HRP960070A2 - Use of quinoxaline and protease inhibitors in a composition for the treatment of aids and/or hiv infections - Google Patents

Description

The proposed invention relates to the use of quinoxaline in combination with protease inhibitors as drugs for the treatment of AIDS and/or HIV-infections.

The human immunodeficiency virus (HIV) causes a persistent-progressive, chronic disease. HIV destroys the immune system (acquired immune deficiency syndrome, AIDS) and the central and peripheral nervous system. In addition, the HI-virus also causes many other clinical manifestations in the ARC/AIDS picture of the disease - especially opportunistic infections (O.I.), caused by other viruses, such as herpes viruses (HSV I and II), cytomegalovirus (CMV) or O.I., caused by bacteria, fungi or parasites.

HIV belongs to the family of retroviruses; one of the important and essential enzymatic activities of that virus in the reproduction cycle is protease (Huff, J.R., J. Med. Chem. (1991), 34, 2305-2314). Low molecular weight peptide and non-peptide analogs of natural protease substrates inhibit HIV replication (Roberts, N.A. et al., Science (1990) 248, 358-361; Lam, P.Y.S. et al., Science (1994), 263, 380-384).

Analogues of natural reverse transcriptase substrates such as azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3-thiacytidine (laraivudine) suppress HIV replication in vitro and in vivo. ATZ serves, for example, to treat patients with ARC/AIDS. However, long-term therapy of HIV-infected patients is accompanied by bone toxicity; as a result, AZT-resistant virus isolates arise. In some patients treated with DDC or DDI, side effects such as peripheral neuropathy have been reported. Therefore, new substances are needed for control for tolerable and effective therapy.

The now found combination of quinoxaline with protease inhibitors is new and its synergistic effect on the spread of HIV when used in the suppression of AIDS or HIV-infections is significantly better than the existing state of the art.

It has now been found that the quinoxalines of the general formulas (I) and (Ia)

[image]

and their tautomeric forms of the general formula Ia

[image]

where

1) n is zero,

one,

two,

three,

or four,

the individual substituents R1 independently represent each other

fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoro-methoxy, hydroxy, C1-C8-alkyl, C5-C8-cycloalkyl, (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, carboxy, (C1-C6-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl or

with up to five mutually independent residues R6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein

R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C1-C6-alkyl, C3-C8-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6 -alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino, (C1-C6-alkyl)-oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl,

R2 and R5, the same or different, independently represent each other

hydrogen, hydroxy, C1-C6-Alkoxy, aryloxy, C1-C6-acyl-oxy, cyano, amino, C1-C6-alkylamino, di(C1-C6-alkyl) amino, arylamino, C1-C6-acylamino, C1- C8-alkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

C2-C8-alkenyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

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

C3-C8-alkynyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

C3-C8-cycloalkyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

C3-C8-cycloalkenyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

(C3-C8-cycloalkyl) - (C1-C4-alkyl),

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

(C3-C8-cycloalkenyl) - (C1-C4-alkyl),

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

C1-C8-alkylcarbonyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl;

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

(C3-C8-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C8-cycloalkenyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

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

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

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

C2-C8-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C8-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C8-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkylamino- and di(C1-C8-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-or 4-methylpiperazin-1-yl-carbonyl, optionally substituted with C1-C4-alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo , carbonyl or phenyl;

C2-C8-alkenylamino- and di(C1-C8-alkenyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

or with up to 5 mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl , arylalkenylcarbonyl, arylalkyloxycarbonyl, aryl(alkylthio)carbonyl, wherein the alkyl residue can contain 1 to 5 carbon atoms each, and R6 is as defined above,

or with up to three mutually independent residues R6 substituted heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl, heteroarylalkylaminocarbonyl, wherein the alkyl residue may contain 1 to 3 carbon atoms,

R3 and R4, the same or different, independently represent each other

hydrogen, C1-C8-alkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl;

C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl;

C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl;

C3-C8-cycloalkyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl;

with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, whereby the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above,

R3 and R4 or R3 and R5 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 8 carbon atoms, which can be optionally substituted with fluorine, chlorine, hydroxy, amino, C1-C6-alkyl, C2-C6 -alkenyl, C2-C6-alkynyl, C1-C6-acyloxy, benzoyloxy, C1-C6-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl;

X represents oxygen, sulfur, selenium or substituted nitrogen N-R2, where R2 can have the above meanings,

with the exception of compounds in which R3 and R4 simultaneously represent H and compounds in which R2 and R5 represent H and R3 and/or R4 represent arylalkyl and compounds in which X represents oxygen and R2 and R5 are hydrogen,

in combination with protease inhibitors very suitable for use as a drug in the suppression of AIDS and HIV-infections.

