AU6094098A - Quinoxaline in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating aids - Google Patents

Description

QUINOXALINES IN A TRIPLE COMBINATION WITH PROTEASE INHIBITORS AND REVERSE TRANSCRIPTASE INHIBITORS AS MEDICAMENTS FOR THE TREATMENT OF AIDS The present invention relates to the use of quinoxalines in a triple combination with 5 protease inhibitors and reverse transcriptase inhibitors as medicaments for the treatment of AIDS and/or HIV infections. The human immunodeficiency virus (HIV) causes a persistently progressive, chronic disease. HIV destroys the immune system (acquired immune deficiency syndrome, AIDS) and the central and peripheral nervous system. Besides this, various other 10 clinical manifestations in the ARC/AIDS syndrome are additionally caused by the HIV virus - in particular opportunistic infections (0.1.), caused by other viruses, such as, for example, herpes viruses (HSV I and II), cytomegalovirus (CMV) or 0.1. caused by bacteria, fungi or parasites. HIV belongs to the retrovirus family; one of the ensymatic activities of these viruses 15 which is important and essential in the replication cycle is the protease activity (Huff, J.R:, J. Med. Chem. (1991), 34, 2305-2314). Small molecular weight peptide and non peptide analogues of the natural substrates of the protease inhibit the replication of HIV (Roberts, N.A. et al., Science (1990) 248, 358 - 361; Lam, P.Y.S. et al., Science (1994), 263, 380-384) in vitro and in vivo. 20 Analogues of the natural substrates of reverse transcriptase such as, for example, azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3' thiacytidine (lamivudine) inhibit the replication of HIV in vitro and in vivo. AZT is used, for example, for the treatment of ARC/AIDS sufferers. The long-term therapy of HIV-infected patients with AZT is accompanied, however, by bone marrow toxicity; 25 moreover AZT-resistant virus isolates result. Intolerabilities such as, for example, a peripheral neuropathy are reported by some patients who have been treated with DDC or DDI. New inhibitors for tolerable and efficacious therapy are therefore necessary. The triple combination of quinoxalines with protease inhibitors and reverse -2 transcriptase inhibitors now found is new and its synergistic action on the replication of HIV when used in the control of AIDS or HIV infections is substantially better than that of the prior art. It has now been found that quinoxalines of the general formula (I) R2 Fe R " R R' 5 and their tautomeric forms of the general formula (Ia) in which 1) n is zero, one, two, 10 three, or four, the individual substituents R1 independently of one another denotes fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C 8 -alkyl, C.-C-cycloalkyl, 15 C,-C 6 -alkoxy, (C-C 6 -alkoxy)-(C -C 4 -alkoxy), C-C 6 -alkylthio, C 1

-C

6 alkylsulphinyl, C-C 6 -alkylsulphonyl, nitro, amino, azido, C-C 6 -alkylamino, di(C,-C 6 -alkyl)amino, piperidino, morpholino, 1 -pyrrolidinyl, 4- - 3 methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C,-C 6 -acyl,

C,-C

6 -acyloxy, C-C 6 -acylamino, cyano, carbamoyl, carboxyl, (C 1

-C

6 alkyl)oxycarbonyl, hydroxysulphonyl, sulphamoyl or 5 a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxysulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to five radicals R 6 which are independent of one another, where R 6 can be 10 fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C,-C,-alkyl, C 3 -C,-cycloalkyl, C,-C 6 -alkoxy, C-C 6 -alkylthio,

C,-C

6 -alkylsulphinyl, C,-C 6 -alkylsulphonyl, C 1

-C

6 -alkylamino, di(Cj-C 6 alkyl)amino, (C,-C 6 -alkyl)oxycarbonyl, phenyl, phenoxy or 2-, 3- or 4-pyridyl,

R

2 denotes hydrogen, C,-C 6 -alkoxy, hydroxyl, picolyl, cyclopropyl or 15 isopropenyloxycarbonyl and

R

5 denotes hydrogen, hydroxyl, C 1

-C

6 -alkoxy, aryloxy, C,-C 6 -acyloxy, cyano, amino, C 1

-C

6 -alkylamino, di(Cl-C 6 -alkyl)amino, arylamino, C -C-acylamino,

C

1

-C

8 -alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1

-C

6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, 20 CI-C 6 -alkoxy, C,-C 6 -alkylamino, di(C,-C 6 -alkyl)amino, C-C 6 -alkylthio, C,-C 6 alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

2 -C-alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C, - C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 -alkylamino, di(C-C 6 -alkyl)amino, C 1

-C

6 -alkylthio, 25 (C-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; -4

C

3 -C-allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 alkoxy, oxo, phenyl; C 3

-C

8 -alkinyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C,-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C,-alkoxy, C,-C,-alkylamino, di(C,-C,-alkyl)amino, 5 C,-C,-alkylthio, C,-C,-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C,-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C 1

-C

6 -alkylamino, di(C,-C 6 -alkyl)amino, C-C 6 -alkylthio, 10 C-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1

-C

6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C,-alkoxy, C,-C 6 -alkylamino, di(C,-C 6 -alkyl)amino, C,-C 6 -alkylthio, C,-C,-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; 15 (C 3

-C

8 -cycloalkyl)-(C,-C 4 -alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C 1 -C,-alkylamino, di(C 1

-C

6 -alkyl)amino,

C,-C

6 -alkylthio, C,-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; 20 (C 3 -C-cycloalkenyl)-(C,-C 4 -alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 -alkylamino, di(C,-C 6 -alkyl)amino,

C,-C

6 -alkylthio, C,-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; 25 C-C 6 -alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C-C 6 -alkoxy, C-C 6 -alkylamino, di(C-C 6 -alkyl)amino, - 5 C,-C,-alkylthio, C,-C,-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

2

-C

8 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl; 5 (C 3

-C

8 -cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo or phenyl;

(C,-C

8 -cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C-C 4 -alkoxy, oxo or phenyl;

(C

3

-C

8 -cycloalkyl)-(Cl-C 3 -alkyl)carbonyl, optionally substituted by fluorine, 10 chlorine or hydroxyl, C 1

-C

4 -alkoxy, oxo or phenyl;

(C

5

-C

6 -cycloalkenyl)-(C,-C 3 -alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo or phenyl;

C-C

8 -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C 4 -alkoxy, Cl-C 4 -alkylamino, di(C 1

-C

4 -alkyl)amino or C,-C 4 15 alkylthio;

C

2

-C

8 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl;

C

2 -C,-alkinyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl; 20 C,-C,-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl;

C

2

-C

8 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, -6

C,-C

4 -alkoxy, oxo or phenyl; C,-C.-alkylamino- and di(C,-C,-alkyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; pyrrolidin- 1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin- 1-yl 5 carbonyl, optionally substituted by C,-C 4 -alkyl, C 2

-C

6 -alkenyl, C,-C 4 -acyl, oxo, thioxo, carboxyl or phenyl;

C

2

-C

8 -alkenylamino- and di(C,-C 6 -alkenyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl;

C,-C

6 -alkylsulphonyl, optionally substituted by fluorine, chlorine, hydroxyl, 10 C,-C 4 -alkoxy, oxo or phenyl;

C-C

6 -alkenylsulphonyl, optionally substituted by fluorine, chlorine, hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl; or an aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, 15 (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, substituted by up to five radicals R 6 which are independent of one another, where the alkyl radical can in each case contain 1 to 5 C atoms and R 6 is as defined above 20 or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio) carbonyl, heteroarylalkylaminocarbonyl, substituted by up to three radicals R 6 which are independent of one another, where the alkyl radical can in each case 25 contain 1 to 3 C atoms, - 7 R 3 and R 4 identically or differently, independently of one another denote hydrogen, C,-C-alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy,

