WO1998032442A1

WO1998032442A1 - Quinoxaline in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating aids

Info

Publication number: WO1998032442A1
Application number: PCT/EP1998/000197
Authority: WO
Inventors: Arnold Paessens; Martin Blunck; Günter Riess; Jörg-Peter Kleim; Manfred Rösner
Original assignee: Bayer Aktiengesellschaft
Priority date: 1997-01-29
Filing date: 1998-01-15
Publication date: 1998-07-30
Also published as: ID22414A; PL334770A1; IL130877A0; AU6094098A; DE19703131A1; NO993670D0; AR011094A1; ZA98679B; CA2278773A1; BR9807523A; JP2001511124A; KR20000070543A; CN1251525A; EP0977570A1; SK99899A3; NO993670L

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

TRINOXALINE IN THREE COMBINATION WITH PROTEASE INHIBITORS AND REVERSE TRANSCRIPE INHIBITORS AS A MEDICINE FOR TREATING AIDS

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

The human immunodeficiency virus (HIV) causes a persistent, progressive, chronic disease. HIV destroys the immune system (acquired immune deficiency

Syndrome, AIDS) and the central and peripheral nervous system. In addition, various other clinical manifestations in the ARC / ALDS clinical picture are also caused by the HIV virus - in particular opportunistic infections (O.I.), caused by other viruses, such as e.g. Heφesviren (HSV I and II), cytomegalovirus (CMV) or O.I., caused by bacteria, fungi or parasites.

HTV belongs to the retrovirus family; One of the essential and essential enzymatic activities of these viruses in the propagation cycle is the protease (Huff, J.R .: J. Med. Chem. (1991), 34, 2305-2314). Small molecular peptide and non-peptide analogues of the natural substrates of the protease inhibit the replication of HTV (Roberts,

N / A. et al., Science (1990) 248, 358-361; Lam, P.Y.S. et al., Science (1994), 263, 380-384) in vitro and in vivo.

Analogs of the natural substrates of reverse transcriptase such as azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3'-thiacytidine (Lamivudine) inhibit the replication of HIV in vitro and in vivo. AZT is used, for example, to treat ARC / AIDS patients. Long-term therapy for HTV-infected patients with AZT is associated with bone marrow toxicity; AZT-resistant virus isolates are also produced. Intolerance, such as peripheral neuropathy, has been reported by some patients treated with DDC or DDI. New inhibitors for tolerable and effective therapy are therefore necessary. The now found triple combination of quinoxalines with protease inhibitors and reverse transcriptase inhibitors is new and their synergistic effect on the multiplication of HIV when used in combating AIDS or HIV infections is significantly better than the prior art.

It has now been found that quinoxalines of the general formula (I)

FT

and their tautomeric forms of the general formula (Ia)

in which

1) zero, one, two, three, or four,

the individual substituents Rl independently of one another fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxy, C ₁ -C ₈ -alkyl, C ₅ -C ₈ -cycloalkyl, C _r C ₆ -alkoxy, (C ₁ -C ₆ -alkoxy) - (C ₁ -C ₄ -alkoxy), C _r C ₆ -alkylthio, C _r C ₆ -alkylsulfinyl, Cι-C ₆ -alkylsulfonyl, nitro, amino, azido, C _r C ₆ -alkylamino, di (C _r C ₆ -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl,

Thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C _r C ₆ -acyl, Cι-C ₆ - acyloxy, Cι-C ₆ -acylamino, cyano, carbamoyl, carboxy, (C _r C ₆ alkyl) - oxycarbonyl, hydroxysulfonyl, sulfamoyl

or

a phenyl-, phenoxy-, phenoxycarbonyl-, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyloxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl- or 3-pyridyl substituted with up to five mutually independent radicals R6 4-pyridyl radical,

where R "

Fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, CC ₆ alkoxy, C _r C ₆ -

Alkylthio, C ₆ -C ₆ -alkylsulfinyl, C _j -C ₆ -alkylsulfonyl, C 1 -C ₆ -alkylamino, di (C ₁ -C ₆ -alkyl) -amino, (C ₁ -C ₆ -alkyoxycarbonyl, phenyl, phenoxy, 2- , Can be 3- or 4-pyridyl,

R ^ hydrogen, Cj-C ₆ alkoxy, hydroxy, picolyl, cyclopropyl or isopropenyloxycarbonyl and

R5 is hydrogen, hydroxy, Cj-Cg-alkoxy, aryloxy, C] -C ₆ -acyloxy, cyano,

Amino, C 1 -C ₆ -alkylamino, di (C ₁ -C ₆ -alkyl) amino, arylamino, C _r C ₆ - acylamino, C 1 -C ₈ -alkyl, optionally substituted with fluorine, chlorine, Bromine, iodine, cyano, amino, mercapto, hydroxy, -CC ₆ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₆ -alkoxy, C _r C ₆ -alkylamino, di (C _r C ₆ -alkyl) amino, C ₁ -C ₆ -alkylthio, C _r C ₆ -alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₈ alkenyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C - Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, Ci-Cg-alkoxy, Ci-C _ό - Alkylamino, di (Cι- - alkyl) amino, Cι-C ₆ -alkylthio, (Cj-Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C ₈ allenyl, optionally substituted by fluorine, chlorine or hydroxy, -CC alkoxy, oxo, phenyl; C ₃ -C ₈ alkynyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C Cö-

Alkoxy, -CC ₆ alkylamino, (-C ₆ -alkyl) amino, C _r C ₆ alkylthio, C _r C ₆ - alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C _ß - cycloalkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₆ alkoxy, C ₁ -C ₆ - Alkylamino, di (C _r C ₆ alkyl) amino, C Cg alkylthio, C ₆ -C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine, chlorine, bromine,

Iodine, cyano, amino, mercapto, hydroxy, C _r C ₆ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C -C ₆ alkoxy, C _r C ₆ alkylamine, di (C _r C ₆ alkyl) amino, C _r C ₆ alkylthio, C _r C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₄ alkyl), optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C _r C ₆ acyloxy, benzoyloxy, benzyloxy, Phenoxy, C _r C ₆ alkoxy, C ₁ -C ₆ alkylamino, di (C _r C ₆ alkyl) amino, C _r C ₆ alkylthio, C _r C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy , Carbamoyl;

(C ₃ -C ₈ cycloalkenyl) - (C _r C alkyl), optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C _r C ₆ acyloxy, benzoyloxy, benzyloxy, phenoxy, C ₁ -C ₆ alkoxy, C _r C ₆ alkylamino, di (C _r C ₆ alkyl) amino, C _r C ₆ alkylthio, Cι-C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxyl or carbamoyl;

Ci-Cg-alkylcarbonyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, Ci-Cg-alkoxy, Ci-Cg-alkylamino, DKCi -Cg-alkyl) - amino -CC ₆ alkylthio, C -C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₈ alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxy, ^ -Al oxy, oxo, phenyl;

(C ₃ -C ₈ cycloalkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxy, -CC alkoxy, oxo, phenyl;

(C ₅ -C ₈ cycloalkenyl) carbonyl, optionally substituted by fluorine,

Chlorine or hydroxy, -CC alkoxy, oxo, phenyl;

(C ₃ -C ₈ cycloalkyl) - (C ₁ -C alkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxyl, -CC alkoxy, oxo, phenyl; (C ₅ -C ₆ cycloalkenyl) - (C ₁ -C alkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C _r C ₄ alkoxy, oxo, phenyl;

C _r C ₈ alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, alkoxy, C alkylamino, di (C 1 -C ₄ alkyl) amino, C _r C ₄ alkylthio;

_{C2-C8-alkenyloxycarbonyl,} optionally substituted by fluorine, chlorine, hydroxyl, C] -C -alkoxy, oxo or phenyl;

C ₂ -C 4 -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, -CC alkoxy, oxo, phenyl;