In the previous definition, the mentioned alkyl groups can be straight or branched. If not defined otherwise, they preferably have 1-8, with particular preference 1-6, and especially 1-4 carbon atoms. These are, for example, methyl, ethyl, propyl, 1-methylmethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and similar groups.

In the previous definition, the mentioned alkenyl groups can be straight or branched and contain 1 to 3 double bonds. If not defined otherwise, they preferably have 2-8, especially 2-6 carbon atoms. These are, for example, 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, pentadienyl and similar groups.

In the previous definition, the mentioned alkynyl groups can be straight or branched and contain 1 to 3 triple bonds. If not defined otherwise, they preferably have 2-8, with particular preference 3-6 carbon atoms. These are, for example, 2-propynyl and 3-butynyl and similar groups.

In the previous definition, the mentioned cycloalkyl and cycloalkenyl groups, if not defined otherwise, preferably have 3-8, with a special advantage of 4-6 carbon atoms. These are, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.

In the previous definition, the mentioned acyl groups can be aliphatic, cycloaliphatic or aromatic. If not defined otherwise, they preferably have 1-8, with particular preference 2-7 carbon atoms. Acyl groups are, for example, formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl groups.

In the previous definition, the mentioned aryl groups are primarily aromatic groups with 6-14 carbon atoms, especially with 6-10 carbon atoms, such as, for example, phenyl, naphthyl.

In the above-mentioned heterocyclic rings, i.e. heteroaryl groups, the heteroatoms are, for example, 0, S, N, in which case N-Z stands at that position of the saturated ring, which contains N, in which Z, H or R5 represents any of above definitions.

Unless otherwise defined, heterocyclic rings preferably have 1-13 carbon atoms and 1-6 heteroatoms, especially 3-9 carbon atoms and 1-4 heteroatoms.

The heteroaryl groups mentioned in the previous definitions include, for example, heteroaromatic residues such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.

Aralkyl groups mentioned in the previous definitions are for example benzyl, phenylethyl, naphthylmethyl or styryl.

The above-mentioned substituents R1 to R5 are preferably triply, with particular preference doubly, and especially singly substituted with any given substituent.

For the respective composite definitions of complex substituents (such as, for example, aryloxycarbonyl), the single substituents described above are also advantageous.

Depending on the different substituents, the compounds of formula I and Ia can have more asymmetric carbon atoms.

The subject of the invention is therefore also pure stereoisomers as well as their mixtures, such as, for example, the corresponding racemate.

Pure stereoisomers of the compounds of formulas I and Ia can be produced directly or subsequently separated by known methods or analogously known methods.

Within the scope of the invention, protease inhibitors are known structurally different peptide analogs, which are suitable for the treatment of retrovirus-induced diseases.

In particular, the following are mentioned:

1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S, 4aS, 8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldaraido]-succinamide (EP 432 695 A2)

[image]

2. 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-Hydroxyindan-1(S)pentanamide

(L-735524, EP 569 083 A1, EP 541 168 A1)

[image]

3. N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide (SC 52 151, PCT WO 92 /08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92/08700 A1)

[image]

4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide (AM 11 686, PCT WO 94/ 04492)

[image]

5. (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-carbonyl)valinyl)amino)-2-( N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436)

[image]

6. (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI 272/Nippon Mining)

[image]

7. Tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid

[image]

8. (3S, 6R) -3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one (VB 11 47 8, PCT WO 9411361)

[image]

9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine (EP 601 486 A)

[image]

10. N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide (EP 560 268 A)

[image]