C,-C

4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C-C 4 -alkylsulphonyl, 5 C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl;

C

2 -C-alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy,

C

1

-C

4 -alkylamino, di(C,-C 4 -alkyl)amino, C 1

-C

4 -alkylthio, C,-C 4 -alkylsulphonyl,

C,-C

4 -alkylsulphinyl, carboxyl or carbamoyl; 10 C 3

-C

8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, Cl-C 4 -alkylamino, di(Cl-C 4 -alkyl)amino, C,-C 4 -alkylthio, C,-C 4 -alkylsulphonyl,

C-C

4 -alkylsulphinyl, carboxyl or carbamoyl;

C

3 -C,-cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, 15 amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C 1

-C

4 -alkylthio, C 1

-C

4 alkylsulphonyl, C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl substituted by up to five radicals R' which are independent of one another, where the alkyl radical in each case can 20 contain 1 to 3 C atoms and R' is as defined above,

R

3 and R 4 can furthermore also denote part of a saturated or unsaturated carbo- or heterocyclic ring having 3 to 8 C atoms, which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C,-alkyl, C 2

-C

6 -alkenyl, C 2

-C

6 -alkinyl,

C,-C

6 -acyloxy, benzoyloxy, C,-C 6 -alkoxy, oxo, thioxo, carboxyl, carbamoyl or 25 phenyl, X denotes oxygen, sulphur, selenium or substituted nitrogen N-R 2 , in which R 2 can -8 have the meanings given above in combination with protease inhibitors and reverse transcriptase inhibitors are very highly suitable for use as medicaments in the control of AIDS and HIV infections. The alkyl groups mentioned in the preceding definitions can be straight-chain or 5 branched. If not defined otherwise, they preferably contain 1-8, particularly preferably 1-6, in particular 1-4, C atoms. Examples are the methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl groups and the like. The alkenyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 double bonds. If not defined otherwise, these groups 10 preferably contain 2-8, in particular 2-6, C 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 the like. The alkinyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 triple bonds. If not defined otherwise, they preferably 15 contain 2-8, particularly preferably 3-6, C atoms. Examples are the 2-propinyl and 3 butinyl group and the like. The cycloalkyl and cycloalkenyl groups mentioned in the preceding definitions contain, if not defined otherwise, preferably 3-8, particularly preferably 4-6, C atoms. Examples are the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl 20 groups. The acyl groups mentioned in the preceding definitions can be aliphatic, cycloaliphatic or aromatic. If not defined otherwise, they preferably contain 1-8, particularly preferably 2-7, C atoms. Examples of acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl 25 or benzoyl groups.

-9 The aryl groups mentioned in the preceding definitions are preferably aromatic groups having 6-14 C atoms, in particular having 6-10 C atoms, such as, for example, phenyl or naphthyl. In the abovementioned heterocyclic rings and heteroaryl groups, suitable heteroatoms 5 in particular are, for example, 0, S, N, where in the case of a saturated N-containing ring in this position, N-Z is present in which Z denotes H or R' having the respective definitions described above. If not defined otherwise, the heterocyclic rings preferably have 1-13 C atoms and 1-6 heteroatoms, in particular 3-9 C atoms and 1-4 heteroatoms. 10 For the heteroaryl groups mentioned in the preceding definitions, possible heteroaromatic radicals, for example, are those such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl. The aralkyl groups mentioned in the preceding definitions are, for example, benzyl, phenylethyl, naphthylmethyl or styryl. 15 The abovementioned substituents R' to R' are preferably substituted 3 times, particularly preferably 2 times, in particular once, by the substituents indicated in each case. For the respective summarized substituent definitions (such as, for example, arylalkoxycarbonyl), the ranges described beforehand as preferred are also preferred for 20 the individual substituents. Depending on the various substituents, compounds of the formulae I and Ia can have two or more asymmetric carbon atoms. The invention therefore relates to both the pure stereoisomers and to mixtures thereof, such as, for example, the accompanying racemate.

- 10 The pure stereoisomers of the compounds of the formulae I and Ia can be prepared directly by known methods or in analogy to known methods or subsequently separated. 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, 5 S. Coffey, M.F. Ansell (Editors); Elsevier, Amsterdam, 1989; Vol. IV Part IJ, pp. 301 311. Heterocyclic Compounds, R.C. Elderfield (Editor); Wiley, New York, 1957; Vol. 6, pp. 491 - 495). In the context of the invention, protease inhibitors are known structurally different peptide analogues which are suitable for the treatment of retrovirus-induced diseases. 10 The following may particularly be mentioned: 1.) 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl) 1-[2-(1 -methylethyl)-4-thiazolyl]-3,6-dioxo-8, 11 -bis-(phenyl-methyl)-, 5 thiazolylmethyl ester [5S-(5R*, 8R*, 10R*, 11R*)]; PCT WO 95/07696; PCT WO 95/20384 Al; PCT WO 95/009614 Al [ABBOTT (ritonavir) ABT 15 538] N H OH NO N N O H II >4N)( N N N 0 O H 0 2.) 3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3 hydroxy-2-methylbenzoyl)amino] -4-(phenylthio)butyl] -[3 S-[2-(2S *,3 S *), 3.alpha., 4a.beta., 8a.beta.]]-, monoethanesulphonate (salt); PCT WO 95/09843; US 5484926; [AGOURON (ViraceptR) AG-1343] -H11 CH 3 0 CHO HO N N H H OH 3.) Carbamic acid, [3-[[(4-aminophenyl)sulphonyl] (2-methylpropyl)amino]-2 hydroxy-1-(phenylmethyl)propyl]-, tetrahydro-3-furanyl ester, [3S-[3R* (1S*, 2R*)]]-; PCT WO 94/05639; [VERTEX PHARM. (Kisseii, Glaxo Wellcome), VX-478] NSo2 NH2 H O 5 4.) (S)-N-[(alphaS)-alpha-[(1R)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro 2(1H)-isoquinolinyl)-1-hydroxyethyl)phenethyl-2-quinaldamido]-succinamide (EP 432 695 A2) N N NN H OH

NH

2 NH-C(CH) 5.) 2(R)-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)- - 12 4(S)-hydroxy-N-(2(R)-hydroxyindan- 1 (S)-yl)pentanamide (L-735524, EP 569 083 Al, EP 541 168 Al) N OHO O N OH HaC CH3 CH3 6.) N-(Quinolin-2-ylcarbonyl)-asparagine- 1 (S)-benzyl-3-(3-tert-butyl- 1 isobutylureido)-2(R)-hydroxypropylamide (SC 52 151, PCT WO 92/08688 Al, 5 WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al) 0 CH3 O NH2 OH CHC4 HH 0 O CH, 7.) N1 -(2R-hydroxy-3 -((3 -methylbutyl)methylsulphonyl)amino)- 1 S-(phenyl methyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide (AM 11 686, PCT WO 94/04492) 0 N NII N N"0 2 -CH3 O0-

NH

2 OH

CH(CH,)

2 0 - 13 8.) (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl) methyl)amino)carbonyl)valinyl)amino)-2-(N-((5 -thiazolyl)methoxy carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436) 0CH C 6 H

H

2 C 3 JI HH HNC N N NN II H NYC

H

3 C 0 I~l

H

3 C

CH

3 C 5 -N 9.) (R)-N-tert-butyl-3-((2S,3 S)-2-hydroxy-3-N-((R)-2-N-(isoquinolin-5 5 yloxyacetyl)amino-3 -methylthiopropanoyl)amino-4-phenylbutanoyl)-5 ,5 dimethyl-1,3-thiazolidine-4-carboxamide (KNI 272/Nippon Mining)

