SK99899A3 - Quinoxaline in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating aids - Google Patents

Abstract

The invention relates to the use of quinoxalines in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating AIDS and/or HIV infections.

Description

QUINOXALINES IN THREE COMBINATION WITH PROTHEASE INHIBITORS AND

REVERSE TRANSCRIPTASE INHIBITES AS AIDS MEDICINES

Technical field

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

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) causes persistent and progressive chronic disease. HIV violates the immune system (acquired immune deficiency syndrome, AIDS) and the central and peripheral nervous systems. In addition, HIV-virus causes many other clinical manifestations in the defense of ARC / AIDS, particularly opportunistic infections (OI) caused by other viruses, such as herpes virus (HSV I and II), cytomegalovirus (CMV) or OI infections. caused by bacteria, fungi or parasites.

HIV belongs to the family of retroviruses. One of the essential and in the cycle of multiplying the essential enzymatic activities of these viruses is the protease (Huff, J. R., Med. Chem. (1991), 34, 2305-2314). Low molecular weight peptide and non-peptide analogs of natural protease substrates inhibit HIV replication (Roberts, NA et al., Science (1990) 248, 358-361; Lam, PYS et al., Science (1994), 263, 380-384) in vitro and in vivo.

Analogs of natural reverse transcriptase substrates such as azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI), and 3'-thiacytidine (Lamivudine) inhibit HIV replication in vitro and in vivo. ΑΖΎ serves, for example, to treat ARC / AIDS. However, long-term therapy of HIV infected patients with AZT is accompanied by bone marrow toxicity; Besides that

31257 / H produces AZT-resistant virus isolates. They have been reported in some patients who have been treated with DDC or DDI intolerance, such as peripheral neuropathy. Thus, new inhibitors for acceptable and effective therapy are highly needed.

SUMMARY OF THE INVENTION

A triple combination of quinoxalines with protease inhibitors and reverse transcriptase inhibitors has now been invented, and its synergistic effect on HIV reproduction when used to combat AIDS or HIV infections is significantly superior to that of the prior art.

It has now been found that the quinoxalines of formula I

R ^:

R as well as their tautomeric forms of formula Ia

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

R ¹ is independently 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 atoms

31257 / H second alkoxy, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, nitro, amino, azido, alkylamino C 1 -C 6 dialkylamino, C 1 -C 6 dialkylamino, piperidine, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, 6-acyl C 1 -C 6 acyloxy, cyano, carbamoyl, carboxy, C 1 -C 6 alkyloxycarbonyl, hydroxysulfonyl, sulfamoyl, or up to five independent phenoxy-substituted phenoxy groups, R ⁶ ú, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein:

R ⁶ is fluorine, chlorine, bromine or iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy , (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkyloxycarbonyl, phenyl a phenoxy group, a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, ₉

R represents a hydrogen atom, a (1-6C) alkoxy group, a hydroxy group, a picolyl group, a cyclopropyl group or an isopropenyloxycarbonyl group.

31257 / H

R ⁵ is hydrogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, C 1 -C 6 acyloxy, cyano, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, and C 1 -C 6 alkylamino; , 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 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, carboxy or carbamoyl;

(C 2 -C 8) alkenyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, alkoxy, 1-phenoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl;

C 3 -C 8 alenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 6 alkoxy, oxo or phenyl; (C 3 -C 8) alkynyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, alkoxy, 1-phenoxy, phenoxy (C 1 -C 6) dialkylamino, (C 1 -C 6) dialkylamino in each alkyl,

31257 / H alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl;

C 3 -C 8 cycloalkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, 1-phenoxy, phenoxy, phenoxy (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl;

C 3 -C 8 cycloalkenyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, 1-phenoxy, phenoxy, phenoxy a (C 1 -C 6) dialkylamino group, a (C 1 -C 6) alkylthio group, a phenylsulfonyl group, an oxo group, a thio group, a carboxy group or a carbamoyl group;

C 3 -C 8 cycloalkylalkyl and C 1 -C 4 alkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy, benzoyloxy, phenoxy, alkoxy 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 of oxo, thioxo, carboxy or carboxy;

cycloalkenylalkyl having 3 to 8 carbon atoms in the cycloalkenyl and 1 to 4 carbon atoms in the alkyl, optionally substituted

31257 / H with 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) alkoxy (C 1 -C 6) dialkylamino, 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, 6-carbon, benzyloxy, benzyloxy atoms, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl;

(C 2 -C 8) alkenylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl;

cycloalkyl of 3 to 8 carbon atoms in the cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 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;

31257 / H cycloalkylalkylcarbonyl having 3 to 8 carbon atoms in cycloalkyl and 1 to 3 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl;

cycloalkenylalkylcarbonyl having 5 to 8 carbon atoms in cycloalkenyl and 1 to 3 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl;

(C 1 -C 8) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 1 -C 4 alkylthio up to 4 carbon atoms;

(C 2 -C 8) alkenyloxycarbonyl 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 -C 4) alkoxy, 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 optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo, or phenyl;

31257 / H alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 8 carbon atoms in each alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy having 1 to 4 carbon atoms, oxo or phenyl;

pyrrolidin-1-yl, morpholino, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl, optionally substituted with C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 acyl, oxo, thio, carboxy, or phenyl;

alkenylamino and dialkenylamino of 2 to 8 carbon atoms in each alkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl;

(C 1 -C 8) alkylsulfonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl;

(C 2 -C 8) alkenylsulfonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl;

or with up 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, arylalkenylkarbonylovú , arylalkoxycarbonyl or aryl (alkylthio) carbonyl, wherein the alkyl radical may each contain 1 to 5 carbon atoms and R ⁶ is as defined above, or up to three independent R ⁶ radicals substituted by a heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl,

31257 / H (heteroarylthio) carbonyl, heteroarylaminocarbonyl, heteroarylalkoxycarbonyl, heteroaryl (alkylthio) carbonyl or heteroarylalkylaminocarbonyl group, the alkyl radical may in each case contain 1 to 3 carbon atoms and R ⁶ is as defined above,

R ³ and R ⁴ may be the same or different and independently represent a hydrogen atom, a C 1 -C 8 alkyl group 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 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl having 1 to 4 carbon atoms, carboxy or carbamoyl;

C 2 -C 8 alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy atoms, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, 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, phenoxy, (C 1 -C 4) alkoxy atoms, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl

31257 / H with carbon atoms, C 1 -C 4 alkylsulphinyl, carboxy or carbamoyl;

C 3 -C 8 cycloalkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy atoms, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy or carbamoyl;

substituted with an aryl, heteroaryl or heteroarylalkyl radical independently of each other by R ⁶ , wherein the alkyl radicals may each contain 1 to 3 carbon atoms and R ⁶ is as defined above, or

R and R may also be part of a saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 8 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 6 carbon atoms, an alkenyl group having 2 to 6 C 2 -C 6 alkynyl, C 1 -C 6 acyloxy, 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 is as defined above, in combination with protease inhibitors and reverse transcriptase inhibitors, are well suited for use as medicaments for the treatment of AIDS and HIV-infections.