11. [3"'S-(3"'R*,4"'s*)]-N-[1'-oxo-(3"[1'"-oxo-2"'-aza-3'" -phenylmethyl-4'"-hydroxy-5'"-(2'"-N-tert.butylcarbamido)phenyl]pentyl-4"-methyl)-1, 2, 3, 4-tetrahydro-iso-quinoline (EP 609 625 A)

[image]

12. Tert.butylamide 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid (AG 1343 Agouron Pharmaceutics Inc. , San Diego USA)

[image]

13. 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)

[image]

Preferred quinoxalines of the general formulas (I) and (Ia) are those

in which

2) n is zero,

one,

two,

or three,

the individual substituents R1 independently represent each other

Fluorine, Chlorine, Bromine, Trifluoromethyl, Trifluoromethoxy, Hydroxy, C1-C4-Alkyl, C5-C6-Cycloalkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4- alkylthio, C1-C4-alkyl-sulfinyl, C1-C4-alkylsulfonyl, nitro, amino, C1-C4-alkyl-amino, di (C1-C4-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl- piperazinyl, thiomorpholino, imidazolyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl, carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxy-sulfonyl, sulfamoyl

or

s to that mutually independent residues R 6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein

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-C6-alkylsulfonyl , C1-C6-alkylamino, di(C1-C4-alkyl)-amino, (C1-C6-alkyl)-oxy-carbonyl, phenyl, phenoxy,

R2 is hydrogen and R5 represents

hydrogen, hydroxy, cyano, amino,

C1-C6-alkyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C2-C8-alkenyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C3-C8-allenyl,

C3-C8-alkynyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C3-C8-cycloalkyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C3-C8-cycloalkenyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

(C3-C8-cycloalkyl) - (C1-C2-alkyl),

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

(C3-C8-cycloalkenyl) - (C1-C2-alkyl),

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C1-C6-alkylcarbonyl,

if necessary substituted with

fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

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

(C3-C6-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cycloalkenyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C3-C6-cycloalkyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cycloalkenyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio;

C2-C6-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C6-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C6-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkylamino- and di(C1-C6-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl;

C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C4-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C4-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

or with up to three mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl- alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-(alkylthio)carbonyl, arylalkyloxycarbonyl, wherein the alkyl residue may contain 1 to 5 C-atoms each, and R6 is as defined above,

or with up to two mutually independent residues R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl,

and

R3 and R4, the same or different, independently represent each other

hydrogen,

C1-C6-alkyl,

optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl;

C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl;

C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl;

C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl;

with up to three mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above,

R3 and R4 can furthermore also be

part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 7 carbon atoms, which can be substituted with fluorine, chlorine, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-acyloxy, benzoyloxy, C1-C4-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl,

X represents oxygen, sulfur, selenium, if necessary in one isomeric form, in combination with protease inhibitors of the series:

1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide,

2. 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-hydroxyindan-1(S)pentanamide,

3. N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide,

4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide,

5. (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-carbonyl)valinyl)amino)-2-( N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane,

6. (R)-N-tert.butyl-3-((2s,3s)-2-hydroxy-3-N-((R)-2-N-isoquinolyl-5-yl-oxyacetyl)amino-3- methylthio-propanoyl)-amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

7. tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid,

8. (3S, 6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one,

9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R, 3S)-epoxy-6-phenyl-hexanoyl]-isoleucine,

10. N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide,

11. [3"'S-(3"'R*,4"'S*)]-N-[1'-oxo-(3"[1'"-oxo-2'"-aza-3'" -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4''-methyl)-1,2,3,4-tetrahydro-iso-quinoline,

12. 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid tert.butylamide,

13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S'-(3.alpha., 6.beta., 7. beta,)],

for use as a medicine in the treatment of AIDS- or HIV-infections.

