SK25196A3 - Quinoxaline application with the combination of proteases as drugs for aids and/or hiv-infections - Google Patents

Abstract

Medicaments comprising, in combination, (a) one or more protease inhibitors and (b) one or more cpds. of formula (I) (or their tautomers of formula (Ia)) are new: n = 0-4; R<1> = F, Cl, Br, I, CF3, CF3O, OH, 1-8C alkyl, Cya, TO, TO-R<1>O, TS, TSO, TSO2, NO2, NH2, N3, NHT, NT2, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, Ac, AcO, AcNH, CN, CONH2, COOH, TOCO, HOSO2 or SO2NH2; or Ph, PhO, PhOCO, PhS, PhSO, PhSO2, PhOSO2, PhSO2O, anilinosulphonyl, PhSO2NH, PhCO, 2-, 3- or 4-pyridyl (all opt. substd. by ≤ 5 R<6>); T = 1-6C alkyl; Cya = 5-8C cycloalkyl; R<1> = 1-4C alkylene; R<6> = F, Cl, Br, I, CN, CF3, CF3O, NO2, NH2, N3, T, Cy, TO, TS, TSO, TSO2, TNH, T2N, TOCO, Ph, PhO or 2-, 3- or 4-pyridyl; R<2>,R<5> = H, OH, TO, ArO, AcO, CN, NH2, TNH, T2N, ArNH or AcNH; 1-8C alkyl, 2-8C alkenyl, 3-8C alkynyl, Cy, Cy', Cy-R<1>, Cy'-R<1> or TCO (all opt. substd. by F, Cl, Br, I, CN, NH2, SH, OH, AcO, PhCOO, PhCH2O, PhO, TO, TNH, T2N, TS, TSO2, PhSO2, oxo, thioxo, carboxy or carbamoyl); 3-8C alkenyl, 2-8C alkenylcarbonyl, CyCO, Cy''CO, Cy-(1-3C alkyl)carbonyl, 5-6C cycloalkenyl- (1-3C alkyl)carbonyl, 1-8C alkenyloxycarbonyl, 2-8C alkynyloxycarbonyl, 1-8C alkylthiocarbonyl, 2-8C alkenylthiocarbonyl, 1-8C alkylaminocarbonyl, di(1-8C alkyl)aminocarbonyl, TSO2, 2-6C alkenylsulphonyl, 2-8C alkenylaminocarbonyl or di((2-6C)alkenyl)- aminocarbonyl (all opt. substd. by F, Cl, OH, RO, oxo or phenyl); 1-8C alkoxycarbonyl (opt. substd. by F, Cl, Br, OH, RO, RNH, (R)2N or RS); pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl (all opt. substd. by R, 2-6C alkenyl, 1-4C acyl, oxo, thioxo, carboxy or phenyl); Ar, ArCO, ArCS, ArS-CO, ArS-CS, ArOCO, ArSO2, ArNHCO, ArNHCS, aryl(1-5C)alkylaminocarbonyl, Ar', arylalkenyl, arylalkynyl, Ar'CO, arylalkenylcarbonyl, Ar'OCO or Ar'SCO (all opt. substd. by 1-5 R<6>); or Het, Het', Het-alkenyl, Het'CO, Het-alkenylcarbonyl, HetOCO, HetSCO, HetNHCO, Het'OCO, Het'SCO or Het'NHCO (all opt. substd. by 1-3 R<6>); Ar = aryl; Ar' = aryl(1-5C)alkyl; Het = heteroaryl; Het' = heteroaryl(1-3C)alkyl; R = 1-4C alkyl; Ac' = 1-6C acyl; Ph = phenyl; Cy = 3-8C cycloalkyl; Cy' = 3-8C cycloalkenyl; Cy'' = 5-8C cycloalkenyl; R<3>, R<4> = H; 1-8C alkyl, 2-8C alkenyl, Cy or Cy' (all opt. substd. by F, Cl, OH, NH2, SH, Ac'O, PhCOO, PhCH2O, PhO, RO, RNH, (R)2N, RS, RSO2, RSO, COOH or CONH2); Ar, aryl(1-3C)alkyl, Het or Het' (all opt. substd. by ≤ 5 R<6>); or R<3>+R<4> or R<3>+R<5> can be part of an unsatd. or satd. carbo- or heterocyclic ring of 3-8 atoms, which is opt. substd. by F, Cl, OH, NH2, T, 2-6C alkenyl, TO, 2-6C alkynyl, 1-6C acyloxy, benzoyloxy, oxo, thioxo, COOH, CONH2 or Ph); Ac' = 1-4C acyl; X = O, S, Se or NR<2>; with the exception of cpds. in which (a) R<3> and R<4> are both H, (b) R<2> and R<5> are H and R<3> and R<4> are arylalkyl, and (c) X is O and R<2> and R<3> are H.

Description

Technical field

The invention relates to the use of quinoxalines in combination with protease inhibitors as medicaments for the treatment of AIDS and / or HIV infections.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) causes persistene-progressive chronic diseases. HIV violates the immune system (acquired immunodeficiency syndrome) and the central and peripheral nervous systems. In addition, many other clinical manifestations of ARC / AIDS are co-induced by HI-virus, particularly opportunistic infections (0.1) caused by other viruses, such as Herpesviruses (HSV I and II), Cytomegalovirus (CMV) or OI caused by bacteria, fungi or parasites.

HIV belongs to the genus Retroviruses; one of the essential and in the reproductive cycles of the essential enzymatic activities of these viruses is the protease (Huff, J. R., J. Med. Chem. (1991), 34, 2305-2314). Low molecular weight peptide and non-peptide analogues 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), 236, 380-384).

Analogs of natural reverse transcriptase substrates, such as azidothymin (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI), and 3'-thiacytidine (Lamivudine) inhibit HIV replication in vitro and in the treatment of ARC / AIDS diseases. infected with HIV, by AZT, in vivo. AZT serves, for example, for long-term therapy of patients, but is accompanied by bone marrow toxicity and, in addition, AZT-resistant virus isolates are produced. Some patients who have been treated with DDC or DDI have been found to be unacceptable, such as peripheral neuropathy. Thus, there is a need for new inhibitors for acceptable and effective therapy.

SUMMARY OF THE INVENTION

The presently found combination of quinoxalins with protease inhibitors is novel and its synergistic effect on HIV reproduction when applied to the treatment of AIDS or HIV-infections is significantly superior to that of the prior art.

It has now been found that quinoxalines of the general formula

and its tautomeric formula Ia

(la) in which the figure is 0, 1, 2, 3 or 4,

R ¹ independently of one another is F, Cl, Br, I, trifluoromethyl, trifluoromethoxy, hydroxy, alkyl of 1 to 8 carbon atoms, cycloalkyl having 5 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxyalkoxy of 1 to 6 carbon atoms in the first alkoxy and 1 to 4 carbon alkylthio of 1 to 6 atoms in the second

I alkoxy groups, atoms, alkylsulfinyl of up to carbon atoms, alkylsulfonyl of up to 6 carbon atoms, nitro, amino, azido, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl group, piperidino 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, acyl of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, acylamino of 1 to 6 carbon atoms, carbamoyl, carboxyl, alkyloxycarbonyl having 1 to 6 carbon atoms in the alkyl, hydroxysulfonyl or sulfamoyl group, or represents one to six mutually independent occurrences of R ⁶ substituted phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulfonyl 1-phenyl, phenoxysulfonyl, phenylsulfonyloxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or

A 4-pyridyl group wherein:

R ⁶ represents fluorine, chlorine, bromine or iodine, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, alkylthio (C 1 -C 6) -alkyl, (C 1 -C 6) alkylsulphinyl,

3-pyridyl or 4-pyridyl, atoms, alkylsulfonyl with alkylamino, 1 dialkylamino with 1 each, atoms, atoms in up to 6 carbon phenoxy, up to alkyl, alkyloxycarbonyl atoms in alkyl, phenyl 2-pyridyl,