The alkyl groups mentioned in the above definitions may be straight or branched. Unless otherwise defined, they preferably contain 1 to 8, especially 1 to 6 and particularly preferably 1 to 4 carbon atoms. As examples

31257 / H, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl and the like can be mentioned.

The alkenyl groups mentioned in the above definitions may be straight or branched and contain one to three double bonds. Unless otherwise defined, they preferably contain 2 to 8 and particularly preferably 2 to 6 carbon atoms. Examples include 2-propenyl, 1-methyletenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 3,3-dichloro-2. a propenyl or pentadienyl group and the like.

The alkynyl groups mentioned in the above definitions may be straight or branched and contain one to three triple bonds. Unless otherwise defined, they preferably contain 2 to 8 and particularly preferably 3 to 6 carbon atoms. Examples are 2-propynyl and 3-butynyl and the like.

The cycloalkyl and cycloalkenyl groups mentioned in the above definitions contain, unless otherwise defined, preferably 3 to 8 and particularly preferably 4 to 6 carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.

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

The aryl groups mentioned in the above definitions are preferably aromatic groups having 6 to 14 carbon atoms, in particular having 6 to 10 carbon atoms, such as phenyl or naphthyl.

In the above-mentioned heterocyclic rings or heteroaryl groups, heteroatoms are particularly suitable

31257 / H, for example, oxygen, sulfur and nitrogen, where in the case of a saturated nitrogen ring there is a NZ group at which Z represents a hydrogen atom or a group R ⁵ , where R ⁵ is as defined above.

Unless otherwise defined, heterocyclic rings preferably 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 definitions are, for example, heteroaromatic radicals, such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, indolyl, quinolyl or an isoquinolyl residue.

The aralkyl groups mentioned in the above definitions are, for example, benzyl, phenylethyl, naphthylmethyl or styryl.

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

For a correspondingly related definition of substituents (such as an arylalkoxycarbonyl group), the ranges per substituent described are equally preferred.

Depending on the various substituents, compounds of formulas I and Ia may have multiple 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 formulas I and Ia can be directly produced by known methods or analogously to known methods, or can be additionally separated.

Compounds of formulas I and Ia can be prepared by known methods or modifications thereof (see, for example, Rodd's Chemistry of Carbon Compounds, S. Coffey, M.F. Ansell (Publisher); Elsevier, Amsterdam, 1989;

31257 / H Part IV, Part IJ, p. 301-311, Heterocyclic Compounds, R. C. Elderfield (Publisher); Wiley, New York, 1957; 6, p. 491 to 495).

Within the scope of the present invention, protease inhibitors are structurally different peptide analogs that are useful in the treatment of diseases induced by retroviruses.

Particular mention may be made of:

1.) 2,4,7,12-tetraazatridecane-13-carboxylic acid, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3, 6-dioxo-8,11-bis (dimethyl phenyl) -, 5-tiazolylmetylester [5S- (5R * _l 8R *, 10R *, 11R *)]; PCT WO 95/07696; PCT WO 95/20384 A1; PCT WO 95/009614 A1 [ABBOTT (Ritonavir) ABT-538]

2.) 3-isoquinolinecarboxamides, N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S- [ 2S *, 3S *), 3.a., 4a.p., 8a.p.]] - _f monoethanesulphonate (salt); PCT WO 95/09843; US 5484926; AGOURON (Viracept ^R ) AG-1343

31257 / H

3.) Carbamic acid, (3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S [ 3R * (1S *, 2R *) J] - PCT WO 94/05639; [VERTEX PHARM. (Kisseii, Glaxo Wellcome), VX-478]

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

5.) 2 (R) -Benzyl-5- (2 (S) - (N-tert-butylcarbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) -4 (S) -hydroxy-N- ( 2 (R) -Hydroxyindan-1 (S) -yl) pentanamide (L735524, EP 569 083 A1, EP 541 168 A1)

CH,

31257 / H

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

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

8.) (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)

31257 / H

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

10. [3 - [(4-Amino-benzenesulfonyl) -isobutylamino] -1-benzyl-2-hydroxy-propyl] -carbamic acid tetrahydro-furan-3-yl ester

CH. (CH,),

11.) (3S, 6R) -3 - (- Ethylbenzyl) -6- (ethylphenethyl) -4-hydroxy-2H-pyran-2-one (UK)

478, PCTWO 94/11361)

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

31257 / H

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

14.) [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)

15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methylbenzoylamino) -4-phenylsulfamylbutyl] decahydroisoquinoline-3-carboxylic acid tert-butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA)

31257 / H

16.) 2H-1,4-diazapin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis- (phenylmethyl) -, [3S '- (3.a., 6.p.). 7 (PCT WO 94/08977)

In the context of the present invention, reverse transcriptase inhibitors are different nucleosides. Preferred are zidovudine (Retrovirus) (AZT), didanosine (DDI), dideoxycytidine (DDC), lamivudine (Epivir, 3TC ^R ), Stavudine (D4T), BW 935U83, BW 1592U89; especially zidovudine and epivir. Said nucleosides can be produced by generally known methods (see Merck-Index, 11th edition of Rahway NJ 1989, Drugs 45 (4, 488 et al., 45 (5), 637 et al., 1993, Drugs 44 (4), 656 and 656). et al., 1992, Clin Pharmacol., Ther., 55, No. 2, 198, 1994, Antiviral-Chem, Chemother, 2, No. 3, 125-132, 1991, Antiviral-Rest., 23, Suppl. 1994, Abstracts of the 34 ^th ICAAC, Orlando 4.7.10.94) A particularly preferred retrovirus (AZT).

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

R ¹ is independently fluorine, bromine, trifluoromethyl, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxyalkoxy having 1 to 4 carbon atoms in the first and second alkoxy, alkylthio of 1 to 4 carbon atoms, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, piperidine, morpholine, 1-pyrrolidinyl, 4-methylpiperazinyl, C 1 -C 4 acyl atoms, acyloxy of 1 to 4 carbon atoms, cyano,

31257 / H carbamoyl, carboxy, C 1 -C 4 alkyloxycarbonyl, hydroxysulfonyl, sulfamoyl, or up to two independent R ⁶ substituents substituted with phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, phenylsulfonyl, a pyridyl or 4-pyridyl group, wherein

R ⁶ is fluorine, chlorine or bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, phenyl or phenyl; phenoxy.