Particular preference is given to quinoxalines of the general formulas (I) and (a) in which

n is zero,

one,

or two,

the individual substituents R1 independently represent each other

Fluorine, Chlorine, Bromine, Trifluoromethyl, Hydroxy, C1-C4-Alkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4-Alkylthio, Nitro, Amino, C1- C4-alkylamino, di(C1-C4-alkyl)-amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl , carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl

or

with up to two mutually independent residues R6 substituted phenyl-, phenoxy-, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, benzoyl-, 2-pyridyl, 3-pyridyl or 4-pyridyl residue,

whereby

R6 can be

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

R2 is hydrogen and R5 is

C1-C6-alkyl,

optionally substituted with C1-C4-Alkoxy or C1-C4-Alkylthio;

C2-C6-alkenyl,

optionally substituted with oxo;

C3-C6-allenyl;

C3-C8-alkynyl, especially 2-butynyl;

C3-C6-cycloalkyl,

C5-C6-cycloalkenyl;

(C3-C6-cycloalkyl) - (C1-C2-alkyl), especially cyclopropyl-methyl, optionally substituted with C1-C4-alkyl;

(C3-C6-cycloalkenyl) - (C1-C2-alkyl), especially cyclohexylmethyl;

C1-C6-alkylcarbonyl,

optionally substituted with fluorine, chlorine, hydroxy, 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;

C2-C6-alkenylcarbonyl;

C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl) amino, C1-C4-alkylthio;

C2-C6-alkenyloxycarbonyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl;

C2-C6-alkynyloxycarbonyl, especially propynyloxycarbonyl, butynyloxycarbonyl;

C1-C6-alkylthiocarbonyl;

C2-C6-alkenylthiocarbonyl, especially allylthiocarbonyl;

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

pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl;

C2-C6-alkenylamino- and di(C1-C6-alkenyl) aminocarbonyl;

C1-C4-alkylsulfonyl;

C1-C4-alkenylsulfonyl;

or with up to two mutually independent residues R6 substituted aryl, especially phenyl,

arylcarbonyl, especially benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl,

arylalkyl, especially benzoyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkylcarbonyl, aryl(alkylthio)-carbonyl, wherein the alkyl residue may contain 1 to 3 C-atoms each, and R6 is as defined above,

or with up to two mutually independent residues R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl,

AND

R3 and R4, the same or different, independently represent each other

hydrogen,

C1-C4-alkyl,

optionally substituted with hydroxy amino, mercapto, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C2-C6-alkenyl,

with up to two mutually independent residues R6 substituted aryl, benzyl, thienyl or thienylmethyl, wherein R6 is as defined above,

R3 and R4 can also be

part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 carbon atoms, which can be substituted with oxo or thioxo if necessary and

X represents oxygen or sulfur as needed in one isomeric form, in combination with protease inhibitors of the series:

1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide,

2. 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-hydroxyindan-1(S)pentanamide,

3. N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide,

4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide,

5. (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-carbonyl)valinyl)amino)-2-( N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane,

6. (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)-amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

7. tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid,

8. (3S,6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one,

9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R, 3S)-epoxy-6-phenyl-hexanoyl]-isoleucine,

10. N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(s)-carboxamide,

11. [3"' S-(3"' R*, 4"' S*)]-N-[1'-oxo-(3"[1"'-oxo-2'"-aza-3"' -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4"-methyl)-1,2,3,4-tetrahydro-iso-quinoline,

12. tertbutylamide 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid,

13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S'-(3.alpha., 6.beta., 7. beta,)],

for use as a medicine in the treatment of AIDS- or HIV-infections.

Particular preference is given to the combination of S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3, 4-dihydro-quinoxazoline-2(1H)-thione of the formula (A)

[image]

and (S)-N-[(alpha)S)-alpha[(1R)-2-[((3S,4aS,8aS)-3-(tert.butyl-carbaraoyl)octahydro-2-(1H)-isoquinolinyl )-1-hydroxyethyl)-phenethyl-2-quinaldamido]-succinaride (Saquinavir) of formula (B)

[image]

for use in the suppression of AIDS or HIV-infections.

Quinoxalines of the general formulas (I) and (Ia) are known [compare EP 509 398 A1]. Said protease inhibitors are also known [compare EP 432 695 A2, EP 569 083 A1, EP 541 168 A1, PCT WO 92/08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92 /08700 A1, PCT WO 94/04492, PCT WO 94/14436, PCT WO 94/11361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977].

