NZ286058A

NZ286058A - Medicaments comprising quinoxaline derivatives and at least one protease inhibitor

Info

Publication number: NZ286058A
Application number: NZ286058A
Authority: NZ
Inventors: Arnold Paessens; Martin Blunck; Gunther Riess; Jorg-Peter Kleim; Manfred Rosner
Original assignee: Bayer Ag
Priority date: 1995-02-27
Filing date: 1996-02-23
Publication date: 1998-09-24
Also published as: SK25196A3; EP0728481A3; DE19506742A1; PL312908A1; HUP9600455A3; JPH08245392A; CA2170222A1; FI960850A; EP0728481A2; FI960850A0; CZ57896A3; HU9600455D0; KR960030951A; HUP9600455A2; ZA961516B; AU710158B2; AU4561596A; BR9600809A; NO960775D0; IL117247A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £86058 New Zealand No. 286058 International No. PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 27.02.1995; Complete Specification Filed: 23.02.1996 Classification:^) A61K31/495,47,425,35,34,55; A61K38/05 Publication date: 24 September 1998 Journal No.: 1432 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Use of quinoxalines in combination with protease inhibitors as medicaments for treating AIDS and/or HIV infections Name, address and nationality of applicant(s) as in international application form: BAYER AKTIENGESELLSCHAFT, a German company of D 51368 Leverkusen, Federal Republic of Germany 2860 5 Patents Form 5 N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION USE OF QUINOXALINES IN COMBINATION WITH PROTEASE INHIBITORS AS MEDICAMENTS FOR TREATING AIDS AND/OR HIV INFECTIONS We, BAYER AKTIENGESELLSCHAFT, a company registered under the laws of the Federal Republic of Germany of, D-51368 Leverkusen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- BAYER AKTIENGESELLSCHAFT «368 Ixvcrimscn Konzemverwaltung RP Patente Konzem JBu/AB/SP - 2860: Use of quinoxalines in combination with protease inhibitors as medicaments for treating AIDS and/or HIV infections The present invention relates to the use of quinoxalines in combination with protease inhibitors as medicaments for treating AIDS and/or HIV infections. The human immunodeficiency virus (HTV) causes a persistent, progressive, chronic disease. HIV destroys the immune system (acquired immunodeficiency syndrome, AIDS) and the central and peripheral nervous system. In addition to this, a large number of other clinical manifestations encompassed within the ARC/AIDS syndrome are caused by the human immunodeficiency virus - in particular opportunistic infections (0.1.) which are elicited by other viruses, such as, for example, herpes viruses (HSVI and II) and cytomegalovirus (CMV), or O.I. which are elicited by bacteria, fungi or parasites. HIV belongs to the retrovirus family; one of the important enzyme activities of these viruses, which is essential for the replication cycle, is that of the protease (Huff, J.R., J. Med. Chem. (1991), 34,2305-2314). Small molecular weight analogues, of a peptide or non-peptide nature, of the natural substrates of the protease inhibit HTV replication (Roberts, N.A. et al., Science (1990) 248, 358 - 361; Lam, P.Y.S. et al., Science (1994), 263, 380-384). Analogues of the natural substrates of the reverse transcriptase such as, for example, azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3'-thiacytidine (Lamivudine) inhibit HIV replication in vitro and in vivo. AZT is used, for G example, for treating ARC/AIDS patients. However, the long-term therapeutic treatment of HIV-infected patients with AZT is accompanied by bone marrow toxicity; in addition to this, AZT-resistant virus isolates develop. Intolerances, such as, for example, a peripheral neuropathy, are reported by some patients who have been treated with DDC or DDI. There is, therefore, a need for new inhibitors which will provide a well-tolerated and effective therapy. The combination of quinoxalines and protease inhibitors which has now been found is novel, and the synergistic effect of these compounds on HIV replication, when they are used in controlling AIDS or HIV infections, represents a considerable improvement as compared with the state of the art It has now been found that quinoxalines of the general formulae (I) and (la) .5 (D r and also their tautomeric forms of the general formula la ,5 (la) R in which 1) n is zero, one, two, three or four, the individual substituents R1 are, independently of each other, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C8-alkyl, Q-Q-cycloalkyl, C,-C6-alkoxy, (Q-Q-alkoxyHQ-Q-alkoxy), Cr