C C alkylthiocarbonyl, optionally substituted by fluorine, chlorine,

Hydroxy, -CC alkoxy, oxo, phenyl;

C ₂ -C ₈ alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, -C-alkoxy, oxo, phenyl;

-C ₈ alkylamino and di (-C ₈ alkyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, -C ₄ alkoxy, oxo, phenyl;

Pyrrolidin-1-yl, Moφholino-, piperidino-, piperazinyl- or 4-methyl-piperazin-1-yl-carbonyl, optionally substituted by C 1 -C 4 -alkyl,

C ₂ -C ₆ alkenyl, C _r C ₄ acyl, oxo, thioxo, carboxy, or phenyl;

C ₂ -C ₈ alkenylamino and di (C ₁ -C ₆ alkenyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Cj-C alkoxy, oxo, phenyl; C _r C ₆ alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C ₄ alkoxy, oxo, phenyl;

Cj-Cg-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxy, Cj- -alkoxy, oxo, phenyl;

or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) - thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylsulfonyl

Arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can each contain 1 to 5 carbon atoms and R ^ is as defined above

or substituted with up to three mutually independent radicals R6

Heteroaryl, Heteroarylalkyl, Heteroarylalkenyl, Heteroarylalkylcarbonyl or Heteroarylalkenylcarbonyl, Heteroaryloxycarbonyl, Heteroarylaminocarbonyl, Heteroarylalkyloxycarbonyl, Heteroaryl (alkylthio) carbonyl, C 1 -alkylthio, carbonyl contain,

R ^ the same or different, independently of one another hydrogen, CC ₈ - alkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C 1 -C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C ₄ -alkoxy C 1 -C ₄ Alkylamino, di (C _r C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkyl sulfonyl, C ₁ -C ₄ alkylsulfinyl, carboxy, carbamoyl;

C ₂ -C ₈ alkylene, optionally substituted with fluorine or chlorine, hydroxy, amino, mercapto, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy C _r C ₄ alkoxy, C _r C ₄ alkylamino, di (C _r C ₄ alkyl) amino, C _r C ₄ alkylthio, C alkyl sulfonyl, C _r C alkyl sulfinyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C _r C -acyloxy, benzoyloxy, benzyloxy, phenoxy, - -alkoxy, C ₁ -C -alkylamino, DC -alkyamino, - -Alkyl-thio,--alkylsulfonyl, C ₁ -C -alkylsulfinyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy, amino, mercapto, C ₁ -C ₄ acyloxy, benzoyloxy, benzyloxy,

Phenoxy -CC ₄ alkoxy, C alkylamino, di (C ₁ -C alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfinyl, carboxy, carbamoyl;

aryl substituted with up to five mutually independent radicals R ",

Arylalkyl, heteroaryl or heteroarylalkyl mean, where the alkyl radical can each contain 1 to 3 carbon atoms and R ^ is as defined above,

R ^ and R ^ can also be part of a saturated or unsaturated carbo- or heterocyclic ring with 3 to 8 carbon atoms, which optionally with

Fluorine, chlorine, hydroxy, amino, C _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ -

Alkynyl, -Cö-acyloxy, benzoyloxy, -C _ό alkoxy, oxo, thioxo,

Carboxy, carbamoyl or phenyl can be substituted,

X represents oxygen, sulfur, selenium or substituted nitrogen NR ² , where R ² can have the meanings given above

in combination with protease inhibitors and reverse transcriptase inhibitors are very well suited for use as medicaments in combating AIDS and HIV infections. The alkyl groups mentioned in the preceding definitions can be straight-chain or branched. Unless otherwise defined, they preferably contain 1-8, particularly preferably 1-6, in particular 1-4 C atoms. Examples are the methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl group and the like.

The alkenyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 double bonds. Unless otherwise defined, these groups preferably contain 2-8, in particular 2-6 C-

Atoms. Examples are the 2-propenyl, 1-methylethenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl 2,3-dimethyl-2-butenyl-3 , 3-di-chloro-2-propenyl, pentadienyl group and the like.

The alkynyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 triple bonds. Unless otherwise defined, they preferably contain 2-8, particularly preferably 3-6, carbon atoms. Examples are the 2-propynyl and 3-butynyl groups and the like.

Unless otherwise defined, the cycloalkyl and cycloalkenyl groups mentioned in the preceding definitions preferably contain 3-8, particularly preferably 4-6 C atoms. Examples are the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.

The acyl groups mentioned in the preceding definitions can be aliphatic, cycloaliphatic or aromatic. Unless otherwise defined, they preferably contain 1-8, particularly preferably 2-7, carbon atoms. Exemplary acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl group. The aryl groups mentioned in the previous definitions are preferably aromatic groups with 6-14 C atoms, in particular with 6-10 C atoms, such as phenyl, naphthyl.

In the heterocyclic rings or heteroaryl groups mentioned above, suitable heteroatoms are in particular, for example, O, S, N, where in the case of an N-containing ring saturated at this point, NZ is present, in which Z, H or R5 means with the respective definitions described above .

Unless otherwise defined, the heterocyclic rings preferably have 1-13

C atoms and 1-6 heteroatoms, in particular 3-9 C atoms and 1-4 heteroatoms.

For the heteroaryl groups mentioned in the preceding definitions, for example heteroaromatic radicals such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl are suitable

Question.

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

The above-mentioned substituents Rl to R ^ are preferably 3-fold, particularly preferably 2-fold, in particular simply substituted with the substituents specified in each case.

For the respective composite substituent definitions (such as arylalkoxycarbonyl), the ranges previously described as preferred for the individual substituents are also preferred.

Depending on the different substituents, compounds of the formulas I and Ia can have several asymmetric carbon atoms. The invention therefore relates both to the pure stereoisomers and mixtures thereof, such as. B. the associated racemate.

The pure stereoisomers of the compounds of the formulas I and Ia can be prepared directly or subsequently by known methods or in analogy to known methods.

The compounds of the formulas I and Ia can be prepared by known methods or modifications thereof (see, for example, Rodd's Chemistry of Carbon Compounds, S. Coffey, MF Ansell (editor); Elsevier, Amsterdam, 1989; Vol. IV Part IJ, Pp. 301-311. Heterocyclic Compounds, RC Elderfield (Editor); Wiley, New York, 1957; Vol. 6, pp. 491-495).

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

In particular, the following should be mentioned:

1.) 2,4,7, 12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5- (l-methyl-ethyl) -l- [2- (l-methylethyl) -4-thiazolyl ] -3,6-dioxo-8, l l-bis- (phenyl-methyl) -

, 5-thiazolylmethyl ester [5S ~ (5R *, 8R *, 10R *, 11R *)]; PCT WO 95/07696;

PCT WO 95/20384 AI; PCT WO 95/009614 AI [ABBOTT (ritonavir) ABT-538]

2.) 3-Isoquinoline carboxamides, N- (l, l-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S - [2- (2S *, 3S *), 3.alpha. , 4a.beta. , 8a beta.]] -, monoethanesulfonate (salt); PCT WO 95/09843; US 5484926; [AGOURON (Viracept ^R ) AG- 1343]

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

4.) (S) -N - [(alphaS) -alpha - [(lR) -2 - [((3S, 4aS, 8aS) -3- (tert.butylcarbamoyl) octa-hydro-2 (lH) -isoquinolinyl ) -l-hydroxyethyl) phenethyl-2-quinaldamido] -suc-cinamide (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) pentanamides

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

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 AI, WO 92/08699 AI, WO 92/08698 AI, WO 92/08701 AI, WO 92/08700 AI)

7.) Nl- (2R-hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -Is- (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) -l, 6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436)

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-l, 3-thiazolidine-4-carboxamide (KNI 272 / Nippon Mining)

10.) {3 - [(4-aminobenzenesulfonyl) isobutylamino] -l-benzyl-2-hydroxypropyl} -carbamic acid tetrahydro-furan-3-yl ester

