removed after the above-
described reaction.

Quinoxalinones of the formula XI where Rl to R3 are as
defined under 1) - 4) can be obtained by known processes
by condensing a phenylenediamine of the formula VI, where
Rl and R2 are as defined under 1) - 4) and R5 is hydrogen,
with an alpha-ketocarboxylic acid of the formula XII

R3-Co-CooH (XII)

where R3 is as defined under 1) - 4).
The reaction is expediently carried out in an inert
solvent in a temperature range of between 0 and 150C;
examples of suitable solvents are alcohols, for example
ethanol or isopropanol, open-chain or cyclic ethers, for
example glycol dimethyl ether or tetrahydrofuran, or
dipolar aprotic solvents, for example N,N-dimethyl-
formamide or acetonitrile.

The reaction described above under F) is expeA; entlycarried out in a two-phase system composed of an organic
solvent or solvent mixture which is not miscible with
water, composed of, for example, halogenated hydrocar-
bons, for example dichloromethane or 1,2-dichloroethane,
or aromatic hydrocarbons, for example toluene or xylene,
and a concentrated aqueous solution of an alkali metal
hydroxide or alkaline earth metal hydroxide, for example
sodium hydroxide or barium hydroxide. The presence of a

~ - 42 - 21^~7~05
phase transfer catalyst such as, for example, benzyl-
triethylammonium chloride or tetrabutylammonium bromide,
is advantageous.
The reaction is usually carried out at temperatures
between 0 and 50C, preferably at room temperature.

Substituents in compounds of the formulae VI and XIII, or
XIV, which are not stable under the reaction conditions
must be replaced by those which can be derivatized to the
required group. The substituents can also be provided
with a customary protective group which can then be
removed after the above-described reaction.

In the reaction described above under G), Z in formula XV
is a suitable leaving group such as, for example,
chlorine, bromine or iodine, a suitable sulfuric acid
radical, an aliphatic or aromatic sulfonate, or option-
ally halogenated acyloxy.

The reaction conditions for this reaction correspond to
those in method A.

The reaction described under H) is preferably effected by
catalytic hydrogenation (using hydrogen) in the presence
of a hydrogenation catalyst, for example palladium-on-
charcoal, at a hydrogen pressure of 1 to 5 bar, or by
means of a reducing agent from the class of the complex
metal hydrides, such as sodium borohydride, sodium
triacetoxyborohydride or sodium cyanoborohydride.

The reaction is expediently carried out in an inert
solvent, such as lower alcohols, for example methanol or
isopropanol, ethers, for example tetrahydrofuran or
glycol dimethyl ether, halogenated hydrocarbons, for
example dichloromethane or dichloroethane, at tempera-
tures between -20 and 100C, preferably at room tempera-
ture. The presence of an acid such as, for example,
acetic acid or trifluoroacetic acid, or of a Lewis acid
such as, for example, titanium tetrachloride, is

2137605
- 43 -
advantageous. If, in compounds of the formulae I and XVI,
subætituents are present which can be hydrogenated or
reduced under the above-described conditions, for example
oxo, the use of an intermediate of the formulae I and XVI
with substituents which are not attacked but which can be
derivatized to the required group, for example hydroxyl,
is necessary. Acid-labile groups such as, for example,
acetals, or groups which react under the reaction condi-
tions, such as, for example, primary amines, are also to
be avoided or to be provided with a customary protective
group.

The reaction described under I) is expD~;ently carried
out in an inert solvent. Examples of suitable solvents
are aromatic hydrocarbons such as toluene or xylene,
lower alcohols such as methanol, ethanol or 1-butanol,
ethers such as tetrahydrofuran or glycol dimethyl ether,
dipolar aprotic solvents such as N,N-dimethylformamide,
N-methyl-2-pyrrolidone, acetonitrile, nitrobenzene,
dimethyl sulfoxide, or mixtures of these solvents. Two-
phase systems with aqueous solutions of bases in thepresence of a phase transfer catalyst such as, for
example, benzyltriethylammonium chloride, are also
possible.
The presence of a suitable base, for example an Al kAl;
metal hydroxide or alkaline earth metal hydroxide such as
potassium hydroxide or barium hydroxide, of an alcoholate
such as sodium ethanolate or potassium tert.-butylate, an
organolithium compound such as butyllithium or lithium
diisopropylamide, an alkali metal hydride or AlkAl;~e
earth metal hydride such as sodium hydride or calcium
hydride, an alkali metal fluoride such as potassium
fluoride, or an organic base such as triethylamine or
pyridine, may be useful. The reaction is usually carried
out at temperatures between -10 and 160C, preferably at
room temperature.

To carry out this reaction, any nucleophilic substituents
in compounds XVII and XVIII which do not participate in

2l~76es
- 44 -
the reaction, such as, for example, hydroxyl, mercapto or
amino groups, are to be derivatized in a suitable manner
or to be provided with customary protective groups such
as, for example, acetyl or benzyl, which can then be
S eliminated.

The compounds XVII which are required for the abovemen-
tioned reaction and in which the definitions described
under 1) - 4) apply to Rl, R2, R3 and R4, n is 0, 1, 2 or
3, X is oxygen and U i8 a suitable leaving group, halogen
such as, for example, chlorine, bromine, iodine, a
halogenated aliphatic or aromatic alcoholate such as, for
example, 2,2,2-trichloroethoxy, chlorophenoxy, or a
heterocycle which is linked via nitrogen such as, for
example, imidazolyl, triazolyl or benzotriazolyl, are
prepared by reacting a compound of the formula I where R5
is hydrogen and X is oxygen, and the definitions des-
cribed under 1) - 4) apply to Rl, R2, R3 and R4, with a
suitable carbonic acid derivative, for example phosgene,
diphosgene, triphosgene, trichloroethyl chloroformate or
carbonyldiimidazole, or with a suitable halo carbonyl
halide, for example bromoacetyl chloride.

The reaction is expediently carried out in an inert
solvent. Examples of suitable solvents are aromatic
hydrocarbons such as toluene or xylene, ethers such as
tetrahydrofuran or glycol dimethyl ether, or halogenated
hydrocarbons such as dichloromethane or dichloroethane.

The presence of a suitable base, for example of an alkali
metal hydroxide or alkaline earth metal hydroxide, such
as potassium hydroxide or barium hydroxide, or an organic
base such as triethylamine or pyridine, may be useful.

The reaction is usually carried out at temperatures
between -30 and 160C, preferably at room temperature.

The present invention furthermore relates to the com-
pounds as described under 1) to 4) in combination with a

21376~5
- 45 -
nucleoside as pharmaceuticals, preferably for treating
viral diseases.

Examples of fields of indication in human medicine which
may be mentioned are:
1) The treatment and prophylaxis of human retroviral
infections
2) For the treatment or the prophylaxis of diseases
(AIDS) caused by HIV I (human immunodeficiency virus;
previously termed HTLV III/LAV) and HIV II, and the
stages associated therewith, such as ARC (AIDS-related
complex) and LAS (lymph adenopathy syndrome), as well
as the immunodeficiency and encephalopathy caused by
this virus.
3) For the treatment or the prophylaxis of an infection
with HTLV-I or HTLV-II
4) For the treatment or the prophylaxis of the AIDS
carrier condition.

Examples of indications in veterinary medicine which may
be mentioned are:
infections with
a) maedivisna (in sheep and goat~)
b) progressive pneumonia virus (PPV) (in sheep and goats)
c) caprine arthritis encephalitis virus (in sheep and
goats)
d) zwoegerziekte virus (in ~heep)
e) (equine) infectious anemia virus
f) infections caused by feline leukemia virus
g) infections caused by feline immunodeficiency virus.

The combinations according to the invention are particu-
larly important for controlling HIV and disease cau~ed byHIV.

The invention furthermore relates to pharmaceuticals
comprising at least one combination of compounds accord-
ing to the invention, and to the use of the above-
mentioned compounds for the preparation of

21 '3760~
- 46 -

phArr-ceuticals, preferably for the treatment of viral
diseases, in particular for the treatment of diseases
caused by HIV.

The present invention furthermore relates to the use of
combinations of the abovementioned compounds for the
preparation of pharmaceuticals for the treatment of viral
diseases.

The pharmaceuticals according to the invention can be
administered enterally (orally), parenterally (intra-
venously), rectally, subcutaneously, intramuscularly or
locally (topically).

They can be administered in the form of solutions,
powders, (tablets, capsules including microcapsules),
ointments (creams or gels) or suppo6itories. Suitable
adjuvants for such formulations are the liquid or solid
fillers and extenders, solvents, emulsifiers, glidants,
flavorings, colorings and/or buffer substances which are
customary in pharmacology.

0.1 - 10, preferably 0.2 - 8 mg/kg of body weight are
administered once or several times daily as an expedient
dosage. The dosage units used depend expediently on the
specific phArr~cokinetics of the substance used, or on
the pharmaceutical formulation used.

For example, the dosage unit of the compounds according
to the invention is 1 - 1500 mg, preferably 50 - 500 mg.

The composition of the combination preparations according
to the invention can vary within wide limits and be
optimized by means of methods of the prior art. A
suitable ratio in the compositon is, for example, between
1:1000 and 1000:1, preferably between 1:100 and 100:1.
Experimental set-up

HIV infection in cell culture

- _ 47 _ 2 137 6 0 5

The HIV test was carried out by the modified method of
Pauwels et al. (cf. Journal of Virological Methods 20
(1988), 309-321). Normal human blood lymphocytes (PBLs)
were enriched using Ficoll-Hypaque and stimulated in RPMI
1640, 20% fetal calf serum using phythemagglutinin
(90 ~g/ml) and interleukin-2 (40 U/ml). For the infection
with the infectious HIV, PBLs were pelleted, and the cell
pellet was subsequently suspended in 1 ml of HIV solution
for the purpose of adsorption and incubated for 1 hour at
37C.
The virus adsorption solution was centrifuged, and the
infected cell pellet was taken up in growth medium in
such a way that 1 x 105 cells were present per ml. The
cells which had been infected in this manner were
pipetted into the wells of 96-microtiter plates at a
density of 1 x 104 cells/well.
As an alternative, H9 cells were employed for the anti-
viral tests in place of the PBLs.
The activity of the test compounds in combination was
tested by means of chequerboard titration.
The first vertical row of the microtiter plate contained
only growth medium and cells which had not been infected
but were otherwise treated exactly as described above
(cell control). The second vertical row of the microtiter
plate contained only HIV-infected cells (virus control)
in growth medium. The remaining wells contained the
compounds according to the invention - alone or in
suitable combinations - in a range of concentrations
starting from the wells of the 3rd vertical row of the
microtiter plate, from which the test substances were
diluted further in steps of 2 (volume per well: 100 ~1).
For the combination, dilutions of substance 2 were
prepared in a separate 96-microtiter plate and subse-
quently pipetted onto the prepared first plate. 100 ~1
aliquots of the prepared HIV-infected cells (see above)
were added to this. This gave test concentrations in a
range of approximately 10-50 times above and below the
IC-50 concentration.