R ² and R ⁵ may be the same or different and independently of one another represent a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an aryloxy group, an acyloxy group having 1 to 6 carbon alkylamino groups having a dialkylamino group having alkyls, carbon atoms, optionally substituted by fluorine, chlorine or iodine, hydroxy, atoms, benzoyloxy, s

atoms, cyano, amino, to arylamino, atoms, in each of 1 to 6 to 6 carbon atoms, acylamino of up to 8 carbon atoms, bromine cyano, amino, mercapto, acyloxy of 1 to 6 carbon benzyloxy groups, 6 to 6 carbon atoms up to 6 carbon up to 6 carbon atoms, oxo, thioxo, up to pin, alkoxy alkylamino with alkylalkyl, alkylthio with alkylsulfonyl phenylsulfonyl carboxy or atoms, atoms, in each atom, with

a carbamoyl group, up to 8 carbon atoms, optionally fluorine, chlorine, bromine or iodine, a pin, an acyloxy group, a benzoyloxy group, an alkoxy group with an alkylamino group, a dialkylamino alkyl group,

alkylthio with phenoxy, atoms, atoms, in each atom, alkenyl substituted with cyano, amino, mercapto, hydroxy of 1-6 carbon atoms, benzyloxy, up to 6 carbon-6 carbon-6 carbon atoms of 1-6 carbon-alkyl up to 6 carbon atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, C3-C8 allenyl, optionally substituted by fluorine, chlorine or bromine, or hydroxy, C1-C4 alkoxy or phenoxy or oxo , C3 -C8 alkynyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, phenoxy (C 1 -C 6) alkoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxy , carboxy or carbamoyl, cycloalkyl of 3 to 8 carbon atoms, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, benzoyloxy, benzyloxy, alkoxy to 1, phenoxy, phenoxy C 1 -C 6, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoylo cycloalkenyl of 3 to 8 carbon atoms, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, alkoxy to 1, benzyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carboxy , cycloalkylalkyl having 3 to 8 carbon atoms in cycloalkyl and 1 to 4 carbon atoms in alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, zoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, cycloalkenylalkyl having 3 to 8 carbon atoms in cycloalkenyl and having 1 to 4 carbon atoms in alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, hydroxy, mercapto, amino, mercapto, amino, (C 1 -C 6) acyloxy, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio C1-6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, C1-6 alkylcarbonyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, cyano mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms carbon atoms, C1-6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, alkenylcarbonyl of 2 to 8 carbon atoms in alkenyl, optionally substituted with fluoro, chloro or br. mu, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 3 -C 8 cycloalkylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl cycloalkenylcarbonyl of 5 to 8 carbon atoms in cycloalkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, cycloalkylalkylcarbonyl of 3 to 8 carbon atoms in cycloalkyl alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, cycloalkenylalkylcarbonyl of 5 to 6 carbon atoms in cycloalkenyl and 1 to 3 carbon atoms in alkyl, p optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 1 -C 8 alkyloxycarbonyl, optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy C1 -C4 alkylamino, C1 -C4 dialkylamino in each alkyl or C1 -C4 alkylthio group, C2 -C8 alkenyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4, oxo or phenyl, C 2 -C 8 alkynyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl C1-C8-alkylthiocarbonyl optionally substituted by fluorine or chlorine, hydroxy, C1-C4alkoxy, oxo or phenyl, alkenyl-thiocarbonyl of 2 to 8 carbon atoms optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl, (C 1 -C 8) alkylaminocarbonyl and (C 1 -C 8) dialkylaminocarbonyl, optionally substituted by fluorine or chlorine, C 1 -C 4 alkoxy, oxo or phenyl, pyrrolidin-1-yl, morpholino, piperidino, piperazinyl or 4-methylpiperazine-1-carbonyl, optionally substituted with C 1 -C 4 alkyl, (C 1 -C 4) acyl, (C 2 -C 6) alkenyl, oxo, thioxo, carboxy or phenyl of C 2 -C 8 alkenyl and C 1 -C 6 dialkenylaminocarbonyl, optionally in each substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 1 -C 6 alkylsulfonyl, optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, or oxo a C 2 -C 6 alkenylsulfonyl group optionally substituted by a fluorine or chlorine atom, a hydroxy group, a C 1 -C 4 alkoxy group, an oxo group or a phenyl group, or one to five independent R ⁶ radicals substituted aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, arylalkenyl, arylazo, arylalkylcarbonyl, arylalkenylkarbonylovú, arylalkoxycarbonyl, aryl (alkylthio) carbonyl group wherein the alkyl moiety may contain 1 to 5 carbon atoms and ^R6 is defined as above,

Or one to three independent radicals R 0 substituted heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl, alkenylcarbonyl, heteroaryloxycarbonyl, thio) carbonyl, heteroarylaminocarbonyl, heteroaryl (heteroarylheteroalkyl) heteroaryl (heteroarylheteroaryl) 3 carbon atoms,

R ³ and R ⁴ are the same or different and independently of one another are hydrogen, C 1 -C 8 alkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy , phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 1 -C 4, carboxy or carbamoyl, C 2 -C 8 alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy (C 1 -C 4) oxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 3 -C 8 -cycloalkyl, optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy, atoms, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy upine or carbamoyl, cycloalkenyl of 3 to optionally substituted by hydroxy, acyloxy with benzoyloxy, alkoxy with alkylamino dialkylamino alkyl, alkylsulfonyl alkylsulfinyl carbon atoms of fluorine or carbon, carbon, furo, , atoms, atoms, substituted with amino, up to 4 benzyloxy, up to 4 carbon to 4 carbon carbon atoms up to 4 carbon 1 to 4 carbon 1 to 4 carbon

alkylthio with p

carboxyl or carbamoyl, or up to five mutually independent occurrences of R ⁶ substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl moiety may contain 1 to 3 carbon atoms and R ⁶ is as defined above, or unsaturated carbocyclic or heterocyclic ring of 3 to 8 carbon atoms, which may be optionally substituted by fluorine or chlorine, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, acyloxy, benzoyloxy, alkoxy having 1 to 6 carbon atoms, oxo, thioxo, carboxy, carbamoyl or phenyl, and

X represents an oxygen, sulfur or selenium atom or a substituted nitrogen of NR ² , where R ² may have the above meaning, except for compounds in which R ³ and R ^{4 are} both hydrogen and compounds in which R ² and R 4 is a hydrogen atom and R ³ and / or R ⁴ are an aralkyl group and compounds in which X is an oxygen atom and R ² and R ^{5 a} hydrogen atom, in combination with protease inhibitors, are well suited for use as medicaments for the treatment of AIDS and HIV- infections.

In the above definition, said alkyl groups may be straight or branched. Unless stated otherwise, they preferably contain 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms and particularly preferably 1 to 4 carbon atoms. Examples are methyl, ethyl, propyl, 1-methylethyl, butyl,

1-methylpropyl, 2-methylpropyl, 1,113 dimethylethyl and the like.

The alkenyl groups mentioned in the above definition may be straight or branched and contain 1 to 3 double bonds. Unless stated otherwise, they preferably contain 2 to 8 carbon atoms, especially 2 to 6 carbon atoms. Examples which may be mentioned are 2-propenyl, 1-methyletenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl a group, 3,3-dichloro-2-propenyl, pentadienyl, and the like.

The alkynyl groups mentioned in the above definition may be straight or branched and contain 1 to 3 triple bonds. Unless stated otherwise, they preferably contain 2 to 8 carbon atoms, in particular 3 to 6 carbon atoms. Examples include 2-propynyl, 3-butynyl and the like.

The cycloalkyl and cycloalkenyl groups mentioned in the above definition contain, unless otherwise indicated, preferably 3 to 8 carbon atoms, especially 4 to 6 carbon atoms. Examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.

The acyl groups mentioned in the above definition may be aliphatic, cycloaliphatic or aromatic. Unless stated otherwise, they preferably contain 1 to 8 carbon atoms, in particular 2 to 7 carbon atoms. Examples are formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl.

The aryl groups mentioned in the above definition are preferably aromatic groups having 6 to 14 carbon atoms, in particular 6 to 10 carbon atoms. Examples are phenyl and naphthyl.

In the above-mentioned heterocyclic rings or heteroaryl groups, for example, oxygen, sulfur and nitrogen are particularly suitable as heteroatoms, and in the case of a saturated nitrogen-containing ring this occurs as NZ, Z being a hydrogen atom or a group R ⁵ , wherein R ⁵ has a the above meaning.

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

Suitable heteroaryl groups mentioned in the above definition are heteroaromatic radicals such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, -pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.

Suitable aralkyl groups mentioned in the above definition are, for example, benzyl, phenethyl, naphthylmethyl or styryl.