R ² represents hydrogen,

R ⁵ represents an alkyl group having 1 to 6 carbon atoms, optionally substituted by a fluorine or chlorine atom, a hydroxy group, an acyloxy group having 1 to 4 carbon atoms, a benzoyloxy group, a benzyloxy group, a phenoxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylamino group C1-C4 dialkylamino in each alkyl, C1-C4 alkylthio, oxo, thioxo, carboxy or carbamoyl group;

(C 2 -C 6) alkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylamino; (C 1 -C 4) alkyl, (C 1 -C 4) alkylthio, oxo, thioxy, carboxy, or carbamoyl;

C 3 -C 8 alenyl optionally substituted by fluorine or chlorine, hydroxy, acyloxy of 1 to 4 carbon atoms

31257 / H carbon atoms, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy of (C 1 -C 4) alkylamino, (C 1 -C 4) alkylthio, oxo, thio or carboxy;

C 3 -C 8 cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy C 1 -C 4 dialkyl, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, thioxo, carboxy or carbamoyl;

C 3 -C 8 cycloalkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, (C 1 -C 4) alkyl, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylthio, oxo, thioxo, carboxy or carbamoyl;

cycloalkylalkyl of 3 to 6 carbon atoms in cycloalkyl and 1 to 2 carbon atoms in alkyl optionally substituted by fluorine or chlorine, hydroxy, alkyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, benzyloxy C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, oxo, thio, carboxy or carbamoyl;

31257 / H cycloalkenylalkyl having 3 to 6 carbon atoms in cycloalkenyl and having 1 to 2 carbon atoms in alkyl, optionally substituted by fluorine or chlorine atom, hydroxy, alkyl having 1 to 4 carbon atoms, acyloxy having 1 to 4 carbon atoms, benzoyloxy benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, thioxo, carboxy or carbamoyl;

(C 1 -C 6) alkylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkyl, (C 1 -C 4) acyloxy, benzoyloxy, benzyloxy, phenoxy (C 1 -C 4) alkoxy , (C 1 -C 6) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkenylamino, 1-pyrrolidinyl, piperidine, morpholino, 1-methylpiperazin-1-yl, (C 1 -C 4) alkylthio atoms, oxo, thioxo, carboxy or carbamoyl;

alkenylcarbonyl having 2 to 6 carbon atoms in the alkenyl, optionally substituted with a fluorine or chlorine atom, or a hydroxy group;

cycloalkylcarbonyl having 3 to 6 carbon atoms in the cycloalkyl;

cycloalkenylcarbonyl having 5 to 6 carbon atoms in the cycloalkenyl;

cycloalkylalkylcarbonyl having 3 to 6 carbon atoms in the cycloalkyl and 1 to 2 carbon atoms in the alkyl;

cycloalkenylalkylcarbonyl having 5 to 6 carbon atoms in the cycloalkenyl and 1 to 2 carbon atoms in the alkyl;

(C 1 -C 6) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy,

31257 / H alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl or alkylthio of 1 to 4 carbon atoms;

(C 2 -C 6) alkenyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy or (C 1 -C 4) alkoxy;

(C 2 -C 6) alkynyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy or (C 1 -C 4) alkoxy;

alkylthiocarbonyl having 1 to 6 carbon atoms in the alkylthio group, optionally substituted by a fluorine or chlorine atom, a hydroxy group or an alkoxy group having 1 to 4 carbon atoms;

alkenylthiocarbonyl having 2 to 6 carbon atoms in the alkenylthio group optionally substituted by a fluorine or chlorine atom, a hydroxy group or an alkoxy group having 1 to 4 carbon atoms;

alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 6 carbon atoms in each alkyl, optionally substituted with a fluorine or chlorine atom, a hydroxy or alkoxy group having 1 to 4 carbon atoms;

pyrrolidin-1-yl, morpholine, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl group;

alkenylamino and dialkenylamino having 2 to 6 carbon atoms in each alkenyl optionally substituted by fluorine or chlorine, hydroxy or alkoxy having 1 to 4 carbon atoms;

(C 1 -C 4) alkylsulfonyl optionally substituted by fluorine or chlorine, hydroxy or (C 1 -C 4) alkoxy;

(C 2 -C 4) alkenylsulfonyl, or up to two independent R ⁶ radicals substituted with aryl, arylcarbonyl, (arylthio) carbonyl, aryloxycarbonyl, arylamino31257 / H carbonyl, (arylamino) thiocarbonyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl aryl (alkylthio) carbonyl, wherein the alkyl radical may each contain 1 to 3 carbon atoms and R ⁶ is as defined above, or up to two independent R ⁶ radicals substituted by 1-naphthylmethyl, 2-naphthylmethyl, 2-picolyl, 3-picolyl, -picolyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 3-furyl, 3-furyl, -picolyloxycarbonyl, 3picolyloxycarbones a 4-picolyloxycarbonyl, 2-furylmethyloxycarbonyl, 3furylmethyloxycarbonyl, 2-thienylmethyloxycarbonyl or 3-thienylmethyloxycarbonyl group, wherein R ⁶ is as defined above,

R ³ and R ⁴ may be the same or different and independently represent a hydrogen atom, a C 1 -C 4 alkyl group optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, a mercapto group, an acyloxy group of 1 to 4 carbon atoms, benzoyloxy, phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkylthio, (C 1 -C 4) alkylsulfonyl, (C 1 -C 4) alkylsulfinyl, carboxy or carbamoyl group; group;

(C 2 -C 6) alkenyl optionally substituted by fluorine or chlorine;

C 3 -C 6 cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl,

31257 / H alkylthio of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, carboxy or carbamoyl;

C 3 -C 8 cycloalkenyl optionally substituted with fluoro or chloro;

and two independent radicals R ⁶ substituted aryl, benzyl, heteroaryl or heteroarylmethyl, wherein R ⁶ is as defined above, or

R ³ and R ⁴ may also be part of a saturated or unsaturated C 3 -C 6 carbocyclic or heterocyclic ring which may be optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, an acyloxy group having 1 to 4 carbon atoms, a benzyloxy group, a 1-alkoxy group up to 4 carbon atoms, oxo, thioxo, carboxy or carbamoyl; and

X is an oxygen or sulfur atom, optionally in isomeric form, useful in combination with protease inhibitors of the series comprising

1.) 2,4,7,12-tetraazatridecane-13-carboxylic acid, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3, 6-dioxo-8,11-bis (phenylmethyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)];

2.) 3-isoquinolinecarboxamides, N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S- [ 2- (2S *, 3S *), 3.a, 4a.β, 8a.β]] -, monoethane sulfonate (salt);

3.) Carbamic acid, [3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S [ 3 R * (1 S *, 2 R *)]] -;

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

31257 / H

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

6.) N- (quinolin-2-ylcarbonyl) -asparagine-1 (S) -benzyl-3- (3-tert-butyl-1-isobutylureido) -2 (R) -hydroxypropylamide

7.) N1- (2R-Hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -1S- (phenylmethyl) propyl) -2S - ((2-quinolinylcarbonyl) amino) butanediamide

8) (2 S, 3 S ₁ 5 S) -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

9.) (R) -N-tert-Butyl-3 - ((2S, 3S) -2-hydroxy-3-N - ((R) -2-N- (isoquinolin-5-yloxyacetyl) amino-3-) methylthiopropanoyl) amino-4-phenylbutanoyl) -5,5-dimethyl-1,3-thiazolidine-4-carboxamide

10.) [3 - [(4-Amino-benzenesulfonyl) -isobutylamino] -1-benzyl-2-hydroxy-propyl] -carbamic acid tetrahydro-furan-3-yl ester

11.) (3S, 6R) -3 - (- Ethylbenzyl) -6- (ethylphenethyl) -4-hydroxy-2H-pyran-2-one

12.) N- [5-L- [N-2-quinolinecarbonyl] -L-asparaginyl] amino- (4R, 3S) -epoxy-6-phenylhexanoylisoleucine

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

14.) [3 '' S- (3'R *, 4'S *)] - N- [1'-oxo-1 '- (3- [1'-oxo-2' ') - aza-3'-phenyl - methyl-4 '' - hydroxy-5 '- (2' '- N-tert-butylcarbamido) phenyl] pentyl-4-methyl) -

1,2,3,4-tetrahydroisoquinoline

15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfamylbutyl] decahydroisoquinoline-3-carboxylic acid tert-butylamide

16.) 2H-1,4-diazapin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis- (phenylmethyl) -, [3S '- (3.a., 6.p.). , 7.p.I and reverse transcriptase inhibitors for use as medicaments for the treatment of AIDS and HIV infections.