- 48 - 2 1~7 60~
The batches were incubated at 37C until the formation of
syncytia on the host cell, which i8 typical for HIV, was
detected under the microscope in the untreated virus
control (between day 3 and day 6 post-infection). In the
untreated virus control, approximately 20-50 syncytia
were found under these test conditions, while no syncytia
were found in the untreated cell control.
The supernatants of the 96-plate were then harvested and
examined for HIV-specific antigen using an HIV-specific
ELISA test (Vironostika HIV Antigen, Organon Tekni k~ ) .
On the basis of the cut-off values of suitable cell or
virus controls or internal test controls, the inhibitory
values were converted into percent (%) inhibitory values,
and the IC-50 values were determined as the concentration
of the treated and infected cells at which 50% of the
virus-specific antigen wa~ suppressed by the treatment
with the compounds. To analyze the synergistic activity
of the compounds, the differential values were determined
of calculated and measured inhibitory values of each
combination (Prichard, M.N. et al., Antimicrob. Agents
Chemoth. (1993), 37, 540-545).
Differential values > zero mean that a synergistic
activity can be described. For example, the compound of
the formula A gave the following results:
(Table la and Table lb)
Formula A

,~, N~S

H 3 C~oJ~N ~ `C H 3
0~0
,,
H3C CH3

Chemical name:

S-4-Isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-

~ 49 ~ ? 137~Q5
3,4-dihydroquinoxaline-2(lH)-thione, melting point 101C.

Table la Tabulated difference between the calculated and
the expected activity of AZT using formula (A)
as an example

Compound of the 50 25 12 6 3
formula (A) nM

AZT nM
0 0 0 0 0 0
0 0 0 0 -17 -4
12 0 0 4 18 23 23
6 0 0 7 29 23 -17
3 0 0 10 33 10 -13
1.5 0 0 -2 40 17 3
0.7 -17 -20 -5 7 17 3
5 Table lb Tabulated differences between the calculated
and experimentally determined inhibitory values
of 3'-TC and the exemplary compound of the
formula (A)

Compound of the 50 25 12 6 3 1.5
formula (A) nM
3TC nM
0 0 0 2 -7 -60
0 0 0 40 70 30
12 0 0 0 47 60 20
6 0 0 0 30 40 22
3 0 0 0 34 17 0

A synergistic activity of the combinations can be found
in the concentration range 0.7-12 nM AZT together with
1-6 nM of the quinoxaline. Equally synergistically active

213760~
- 50 -
are the quinoxaline and 3TC in the concentration range of
1.5-6 nM and 3-2S nM, respectively. To measure a
synergistic toxicity of the compounds, substance
concentrations were tested around the Tox-50 value of the
individual compounds and evaluated in the same manner.
None of the tested combinations showed synergistic
toxicity.

The examples which follow and the content of the patent
claims illustrate the present invention in greater
detail.

Example I
(3S)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(lH)-one

A) (S)-N-(3-Chloro-6-nitrophenyl)alanine

2,4-Dichloronitrobenzene (21.0 g, 0.109 mol) and 23.0 g
(0.258 mol) of L-alanine were refluxed for 48 hours in
400 ml of 2-methoxyethanol with an addition of 120 ml of
2N sodium hydroxide solution. The mixture was
subsequently concentrated in vacuo, and the residue was
taken up in aqueous sodium hydrogen carbonate solution.
the mixture was extracted three times using ethyl
acetate, the extract was then acidified with 6N
hydrochloric acid, and the yellow product was extracted
using ethyl acetate. The organic phase was washed once
with saturated aqueous sodium chloride solution and dried
(magnesium sulfate), and the solvent was removed under
reduced pressure. 14.7 g (55%) of a yellow solid of
melting point 167-169C remained (after crystallization
from ethyl acetate).
1H NMR (270 MHz, d6-DMS0): ~ = 1.47 (d, J = 7 Hz, 3 H),
4.57 (quintet, J = 7 Hz, 1 H), 6.77 (dd, J = 9, 2 Hz,
1 H), 7.11 (d, J = 2 Hz, 1 H), 8.12 (d, J = 9 Hz, 2 H),
8.41 (br. d, J = 7 Hz, 1 H), 13.2 ppm (br., 1 H).
MS: (M + H)t = 245

213760$
- 51 -
B) (3S)-6-Chloro-3-methyl-3,4-dihydroqn;nnxAl;n-2(1H)-one

The product of Example IA (14.0 g, 0.057 mol) was dis-
solved in 400 ml of methanol and hydrogenated with Raney
nickel catalysis at room temperature, using 1 atm hydro-
gen. After the calculated amount of hydrogen had beentaken up, the catalyst was removed by filtration with
6uction, and the reaction solution was concentrated in
vacuo. The residue was purified by silica gel
chromatography using ethyl acetate/heptane = 1:2 and 1:1
as the eluent. The yield was 6.0 g (53%) of a brownish
solid of melting point 122-123C (after recrystallization
from isopropanol/heptane).
1H NMR (60 MHz, d6-DMSO): ~ = 1.23 (d, J = 11 Hz, 3 H),
3.81 (dq, J = 11, 4 Hz, 1 H), 6.27 (br., 1 H), 6.3 - 6.9
(m, 3 H), 10.3 ppm (br., 1 H).
MS: (M + H)+ = 197
[~]D23 = +77.3 (c = 1, MeOH)

C) (3R)-6-Chloro-3-methyl-3,4-dihydroq~l;noYAl;n-2(1H)-one

The compound was prepared from D-alanine by the methods
described under Example IA and IB. Melting point
123-124C (after recrystallization from isopropanol/hep-
tane)
The NMR data agree with those of the compound described
in Example IB.
t~]D23 = -81.0 (c = 1, MeOH)

D) (3RS)-6-Chloro-3-methyl-3,4-dihydroquinoxalin-
2(lH)-one

The compound was prepared starting from D,L-alanine by
the methods described in Examples IA and IB. Melting
point 110C (after recrystallization from
isopropanol/heptane)
The NMR data agree with those of the compound described
in Example IB.

- 52 -
The following compounds of the formula I were synthesized
analogouæly using the corresponding haloaromatic com-
pounds and amino acid derivatives:

Example II
(3S)-3-Benzyl-7-chloro-3,4-dihydroquino~Al; n- 2(lH)-one

A) (S)-N-(4-chloro-2-nitrophenyl)-phenylalanine

L-Phenylalanine (8.3 g, 0.05 mol) and 4.8 g (0.025 mol)
of 2,5-dichloronitrobenzene were dissolved in 40 ml of
anhydrous dimethyl sulfoxide (DMSO), and the stirred
solution was heated to 80C under an argon atmosphere.
Potassium tert.-butylate (4.2 g, 0.025 mol), dissolved in
30 ml of DMSO, was added dropwise in the course of 40
minutes. Stirring was continued for 3 hours at 80 to
90C, the mixture was allowed to cool, and unreacted
phenylalanine was removed by filtration with suction and
washed with water. The collected alkaline filtrates were
extracted twice using diethyl ether to remove unreacted
dichloronitrobenzene. The mixture was then acidified
using glacial acetic acid and extracted several times
using ethyl acetate, and the extracts were dried over
magnesium sulfate and evaporated.

The product was obtained in the form of a red oil (6.7 g,
84%), which was further reacted without purification.

B) (3S)-3-Benzyl-7-chloro-3,4-dihydroqllinox~lin-2(1H)-one

The product of Example IIA (12 g) was dissolved in 300 ml
of anhydrous methanol and hydrogenated at room tempera-
ture with palladium/charcoal catalysis, using 1 atm
hydrogen. When the reaction had ended, solids were
filtered off with suction, the liquid was concentrated,
and the concentrate was chromatographed on silica gel
using diisopropyl ether as the eluent. This gave 1.32 g
of the desired product which crystallized from iso-
propanol, melting point 185.

~1 3rl~jO5
- - - 53 -
H NMR (270 MHz, d6-DMSO): ~ = 2.9 (m, 2 H), 4.08 (m,
1 H), 6.09 (d, 1 H), 6.7 (m, 2 H), 6.78 (m, 1 H), 7.2 (m,
5 H), 10.34 ppm (br. s, 1 H).
MS: (M + H)+ = 273, (M - 92)+ = 181.

The compounds in Table 2 were prepared as described in
the above examples.

Table 2
H

/N~
R n
\N/~

Rs R



No. R1n R3 Rs M.p. C
1 5-Cl CH3 H Wax
2 6-Cl C2Hs H 120
3 6-Cl C2H4COOH H
4 6-Cl -CH2CH2CO-
6-Cl (CH3)2cH H
6 6-Cl (CH3)2CHcH2 H Oil
7 6-Cl C2HS(CH3)CH H Oil
8 6-Cl C6HScH2 H 156-157
9 6-Cl CH3SCH2CH2 H 97
6-Cl CH3SCH2 H 149

_ 54 _ ? 13760~


No.R1n R3 R5 M.p.C

11 6-Cl CH2(OH) H

12 6-Cl CH3CH2CH2 H 75-77

13 7-Cl CH3 H 142

14 7-Cl (CH3)2cH H Oil

7-Cl CH3SC2H4 H 98

16 8-Cl CH3 H

176,7-Cl2 CH3 H

18 7-F CH3 H 230

19 6-F CH3 H Wax

6-F CH3 C3H5 182

21 6-F C6H5CH2 C3H5

22 7-CF3 CH3 H 147

236-CH3OC2H4O CzH5 H 107

24 6-Cl C2H4OH H 211

6-Cl CH2-S-Bn H 170

26 6-Cl CH2-S-i.-Pr H 190

27 6-Cl CH2O-t.-Bu H 128
28 6-CL C4H~ H 115


Bn = benzyl
i-Pr = isopropyl
t-Bu = tert.-butyl

~1 ~76i~
- 55 -
Example III

(3S)-4-N-(Benzyloxycarbonyl)-6-chloro-3-methyl-3,4-di-
hydroquinoxalin-2(lH)-one

The compound of Example IB (1.0 g, 5.1 mmol) was dis-
solved in 20 ml of dichloromethane. 10 ml of 2N aqueous
sodium hydrogen carbonate solution were added, and 0.9 ml
(90%; 5.7 mmol) of benzyl chloroformate was added with
ice-cooling and vigorous stirring. The two-phase system
was subsequently stirred for 60 hours at room tempera-
ture. After 30 hours, another 0.2 ml (1.3 mmol) of benzyl
chloroformate was added. When the reaction was complete,
the phases were separated, the organic phase was washed
once with water and dried (magnesium sulfate), and the
solvent was removed in vacuo. The product was purified by
silica gel chromatography with methyl tert.-butyl ether/
heptane = 1:1 as the eluent. This gave 1.65 g (98%) of a
white, foam-like product.
lH NMR (270 MHz, d6-DMSO): ~ = 1.15 (d, J = 7 Hz, 3 H),
4.85 (q, J = 7 Hz, 1 H), 5.20 (d, J = 12 Hz, 1 H), 5.27
(d, J = 12 Hz, 1 H), 6.97 (d, J = 7 Hz, 1 H), 7.19 (dd,
J = 8.2 Hz, 1 H), 7.3 - 7.45 (m, 5 H), 7.67 (d, J = 2 Hz,
1 H), 10.81 ppm (br. s, 1 H).
MS: (M + H)+ = 381

Example IV

(3S)-4-N-(Benzyloxycarbonyl)-6-chloro-3-methyl-8-nitro-
3,4-dihydroquinoxalin-2(lH)-one

The compound of Example III (1.5 g, 4.5 mmol) was
nitrated in glacial acetic acid (15 ml). A total of 5 ml
(124.3 mmol) of fuming nitric acid were added dropwise in
the course of 4 hours at 0C to room temperature. The
mixture was subsequently poured into 100 ml of ice-water,
and the product, which was obtained in the form of a
yellow solid, was filtered off, washed thoroughly with
water, and dried. Melting point 85C (subl.).