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

12.) N- [5-L- [N- (2-quinolinecarbonyl) -L-asparaginyl] amino- (4R, 3S) -epoxy-6-phenyl-hexanoyl] -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) -carboxamides (EP 560 268 A)

14.) ^[3, 'S- ^(3', R *, ^{4 'S} *)] - N- [l' -oxo-l '- (3 "- ^[l," -oxo-2 "' -aza-3 '"-phenyl-methyl-4'" -hydroxy-5 "'- (2"' -N-tert.butylcarbamido) phenyl] pentyl-4 "-methyl) -l, 2,3,4 tetrahydroisoquinoline (EP 609 625 A)

15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfamyl-butyl] -decahydro-isoquinoline-3-carboxylic acid-tert.butylamide (AG 1343 Agouron Pharmaceuticals Inc. , San Diego USA)

^C ₆ H ₅

16.) 2H-l, 4-diazepin-2-one, hexahydro-6-hydroxy-l, 3,4,7-tetrakis (phenylmethyl) -, [3S '- (3.alpha., 6.beta ., 7.beta,)] (PCT WO 94/08977)

OH

In the context of the invention, reverse transcriptase inhibitors stand for different nucleosides. Zidovudine (Retrovir) (AZT) and didanosine are preferred (DDI), dideoxycytidine (DDC), lamivudine (Epivir, 3-TC ^®), stavudine (d4T), BW 935U83, BW 1592U89. ; especially zidovudine and epivir. The nucleosides mentioned can be prepared by generally known methods (cf. Merck Index, 11th edition Rahway, NJ 1989, Drugs 45 (4), 488 ff., 45 (5), 637 ff., 1993, Drugs 44 (4th ), 656 ff., 1992, Clin. Pharmacol. Ther. 55, No. 2, 198, 1994,

Antiviral Chem. Chemother. 2, No. 3, 125-32, 1991, antiviral residue. 23, Suppl. 1, 67, 1994, Abstracts of the 34 * ICAAC, Orlando October 4-7, 1994). Retrovir (AZT) is particularly preferred.

Quinoxalines of the general formulas (I) and (Ia) are preferred,

in which

n zero, one or two,

the individual substituents

Rl independently of one another fluorine, chlorine, bromine, trifluoromethyl, hydroxy,

C _r C ₄ alkyl, C _r C ₄ alkoxy, (C _r C ₄ alkoxy) - (C _r C ₄ alkoxy),

Ci- -alkylthio, nitro, amino, C _r C ₄ -alkylamino, di (C ₁ -C -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C _r C ₄ -acyl, C _r C - Acyloxy, C _r C ₄ acylamino, cyano, carbamoyl, carboxy, (C ₁ -C alkyl) oxycarbonyl, hydroxysulfonyl, sulfamoyl

or a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two mutually independent radicals R6,

in which

R ^east fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C ₁ -C ₄ - alkyl, C _r C ₄ alkoxy, _(Cι-C4 alkyl) -oxycarbonyl, phenyl, phenoxy,

can be,

R ^{2 is} hydrogen and

R5 C _j -Cg alkyl, optionally substituted with fluorine, chlorine, hydroxy,

C ₁ -C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, C ₁ -C alkoxy, C ₁ -C ₄ alkylamino, di (C ₄ -C ₄ alkyl) amino, C ₁ -C alkylthio, oxo, thioxo, carboxy, carbamoyl ;

C ₂ -C ₆ alkenyl, optionally substituted with fluorine, chlorine, hydroxy,

Cι-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C ₁ -C ₄ alkoxy, CC ₄ - alkylamino, di (C ₁ -C ₄ alkyl) amino, Cj-C ₄ alkylthio, oxo, thioxo, carboxy , Carbamoyl;

C -C ₈ allenyl, C ₃ -C ₈ alkynyl, optionally substituted with fluorine,

Chlorine, hydroxy, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₄ alkoxy, C ₁ -C ₄ alkylamino, di (C _r C ₄ alkyl) amino, C _r C ₄ alkyl thio, oxo, thioxo, carboxy, carbamoyl; C ₃ -C cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, C _r C alkyl, Cj -C acyloxy, benzoyloxy, benzyloxy, phenoxy, CC ₄ alkoxy, C _r C ₄ alkylamino, di (C _r C ₄ alkyl) amino, C _r C alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C cycloalkenyl, optionally substituted with fluorine, chlorine, hydroxy, - alkyl, - acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₄ alkoxy, C _r C ₄ alkylamino, di (C _r C ₄ alkyl) amino, C _r C ₄ alkyl thio, oxo, thioxo, carboxy, carbamoyl;

(C ₃ -C ₆ -cycloalkyl) - (-C-C ₂ -alkyl), optionally substituted with fluorine, chlorine, hydroxy, C -alkyl, Cτ-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cι-C ₄ - alkoxy, Cι-C ₄ alkylamino, di _(Cj-C4 alkyl) amino, C _j -C -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

(C ₃ -C ₆ cycloalkenyl) - (C ₁ -C ₂ alkyl), optionally substituted with fluorine, chlorine, hydroxy, C _j - alkyl, -C-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cι- C -alkoxy, -CC ₄ -alkylamino, di (-C ₄ -alkyl) amino, C _j ^ -alkylthio, oxo, thioxo, carboxy, carbamoyl;

C Cg-alkylcarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C ₁ -C ₄ -alkyl, C ^ -acyloxy ^" , benzoyloxy, benzyloxy, phenoxy, C _r C -alkoxy, C _r C -alkylamino, C ^ C- ^ Alkenylamino, di (C ₁ -C ₄ alkyl) amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-l-yl, C _r C alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₆ alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxy;

(C ₃ -C ₆ cycloalkyl) carbonyl, (Cs-Cg-Cycloalkeny carbonyl,

(C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₂ alkyl) carbonyl,

(C ₅ -C ₆ cycloalkenyl) - (C ₁ -C ₂ alkyl) carbonyl,

C ₁ -C ₆ alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylamino, di (C ₁ -C ₄ -alkyl) amino, C ₁ -C ₄ -alkylthio;

C ₂ -C ₆ alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, - -alkoxy;

C ₂ -C ₆ alkynyloxycarbonyl, optionally substituted by fluorine, chlorine,

Hydroxy, Cj-C alkoxy;

C Cg-alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C -alkoxy;

C ₂ -C ₆ alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C ₄ alkoxy;

C _j -Cg alkylamino and di (-C ₆ alkyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C ₄ alkoxy;

Pyrrolidin-1-yl, morpholino, piperidino, piperazinyl, or 4-methyl-p iperazin-1-y 1-carbony 1; C ₂ -C ₆ alkenylamino and di (-C ₆ -alkenyf) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C alkoxy;

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

-C-C ₄ alkenylsulfonyl;

or aryl, arylcarbonyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, substituted by up to two mutually independent radicals R6,

Arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can in each case contain 1 to 3 carbon atoms and R6 is as defined above

or 1- or 2-naphthylmethyl, 2-, 3- or 4-picofyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, substituted with up to two mutually independent radicals R6,

2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3-thienylmethyloxycarbonyl,

and

R ^ and R ^ are the same or different, independently of one another hydrogen,

C _j -C ₄ alkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C _j -C acyloxy, benzoyloxy, phenoxy, C _r C ₄ alkoxy, C ₁ -C ₄ alkylamino, Di (C _r C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkyl sulfonyl, C ₁ -C alkyl sulfinyl, carboxy, carbamoyl; C ₂ -C ₆ alkenyl, optionally substituted with fluorine or chlorine;