31257 / H

Particularly preferred are quinoxalines of formulas 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, alkylthio of 1 to 4 carbon atoms, nitro, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, piperidine, morpholine, 1-pyrrolidinyl, 4-methylpiperazines C1 -C4 acyl, C1 -C4 acyloxy, cyano, carboxy, C1 -C4 alkoxycarbonyl, hydroxysulfonyl, sulfamoyl, or up to two independent substituents of R @ ^6; , phenoxy, phenylthio, phenylsulfone yl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group, wherein:

R ⁶ represents fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, phenyl, phenoxy,

R ² represents hydrogen,

R ⁵ is C 1 -C 6 alkyl optionally substituted with C 1 -C 4 alkoxy or C 1 -C 4 alkylthio;

(C 2 -C 6) alkenyl optionally substituted by oxo;

C 3 -C 6 alenyl;

31257 / H is alkynyl of 3 to 8 carbon atoms, in particular 2-butynyl;

cycloalkyl having 3 to 6 carbon atoms;

cycloalkenyl of 5 to 6 carbon atoms;

cycloalkylalkyl having 3 to 6 carbon atoms in cycloalkyl and having 1 to 2 carbon atoms in alkyl, in particular cyclopropylmethyl, optionally substituted alkyl having 1 to 4 carbon atoms;

cycloalkenylalkyl having 3 to 6 carbon atoms in cycloalkenyl and having 1 to 2 carbon atoms in alkyl, in particular cyclohexenylmethyl;

(C 1 -C 6) alkylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkenylamino, (C 1 -C 4) alkylamino; 1-4 carbon atoms in each alkyl, 1-pyrrolidinyl, piperidinyl, morpholinyl, 1-methylpiperazin-1-yl or alkylthio of 1 to 4 carbon atoms;

alkenylcarbonyl having 2 to 6 carbon atoms;

(C 1 -C 6) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 1 -C 4 alkylthio up to 4 carbon atoms;

(C 2 -C 6) alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl;

(C 2 -C 6) alkynyloxycarbonyl, especially propynyloxycarbonyl or butinyloxycarbonyl;

31257 / H alkylthiocarbonyl having 1 to 6 carbon atoms in the alkylthio group;

alkenylthiocarbonyl having 2 to 6 carbon atoms in the alkenylthio group, in particular allylthiocarbonyl;

alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 6 carbon atoms in each alkyl;

pyrrolidin-1-yl, morpholino, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl group;

alkenylamino and dialkenylamino having 2 to 6 carbon atoms in each alkenyl;

(C 1 -C 4) alkylsulfonyl;

(C 2 -C 4) alkenylsulfonyl, or up to two R ⁶ independently substituted aryl, especially phenyl, arylcarbonyl, especially benzoyl, (arythio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, arylamino, arylamino), (arylamino) or a phenethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl (alkylthio) carbonyl group, wherein the alkyl radical may each contain 1 to 3 carbon atoms and R ⁶ is as defined above, or up to two independently substituted R ⁶ substituted 1-naphthylmethyl, ⁶ -naphthylmethyl, 2-picolyl, 3-picolyl, 4-picolyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, furylcarbonyl, 2tie nylkarbonylovú, 3-thienylcarbonyl, 2-pikolyloxykarbonylovú, 3pikolyloxykarbonylovú, 4-pikolyloxykarbonylovú, 2-furylmetyloxykarbonylovú, 3furylmetyloxykarbonylovú, 2-tienylmetyloxykarbonylovú 3tienylmetyloxykarbonylovú or a group, wherein R ⁶ is as defined above,

31257 / H

R ³ and R ⁴ may be the same or different and independently of one another represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, optionally substituted by hydroxy, mercapto, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, alkylsulfonyl C 1 -C 4 alkyl, C 1 -C 4 alkylsulfinyl, carboxy or carbamoyl;

(C 2 -C 6) alkenyl;

and two independent radicals R ⁶ substituted aryl, benzyl, thienyl or thienylmethyl radical, wherein R 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 represents an oxygen or sulfur atom, in combination with protease inhibitors of the series comprising

1.) 2,4,7,12-tetraazatridecane-13-carboxylic acid, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3, [5S- (5R *, 8R *, 10R *, 11R *)] 6-dioxo-8,11-bis (phenylmethyl) -5-thiazolylmethyl ester;

2.) 3-isoquinolinecarboxamides, N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S- [ 2- (2S *, 3S *), 3.a, 4a.β, 8a.β]] -, monoethane sulfonate (salt);

3.) Carbamic acid, [3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S] [3R * (1 S *, 2 R *)] J;

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

31257 / H

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

6.) N- (quinolin-2-ylcarbonyl) -asparagine-1 (S) -benzyl-3- (3-tert-butyl-1-isobutylureido) -2 (R) -hydroxypropylamide

7.) 2 (1H) -pyrimidinone, 4-amino-1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] -, [(2R-cis) - (9CI)] (Epvirus) and reverse transcriptase inhibitors for use as medicaments for the treatment of AIDS and HIV infections.

Particularly preferred is the combination of S-4-isopropoxycarbonyl-6-methoxy-3 (methylthiomethyl) -3,4-dihydroquinoxazoline-2 (1H) -thione of formula A

H.

(A) and 1 (2H) quinoxaline carboxylic acid, 2-ethyl-7-fluoro-3 _l 4-dihydro-3-oxo-,

[(S) - (9Cl)] 1-methyl ester of formula B

CH.

with (S) -N - [(aS) -α - [(1R) -2 - [((3S, 4aS, 8aS) -3- (tert-butylcarbamoyl) -octahydro-2 (1H) -isoquinolinyl) -1-hydroxyethyl Phenethyl-2-quinaldamido] succinamide (saquinavirus) of formula C

31257 / H

or 2 (R) -benzyl-5- (2 (S) - (N-tert-butylcarbamoyl) -4- (3-pyridylmethyl) piperazine-

-yl) -4 (S) -hydroxy-N- (2 (R) -hydroxyindan-1 (S) -yl) pentanamide of formula D

(H) _CH3, or 2,4,7,12-tetraazatridecan-13-carboxylic acid, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-years) -4- thiazolyl] -3,6-dioxo-8,11-bis- (phenylmethyl) -5,5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)] of formula E

and retrovirus (AZT) or epivirus for use in the treatment of AIDS, respectively

HIV infections.

31257 / H

The quinoxalines of formulas I and Ia are known (see EP 509 398 A1; EP 708 093; EP 657 166). The above-mentioned protease inhibitors are also known (see, for example, EP 432 659 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; EP 609 625 A; PCT WO 94/08977).