~13~
- - 56 -
H NMR (270 MHz, d6-DMSO): ~ = 1.22 (d, J = 8 Hz, 3 H),
4.89 (q, J = 8 Hz, 1 H), 5.24 (d, J = 12 Hz, 1 H), 5.31
(d, J - 12 Hz, 1 H), 7.35 - 7.5 (m, 5 H), 7.69 (8, 1 H),
8.00 (s, 1 H), 11.11 ppm (br. s, 1 H).
MS: (M + H)+ = 376

Example V

(3S)-8-Amino-4-N-(benzyloxycarbonyl)-6-chloro-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The compound of Example IV (1.5 g, 4.0 mmol) was dis-
solved in 150 ml of methanol and hydrogenated at room
temperature with Raney nickel catalysis, using 1 atm
hydrogen. When the calculated amount of hydrogen had been
taken up, the catalyst was removed by filtration with
suction, and the filtrate was concentrated in vacuo. The
product was purified by silica gel chromatography using
ethyl acetate/heptane = 2:1 as eluent. The yield was
0.68 g (49%) of brownish solid of melting point
152-154C.
1H NMR (270 MHz, d6-DMSO): ~ = 1.11 (d, J = 8 Hz, 3 H),
4.79 (~, J = 8 Hz, 1 H), 5.15 (d, J = 12 Hz, 1 H), 5.24
(d, J = 12 Hz, 1 H), 5.38 (br. s, 2 H), 6.42 (8, 1 H),
7.3-7.4 (m, 6 H), 10.59 ppm (br. s, 1 H).
MS: (M + H)+ = 346

Example VI

A) (3S)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1-yl)-
3,4-dihydroquinoxalin-2(lH)-one

The compound of Example IB ~1.0 g, 5.0 mmol) was dis-
solved in 20 ml of acetonitrile and alkylated with
3-methyl-2-buten-1-yl bromide (90%; 0.92 ml, 7.0 mmol) at
room temperature in the presence of 1.0 g (7.0 mmol) of
pulverulent potassium carbonate. After 7 hours, the
reaction had ended. The mixture was filtered off with
suction, the filtrate was concentrated in vacuo, and the

_ 57 _ 2137 6 ~

product was purified by silica gel chromatography using
ethyl acetate/heptane = 1:2 as eluent. The yield was
0.97 g (72%) of brownish solid of melting point 117-118C
(after crystallization from methyl tert.-butyl ether/
heptane).
H NMR (270 MHz, d6-DMSO): ~ ~ 1.02 (d, J = 8 Hz, 3 H),
1.74 (s, 6 H), 3.69 (dd, J = 14, 8 Hz, 1 H), 3.85 - 3.9
(m, 2 H), 5.19 (m, 1 H), 6.65 - 6.8 (m, 3 H), 10.47 ppm
(br- s, 1 H).
MS: (M + H)+ = 265
[~]D23 = +168.0 (c = 1, MeOH)

B) (3R)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1-yl)-
3,4-dihydroquinoxalin-2(lH)-one

The compound was prepared by the method described in
Example VIA, starting from the compound of Example IC.
Melting point 115-117C (after recrystallization from
isopropanol/diethyl ether)
The NMR data agreed with those of the compound described
in Example VIA.
t~]D23 = -172 (c = 1, MeOH)

C) (3RS)-6-Chloro-3-methyl-4-N-(3-methyl-2-buten-1-yl)-
3,4-dihydroquinoxalin-2(lH)-one

The compound was prepared by the method described in
Example VIA starting with the compound of Example ID.
Melting point 148-149C (after recrystallization from
isopropanol/diethyl ether)
The NMR data agreed with those of the compound described
in Example VIA.

2~37~05
- 58 -
Example VII
(3S)-6-Chloro-3-methyl-4-N-(2-buten-1-yl)-3,4-dihydro-
quinoxalin-2(lH)-one

The substance waæ prepared analogously to the compound
described in Example VIA, but with 2-buten-1-yl bromide
as the alkylating agent. Melting point 87-88C (after
crystallization from diethyl ether/heptane)
H NMR (270 MHz, d6-DMSO): 6 = 1.01 (d, J = 8 Hz, 3 H),
1.70 (dd, J = 8, 1 Hz, 3 H), 3.63 (dd, J = 16, 6 Hz,
1 H), 3.85 - 4.0 (m, 2 H), 5.47 (m, 1 H), 5.75 (m, 1 H),
6.65 - 6.8 (m, 3 H), 10.48 ppm (br. s, 1 H).
MS: (M + H)+ = 251

Example VIII
4-N-(Isopropenyloxycarbonyl)-3,3,7-trimethyl-3,4-di-
hydroquinoxalin-2(lH)-one

3,3,7-Trimethyl-3,4-dihydroquinoxalin-2(lH)-one (0.4 g,
2.1 mmol) were dissolved in 10 ml of anhydrous pyridine,
and the stirred solution was treated at room temperature
with 0.24 ml (2.2 mmol) of isopropenyl chloroformate. The
mixture was stirred for 6 hours at room temperature and
treated with water, the precipitate which formed was
filtered off with suction, washed with water and dried.
This gave 0.4 g (69%) of colorless crystals of melting
point 185C.
lH NMR (270 MHz, d6-DMSO): ~ = 1.5 (s, 6 H), 1.9 (s, 3 H),
2.25 (s, 3 H), 4.7 (m, 2 H), 6.7 - 6.9 (m, 2 H), 7.15 (d,
J = 8 Hz, 1 H), 10.6 ppm (br. s, 1 H).
MS: + = 274

Example IX
(3S)-6-Chloro-4-N-(4-methoxyphenoxycarbonyl)-:3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The compound of Example IB (0.5 g, 2.55 mmol) was dis-
solved in 10 ml of anhydrous N,N-dimethylformamide, and
0.41 ml (2.8 mmol) of triethylamine were added. To the

2137~05
- 59 -
stirred mixture there was first added dropwise 0.42 ml
(2.8 mmol) of 4-methoxyphenyl chloroformate and, after
2 hours, another 0.21 ml (1.9 mmol). When the reaction
was complete (18 hours), the solvent was stripped off
under reduced pressure, the residue was taken up in ethyl
acetate, and the mixture was washed with water and dried
(sodium sulfate). 0.48 g (54%) of a white solid remained
after concentration. Melting point 187-190C (after
recrystallization from isopropanol)
lH NMR (270 MHz, d6-DMSO): ~ z 1.24 (d, J = 8 Hz, 3 H),
3.77 (s, 3 H), 4.94 (q, J = 8 Hz, 1 H), 6.97 (dd, J = 8,
2 Hz, 1 H), 7.03 (d, J = 8 Hz, 1 H), 7.2 - 7.3 (m, 3 H),
7.78 (s, 1 H), 10.89 ppm (br. s, 1 H).
MS: (M + H)+ = 347

Example X
(3S)-6-Chloro-4-N-(4-fluorophenoxycarbonyl)-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The compound was prepared analogously to the compound
described in Example VIA, but 4-fluorophenyl chloro-
formate was used as acylating agent. Melting point168-170C (after crystallization from isopropanol)
1H NMR (270 MHz, d6-DMSO): ~ = 1.24 (d, J = 8 Hz, 3 H),
4.94 (q, J = 8 Hz, 1 H), 7.03 (d, 8 Hz, 1 H), 7.2 - 7.5
(m, 5 H), 7.83 (d, J = 2 Hz, 1 H), 10.90 ppm (br. s,
1 H).
MS: (M + H)+ = 335

Example XI
(3S)-6-Chloro-4-N-(4-chlorophenoxycarbonyl)-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The compound was prepared analogously to the compound
described in Example VIA, but 4-chlorophenyl chloro-
formate was used as acylating agent. Melting point
185-188C (after crystallization from isopropanol/diethyl
ether)

21~76~
- 60 -
1H NMR (270 MHz, d6-DMSO): 6 = 1.25 (d, J = 8 Hz, 3 H),
4.94 (q, J = 8 Hz, 1 H), 7.04 (d, 8 Hz, 1 H), 7.25 (dd,
J = 8, 2 Hz, 1 H), 7.35 - 7.6 (m, 4 H), 7.80 (s, 1 H),
10.91 ppm (br. s, 1 H).
MS: (M + H)+ = 351

Example XII
(3S)-4-N-(2-Bromoethyloxycarbonyl)-6-chloro-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The compound was prepared analogously to the compound
described in Example VIA, but 2-bromoethyl chloroformate
was used for the acylation. Melting point 133-136C
(after crystallization from isopropanol)
lH NMR (270 MHz, d6-DMSO): ~ = 1.16 (d, J = 8 Hz, 3 H),
3.7 - 3.8 (m, 2 H), 4.4 - 4.6 (m, 2 H), 4.86 (q,
J = 8 Hz), 6.99 (d, 8 Hz, 1 H), 7.21 (dd, 8, 2 Hz, 1 H),
7.74 (d, J = 2 Hz, 1 H), 10.84 ppm (br. 8, 1 H).
MS: (M + H)+ = 348

Example XIII
(3S)-6-Chloro-N-(isopropenyloxycarbonyl)-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

The substance was prepared analogously to the compound
described in Example VIA, but isopropenyl chloroformate
was used for the acylation. Melting point 158-159C
1H NMR (270 MHz, CDCl3): ~ = 1.33 (d, J - 8 Hz, 3 H), 2.02
(s, 3 H), 4.79 (s, 1 H), 4.83 (8, 1 H), 5.17 (q,
J = 8 Hz, 1 H), 6.86 (d, J = 8 Hz, 1 H), 7.12 (dd, J = 8,
2 Hz, 1 H), 7.74 (br. s, 1 H), 9.28 ppm (br. 8, 1 H).
MS: (M + H)+ = 281

Example XIV
(3S)-6-Chloro-3-methyl-4-N-(vinyloxycarbonyl)-3,4-di-
hydroquinoxalin-2(lH)-one

The substance was prepared analogously to the compound
described in Example VIA, but vinyl chloroformate was

- 61 ~ 21376Q~
used for the acylation. Melting point 177-179C
H NMR (270 MHz, CDCl3): ~ = 1.33 (d, J = 8 Hz, 3 H), 4.96
(dd, J = 14, 2 Hz, 1 H), 5.20 (q, J = 8 Hz, 1 H), 6.83
(d, J = 8 Hz, 1 H), 7.12 (dd, J = 8, 2 Hz, 1 H),
7.2 - 7.3 (m, 2 H), 7.71 (br. s, 1 H), 9.42 ppm (br. 8,
1 H)-
MS: (M + H)+ = 267

Example XV and Example XVI

6-Chloro-3,4-dihydroquinoxalin-2(lH)-one was reacted with
3-methyl-2-buten-1-yl bromide analogously to the process
described in Example VIA. It was possible to isolate two
products by silica gel chromatography.
6-Chloro-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydro-
quinoxalin-2(lH)-one
Melting point 150-151C (after recrystallization from
ethyl acetate)
1H NMR (270 MHz, d6-DMSO): ~ = 1.72 (s, 6 H), 3.67 (s,
2 H), 3.80 (d, J = 7 Hz, 2 H), 5.20 (m, 1 H), 6.7 - 6.8
(m, 3 H), 10.49 ppm (br. s, 1 H).
MS: (M + H)+ = 251

6-Chloro-4-N-(3-methyl-2-buten-1-yl)-3-(1,1-dimethyl-
2-propen-1-yl)-3,4-dihydroquino~l;n-2(1H)-one
Melting point 110-112C (after crystallization from
heptane)
1H NMR (270 MHz, d6-DMSO): ~ = 0.94 (s, 3 H), 0.97 (s,
3 H), 1.65 (s, 3 H), 1.66 (s, 3 H), 3.77 (dd, J = 16,
7 Hz, 1 H), 4.23 (dd, J = 16, 7 Hz, 1 H), 4.8 - 4.9 (m,
2 H), 5.02 (m, 1 H), 5.75 (dd, J = 17, 11 Hz, 1 H),
6.6 - 6.7 (m, 3 H), 10.49 ppm (br. s, 1 H).
MS: (M + H)+ = 319

The following compounds of the formula I were synthesized
from the corresponding unsubstituted quinoxalinones in
analogous manner and, if appropriate, derivatized
further:

- 62 - 2~137~05




o o , U~
o~ ~ o
o



U ,. ~
m :~ U m u
O "~ P: U U 0 U 0

C~ U~
ly _ Z Z--
\ /




~ ~ m m m m mr'
~ U C~ U U U




7k m m m m m




C: U U
~ U7 U~

r~

_I ~ ~ ~ U~
E~



No . Rln R2 R3 R5 M . p . C
6 6-Cl H CH3 ALAC 180 - 1827 6-Cl H CH3 ALOC 124 - 127 6-Cl H CH3 SO2CH3 184
9 6-Cl H CH3 SO2C6Hs 253
6-Cl H CH3 So2c6H4-4-cH3 259 - 262
11 6-Cl H CH3 SO2C6H4-4-Cl > 270
12 6-Cl H CH3 So2c6H4-4-No2 > 270
13 6-Cl H CH3 SOzCH=CH2 180 - 182
14 6-Cl H CH3 COCH20CH3 202 ~A i6-Cl H CH3 CSNH-C6H4-4-CN 216 G
16 6 -C l H CH3 COCH2CH ( CH3)2 Foam




No . Rln R2 R3 R5 M. p . C
17 6-Cl H CH3 COC6H5 108 - 109
18 6-Cl H CH3 COCl 138
19 6-Cl H CH3 COCH2CH2CH=cH2 Foam
6-Cl H CH3 C2H4OCH3 78 - 79
21 6-Cl H CH3 CE~2C6Hs 155 - 156
22 6-Cl H CH3 2-CO-C4H30 105 - 107
23 6-Cl H CH3 COOCH2CH3 149 - 153
24 6-Cl H CH3 COO(CH2)2CH3 113 - 116
6-Cl H CH3 COO(CH2)3CH3 80 - 82 ~i
26 6-Cl H CH3 COOCH2CH(CH3)2 131 - 132 O
c~
27 6-Cl H CH3 COCH2CH=CH2 130



No . Rln RZ R3 R5 M . p . C
28 6-Cl H CH3 COCH2CH=CHCH3 155
29 6-Cl H C2H5 C5Hg 128
6-Cl H C2H5 IPOC 175
31 6-Cl H C2H5 CHO 204
3_ 6-Cl H CzH5 AIOC 148 - 150
33 6-CH3OC2H4O H C2H5 IPOC 173 ~n
34 6-Cl H C3H7 IPOC 149 - 150
6-Cl H C3H7 AIOC 135 7,~
36 6-Cl H CH(CH3)2 C5H~ 126 - 128 c~3
37 6-Cl H CH(CH3)2 IPOC 144 - 145 o
38 6-Cl H CH ( CH3)z AI,OC




No. R1n R2 R3 R5 M.p
39 6-Cl H C2H4COOH C5Hg
6-Cl H C4Hg C5Hg
41 6-Cl H CH2C6H5 C5Hg 134
42 6-Cl CH2C6H5 IPOC 165
43 6-Cl H C2H4SCH3 C5Hg Oil
44 6-Cl H C2H4SCH3 IPOC 135
6-Cl H C2H4SOCH3 IPOC Oil
46 6-Cl H CH2(OH) C5Hg
47 6-Cl H CH2CH(CH3)2 C5Hg Oil
48 6-Cl H CH2CH(CH3)2 ALOC 140
49 6-Cl H CH2CH(CH3)2 IPOC 148



No . Rln R2 R3 R5 M . p . C
6, 7-Cl2 H CH3 C5Hg
S l 8-Cl H CH3 C5Hg
52 5-C1 N C13a C58, 150 decomp.
53 7-Cl H CH3 C5Hg Oil
54 7-C1 H CH3 ALOC 129
7--C1 11 Cl13 IPOC 166
56 7-C1 8 Cn(CEI3)z c5~3 221
57 7--C1 11 CH(C~3)z IPOC 151
58 7-C1 1~ Cn(CI13)z ALOC 142
59 7-C1 8 CElzC6l13 c5~3 Oil
7-C1 H CIIzC3Hs IPOC 178



No . Rln R2 R3 Rs M. p . C
61 7 -Cl H C2H4SCH3 C5Hg 98
62 7-Cl H C2H4SCH3 IPOC 148
63 7 -Cl H C2H4SCH3 ALOC 116
64 7--F H CH3 C5H~ 75
7-F H CH3 ALOC 155
66 7 -F H CH3 IPOC 168 CD
67 6--F H CH3 C5Hg 153
68 6-F 11 C113 AI.OC 120
69 6--F H CH3 IPOC 175
7-CF3 H CH3 C5H9 145 c,~
71 7-CF3 H CH3 IPOC 186



No . Rln R2 R3 R5 M . p . C
7 2 7 -C6H50 H CH3 C5Hg 10 7
73 7-C6H50 H CH3 IPOC 172
74 6-Cl H C2H4SO2cH3 IPOC 160 decomp.
7 5 6-Cl H CH2SCH3 C5Hg 118
7 6 6-Cl H CH2SCH3 IPOC 182
77 6-Cl n CN250CH3 IPOC 202 decomp.
78 6-Cl H CH2502CH3 IPOC 212 decomp.
79 6-Cl H CH(CH,)CN2CH3 C5No B7
8 0 6 -Cl H CH ( CH3 ) CHzCH3 ALOC 7 4 _ ~
81 6-Cl H CH(CH3)CH2CH3 IPOC 142
8 2 6-F H CH3 COCH3 18 6

- ~o 21'37~5




O er O
~r
U ,, ,
o
D~ In N CQ ~ N Cl ~ CO



ta ~ u u
m mm~ N m
ON U UN u m m N ~ mN
m o m m u u m m u
UUUU----UUo
oIooooooo
P~ u ~ u u u u u u u m




m m m m m m m m ~ m m
~UUUUUUUUUUU



m m
U U

m m m m m m m m m u




UUUUUUUUUUU
,~IIIIIIIIII I



o ~ ~ U~ ~ I~ ~ O~ O _I ~ ~



No . R1n R2 R3 R5 M . p . C
94 6-Cl CH2Ph CH3 H 126 - 127
6-Cl C2H5CH(CH3)2 CH3 H 70 - 72
96 6-Cl CH3 CH3 C5Hg Oil
97 6-Cl CH3 CH3 H 115
98 6-Cl COOC(CH3)3 CH3 H 82 - 83
99 7-Cl C5Hg CH3 C5Hg Resin -
100 7-Cl C5Hg CH3 H 108
101 7-PhOSO2 C5Hg CH3 C5Hg Oil
102 7-PhOSO2 C5Hg CH3 H Oil ~
103 C2H4OCH3 CH3 CZH4ocH3 Oil o
104 6-Cl H CH3 SO2C4H3s 264



No . Rln R2 R3 R5 M . p . C

105 6-Cl H -CH2CH2OCH2- 210

106 6-Cl H CH3 COCH2N(C2Hs)2 108

107 6-Cl H CH3 COCH2N(CH3)2 166

108 6--Cl H CH3 COCH2N(C2H4)2O 190

109 6-Cl H CH3 COCH2N(CH2)4 185

110 6-Cl H CH3 COCH2N(CH2)s 164 ~,

111 6-Cl H CH3 COCH2-(4-methyl- 176
piperazin-l-yl )
112 6-Cl H CH3 CO-4-C5H4N 214 ~

113 6-Cl H CH3 COCH2NHcH2cHZcH2 152 ~3

114 6-Cl H CH3 COCH2C4H3S 155 - 156



No . Rl~ R2 R3 R5 M. p . C
115 6-Cl H CH20-t.-Bu CsH9 Oil
116 6-Cl H CH20-t.-Bu ALOC Oil
117 6-Cl H CH20-t . -Bu IPOC 154
118 6-Cl H CH2S-I . -Pr C5H9 Oil
119 6-Cl H CH2S-i.-Pr IPOC 158
120 6-Cl H CH2S-Bn C5Hg Oil
121 6-Cl H CH2-S-Bn IPOC Oil
122 6, 7-Cl2 H CH3 C5Hg 160
123 6~7-Cl2 H CH3 IPOC
124 6-Cl H C4H~ IPOC 158 ~r~
125 6-Cl H C4Hg ALOC 100
126 6-Cl H CH3 (C4H3S)-2-CH2CO 156
o




127 6-Cl H CH2SCH3 COOCH(CH3)2 157
128 6-CH30 H CH2SCH3 IPOC 152
129 6-CH30 H CH2SCH3 COOCH(CH3)2 165

21'37~05

Key: C5Hg = 3-methyl-2-buten-1-yl
C4H7 = 2-butenyl
C5Hll = 3-methyl-1-butyl
C6Hll = 2,2-dimethylcyclopropyl-1-methyl
sC6Hll= 4-methyl-3-penten-2-yl
C3H3 = 2-propen-1-yl
(CH3 )2CCHCO = 3,3-dimethylacryl
IPOC = isopropenyloxycarbonyl
ALAC = allylaminocarbonyl
ALOC = allyloxycarbonyl
C4H30 ' furanyl
C4H3S = thienyl
C5H4N = pyridyl
Ph = phenyl

21~7613~
- 75 -
Example XVII
6,7-Dimethoxy-3-methyl-3,4-dihydroquinoxalin-2(lH)-one

4,5-Dimethoxy-1,2-dinitrobenzene (34.2 g, 0.15 mol~ was
hydrogenated in 500 ml of methanol with Raney nickel
catalysis using 1 atm hydrogen. After the calculated
amount of hydrogen had been taken up, the process was
stopped, the catalyst wa~ removed by filtration with
suction, and the solvent was stripped off in vacuo. To
remove the water completely, the mixture was taken up
twice in methanol and reconcentrated. 4,5-Dimethoxy-
1,2-phenylene~ ine (24.0 g), which remained as a brown
oil, was refluxed for 48 hours in 200 ml of ethanol (96%)
together with 17.1 ml (0.15 mol) of methyl 2-chloro-
propionate, with an addition of 21.0 ml (0.15 mol) of
triethylamine. The solution, which was very dark, was
concentrated, the concentrate was taken up in ethyl
acetate, the mixture was washed twice with water and
dried (sodium sulfate), and the solvent was stripped off
in vacuo.
The crude product was crystallized by stirring with
diethyl ether (6.2 g, 19%). A analytically pure sample of
melting point 151C was obtained by silica gel chromato-
graphy using ethyl acetate as the eluent.
lH NMR (60 MHz, d6-DMSO): ~ = 1.22 (d, J z 7 Hz, 3 H),
3.63 (s, 3 H), 3.67 (~, 1 H), 3.6 - 3.7 (m, 1 H), 5.62
(br. s, 1 H), 6.40 (8, 1 H), 6.45 (s, lH), 9.90 ppm
(br. s, 1 H).
MS: M~ = 222

The following compounds of the formula I were synthesized
in analogous manner and, if appropriate, derivatized
further:
H

~ 76 _ 2 13 1 6 O~i

Table 4

No. R1n R3 R5 X M.p. C

6, 7 - ( CH30 ) 2 CH3 IPOC O 133

2 6, 7 - ( CH30 ) 2 CH3 IPOC S

3 6-C6H5S CH3 C5HE, O 115

4 7 -C6H5S CH3 CsH~, O 10 7
6-C6H5S CH3 H O
6 7-C6H5S CH3 H O

7 6,7(CH30)2 CH3 H 0 151

Key: C5Hg = 3-methyl-2-buten-1-yl
IPOC = isopropenyloxycarbonyl

Example XVIII
( 3RS)-6-Chloro-4-N-(cyclopropyl)-3-methyl-3,4-dihydro-
quinoxalin-2( lH) -one

A) (2RS)-N-(4-Chloro-2-cyclopropylaminophenyl)-(2-bromo-
propionamide)

4-Chloro-2-cyclopropylaminonitrobenzene (2.10 g,
0.01 mol) was hydrogenated in 100 ml of methanol with
Raney nickel catalysis, using 1 atm hydrogen. After the
calculated amount of hydrogen had been taken up, the
process was stopped, the catalyst was removed by
filtration with suction, and the solvent was stripped off
in vacuo. To remove water completely, the mixture was
taken up twice in methanol and reconcentrated. 4-Chloro-
2-cyclopropylaminoaniline (1.80 g), which remained in the
form of a brown oil, was dissolved in 50 ml of anhydrous
1,2-dimethoxyethane and cooled to -60C, with stirring.