H

3 C CH N N

CH

3 N H NH CHH CH N N NN H HY 0 0 10.) {3-[(4-Aminobenzenesulphonyl)isobutylamino]-1 -benzyl-2 hydroxypropyl}carbamic acid tetrahydrofuran-3-yl ester 0 N CONNH OH

CH(CH)

2 11.) (3 S,6R)-3 -(-ethylbenzyl)-6-(-ethylphenethyl)-4-hydroxy-2H-pyran-2-one - 14 (VB 11 478, PCT WO 94/11361) OH CH, 0 0 01**' CH3 12.) N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3 S)-epoxy-6 phenylhexanoyl]isoleucine (EP 601 486 A) y N \ OCH3 O , NH 2 0 0 AC CH H3C3 0 13.) N-tert-butyl-1 -[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinyl 5 carbonyl)asparaginyl]amino]butyl-4(R)-(phenylthio)piperidine-2(S)-carboxamide (EP 560 268 A)

NH

2 0 O OH N H C(CHal 3 14.) [3 "'S-(3 'R*,4'S*)]-N-[1'-oxo-l'-(3"-[1"'-oxo-2"'-aza-3"'-phenylmethyl-4"' hydroxy-5"'-(2"'-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-1,2,3,4 tetrahydroisoquinoline (EP 609 625 A) - 15 N 0 NH C(CHal 3 15.) 2-[2-Hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylsulphamylbutyl] decahydroisoquinoline-3-carboxylic acid tert-butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA) CAH, S 0 NH-C(CHal 3 CH, O HO NH OH H 16.) 2H-1,4-Diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-, 5 [3S'-(3.alpha., 6.beta., 7.beta.)] (PCT WO 94/08977) Y~O N OH Reverse transcriptase inhibitors in the context of the invention represent different nucleosides. Zidovudine (Retrovir) (AZT), didanosine (DDI), dideoxycytidine (DDC), lamivudine (Epivir, 3-TC*), stavudine (D4T), BW 935U83 and BW 1592U89 are preferred, in particular zidovudine and Epivir. The nucleosides mentioned can be 10 prepared by generally known processes (cf. Merck Index, 11th Edition Rahway, N.J. 1989, Drugs 45 (4), 488 ff., 45 (5), 637 ff., 1993, Drugs 44 (4), 656 ff., 1992, Clin.

- 16 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 34 th ICAAC, Orlando 4.

7.10.94). Retrovir (AZT) is particularly preferred. Preferred quinoxalines of the general formulae (I) and (Ia) are those 5 in which n is zero, one, or two, the individual substituents 10 R' independently of one another denotes fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C 1

-C

4 -alkyl, C,-C 4 -alkoxy, (C,-C 4 -alkoxy)-(C,-C 4 alkoxy), C,-C 4 -alkylthio, nitro, amino, C-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, CI-C 4 -acyl, C,-C 4 acyloxy, C,-C 4 -acylamino, cyano, carbamoyl, carboxyl, (C 1

-C

4 15 alkyl)oxycarbonyl, hydroxysulphonyl or sulphamoyl or a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2 pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two radicals R' which are independent of one another, 20 where R' 6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino,

C-C

4 -alkyl, C,-C 4 -alkoxy, (C,-C 4 -alkyl)oxycarbonyl, phenyl or phenoxy, - 17 R 2 denotes hydrogen and

R

5 denotes C 1

-C

6 -alkyl, optionally substituted by fluorine, chlorine, hydroxyl,

C,-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or 5 carbamoyl;

C

2

-C

6 -alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

C

3 -C-allenyl, C 3

-C

8 -alkinyl, optionally substituted by fluorine, chlorine, 10 hydroxyl, Cl-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy,Cl-C 4 alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

4 -alkoxy, C,-C 4 15 alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C,-Cr-cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C-C 4 alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 alkylamino, di(C,-C 4 -alkyl)amino, CI-C 4 -alkylthio, oxo, thioxo, carboxyl or 20 carbamoyl;

(C

3

-C

6 -cycloalkyl)-(C,-C 2 -alkyl), optionally substituted by fluorine, chlorine, hydroxyl, C 1

-C

4 -alkyl, C 1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C-C 4 alkoxy, Cl-C,-alkylamino, di(Cl-C 4 -alkyl)amino, C 1

-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 25 (C 3

-C

6 -cycloalkenyl)-(Cl-C 2 -alkyl), optionally substituted by fluorine, chlorine, - 18 hydroxyl, C,-C 4 -alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C,-C,-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, 5 C,-C 4 -alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C-C 4 -alkoxy,

C,-C

4 -alkylamino, C 1

-C

4 -alkenylamino, di(C-C 4 -alkyl)amino, 1 -pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

C

2 -C,-alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl; 10 (C 3 -C,-cycloalkyl)carbonyl, (C,-C,-cycloalkenyl)carbonyl,

(C

3

-C

6 -cycloalkyl)-(C-C 2 -alkyl)carbonyl,

(C

5

-C

6 -cycloalkenyl)-(C-C 2 -alkyl)carbonyl,

C

1

-C

6 -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, 15 hydroxyl, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino or CI-C4 alkylthio;

C

2

-C

6 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C-C 4 -alkoxy;

C

2 -C-alkinyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl 20 or C,-C 4 -alkoxy;

C,-C

6 -alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; - 19 C 2 -C,-alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; C,-C,-alkylamino and di(C,-C 6 -alkyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C 1

-C

4 -alkoxy; 5 pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-, or 4-methylpiperazin-1 ylcarbonyl;

C

2

-C

6 -alkenylamino and di(C,-C 6 -alkenyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or CI-C 4 -alkoxy;

C-C

4 -alkylsulphonyl, optionally substituted by fluorine, chlorine, hydroxyl or 10 C 1

-C

4 -alkoxy;

C

1

-C

4 -alkenylsulphonyl; or aryl, arylcarbonyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylsulphonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, 15 substituted by up to two radicals R 6 which are independent of one another, where the alkyl radical can in each case contain 1 to 3 C atoms and R 6 is 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 20 furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4 picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3 thienylmethyloxycarbonyl, substituted by up to two radicals R 6 which are independent of one another, and - 20 R 3 and R4 identically or differently, independently of one another denote hydrogen,

C,-C

4 -alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C,-C 4 -alkylsulphonyl, C 1

-C

4 5 alkylsulphinyl, carboxyl or carbamoyl;

C,-C

6 -alkenyl, optionally substituted by fluorine or chlorine;

C

3

-C

6 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C 1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 -alkoxy,

C

1

-C

4 -alkylamino, di(Cl-C 4 -alkyl)amino, C 1

-C

4 -alkylthio, C,-C 4 -alkylsulphonyl, 10 C,-C 4 -alkylsulphinyl, carboxyl, carbamoyl;

C

3 -C.-cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl substituted by up to two radicals R 6 which are independent of one another,

R

3 and R 4 can furthermore also be part of a saturated or unsaturated carbo- or 15 heterocyclic ring having 3 to 6 C atoms, which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C 1