The aforementioned substituents R ¹ to R ⁵ are preferably three, particularly twice and particularly preferably once substituted by the abovementioned substituents.

For the definition of the corresponding compound substituents (such as an alkoxycarbonyl group), the substituents listed above are also preferred for the corresponding individual groups. ^IN

Depending on the various substituents, the compounds of formulas I and Ia may have more asymmetric carbon atoms.

Thus, the present invention relates both to pure stereoisomers and to mixtures thereof, such as the corresponding racemates.

Pure stereoisomers of the compounds of formula I and Ia can be prepared by known methods or analogously to known methods, or can be additionally separated.

Within the scope of the present invention, protease inhibitors are known to have structurally different analogues of peptides which are suitable for the treatment of diseases induced by retroviruses.

Particular mention may be made of:

(S) -N - [(aS) -? - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) - isoquinolinyl) -1-hydroxyethyl) -phenethyl-2-quinaldimido] succinamide (EP 432 695 A2)

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

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)

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

4th

5. (2S, 3S, 5S) -5- (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)

6. (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 (KNI 272 / Nippon Mining)

7. {3- [4-Aminobenzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl) -carbamic acid tetrahydro-furan-3-yl ester

(3S, 6R) -3- (α-ethylbenzyl) -6- (α-ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 94/11361)

8th

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

ABOUT

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

11. [3 '' 'S- (3' '' R *, 4 'S *] -N- [1' -OXO-1 '- (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)

12. 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfonylbutyl] -decahydro-isoquinoline-3-carboxylic acid tert-butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego, USA)

13. 2Η-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenylmethyl) -, [3S'-3.a, 6.β, 7.β, (PCT WO 94/08977)

OH

Preferred are the quinoxalines of formula I and Ia in which n is 0, 1, 2 or 3,

R ¹ is independently fluoro, chloro or bromo, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 1 alkoxy 4 carbon atoms in the first and second alkoxy groups, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino up to 4 carbon atoms in each alkyl, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, acyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, acylamino atoms, cyano, carbamoylo C 1 -C 4 -alkyloxycarbonyl, hydroxy, sulphonyl or sulphamoyl, or R ^{6 is} substituted by phenyl, phenoxy, phenoxycarbonyl, phenyloxy, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl, phenylsulphonyl , anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or

A 4-pyridyl group wherein:

R ⁶ represents a trifluoromethyl alkyl group having both a cycloalkyl group and a fluorine group, a 1-chloro nitro group, to an alkoxy group having an alkylthio group, an alkylsulfinyl alkylsulfonyl alkylamino group,

up to up to up to 1 carbon atom of 1 to 4 carbon atoms or of bromine, amino, atoms, atoms, atoms, atoms, atoms, atoms, in each alkyl, alkyloxycarbonyl (C 1 -C 4) alkyl, phenyl or phenoxy group;

R ² is hydrogen, and

R ⁵ represents a hydrogen atom, a hydroxy group, a cyano group, an amino group, an alkyl group having 1 to 8 carbon atoms, optionally substituted by a fluorine, chlorine, bromine or iodine atom, cyano, amino, mercapto, hydroxy group of 1 to 4 carbon atoms, benzyloxy (C 4-C 4-C až-C až-C 4), acyloxy-benzoyloxy, alkoxy-alkylamino-dialkylamino-alkyl, oxo, carbamoyl, phenoxy, atoms, atoms, i, or up to

thioalkylthio, C 2 -C 8 alkenyl substituted by fluorine, chlorine, cyano, amino, hydroxy, acyloxy, benzoyloxy, phenoxy, alkoxy of 1-alkyloxy, 1-dialkylamino, thio, , up to atoms, bromine mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, in each atom, i or optionally or iodine, carbon up to 4 carbon atoms up to 4 carbon carboxy, a 3 to 8 carbon allenyl group, a 3 to 8 alkynyl group 8 carbon atoms optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy24, acyloxy, benzoyloxy, alkoxy with alkylamino, dialkylamino, alkyl to oxo, carbamoyl benzyloxy, 1-4 carbon to 4 carbon carbon atoms to 4 carbon carboxy

thioalkyl, thio, atoms, phenoxy, atoms, atoms, in each atom, t or 3-8 fluoro, cycloalkyl substituted with cyano, amino, hydroxy, acyloxy, benzoyloxy, alkoxy, 1-phenoxy with 1 to alkyl, alkylthio with oxo, carbamoyl, carbon atoms, chlorine, optionally bromine or iodine, mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, or carbon atoms up to 4 thio, C 3 -C 3 cycloalkenyl optionally substituted with iodine, cyano, hydroxy, acyloxy of carbon to fluorine, chlorine, amino, atoms of bromine or mercapto, of up to 4 carbon atoms, benzoyloxy, benzyloxy C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, thioxy, carboxy or carbamoyl, cycloalkylalkyl 8-cycloalkylalkyl cycloalkyl and 1 to 2 carbon atoms in alkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 4 carbon atoms, benzoyloxy, 1-phenoxy, benzyloxy, benzyloxy, C 4 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, oxo, thioxo, carboxy or carbamoyl, C 3 -C 8 cycloalkenylalkyl cycloalkenyl having from 1 to 2 carbon atoms in the alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 4 carbon atoms, benzoyloxy, alkoxy, benzyloxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio. (C1 -C6) alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acylo, acyloxy , benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, alkylthio of 1 to 4 carbon atoms, oxo, carboxy, thio, carboxy , alkenylcarbonyl of 2 to 6 carbon atoms in the alkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, cycloalkylcarbonyl of 3 to 6 carbon atoms in cy Cloalkyl, optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 5 -C 6 cycloalkenylcarbonyl, optionally substituted by fluorine or chlorine, C 1 -C 4 hydroxy atoms, oxo or phenyl, cycloalkylalkylcarbonyl of 3 to 6 carbon atoms in cycloalkyl and 1 to 2 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxoalkyl or phenyl, cycloalkyl or phenylalkyl, C 5 -C 6 cycloalkenyl and C 1 -C 2 alkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, alkyloxycarbonylo C 1 -C 6 alkyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl or alkylthio group C 1 -C 4 alkenyloxycarbonyl, C 2 -C 6 alkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 2 -C 6 alkynyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, alkylthiocarbonyl of 1 to 6 carbon atoms in the alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon alkenylthiocarbonyl of 2 to 6 carbon atoms in the alkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, alkylaminocarbonyl of 1 to 6 carbon atoms C 1 -C 6 alkyl and dialkylaminocarbonyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, pyrrolidin-1-yl, morpholino, piperidino, piperazino, piperazino, 4-methyl-piperazin-1-ylcarbonyl, alkenylaminocarbonyl of 2 to 6 carbon atoms in the alkenyl and dialkenylaminocarbonyl of 1 to 6 carbon atoms in each alkenyl, optionally substituted with fluorine or chlorine, hydroxy, alkoxy C 1 -C 4 -alkyl, oxo or phenyl, C 1 -C 4 -alkylsulfonyl, optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 -alkoxy, oxo or phenyl, C 1 -C 4 -alkenylsulfonyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, or one to three independent R ⁶ radicals substituted by aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) (arythio) arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalryloxycarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl R ⁶ is as defined above or substituted by 1 to 2 naphthylmethyl, 2-naphthylmethyl, 2-picolylyl, 3-picolylyl, 4picolylyl substituted by one or two independent R ⁶ radicals. , furylmethyl, thienylmethyl,

2-furylmethyl, 32-thienylmethyl, 32-pyrrolylmethyl,

3-pyrrolylmethyl,

2-pyridylcarbonyl,

3-pyridylcarbonyl,

2-furylcarbonyl,

2-thienylcarbonyl,

4-pyridylcarbonyl,

3-furylcarbonyl,

3-thienylcarbonyl,

2-thienylacetyl, 3-thienylacetyl, 2-picolyloxycarbonyl, 3-picolyloxycarbonyl, 4-picolyloxycarbonyl, 2-furylmethyloxycarbonyl, 3-furylmethyloxycarbonyl,