C6-alkylthio, C,-C6-alkylsulphinyl, C,-C6-alkylsulphonyl, nitro, amino, azido, C,-C6-alkylamino, di(C,-C6-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomoipholino, imidazolyl, triazolyl, tetrazolyl, C,-C6-acyl, C,-C6-acyloxy, C,-C6-acylamino, cyano, carbamoyl, carboxyl, (C,-C6-alkyl)-oxycarbonyl, hydroxysulphonyl or sulphamoyl, or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxysulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five R6 radicals which are independent of each other, where R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, Q-Q-alkyl, Q-Q-cycloalkyl, C,-C6-alkoxy, CrC6-alkylthio, C,-C6-alkylsulphiny 1, CrC6-alkylsulphonyl, C,-C6-alkylamino, di(CrC6-alkyl)amino, (C,-C6-alkyl)-oxycaibonyl, phenyl, phenoxy or 2-, 3- or 4-pyridyl, R2 and R5 are identical or different and are, independently of each other, hydrogen, hydroxyl, CrC6-alkoxy, aryloxy, CrC6-acyloxy, cyano, amino, C,-C6-alkylamino, di(C,-C6-alkyl)amino, arylamino, C,-C6-acylamino, CrC8-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, CrC6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(CrC6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; . , 286 0 5 Q-Q-alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, Q-Q-acyloxy, benzoyloxy, benzyloxy, phenoxy, C^g-alkoxy, Ci-C6-alkylamino, di(C,-C6-alkyl)amino, CrC6-alkylthio, Cj-Cg-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-allenyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; C3-Cg-alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, Q-Q-alkoxy, CpQ-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC6-alkoxy, CrC6-alkylamino, di(CrC6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; Cj-Cg-cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkyl)-(C|-C4-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6- - ■ 286058 acyloxy, benzoyloxy, benzyloxy, phenoxy, Q-Q-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (Q-Q-cycloalkenylHQ-C^alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC6-alkoxy, C,-Cralkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C^g-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C,-C6-alkylcarbonyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-Q-alky lsulphony 1, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; Q-Cg-alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C8-cycloalkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C1-C4-alkoxy, oxo or phenyl; (C5-C8-cycloalkenyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-Cg-cycloalkyl)-(C|-C3-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C5-C6-cycloalkenylHCrC3-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; - - 28o;nu C,-C8-alkyloxycarbonyl which is oplionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino or C,-C4-alkylthio; Q-Cg-alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; Q-Q-alkinyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, CrC4-alkoxy, oxo or phenyl; CpCg-alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; Q-Cg-alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-Q-alky laminocarbonyl and di(CrQ-alkyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; pyrrolidin-1 -yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-l-yl-carbonyl which are optionally substituted by C,-C4-alkyl, Q-Cg-alkenyl, CrC4-acyl, oxo, thioxo, carboxyl or phenyl; Cj-Cg-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; CrC6-alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; c 0 V U D U or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, aiylsulphonyl, aiylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, aryialkenylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)caibonyl which are substituted by up to five R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 5 C atoms and R6 is defined as above or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaiyloxycarbonyl, (heteroaiylthio)carbonyl, heteroary 1 ami nocar bony 1, heteroaryl alky loxycarbony 1, heteroaryl(alkylthio)carbonyl or heteroarylalkylaminocarbonyl which are substituted by up to three R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms, and R4 are identical or different and are, independently of each other, hydrogen, or C,-C8-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; Q-Cg-alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino, CrC4-alkylthio, C,-C4-alkylsulphonyl, CrC4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, CrC4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, t 2 6 o u n 5 C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkyIthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; aryl. arylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to five