-C

4 -acyloxy, benzoyloxy, C,-C 4 -alkoxy, oxo, thioxo, carboxyl, carbamoyl, and X denotes oxygen or sulphur, optionally in an isomeric form, in combination with protease inhibitors of the series: 20 1.) 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1 [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis-(phenylmethyl)-, 5-thiazolyl methyl ester [5S-(5R*, 8R*, 1OR*, 11 R*)] 2.) 3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3 hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-[3 S-[2-(2S *, 3S*), - 21 3.alpha., 4a.beta., 8a.beta.]]-, monoethanesulphonate (salt) 3.) Carbamic acid, [3-[[(4-aminophenyl)sulphonyl] (2-methylpropyl)amino]-2 hydroxy-1-(phenylmethyl)propyl]-, tetrahydro-3-furanyl ester, [3S-[3R* (IS*, 2R*)]] 5 4.) (S)-N-[(alphaS)-alpha-[(1R)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro 2-(1H)-isoquinolinyl)-1-hydroxyethyl)phenethyl-2-quinaldamido]succinamide 5.) 2(R)-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl) 4(S)-hydroxy-N-(2(R)-hydroxyindan- 1 (S)-yl)pentanamide 6.) N-(Quinolin-2-ylcarbonyl)asparagine- 1 (S)-benzyl-3-(3-tert-butyl- 1 10 isobutylureido)-2(R)-hydroxypropylamide 7.) N1 -(2R-hydroxy-3-((3-methylbutyl)methylsulphonyl)amino)-1 S (phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide 8.) (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl) methyl) amino) c arb onyl) v al in yl) amino) -2- (N -((5 -thi azo lyl ) m etho xy 15 carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane 9.) (R)-N-tert-butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolin-5 yloxyacetyl)amino-3 -methylthiopropanoyl)amino-4-phenylbutanoyl)-5 ,5 dimethyl-1,3-thiazolidine-4-carboxamide 10.) { 3- [(4-Aminobenzenesulphonyl)isobutylamino] -1 -benzyl-2-hydroxy 20 propyl}carbamic acid tetrahydrofuran-3-yl ester 11.) (3S,6R)-3-(-ethylbenzyl)-6-(-ethylphenethyl)-4-hydroxy-2H-pyran-2-one 12.) N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6 phenylhexanoyl]isoleucine 13.) N-tert-butyl- 1 -[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinyl 25 carbonyl)asparaginyl]amino]butyl-4(R)-(phenylthio)piperidine-2(S)-carboxamide 14.) [3"'S-(3'"R*,4"'S*)]-N-[1'-oxo-l'-(3"-[1"'-oxo-2"'-aza-3 '-phenylmethyl-4'" hydroxy-5"'-(2"'-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-1,2,3,4 tetrahydroisoquinoline 15.) 2-[2-Hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenyl 30 sulphamylbutyl]decahydroisoquinoline-3-carboxylic acid tert-butylamide 16.) 2H-1,4-Diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-, [3S'-(3.alpha., 6.beta., 7.beta.)] - 22 and reverse transcriptase inhibitors for use as medicaments in the control of AIDS and HIV infections. Particularly preferred quinoxalines of the general formulae (I) and (Ia) are those in which 5 n denotes zero, one, or two, the individual substituents R' independently of one another denotes fluorine, chlorine, bromine, 10 trifluoromethyl, hydroxyl, C,-C 4 -alkyl, C,-C 4 -alkoxy, (C,-C 4 -alkoxy)-(C,-C 2 alkoxy), C 1

-C

4 -alkylthio, nitro, amino, C,-C,-alkylamino, di(C,-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C-C 4 -acyl, C,-C 4 acyloxy, C,-C 4 -acylamino, cyano, carbamoyl, carboxyl, (C 1

-C

4 alkyl)oxycarbonyl, hydroxysulphonyl, sulphamoyl 15 or a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2 pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two radicals R 6 which are independent of one another, where 20 R' can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino,

C,-C

4 -alkyl, C 1

-C

4 -alkoxy, (C,-C 4 -alkyl)oxycarbonyl, phenyl, phenoxy

R

2 denotes hydrogen and - 23 R 5 denotes C 1

-C

6 -alkyl optionally substituted by C,-C 4 -alkoxy or C,-C 4 -alkylthio;

C

2 -C,-alkenyl, optionally substituted by oxo;

C

3

-C

6 -allenyl;

C

3

-C

8 -alkinyl, in particular 2-butinyl; 5 C 3

-C

6 -cycloalkyl;

C

5

-C

6 -cycloalkenyl;

(C

3

-C

6 -cycloalkyl)-(C,-C 2 -alkyl), in particular cyclopropylmethyl, optionally substituted by CI-C 4 -alkyl; (C-C,-cycloalkenyl)-(C,-C 2 -alkyl), in particular cyclohexenylmethyl; 10 C-C 6 -alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C 4 -alkoxy, C-C 4 -alkylamino, C-C 4 -alkenylamino, di(C, -C 4 -alkyl)amino, 1 -pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin 1-yl, CI-C 4 -alkylthio;

C

2

-C

6 -alkenylcarbonyl; 15 C,-C,-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C 4 -alkoxy, C-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, CI-C4 alkylthio;

C

2

-C

6 -alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; 20 C 2 -C-alkinyloxycarbonyl, in particular propinyloxycarbonyl, - 24 butinyloxycarbonyl; C,-C,-alkylthiocarbonyl;

C

2

-C

6 -alkenylthiocarbonyl, in particular allylthiocarbonyl;

C,-C

6 -alkylamino and di(C 1

-C

6 -alkyl)aminocarbonyl; 5 pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1 ylcarbonyl;

C

2

-C

6 -alkenylamino and di(C,-C 6 -alkenyl)aminocarbonyl;

C,-C

4 -alkylsulphonyl;

C

1

-C

4 -alkenylsulphonyl; 10 or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, substituted by up to two radicals R 6 15 which are independent of one another, where the alkylradical can in each case contain 1 to 3 C atoms and R 6 is 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 20 picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3 thienylmethyloxycarbonyl, substituted by up to two radicals R 6 which are independent of one another, - 25 and

R

3 and R 4 identically or differently, independently of one another denote hydrogen,

C,-C

4 -alkyl, optionally substituted by hydroxyl, mercapto, C,-C 4 -alkoxy, C,-C 4 alkylthio, C,-C 4 -alkylsulphonyl, C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl; 5 C 2

-C

6 -alkenyl, aryl, benzyl, thienyl or thienylmethyl substituted by up to two radicals R 6 which are independent of one another, where R 6 is as defined above,

R

3 and R 4 can also be part of a saturated or unsaturated carbo- or heterocyclic ring having 3 to 6 C atoms, which can optionally be substituted by oxo or thioxo 10 and X denotes oxygen or sulphur in combination with protease inhibitors of the series: 1.) 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1 [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis-(phenylmethyl)-, 5-thiazolyl 15 methyl ester [5S-(5R*, 8R*, 1OR*, 11R*)] 2.) 3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3 hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-[3S-[2-(2S*, 3S*), 3.alpha., 4a.beta., 8a.beta.]]-, monoethanesulphonate (salt) 3.) Carbamic acid, [3-[[(4-aminophenyl)sulphonyl] (2-methylpropyl)amino]-2 20 hydroxy-1-(phenylmethyl)propyl]-, tetrahydro-3-furanyl ester, [3S-[3R* (IS*, 2R*)]] 4.) (S)-N-[(alphaS)-alpha-[(1R)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro 2(lH)-isoquinolinyl)-1-hydroxyethyl)phenethyl-2-quinaldamido]succinamide 5.) 2(R)-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl) 25 4(S)-hydroxy-N-(2(R)-hydroxyindan- 1 (S)-yl)pentanamide - 26 6.) N-(Quinolin-2-ylcarbonyl)asparagine- 1 (S)-benzyl-3-(3-tert-butyl- 1 isobutylureido)-2(R)-hydroxypropylamide 7.) 2(1H)-Pyrimidinone, 4-amino-1-[2-(hyroxymethyl)-1,3-oxathiolan-5-yl]-, [(2R cis)-(9CI)] (Epivir) 5 and reverse transcriptase inhibitors for use as medicaments in the control of AIDS and HIV infections. A very particularly preferred combination is that of S-4-isopropoxycarbonyl-6-methoxy 3-(methylthio-methyl)-3,4-dihydro-quinoxazoline-2(1H)-thione of the formula (A) H N HC-O N CHA 0 0