The use of a combination of these compounds in the treatment of retrovirus-induced diseases - and particularly HIV-induced diseases - offers advantages compared to monotherapy with individual compounds. The beneficial and superior use of the combination of these compounds for the treatment of AIDS- and HIV-infections derives mainly from the synergistic antiviral efficacy, but additionally also from the unchanged tolerability of the substances in combination in the area of toxicity, where 50% of the cells survive - compared to Tox-50 individually components. For other combinations, it is known - for example, AZT in combination with Ganciclovir, that the use of the combination is accompanied by synergistic toxicity [compare M.N. Prichard et al., Antimicrob. Agents Chemotherapy (1991), 35, 1060-1065].

The reduced effective dose, resulting from the use of a combination of treatment substances, therefore limits the likelihood of the formation of resistant viral isolates.

The invention provides a combination of two classes of HIV reverse transcriptase and HIV protease compounds for the prevention and treatment of HIV infections, and for the treatment of HIV-induced diseases such as AIDS Related Complex (ARC) or AIDS.

HIV infection in cell culture

The HIV test was performed according to the method of Pauwels et al., [compare Journal of Virological Methods 20, (1988), 309-321].

Normal human blood lymphocytes (PBL s) were concentrated over Ficoll-Hypaque and stimulated in RPMI 1640, 20% fetal calf serum with phytomagglutinin (90 μg/ml) and interleukin-2 (40 U/ml). For infection with infectious HIV, PBL S were pelleted, and the cell pellet was finally suspended in 1 ml HI-absorbing virus solution and incubated for 1 hour at 37°C.

The viral absorption solution was centrifuged, and the infected cell pellet was taken up in the growth medium, so that 1x105 cells per ml were established. Thus infected cells were pipetted at 1x104 cells/well into the wells of a 96-well microtiter plate.

Alternatively, instead of PBL', H9 cells were used for antiviral tests.

The test of the combined action of the test substances was carried out by titration of the checkerboard (Chequerboard-titration).

The first vertical row of the microtiter plate contained only growth medium and cells that were not infected, but were otherwise treated exactly as described above (cell control). The second vertical row of the microtiter plate contained HIV-infected cells alone (viral control) in the growth medium. The remaining wells contained the compounds according to the invention - alone or in appropriate combinations - in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were further diluted in two stages (50 μl volume per well). For the combination, dilutions of the 2nd substance were prepared on a separate 96 microtitre plate and at the end they were pipetted onto the first prepared plate. To this was added 100 μl of prepared HIV-infected cells (see above). This covered test concentrations in the area of approx. 10-50-fold above and below IC50 concentrations.

The test substances were incubated at 37°C until the formation of syncytia on host cells typical of HIV could be seen microscopically in the untreated viral control (between the third and sixth day after infection). Under these test conditions, approximately 20 - 50 syncytiums were formed in the untreated viral control, while untreated cell controls did not have a single syncytium.

Then the rest of the 96-well plate was collected and investigated with an HIV-specific ELISA-tester for HIV-specific antigens (Vironostika HIV Antigen, Organon Tehnika).

Suppression values were recalculated in accordance with the cut-off value from the corresponding cell, i.e. virus control, i.e. inert test controls in percentage (%)-suppression value, and the IC50-values were ordered as concentrations of treated and infected cells, where the treatment with the compounds, 50% of virus-specific antigens were suppressed. For the analysis of synergistic efficiency, the different values of the calculated and measured suppression values of each combination were determined (Prichard. M.N. et al., Antimicrob. Agents Chemoth. (1993), 37. 540-545).

A differential value > zero means that a synergistic effect occurs. For example, the following results were obtained:

Table 1. Table of different values for the calculated and measured effect of Saquinavir (B) with an example of formula (A).

[image]

In the concentration range 0.7 - 6 Nm of the example of the formula (A) with 6 - 50 nM of the protease inhibitor (B) a synergistic efficiency of the combination was obtained.

To measure the synergistic toxicity of the compounds, substance concentrations were tested for the Tox-50 value of the individual compound and examined microscopically for cellular toxic properties, i.e. vital staining was performed using Trypan blue. None of the tested combinations showed synergistic toxicity.