C ₃ -C ₆ cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₄ alkoxy, C _r C ₄ alkylamino, di ( C _r C ₄ alkyl) amino, C _r C ₄ alkyl thio, C ₁ -C ₄ alkylsulfonyl, C ₁ -C alkylsulfinyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine or chlorine;

aryl substituted with up to two mutually independent radicals R ^,

Mean benzyl, heteroaryl or heteroarylmethyl,

R3 and R ^ can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 C atoms, which may optionally contain fluorine, chlorine, hydroxy, amino, Cj- acyloxy, benzoyloxy, Cj-Calk- oxy, oxo, thioxo, carboxy, carbamoyl can be substituted, and

X means oxygen or sulfur,

optionally in an isomeric form, in combination with protease inhibitors of

Line:

1.) 2,4,7, 12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5- (l-methyl-ethyl) -l- [2- (l-methylethyl) -4-thiazolyl ] -3,6-dioxo-8, l l-bis- (phenyl-methyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]

2.) 3-Isoquinoline carboxamides, N- (l, l-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S - [2- (2S *, 3S *), 3.alpha., 4a.beta. , 8a beta.]] -, monoethanesulfonate (salt) 3.) Carbamic acid, [3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-l- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S- [3R *

(IS *, 2R *)]] - 4.) (S) -N - [(alphaS) -alpha - [(1 R) -2 - [((3S, 4aS, 8aS) -3- (tert.butylcarbamoyl ) -octa-hydro-2 (lH) -isoquinolinyl) -l-hydroxyethyl) phenethyl-2-quinald-amido] - succinamide 5.) 2 (R) -benzyl-5- (2 (S) - (N-tert .butylcarbamoyl) -4- (3-pyridyl-methyl) piperazine-

1 -yl) -4 (S) -hydroxy-N- (2 (R) -hydroxyindan- 1 (S) -yl) pentanamide 6.) N- (quinolin-2-ylcarbonyl) -asparagine-l (S) - benzyl-3- (3-tert-butyl-l-isobutylureido) -2 (R) -hydroxypropylamide

7.) N 1 - (2R-hydroxy-3 - ((3-methylbutyl) methylsulfony l) amino) - 1 S- (phenylmethyl) propyl) -2S - ((2-quinolinylcarbonyl) amino) butanediamide 8.) (2S, 3S, 5S) -5 (N- (N - ((N-methyl-N - ((2-isopropyl-4-oxazolyl) methyl) amino) - carbonyl) valinyl) amino) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -1, 6-di-phenyl-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) -isobutyl-amino] -l- 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-pheny 1-hexanoy 1] - isoleucine 13.) N-tert-butyl-l- [2- (R) -hydroxy-4-phenyl ) -3 (S) - [[N- (2-quinolinylcarbonyl) - asparaginyl] amino] butyl-4 (R) - (phenylthio) piperidine-2 (S) carboxamides

14.) [3 ^, "S- (3"'R *, 4 ^, "S *)] - N- [l ^, -oxo-l' - (3" - [l '"-oxo-2' -aza -3 ' ^* ' -phenyl-methyl-4 '"-hydroxy-5'" - (2 "'-N-tert.butylcarbamido) phenyl] pentyl-4''- methyl) -l, 2,3,4- tetrahydroisoquinoline 15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfamyl-butyl] -decahydro-isoquinoline-3-carboxylic acid-tert.butylamide 16.) 2H-1, 4-diazepin-2-one, hexahydro-6-hydroxy-1, 3,4,7-tetrakis (phenylmethyl) -, [3S '- (3.alpha., Ό.beta ., 7.beta,)]

and reverse transcriptase inhibitors for use as drugs in the control of AIDS and HIV infections.

Quinoxalines of the general formulas (I) and (Ia) are particularly preferred,

in which

n zero, one or two,

the individual substituents

Rl independently of one another fluorine, chlorine, bromine, trifluoromethyl, hydroxy, C _r C ₄ alkyl, C _r C ₄ alkoxy, (C _r C ₄ alkoxy) - (C _r C ₂ alkoxy), C _r C ₄ - Alkylthio, nitro, amino, C ₁ -C 4 -alkylamino, di (C _! -C ₄ -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C _r C ₄ -acyl,

C 1 -C ₄ -acyloxy, C 1 -C ₄ -acylamino, cyano, carbamoyl, carboxy, (-C - alkyl) -oxycarbonyl, hydroxysulfonyl, sulfamoyl

or

a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two mutually independent radicals R °,

in which R ⁶ fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C ₁ -C ₄ alkyl, C _r C ₄ alkoxy, (- -alkyoxycarbonyl, phenyl, phenoxy

can be,

R ^{2 is} hydrogen and

R ⁵ Cj- alkyl optionally substituted with Cj- alkoxy or C _r C ₄ -

Alkylthio;

C ₂ -C ₆ alkenyl, optionally substituted with 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 ₆ cycloalkyl) - (C ₁ -C ₂ alkyl), in particular cyclopropylmethyl, optionally substituted with C ₁ -C ₄ alkyl;

(C ₃ -C ₆ cycloalkenyl) - (C ₁ -C ₂ alkyl), especially cyclohexenylmethyl;

Ci-Cg-alkylcarbonyl, optionally substituted with fluorine, chlorine, hydroxy, benzyloxy, phenoxy, C -alkoxy, C ₁ -C -alkylamino, CC ₄ - Alkenylamino, di (C _r C ₄ alkyl) amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-l-yl, CC alkylthio;

C ₂ -C ₆ alkenylcarbonyl;

C ₁ -C ₄ -alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, - -alkoxy, C ₁ -C ₄ -alkylamino, di (C _r C ₄ -alkyl) - amino, - -alkylthio;

C ₂ -C ₆ alkenyloxycarbonyl, especially vinyloxy carbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl;

C ₂ -C ₆ alkynyloxycarbonyl, in particular propynyloxycarbonyl, butynyloxycarbonyl;

C i -C alkyl thiocarbonyl;

C ₂ -Cg alkenylthiocarbonyl, especially allylthiocarbonyl;

Ci-Cg-alkylamino and di (-C-C ₆ alkyl) aminocarbonyl;

Pyrrolidin-1-yl, morpholino, piperidino, piperazinyl or 4-methylpiperazin-1-y 1-carbony 1;

C ₂ -C ₆ alkenylamino and di (C ₁ -C ₆ alkenyl) aminocarbonyl;

C _r C ₄ alkylsulfonyl;

C _r C ₄ alkenylsulfonyl; or aryl substituted with up to two independent radicals, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, in particular

Benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can contain 1 to 3 carbon atoms and R ^ is as defined above

or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, substituted with up to two mutually independent radicals R ^, 2 -, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyl-oxycarbonyl , 2- or 3-thienylmethyloxycarbonyl,

and

R ^ and R ^ the same or different, independently of one another hydrogen, C - alkyl, optionally substituted with hydroxy, mercapto, -CC alkoxy,

C ₁ -C ₄ alkylthio, C _r C ₄ alkylsulfonyl, C _r C ₄ alkylsulfinyl, carboxy, carbamoyl;

C ₂ -C ₆ alkenyl,

aryl, benzyl, thienyl or thienylmethyl substituted with up to two mutually independent radicals R6, where R> is as defined above, R3 and R ^ can also be part of a saturated or unsaturated carbo- or heterocyclic ring with 3 to 6 carbon atoms, which can optionally be substituted with oxo or thioxo and

X means oxygen or sulfur

in combination with protease inhibitors of the series:

1.) 2,4,7, 12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5 (l-methyl-ethyl) -l- [2- (l-methylethyl) -4-thiazolyl] -3,6-dioxo-8, 1 lbis- (phenyl-methyl) -,

5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)] 2.) 3-isoquinoline carboxamides, N- (1, 1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3rd -hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] - [3S- [2- (2S *, 3S *), 3.alpha., 4a.beta., 8a beta.]] -, monoethanesulfonate (Salt) 3.) carbamic acid, [3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-l- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S- [3R * (IS *, 2R *)]] - 4.) (S) -N - [(alphaS) -alpha - [(lR) -2 - [((3S, 4aS, 8aS) -3 - (tert.butylcarbamoyl) -octa-hydro-2 (1H) -isoquinolinyl) -l-hydroxyethyl) phenethyl-2-quinald-amido] - succinamide