H

3 C

CH

3 or 1(2H)-quinoxalinecarboxylic acid, 2-ethyl-7-fluoro-3,4-dihydro-3-oxo-, 1 -methylethyl 10 ester [(S)-(9CI)] of the formula (B) H F: CH, F o H3C CHI with (S)-N-[(alphaS)-alpha-[(1R)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro 2(1H)-isoquinolinyl)-1-hydroxyethyl)phenethyl-2-quinaldamido]succinamide (saquinavir) of the formula (C) - 27 N' (C) 0 O

NH

2 NH-C(CH) or 2(R)-benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S) hydroxy-N-(2(R)-hydroxyindan-1(S)-yl)pentanamide of the formula (D) N OHO HaC CH3 CH3 or 2,4,7,12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1 methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis-(phenylmethyl)-, 5-thiazolylmethyl ester 5 [5S-(5R*, 8R*, 1OR*, 11R*)] N N N (E) HH 0 ZNI and Retrovir (AZT) or Epivir for use in the control of AIDS and HIV infections. The quinoxalines of the general formulae (I) and (Ia) have been disclosed - 28 [cf. EP 509 398 Al; EP 708 093; EP 657 166]. The abovementionedprotease inhibitors are likewise known [cf. EP 432 695 A2, EP 569 083 Al, EP 541 168 Al, PCT WO 92/08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al, PCT WO 94/04492, PCT WO 94/14436, PCT WO 9411361, 5 EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977]. The use of the combination of these compounds in the treatment of retrovirus-induced, but in particular HIV-induced, diseases offers advantages in comparison to monotherapy or double combinations of the individual compounds. The advantageous and superior use of the combination of these compounds for the treatment of AIDS or 10 HIV infections results mainly from the synergistic antiviral activity, but additionally also from the unchanged tolerability of the substances in combination in the range of toxicity at which 50% of the cells survive - in comparison with the tox-50 of the individual components. It is known for other combinations - e.g. AZT in combination with ganciclovir, that when using a combination a synergistic toxicity results 15 [cf. M.N. Prichard et al., Antimicrob. Agents Chemotherapy (1991), 15, 1060-1065]. A reduced active dose results from the use of the triple combination of the substances for the treatment. Moreover, the use of the triple combination reduces the probability of the formation of resistant virus isolates. The invention relates to the combination of three compound classes of inhibitors of 20 HIV reverse transcriptase and HIV protease for the prevention and treatment of infections with HIV, and for the treatment of the diseases induced by HIV, such as AIDS-related complex (ARC) or AIDS.

- 29 HIV infection in cell culture The HIV test was carried out with modifications according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, (1988), 309-321]. Normal human blood lymphocytes (PBLs) were enriched by means of Ficoll-Hypaque 5 and stimulated with phythaemagglutinin (90 ig/ml) and interleukin-2 (40 U/ml) in RPMI 1640, 20% foetal calf serum. For infection with the infectious HIV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HIV virus solution for adsorption and incubated at 37*C for 1 hour. The virus adsorption solution was centrifuged and the infected cell pellet taken up in 10 growth medium such that the concentration was adjusted to 1 x 10' cells per ml. The cells infected in this way were pipetted at 1 x 104 cells/well into the wells of 96-well microtitre plates. Alternatively, instead of the PBLs H9 cells were employed for the antiviral tests. The testing of the combinatorial action of the test substances was carried out by means 15 of checkerboard titration. The first vertical row of the microtitre plate contained only growth medium and cells which had not been infected, but otherwise treated exactly as described above (cell control). The second vertical row of the microtitre plate contained only HIV-infected cells (virus control) in growth medium. The other wells contained the compounds 20 according to the invention - on their own or in corresponding combinations - at different concentrations, starting from the wells of the 3rd vertical row of the microtitre plates, from which the test substances were further diluted in steps of 2 (50 pl volume per well). For the combination, dilutions of the 2nd substance were prepared in a separate 96-well microtitre plate and then pipetted onto the prepared first plate. The 25 third compound was initially introduced in a fixed concentration in each case, so that, for example 4 dilution stages (corresponding to 4 test batches) of the 3rd inhibitor were tested. In each case, 100 pl of the prepared HIV-infected cells were added (see above).

- 30 Thus test concentrations of the 3 inhibitors in the range about 10 - 50-fold above and below the ICO concentrations of the individual compounds were covered. The test batches were incubated at 37*C until in the untreated virus control the syncytia formation typical of HIV was microscopically detectable in the host cell (between day 5 3 and 8 after infection). In the untreated virus control, under these test conditions approximately 20 - 50 syncytia resulted, while the untreated cell control contained no syncytia. The supernatants of the 96-well plate were then harvested and investigated for HIV specific antigen in an HIV-specific ELISA test (Vironostika HIV antigen, Organon 10 Teknika). The inhibitory values were converted into per cent (%) inhibitory values according to the cut-off values from corresponding cell or virus controls or internal test controls, and the IC, values were determined as the concentrations of the treated and infected cells at which 50% of the virus-specific antigen was suppressed by the treatment with the 15 compounds. For analysis of the synergistic activity of the compounds, the differences between calculated and measured inhibitory values of the combinations were determined (Prichard, M.N. et al., Antimicrob. Agents Chemoth. (1993), 317, 540-545). The triple combination surprisingly showed synergistic activity in concentration ranges in which no antiviral action is observed by means of individual treatment or double 20 combination. Thus 0.5 nM Retrovir and even 0.1 nM Retrovir in combination with 0.1 to approximately 10 nM of the quinoxaline and approximately 70 to 6 nM indinavir or 0.2 to 6 nM of the quinoxaline with approximately 10 to 50 nM indinavir exhibit a strong synergistic action. Examples of this are the combination of Retrovir with S-4 25 isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydro-quinoxazoline-2(1H) thione of the formula (A) and with indinavir or the combination of Retrovir with 1(2H)-quinolinecarboxylic acid, 2-ethyl-7-fluoro-3,4-dihydro-3-oxo-, 1-methylethyl ester - 31 [(S)-(9CI)] of the formula (B) and with indinavir. It was surprisingly found that a synergistic action on the HIV is achieved by the use of the triple combination of the compounds. This was illustrated by triple combination studies of the quinoxaline derivative with indinavir and Retrovir. 5 The triple combinations according to the invention are used for the treatment and prophylaxis of diseases caused by retroviruses, in human and veterinary medicine. Indication areas which can be mentioned, for example, in human medicine are: 1.) The treatment and prophylaxis of human retrovirus infections. 2.) The treatment or prophylaxis of diseases (AIDS) caused [lacuna] HIV I (human 10 immunodeficiency virus; earlier called HTLV III/LAV) and the stages associated therewith such as ARC (AIDS-related complex) and LAS (lymphadenopathy syndrome), and the immunodeficiency and encephalopathy caused by this virus. 3.) The treatment or the prophylaxis of an HTLV-I or HTLV-II infection. 15 4.) The treatment or the prophylaxis of the AIDS-carrier state (AIDS-transmitter state). Examples of indications in veterinary medicine which can be mentioned are: infections with a) maedivisna (in sheep and goats) 20 b) progressive pneumonia virus (PPV) (in sheep and goats) - 32 c) caprine arthritis encephalitis virus (in sheep and goats) d) zwoegersiekte virus (in sheep) e) infectious anaemia virus (of the horse) f) infections caused by the feline leukaemia virus 5 g) infections caused by the feline immunodeficiency virus (FIV) h) infections caused by the simian immunodeficiency virus (SIV) From the indication area in human medicine, the abovementioned items 2, 3 and 4 are preferred. The present invention includes pharmaceutical preparations which, besides non-toxic, 10 inert pharmaceutically suitable excipients, contain one or more compounds of the formulae (I)/(Ia) in combination with a protease inhibitor and a reverse transcriptase inhibitor or which consist of one or more active compounds of the formulae (I)/(Ia), the protease inhibitor and the reverse transcriptase inhibitor, and processes for the production of these preparations, in particular the combination of the test compounds. 15 The active compounds of the formulae (I) and (Ia), the protease inhibitors and the reverse transcriptase inhibitors should be present in the abovementioned pharmaceutical preparations in a concentration of approximately 0.1 to 99.5% by weight, preferably of approximately 0.5 to 95% by weight, of the total mixture. Apart from the compounds of the formulae (I)/(Ia) in combination with a protease 20 inhibitor and a reverse transcriptase inhibitor, the abovementioned pharmaceutical preparations can also contain other pharmaceutical active compounds. The abovementioned pharmaceutical preparations are prepared in a customary manner - 33 by known methods, e.g. by mixing the active compound(s) with the excipient(s). In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound(s) according to the invention in total amounts of approximately 0.5 to approximately 500, preferably 1 to 100, mg/kg of body weight 5 every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose contains the active compound(s) preferably in amounts of approximately 1 to approximately 80, in particular 1 to 30, mg/kg of body weight. However, it may be necessary to deviate from the doses mentioned, namely depending on the species and the body weight of the subject to be treated, the nature 10 and the severity of the disease, the type of preparation and the administration of the medicament, and also on the time or interval within which administration takes place. Double combinations in the treatment of HIV-infected patients show a superior efficacy to monotherapy. However, resistant viruses can also occur under a therapy scheme of this type. The triple combination described here acts synergistically on the replication 15 of the HIV and thus more effectively suppresses the formation of resistant viruses.