R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms and R6 is defined as above, R3 and R4 or R3 and R5 can, in addition, also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 8 C atoms which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C6-alkyl, Q-Q-alkenyl, Q-Q-alkinyl, Q-Q-acyloxy, benzoyloxy, CrC6-alkoxy, oxo, 10 thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur, selenium or substituted nitrogen N-R2, in which R2 can have the abovementioned meanings, with the exception of the compounds in which R3 and R4 simultaneously denote H and compounds in which R2 and R5 denote H and R3 and/or R4 denote arylalkyl and 15 compounds in which X denotes oxygen and R2 and R5 denote hydrogen, are very well suited, in combination with protease inhibitors, for use as medicaments in the control of AIDS and HIV infections. The alkyl groups mentioned in the preceding definitions can be straight-chain or branched. Unless otherwise defined, they preferably contain 1-8, particularly preferably 20 1-6, in particular 1-4, C atoms. Examples are the methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl groups, and the like. The alkenyl groups mentioned in the preceding definitions can be straight-chain or branched and contain from 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, 1-25 methylethenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 3,3-dichloro-2-propenyl and pentadienyl groups, and the like. ■U A 30 611 Foreign Countrigfi -8- t 2b t i ') 0 The alkinyl groups mentioned in the preceding definitions can be straight-chain or branched and contain from 1 to 3 triple bonds. Unless otherwise defined, they preferably contain 2-8, particularly preferably 3-6, C atoms. Examples are the 2-propinyl and 3-butinyl 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 and cyclohexenyl groups. The acyl groups mentioned in the preceding definitions can be aliphatic, cycloaliphalic 10 or aromatic. Unless otherwise defined, they preferably contain 1-8, particularly preferably 2-7, C atoms. Examples of acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyiyl, isobutyiyl, pivaloyl, cyclohexanoyl and benzoyl groups. The aryl groups mentioned in the preceding definitions are preferably aromatic groups 15 having 6-14 C atoms, in particular having 6-10 C atoms, such as, for example, phenyl and naphthyl. Examples of suitable heteroatoms in the abovementioned heterocyclic rings or heteroaryl groups are, in particular, O, S and N, where N-Z, in which Z is H or R5 having the respective, above-described definitions, is present in the case of a N-20 containing ring which is saturated at this position. 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. Examples of suitable heteroaromatic radicals for the heteroaiyl groups mentioned in the preceding definitions are radicals such as 2- or 3-thienyl, 2- or 3-fiiryl, 2-, 3- or 4-25 pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl. Examples of the aralkyl groups listed in the preceding definitions are benzyl, Ijo A 30 Wl Foraign Countrion - 9 - I . . 28C0P8 phenylethyl, naphthylmethyl and styiyl. The abovemeationed substituents R1 to R5 are preferably substituted 3 times, particularly preferably 2 times, in particular once, with the substituents which are given in each case. 5 The ranges for the individual substituents which were previously described as being preferred are likewise preferred for the respective composite substituent definitions (such as, for example, aiylalkoxycarbonyl). Depending on the different substituents, compounds of the formulae I and la can possess several asymmetric carbon atoms. 10 The invention relates, therefore, both to the pure stereoisomers and to mixtures thereof, such as, for example, the affiliated racemate. The pure stereoisomers of the compounds of the formulae I and la can be prepared directly, or resolved subsequently, using known methods or in analogy with known methods. 15 Within the scope of the invention, protease inhibitors denote known peptide analogues of differing structure which are suitable for treating retrovirus-induced diseases. r" ft ^ F(i>r»iga£oui3tP£s - 10- t t f 286 The following may, in particular, be mentioned: 1. (S)-N-[(alphaS)-alpha-[(lR)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydr(>-2( 1 H)-isoquinoliny 1)-1 -hydroxyethy l)phenethy l-2-quinaldamido]succinamide (EP 432 695 A2) 5 2. 2(R}-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl}4-(3-pyridylmethyl)piperaan-l-yl)-4(S)-hydroxy-N-(2(R)-hydroxymdan-1 (S)-y l)pentanamide (L-735524, EP 569 083 Al, EP 541 168 Al) iji a 30 on ruiugii cutmuii» - li - , . 