Surprisingly, it was found that a synergistic effect on HIV was achieved by using a combination of compounds. This was demonstrated, for example, by studying the combination of quinoxaline derivatives with Saquinavir (table 1).

The combinations according to the invention serve for the treatment and prophylaxis of diseases caused by retroviruses in human medicine and veterinary medicine.

The areas of indication in human medicine can be mentioned, for example:

1.) treatment and prophylaxis of human retroviral infections,

2.) treatment or prophylaxis of diseases caused by the HIV I virus (human immunodeficiency virus; previously called HTLV III/LAV) (AIDS) and their accompanying conditions such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome), as well as immune weakness and encephalopathy caused that virus,

3.) treatment or prophylaxis of HTLV-I or HTLV-II infection,

4.) treatment or prophylaxis of the AIDS-carrier condition.

Indications in veterinary medicine include, for example, infections with:

a) Maedivisna (in sheep and goats),

b) progressive pneumovirus (PPV) (in sheep and goats),

c) caprine arthritis encephalitis virus (in sheep and goats),

d) Zwoegerziekt virus (in sheep),

e) infectious anemia virus (horse),

f) infections caused by feline leukemia virus,

g) infections caused by feline immunodeficiency virus (FIV),

h) infections caused by simian immunodeficiency virus (SIV).

First of all, it is the area of indications in human medicine mentioned above under points 2, 3 and 4.

The proposed invention includes pharmaceutical preparations, which, in addition to a non-toxic, inert pharmaceutically suitable carrier substance, contain one or more compounds of the formulas (I)/(Ia) in combination with one of the mentioned protease inhibitors or which consist of one or more active substances of the formulas (I )/(Ia) and protease inhibitors, and procedures for the production of these preparations, especially combinations of test compounds.

Active substances of formulas (I) and (Ia) and protease inhibitors in the above-mentioned pharmaceutical preparations must be present primarily in a concentration of approx. 0.1 to 99.5 wt. %, especially from approx. 0.5 to 95 wt. % of the total mixture.

In addition to the compounds of formulas (I) and (Ia), the above-mentioned pharmaceutical preparations in combination with one of the above-mentioned protease inhibitors may also contain further pharmaceutical active substances.

The production of the above-mentioned pharmaceutical preparations is carried out in the usual way by known methods, for example by mixing one or more active substances with one or more carrier substances.

In order to achieve the desired result, both in human medicine and also in veterinary medicine, it has generally been shown to be useful to give one or more active substances in a total amount of approx. 0.5 to approx. 500, preferably 1 to 100 mg/kg of body weight every 24 hours. A single dose contains one or more active substances in an amount of approx. 1 to approx. 80, especially 1 to 30 mg/kg of body weight. However, it may still be necessary to deviate from the stated dosage, depending on the type and body weight of the treated patient, the type and severity of the rash, the type of preparation and application of the drug, and the time interval, i.e., the interval in which the drug is administered.

Claims (5)