Claims (12)

1. Medicaments containing in a triple combination quinoxalines of the general formula (I) R 2 N R R' and their tautomeric forms of the general formula (Ia) RnN R 3 (,a) 5 in which 1) n is zero, one, two, three, 10 or four, the individual substituents R' independently of one another denotes fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C-C,-alkyl, C-C, cycloalkyl, C,-C 6 -alkoxy, (C,-C 6 -alkoxy)-(C,-C 4 -alkoxy), C 1 -C 6 -alkylthio, 15 C-C 6 -alkylsulphinyl, C,-C 6 -alkylsulphonyl, nitro, amino, azido, C,-C 6 alkylamino, di(C, -C 6 -alkyl)amino, piperidino, morpholino, 1 -pyrrolidinyl, - 35 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C 1 -C 6 -acyl, C 1 -C 6 -acyloxy, C,-C 6 -acylamino, cyano, carbamoyl, carboxyl, (C-C-alkyl)oxycarbonyl, hydroxysulphonyl, sulphamoyl or 5 a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxysulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to five radicals R 6 which are independent of one another, 10 where R 6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C,-C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, C,-C 6 -alkylthio, C,-C-alkylsulphinyl, CI-C 6 alkylsulphonyl, C 1 -C 6 -alkylamino, di(C,-C 6 -alkyl)amino, (C 1 -C 6 15 alkyl)oxycarbonyl, phenyl, phenoxy or 2-, 3- or 4-pyridyl, R 2 denotes hydrogen, C,-C 6 -alkoxy, hydroxyl, picolyl, cyclopropyl or isopropenyloxycarbonyl and R 5 denotes hydrogen, hydroxyl, C 1 -C 6 -alkoxy, aryloxy, C 1 -C 6 -acyloxy, cyano, amino, C 1 -C 6 -alkylamino, di(C,-C 6 -alkyl)amino, arylamino, 20 C,-C 6 -acylamino, C,-C 8 -alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, C,-C 6 -alkyl amino, di(C -C 6 -alkyl)amino, C,-C 6 -alkylthio, C,-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; 25 C 2 -C 8 -alkenyl, optionally substituted by fluorine, chlorine, bromine, - 36 iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, CI - C 6 -alkylamino, di(C 1 -C 6 alkyl)amino, C 1 -C 6 -alkylthio, C,-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; 5 C 3 -C.-allenyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo, phenyl; C 3 -C 8 -alkinyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 alkylamino, di(C,-C 6 -alkyl)amino, C,-C 6 -alkylthio, C, -C,-alkylsulphonyl, 10 phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C,-cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, C,-C 6 -alkylamino, di(CI-C 6 alkyl)amino, C,-C 6 -alkylthio, C,-C 6 -alkylsulphonyl, phenylsulphonyl, 15 oxo, thioxo, carboxyl or carbamoyl; C-C.-cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 6 -alkoxy, C,-C 6 -alkylamino, di(CI-C 6 alkyl)amino, C-C 6 -alkylthio, C 1 -C 6 -alkylsulphonyl, phenylsulphonyl, 20 oxo, thioxo, carboxyl or carbamoyl; (C 3 -C 8 -cycloalkyl)-(C,-C,-alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 alkylamino, di(C 1 -C 6 -alkyl)amino, C,-C 6 -alkylthio, C-C 6 -alkylsulphonyl, 25 phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (C-C 8 -cycloalkenyl)-(C-C 4 -alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 6 - - 37 acyloxy, benzoyloxy, benzyloxy, phenoxy, C-C 6 -alkoxy, C,-C 6 alkylamino, di(C,-C 6 -alkyl)amino, C,-C,-alkylthio, C,-C,-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C,-C 6 -alkylcarbonyl, optionally substituted by fluorine, chlorine, 5 bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 6 -alkoxy, C,-C 6 -alkylamino, di(C,-C 6 -alkyl)amino, C,-C,-alkylthio, C,-C,-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 8 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or 10 hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; (C 3 -C 8 -cycloalkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; (C-C 8 -cycloalkenyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; 15 (C 3 -C 8 -cycloalkyl)-(Cl-C 3 -alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; (C,-C,-cycloalkenyl)-(C,-C 3 -alkyl)carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; C,-C 8 -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, 20 bromine, hydroxyl, C,-C 4 -alkoxy, C 1 -C 4 -alkylamino, di(Cl-C 4 alkyl)amino or CI-C 4 -alkylthio; C2-C 8 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; - 38 C-C,-alkinyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C,-alkoxy, oxo or phenyl; C,-C 8 -alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C,-alkoxy, oxo or phenyl; 5 C 2 -C 8 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C,-alkoxy, oxo or phenyl; C,-C 8 -alkylamino- and di(CI-C.-alkyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-Calkoxy, oxo or phenyl; pyrrolidin- 1 -yl, morpholino-, piperidino-, piperazinyl- or 4 10 methylpiperazin-1-yl-carbonyl, optionally substituted by C,-C 4 -alkyl, C 2 -C 6 -alkenyl, C,-C 4 -acyl, oxo, thioxo, carboxyl or phenyl; C 2 -C-alkenylamino- and di(C,-C 6 -alkenyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; C 1 -C 6 -alkylsulphonyl, optionally substituted by fluorine, chlorine, 15 hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; C,-C 6 -alkenylsulphonyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; or an aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminoc arbonyl, 20 (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, aryalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, substituted by up to five radicals R' which are independent of one another, where the alkyl radical can in each case contain 1 to 5 C atoms and R 6 is as defined above - 39 or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio) carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl, heteroarylalkylaminocarbonyl, substituted 5 by up to three radicals R' which are independent of one another, where the alkyl radical can in each case contain 1 to 3 C atoms, R 3 and R 4 identically or differently, independently of one another denote hydrogen, CI-C 8 -alkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, 10 phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, CI-C 4 alkylthio, C,-C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 2 -C,-alkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, 15 C,-C 4 -alkoxy, C 1 -Cralkylamino, di(C,-C 4 -alkyl)amino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulphonyl, C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C 1 -C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, 20 C1-C 4 -alkylsulphonyl, C-C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 3 -C,-cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C 1 -C 4 alkylthio, C-C 4 -alkylsulphonyl, C-C 4 -alkylsulphinyl, carboxyl or 25 carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl substituted by up to five radicals R' which are independent of one another, where the alkyl - 40 radical in each case can contain 1 to 3 C atoms and R' is as defined above, R 3 and R 4 can furthermore also denote part of a saturated or unsaturated carbo or heterocyclic ring having 3 to 8 C atoms, which can optionally be 5 substituted by fluorine, chlorine, hydroxyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkinyl, C,-C 6 -acyloxy, benzoyloxy, C 1 -C 6 -alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur, selenium or substituted nitrogen N-R 2 , in which R 2 can have the meanings given above 10 with protease inhibitors and reverse transcriptase inhibitors.