2P N-(Quinolin-2-ylcarbonyl)-asparagine-l(S)-benzyl-3-(3-tert-butyl-l-isobutylureido)-2(R)-hydroxypropylamide (SC 52 151, PCT WO 92/08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al) N l-(2R-hydroxy-3-((3-methylbutyl)methylsulphonyl)amino)-l S-(phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide (AM 11 686, PCT WO 94/04492) (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) 286 0 £ o u J u (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) {3-[(4-Amino-benzenesulphony l)-isobutyl-amino]-l -benzyl-2-hydroxypropyl}-carbamic acid tetrahydro-furan-3-yl ester A 1 c6h5 o nh N-S°2 NH. oh Is ch(ch3)2 (3S,6R)-3-(a-Ethylbenzyl)-6-(a-ethylphenethyl)-4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361) L" ^ y3rgFEg&I!l 11! s -13- t 0 0 |R 0 K O L U Q U J o 9. N-[5-L-[N-(2<juinolinecarbonyl)-L-asparaginyl]arTiino-(4R,3 S)-epoxy-6-phenyl-he: anoyl]-isoleucine (EP 601 486 A) 0CH3 ch, 10. N-tert-butyl-l-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl) asparaginyl]amino]butyl-4(R)-(phenylthio)piperidirie-2(S)-carboxamide 5 (EP 560 268 A) 11. [3"lS-(3,"R*,4",S*)]-N-[r-oxo-l,-(3l,-[rM-oxo-2",-aza-3,"-phenylmethyl-4"1-hydroxy-5"'-(2",-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-l,2,3,4-tetrahydroisoquinoline (EP 609 625 A) I^_A-2£Lg /] rl Fnrai^Cauntrks - 14 - I 28 u 0 5 8 K 12. 2-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulphany lbutyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA) CH, CgHc I s o^nh-c(ch3)3 h" 13. 2H-1,4-Diazepin-2-one,hexahydro-6-hydroxy-1,3,4,7-tetrakis(pheny lmethyl)-, 5 [3S'-(3 .alpha, 6.beta, 7.beta)] (PCT WO 94/08977) oh Quinoxalines of the general formulae (I) and (la) are preferred in which 10 2) n is zero, one, two or three, the individual substituents R1 are, independently of each other, Lin A 30 PM ' Luiu^n Countrion • - 15 - c. U V w v/ fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C4-alkyl, C5-C6-cycloalkyl, CrC4-alkoxy, (CrC4-alkoxy)-{CrC4-alkoxy), C,-C4-alkylthio, C,-C4-alkyl-sulphinyl, CrC4-alkylsulphonyl, nitro, amino, C,-C4-alkylamino, di(CrC4-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, thiomorpholino, imidazolyl, C,-C4-acyl, C,-C4-acyloxy, Cr C4-acylamino, cyano, carbamoyl, carboxyl, (C,-C4-alkyl)-oxycarbonyl, hydroxysulphonyl or sulphamoyl, or are a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxysulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two R6 radicals which are independent of each other, where R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, Q-Cj-cycloalkyl, CrC4-alkoxy, C,-C4-alkylthio, C,-C4-alkyl-sulphinyl, Cr C4-alkylsulphonyl, CrC4-alkylamino, di(C,-C4-alkyl)-amino, (C,-C4-alkyl)-oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is hydrogen, hydroxyl, cyano, amino, C,-C6-alkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Cj-Cg-alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4- • • 28 6 U o 8 acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, Ci-C4-alkylamino, di(CrC4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Cj-Cg-allenyl, Cj-Q-alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, Ci-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, C( Q-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Q-Q-cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(C, -C4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C,-C8-cycloalkyl)-(CrQ-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3-Cg-cycloalkenyl)-(C,-C2-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, 28605 di(C,-C4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C rC6-alky lcarbony 1 which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, Q-Q-alkylamino, di(C1-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Q-Q-alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C6-cycloalkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C5-C6-cycloalkenyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, CrC4-alkoxy, oxo or phenyl; (C3-C6-cycloalkyl)-(C1-C2-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C5-C6-cycloalkenyl)-(C1-C2-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino or C,-C4-alkylthio; Q-Q-alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, Cj-C4-alkoxy, oxo or phenyl; Q-Q-alkinyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; Q-Cg-alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkylaminocarbonyl and di(CrC6-alkyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; pyrrolidin-l-yl or morpholino-, piperidino, piperazinyl- or 4-methy. oiperazin-1 -yl-carbonyl; Q-Q-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C4-alkylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C4-alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; or aryl, aryicarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl which are substituted by up to three R5 radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 5 C atoms and R6 is defined as above or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-fiirylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3- « f tu v v I » furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-fiirylmethyloxycarbonyI or 2- or 3-Ihienylmethyloxycarbonyl which are substituted by up to two R6 radicals which are independent of each other, and R3 and R4 are identical or different and are, independently of each other, hydrogen, CrC6-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, 10 CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4- alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; Q-Cg-alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, CrC4-alkylamino, di(CrC4-alkyl)amino, CrC4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(CrC4-alkyl)amino, CrC4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; 25 or aryl, arylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to three R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms and R6 is defined as Lfc A 30 044 - ruiu|_n rniiiiiijiiy - 20 - above, R3 and R4 can, in addition, also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 7 C atoms which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, CrC4-alkyl, Cj-Q-alkenyl, Q-Q-alkinyl, C,-C4-acyloxy, benzoyloxy, C,-C4-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur or selenium optionally in an isomeric form, in combination with protease inhibitors of the group: 1. (S)-N-[(alphaS)-alpha-[(lR)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2( 1 H)-isoquinolinyl)-1 -hydroxyethyl)phenethyl-2-quinaldamido]succinamide 2. 2(R)-Benzy l-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1 -yl)-4(S)-hydroxy-N-(2(R)-hydroxy indem-1 (S)-yl)pentanamide 3. N-(Quinolin-2-ylcarbonyl)-asparagine-l(S)-benzyl-3-(3-tert-butyl-l-isobutylureido)-2(R)-hydroxypropylamide 4. N1 -(2R-hy droxy-3-((3-rnethy lbutyl)methylsulphonyl)amino)-l S-(phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide 5. (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-l,6-diphenyl-3-hydroxyhexane 6. (R)-N-tert-butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl)amino-4-phenylbutanoyl)-5,5-dimethy 1-1,3-thiazolidine-4-carboxamide 7. £ Q U U 3 {3-[(4-Amino-benzenesulphonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid tetrahydrofuran-3-yl ester 8. (3S,6R)-3-(a-Ethylben2yl)-6-(a-ethylphenethyl)-4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361) 9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine 10. N-tert-butyl-l-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)-asparaginyl]amino]butyl-4(R)-(phenylthio)piperidine-2(S)-carboxamide 11. [3",S-(3,,,R*,4l"S*)]-N-[r-oxo-T-(3,,-[r"-oxo-2IM-aza-3",-phenylmethyl-4'"-hydroxy-5"l-(2"t-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-l,2,3,4-tetrahydroisoquinoline 12. 2-[2-Hy droxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulphanylbutyl]-decahydro-isoquinolme-3-carboxylic acid tert-butylamide 13. 2H-1,4-Diazepin-2-one,hexahydro-6-hydroxy-1,3,4,7-tetrakis(pheny lmethy 1)-, [3S-(3.alpha, 6.beta, 7.beta)] for use as medicaments in the treatment of AIDS and/or HIV infections. Quinoxalines of the general formulae (I) and (la) are particularly preferred in which n is zero, one or two, the individual substituents R1 are, independently of each other, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C,-C4-alkyl, C,-C4-alkoxy, (CpQ-alkoxyKCi-Q-alkoxy), CrC4-alkylthio, nitro, amino, C,-C4-alkylamino, di(C1-C4-alicyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C,-C4-acyl, C|-C4-acyloxy, C,-C4-acylamino, cyano, carbamoyl, carboxyl, (C,-C4-alkyl)-oxycarbonyl5 hydroxysulphonyl or sulphamoyl, are a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two R6 radicals which are independent of each other, where R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, C,-C4-alkoxy, (C,-C4-alkyl)-oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is C,-C6-alkyl which is optionally substituted by C,-C4-alkoxy or C,-C4-alkylthio; Cj-Q-alkenyl, which is optionally substituted by oxo; C3-C6-allenyl, C3-C8-alkinyl, in particular 2-butinyl; C3-C6-cycloalkyl; C5-C6-cycloalkenyl; /, 0 y \j j ij ^ (Q-Q-cycloalkylHQ-Cralkyl), in particular cyclopropylmethyl, which is optionally substituted by