The use of combinations of these compounds provides advantages in the treatment of diseases caused by retroviruses, particularly HIV-induced, compared to monotherapy or a double combination with the individual compounds. Advantageous and superior use of the combination of these compounds for the treatment of AIDS or HIV-infections is due mainly to the synergistic antiviral effect, but additionally also to the unchanged acceptability of the substances in the combination in the toxicity area at which 50% of cells survive compared to tox-50 single components. . For individual combinations, it is known, for example, in the combination of AZT with ganciclovir that synergistic toxicity occurs when using the combination (see M.N.Prichard et al., Antimicrob. Agents Chemotherapy (1991), 35, 1060-1065).

The use of a triple combination of substances resulted in a lower effective dose for treatment. In addition, the use of a triple combination of drugs reduces the likelihood of forming resistant virus isolates.

The invention relates to the combination of three classes of HIV-reverse transcriptase inhibitor and HIV-protease compounds for the prevention and treatment of HIV infections as well as for the treatment of HIV-induced diseases such as AIDS Relkated Complex (ARC) or AIDS.

HIV-infection in cell culture

The HIV assay is performed with the modification of the method of Pauwels et al. (See Journal of Virological Methods 20, (1988), 309-321).

Normal human blood lymphocytes (PBLs) are enriched through FicolHypaque and stimulated in RPMI 1640, 20% fetal calf serum with pytaemagglutinin (90 pg / ml) and intertelukin-2 (40 U / ml). For infection

31257 / H infectious HIV, PBLs are pelleted and the cell pellets are then suspended in 1 ml of HIV virus solution for adsorption and incubated for one hour at 37 ° C.

The virus adsorption solution is centrifuged and the infected cell pellets are introduced into the growth medium to a concentration of 1 x 10 ⁵ cells per ml. The cells so infected are pipetted into 96-well microtiter plates at a concentration of 1 x 10 ⁴ cells per dish.

Alternatively, they are used instead of PBL with H9 cells for an antiviral assay.

Testing of the combinatorial effect of test substances is performed by Schachbrett titration (chequerboardtitration).

The first vertical row of the microtiter plate contains only growth medium and cells that are not infected but otherwise processed as described above (cell control). The second vertical row of the microtiter plate contains only HIV-infected cells (virus control) in the growth medium. The other dishes contain the compounds of the present invention - individually or in corresponding combinations - at different concentrations, starting from the third vertical row of the microtiter plate, further diluted from the test substance in the second step (50 μΙ of volume per dish). For the combination, a dilution of the second compound is made on a separate 96-well microtiter plate and then pipetted onto the prepared first plate. The third compound is used at a fixed concentration by, for example, testing four dilution steps (corresponding to 4 batches tested) of the 3rd inhibitor. 100 μΙ of pre-prepared HIV-infected cells (so) are always added. The covered test concentrations of three inhibitors of about ten times to päťdesiatnásobnej above and below the _IC-5 concentrations of the compound.

The test batches are incubated at 37 ° C until, in the unprocessed viral control, the formation of syncytia typical of HIV (between days 3 and 8 after infection) is microscopically detectable on the host cells. In an untreated virus control, it occurs under these conditions

31257 / H assay of about 20 to 50 syncyties, while untreated cell control showed no syncytia.

The liquids from the microtiter plate are then collected and examined in the HIV-specific ELISA for HIV-specific antigen (Vironostika H1V Antigen, Organon Teknika).

The inhibition values are calculated according to the "cut-off" values from the corresponding cell or viral controls, respectively as a percentage, and IC 50 values are found as the concentration of treated and infected cells at which 50% of the virus-specific antigen was inhibited by compound treatment. To analyze the synergistic effect of the compounds, differentiation of calculated and measured inhibition values by the combination is determined (Prichard, M. N. et al., Antimicrob. Agents Chemoth. (1993), 37, 540-545).

Surprisingly, the triple combination exhibits a synergistic effect in concentration ranges in which no antiviral effect is observed when treated with a single agent or a double combination.

Thus, it exhibits 0.5 nM retrovirus, as well as 0.1 nM retrovirus in combination with 0.1 to 10 nM quinoxaline and about 70 to 6 nM indinavir and 0.2 to 6 nM quinoxaline with about 10 to 50 nM indinavir respectively, strong synergistic effect. Examples include a combination of a retrovirus with S-4-isopropylcarbonyl-6-methoxy-3- (methylthiomethyl) -3,4-dihydroquinoxazoline-2 (1H) -thion of formula (A) and an indinavir, or a combination of a retrovirus with 1 (2H) 1-quinolinecarboxylic acid, 2-ethyl-7-fluoro-3,4-dihydro-3-oxo-, 1-methyl ester [(S) - (9Cl)] of formula (B) and with indinavir.

Surprisingly, it has been found that the use of a triple combination of compounds provides a synergistic effect on HIV. This has been demonstrated, for example, by a triple combination of a quinoxaline derivative with an indinavirus and a retrovirus.

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

As an indication area in human medicine, for example:

31257 / H

1.) Treatment and prophylaxis of human infections with retroviruses.

2.) Treatment or prophylaxis of HIV I (human immunodeficiency virus; formerly called HTLV III / LAV) caused by diseases (AIDS) and their associated stages such as ARC (AIDS related complex) and LAS (Lymphadenopathie-Syndrome) and by this virus caused by weakened immunity and encephalopathy.

3.) Treatment or prophylaxis of HTLV-I or HTLV -II infections.

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

Indications in veterinary medicine include, for example:

infections

(a) Maedivisní (in sheep and goats)

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

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

(d) Zwoegrsiekte Virus (sheep)

(e) infectious anemia virus (in horses)

(f) caused by feline leukemia virus

(g) caused by feline immunodeficiency virus (FIV)

(h) caused by simian immunodeficiency virus (SIV)

Of the indication areas in human medicine, the indications mentioned in points 2, 3 and 4 are preferred

The present invention also provides pharmaceutical compositions comprising, in addition to non-toxic inert pharmaceutically acceptable carriers, one or more compounds of Formulas I and Ia in combination with a protease inhibitor and a reverse transcriptase inhibitor, or one or more active ingredients of Formulas I and Ia, an inhibitor protease and reverse transcriptase inhibitor as well as a process for the preparation of these preparations, in particular by combining the test compounds.

31257 / H

The active compounds of the formulas I and Ia, protease inhibitors and reverse transcriptase inhibitors should be present in the above pharmaceutical preparations in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the total mixture.

In addition to the compounds of formulas I / Ia in combination with a protease inhibitor and a reverse transcriptase inhibitor, the aforementioned pharmaceutical preparations can also contain other pharmaceutical active substances.

The preparation of the aforementioned pharmaceutical preparations is carried out by customary methods by known methods, for example by mixing the active compound (s) with the carrier or carriers.

In general, it has proven advantageous in both human and veterinary medicine to administer the active compound (s) of the present invention to achieve the desired results in a total amount of about 0.5 to 500, preferably 1 to 100 mg / kg body weight per 24 hours. 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 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the above dosages depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and the administration of the medicament, as well as the time period or interval during which the administration is carried out.