21'37605
77
A solution of 1.1 ml (0.01 mol) of 2-bromopropionyl
chloride in 5 ml of anhydrous 1,2-dimethoxyethane was
slowly added dropwise, and stirring of the reaction
mixture was continued for 2 hours at -60 - -70C. The
mixture was then allowed to warm to approx. -20C and
poured into 150 ml of ice-cold, saturated aqueou~ sodium
hydrogen carbonate solution. The mixture was extracted
twice using ethyl acetate, and the organic phase was
washed once with water, dried (sodium sulfate) and
concentrated in vacuo. After crystallization with diethyl
ether/pentane, 2.51 g (79%) of the desired product of
melting point 130C remained.
H NMR (270 MHz, d6-DMSO): ~ = 0.4 - 0.5 (m, 2 H),
0.7 - 0.8 (m, 2 H), 1.75 (d, J = 7 Hz, 3 H), 2.39 (m,
1 H), 4.72 (q, J = 7 Hz, 1 H), 5.6 (br. s, 1 H), 6.66
(dd, J = 8, 2 Hz, 1 H), 6.96 (d, J = 2 Hz, 1 H), 7.21 (d,
J = 8 Hz, 1 H), 9.36 ppm (br. s, 1 H).
MS: (M + H)+ = 319, 317

B) (3RS)-6-Chloro-4-N-(cyclopropyl)-3-methyl-3,4-dihydro-
quinoxalin-2(lH)-one

The compound of Example XVIIIA (318 mg, 1.0 mmol) was
dissolved in 20 ml of ethanol (96%), 0.28 ml (2.0 mmol)
of triethylamine were added, and the mixture was refluxed
for 18 hours. The solvent was removed under reduced
pressure, and the reaction product was purified by silica
gel chromatography using ethyl acetate/heptane = 1:2 as
eluent. The yield was 200 mg (85%) of white crystals of
melting point 167C (after crystallization from pentane).
1H NMR (270 MHz, d6-DMSO~: ~ = 0.40 (m, 1 H), 0.63 (m,
1 H), 0.76 (m, 1 H), 0.98 (m, 1 H), 1.12 (d, J = 7 Hz,
3 H), 2.47 (m, 1 H), 3.87 (q, J = 7 Hz, 1 H), 6.78 ~s,
2 H), 7.0 (s, 1 H), 10.46 ppm (br. s, 1 H).
MS: (M + H)+ = 237

The following compounds of the formula I were synthesized
analogously to the procedure described in Example XVIII
using the correspondingly substituted ortho-nitroanilines

2137~0~
- - 78 -
and 2-halo carboxylic acid derivatives and, if
appropriate, derivatized further:

Table 5



~ ~//
Rln
~/\N/~
R 4
R 5




No .Rln R3 R4 R5 X M. p . C
1 6-Cl CH3 H C6H5 191
2 6-Cl CH3 CH3 C3H5 0
3 6-Cl CH3 CH3 C3H5 S
4 6-Cl CH3 CH3 C3H5 0
5 6-Cl CH3 CH3 C3H5 S


Key:C3H5 = cyclopropyl
C6H5 = phenyl

Example XIX
7-Chloro-l-N-(cyclopropyl)-3,3-dimethyl-3,4-dihydro-
quinoxalin-2( lH) -one

4-Chloro-2-cyclopropylaminonitrobenzene(2.0 g,9.4 mmol)
was hydrogenated as described in Example XVIIIA. The
resulting4-chloro-2-cyclopropylaminoaniline (1.70 g) was
taken up in 20 ml of dichloromethane. 1.6 ml (2.01 mmol)
of chloroform, 1.8 ml (2.45 mmol) of acetone and 0.10 g
(0.4 mmol) of benzyltriethylammonium chloride were added,

~ - 79 _ ?1~76~5

and the reaction solution was cooled to 10C. 4 ml of 50%
strength sodium hydroxide solution were slowly added
dropwise with vigorous stirring, during which process the
reaction temperature should not exceed 10C. After
stirring for 5 hours at 10C, the phases were diluted and
separated. The organic phase was washed once with water,
dried (magnesium sulfate) and evaporated in vacuo. The
crude product was purified by silica gel chromatography
using ethyl acetate/heptane = 1:2 as the eluent. the
yield was 1.0 g (42%) of white crystals of melting point
132-133C (after recrystallization from toluene/heptane).
H NMR (270 MHz, d6-DMS0): ~ s 0.45 - 0.55 (m, 2 H),
1.05 - 1.1 (m, 2 H), 1.19 (8, 6 H), 2.71 (m, 1 H), 6.09
(br. s, 1 H), 6.71 (d, J = 8 Hz, 1 H), 6.88 (dd, J = 8,
2 Hz, 1 H), 7.19 ppm (d, J = 2 Hz, 1 H).
MS: (M + H)+ = 251

The following compounds of the formula I were synthesized
in analogous manner and, if appropriate, derivatized
further:

21376~5
- -- 80 --
Table 6:
H

~N~ O
Rln

~/\N/~

5 R4

No .Rln R3 R4 R5 M . p . C

6-Cl CH3 CH3C5H9 179

2 7-Cl CH3 CH3CsHg 171

3 6, 7- ( CH30 ) 2 CH3 CH3 H
4 6, 7- ( CH30 ) 2 CH3 CH3C5Hg

CH3 CH3~C6Hll 113
6 C6H5 CH3 H

7 C6Hs CH3C5Hg
8 6-Cl CH3 CH3IPOC 128

9 7-Cl CH3 CH3IPOC 169
7 -CH3 CH3 CH3C5H~ 16 8

11 6 -CH30 CH3 CH3 H 2 0 0

12 6-CH30 CH3 CH3C5H~ 138

13 6/7-COOH CH3 CH3 H > 240

14 6 / 7 -COOH CH3 CH3C5H~ 18 0

213~Q~
- 81 -

No. Rln R3 R4 R5 M.p. C

15 8-CH3 CH3 CH3 H 140

16 8-CH3 CH3 CH3 C5Hg 160

17 8-CH3 CH3 CH3 IPOC 127

186/7-CH3 C2H5 C2H5 H 160

19 6-CH3 C2H5 C2H5C5Hg 100

20 7-CH3 C2H5 C2H5C5Hg 110

21 7-F CH3 CH3 H 120

22 7-F CH3 CH3 C5H~ 155

237-C2H5O CH3 CH3 H 155

247-C2H5O CH3 CH3 C5Hg 123

25 6-COOH CH3 CH3 C5Hg 245

267,8-(CH3)2 CH3 CH3 H 196

277,8-(CH3)2 CH3 CH3 C5Rg 155

286,7-(CH3)2 CH3 CH3 H 248

296,7-(CH3)2 CH3 CH3 C5Hg 200
30 6-Cl,7- CH3 CH3 H 211
(2,3-Cl2C6H3O)
31 6-Cl,7- CH3 CH3 C5Hg 205
(2,3-Cl2C6H3O)
32 7-F CH3 CR3 IPOC 175

337-C2H5O CH3 CH3 IPOC 150

346/7-CH3 CH3 CH3 IPOC 152

21'3760~
-- 82 --

No. R1 R3 R4 R5 M. p . C

7,8-(CH3)2 CH3 CH3IPOC 147
36 6,7-(CH3)2CH3 CH3 CH3IPOC 161

37 7 -C6H5 CH3 CH3 H 167
38 7 -C6H50 CH3 CH3C5H~ 138

39 7 -C6H50 CH3 CH3IPOC 181

5-CH3 CH3 CH3 H 182

41 6-CH30, CH3 CH3 H > 240
7- ( 4-pyridyl)

42 6-Cl, CH3 CH3 H 219
7 -piperidino

43 6/7-Cl,7/6- CH3 CH3 H 236
morpholino
(mixture)
44 6/7- (N-methyl- CH3 CH3 H > 240
piperazin-1-yl)

6/7-Cl,7/6- CH3 CH3 H 147
(N-methyl-
piperazin-l-yl)

46 6-Cl CH3 CH3 H 152-154

47 7 -Cl CH3CH3 H
48 6-Cl CH3 CH3ALOC 128-129

49 7-Cl CH3 CH3ALOC 144

6 -Cl CH3 CH3COOCH ( CH3) 2 118

51 7-Cl CH3 CH3COOCH(CH3)2 171

21'37'6'~5
- 83 -

No.Rln R3 R4 R5 M.p. C

527-(4-F-Ph-SO2O) C~3 C~3 H

537-(4-F-Ph-SOaO) CH3 CH3 IPOC 204

54 6-Cl,7-piperidino CH3 CH3IPOC 152

556-Cl,7- CH3 CH3IPOC 113
morpholino
566-Cl,7-(N- CR3 CH3IPOC 168
methyl-
piperazin-1-yl)

576-Cl,7-NEt2 CH3 CH3 H 141
586-Cl,7-NEt2 CH3 CH3IPOC Oil

596,7-Cl2 CH3 C~3 H 232
606,7-Cl2 CH3 CH3IPOC 171

617-(N-methyl- CH3 CH3 H 198
piperazinyl-l-yl)
627-(N-methyl- CH3 CH3IPOC 123
piperazinyl-1-yl)
636-CH30 CH3 CH3IPOC 128

64 7-Cl -(CH2)3- IPOC 172

65 7-Cl -(CH2)4- IPOC 181

66 6-Cl -(CH2) 3- IPOC 157-158

67 6-Cl - (Q2) 4- IPOC 179-180

686-Clq CH3 CH3COOC2~s 137

69 6-Cl CH3 CH3COOC3H7 125

?.137605
- 84 -
Key: C5Hg = 3-methyl-2-buten-1-yl
sC6Hl1 = 4-methyl-3-penten-2-yl
IPOC = isopropenyloxycarbonyl

Example XX
3,3-Dimethyl-4-N-t3-methyl-2-buten-1-yl)-3,4-dihydro-
q1l i nox~ 1 in-2(lH)-one

The compound waæ prepared analogously to the compound
described in Example VIA, starting from 3,3-dimethyl-
3,4-dihydroquinoxalin-2(lH)-one (J. T. Lai, Synthesis
1982, 71). Melting point 146-147C (after crystallization
from methyl tert.-butyl ether/heptane)
H NMR (270 MHz, d6-DMSO): ~ = 1.27 (s, 3 H), 1.68 (s,
3 H), 1.72 (s, 3 H), 3.88 (d, J = 7 Hz, 1 H), 5.15 (m,
1 H), 6.60 (d, J = 7 Hz, 1 H), 6.67 (t, J = 7 Hz, 1 H),
6.78 (d, J = 7 Hz, 1 H), 6.87 (t, J = 7 Hz, 1 H),
10.33 ppm (br. s, 1 H).
MS: (M + H)+ = 245

Example XXI
4-N-(3-Methyl-2-buten-1-yl)-3,4-dihydroquinoxalin-
2(lH)-one-3-spiro-1'-cyclohexane