C,-C4-alkyl; (CVQ-cycloalkenylHCrQ-alkyl), in particular cyclohexenylmethyl; CI-C6-alkylcarbonyl 5 which is optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C4-alkoxy, Q-Q-alkylamino, C,-C4-alkenylamino, di(C,-C4-alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1 -yl or C,-C4-alkylthio; Cj-Q-alkenylcarbonyl; 10 C, -C6-alkyloxycarbony 1 which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino or C,-C4-alkylthio; Q-Q-alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; 15 C2-C6-alkinyloxycarbonyl, in particular propinyloxycarbonyl or butinyloxycarbonyl; C,-C6-alkylthiocarbonyl; Q-Cg-alkenylthiocarbonyl, in particular allylthiocarbonyl; C,-C6-alkylaminocarbonyl and ditQ-Q-alkyOaminocarbonyl; 20 pyrrolidin- 1-yl or morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1 - yl-carbonyl; (VC6-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl; l^A 30 011 Tuiupt Cauntrk, - 24 - C,-C4-alkylsuIphonyl; 20605 C,-C4-alkenylsulphonyl; or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, aiylsulphonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl which are substituted by up to two R6 radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 3 C atoms and R6 is defined as above or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbony) or 2- or 3-thienylmethyloxycaronyl which are substituted by up to two R6 radicals which are independent of each other, R3 and R4 are identical or different and are, independently of each other, hydrogen, C,-C4-alkyl which is optionally substituted by hydroxyl, mereapto, C,-C4-alkoxy, C,-C4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; Q-Q-alkenyl, aryl, benzyl, thienyl or thienylmethyl which are substituted by up to two R6 radicals which are independent of each other and where R6 is defined as above, I ? 3 8 0 5 8 • • LO R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 6 C atoms which can optionally be substituted by oxo or thioxo, and X denotes oxygen or sulphur 5 optionally in an isomeric form in combination with protease inhibitors of the group: 1. CS)-N-[(alphaS)-alpha-[(lR)-2-[((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2( 1 H)-isoquinolinyl)-l-hydroxyethyl)phenethyl-2-quinaldamido]succinamide 2. 2(R}-Benzyl-5-(2(S)-(N-tert-butylcarbamoyl)-4-(3-pyridylmethyl)piperazin- i -yl)-4(S)-hydroxy-N-(2(R>hydroxyindem-l(S)-yl)pentanamide 10 3. N-(Quinolin-2-ylcarbonyl)-asparagine-l(S)-benzyl-3-(3-tert-butyl-l-isobutylureido)-2(R)-hydroxypropylamide 4. Nl-(2R-hydroxy-3-((3-methylbutyl)methylsulphonyl)amino)-lS-(phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)amino)butanediamide 5. (2S,3S,5S)-5(N-(N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)-15 carbonyl)valiny l)amino)-2-(N-((5-thiazoly l)methoxycarbony l)amino)-1,6- diphenyl-3-hydroxyhexane 6. (R)-N-tert-butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide 30 0*11 rai'oitri ^niintri" -26- . . 286058 7. {3-[(4-Amino-benzenesulphonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid tetrahydro-furan-3-yl ester 8. (3S,6R)-3-{a-Ethylbenzyl)-6-(a-ethylpheneihyl)-4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361) 5 9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine 10. N-tert-buty 1-1 -[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)-asparaginyl]amino]butyl-4(R)-(phenylthio)piperidine-2(S)-carboxamide 11. [3'l,S-(3"lR*,4,,lS*)]-N-[r-oxo-r-(3''-[r,-oxo-2m-aza-3m-phenylmethyl-4"'-10 hydroxy-5"'-(2III-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-l,2,3,4- tetrahydroisoquinoline 12. 2-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulphanylbutyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide 13. 2H-l,4-Diazepin-2-one,hexahydro-6-hydroxy-l,3,4,7-tetrakis(phenylmethyl>, 15 [3S-(3.alpha, 6.beta, 7.beta)] for use as medicaments in the treatment of AIDS and/or HTV infections. The combination which is very particularly preferred for use in the control of AIDS and/or HIV infections is that of S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxazolin-2(lH)-thione of the formula (A) Lc A 30 044 u ruiti^u QjuiHi'iuH - 27- jCXT. <A H3C^ch3 and (S)-N-[(alphaS)-alpha-[(lR)-2-[((3S,4aS,8aS)-3-(tert-butylcaibamoyl)-octahydro-2(lH)-isoquinolinyl)-l-hydroxyethyl)phenethyl-2-quinaldamido]-succinamide (Saquinavir) of the formula (B) The quinoxalines of the general formulae (I) and (la) are known [cf. EP 509 398 Al]. 