CA2137605A1

CA2137605A1 - Combination preparations comprising a quinoxaline and a nucleoside

Info

Publication number: CA2137605A1
Application number: CA002137605A
Authority: CA
Inventors: Christoph Meichsner; Gunther Riess; Jorg-Peter Kleim; Manfred Rosner; Arno Paessens; Martin Blunck
Original assignee: Individual
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1993-12-09
Filing date: 1994-12-08
Publication date: 1995-06-10
Also published as: CN1108935A; EP0657166A1; ZA949785B; DE59410271D1; HUT70037A; IL111909A0; KR950016754A; AU697486B2; NZ270088A; ATE236642T1; AU8042194A; HU221498B; HU9403518D0; EP0657166B1; DE4342024A1; JPH07196511A

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)

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 I

R n ~ ~// (I) R S

and their tautomeric forms of the formula Ia R~ R2 N R 3 (Ia) 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-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 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 (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~

(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 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 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 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 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-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;

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 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 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 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.

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) 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) RS

or ~R 3 (IVa) 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

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

~\N/

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

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

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~

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~

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

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

21'~7~Q5 co-r ~ R3 VII

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) 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

~R 3 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 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 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 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 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~

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 ,, 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

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

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~

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$

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.

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 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

19 6-F CH3 H Wax 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~

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~

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 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 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~

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 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 67 6--F H CH3 C5Hg 153 68 6-F 11 C113 AI.OC 120 7-CF3 H CH3 C5H9 145 c,~

No . Rln R2 R3 R5 M . p . C
7 2 7 -C6H50 H CH3 C5Hg 10 7 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 - ~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)2 157 129 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~

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 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 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~

and 2-halo carboxylic acid derivatives and, if appropriate, derivatized further:

Table 5 ~ ~//
Rln ~/\N/~

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 Table 6:
H

~N~ O
Rln ~/\N/~

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 7 C6Hs CH3C5Hg 8 6-Cl CH3 CH3IPOC 128 9 7-Cl CH3 CH3IPOC 169 7 -CH3 CH3 CH3C5H~ 16 8 12 6-CH30 CH3 CH3C5H~ 138 13 6/7-COOH CH3 CH3 H > 240 14 6 / 7 -COOH CH3 CH3C5H~ 18 0 213~Q~

No. Rln R3 R4 R5 M.p. C

16 8-CH3 CH3 CH3 C5Hg 160 19 6-CH3 C2H5 C2H5C5Hg 100 20 7-CH3 C2H5 C2H5C5Hg 110 22 7-F CH3 CH3 C5H~ 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) 21'3760~

No. R1 R3 R4 R5 M. p . C

7,8-(CH3)2 CH3 CH3IPOC 147 36 6,7-(CH3)2CH3 CH3 CH3IPOC 161 38 7 -C6H50 CH3 CH3C5H~ 138 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 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) 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 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 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).

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 Table 7 H

~ \//

Rl n R3 ~\N/~

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~

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 31 6-CH30 CH2SCH3 ~COOCH(Q3)2 163 32 6-Cl CH2SCH3 HCH2C6H4-2-Cl Oil 2137~Q5 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

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 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~

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 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:

Table 8 H

R 1 ~/N\~/

n ~N/~R 3 No.Rln R R4 R5 M.p. C

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 No. Rln R3 R4 R5 M.p. C

15 7-C6Hs-so2 H CH3 IPOC 108 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 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 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~

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:

Table 9 ~N ~ H

~ ~R3 No. R3 R4 R5 M.p. C
1 H (CH3)2CHcH2 C5Hg 2 H CH3 H 100 decomp. (HCl) 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.

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/~

- 21375Q~

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~

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~

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~

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 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~

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

Table 11 ~ \//

R n ¦ R 3 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~

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.

Claims

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

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, 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;

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, 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, 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.