Double combinations show effects in excess of monotherapy in the treatment of HIV-infected patients, but equally resistant viruses may occur in such a treatment regimen. The triple combination described herein acts synergistically to multiply HIV and thereby effectively suppresses the emergence of resistant viruses.

Claims (16)

PATENT CLAIMS Medicament, characterized in that it contains in triple combination quinoxalines of the general formula I R ² (i) and also their tautomeric forms of formula Ia R wherein n is 0, 1, 2, 3 or 4, R ¹ is independently 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 (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, nitro, amino, azido, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, piperidine, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholine, imidazolyl, triazolyl, acrazolyl, acrazolyl 1 to 6 carbon atoms, 31257 / H acyloxy having 1 to 6 carbon atoms, cyano, carbamoyl, carboxy, alkyloxycarbonyl having 1 to 6 carbon atoms in the alkyl, hydroxysulfonyl group, sulfamoyl group or up to five independent phenoxy, R ⁶ substituted phenoxy, R ⁶ substituted phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein: R ⁶ is fluorine, chlorine, bromine or iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy , (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulphinyl, (C 1 -C 6) alkylsulphonyl, (C 1 -C 6) alkylamino, (C 1 -C 6) alkylamino, (C 1 -C 6) alkyloxycarbonyl up to 6 carbon atoms in alkyl, phenyl, phenoxy, 2-pyridyl, 3-pyridyl or 4-pyridyl, R ² is hydrogen, alkoxy of 1 to 6 carbon atoms, a hydroxy group, picolyl group, a cyclopropyl group or isopropenyloxycarbonyl, R ⁵ is hydrogen, hydroxy, C 1 -C 6 alkoxy, aryloxy, C 1 -C 6 acyloxy, cyano, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, and C 1 -C 6 alkylamino; , 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, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, benzoyloxy, , alkoxy having 1 31257 / H to 6 carbon atoms, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, phenylsulfonyl, oxo, carboxy or a carbamoyl group; (C 2 -C 8) alkenyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, alkoxy, 1-phenoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl; C 3 -C 8 alenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 6 alkoxy, oxo or phenyl; (C 3 -C 8) alkynyl, optionally substituted with fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, alkoxy to 1, phenoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl; C 3 -C 8 cycloalkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, 1-phenoxy, phenoxy, phenoxy C1-6 alkylamino; 31257 / H 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; C 3 -C 8 cycloalkenyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy of 1 to 6 carbon atoms, benzoyloxy, benzyloxy, 1-phenoxy, phenoxy, phenoxy (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl; C 3 -C 8 cycloalkylalkyl and C 1 -C 4 alkyl optionally substituted by fluorine, chlorine, bromine or iodine, cyano, amino, mercapto, hydroxy, acyloxy, benzoyloxy, 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, , 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, cyano, amino, mercapto, hydroxy, acyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, , (C 1 -C 6) alkoxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino in each alkyl, (C 1 -C 6) alkylthio, alkylsulfonyl 31257 / H of 1 to 6 carbon atoms, 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, 6-alkoxy, benzyloxy, phenyloxy atoms, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy or carbamoyl; (C 2 -C 8) alkenylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl; cycloalkyl of 3 to 8 carbon atoms in the cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 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; cycloalkylalkylcarbonyl of 3 to 8 carbon atoms in cycloalkyl and 1 to 3 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl; cycloalkenylalkylcarbonyl having 5 to 8 carbon atoms in the cycloalkenyl and 1 to 3 carbon atoms in the alkyl, optionally substituted 31257 / H is fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl; (C 1 -C 8) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 1 -C 4 alkylthio up to 4 carbon atoms; (C 2 -C 8) alkenyloxycarbonyl 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 -C 4) alkoxy, 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 optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo, or phenyl; alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 8 carbon atoms in each alkyl, optionally substituted with fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl; pyrrolidin-1-yl, morpholino, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl, optionally substituted with C 1 -C 4 alkyl, C 2 -C 6 alkenyl 31257 / H carbon atoms, acyl group having 1 to 4 carbon atoms, oxo group, thioxo group, carboxy group or phenyl group; alkenylamino and dialkenylamino of 2 to 8 carbon atoms in each alkenyl optionally substituted by fluorine or chlorine, hydroxy, alkoxy of 1 to 4 carbon atoms, oxo or phenyl; (C 1 -C 8) alkylsulfonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl; (C 2 -C 8) alkenylsulfonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkoxy, oxo or phenyl; or with up to five mutually independent occurrences of R ⁶ substituted aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkyl, arylsulfonyl, arylalkyl, arylalkenylkarbonylovú, arylazo, arylalkylcarbonyl, arylalkenylkarbonylovú , arylalkoxycarbonyl or aryl (alkylthio) carbonyl, wherein the alkyl radical may each contain 1 to 5 carbon atoms and R ⁶ is as defined above, or up to three independent R ⁶ radicals substituted by a heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkylcarbonyl, a (heteroarythio) carbonyl, heteroarylaminocarbonyl, heteroarylalkoxycarbonyl, heteroaryl (alkylthio) carbonyl or heteroarylalkylaminocarbonyl group, the alkyl radical of which may contain: either 1 to 3 carbon atoms and R ⁶ is as defined above, R ³ and R ⁴ may be the same or different and independently of one another represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, 31257 / H mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino of alkyl of 1 to 4 carbon atoms C 4 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy or carbamoyl; C 2 -C 8 alkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) -alkoxy atoms, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, 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, phenoxy, (C 1 -C 4) alkoxy atoms, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy or carbamoyl; C 3 -C 8 cycloalkenyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, 31257 / H alkylthio of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, carboxy or carbamoyl; substituted with an aryl, heteroaryl or heteroarylalkyl radical independently of each other by R ⁶ , wherein the alkyl radicals may each contain 1 to 3 carbon atoms and R 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 8 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 6 carbon atoms, an alkenyl group having 2 up