2. Medicaments according to Claim 1 containing quinoxalines of the general formulae (I) and (Ia), in which n is zero, one, 15 or two, the individual substituents R' independently of one another denotes fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C-C 4 -alkyl, C-C 4 -alkoxy, (C-C 4 -alkoxy) (C,-C 4 -alkoxy), CI-C 4 -alkylthio, nitro, amino, C-C 4 -alkylamino, 20 di(C-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4 methylpiperazinyl, C,-C 4 -acyl, C-C 4 -acyloxy, C -C 4 -acylamino, cyano, carbamoyl, carboxyl, (C-C 4 -alkyl)oxycarbonyl, hydroxysulphonyl or sulphamoyl or - 41 a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two radicals R' which are independent of one another where 5 R can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C 4 -alkyl, C,-C 4 -alkoxy, (C,-C 4 -alkyl)oxycarbonyl, phenyl or phenoxy, R 2 denotes hydrogen and R 5 denotes C,-C 6 -alkyl, optionally substituted by fluorine, chlorine, 10 hydroxyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 6 -alkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 15 alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C,-allenyl, C-C,-alkinyl, optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 alkoxy, C-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C-C 4 -alkylthio, oxo, 20 thioxo, carboxyl or carbamoyl; C 3 -C-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkylamino, di(C-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; -42 C 3 -C.-cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxyl, C-C-alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C-alkoxy, C 1 -C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 5 (C-C,-cycloalkyl)-(C,-C 2 -alkyl), optionally substituted by fluorine, chlorine, hydroxyl, C,-C,-alkyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C,-C 4 -alkylamino, di(C-C 4 -alkyl)amino, C,-C 4 alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C 3 -C 6 -cycloalkenyl)-(C,-C 2 -alkyl), optionally substituted by fluorine, 10 chlorine, hydroxyl, C,-C 4 -alkyl, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, CI-C 4 alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 1 -C 6 -alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, C-C 4 -alkyl, C,-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, 15 C,-C 4 -alkoxy, C,-C 4 -alkylamino, C,-C 4 -alkenylamino, di(C-C 4 alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin 1-yl, C-C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; C 2 -C 6 -alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxyl; 20 (C 3 -C,-cycloalkyl)carbonyl, (C-C,-cycloalkenyl)carbonyl, (C 3 -C 6 -cycloalkyl)-(C-C 2 -alkyl)carbonyl, (C 5 -C 6 -cycloalkenyl)-(C-C 2 -alkyl)carbonyl, - 43 C,-C 6 -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, CI-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 alkyl)amino or Cl-C 4 -alkylthio; C 2 -C 6 -alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, 5 hydroxyl or C,-C 4 -alkoxy; C 2 -C 6 -alkinyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; C,-C 6 -alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; 10 C-C 6 -alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; C,-C 6 -alkylamino and di(C,-C 6 -alkyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or C,-C 4 -alkoxy; pyrrolidin- 1 -yl, morpholino-, piperidino-, piperazinyl-, or 4 15 methylpiperazin- 1 -ylcarbonyl; C 2 -C 6 -alkenylamino and di(C,-C 6 -alkenyl)aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxyl or CI-C 4 -alkoxy; C 1 -C 4 -alkylsulphonyl, optionally substituted by fluorine, chlorine, hydroxyl or C-C 4 -alkoxy; 20 C 1 -C 4 -alkenylsulphonyl; or aryl, arylcarbonyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylsulphonyl, - 44 arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, substituted by up to two radicals R' which are independent of one another, where the alkyl radical can in each case contain 1 to 3 C atoms and R' is as defined 5 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 10 thienylmethyloxycarbonyl, substituted by up to two radicals R' which are independent of one another, and R 3 and R 4 identically or differently, independently of one another denotes hydrogen, C,-C 4 -alkyl, optionally substituted by fluorine, chlorine, 15 hydroxyl, amino, mercapto, Cl-C 4 -acyloxy, benzoyloxy, phenoxy, CI-C 4 alkoxy, C 1 -C 4 -alkylamino, di(CI-C 4 -alkyl)amino, C,-C 4 -alkylthio, C,-C 4 alkylsulphonyl, C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 2 -C 6 -alkenyl, optionally substituted by fluorine or chlorine; C 3 -C 6 -cycloalkyl, optionally substituted by fluorine, chlorine, hydroxyl, 20 amino, mercapto, Cl-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, C,-C 4 -alkylthio, C 1 -C 4 -alkylsulphonyl, C-C 4 -alkylsulphinyl, carboxyl, carbamoyl; C 3 -C 8 -cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl substituted by up to two 25 radicals R 6 which are independent of one another, - 45 R 3 and R 4 can furthermore also be part of a saturated or unsaturated carbo- or heterocyclic ring having 3 to 6 C atoms, which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C 4 -acyloxy, benzoyloxy, C,-C 4 -alkoxy, oxo, thioxo, carboxyl, carbamoyl, and 5 X denotes oxygen or sulphur, optionally in an isomeric form. 3. Medicaments according to Claim 1 containing quinoxalines of the general formulae (I) and (Ia), in which 10 n denotes zero, one, or two, the individual substituents R' independently of one another denotes fluorine, chlorine, bromine, 15 trifluoromethyl, hydroxyl, C,-C 4 -alkyl, C,-C 4 -alkoxy, (C,-C 4 -alkoxy) (C,-C 2 -alkoxy), C,-C 4 -alkylthio, nitro, amino, C,-C 4 -alkylamino, di(C,-C 4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4 methylpiperazinyl, C,-C 4 -acyl, C,-C 4 -acyloxy, C,-C 4 -acylamino, cyano, carbamoyl, carboxyl, (C,-C 4 -alkyl)oxycarbonyl, hydroxysulphonyl, 20 sulphamoyl or a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to - 46 two radicals R' which are independent of one another, where R 6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C,-alkyl, C,-C,-alkoxy, (C,-C 4 -alkyl)oxycarbonyl, 5 phenyl, phenoxy R 2 denotes hydrogen and R 5 denotes C,-C 6 -alkyl optionally substituted by C,-C 4 -alkoxy or CI-Cr alkylthio; C 2 -C 6 -alkenyl, optionally substituted by oxo; 10 C 3 -C 6 -allenyl; C 3 -C 8 -alkinyl, in particular 2-butinyl; C 3 -C 6 -cycloalkyl; C 5 -C 6 -cycloalkenyl; (C 3 -C 6 -cycloalkyl)-(Cl-C 2 -alkyl), in particular cyclopropylmethyl, 15 optionally substituted by C,-C 4 -alkyl; (C 3 -C 6 -cycloalkenyl)-(C,-C 2 -alkyl), in particular cyclohexenylmethyl; Cl-C,-alkylcarbonyl, optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C 4 -alkoxy, C,-C 4 -alkylamino, C 1 -C 4 alkenylamino, di(C,-C 4 -alkyl)amino, 1 -pyrrolidinyl, piperidino, 20 morpholino, 4-methylpiperazin-1-yl, C,-C 4 -alkylthio; - 47 C 2 -C,-alkenylcarbonyl; C,-C 6 -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C 4 -alkoxy, C-C 4 -alkylamino, di(C,-C 4 alkyl)amino, C 1 -C 4 -alkylthio; 5 C 2 -C-alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; C 2 -C-alkinyloxycarbonyl, in particular propinyloxycarbonyl, butinyloxycarbonyl; 10 C-C 6 -alkylthiocarbonyl; C 2 -C 6 -alkenylthiocarbonyl, in particular allylthiocarbonyl; C,-C 6 -alkylamino and di(C,-C 6 -alkyl)aminocarbonyl; pyrrolidin- 1-yl, morpholino-, piperidino-, piperazinyl- or 4 methylpiperazin- 1 -ylcarbonyl; 15 C 2 -C 6 -alkenylamino and di(C,-C 6 -alkenyl)aminocarbonyl; C,-C 4 -alkylsulphonyl; C,-C 4 -alkenylsulphonyl; or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, 20 (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, - 48 arylalkylcarbonyl, arylalkoxycarbonyl, aryl(alkylthio)carbonyl, substituted by up to two radicals R 6 which are independent of one another, where the alkyl radical can in each case contain 1 to 3 C atoms and R' is as defined above 5 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 thienylmethyloxycarbonyl, substituted by up to two radicals R 6 which 10 are independent of one another, and R 3 and R 4 identically or differently, independently of one another denote hydrogen, C,-C 4 -alkyl, optionally substituted by hydroxyl, mercapto, C 1 -C 4 -alkoxy, C,-C 4 -alkylthio, C, -C 4 -alkylsulphonyl, C,-C 4 15 alkylsulphinyl, carboxyl or carbamoyl; C-C,-alkenyl, aryl, benzyl, thienyl or thienylmethyl substituted by up to two radicals R' which are independent of one another, where R' is as defined above, R 3 and R 4 can also be part of a saturated or unsaturated carbo- or heterocyclic 20 ring having 3 to 6 C atoms, which can optionally be substituted by oxo or thioxo and X denotes oxygen or sulphur.