5 The above-listed protease inhibitors are likewise known [cf. EP 432 695 A2, EP 569 083 Al, EP 541 168 Al, PCT WO 92/08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al, PCT WO 94/04492, PCT WO 94/14436, PCT WO 9411361, 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, as compared with 10 the monotherapy using the individual compounds, in the treatment of retrovirus-induced, in particular, however, HTV-induced, diseases. While the advantageous and superior employment of the combination of these compounds for treating AIDS infections or HIV infections is due in the main to the synergistic antiviral activity of the compounds, it is also due to the fact that the tolerability of the substances, when 15 administered in combination, is unaltered, in the range of toxicity in which 50% of the cells survive, as compared with the tox-50 of the individual components. In the case of other combinations of compounds, for example AZT in combination with ganciclovir, 286058 (A) 28605 B it is known that the use of these combinations results in synergistic toxicity [cf. M.N. Prichard et al.; Antimicrob. Agents Chemotherapy (1991), 15, 1060-1065]. In addition to this, the reduction in the effective dose which results from using the combination of the substances for the treatment diminishes the probability of the 5 development of resistant virus isolates. The invention deals with the combination of two classes of compound of the HIV reverse transcriptase and the HTV protease for preventing and treating infections with HIV and for treating the diseases, such as AIDS-related complex (ARC) or AIDS, which are induced by HTV. 10 HTV infection in cell culture The HIV test was done according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, (1988) , 309 -321]with slight modifications. Normal human blood lymphocytes (PBL's) were enriched using Ficoll-Hypaque and stimulated with phytohaemagglutinin (90 ng/ml) and interleukin-2 (40 U/ml) in RPM 15 1640 containing 20% foetal calf serum. For infection with the infectious HTV, the PBL's were pelleted and the cell pellet was then suspended, for adsorption, in 1 ml of HI virus solution, with this suspension being incubated at 37°C for 1 hour. The virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium at a cell density of 1 * 10s cells per ml. 1 x 104 cells which had 20 been infected in this manner were pipetted into each of the wells of 96-well microtitre plates. As an alternative, H9 cells were used for the antiviral tests in place of the PBL's. The combined effect of the test substances was tested by means of chequerboard titration. 25 The first, vertical row of the microtitre plate contained only growth medium and cells which were not infected but which had otherwise been treated precisely as described f o u U j o ^ * above (cell control). Only HTV infected cells (virus control) in growth medium were added to the second vertical row of the microtitre plate. Hi" remaining wells contained the novel compounds - either alone or in appropriate combinations - in differing concentrations, proceeding from the wells of the 3rd vertical row of the microtitre 5 plate, from which the test substances were further diluted in doubling-dilution steps (50 |il volume per well). In making the combinations, dilutions of the 2nd substance were prepared on a separate 96-well microtitre plate and then pipetted into the previously prepared first plate. 100 |il of the previously prepared HIV-infected cells (see above) were then added to each of these remaining wells. This resulted in test concentrations 10 being covered within approximately the 10-50-fold range above and below the IC^ concentrations. The test mixtures were incubated at 37°C until it was possible, using a microscope, to detect the syncytial formation which is typical for HIV in the host cells in the untreated virus control (between days 3 and 6 after infection). Under these test conditions, some 15 20-50 syncytia were obtained in the untreated virus control while no syncytia were present in the untreated cell control. The supematants were then harvested from the 96-well plate and screened for HIV-specific antigen in an HTV-specific ELISA test (Vironostika HTV antigen, Organon Teknika). The inhibition values were converted into per cent (%) inhibition values in accordance 20 with the cut-off values from corresponding cell controls, virus controls or internal test controls, 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. In order to analyse the synergistic activity of the compounds, the values for the differences between calculated and measured inhibition 25 values were determined for each combination (Prichard, M.N. et al., Antimicrob. Agents Chemoth. (1993), 3Z 540-545). Difference values > zero denote that there was a synergistic