to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, benzyloxy, alkoxy of 1 to 6 carbon atoms, oxo, thio, carboxy, carbamoyl or phenyl; and X represents an oxygen, sulfur or selenium atom or a substituted nitrogen of NR ² , wherein R ² is as defined above, in combination with protease inhibitors and reverse transcriptase inhibitors. Medicament according to claim 1, characterized in that it contains quinoxalines of the formulas 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, C 1 -C 4 alkoxy, alkylthio C 1 -C 4, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, piperidine, morpholine, 1-pyrrolidinyl, 4-methylpiperazinyl, C 1 -C 4 acyl 4 carbon 31257 / H atoms, C 1 -C 4 acyloxy, cyano, carbamoyl, carboxy, C 1 -C 4 alkyloxycarbonyl, hydroxysulfonyl, sulfamoyl, or up to two independently-substituted phenyl groups R ⁶ , phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein: R ⁶ is fluorine, chlorine or bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, phenyl or phenyl; phenoxy, R ² represents hydrogen, R ⁵ represents an alkyl group having 1 to 6 carbon atoms, optionally substituted by a fluorine or chlorine atom, a hydroxy group, an acyloxy group having 1 to 4 carbon atoms, a benzoyloxy group, a benzyloxy group, a phenoxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms C1-C4 dialkylamino in each alkyl, C1-C4 alkylthio, oxo, thioxo, carboxy or carbamoyl group; (C 2 -C 6) alkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylamino; (C 1 -C 4) alkyl, (C 1 -C 4) alkylthio, oxo, thioxy, carboxy, or carbamoyl; 31257 / H alenyl of 3 to 8 carbon atoms, optionally substituted by fluorine or chlorine, hydroxy, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, alkoxy of 1 to 4 carbon atoms, alkylamino C 1 -C 4 dialkylamino in each alkyl of C 1 -C 4 alkylthio, oxo, thioxy, carboxy or carbamoyl; C 3 -C 8 cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 dialkyl, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, thioxo, carboxy or carbamoyl; C 3 -C 8 cycloalkenyl optionally substituted by fluorine or chlorine, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl; C 1 -C 4 dialkyl, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, oxo, thioxo, carboxy or carbamoyl; cycloalkylalkyl having 3 to 6 carbon atoms in cycloalkyl and 1 to 2 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, , (C1-C4) alkoxy, (C1-C4) alkylamino, (C1-C4) dialkylamino in each alkyl, 31257 / H alkylthio of 1 to 4 carbon atoms, oxo, thioxo, carboxy or carbamoyl; cycloalkenylalkyl having 3 to 6 carbon atoms in cycloalkenyl and having 1 to 2 carbon atoms in alkyl, optionally substituted by fluorine or chlorine, hydroxy, alkyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, benzyloxy C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl, C 1 -C 4 alkylthio, oxo, thio, carboxy or carbamoyl; (C 1 -C 6) alkylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, (C 1 -C 4) alkyl, (C 1 -C 4) acyloxy, benzoyloxy, benzyloxy, phenoxy (C 1 -C 4) alkoxy , (C 1 -C 6) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkenylamino, 1-pyrrolidinyl, piperidine, morpholino, 1-methylpiperazin-1-yl, (C 1 -C 4) alkylthio atoms, oxo, thioxo, carboxy or carbamoyl; alkenylcarbonyl having 2 to 6 carbon atoms in the alkenyl, optionally substituted with a fluorine or chlorine atom, or a hydroxy group; cycloalkylcarbonyl having 3 to 6 carbon atoms in the cycloalkyl; cycloalkenylcarbonyl having 5 to 6 carbon atoms in the cycloalkenyl; cycloalkylalkylcarbonyl having 3 to 6 carbon atoms in the cycloalkyl and 1 to 2 carbon atoms in the alkyl; 31257 / H cycloalkenylalkylcarbonyl having 5 to 6 carbon atoms in cycloalkenyl and 1 to 2 carbon atoms in alkyl; (C 1 -C 6) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 1 -C 4 alkylthio up to 4 carbon atoms; (C 2 -C 6) alkenyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy or (C 1 -C 4) alkoxy; (C 2 -C 6) alkynyloxycarbonyl optionally substituted by fluorine or chlorine, hydroxy or (C 1 -C 4) alkoxy; (C 1 -C 6) alkylthiocarbonyl optionally substituted with fluoro or chloro, (C 1 -C 4) hydroxy or (C 1 -C 4) alkoxy; alkenylthiocarbonyl having 2 to 6 carbon atoms in the alkenylthio group optionally substituted by a fluorine or chlorine atom, a hydroxy group or an alkoxy group having 1 to 4 carbon atoms; alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 6 carbon atoms in each alkyl, optionally substituted with a fluorine or chlorine atom, a hydroxy group or a C 1 -C 4 alkoxy group; pyrrolidin-1-yl, morpholine, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl group; alkenylamino and dialkenylamino having 2 to 6 carbon atoms in each alkenyl optionally substituted by fluorine or chlorine, hydroxy or alkoxy having 1 to 4 carbon atoms; 31257 / H alkylsulfonyl having 1 to 4 carbon atoms, optionally substituted by fluorine or chlorine, hydroxy or alkoxy having 1 to 4 carbon atoms; (C 2 -C 4) alkenylsulfonyl, or up to two R ⁶ independently substituted aryl, arylcarbonyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylamino, arylalkylamino, arylalkylamino, arylalkylamino, arylalkylamino, arylalkylamino alkylthio) carbonyl, where the alkyl radical can comprise from 1 to 3 carbon atoms and R ⁶ is as defined above, or up to two independent radicals R ⁶ substituted 1naftylmetylovú, 2-naphthylmethyl, 2-picolyl, 3-picolyl, 4-picolyl 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-furylcarbonyl, 3-furylcarbonyl, 3-furylcarbonyl, 3-furylcarbonyl, , 3picolyloxycarbonyl, 4-pikolyloxykarbonylovú, 2-furylmetyloxykarbonylovú, 3furylmetyloxykarbonylovú, 2-tienylmetyloxykarbonylovú 3tienylmetyloxykarbonylovú or a group, wherein R ⁶ is as defined above, by x R and R may be the same or different and independently represent a hydrogen atom, a C 1 -C 4 alkyl group 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, 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 carbon atoms, carboxy or carbamoyl; 31257 / H alkenyl of 2 to 6 carbon atoms, optionally substituted with fluorine or chlorine; C 3 -C 6 cycloalkyl optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyloxy of 1 to 4 carbon atoms, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy atoms, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy or carbamoyl; C 3 -C 8 cycloalkenyl optionally substituted with fluoro or chloro; and two independent radicals R ⁶ substituted aryl, benzyl, heteroaryl or heteroarylmethyl, wherein R ⁶ is as defined above, or R ³ and R ⁴ may be such portions of a saturated or unsaturated C 3 -C 6 carbocyclic or heterocyclic ring which may be optionally substituted by a fluorine or chlorine atom, a hydroxy group, an amino group, an acyloxy group having 1 to 4 carbon atoms, a benzyloxy group, a 1-alkoxy group up to 4 carbon atoms, oxo, thioxo, carboxy or carbamoyl; and X represents an oxygen or sulfur atom, optionally in isomeric form. Medicament according to claim 1, characterized in that it contains quinoxalines of the formulas I and Ia in which n is 0, 1 or 2, 31257 / H 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, alkylthio of 1 to 4 carbon