4. Medicaments according to Claims 1 to 3 containing one or more protease inhibitors selected from the group consisting of - 49 1.) 2,4,7,12-Tetraazatridecan- 13-oic acid, 1 0-hydroxy-2-methyl-5 -(1 methylethyl)-1 -[2-(1 -methylethyl)-4-thiazolyl]-3,6-dioxo-8, 11 -bis (phenyl-methyl)-, 5-thiazolylmethyl ester [5S-(5R*, 8R*, 10R*, 11R*)]; PCT WO 95/07696; PCT WO 95/20384 Al; PCT WO 95/009614 Al 5 [ABBOTT (ritonavir) ABT-538] N OH I N NN §H H 0K O H 0 2.) 3-Isoquinolinecarboxamide, N-(1,1 -dimethylethyl)decahydro-2-[2 hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl] [3S-[2-(2S*,3S*), 3.alpha., 4a.beta., 8a.beta.]]-, monoethanesulphonate (salt); PCT WO 95/09843; US 5484926; [AGOURON (ViraceptR) AG 10 1343] H H OH 3.) Carbamic acid, [3-[[(4-aminophenyl)sulphonyl] (2-methylpropyl)amino] 2-hydroxy-1-(phenylmethyl)propyl]-, tetrahydro-3-furanyl ester, [3S-[3R* (IS*, 2R*)]]-; PCT WO 94/05639; [VERTEX PHARM. (Kisseii, Glaxo Wellcome), VX-478] -50 0 0 N N H OH 4.) (S)-N-[(alpha-S)-alpha-[(lR)-2-[((3S,4aS,8aS)-3-(tert butylcarbamoyl)octahydro-2-(1 H)-i so quino I inyl) -1 hydroxyethyl)phenethyl-2-quinaldamido]succinamide (EP 432 695 A2) 0 H HO NN ZQ H 00 NH2 NH-C(CH,)

5.) 2(R)-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3 5 pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2(R)-hydroxyindan-1(S) yl)pentanamide (L-735524, EP 569 083 Al, EP 541 168 Al) OOH N CHN 0 N OH H3C CH3 CH3 - 51 6.) N-(Quinolin-2-ylcarbonyl)asparagine- 1 (S)-benzyl-3-(3-tert-butyl- 1 isobutylureido)-2(R)-hydroxypropylamide (SC 52 151, PCT WO 92/08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al) 0 CH 3 0 NH2 OH r- CH3 CH3 NA N N N CH 3 N 00 CH 3 5 7.) NI -(2R-hydroxy-3-((3-methylbutyl)methylsulphonyl)amino)- IS (phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide (AM 11 686, PCT WO 94/04492) o N N-SO 2 -CH 3 NH 2 OH CH(CH) 2 0

8.) (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4 oxazolyl)methyl)amino)c arbonyl)valinyl)amino)-2-(N-((5 10 thiazolyl)methoxycarbonyl)amino)- 1,6-diphenyl-3 -hydroxyhexane (A 84 538, PCT WO 94/14436) OCH O Cf0H oHH H HaC N NN NkNN N HCH 3 C CH 3 COH 5 - 52 9.) (R)-N-tert-butyl-3-((2S,3 S)-2-hydroxy-3 -N-((R)-2-N-(isoquinolin-5 yloxyacetyl)amino-3-methylthiopropanoy)amino-4-phenylbutanoy)..s,5 dimethyl- 1,3 -thiazolidine-4-carboxamide (KNI 272/Nippon Mining) HC 4 ct-I 3 o~ CH3 H OH N N 0 0 5 hydroxypropyl} carbamic acid tetrahydrofuran-3-yl ester H N " S02 OH CH(CN, 2

11.) (3S,6R)-3-(-ethylbenzy1)-6-(-ethylphenethy1)-4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 94/11361) CH 3

12.) N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3 S)-epoxy-6 phenylhexanoyl]isoleucine (EP 601 486 A) - 53 H 0 H 0 0 A OCH 3 0 NH2 0 O0a CHa H 3 C 0

13.) N-tert-butyl-1 -[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2 quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-(phenylthio)piperidine 2(S)-carboxamide (EP 560 268 A) NH 2 0 0~ OH N NH C(CHa)l

14.) [3 S-(3"'R*,4'"S*)]-N-[l'-oxo-l'-(3"-[1"'-oxo-2"-aza-3"'-phenylmethyl 5 4"'-hydroxy-5"'-(2"'-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl) 1,2,3,4-tetrahydroisoquinoline (EP 609 625 A) CH 3 O I H ! N N O NH C(CH,) 3

15.) 2-[2-Hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4 phenylsulphanylbutyl]decahydroisoquinoline-3-carboxylic acid tert butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA) - 54 CH 5 S 0 NH-C(CH) 3 CH 3 O HO N N H H OH

16.) 2H-1,4-Diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7 tetrakis(phenylmethyl)-, [3S'-(3.alpha., 6.beta., 7.beta.)] (PCT WO 94/08977) -"0 N N N OH 5. Medicaments according to Claims I to 4 containing one or more reverse 5 transcriptase inhibitors from the group consisting of zidovudine (Retrovir) (AZT), didanosine (DDI), dideoxycytidine (DDC), lamivudine (3-TC*), stavudine (D4T), BW 935U83, BW 1592U89 and Epivir. 6. Use of the quinoxalines, the protease inhibitors and the reverse transcriptase inhibitors from Claims 1 to 5 for the production of medicaments for the therapy 10 of HIV infections.