The compound was prepared analogously to the compound
described in Example VIA, starting from spiro[cyclo-
hexane-1,3'-(3',4'-dihydroquinoxalin-(l'H)-one)] (J. T.
Lai, Synthesis 1982, 71). Melting point 82-83C (after
crystallization from heptane)
H NMR (270 MHz, d6-DMSO): ~ = 1.25 - 1.75 (m, 10 H), 3.75
(d, J = 6 Hz, 2 H), 5.07 (m, 1 H), 6.7 - 7.0 (m, 4 H),
10.15 ppm (br. s, 1 H).
MS: (M + H)+ = 285

2137605
- 85 -
Example XXII
4-N-(3-Methyl-2-buten-1-yl)-3,4-dihydroquinoxaline-
2( lH) -thione-3-spiro-1'-cyclohexane

The compound of Example XXI (500 mg, 1.8 mmol) was
refluxed for 1.5 hours under argon together with 370 mg
(0.9 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-
2,4-diphosphetane 2,4-disulfide (Lawesson' 8 reagent) in
10 ml of anhydrous toluene. The mixture was subsequently
concentrated in vacuo, and the products were isolated by
silica gel chromatography using methyl tert.-butyl
ether/heptane = 10:1 as eluent. The yield was 50 mg (9%)
of yellow crystals of melting point 125C.
H NMR (270 MHz, d6-DMSO): ~ = 1.1 - 1.9 (m, 16 H), 3.64
(d, J = 7 Hz, 2 H), 4.99 (m, 1 H), 6.95 - 7.1 (m, 3 H),
7.18 (d, J = 7 Hz, 1 H), 12.2 ppm (br. s, 1 H).
MS: (M + H)+ = 301

3,4-Dihydroquinoxaline-2(lH)-thione-3-spiro-1'-cyclo-
hexane was isolated as a further product in a yield of
110 mg (26%); yellow crystals of melting point 178C.
~H NMR (270 MHz, CDC13 ~ = 1.25 - 2.2 (m, 10 H), 4.18 (br.
s, 1 H), 6.7 - 6.8 (m, 3 H), 6.97 (m, 1 H), 9.42 ppm (br.
s, 1 H).
MS: (M + H)~ = 233.
Example XXIII
(3S)-6-Chloro-4-N-(isopropenyloxycarbonyl)-3-methyl-
3,4-dihydroquinoxaline-2( lH) -thione

The compound of Example XIII (0.5 g, 1.78 mmol), dis-
solved in 10 ml of anhydrous pyridine, was refluxed for
4 hours together with 0.47 g (2.12 mmol) of phosphorus
pentasulfide. The mixture was concentrated in vacuo, and
the residue was chromatographed on silica gel using ethyl
acetate/heptane = 1:1 as eluent. This gave 0.25 g (47%)
of a yellow crystalline solid of melting point 148-150C
(after recrystallization from ethyl acetate/heptane).

7605
- 86 -
H NMR (270 MHz, d6-DMSO): ~ = 1.24 (d, J = 7 Hz, 3 H),
1.96 (s, 3 H), 4.8 - 4.9 (m, 2 H), 5.28 (q, J = 7 Hz,
1 H), 7.22 (d, J = 8 HZ, 1 H), 7.30 (dd, J = 8, 2 HZ,
1 H), 7.72 (br. 8, 1 H), 12.84 ppm (br. 8, 1 H).
MS: (M + H)+ = 297.

The following compounds of the formula I were synthesized
in analogous manner from the correspo~A;n~ 3,4-dihydro-
quinoxalin-2(1H)-ones:

7~5
- 87 -
Table 7
H

~ \//

Rl n R3
~\N/~
R 4
R 5




No . Rln R3 R4 R5 M . p . C
CH3 H C5H~ 119
2 6-Cl CH3 H C5Hg 109-110
3 6-Cl CH3 ~C6H5CH2 92
4 6-Cl H -CH2CH2CS-
6-Cl H -CH2CH2CH2CS-
6 C6H5 CH3C5Hg
7 6-Cl CH3 CH3C5Hg 157
8 7-Cl CH3 CH3C5Hg 16 0
9 7-Cl CH3 CH3 H 170
6-Cl CH3 H ALOC 143-145
11 6-Cl CH3 CH3IPOC 153
12 7-Cl C~3 CH3IPOC 174
13 6-Cl CH3 CH3 H 175
14 6-Cl C2H5 H IPOC 176-177

21'376Q~
- 88 -

No. R1n R3 R4 R5 M.p. C

6-Cl C2H5 H ALOC 159-161

166,7-(CH3)2 CH3 CH3C5H~ 173

17 6-Cl C3H7 H IPOC 154-155

18 6-Cl C3H7 H ALOC 98-100

19 6-Cl CH3 H(2-C5H4N)-CH2 175-178

6-Cl CH3 H(3-C5H4N)-CH2 77

21 6-Cl CH3 CH3ALOC 153-154

22 6-Cl CH3 CH3COOCH(CH3)2 151

23 6-Cl CH2SCH3 H IPOC 128

24 6-Cl CH3 CH3COOC2H5 163

6-Cl CH3 CH3COOC3H7 164

26 6-Cl C2H5 H(2-C5H4N)-CH2 162-164

27 6-Cl C4Hg H IPOC 132

28 6-Cl CH2SCH3 HCOOCH(CH3)2 124

29 6-Cl CH2SCH3 I(2-C5H4N)-CH2 159

30 6-CH30 CH2SCH3 H IPOC 154

31 6-CH30 CH2SCH3 ~COOCH(Q3)2 163

32 6-Cl CH2SCH3 HCH2C6H4-2-Cl Oil

2137~Q5
-- 89 --
Key: C5Hg = 3-methyl-2-buten-1-yl
IPOC -- isopropenyloxycarbonyl
ALOC = allyloxycarbonyl
C5H4N = pyridyl

Example XXIV
(3RS)-3-Methyl-4 -N- ( 3-methyl-2-buten-1-yl)-2-methylthio-
3,4-dihydroquinoxaline

( 3RS ) - 3 -Methyl-4 -N- ( 3 -methyl-2 -buten- 1 -yl ) -
3,4-dihydroquinoxaline-2( lH ) -thione (Table 7, No . 1 )
(0.49 g, 2.0 mmol) was dissolved in 20 ml of ethanol
(96%), and the solution was treated with 5.1 ml
(2.2 mmol) of a 1% strength sodium ethanolate solution.
After the mixture had been stirred for 15 minutes at room
temperature, 0.14 ml (2.2 mmol) of methyl iodide was
added dropwise, and the mixture was stirred for a further
2 hours at room temperature. The reaction solution was
concentrated, and the residue was chromatographed on
silica gel. 500 mg (96%) of a yellow oil were isolated
using ethyl acetate/heptane = 1:6.
lH NMR d6-DMSO): ~ = 0.96 (d, J = 7 HZ, 3 H), 1.72 (s,
6 H), 2.44 (s, 3 H), 3.71 (dd, J = 15, 6 Hz, 1 H), 3.89
(dd, J = 15, 6 HZ, 1 H), 4.00 (q, J = 7 HZ, 1 H), 5.20
(m, 1 H), 6.65 - 6.75 (m, 2 H), 7.02 (t, J = 8 Hz, 1 H),
7.11 ppm (d, J = 8 Hz, 1 H).
MS: (M + H)+ = 261

The following compound of the formula I was synthesized
in the same manner:

4-Isopropenyloxycarbonyl-2-(isopropenyloxycarbonyl)-thio-
3,3,7,8-tetramethyl-3,4-dihydroqll; nQyA1 ine.
Melting point: 115C

2137605
-- 90
Example XXV
(3RS~-3-Methyl-4-N-(3-methyl-2-buten-1-yl)-3,4-dihydro-
quinoxalin-2(lH)-one

(3RS)-3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (4.86 g,
0.03 mol) dissolved in 50 ml of N,N-dimethylformamide,
was alkylated with 4.2 ml (0.033 mol) of 3-methyl-
2-buten-1-yl bromide (90%) in the presence of 4.60 g
(0.033 mol) of pulverulent potassium carbonate. The
reaction mixture was stirred at room temperature until
reaction of the educt was complete. The solvent was then
stripped off in vacuo, the residue was taken up in ethyl
acetate and water, the phases were separated, the aqueous
phase was extracted twice with ethyl acetate, and the
combined organic extracts were washed twice with water.
Drying over sodium sulfate, concentration in vacuo and
crystallization from pentane gave 5.80 g (84%) of white
crystalline product of melting point 92-93C.
H NMR (270 MHz, d6-DMSO): ~ = 0.99 (d, J = 7 Hz, 3 H),
1.72 (s, 6 H), 3.67 (dd, J = 15, 7 Hz, 1 H), 3.86 (q,
J = 7 Hz, 1 H), 3.88 (dd, J - 15, 7 Hz, 1 H), 5.21 (m,
1 H), 6.65 - 6.9 (m, 4 H), 10.31 ppm (br. s, 1 H).
MS: (M + H)~ = 231

Example XXVI
3,3a-Dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione

2-Fluoronitrobenzene (14.1 g, 0.1 mol) and L-glut~ic
acid (45.0 g, 0.3 mol) were heated in 100 ml of
2-methoxyethanol at 95C, with stirring, and 300 ml of 2N
sodium hydroxide solution were added dropwise. Stirring
was then continued for another 3 hours at this tempera-
ture. After cooling, the solution was treated with 400 ml
of methanol and hydrogenated under atmospheric pressure
with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was
removed by filtration with suction, and the solution was
concentrated under reduced pressure.
The residue was acidified with 250 ml of 2N hydrochloric

2137~05
-- 91 --
acid and heated in a steam bath for approx. 30 minutes.
The precipitate which resulted in thi~ process was
filtered off with suction, washed with water and alcohol
and subsequently dried, melting point 255~C, decomposi-
tion.
lH NMR (60 MHz, d6-DMSO): ~ = 1.9 - 2.7 (m, 4 H), 4.5 (t,
J = 8 Hz, 1 H), 6.8 - 7.3 (m, 3 H), 7.8 - 8.2 (m, 1 H),
10.7 ppm (br. s, 1 H).
MS: (M + H)+ = 202

Example XXVII
7-Phenoxysulfonyl-3,3a-dihydropyrrolo[1,2-a]quinoxaline-
1,4(2H,5H)-dione

The compound was obtained in analogous manner by reacting
phenyl 4-chloro-3-nitrobenzenesulfonate with L-glutamic
acid, melting point 140C (decomp.).
lH NMR (60 MHz, d6-DMSO): ~ = 1.6 - 2.5 (m, 4 H), 4.07 (t,
J = 6 Hz, 1 H), 6.7 - 7.6 (m, 8 H), 10.57 ppm (br. s,
1 H)-
MS: (M + H)+ = 358

Example XXVIII
3-Carboxymethyl-3,4-dihydroquinoxalin-2(lH)-one

2-Fluoronitrobenzene (14.1 g, 0.1 mol) and L-aspartic
acid (40.0 g, 0.3 mol) were heated to 95C in 100 ml of
2-methoxyethanol, with stirring, and 300 ml of 2N sodium
hydroxide solution were added dropwise. Stirring was then
continued for 1 hour at this temperature. After the
solution had cooled, it was treated with 500 ml of
methanol and hydrogenated under atmospheric pressure with
Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was
removed by filtration with suction, and the solution was
concentrated under reduced pressure.
The residue was acidified with 500 ml of 2N hydrochloric
acid, the mixture was subsequently concentrated,
neutralized with sodium acetate and extracted with ethyl

~137~
- 92 -
acetate. The mixture was dried with sodium sulfate, the
solvent was stripped off, and the residue was then
obtained which was first oily and crystallized upon
stirring with water, melting point 152-154C.
lH NMR (60 MHz, d6-DMSO): ~ = 2.5 - 2.7 (dd partly
concealed, 2 H), 4.1 (td, J = 6, 2 Hz, 1 H), 5.98 (br. s,
1 H), 6.5 - 6.9 (m, 4 H), 10.30 (br. s, 1 H), 12.37 ppm
(br. s, 1 H).
MS: Mt = 206
CHN analysis: calculated C 58.2; H 4.8; N 13.6%
found C 58.4; H 4.7; N 13.7

Example XXIX
7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(lH)-one

A) Methyl N-t(2-nitro-4-phenoxysulfonyl)phenyl]glycinate

Phenyl 4-chloro-3-nitrobenzenesulfonate (62.7 g, 0.2 mol)
and methyl glycinate hydrochloride (100.4 g, 0.8 mol),
dissolved in 250 ml of methanol, were treated with 200 ml
of triethylamine, and the mixture was refluxed for 15
minutes. After cooling, the mixture was treated with 1 1
of 2N acetic acid, subjected to filtration with suction
and washed with water. The residue was recrystallized
from ethyl acetate and washed with methanol and diiso-
propyl ether, melting point 120-123C.