atoms, nitro, amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl, piperidine, morpholine, 1-pyrrolidinyl, 4-methylpiperazines C 1 -C 4 acyl, C 1 -C 4 acyloxy, cyano, carbamoyl, carboxy, C 1 -C 4 alkyloxycarbonyl, hydroxysulfonyl, sulfamoyl, or up to two independently of one another ⁶ substituted phenyl, phenoxy , phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein: R ⁶ is fluorine, chlorine or bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyloxycarbonyl, phenyl or phenyl; phenoxy, R ² represents hydrogen, 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 alenyl; (C až-C 8) alkynyl, in particular 2-butynyl; 31257 / H cycloalkyl having 3 to 6 carbon atoms; cycloalkenyl of 5 to 6 carbon atoms; cycloalkylalkyl having 3 to 6 carbon atoms in cycloalkyl and having 1 to 2 carbon atoms in alkyl, in particular cyclopropylmethyl, optionally substituted with alkyl having 1 to 4 carbon atoms; cycloalkenylalkyl having 3 to 6 carbon atoms in cycloalkenyl and having 1 to 2 carbon atoms in alkyl, in particular cyclohexenylmethyl; (C 1 -C 6) alkylcarbonyl optionally substituted by fluorine or chlorine, hydroxy, benzyloxy, phenoxy, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkenylamino, (C 1 -C 4) -alkylamino; 1 to 4 carbon atoms in each alkyl, 1-pyrrolidinyl, piperidine, morpholino, 1-methylpiperazin-1-yl or C 1 -C 4 alkylthio group; alkenylcarbonyl having 2 to 6 carbon atoms; (C 1 -C 6) alkoxycarbonyl optionally substituted by fluorine, chlorine or bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 1 -C 4 alkylthio up to 4 carbon atoms; (C 2 -C 6) alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; (C 2 -C 6) alkynyloxycarbonyl, especially propynyloxycarbonyl or butinyloxycarbonyl; alkylthiocarbonyl having 1 to 6 carbon atoms in the alkylthio group; 31257 / H alkenylthiocarbonyl having 2 to 6 carbon atoms in the alkenylthio group, in particular allylthiocarbonyl; alkylaminocarbonyl and dialkylaminocarbonyl having 1 to 6 carbon atoms in each alkyl; pyrrolidin-1-yl, morpholine, piperidine, piperazinyl or 4-methylpiperazin-1-ylcarbonyl group; alkenylamino and dialkenylamino having 2 to 6 carbon atoms in each alkenyl; (C 1 -C 4) alkylsulfonyl; (C 2 -C 4) alkenylsulfonyl, or up to two R ⁶ independently substituted aryl, especially phenyl, arylcarbonyl, especially benzoyl, (arythio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, arylamino, arylamino), (arylamino) or a phenethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl (alkylthio) carbonyl group, wherein the alkyl radical may each contain 1 to 3 carbon atoms and R ⁶ is as defined above, or up to two independently substituted R ⁶ substituted 1-naphthylmethyl, ⁶ -naphthylmethyl, 2-picolyl, 3-picolyl, 4-picolyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, 3-pyridylcarbonyl, furylcarbonyl, 2tie nylkarbonylovú, 3-thienylcarbonyl, 2-pikolyloxykarbonylovú, 3pikolyloxykarbonylovú, 4-pikolyloxykarbonylovú, 2-furylmetyloxykarbonylovú, 3furylmetyloxykarbonylovú, 2-tienylmetyloxykarbonylovú 3tienylmetyloxykarbonylovú or a group, wherein R ⁶ is as defined above, R ³ and R ⁴ may be the same or different and independently represent a hydrogen atom, a C 1 -C 4 alkyl group optionally substituted by a hydroxy group, a mercapto group, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylthio group, 31257 / H alkylsulfonyl of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, carboxy or carbamoyl; (C 2 -C 6) alkenyl; and two independent radicals R ⁶ substituted aryl, benzyl, thienyl or thienylmethyl radical, wherein R 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 represents an oxygen or sulfur atom. Medicament according to claims 1 to 3, characterized in that it contains one or more protease inhibitors from the group consisting of: 1.) 2,4,7,12-tetraazatridecane-13-carboxylic acid, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methyl-4-thiazolyl)] -3,6-dioxo-8,11-bis- (phenylmethyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]; PCT WO 95/07696; PCT WO 95/20384 A1; PCT WO 95/009614 A1 [ABBOTT (Ritonavirus) ABT538] 2.) 3-isoquinolinecarboxamides, N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S- [ 2 (2S *, 3S *), 31257 / H 3.α., 4α.p, 8αβ] -, monoethane sulfonate (salt); PCT WO 95/09843; US 5484926; (AGOURON (Viracept) AG-1343) 3.) carbamic acid, [3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S [ 3 R * (1 S *, 2 R *)] -; PCT WO 94/05639; [VERTEX PHARM. (Kisseii, Glaxo Wellcome) VX-478] (4) (S) -N - [(aS) -α - [(1R) -2 - [((3S, 4aS, 8aS) -3- (tert-butylcarbamoyl) octahydro-2- (1H) -isoquinolinyl) (1-hydroxyethyl) phenethyl-2-quinaldamido] succinamide (EP 432 695 A2) 31257 / H 5.) 2 (R) -Benzyl-5- (2 (S) - (N-tert-butylcarbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) -4 (S) -hydroxy-N- ( 2 (R) -Hydroxyindan-1 (S) -yl) pentanamide (L- 735524, EP 569 083 A1, EP 541 168 A1) ₃ 6.) N- (quinolin-2-ylcarbonyl) -asparagine-1 (S) -benzyl-3- (3-tert-butyl-1-isobutylureido) -2 (R) -hydroxypropylamide (SC 52 151, POT WO 92/08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92/08700 A1) 7.) N1- (2R-hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -1S- (phenylmethyl) propyl-2S - ((2-quinolinecarbonyl) amino) butanediamide (AM 11 686, PCT WO 94 / 04492) 31257 / H 8) (2 S ₁ 3 S, 5 S) -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) 9) (R) -N-tert-butyl 3 - ((2 S ₁ 3 S) -2-hydroxy-3-N - ((R) -2-N- (isoquinolin-5yloxyacetyOamino-S ^ metyltiopropanoyOamino -fenylbutanoyO -SS-dimethyl-I.Stiazolidine-4-carboxamide (KNI 272 / Nippon Mining) h ₃ c ------ ch ₃ 10. [3 - [(4-Amino-benzenesulfonyl) -isobutylamino] -1-benzyl-2-hydroxy-propyl] -carbamic acid tetrahydro-furan-3-yl ester CH (CH _3), (11) (3S, 6R) -3 - (- ethylbenzyl) -6 - (- ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 94/11361) 31257 / H 12.) N-1S-L-1N-N-quinolinecarbonyl-L-asparaginyl-amino-R, SS-epoxy- 6-phenylhexanoyl] isoleucine (EP 601 486 A) 13.) N-tert-Butyl-1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinylcarbonyl) asparaginyl] amino] butyl-4 (R) - (Phenylthio) piperidine-2 (S) -carboxamide (EP 560 268 A) 14.) [3 '' S- (3 '' R _I 4 ''S *)] - N- [1'-oxo-1' - (3 - [1 -oxo-2-aza-3 '-phenyl-methyl-4''' -hydroxy-5 '''-(2''-N-tert-butylcarbamido) phenyl] pentyl-4''-methyl) - 1,2,3,4-tetrahydroisoquinoline (EP 609 625 A) 31257 / H 15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methylbenzoylamino) -4-phenylsulfamylbutyl] -decahydroisoquinoline-3-carboxylic acid tert-butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA) 16.) 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenylmethyl) -, [3δ '- (3.α., 6.β., 7. (PCT WO 94/08977) Medicament according to claims 1 to 4, characterized in that it contains one or more reverse transcriptase inhibitors selected from the group consisting of zidovudine (retrovirus) (AZT), didanosine (DDI), dideoxycytidine (DDC), lamivudine (3-TC®), stavudine (D4T), BW 935U83, BW1592U89, and epivirus. Use of quinoxalins, protease inhibitors and reverse transcriptase inhibitors according to claims 1 to 5 for the manufacture of medicaments for the treatment of HIV-infections.