1. A drug containing in combination one or more protease inhibitors and one or more quinoxalines of the general formulas (I) and (Ia) [image] and their tautomeric forms of the general formula Ia [image] indicated by that 1) n is zero, one, two, three, or four, individual substituents R1 represent independently of each other fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C8-alkyl, C5-C8-cycloalkyl, C1-C6-alkoxy, (C1-C6-Alkoxy) - (C1-C4-Alkoxy), C1-C6-alkylthio, C1-C66-alkylsulfinyl, 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-acyl-oxy, C1-C6-acylamino, cyano, carbamoyl, carboxy, (C1-C6-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfaroyl or with up to five mutually independent residues R6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or a 4-pyridyl residue, whereby R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C1-C6-alkyl, C3-C8-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6 -alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino, (C1-C6-alkyl)-oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R2 and R5, the same or different, independently represent each other hydrogen, hydroxy, C1-C6-Alkoxy, aryloxy, C1-C6-acyl-oxy, cyano, amino, C1-C6-alkylamino, di(C1-C6-alkyl) amino, arylamino, C1-C6-acylamino, C1- C8-alkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; C2-C8-alkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; C3-C8-allenyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C3-C8-alkynyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; C3-C8-cycloalkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; C3-C8-cycloalkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; (C3-C8-cycloalkyl) - (C1-C4-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; (C3-C8-cycloalkenyl) - (C1-C4-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydrocny, 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, carboxy, carbamoyl; C1-C6-alkylcarbonyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, 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, carboxy, carbamoyl; C2-C8-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C8-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C8-cycloalkenyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C8-cycloalkyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C8-cycloalkenyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C8-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C8-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C8-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkylamino- and di(C1-C8-alkyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-or 4-methylpiperazin-1-yl-carbonyl, optionally substituted with C1-C4-alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo , carboxy, or phenyl; C2-C8-alkenylamino- and di(C1-C8-alkenyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; or with up to 5 mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl- alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-alkoxycarbonyl, aryl(alkylthio)carbonyl, wherein the alkyl residue can contain 1 to 5 C-atoms each, and R6 is as defined above, or with up to three mutually independent radicals R6 substituted heteroaryl, heteroarylalkyl, heteroaryl-alkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl, heteroarylalkylaminocarbonyl, wherein the alkyl residue may contain 1 to 3 carbon atoms, R3 and R4, the same or different, independently represent each other hydrogen, C1-C8-alkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl; C2-C8-alkyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, -hydroxy 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, carboxy, carbamoyl; C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl; with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, whereby the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above, R3 and R4 or R3 and R5 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 8 carbon atoms, which can be optionally substituted with fluorine, chlorine, hydroxy, amino, C1-C6-alkyl, C2-C6 -alkenyl, C2-C6-alkynyl, C1-C6-acyloxy, benzoyloxy, C1-C6-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl; X represents oxygen, sulfur, selenium or substituted nitrogen N-R2, where R2 can have the above meanings, with the exception of compounds in which R3 and R4 simultaneously represent H and compounds in which R2 and R5 represent H, with R3 and/or R4 representing arylalkyl and compounds in which X represents oxygen and R2 and R5 are hydrogen. 2. The drug according to claim 1, characterized in that it contains one or more quinoxalines of the general formulas (I) and (Ia) in which 2) n is zero, one, two, or three, the individual substituents R1 independently represent each other Fluorine, Chlorine, Bromine, Trifluoromethyl, Trifluoromethoxy, Hydroxy, C1-C4-Alkyl, C5-C6-Cycloalkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4- alkylthio, C1-C4-alkyl-sulfinyl, C1-C4-alkylsulfonyl, nitro, amino, C1-C4-alkyl-amino, di (C1-C4-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl- piperazinyl, thiomorpholino, imidazolyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl, carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxy-sulfonyl, sulfamoyl or s to that mutually independent residues R 6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein 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-C6-alkylsulfonyl , C1-C6-alkylamino, di(C1-C4-alkyl)-amino, (C1-C6-alkyl)-oxy-carbonyl, phenyl, phenoxy, R2 is hydrogen and R5 represents hydrogen, hydroxy, cyano, amino, C1-C6-alkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C2-C8-alkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-allenyl, C3-C8-alkynyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkyl) - (C1-C2-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkenyl) - (C1-C2-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C1-C6-alkylcarbonyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C2-C6-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C6-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C6-cycloalkyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C6-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C6-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C6-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylamino- and