5.) 2 (R) -Benzyl-5- (2 (S) - (N-tert.butylcarbamoyl) -4- (3-pyridyl-methyl) piperazine-

1 -yl) -4 (S) -hydroxy-N- (2 (R) -hydroxy indan-1 (S) -yl) pentanamide 6.) N- (quinolin-2-ylcarbonyl) -asparagine-l (S) -benzyl-3- (3-tert-butyl-l-isobutylureido) -2 (R) -hydroxypropylamide 7.) 2 (1H) -pyrimidinones, 4-amino-l- [2- (hydroxymethyl) -l, 3-oxathiolan-5-yl] -,

[(2R-cis) - (9CI)] (Epivir)

and reverse transcriptase inhibitors for use as drugs in the control of AIDS and HIV infections. The combination of S-4-isopropoxycarbonyl-6-methoxy-3- (methylthio-methyl) -3,4-dihydroquinoxazoline-2 (1H) -thione of the formula (A) is very particularly preferred

H ₃ C CH ₃

or 1 (2H) -quinoxalinecarboxylic acid, 2-ethyl-7-fluoro-3,4-dihydro-3-oxo, 1-methylethyl ester [(S) - (9CI)] of the formula (B)

with (S) -N - [(alphaS) -alpha - [(lR) -2 - [((3S, 4aS, 8aS) -3- (tert.butylcarbamoyl) -octa-hydro-2 (lH) -isoquinolinyl) -l-hydroxyethyl) phenethyl-2-quinaldamido] succinamide (saquinavir) of the formula (C)

or 2 (R) -benzyl-5- (2 (S) - (N-tert.butylcarbamoyl) -4- (3-pyridylmethyl) piperazin-l-yl) -4 (S) -hydroxy-N- (2 ( R) -hydroxyindan-l (S) -yl) pentanamides of the formula (D)

or 2,4,7, 12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl 1-5 (1-methyl-ethyl) -l- [2- (l-methylethyl) -4-thiazolyl] - 3,6-dioxo-8,1 lbis- (phenyl-methyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]

and Retrovir (AZT) or Epivir for use in combating AIDS and HIV infections.

The quinoxalines of the general formulas (I) and (Ia) are known [cf. EP 509 398 AI; EP 708 093; EP 657 166]. The protease inhibitors listed above are also known [cf. EP 432 695 A2, EP 569 083 AI, EP 541 168 AI, PCT WO 92/08688 AI, WO 92/08699 AI, WO 92/08698 AI, WO 92/08701 AI, WO 92/08700 AI, PCT WO 94/04492, PCT WO 94/14436, PCT WO 9411361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977].

The use of the combination of these compounds offers advantages in the treatment of retrovirus-induced - but especially HIV-induced diseases - compared to monotherapy or combinations of two with the individual compounds. The advantageous and superior use of the combination of these compounds for the treatment of AIDS or HIV infections results primarily from the synergistic antiviral activity, but also from the unchanged tolerance of the substances in combination in the area of toxicity at 50 % of the cells survive - compared to the Tox-50 of the individual components. It is known for other combinations - e.g. AZT in combination with ganciclovir that synergistic toxicity occurs when a combination is used [cf. M.N. Prichard et al. ; Antimicrobial. Agents Chemotherapy (1991), 35, 1060-1065].

The use of the triple combination of the substances results in a reduced effective dose for the treatment. In addition, the use of the triple combination reduces the likelihood of developing resistant virus isolates.

The invention relates to the combination of three classes of compounds of HIV reverse transcriptase inhibitors and HIV protease for the prevention and treatment of infections with HIV, and for the treatment of HIV-induced diseases such as AIDS Related Complex (ARC) or AIDS. HIV infection in cell culture

The HIV test was 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's) were enriched via Ficoll-Hypaque and stimulated in the RPMI 1640, 20% fetal calf serum with phythema agglutinin (90 μglmϊ) and interleukin-2 (40 U / ml). For infection with the infectious HIV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HIV virus solution for adsorption and incubated for 1 hour at 37 ° C.

The virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium so that 1 × 10 ^ cells per ml were set. The cells infected in this way were pipetted into 1 × 10 ⁴ cells / well into the wells of 96-well microtiter plates.

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

The combinatorial effect of the test substances was tested by means of checkerboard titration (checkerboard titration).

The first vertical row of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as described above (cell control). The second vertical row of the microtiter plate only received HIV-infected cells (virus control) in growth medium. The other wells contained the compounds according to the invention - alone or in appropriate combinations - in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were further diluted in steps of two (50 μl volume per well). For the combination, dilutions of the second substance were made on a separate 96-well microtiter plate and then pipetted onto the prepared first plate. The the third compound was presented in a fixed concentration, so that, for example, 4 dilution stages (corresponding to 4 test batches) of the 3rd inhibitor were tested. In each case 100 μl of the prepared HIV-infected cells were added (see above). This covered test concentrations of the three inhibitors in the range of approx. 10 - 50 times above and below the IC5Q concentrations of the individual compounds.

The test batches were incubated at 37 ° C. until, in the untreated virus control, the syncytia formation typical of HIV on the host cell (between days 3 and 8 after infection) was microscopically detectable. Under the test conditions, the untreated virus control resulted in about 20-50 syncytia, while the untreated cell control showed no syncytia.

The supernatants from the 96-well plate were then harvested and examined for HIV-specific antigen in an HIV-specific ELISA test (Vironostika HIV

Antigen, Organon Teknika).

The inhibition values were calculated according to the cut-off values from the corresponding cell or Virus controls or internal test controls are converted into percent (%) inhibition values, and the IC50 values were determined as the concentrations of the treated and infected cells at which 50% of the virus-specific antigen was suppressed by the treatment with the compounds. To analyze the synergistic activity of the compounds, the difference values between calculated and measured inhibition values of the combinations were determined (Prichard, M.N. et al., Antimicrob. Agents Chemoth. (1993), 37, 540-545).

The combination of three surprisingly shows synergistic activity in concentration ranges in which no antiviral effect is observed by single treatment or double combination. For example, 0.5 nM retrovir and 0.1 nM retrovir in combination with 0.1 to about 10 nM of quinoxaline and about 70 to 6 nM indinavir and 0.2 to 6 nM of quinoxaline each have about 10 to 50 nM indinavir has a strong synergistic effect. Examples include the combination of retrovir with S-4-isopropoxycarbonyl-6-methoxy-3- (methylthio-methyl) -3,4-dihydro-quinoxazoline-

2 (1H) -thione of formula (A) and with indinavir or the combination of retrovir with 1 (2H) -quinolinecarboxylic acid, 2-ethyl-7-fluoro-3,4-dihydro-3-oxo, 1-methylethyl ester [(S) - (9C1)] of formula (B) and with indinavir.

It has surprisingly been found that by using the triple

Combination of the compounds has a synergistic effect on HIV. This has been demonstrated by three combination studies of the quinoxaline derivative with indinavir and retrovir.

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

Areas of indication in human medicine include:

1.) The treatment and prophylaxis of human retrovirus infections.

2.) Treatment or prophylaxis of diseases caused by HIV I (human immunodeficiency virus; formerly called HTLV III / LAV)

(AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) as well as the immune deficiency and encephalopathy caused by this virus. 3.) The treatment or prophylaxis of an HTLV-I or HTLV-II infection.

4.) The treatment or prophylaxis of the AIDS carrier state (AIDS carrier state).