B) 7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(lH)-one

Methyl N-[(2-nitro-4-phenoxysulfonyl)phenyl]glycinate
(36.6 g, 0.1 mol) was hydrogenated under atmospheric
pressure in a mixture of 250 ml of N,N-dimethylformamide
and 250 ml of methanol, with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was
removed by filtration with suction, and the solution was
freed from solvent in vacuo. The residue was dissolved in
40 ml of 2-methoxyethanol, and the mixture was heated for
one hour in a steam bath. The resulting precipitate was
filtered off with suction and washed with methanol,

21'~7605
- 93 -
melting point 253-254C.
H NMR (60 MHz, d6-DMSO): ~ = 4.0 (d, J = 4 Hz, 2 H),
6.6 - 7.6 (m, 9 H), 10.43 ppm (br. 8, 1 H).
MS: (M + H)+ = 305

Example XXX
4-(3-Methyl-2-buten-1-yl)-7-phenoxysulfonyl-3,4-dihydro-
quinoxalin-2(lH)-one

7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(lH)-one
(1.52 g, 5.0 mmol) in 20 ml of N,N-dimethylacetamide was
stirred for 8 hours at 100C with 2 ml of 3-methyl-
2-buten-1-yl bromide. After cooling, the mixture was
treated with water and extracted with ethyl acetate. The
solution was dried using magnesium sulfate and then
concentrated, and the residue was chromatographed over a
silica gel column using ethyl acetate/heptane = 1:1. The
fractions which contained the substance were evaporated
on a rotary evaporator, and the product was subsequently
stirred with pentane and filtered off with suction,
melting point 132C.
lH NMR (270 MHz, d6-DMSO): ~ = 1.73 (8, 6 H), 3.90 (8,
2 H), 3.93 (partly concealed d, J = 6 Hz, 2 H), 5.20 (br.
t, J = 6 Hz, 1 H), 6.75 - 7.45 (m, 8 H), 10.66 ppm (s,
1 H).
MS: (M + H)+ = 373

The following compound~ of the formula I were synthesized
in analogous manner using the corresponding haloaromatic
substances and amino acid derivatives and, if appro-
priate, derivatized further on nitrogen atom 4:

- 2137605
- 94 -

Table 8
H

R 1 ~/N\~/

n ~N/~R 3
1 5 R4


No.Rln R R4 R5 M.p. C
17-C6H5-O-SO2 HCH2OH H 199
27-C6H5-O-SO2 HCH2OH C5Hg 120
37-C6H5-O-SO2 HCH2COOH H 230 decomp.
47-C6H5-O-SO2 HCH2COOH C5Hg
57-C6H5-O-SO2 HCH2CONH2 H 272 decomp.
67-C6H5-O-SO2 HCH2CONH2 C5Hg
77-C6H5-O-SO2 H CH2-4-Imi H 216 decomp.
87-C6H5-O-SO2 H CH2-4-Imi C5H9
97-C6H5-CO H H H 280 decomp.
107-C6H5-CO H H C6H5-CO277 decomp.
117-C6H5-O-sO2 H CH3 H 148
127-C6H5-O-so2 H CH3 C5H9 Oil
137-C6Hs-so2 H CH3 H 198
147-C6H5-sO2 H CH3 C5Hg Oil

21'3~6Q5
- 95 -

No. Rln R3 R4 R5 M.p. C

15 7-C6Hs-so2 H CH3 IPOC 108

16 7-C6H5-O-SO2 H H H
17 7-C6H5-O-sO2 H H COCH3 270
18 7-C6H5-O-SO2 H CH3 IPOC Resin


Key: C5Hg = 3-methyl-2-buten-1-yl
4-Imi = 4-imidazolyl
IPOC = isopropenyloxycarbonyl

Example XXXI
6-Chloro-7-phenoxysulfonyl-1,2,3,3a-tetrahydro-
pyrrolo[2,1-c]-quinoxalin-4(5H)-one

A) Phenyl 2,4-dichloro-3-nitrobenzenesulfonate

2,6-Dichloronitrobenzene was stirred for 7 hours at 130C
with an excess of chlorosulfonic acid. After cooling, the
mixture was poured onto ice, the sulfochloride wa~
filtered off with suction, washed to neutrality and dried
over sodium hydroxide, melting point 91C. The resulting
sulfochloride (29.05 g, 0.1 mol) and phenol (ll.S g,
0.12 mol) were dissolved in 150 ml of acetone and treated
with 14 ml of triethylamine at 10C. ~he mixture was
stirred for 1 hour with cooling, stirring was then
continued for a further 4 hours at room temperature, the
mixture was then treated with 200 ml of water, the
resulting precipitate was filtered off with suction at
10C, washed with water and dried in vacuo at 80C,
melting point 102C.

2137~Q5
- 96 -
B) N-[(3-Chloro-2-nitro-4-phenoxysulfonyl)phenyl]proline

Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (34.8 g,
0.1 mol), 69.0 g (0.6 mol) of L-proline, 200 ml of 2N
sodium hydroxide solution and 200 ml of 2-methoxyethanol
were stirred for 10 minutes at 80C. The clear solution
was acidified at 50C using concentrated hydrochloric
acid and poured onto ice. The precipitate was filtered
off with suction, washed with water to neutrality and
dried at 80C. Melting point 148C (after recrystalliza-
tion from methanol)

C) 6-Chloro-7-phe~o~ysulfonyl-1,2,3,3a-tetrahydrG~yL olo-
[2,1-c]-quinoxalin-4(5H)-one

N-t(3-Chloro-2-nitro-4-phenoxysulfonyl)phenyl]proline
(38.0 g, 0.075 mol) in 500 ml of methanol and 25 ml of
concentrated ammonia solution was hydrogenated under
atmospheric pressure with Raney nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was
removed by filtration with suction, the solution was
concentrated, the residue together with 2N hydrochloric
acid was heated for approximately 30 minutes in a steam
bath, cooled, subjected to filtration with suction and
washed with water to neutrality. Melting point 197C
(after recrystallization from glacial acetic acid)

Example XXXII
8-(4-Methyl-1-piperazinyl)-3-(2-methylpropyl)-5-phenoxy-
sulfonyl-3,4-dihydroquinoxalin-2(lH)-one

A) Phenyl 2-chloro-4-(4-methyl-1-piperazinyl)-3-nitro-
benzenesulfonate

Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (17.4 g,
0.05 mol) and 25 ml of methylpiperazine in 100 ml of
isopropanol were refluxed for 10 minutes and subsequently
concentrated. The residue was stirred with 50 ml of 50%
methanol, filtered off with suction, and washed with 50%

~137~05
- 97 -
methanol and finally with water. Melting point 94-95C
(after recrystallization from cyclohexane)

B) N-~(3-(4-Methyl-1-piperazinyl)-2-nitro-6-phenoxy-
sulfonyl)-phenyl]leucine hydrochloride

Phenyl 2-chloro-4-(4-methyl-1-piperazinyl)-3-nitro-
benzenesulfonate (41.1 g, 0.1 mol) and L-leucine (39.3 g,
0.3 mol) were stirred for 8 hours at 95C in a mixture of
100 ml of N,N-dimethylformamide, 50 ml of 2-methoxy-
ethanol and 100 ml of 2N sodium hydroxide solution. When
cold, the reaction mixture was acidified with
concentrated hydrochloric acid. The precipitate was taken
up in ethyl acetate, and the mixture was dried using
sodium sulfate and freed from solvent in vacuo. This gave
an orange oil.

C) 8-(4-Methyl-1-piperazinyl)-3-(2-methylpropyl)-
5-phenoxysulfonyl-3,4-dihydroquinoxalin-2(lH)-one hydro-
chloride

N-[(3-(4-Methyl-1-piperazinyl)-2-nitro-6-phenoxy-
sulfonyl)-phenyl]leucine hydrochloride (25.3 g, 0.05 mol)
in 250 ml of methanol and 25 ml of glacial acetic acid
was hydrogenated under atmospheric pressure using Raney
nickel as catalyst.
When the uptake of hydrogen had ended, the catalyst was
removed by filtration with suction, the solution was
concentrated, and the residue together with 2N of hydro-
chloric acid was heated for approximately 10 minutes in
a steam bath and then concentrated in vacuo. The residue
was dissolved in water, the mixture was rendered alkaline
using ammonia, and this was taken up in ethyl acetate.
The oil which remained after concentration was dissolved
in 400 ml of diisopropyl ether, and the mixture was
rendered neutral using ethanolic hydrochloric acid. The
precipitate was filtered off with suction, washed with
diisopropyl ether and dried, melting point 90C and above
(decomp.).

~2 1i~7 ~ o~

- 98 -

MS: M+ z 458

The following compounds of the formula I were synthesized
in analogous manner using the corresponding haloaromatic
substances and amino acid derivatives and, if appro-
priate, derivatized further on nitrogen atom 4:
CH3
Table 9 ~N ~ H




~ ~R3



No. R3 R4 R5 M.p. C
1 H (CH3)2CHcH2 C5Hg

2 H CH3 H 100 decomp. (HCl)
3 H CH3 C5H9

4 H H H 126 - 127 (base)
H H C5H~


Key: C5Hg = 3-methyl-2-buten-1-yl

Example XXXIII
(3RS)-4-N-Cyclohexyl-3-methyl-3,4-dihydroquinoxalin-
2(H)-one

(3RS)-3-Methyl-3,4-dihydroqllinoxAlin-2(1H)-one (0.81 g,
0.005 mol) and 1 ml (0.1 mol) of cyclohexanone were
introduced into 20 ml of 1,2-dichloroethane.

760S
99
Trifluoroacetic acid (1.9 ml, 0.025 mol) was added
dropwise, during which process a clear solution formed
with gentle heating. 2.1 g (0.01 mol) of sodium
triacetoxyborohydride were added, the exothermic reaction
was then allowed to proceed for 30 minutes with stirring,
and quenching was then effected by adding saturated
aqueous sodium hydrogen carbonate solution. The phases
were separated, the organic phase was washed with
saturated aqueous sodium chloride solution, dried
(magnesium sulfate) and concentrated. The crude product
was chromatographed on silica gel using ethyl
acetate/heptane = 1:1. 1.15 g (94%) of the desired
product were obtained, melting point 131-132C
(toluene/heptane).
lH NMR (270 MHz, d6-DMS0): ~ = 0.97 (d, J = 7 Hz, 3 H),
1.0 - 2.0 (m, 10 H), 3.39 (m, 1 H), 3.91 (q, J = 7 Hz,
1 H), 6.68 - 6.94 (m, 4 H), 10.27 ppm (br. s, 1 H).
MS: (M + H)t = 245.