2-thienylmethyloxycarbonyl oxycarbonyl a

R ³ and R ⁴ are the same or different hydrogen atom, group or 3-thienylmethyl independently represent an alkyl group having 1 to 6 carbon atoms, optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, a mercapto group, an acyloxy group having 1 to 4 carbon atoms , benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl , (C 1 -C 4) alkylsulphinyl, carboxy or carbamoyl, (C 2 -C 8) alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy (C 1 -C 4), benzoyloxy upine, phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (alkylsulfinyl) alkylsulfinyl C 1 -C 4, carboxy or carbamoyl, C 3 -C 8 cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, benzyloxy, benzyloxy, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl carbon atoms, carboxy or carbamoyl, cycloalkenyl or hydroxy, acyloxy with benzoyloxy, alkoxy with alkylamino dialkylamino alkyl, alkylsulfonyl alkylsulfinyl carbon atoms, mercapto, , chlorine, having from 3 to substituted amino, 1 to 4 benzyloxy, up to 4 carbon to 4 carbon carbon atoms up to 4 to 5 carbon atoms;

alkylthio with p

substituted by aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl radical may contain 1 to 3 carbon atoms and R ⁶ is as defined above, or a carboxy or carbamoyl group, a carbon-carbon or up to five independent R ⁶ radicals substituted by an R ⁶ radical;

R ³ and R ⁴ may furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 carbon atoms, which may be optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having C 2 -C 4, C 2 -C 4 alkynyl, acyloxy, benzoyloxy, C 1 -C 4 alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl, and

X represents an oxygen, sulfur or selenium atom, optionally in its isomeric form, in combination with protease inhibitors from the group consisting of:

(S) -N - [(aS) -α - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) -isoquinolinyl) - 1-hydroxyethyl) -phenethyl-2-quinaldimido] -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) -yl) pentanamide

3. N- (quinolin-2-yl-carbonyl) -asparagine-1 (S) -benzyl-

3- (3-tert-butyl-l-isobutyl-ureido) -2 (R) -hydroxypropylamid

4. N- (2R-Hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -1S- (phenylmethyl) propyl) 2S - ((2-quinolinecarbonyl) amino) butanediamide

5. (2S, 3S, 5S) -5- (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- (isoquinolin-5-yloxyacetyl) amino-3) -metyltiopropanoyl) amino-4-phenylbutanoyl) -5,5-dimethyl-3tiazolidín-4-carboxamide

7. {3- [4-Amino-benzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxy-propyl} -tetrahydrofuran-3-yl ester

-carbamic

8. (3S, 6R) -3- (α-Ethylbenzyl) -6- (α-ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 94/11361)

9. N- [5-L- [N- (2-quinolinecarbonyl) -L-asparginyl] amino-

- (4R, 3S)) - epoxy-6-phenyl-hexanoyl] -isoleucine

10. N-tert-Butyl-1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinecarbonyl) asparaginyl] amino] butyl-4 (R) - (phenylthio) piperidine-2 (S) -carboxamide

11. [3 '' 'S- (3' R *, 4 '' 'S *) - N- [1' -OXO-1 '- (3' '- [1' '-OXO-2' '' - aza-3 '' - phenylmethyl-4 '' - hydroxy-5 '- (2' - '- N-tert-butylcarbamido) phenyl] pentyl-4' '- methyl) -1,2,3 , 4-tetrahydroisoquinoline

12. 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfonylbutyl] -decahydro-isoquinoline-3-carboxylic acid tert-butylamide

13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenylmethyl) -, (3S'-3. <X, 6.β, 7.β] na use as medicaments in the treatment of AIDS- or HIV-infections.

Particularly preferred are the quinoxalines of the formula I and Ia in which n is 0, 1 or 2,

R ¹ is independently fluoro, chloro or bromo, trifluoromethyl, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkoxy and C 1 -C 2 alkoxy atoms in the second alkoxy, C 1 -C 4 alkylthio, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazine, (C 1 -C 4) acyl, (C 1 -C 4) acyloxy, (C 1 -C 4) acylamino, cyano, carbamoyl, carboxy, (C 1 -C 4) alkyloxycarbonyl, hydroxysulfonyl or hydroxysulfonyl group, means one to six of each other m independent occurrences of ^R6 substituted phenyl, phenoxy, phenylthio, phenylsulphonyl, fenoxysulfonylovú, benzoyl,

A 2-pyridyl, 3-pyridyl or 4-pyridyl group wherein:

R ⁶ represents a fluorine, chlorine or bromine atom, a trifluoromethyl group, a nitro group, an amino group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, an C 1 -C 4 alkyloxycarbonyl group, a phenyl group or a phenoxy group

R ² is hydrogen, and

R ^{5 is} C 1 -C 6 alkyl optionally substituted by C 1 -C 4 alkoxy or C 1 -C 4 alkylthio, C 2 -C 6 alkenyl optionally substituted by oxo, C 3 -C 6 allenyl atoms, C 3 -C 8 alkynyl, especially 2-butynyl, C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, C 3 -C 8 cycloalkylalkyl and C 1 -C 2 cycloalkyl alkyl atoms, especially cyclopropylmethyl, optionally substituted with C1-C4 alkyl, cycloalkenylalkyl of 3 to 6 carbon atoms in cycloalkenyl and 1 to 2 carbon atoms in alkyl, in particular cyclohexenylmethyl, alkylcarbonyl of 1 to 6 carbon atoms in alkyl, pr optionally substituted by fluorine or chlorine, hydroxy, benzyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, alkenylamino of 1 to 4 carbon atoms pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl or C 1 -C 4 alkylthio, C 2 -C 6 alkenylcarbonyl, C 1 -C 6 alkyloxycarbonyl optionally substituted with fluoro , chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 2 -C 6 alkenyloxycarbonyl iv alkenyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl and pentenyloxycarbonyl, alkynyloxycarbonyl of 2 to 6 carbon atoms in alkynyl, especially propynyloxycarbonyl, especially propynyloxycarbonyl (C 2 -C 6) alkenyl, in particular allylthiocarbonyl, (C 1 -C 6) alkylaminocarbonyl and (C 1 -C 6) dialkylaminocarbonyl, pyrrolidin-1-yl, morpholino, piperazino or piperidino; 4-methyl-piperazin-1-yl-carbonyl, alkenylaminocarbonyl of 2 to 6 carbon atoms in the alkenyl and dialkenylaminocarbonyl of 1 to 6 carbon atoms in each alkenyl, alkyls ulfonylovú having 1 to 4 carbon atoms, alkenylsulfonyl group having 1 to 4 carbon atoms, or from one to two independent residues ^R6 substituted aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio) carbonyl, aryloxycarbonyl, aryloaminokarbonylovú, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, in particular benzyl or phenethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can comprise from 1 to 3 carbon atoms and R ⁶ is as defined above, or from one to two mutually R ⁶ substituted with 1-naphthylmethyl, 2-naphthylmethyl, 2-picolylyl, 3-picolylyl, 4picolylyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienyl, 2 pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-furylcarbonyl, 3-furylcarbonyl, 2-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, thienylacetyl, 2-picolyloxycarbonyl, 3-picolyloxycarbonyl, 4-picolyloxycarbonyl, 2-furylmethyloxycarbonyl,

3-furylmethyloxycarbonyl, 2-thienylmethyloxycarbonyl or 3-thienylmethyloxycarbonyl; and

R ³ and R ⁴ are the same or different and independently of one another are hydrogen, C 1 -C 4 alkyl, optionally substituted by hydroxy, mercapto, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, alkylsulfonyl (C 1 -C 4) alkyl, (C 1 -C 4) alkylsulphinyl, carboxy or carbamoyl, (C 2 -C 6) alkenyl, or up to two independent R ⁶ radicals substituted with aryl, benzyl, thienyl or thienylmethyl; ⁶ is as defined above, or

R ³ and R ⁴ may also be part of a saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 6 carbon atoms, which may optionally be substituted by an oxo or thioxo group, and

X is an oxygen or sulfur atom, optionally in its isomeric form, in combination with protease inhibitors from the group consisting of:

(S) -N - [(aS) -α - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) -isoquinolinyl) - 1-hydroxyethyl) -phenethyl-2-quinaldimido] -succinamide

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

3. N- (quinolin-2-yl-carbonyl) -asparagine-1 (S) -benzyl-

3- (3-tert-butyl-l-isobutyl-ureido) -2 (R) -hydroxypropylamid

4. N- (2R-Hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -

-1S- (phenylmethyl) propyl) 2S - ((2-quinolinecarbonyl) amino) butanediamide

5. (2S, 3S, 5S) -5- (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- (isoquinolin-5-yloxyacetyl) amino-3) (methylthiopropanoyl) amino-4-phenylbutanoyl) -5,5-dimethyl-1,3-thiazolidine-4-carboxamide