Examples of indications in veterinary medicine are:

Infections with

a) Maedivisna (for sheep and goats)

b) progressive pneumonia virus (PPV) (in sheep and goats)

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

d) double-infected virus (in sheep)

e) infectious anemia (horse) virus

f) infections caused by the feline leukemia virus

g) infections caused by the virus of cat immunodeficiency (FIV)

h) infections caused by the monkey immunodeficiency virus (SIV)

Points 2, 3 and 4 from the indication area in human medicine are preferred. The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formulas (I) / (Ia) in combination with a protease inhibitor and a reserve transcriptase inhibitor or which consist of one or more active ingredients of the Formulas (I) / (Ia), the protease inhibitor and the

Reverse transcriptase inhibitor exist, as well as processes for the preparation of these preparations, in particular the combination of the test compounds.

The active ingredients of the formulas (I) and (Ia), the protease inhibitors and the reverse transcriptase inhibitors are said to be present in the pharmaceuticals listed above

Preparations are present in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture.

In addition to the compounds of the formulas (I) / (Ia) in combination with a protease inhibitor and a reverse transcriptase inhibitor, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).

In general, it has proven advantageous in both human and veterinary medicine to optionally add the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight per 24 hours in the form of several single doses to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, 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 application of the drug, and the period or interval within which the administration takes place.

Two combinations in the treatment of HIV-infected patients show an efficacy superior to monotherapy. However, resistant viruses can also occur under such a therapy scheme. The combination of three described here has a synergistic effect on the multiplication of HIV and thus effectively suppresses the development of resistant viruses.

Claims

claims

1. Medicament containing a combination of three quinoxalines of the general formula (I)

FT

and their tautomeric forms of the general formula (Ia)

in which

1) zero, one, two, three, or four,

the individual substituents

Rl independently of one another fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxy, C ^ Cs-alkyl, C ₅ -C ₈ -cycloalkyl, C _r C ₆ -alkoxy, (C _r C ₆ -alkoxy) - (C _r C ₄ alkoxy), C _r C ₆ alkylthio, Ci-Co-alkylsulfinyl, C Cg-alkylsulfonyl, nitro, amino, azido, C -alkylamino, di (C ₁ -C ₆ -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl , Tetrazolyl, C _r C ₆ -acyl, - -acyloxy, C _r C ₆ -acyl-amino, cyano, carbamoyl, carboxy, (Cj- -alkyoxycarbonyl, hydroxysulfonyl, sulfamoyl

or

a phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyloxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-py substituted with up to five mutually independent radicals R ^ - ridyl or 4-pyridyl radical,

where R "

Fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy,

Nitro, amino, azido, C _r C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C _r C ₆ alkoxy, C ^ Cg alkylthio, C _r C ₆ alkylsulfinyl, C _r C ₆ alkylsulfonyl, C ₁ -C ₆ -alkylamino, DC -alkyl-amino, (C _r C ₆ -alkyl) -oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl can be

R ^{2 is} hydrogen, C _r C ₆ alkoxy, hydroxy, picolyl, cyclopropyl or isopropenyloxycarbonyl and

R ^{5 is} hydrogen, hydroxy, C ^ - alkoxy, aryloxy, C _r C ₆ -acyloxy,

Cyano, amino, Ci-Cg-alkylamino, di (C _r C ₆ alkyl) amino, aryl amino, C _j -Cg acylamino, C ^ Cs alkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano , Amino, mercapto, hydroxy, C _r C ₆ acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₆ alkoxy, C _r C ₆ alkylamino, di (C _r C ₆ alkyl) amino, -Cg-alkylthio, C _r C ₆ - alkylsulfonyl, Phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₈ alkenyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Cj-C ₆ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C ^ Cg- alkoxy, C ^ Cg- Alkylamino, DKCI-alkylamino, C _r C ₆ alkylthio, C _r C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C ₈ allenyl, optionally substituted by fluorine, chlorine or hydroxy, C -alkoxy, oxo, phenyl; C ₃ -C ₈ alkynyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Cj- acyloxy, benzoyloxy, benzyloxy, phenoxy, Cp - alkoxy, C ^ Cg-alkylamino, C Cg -alkyOamino,

C _r C ₆ alkylthio, C _r C ₆ alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₃ ~ C ₈ cycloalkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Cj- acyloxy,

Benzoyloxy, benzyloxy, phenoxy, C ₁ -C ₆ -alkoxy, C Cg-alkylamino, DC ^ Cö-alky -amino, - C Cg-alkylthio, C ^ Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, Carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine, chlorine,

Bromine, iodine, cyano, amino, mercapto, hydroxy, - -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cj-C ₆ -alkoxy, Cj-Cg-alkylamino, D -Cg-alkyamino, C _r C ₆ - Alkylthio, C -alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; (C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₄ alkyl), optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C _r C ₆ acyloxy, benzoyloxy, benzyloxy, Phenoxy, C _r C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, DKC Cg-alkyOamino, C _r C ₆ -alkylthio, C ^ - alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

(C ₃ -C Cycloalkenyl) - (-C -C alkyl), optionally substituted with

Fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy,

Cj-Cö-acyloxy, benzoyloxy, benzyloxy, phenoxy, Cj-Cg-alkoxy, C Cg-alkylamino, DiCCx-Cö-alkyamino, C _r C ₆ -alkylthio, C _r C ₆ -

Alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C _j -Cg alkylcarbonyl optionally substituted with fluorine, chlorine,

Bromine, iodine, cyano, amino, mercapto, hydroxy, C _r C ₆ -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cj-Cg-alkoxy, Cj- -alkylamino, di (C _r C ₆ -alkyl) -amino C _r C ₆ alkylthio, C _r C ₆ alkyl sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₈ alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxy, Cj- alkoxy, oxo, phenyl;

(C ₃ -C ₈ cycloalkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxy, - - alkoxy, oxo, phenyl;

(C ₅ -C ₈ cycloalkenyl) carbonyl, optionally substituted by

Fluorine, chlorine or hydroxy, C _j -C ₄ alkoxy, oxo, phenyl;

(C ₃ -C ₈ cycloalkyl) - (C ₁ -C ₃ alkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C _r C ₄ - alkoxy, oxo, phenyl; (C ₅ -C ₆ cycloalkenyl) - (C ₁ -C alkyl) carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C - alkoxy, oxo, phenyl;

Cj-Cs-alkyloxycarbonyl, optionally substituted by fluorine,

Chlorine, bromine, hydroxy, C _r C alkoxy, C _r C ₄ alkylamino, di- (C ι -C l -alky) -amino, C _r C ₄ alkylthio;

C ₂ -C ₈ alkenyloxycarbonyl, optionally substituted by fluorine,

Chlorine, hydroxy, Cj-C - alkoxy, oxo, phenyl;

C2-C-alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C _r C -alkoxy, oxo, phenyl;

-C-C ₈ alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Cχ-C ₄ alkoxy, oxo, phenyl;

C ₂ -C ₈ alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C _r C ₄ alkoxy, oxo, phenyl;

-C ₈ alkylamino and di (-C ₈ alkyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Cχ-C - alkoxy, oxo, phenyl;

Pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-l-yl-carbonyl, optionally substituted by CC ₄ -alkyl, C ₂ -Cg-alkenyl, Cj-C ₄ -acyl, oxo, Thioxo, carboxy, or phenyl; C ₂ -C ₈ alkenylamino and di (-C-C ₆ alkenyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C ₁ -C alkoxy, oxo, phenyl;

Cj- alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxy, C C - alkoxy, oxo, phenyl;