di(C1-C6-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl; C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C4-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C4-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; or with up to three mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylamino-carbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl-alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-( alkylthio)carbonyl, arylalkyloxycarbonyl, wherein the alkyl residue can contain 1 to 5 C-atoms each, and R6 is as defined above, or with up to two mutually independent radicals R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, and R3 and R4, the same or different, independently represent each other hydrogen, C1-C6-alkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl; C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy 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, carboxy, carbamoyl; C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy 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, carboxy, carbamoyl; with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above R3 and R4 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 7 carbon atoms, which can be substituted with fluorine, chlorine, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-acyloxy, benzoyloxy, C1-C4-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl; X represents oxygen, sulfur, selenium, if necessary in one isomeric form. 3. The drug according to claim 1, characterized in that it contains one or more quinoxalines of the general formulas (I) and (Ia) in which n is zero, one, or two, individual substituents R1 independently of each other can be Fluorine, Chlorine, Bromine, Trifluoromethyl, Hydroxy, C1-C4-Alkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4-Alkylthio, Nitro, Amino, C1- C4-alkylamino, di (C1-C4-alkyl)-amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl , carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl or one with up to two mutually independent residues R6 substituted phenyl-, phenoxy-, phenylthio-, phenylsulfinyl, phenoxysulfonyl-, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4-pyridyl residue, whereby R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1-C4-alkyl, C1-C4-alkoxy, (C1-C4-alkyl)-oxycarbonyl, phenyl, phenoxy, R2 is hydrogen and R5 is C1-C6-alkyl, optionally substituted with C1-C4-Alkoxy or C1-C4-Alkylthio; C2-C6-alkenyl, optionally substituted with oxo, C3-C6-allenyl, C3-C8-alkynyl, especially 2-butynyl; C3-C6-cycloalkyl, C5-C6-cycloalkenyl; (C3-C6-cycloalkyl) - (C1-C2-alkyl), especially cyclopropyl-methyl, optionally substituted with Cx-Ct-alkyl; (C3-C6-cycloalkenyl) - (C1-C2-alkyl), especially cyclohexylmethyl; C1-C6-alkylcarbonyl, optionally substituted with fluorine, chlorine, hydroxy, 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; C2-C6-alkenylcarbonyl; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamirio, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C6-alkenyloxycarbonyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; C2-C6-alkynyloxycarbonyl, especially propynyloxycarbonyl, butynyloxycarbonyl; C1-C6-alkylthiocarbonyl; C2-C6-alkenylthiocarbonyl, especially allylthiocarbonyl; C1-C6-alkylamino- and di(C1-C6-alkyl!) aminocarbonyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl; C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl; C1-C4-alkylsulfonyl; C1-C4-alkenylsulfonyl; or with up to two mutually independent residues R6 substituted aryl, especially phenyl, arylcarbonyl, especially benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, especially benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkylcarbonyl, aryl(alkylthio)-carbonyl, wherein the alkyl residue can contain 1 to 3 C-atoms each, and R6 is as defined above, or with up to two mutually independent radicals R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, and R3 and R4, the same or different, independently represent each other hydrogen, C1-C4-alkyl, optionally substituted with hydroxy amino, mercapto, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylsulfinyl, carboxy, carbamoyl; C2-C6-alkenyl, with two mutually independent residues R6 substituted aryl, benzyl, thienyl or thienylmethyl, where R6 is as defined above, R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 carbon atoms, which can be substituted with oxo or thioxo if necessary and X represents oxygen or sulfur as needed in one isomeric form. 4. The drug, according to claims 1 to 3, characterized by the fact that as a protease inhibitor it contains one or more compounds from the group 1) (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide, 2) 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-hydroxyindem-1(S)-yl)pentanamide, 3) N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide, 4) N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide, 5) (2S, 3S, 5S) - 5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-carbonyl)valinyl)amino)-2-( N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 6) (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, 7) tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid, 8) (3S, 6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one, 9) N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine, 10) N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3 (S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide, 11) [3"'S-(3"'R*,4"'S*)]-N-[1'-oxo-(3"[1"'-oxo-2"'-aza-3"' -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4-methyl)-1,2,3,4-tetrahydro-iso-quinoline, 12) 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid tert.butylamide, 13) 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S'-(3.alpha., 6.beta.,7. beta,)]. 5. Medicine, characterized by the fact that it contains a combination of S-4-isopropoxy-carbonyl-6-methoxy-3-(methylthio-methyl)-3, 4-dihydro-quinoxaline-2(1H)-thione of formula (A) [image] and (S)-N-[(alpha)S)-alpha[(1R)-[((3S, 4aS, 8aS)-3-(tert.butyl-carbamoyl)octa-hydro-2-(1H)-isoquinolinyl )-1-hydroxyethyl)-phenethyl-2-quinaldamido]-succinamide (Saquinavir) of formula (B) [image]