7. (3- [4-Aminobenzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid tetrahydro-furan-3-yl ester

8. (3S, 6R) -3- (α-ethylbenzyl) -6- (α-ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 94/11361)

9. N- [5-L- [N- (2-quinolinecarbonyl) -L-asparginyl] amino-

- (4R, 3S)) - epoxy-6-phenyl-hexanoyl] -isoleucine

10. N-tert-Butyl-1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinecarbonyl) asparaginyl] amino] butyl-4 (R) - (phenylthio) piperidine-2 (S) -carboxamide

11. [3 '' ¹ S- (3 ' ¹ ' R *, 4 'S *] - N- [1'-0x0-1' - (3 '' - [1 '' -OXO-)

2 '''-aza-3''' - phenylmethyl-4 '''-hydroxy-5' - (2 '''- N-terc.butylkarbamido) feny1] pentyl-4 ^11-methyl) -1 , 2,3,4-tetrahydroisoquinoline

12. 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfonylbutyl] -decahydro-isoquinoline-3-carboxylic acid tert-butylamide

13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenylmethyl) -, [3S'-3.a, 6.β, 7.β] for use as medicaments in the treatment of AIDS- or HIV-infections.

Very particularly preferred is the combination of S-4-isopropoxy-39-carbonyl-6-methoxy-3-methylthiomethyl) -3,4-dihydroquinazoline-2 (1H) -thione of formula A

and (S) -N - [(aS) -α - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) -isoquinolinyl) -1 -hydroxyethyl) -phenethyl-2-quinaldimido] -succinamide (Saquinavir) of formula B

for use in the treatment of AIDS or HIV infections.

Quinoxalines of formulas I and Ia are known (see EP 509 398 A1). The above-mentioned protease inhibitors are also known (see EP 432 695 A2, EP 569 083 A1, EP 541 168 A1, PCT WO 92/08688 A1, PCT WO 92/08701 A1, PCT WO 92/08700 A1, PCT WO 94 / No. 04492, PCT WO 94/14436, PCT WO 94/11361, EP 601 486 A,

EP 560 268 A, EP 609 625 A and PCT WO 94/08977).

The use of a combination of these compounds provides advantages in the treatment of diseases induced by retroviruses, in particular induced by HIV, as compared to monotherapy with individual compounds. The preferred and more potent use of the combination of these compounds for the treatment of AIDS or HIV-infections is mainly due to the synergistic antiviral effect, but additionally also to the unchanged compatibility of the combinations in toxicity, substance in cells compared to Gancioclovirus. synergistic toxicity (see M. Agents Chemotherapy (1991), 35, surviving 50% of the tox-50 single components, for example, for AZT in combination using the combination of N. Prichard et al., Antimicrob. 1060-1065).

In addition, the reduced effective dose given by the combination of substances to be treated reduces the likelihood of forming resistant viral isolates.

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

DETAILED DESCRIPTION OF THE INVENTION

HIV-infection in cell culture

The HIV test is carried out with modifications according to the method of Pauwels et al. (see Journal of Virological Methods, 20 (1988), 309-321).

Normal human blood lymphocytes (PBL) are enriched with Ficoll-Hypaque and stimulated in RPMI 1640, 20% fetal calf serum, with phytemagglutinin (90 µg / ml) and interleukin 2 (40 U / ml). For infectious HIV infection, PBLs are pelleted and the cell pellets are then suspended in 1 ml of HI-virus adsorption solution and incubated for 1 hour at 37 ° C.

The viral adsorption solution is centrifuged and the infected cell pellets are removed into growth medium to achieve 1 x 10 ⁵ cells per ml. The infected cells are pipetted into 96-well microtiter plate dishes at 1 x 10 ⁴ cells per dish.

Alternatively, instead of PBL, H9 cells are used for the antiviral assay.

Testing of the combinatorial effect of the test substances is carried out by Schachbrett titration (Checkerboard titration).

The first vertical row of the microtiter plate contains only growth medium and cells that are not infected but otherwise processed as above (cell control). The second vertical row of the microtiter plate contains only HIV-infected cells (virus control). The other dishes contain the compounds of the present invention, alone or in corresponding combinations, in various concentrations starting from the dishes of the third vertical row of microtiter plate in which it is further diluted (50 μΐ volume per dish) in a second step. For combination, the compounds of the second substance are prepared on a separate 96-well microtiter plate and then pipetted onto the prepared first microtiter plate. 100 μ 100 of prepared HIV-infected cells (so) can be used for this purpose. This covers the test concentrations in the range of about 10 to 50 fold above and below the IC ₅₀ concentration.

The test batches are incubated at 37 ° C until the untreated control is microscopically detectable for HIV-typical syncytia formation on host cells (between 3 and 6.

day after infection). In the untreated virus control, about 20 to 50 syncyties result under these test conditions, while the untreated cell control has no syncytia. The excess microtiter plate is then removed and examined by

HIV-specific ELISA for HIV-specific antigen (Vironostika HIV Antigen, Organon Teknika).

Inhibitory values are calculated according to Cut-Off-values from the corresponding cell, respectively viral, or inert test controls as a percentage (% inhibition value) and IC ₅₀ values ^are obtained as the concentrations of treated and infected cells at which the virus-specific 50% antigen suppressed by treatment with test compounds. To analyze the synergistic effect of the compounds, the differential values of the calculated and measured inhibitory values of each combination are determined (Prichard, MN et al., Antimicrob. Agents Chemoth. (1993), 37, 540-545).

A differential value of > 0 indicates a synergistic effect. For example, the results shown in the following table are achieved:

Table 1 Differential table for the calculated and measured effect of Saquinavir (B) with an example of formula (A)

Ex. of formula (A) nm 50 25 12 6 3 1.5 0.7 Saquinavirus (B) nm 50 0 0 0 13 32 30 16 25 0 0 0 29 49 20 3 12 0 0 0 37 40 0 0 6 0 0 0 32 57 23 0 3 0 0 0 27 0 0 0

Within the concentration range of 0.7 to 6 nM of the example of formula (A), a 6 to 50 nM protease inhibitor (B) results in a synergistic effect of the combination.

To measure the synergistic toxicity of the compounds, the concentrations of the substances with the tox-50 value of the individual compounds are examined and the cell toxic properties are examined microscopically, or the vitreous trypan blue staining is performed. None of the combinations tested showed synergistic toxicity.

Surprisingly, it has been found that the use of a combination of compounds provides a synergistic effect on HIV. This is shown, for example, in a combination study of a quinoxaline derivative with Saquinavirus (Table 1).

The combination of the present invention serves for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.

Indicative areas in human medicine include:

1. Treatment and prophylaxis of human retroviral infections.

2. Treatment and prophylaxis of diseases caused by HIV I, (human immunodeficiency virus, formerly referred to as HTLV III / LAV), i. AIDS and associated stages such as ARC (AIDS Related Complex) and LAS (Lymphadenophatie - Syndrome), as well as the virus-induced weakening of immunity and encephalopathy.

3. Treatment or prophylaxis of HTLV-I infection or HTLV-II infection.

4. Treatment or prophylaxis of AIDS carriers (AIDS carrier status).

Indicative areas in veterinary medicine include:

infections caused by:

(a) Maedivisna (sheep and goat)

(b) progressive Pneumoniavirus (PPV) (in sheep and goats)

(c) Caprine arthritis encephalitis virus (in sheep and goats)

(d) Zwoegerziekte virus (in sheep)

(e) infectious anemia virus (in horses)

f) infection with feline leukemia virus

(g) feline immunodeficiency virus (FIV) infection

h) infection with simian immunodeficiency virus (SIV).

Preference is given to the above-mentioned points 2, 3 and 4 of the human indication areas.

The present invention further provides pharmaceutical compositions comprising, in addition to non-toxic, inert and pharmaceutically acceptable carriers, one or more compounds of formulas I / Ia in combination with any of the aforementioned protease inhibitors, or any one or more compounds of formulas I / Ia and some of the aforementioned protease inhibitors remaining, as well as a process for the preparation of these compositions, in particular combinations of test compounds.

The active compounds of the formula I and Ia and the protease inhibitors should preferably be present in the abovementioned pharmaceutical compositions in a concentration of about 0.1 to 99.5% by weight, in particular 0.5 to 95% by weight of the total mixture.