Cx-Cg-alkenylsulfonyl, optionally substituted by fluorine, chlorine, hydroxy, Cj- - alkoxy, oxo, phenyl;

or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) -thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl, aryl, arylsulfonyl, aryl, arylcarbonyl, aryl (thiocarbonyl) Arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where the alkyl radical can contain 1 to 5 carbon atoms and R ^ is as defined above

or with up to three mutually independent radicals R ^ substituted heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio) carbonyl, heteroarylaryocarbonyl, heteroaryylaryoaryoaryylaryyl, carbonyl, heteroaryylaryooxyylylcarbonyl, heteroaryylaryooxyylyl carbonyl, heteroaryylaryooxyylyl carbonyl, heteroaryylaryooxyylyl carbonyl, heteroaryylaryooxyylyl carbonyl, heteroaryylaryoaryoaryl carbonyl, the alkyl radical may contain 1 to 3 carbon atoms,

R ^{4 are} identical or different, independently of one another, hydrogen,

C _r C ₈ alkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C ₁ -C ₄ acyloxy, benzoyloxy, benzyloxy, phen oxy, C _r C ₄ alkoxy CpC ₄ alkylam.n0, di (C _r C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkylsulfonyl, C _r C ₄ alkylsulfinyl, carboxy, carbamoyl ;

C ₂ -C alkenyl optionally substituted with fluorine or chlorine, hydroxyl, amino, mercapto, _{Cι-C4-acyloxy,} benzoyloxy, benzyloxy, phenoxy C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylamino, di ( C ₁ -C ₄ alkyl) - amino, -C -C alkyl thio, C _r C ₄ alkylsulfonyl, C ₁ -C alkylsulfyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, Cj- acyloxy, benzoyloxy, benzyloxy, phenoxy, Cχ-C ₄ - alkoxy C-C ₄ alkylamino, di (C ₁ - C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkyl sulfonyl, C _r C ₄ alkyl sulfinyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine or

Chlorine, hydroxy, amino, mercapto, C -acyloxy, benzoyloxy,

Benzyloxy, phenoxy Cι-C alkoxy, C ₁ -C ₄ alkylamino, di (Cι-C ₄ - alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkylsulfonyl, C _r C ₄ alkyl sulfinyl , Carboxy, carbamoyl;

substituted with up to five mutually independent radicals R ^

Aryl, arylalkyl, heteroaryl or heteroarylalkyl, where the alkyl radical can each contain 1 to 3 carbon atoms and R ^ is as defined above,

R ⁴ can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having 3 to 8 C atoms, which may optionally be substituted with fluorine, chlorine, hydroxy, amino, C _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ acyloxy, benzoyloxy, Ci-Cg-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl may be substituted,

X means oxygen, sulfur, selenium or substituted nitrogen

NR ² , wherein R ² can have the meanings given above

with protease inhibitors and reverse transcriptase inhibitors.

Medicament according to claim 1 containing quinoxalines of the general formulas (I) and (Ia), in which

n zero, one or two,

the individual substituents

Rl independently of one another fluorine, chlorine, bromine, trifluoromethyl, hydroxy, C _r C ₄ -alkyl, C _r C ₄ -alkoxy, (C _r C ₄ -alkoxy) - (C _r C ₄ - alkoxy), C _r C ₄ - Alkylthio, nitro, amino, -C-alkylamino, di (Cχ-C -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, Cχ-C ₄ -acyl, C ₁ -C ₄ -acyloxy, C ₁ -C -Acyl- amino, cyano, carbamoyl, carboxy, (-C-C ₄ alkyl) -oxycarbonyl, hydroxysulfonyl, sulfamoyl

or

a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted with up to two mutually independent radicals R6, in which

R6 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C ₁ -C -alkyl, Cj-C -alkoxy, (C ₁ -C -alkyl) -oxycarbonyl,

Phenyl, phenoxy,

can be,

R ^{2 is} hydrogen and

R5 C Cg-alkyl, optionally substituted with fluorine, chlorine, hydroxy, Cχ-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, CC ₄ - alkoxy, C ₁ -C ₄ alkylamino, di (C ₁ -C alkyl) amino, -C ₄ - alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₂ -C ₆ alkenyl, optionally substituted with fluorine, chlorine, hydroxy, -C-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cp -alkoxy, C ₁ -C ₄ -alkylamino, di (C ₁ -C ₄ - alkyl) amino, C ₁ -C ₄ alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C ₈ allenyl, C ₃ -C ₈ alkynyl, optionally substituted with fluorine, chlorine, hydroxy, C _j ^ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C ₁ -C alkoxy, C ₁ -C alkylamino , Di (C ₁ -C ₄ alkyl) amino, Cχ-C - alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, C alkyl, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C alkoxy, C _j -C ^ alkylamino, Di (C ₁ -C ₄ alkyl) amino, C _r C ₄ alkylthio, oxo, thioxo, carboxy, carbamoyl; C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine, chlorine, hydroxy, -C-C ₄ alkyl, Cj-C ₄ -acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₄ alkoxy, C _r C ₄ alkylamino , Di (C _r C ₄ alkyl) amino, Cχ-C alkylthio, oxo, thioxo, carboxy, carbamoyl;

(C ₃ -C ₆ cycloalkyl) - (C ₁ -C ₂ alkyl), optionally substituted with fluorine, chlorine, hydroxy, Cχ-C alkyl, - acyloxy, benzoyloxy, benzyloxy, phenoxy, CC ₄ - alkoxy, C 1 -C ₄ alkylamino, di (C 1 -C ₄ alkyl) amino, C 1 -C 4 alkylthio, oxo, thioxo, carboxy, carbamoyl;

(C ₃ -C ₆ cycloalkenyl) - (C ₁ -C ₂ alkyl), optionally substituted with fluorine, chlorine, hydroxy, Cj-C ₄ alkyl, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, Cj- C ₄ - alkoxy, Cj - alkylamino, di (Cj - C ₄ - alkyl) amino, CC ₄ - alkylthio, oxo, thioxo, carboxy, carbamoyl;

C -alkylcarbonyl, optionally substituted with fluorine, chlorine,

Hydroxy, C _] , -C ₄ -alkyl, -C-C ₄ -acyloxy, benzoyloxy, benzyloxy,

Phenoxy, C _j -C ₄ alkoxy, C -C ₄ alkylamino, Cj-C ₄ alkenylamino, di (C _r C ₄ alkyl) amino, 1-pyrrolidinyl, piperidino, morpholino,

4-methylpiperazin-l-yl, Cj-C ₄ - alkylthio, oxo, thioxo, carboxy, carbamoyl;

C ₂ -Cg alkenylcarbonyl, optionally substituted by fluorine, chlorine or hydroxy;

(C ₃ -C ₆ cycloalkyl) carbonyl,

(C ₅ -C ₆ cycloalkenyl) carbonyl, (C ₃ -C ₆ cycloalkyl) - (C _r C ₂ alkyl) carbonyl,

(C ₅ -C ₆ cycloalkenyl) - (C _r C ₂ alkyl) carbonyl,

C Cg-alkyloxycarbonyl, optionally substituted by fluorine,

Chlorine, bromine, hydroxy, C _r C ₄ alkoxy, C _r C ₄ alkylamino, di (C _r C ₄ alkyl) amino, C _r C ₄ alkylthio;

C ₂ -C ₆ alkenyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C _r C ₄ alkoxy;

C ₂ -C _ö -alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, CC ₄ - alkoxy;

Ci-Co-alkylthiocarbonyl, optionally substituted by fluorine,

Chlorine, hydroxy, Cχ-C ₄ alkoxy;

C ₂ -C ₆ alkenylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C -alkoxy;

Cx- alkylamino and di (C ₁ -C ₆ alkyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Cj-C ₄ alkoxy;

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

C ₂ -C ₆ alkenylamino and di (C ₁ -C ₆ alkenyl) aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, CC - alkoxy; C ₁ -C alkylsulfonyl, optionally substituted by fluorine, chlorine, hydroxy, C _r C ₄ alkoxy;

C 1 -C ₄ alkenylsulfonyl;

or aryl, arylcarbonyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (wherein can each contain 1 to 3 carbon atoms and R ^ is as defined above

or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, substituted with up to two mutually independent radicals R ^,

and

R ^ and R ^{4 are the} same or different, independently of one another hydrogen,

C 1 -C ₄ -alkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C _r C ₄ -acyloxy, benzoyloxy, phenoxy, C _r C ₄ -