The following compounds of the formula I were synthesized
in analogous manner.

Table 10



~ \//
Rln
~\N/~
R 4
R 5

- 21375Q~
- 100 -

No. R1n R3 R4 R5 M.p. C

1 CH3 H C2Hs 106-107
2 CH3 H CH2C(CH3)3 162

3 CH3 H c-C5H~ 120

4 6-Cl CH3 H c-C4H7 100

6-Cl CH3 H CsH11 94 95

6 6-Cl CH3 H CH2C(CH3)3 158-160

7 6-Cl C2H5 H CH2C(CH3)3 158-159

8 6-Cl CH3 H CH=CHCHO 140-146

9 6-Cl CH3 H CH2C.CH3 166-168

6-Cl CH3 H 2-picolyl 198-199

11 6-Cl CH3 H 3-picolyl 136

12 6-Cl CH3 H 4-picolyl 191-193

13 6-Cl CH3 H furanyl-2- 116-118
methyl

21'37~0~
- 101 -

No. Rln R3 R4R5 M.p. C
14 6-Cl CH3 HCH2C6H4-4-Br 149-150
6-Cl CH3 HCH2C6H4-4-CN 95-96
16 6-Cl CH3 HCH2C6H4-4-NO2 117
17 6-Cl CH3 HCH2C6H4-3-NO2 125
18 6-Cl CH3 HCH2C6H4-2-NO2 153-154
19 6-Cl CH3 HCH2C6H4-4-Cl 122-123
6-Cl CH3 HCH2C6H4-3-Cl 156-157
21 6-Cl CH3 HCH2C6H4-2-Cl 138
22 6-Cl CH3 HCH2C6H4-4-F 147
23 6-Cl CH3 HCH2C6H4~4~C6Hs 164-165
24 6-Cl CH3 HCH2C6H4~4~Oc6Hs Oil
6-Cl CH3 HCH2C6H4-4-CH3 60-62
26 6-Cl CH3 HCH2C6H4-4-COOCH3 139
27 6-Cl CH3 HCHZc6H4-2~6-cl2 190-191
28 6-Cl CH3 HCH2C6H4-3,5-Cl2 139-140
29 6-Cl CH3 Hnaphthyl-1-methyl 164-166
6-Cl CH3 Hnaphthyl-2-methyl 161-164
31 6-Cl CH3 HCH2CH2OCH3 78-79
32 6-Cl CH3 H cyclohex-2-enyl Oil
33 6-Cl CH3 H C2H4-C6Hs 128
34 6-Cl CH3 Hthienyl-3-methyl 141-142

?.1 ~7~n~
- 102 -

No. R1n R3 R4 R5 M.p. C

6-Cl CH3 E~5-methylthienyl)-58-60
2-methyl
36 6-Cl CH3 H(3-methylthienyl)-2- 124
methyl

37 6-Cl CH3 H thienyl-2-methyl121-123

38 6-Cl CH3 H CH2CH=CH-C6H5

39 6-Cl CH2SCH3 F CH2C6H4-2-Cl 128

6-Cl CH2SCH3 E CH2C6H4-2-NO2 134

41 6-Cl CH2SCH3 H 2-picolylOil

42 6-Cl CH2SCH3 H CH2H6H3-2,4-Cl2 143

43 6-Cl CH2S-i.PrE CH2C6H3-2,4-Cl2 Oil

44 6-Cl CH2S-Bn E CH2C6H3-2,4-Cl2 Oil

6-Cl CH2-S-H H CH2C6H3-2,4-Cl2

46 6-Cl C2H5 H 2-picolyl 160-162

47 6-Cl CH3 H '6-CH3)2-picolyl 158


Key: C5H~1 = 3-methyl-1-butyl
c-C4H7 = cyclobutyl
c-C5Hg = cyclopentyl

Example XXXIV

~3Rs)-3-Methyl-4-N-(3-oxo-l-butyl)-3~4-dihydroquin~yAli n-
2(lH)-one

3-Methyl-3,4-dihydroquinoxalin-2(lH)-one (0.5 g,
3.1 mmol) together with 0.35 ml (4.3 mmol) of methyl

'21~760~
- 103 -
vinyl ketone and a catalytic amount of triethylamine were
ætirred for 20 hours at room temperature in 20 ml of
anhydrous ethanol. Silica gel chromatography with methyl
tert.-butyl ether/heptane = 2:1 gave 620 mg ~87%) of the
desired product, melting point 108-109C (methyl tert.-
butyl ether/heptane).
H NMR (270 MHz, d6-DMSO): ~ = 1.03 (d, J = 7 Hz, 3 H),
2.11 (s, 3H), 2.77 (t, J - 6 ~z, 2 H), 3.30 (m, 1 H),
3.50 (m, 1 H), 3.88 (q~ J s 7 Hz, 1 H), 6.68 (m, 1 H),
6.78 (m, 1 H), 6.88 (m, 1 H), 10.31 ppm (br. 8, 1 H).
MS: (M + H)+ = 233, M+ s 232

Example XXXV
(3S)-6-Chloro-4-N-chlorocarbonyl-3-methyl-3,4-dihydro-
quinoxalin-2(lH)-one

The compound of Example IB (2.0 g, 0.01 mol) in 100 ml of
anhydrous toluene was heated with bis-(trichloromethyl)
carbonate (triphosgene) (1.5 g, 0.005 mol) for 1 hour at
80C in the presence of 2 ml (0.014 mol) of triethyl-
amine. After cooling, the mixture was washed with water
and saturated aqueous sodium chloride solution and dried
(magnesium 6ulfate), and the ~olvent was removed under
reduced pressure. The residue (2.5 g) crystallized after
stirring with heptane, its purity being sufficient for
preparative purposes. A sample of analytical purity was
obtained by silica gel chromatography using ethyl
acetate/heptane = 1:1 as eluent. Melting point 142-144C.
H NMR (270 MHz, d6-DMSO): ~ = 1.25 (d, J = 7 Hz, 3 H),
3.83 (q, J = 7 Hz, 1 H), 6.61 (dd, J = 6, 2 Hz, 1 H),
6.70 (8, 2H), 10.3 ppm (br. ~, 1 H).
MS: (M + H)+ = 259

21'~76~5
- 104 -
Example XXXVI

(3S)-6-Chloro-4-N-(2-methoxyethoxycarbonyl)-3-methyl-
3,4-dihydroquinoxalin-2(lH)-one

To a solution of 0.24 ml (3.0 mmol) of 2-methoxyethanol
in 10 ml of anhydrous 1,2-dimethoxyethane there was added
0.16 g of a 55% suspension of sodium hydride in mineral
oil, and the reaction mixture was stirred for 30 minutes
at room temperature. 0.50 g (1.9 mmol) of the compound of
Example XXXV was subsequently added, with ice-cooling,
and the mixture was allowed to warm to room temperature
and stirred for a further 30 minutes. The mixture was
treated with saturated aqueous sodium chloride solution,
extracted several times with ethyl acetate, the organic
phase was washed once with saturated aqueous sodium
chloride solution and dried (magnesium sulfate), and the
solvent was removed in vacuo. After silica gel chromato-
graphy (ethyl acetate/heptane = 1:1) and crystallization
from ether/heptane, 0.29 g (51%) of the desired product
was obtained, melting point 93-94C.
1H NMR (200 MHz, d6-DMSO): ~ = 1.13 (d, J = 7.5 Hz, 3 H),
3.32 (s, 3 H), 3.6 (m, 2H), 4.24 (m, 1 H), 4.35 (m, 1 H),
4.81 (q, J = 7.5 Hz, 1 H), 6.98 (d, J = 9 Hz, 1 H), 7.2
(dd, J = 9, 3 Hz, 1 H), 7.66 (d, J = 3 Hz, 1 H, 10.81 ppm
(br. 2, 1 H).
MS: (M + H)+ = 299

Example XXXVII

(3S)-6-Chloro-3-methyl-4-N-[(phenylthio)carbonyl)]-
3,4-dihydroquinoxalin-2(lH)-one

To a solution of 0.31 ml (3.0 mmol) of thiophenol in
10 ml of 1,2-dimethoxyethane there was added 0.17 g of a
55% suspension of sodium hydride in mineral oil, with
ice-cooling, and the mixture was stirred for 1 hour at
room temperature. 0.5 g (1.9 mmol) of the compound of
Example XXXV were introduced, again with ice-cooling, and

~1 ~76~
- 105 -
stirring was then continued for 2 hours at room tempera-
ture. For working-up, the mixture was treated with
saturated aqueous sodium chloride solution, extracted
twice with ethyl acetate and dried (sodium sulfate), and
the solvent was stripped off. The solid residue was
recrystallized from heptane/isopropanol, 0.35 g (35%),
melting point 194-195C.
1H NMR (200 MHz, d6-DMSO): ~ = 1.10 (d, J = 7 Hz, 3 H),
4.93 (q, J = 7 Hz, 1 H), 7.08 (d, J ~ 9 Hz, 1 H), 7.33
(dd, J = 9, 3 Hz, 1 H), 7.4 - 78.6 (m, 5 H), 7.78 (d,
J = 3 Hz, 1 H), 10.16 ppm (br. 6, 1 H).
MS: (M + H)+ = 333, (M - C6H5SH + H)+ 223

The following compounds of the formula I were synthesized
in analogous manner.

2~3760S
- - 106 -

Table 11



~ \//

R n ¦ R 3
15 R 4


No. Rln R3 R4 R5 M.p. C
1 6-Cl CH3 H COOCH2CH=CHCH3 116-117
2 6-Cl CH3 H COOCH2=C(CH3)2 87-89
3 6-Cl CH3 H COOCH2C.CH 147
4 6-Cl CH3 H COOCH2C~CCH3 135
6-Cl CH3 H COSCR~C6~5 158
6 6-Cl CH3 H COSCH2CH=CH2 Oil
7 6-Cl CH3 H COOCH2C(CH3)=C~2 125-127
8 6-Cl CH3 H COOC ( CH3 ) 3
9 6-Cl CH3 H COO-cyclohex-2-en-1-yl
10 6-Cl CH3 H COOCH ( CH20CH ( CH3 ) 2 ) 2 Oil
11 6-Cl CH3 H COOCH(CH3)2 141-142
12 6-Cl Q3 H Cooc2H4N(cH3)2 Oil
13 6-Cl CH3 H COOC2H4SCH3 10 8-110

~1~7~0~
- 107 -

No .R1n R3 R4 R5 M . p . C

14 6-Cl CH3 H COSC6H5 194-195

6-Cl CH3 H COOCH2c6H4-2-NO2 227-231

16 6-Cl CH3 H CoocH2c6H4-3-No2 183-185

17 6-Cl CH3 H COOCH2C6H4-4-Cl 177-180

18 6-Cl CH3 H COOCH2C6H4-2-Cl 164

19 6-Cl CH3 H COOCH2CH=CHCH2CH3 Oil

6-Cl CH3 H C00(3-picolyl) 160-161

21 6-Cl CH3 H C00(2-picolyl) 114-116

22 6-Cl CH3 H CooCH2C6H4-4-NO2 230-233

23 6-Cl CH3 H COOCH2CH2C ( CH3 ) =CH2 Oil

24 6-Cl CH3 H CO- ( 4-methyl Oil
piperazin-1-yl)

6-Cl CH3 H CO~N(CH2)s 218-220

26 6-Cl CH3 H CO-N(CH2) 4 200-203

27 6-Cl CH3 H CO-morpholin-1-yl 193-195

28 6-Cl CH3 H CO-HNCH2Ph 94-96

29 6-Cl CH3 H Cyclopropylmethyl- 119-122
oxycarbonyl

Compound 31 of Table 7 i8 particularly important for the
present invention.