In addition to the compounds of formulas I / Ia and the proteases mentioned above, the above combinations of inhibitors may also contain other pharmaceutical active ingredients.

The production of the aforementioned pharmaceutical compositions is carried out by conventional methods using known methods, for example by mixing the active compound (s) with the carrier or carriers.

In general, in both human and veterinary medicine, it has proven advantageous to administer the active ingredient (s) of the present invention in a total amount of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight to achieve the desired effect. 24 hours, optionally in the form of multiple individual doses. A single dose contains the active compound (s) preferably in an amount of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to withhold these doses, depending on the type and body weight of the object being treated, the type and severity of the disease, the type of preparation and drug application, as well as the time period and interval during which administration takes place.

Claims (13)

PATENT CLAIMS A medicament comprising, in combination, one or more protease inhibitors and one or more quinoxalines of the formula I as well as tautomeric forms Ia (Ia) in which n is 0, 1, 2, 3 or 4, independently of one another is a fluorine atom , chlorine, bromine or iodine, trifluoromethyl, trifluoromethoxy, - 47 hydroxy, C 1 -C 8 -alkyl, C 5 -C 8 -cycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxyalkoxy having 1 to 4 carbon atoms in the second alkoxy, an alkylthio group having 1 to an alkylsulfinyl group an alkylsulfonyl group 6 to 6 carbon to 6 to 6 carbon atoms, atoms, atoms, nitro, amino, azido, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl, piperidino, morpholino, 1-pyrrolidinyl, 4-pyrrolidinyl methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, acyl of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, acylamino of 1 to 6 carbon atoms, cyano, carboxy, carbamoyloxy, carbamoyloxy up to 6 carbon atoms in the alkyl, hydroxysulfonyl or sulfamoyl group, or is substituted by phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, anilinylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl ú, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or A 4-pyridyl group wherein: R ⁶ represents fluorine, chlorine, bromine or iodine, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl (C 1 -C 6) alkyl, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, (C 1 -C 6) alkylamino, (C 1 -C 6) alkylamino, (C 1 -C 6) alkyloxycarbonyl alkyl, phenyl, phenoxy, A 2-pyridyl group, 3-pyridyl or 4-pyridyl, and r 5 may be the same or different and independently of one another are hydrogen, hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, acyloxy of 1 to 6 carbon atoms, cyano, amino, alkylamino (C 1 -C 6) dialkylamino (C 1 -C 6) alkyl, arylamino, (C 1 -C 6) acylamino, (C 1 -C 8) alkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbonated alkylsulfonyl of 1 to 6 carbon atoms , until in each carbon 6 carbon alkyl, atoms, atoms, atoms 1 to oxo, thioxo, carboxy or carbamoyl, alkenyl of 2 to 8 carbon atoms, optionally substituted with fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1, 6, benzo, , phenoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl oxo, thio, carboxy or carbamoyl, C 3 -C 8 allenyl, optionally substituted by fluorine, chlorine or bromine, or hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, alkynyl with 3 to 8 carbon atoms substituted by fluorine, chlorine, cyano, amino, hydroxy, acyloxy, benzoyloxy, phenoxy, alkoxy having 1 alkylamino having 1 to alkyl, alkylthio to alkylsulfonyl or alkylsulfonyl; or iodine, mercapto, up to 6 carbon benzyloxy, carbon atoms, carbon carbon atoms up to 6 carbon to atoms, in each atom, 1 to 6 carbon atoms, oxo, thioxo, s C 3 -C 8 cycloalkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, hydroxy, acyloxy, benzoyloxy, mercapto, (1-6C) benzyloxy, phenoxy, (1-6C) alkoxy, (1-6C) alkylamino, (1-6C) alkylamino, (1-6C) alkylthio, (1-6C) alkylsulfonyl atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, cycloalkenyl of 3 to 8 carbon atoms, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, ac, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, cycloalkylalkyl of 3 to 8 carbon atoms in cycloalkyl and 1 to 4 carbon atoms in alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, amine, cyano , hydroxy, C 1 -C 6 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, in each C 1 -C 6 alkyl, atoms, alkylsulfonyl of 1 to 6 carbon atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, cycloalkenylalkyl of 3 to 8 carbon atoms in cycloalkenyl and of 1 to 4 carbon atoms in alkyl or substituents fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy having 1 to 6 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy having 1 to 6 carbon atoms, 1 to 6 carbon atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl, (C 1 -C 6) alkylcarbonyl, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 6 carbon atoms atoms, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, phenylsulfonyl, oxo, thio, carboxy or carbamoyl, C 2 -C 8 alkenylcarbonyl in alkenyl optionally substituted by fluorine, chlorine or bromine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, cycloalkylcarbonyl of 3 to 8 carbon atoms in cycloalkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy up to 4 carbon atoms, oxo or phenyl, cycloalkenylcarbonyl of 5 to 8 carbon atoms in the cycloalkenyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl C 3 -C 8 cycloalkylalkylcarbonyl, C 1 -C 3 alkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 5 -C 6 cycloalkenylalkylcarbonyl cycloalkenyl atoms having 1 to 3 carbon atoms in the alkyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, alkyloxycarbonyl of 1 to 8 carbon atoms in the alkyl, optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl or C 1 -C 4 alkylthio, C 2 -C 4 alkenyloxycarbonyl C 8 alkenyl, optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 2 -C 8 alkynyloxycarbonyl, optionally substituted by fluorine or chlorine, hydroxy, C 1-4 alkyl, oxo or phenyl, C 1 -C 8 alkylthiocarbonyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 2 -C 8 alkenylthiocarbonyl alkenyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, alkylaminocarbonyl of 1 to 8 carbon atoms in alkyl and dialkylaminocarbonyl C 1 -C 8 alkyl in each alkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, pyrrolidin-1-yl, morpholino, piperidino, piperazinyl or 4-methylpiperazine 1-ylcarbonyl, optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 acyl, C 2 -C 6 alkenyl, oxo, thioxo, carboxy or phenyl, C 2 -C 8 alkenylaminocarbonyl alkenyl and C 1 -C 6 dialkenylaminocarbonyl, optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 1 -C 6 alkylsulfonyl, optionally substituted bolded with fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 2 -C 6 alkenylsulfonyl, optionally substituted with fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy or phenyl, oxo group, or by one to five mutually independent occurrences of R ⁶ substituted aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, arylalkenyl, arylazo, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl (alkylthio) carbonyl, wherein the alkyl radical may in each case contain 1 to 5 carbon atoms and R ⁶ is as defined above, or one to three independent R radicals ⁶ substituted heteroaryl, heteroarylalkyl, hetero arylalkenyl, heteroarylalkylcarbonyl, alkenylcarbonyl, heteroaryloxycarbonyl, thio) carbonyl, heteroarylaminocarbonyl, heteroaryl (heteroarylheteroarylalkoxycarbonyl, heteroaryl (alkylthio) carbonyl, heteroaryl (alkylthio) (heteroaryl) R ³ and R ⁴ are the same or different and independently of one another are hydrogen, C 1 -C 8 alkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy , phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 1 -C 4, carboxy or carbamoyl, C 2 -C 8 alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy (C 1 -C 4) oxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 3 -C 8 cycloalkyl, optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, alkoxy, benzyloxy, benzyloxy