Alkoxy, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C alkylsulfonyl, C _r C ₄ alkylsulfinyl, carboxy, carbamoyl;

C ₂ -C ₆ alkenyl, optionally substituted with fluorine or chlorine; C ₃ -C ₆ cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C _r C ₄ acyloxy, benzoyloxy, benzyloxy, phenoxy, C _r C ₄ alkoxy, Ci-C ^ alkylamino, di (C ₁ -C ₄ alkyl) amino, C _r C ₄ alkylthio, C _r C ₄ alkylsulfonyl, C _r C ₄ alkylsulfinyl, carboxy, carbamoyl;

C ₃ -C ₈ cycloalkenyl, optionally substituted with fluorine or chlorine;

aryl, benzyl, heteroaryl or heteroarylmethyl substituted with up to two mutually independent radicals R ^,

R ^ and R ⁴ can also be part of a saturated or unsaturated carbo- or heterocyclic ring with 3 to 6 carbon atoms, optionally with fluorine, chlorine, hydroxy, amino, -C-C ₄ -acyloxy, benzoyloxy, Cj-C ₄ - Alkoxy, Oxo, Thioxo, Carboxy, Carbamoyl can be substituted, and

X means oxygen or sulfur,

optionally in an isomeric form. ^•

3. Medicament according to claim 1 containing quinoxalines of the general formula (I) and (Ia), in which

n zero, one or two,

the individual substituents R ¹ independently of one another fluorine, chlorine, bromine, trifluoromethyl,

Hydroxy, C _r C ₄ alkyl, C _r C ₄ alkoxy, (C ₁ -C ₄ alkoxy) - (C ₁ -C ₂ alkoxy), Cj-C ₄ - alkylthio, nitro, amino, C _r C _4- alkylamino, di (C} -C -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl,

4-methylpiperazinyl, Cj-C-acyl, Cj-C ₄ -acyloxy, C-acylamino, cyano, carbamoyl, carboxy, (Cj-C ₄ -alkyl) -oxycarbonyl, hydroxysulfonyl, sulfamoyl

or

a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two mutually independent radicals R6,

in which

R6 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C _r C ₄ alkyl, C _r C ₄ alkoxy, (C _r C ₄ alkyl) oxycarbonyl, phenyl, phenoxy

can be,

R ^{2 is} hydrogen and

R5 Cx-Cg-alkyl optionally substituted with C -alkoxy or C _r C ₄ -alkylthio;

C ₂ -C ₆ alkenyl, optionally substituted with oxo; C ₃ -C ₆ allenyl;

C ₃ -C alkynyl, especially 2-butynyl;

C ₃ -C ₆ cycloalkyl;

C5-Cg-cycloalkenyl;

(C ₃ -C6-Cycloalkyl) - (-C-C ₂ -alkyl), in particular cyclopropylmethyl, optionally substituted with -C-C ₄ -alkyl;

(C ₃ -C 6 cycloalkenyl) - (C ₁ -C ₂ alkyl), in particular cyclohexenylmethyl;

Ci-Cg-alkylcarbonyl, optionally substituted with fluorine, chlorine,

Hydroxy, benzyloxy, phenoxy, Cχ-C ₄ alkoxy, -CC alkylamino, Ci- alkenylamino, di (C ₁ -C ₄ alkyl) amino, 1-pyrrolidinyl, piperidino, Moφholino, 4-methylpiperazin-l- yl, Cj-C ₄ alkylthio;

C -C ₆ alkenylcarbonyl;

Ci-Cg-alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, Cχ-C - alkoxy, Cι-C ₄ alkylamino, di- (C i -C ₄ alkyl) amino, C _\ -C ₄ - Alkylthio;

C ₂ -C 6 alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; C ₂ -C 6 alkynyloxycarbonyl, in particular propynyloxycarbonyl, butynyloxycarbonyl 1;

Ci-Cg-alkylthiocarbonyl;

-Cg-alkenylthiocarbonyl, especially allylthiocarbonyl;

C Cg alkylamino and di (-C ₆ alkyl) aminocarbonyl;

Pyrrolidin-1-yl, Moφholino-, Piperidino-, Piperazinyl-, or

4-methylpiperazin-l-yl-carbonyl;

C ₂ -C 6 alkenylamino and di (Cχ-C ₆ alkenyl) aminocarbonyl;

C _r C ₄ alkylsulfonyl;

C _j - alkenylsulfonyl;

or aryl, in particular phenyl, arylcarbonyl, in particular substituted with up to two mutually independent radicals R "

Benzoyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl, where Can contain atoms and R ^ is as defined above

or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, substituted with up to two mutually independent radicals R ^, 2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- or 3-thienylmethyloxycarbonate 1,

and

C 1 -C 4 -alkyl, optionally substituted with hydroxy, mercapto, C _r C ₄ -alkoxy, C _r C ₄ -alkylthio, C _r C ₄ -alkylsulfonyl, C _r C ₄ -

Alkylsulfinyl, carboxy, carbamoyl;

C ₂ -C ₆ alkenyl,

substituted with up to two mutually independent radicals R ^

Aryl, benzyl, thienyl or thienylmethyl, where R> is as defined above,

R3 and ^R4 also may be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 C-atoms, which may optionally be substituted with oxo or thioxo and

X means oxygen or sulfur.

4. Medicament according to claims 1 to 3 containing one or more

Protease inhibitors selected from the group

1.) 2,4,7, 12-tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5- (l-methylethyl) -l- [2- (l-methylethyl) -4-thiazolyl] - 3,6-dioxo-8, l l-bis- (phenyl-methyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]; PCT WO 95/07696; PCT WO 95/20384 AI;

PCT WO 95/009614 AI [ABBOTT (ritonavir) ABT-538]

2.) 3-isoquinoline carboxamides, N- (l, l-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) - butyl] - [ 3S- [2- (2S *, 3S *), 3rd alpha. , 4a.beta. , 8a beta.]] -, monoethanesulfonate (salt); PCT WO 95/09843; US 5484926; [AGOURON (ViraceptR) AG- 1343]

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

4.) (S) -N - [(alphaS) -alpha - [(lR) -2 - [((3S, 4aS, 8aS) -3- (tert.butylcarbamoyl) octa-hydro-2 (lH) -isoquinolinyl) -l-hydroxyethyl) phenethyl-2-quinaldamido] -succinamides (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) pentane amide (L-735524, EP 569 083 AI, EP 541 168 AI)

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 AI, WO 92/08699 AI, WO 92/08698 AI, WO 92/08701 AI, WO 92/08700 AI)

7.) Nl- (2R-hydroxy-3 - ((3-methylbutyl) methylsulfonyl) amino) -Is- (phenyl-methyl) 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) -l, 6-di-phenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436)

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-l, 3-thiazolidine-4-carboxamide (KNI 272 / Nippon Mining)

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

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

15.) 2- [2-Hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) -4-phenylsulfanyl-butyl] -decahydro-isoquinoline-3-carboxylic acid-tert.butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA)

? ₆ H ₅

16.) 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-l, 3,4,7-tetrakis (phenyl-methyl) -, [3S '- (3.alpha., Ό .beta., 7.beta,)] (PCT WO 94/08977)

OH Medicament according to claims 1 to 4 containing one or more reverse transcriptase inhibitors from the group zidovudine (retrovir) (AZT), didanosine (DDI), dideoxycytidine (DDC), lamivudine (3-TC ^® ), stavudine (D4T), BW 935U83, BW 1592U89 and Epivir.

Use of the quinoxalines, the protease inhibitors and the reverse transcriptase inhibitors from claims 1 to 5 for the manufacture of medicaments for the therapy of HIV infections.