atoms, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy a C 1 -C 8 cycloalkenyl group optionally substituted by a fluorine or chlorine atom, a hydroxy group, an acyloxy group with a benzoyloxy group, an alkoxy group with an amino group, a mercapto group, 1 to 4 carbon atoms, benzyloxy, phenoxy, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl , carboxy or carbamoyl, or up to five independent R ⁶ radicals substituted by aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl radical may contain 1 to 3 carbon atoms and R 6 is as defined above, or R ³ and R ⁴ or R ³ and R ⁵ may furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 8 carbon atoms, which may optionally be substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, an alkyl group of 1 up to 6 carbon atoms, 2 to 6 carbon alkenyl, 2 to 6 carbon alkynyl, acyloxy, benzoyloxy, 1 to 6 carbon alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl, and X represents an oxygen, sulfur or selenium atom or a substituted nitrogen of NR ² , wherein R ² may have the meaning given above, except for compounds in which R ³ and R ^{4 are} both hydrogen and compounds in which R ² and R ⁵ are hydrogen and R &lt; ^{3 &gt;} and / or R &^lt; ⁴ &gt; is an aralkyl group and compounds wherein X is an oxygen atom and R &lt; ² &gt; and R &lt; ⁵ & gt ^{; are} hydrogen. A medicament according to claim 1, comprising one or more quinoxalines of formula I and Ia, in which n is 0, 1, 2 or 3, R ¹ is independently fluoro, chloro or bromo, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 1 alkoxy 4 carbon atoms in the first and second alkoxy groups, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino up to 4 carbon atoms in each alkyl, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, acyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, acylamino of 1 to 4 carbon atoms, cyano, carbamoyl, carboxy to 4alkyloxy in an alkyl, hydroxysulfonyl or sulfamoyl group, or up to six phenyl, phenylsulfinyl, phenylsulfonyloxy-, benzoyl, independently Reno-phenoxy, means a single substituted phenylthio-, phenoxysulfonyl-, phenylsulfonylamino-, 3-pyridyl-, 3-pyridyl-, 3-pyridyl, phenylsulfonyl, anilinosulfonyl, 2-pyridyl, wherein R ⁶ represents a fluorine atom, a trifluoromethyl group, an alkyl group having a cycloalkyl group, an alkoxy group, an alkylthio group, an alkylthio group, an alkylsulfinyl alkylsulfonyl alkylamino group of chlorine or bromine, a nitro group, an amino group, and 4 to 5 carbon atoms; up to 4 to up to carbon 7 carbon carbon 4 carbon 4 carbon atoms, atoms, atoms, atoms, atoms, atoms, atoms, 1 group having 1 dialkylamino group having 1 to 4 carbon atoms in each alkyl, alkyloxycarbonyl group having 1 to 4 carbon atoms in alkyl, phenyl group or phenoxy group, R ² is hydrogen, and R ⁵ is hydrogen, amino, hydroxy, cyano, (C 1 -C 8) alkyl substituted with fluoro, chloro, cyano, amino, hydroxy, acyloxy, benzoyloxy, phenoxy, (C 1 -C 1) alkylamino, (C 1 -C 1) alkylamino) with oxo, carbamoyl, thioxo, carbon atoms, optionally bromine or iodine, mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, in each atom, i or From 4 to 4 carbon atoms to 4 to 4 carboxy carboxyls, alkenyl with 2 to substituted fluorine, chlorine, cyano, amino, hydroxy, acyloxy, benzoyloxy, phenoxy, alkoxy with 1 alkyl-1 dialkylamino , carbamoyl, optionally 8 carbon atoms, bromine or iodine, mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, each, or up to thio, allenyl with 3 alkynyl substituted with up to 4 carbon atoms in up to 4 carbon atoms and up to 8 carbon atoms, optionally bromine or iodine, 3-8 carbon atoms, fluorine, chlorine, cyano, amino, hydroxy, acyloxy with atoms, benzoyloxy, mercapto, C 1 -C 4 benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, carboxy or thio C 3 -C 8 -cycloalkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, hydroxy, acyloxy atoms, benzoyloxy, mercapto, C 1 -C 4 benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, carboxy or thio C 3 -C 8 -cycloalkenyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzoalkoxy, phenoxy, phenoxy, phenoxy C1 -C4 alkylamino, C1 -C4 dialkylamino in each alkyl, C1 -C4 alkylthio, oxo, thioxo, carboxy or carbamoyl, cycloalkylalkyl of 3 to 8 carbon atoms and the like cycloalkyl atoms having from 1 to 2 carbon atoms in the alkyl, optionally substituted by fluorine, chlorine, bromine or iodine, cyano, hydroxy, acyloxy, benzoyloxy, phenoxy, alkoxy having 1 dialkyl alkyloxy having 1 dialkylamino, , carbamoyl, amino, p 1 thioxo, mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, each, or up to 4 carbon atoms in up to 4 carbon <carboxy 4 carbon C 3 -C 8 fluoro, amino, cycloalkenylalkyl with s cycloalkenyl and 1 to 2 carbon atoms in alkyl optionally substituted with iodine, cyano, hydroxy, acyloxy, benzoyloxy, phenoxy to 1-alkoxy, 1 to 1 alkoxy 4 alkyls, alkylthio with 1 oxo, thioxo, carbamoyl, up to chlorine, bromine or, mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, in each atom, t or 4 carbon atoms of up to 4 carbon carboxy of up to 6 carbon atoms of fluorine, amino, i alkyl of 1, optionally substituted by iodine, cyano, hydroxy, acyloxy, benzoyloxy, 1-alkyloxy, 1-alkoxy, 1-alkoxy to alkyl, alkylthio with oxo, carbamoyl, thioxo, up to chlorine, bromine or mercapto, up to 4 carbon benzyloxy, carbon atoms, atoms, each carbon atom, or C 4 -C 4 -C 4 alkenylcarbonyl C 2 -C 6 alkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 3-6 cycloalkylcarbonyl cycloalkyl atoms optionally substituted by fluorine or chlorine, hydroxy, C1-C4 alkoxy, oxo or phenyl, cycloalkenylcarbonyl of 5 to 6 carbon atoms in cycloalkenyl optionally substituted by fluorine or chlorine to hydroxy, C 4 -C 4 -alkyl, oxo or phenyl, C 3 -C 6 cycloalkylalkylcarbonyl, C 1 -C 2 alkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy carbon atoms, oxo or phenyl, cycloalkenylalkylcarbonyl of 5 to 6 carbon atoms in cycloalkenyl and 1 to 2 carbon atoms in the alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo, or phenyloxy, (C 1 -C 6) alkyl optionally substituted by fluorine, chlorine or bromine, hydroxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylamino or (C 1 -C 4) alkylthio C 1 -C 4 alkenyloxycarbonyl, C 2 -C 6 alkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkoxy, oxo or phenyl, C 2 -C 6 alkynyloxycarbonyl alkynyl, optionally substituted by fluorine or chlorine, hydroxy, C1-C4alkoxy, oxo or phenyl, C1-C6alkylthiocarbonyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy up to 4 carbon atoms, oxo or phenyl, alkenylthiocarbonyl of 2 to 6 carbon atoms in the alkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, alkylaminocarbonyl of 1 to 6 carbon atoms alkyl atoms and a C 1 -C 6 dialkylaminocarbonyl group optionally substituted by a fluorine or chlorine atom, a hydroxy group, a C 1 -C 4 alkoxy group, an oxo group or a phenyl group, a pyrrolidin-1-yl group, morpholino, piperidino, piperazinyl or 4-methylpiperazin-1-ylcarbonyl, alkenylaminocarbonyl of 2 to 6 carbon atoms in the alkenyl and dialkenylaminocarbonyl of 1 to 6 carbon atoms in each alkenyl, optionally substituted with fluoro, chloro, or fluoro (C 1 -C 4) alkoxy, oxo or phenyl, (C 1 -C 4) alkylsulfonyl, optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkoxy or phenyl, (C 1 -C 4) alkenylsulfonyl carbon atoms, optionally substituted by fluorine, chlorine, hydroxyl, alkoxy of 1 to 4 carbon atoms, oxo or phenyl, or one to three independent occurrences of ^R6 substituted aryl, arylcarbonyl, aryl (thiocarbonyl ), (Arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, arylalkenyl, arylazo, arylalkylcarbonyl, arylalkenylkarbonylovú, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can in each case contain 1 to 5 carbon atoms and R ⁶ is as defined above, or one to two independent R ⁶ radicals substituted with 1-naphthylmethyl, 2-naphthylmethyl, 2-picolylyl, 3-picolylyl, 4-polyolylyl furylmethyl thienylmethyl, group, group, 2-furylmethyl, 32-thienylmethyl, 32-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-furylcarbonyl, 3-furylcarbonyl, 2-thienylcarbonyl, 3-thienylcarbonyl, 2-thienylacetyl, 3-thienylacetyl, 2-picolyloxycarbonyl, 3-picolyloxycarbonyl, 4-picolyloxycarbonyl, 2-furylmethyloxycarbonylthienylcarbonyl, 3-thienyloxycarbonyl, 2-thienylcarbonyl, 3-thienylacetyloxycarbonyl, 3-thienylmethyloxycarbonyl; and R ³ and R ⁴ are the same or different and independently of one another are hydrogen, C 1 -C 6 alkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy , phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 1 -C 4, carboxy or carbamoyl, C 2 -C 8 alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy (C 1 -C 4) oxy, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl C 3 -C 8 cycloalkyl, optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, alkoxy, benzyloxy, benzyloxy atoms, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy an upine or carbamoyl group, a cycloalkenyl group having 3 to optionally substituted hydroxy, an acyloxy group having a benzoyloxy group, an alkoxy group having an alkylamino group, a dialkylaminoalkyl group, an alkylsulfonyl group an alkylsulfinyl group carboxy group or a carbamoyl group, Carbon atoms of fluorine or atoms, chlorine, mercapto, carbon atoms, phenoxy, atoms, atoms, in each atom,. atoms,. amino-substituted atoms, 1 to 4 benzyloxy, 1 to 4 carbon to 4 carbon atoms up to 4 1 to 1 to 1 to p alkylthio with carbon 4 carbon 4 C, or up to five radicals R independently from each other ^{6-substituted} aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl moiety may contain 1 to 3 carbon atoms and R ⁶ is as defined above, or R ³ and R ⁴ may furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 carbon atoms, which may be optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having C 2 -C 4, C 2 -C 4 alkynyl, acyloxy, benzoyloxy, C 1 -C 4 alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl, and X represents an oxygen, sulfur or selenium atom, optionally in its isomeric form. A medicament according to claim 1, comprising one or more quinoxalines of the formula I and Ia, in which n is 0, 1 or 2, independently of one another is fluorine, chlorine or bromine, trifluoromethyl, hydroxy, alkyl of 1 to 1 C 4 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkoxy in the first alkoxy and C 2 -C 2 alkoxy, C 1 -C 4 alkylthio, nitro, amino, C 1 -C 4 alkylamino atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C 1 -C 4 acyl, C 1 -C 4 acyloxy, C 1 -C 4 acylamino, cyano, carbamoyl, carboxy, C 1 -C 4 alkyloxycarbonyl, C 1 -C 4 alkyl, or a sulfamoyl group; or g means one to six independent R groups substituted by phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, A 2-pyridyl, 3-pyridyl or 4-pyridyl group wherein: R ⁶ is fluorine, chlorine or bromine, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, phenyl or phenoxy R ² is hydrogen, and R ^{5 is} C 1 -C 6 alkyl optionally substituted by C 1 -C 4 alkoxy or C 1 -C 4 alkylthio, C 2 -C 6 alkenyl optionally substituted by oxo, C 3 -C 6 allenyl C 3 -C 8 alkynyl, especially 2-butynyl, C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, C 3 -C 8 cycloalkylalkyl having 1 to 2 carbon atoms in alkyl, in particular cyclopropylmethyl, optionally substituted with C1-C4 alkyl, C3-C6 cycloalkenylalkyl with 1 to 2 carbon atoms in alkyl, in particular cyclohexenylmethyl, C1-C6 alkylcarbonyl alkyl, pr optionally substituted by fluorine or chlorine, hydroxy, benzyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, alkenylamino of 1 to 4 carbon atoms pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl or C 1 -C 4 alkylthio, C 2 -C 6 alkenylcarbonyl, C 1 -C 6 alkyloxycarbonyl optionally substituted with fluoro , chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 2 -C 6 alkenyloxycarbonyl iv alkenyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl and pentenyloxycarbonyl, alkynyloxycarbonyl of 2 to 6 carbon atoms in alkynyl, especially propynyloxycarbonyl, especially propynyloxycarbonyl (C 2 -C 6) alkenyl, in particular allylthiocarbonyl, (C 1 -C 6) alkylaminocarbonyl and (C 1 -C 6) dialkylaminocarbonyl, pyrrolidin-1-yl, morpholino, piperazino or piperidino; 4-methyl-piperazin-1-yl-carbonyl, alkenylaminocarbonyl of 2 to 6 carbon atoms in the alkenyl and dialkenylaminocarbonyl of 1 to 6 carbon atoms in each alkenyl, alkyls ulfonylovú having 1 to 4 carbon atoms, alkenylsulfonyl group having 1 to 4 carbon atoms, or from one to two independent residues ^R6 substituted aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio) carbonyl, aryloxycarbonyl, aryloaminokarbonylovú, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, in particular benzyl or phenethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can comprise from 1 to 3 carbon atoms and R ⁶ is as defined above, or from one to two mutually R ⁶ substituted with 1-naphthylmethyl, 2-naphthylmethyl, 2-picolylyl, 3-picolylyl, 4picolylyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienyl, 2 pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-furylcarbonyl, 3-furylcarbonyl, 2-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, 3-thienylcarbonyl, thienylacetyl, 2-picolyloxycarbonyl, 3-picolyloxycarbonyl, 4-picolyloxycarbonyl, 2-furylmethyloxycarbonyl, 3-furylmethyloxycarbonyl, 2-thienylmethyloxycarbonyl or 3-thienylmethyloxycarbonyl or 3-thienylmethyloxycarbonyl and 3-thienylmethyloxycarbonyl and 3-thienylmethyloxycarbonyl and 3-thienylmethyloxycarbonyl; R ³ and R ⁴ are the same or different and independently of one another are hydrogen, C 1 -C 4 alkyl, optionally substituted by hydroxy, mercapto, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, alkylsulfonyl (C 1 -C 4) alkyl, (C 1 -C 4) alkylsulphinyl, carboxy or carbamoyl, (C 2 -C 6) alkenyl, or up to two independent R ⁶ radicals substituted with aryl, benzyl, thienyl or thienylmethyl; ⁶ is as defined above, or R ³ and R ⁴ may furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 6 carbon atoms, which may optionally be substituted by an oxo or thioxo group, and X represents an oxygen or sulfur atom, optionally in its isomeric form. Medicament according to claims 1 to 3, characterized in that it contains, as a protease inhibitor, one or more compounds selected from the group consisting of: (S) -N - [(aS) -α - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) -isoquinolinyl) ) -1-hydroxyethyl) phenethyl-2-chinaldimido] -succinamide 2. 2 (R) -Benzyl-5- (2 (S) - (N-tert-butylcarbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) -4 (S) -hydroxy-N (2 (R) ) hydroxy-indan-1 (S) yl) -pentaneamide 3. N- (quinolin-2-yl-carbonyl) -asparagine-1 (S) -benzyl- 3- (3-tert-butyl-l-isobutyl-ureido) -2 (R) -hydroxypropylamid 4. N- (2R-Hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -1S- (phenylmethyl) propyl) 2S - ((2-quinolinecarbonyl) amino) butanediamide 5. (2S, 3S, 5S) -5- (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- (isoquinolin-5-yl-oxy-acetyl) amino-3-metyltiopropanoyl) amino-4-phenylbutanoyl) -5,5-dimethyl-3tiazolidín-4-carboxamide 7. (3- [4-Aminobenzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl) -carbamic acid tetrahydro-furan-3-yl ester 8. (3S, 6R) -3- (α-Ethylbenzyl) -6- (α-ethylphenethyl) -4-hydroxy- 2H-pyran-2-one (VB 11 478, PCT WO 94/11361) 9. N- [5-L- [N- (2-quinolinecarbonyl) -L-asparginyl] amino- - (4R, 3S)) - epoxy-6-phenyl-hexanoyl] -isoleucine 10. N-tert-Butyl-1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinecarbonyl) asparaginyl] amino] butyl-4 (R) - (phenylthio) piperidine-2 (S) -carboxamide 11. [3 ^'1' S- (3 ¹ '' R *, 4 ^'1'S *] - N- [1'-Oxo-1 ¹ - (3''- [1 ^11' _oxo-9 - 2 '''-aza-3''' - phenylmethyl-4 '''-hydroxy-5''' - (2 '''- N-tert-butylcarbamido) phenyl] pentyl-4''- methyl) -1 , 2,3,4-tetrahydroisoquinoline 12. 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfonyl-butyl] -decahydro-isoquinoline-3-carboxylic acid tert-butylamide 13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenylmethyl) -, [3S'-3.α, 6.β, 7.β]. -t a Medicament comprising in combination S-4-isopropoxycarbonyl-6-methoxy-3-methylthiomethyl) -3,4-dihydroquinoxaline-2 (1H) -thione of the formula A (A) and (S) -N - [(aS) -α - [(1R) -2 - [((3S-4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2 (1H) - isoquinolinyl) -1-hydroxyethyl) -phenethyl-2-quinaldimido] -succinamide (Saquinavir) of formula B