effect. As an example, the following results were obtained: Tab. 1 Table indicating the differences in the calculated and measured effects of 30 saquinavir (B) together with the example of the formula (A) 30 ni'1 - Finely Countries" - 30 - cJ 00 0 o Example of formula (A) nM 50 25 12 6 3 1.5 0.7 Saquinavir (B) nM 50 0 0 0 13 32 30 16 25 0 0 0 29 49 20 3 12 0 0 0 37 40 0 0 6 0 0 0 32 57 23 0 3 0 0 0 27 0 0 0 Synergistic activity is obtained for the combinations within the concentration window of 0.7 - 6 nM for the example of the formula (A) and 6 - 50 nM for the protease inhibitor (B). In order to measure the synergistic toxicity of the compounds, substance concentrations were tested which were around the tox-50 value of the individual compounds; the tests involved microscopic examination for cell-toxic features and vital staining using trypan blue. None of the combinations which was examined exhibited any synergistic toxicity. It was found, surprisingly, that a synergistic effect on HIV is obtained by using the combination of the compounds. This was demonstrated, in an exemplary manner, by studies on the combination of the quinoxaline derivative and saquinavir (Tab. 1). The novel combinations can be used in human and veterinary medicine for the treatment and prophylaxis of diseases which are caused by retroviruses. The following may be mentioned, by way of example as indications in human medicine: 1.) The treatment and prophylaxis of retroviral infections in humans. 2.) For the treatment or prophylaxis of diseases (AIDS), and the phases which are associated therewith, such as ARC (AIDS-related complex) and LAS (lymphadenopathy syndrome) which are caused by HIV I (human immunodeficiency virus; previously termed HTLV III/LAV), and also of the immune deficiency and encephalopathy which are caused by the virus. 3.) For the treatment or the prophylaxis of an HTLV-I or HTLV-II infection. 4.) For the treatment or the prophylaxis of the AIDS-carrier state. The following may be listed, by way of example, as indications in veterinary medicine: Infections with a) maedivisna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) c) caprine arthritis-encephalitis virus (in sheep and goats) d) zwoegersiekte virus (in sheep) e) infectious anaemia virus (of the horse) f) infections which are caused by feline leukaemia virus g) infections which are caused by feline immunodeficiency virus (FIV) h) infections which are caused by simian immunodeficiency virus (SIV). The human medicine indications listed in items 2, 3 and 4 above are preferred. The present invention includes pharmaceutical preparations which, in addition to non-U.A30 (1H FWeigii Lounliies - 32- </div>

Claims

9 9 A n n ?< . • j v kJ W* 9 toxic, inert, pharmaceutically suitable carrier substances, contain one or more compounds of the formulae (I) / (la) in combination with one of the given protease inhibitors, or which consist of one or more active compounds of the formulae (I) / (la) and the protease inhibitors, and also processes for producing these preparations, in 5 particular the combination of the test compounds. The active compounds of the formulae (I) and (la), and the protease inhibitors, are to be present in the above-listed pharmaceutical preparations at a concentration which is preferably from about 0.1 to 99.5 % by weight, preferably of from about 0.5 to 95% by weight, of the total mixture. 10 The above-listed pharmaceutical preparations can also contain further pharmaceutical active compounds in addition to the compounds of the formulae (I) / (la) in combination with one of the abovementioned protease inhibitors. The above-listed pharmaceutical preparations are prepared in a customary manner using known methods, for example by mixing the active compound(s) with the carrier 15 substance(s). In general, it has been found to be advantageous, both in human and veterinary medicine, to administer the novel active compound(s) in total quantities of from about 0.5 to about 500, preferably of from 1 to 100, mg/kg of body weight every 24 hours, where appropriate in the form of several single doses, in order to achieve the desired 20 results. A single dose preferably contains the active compound(s) in quantities of from about 1 to about 80, in particular of from 1 to 30, mg/kg of body weight. However, it may be necessary to deviate from the given dosages depending, specifically, on the nature and the body weight of the subject to be treated, on the nature and the severity of the disease, on the nature of the preparation and the administration of the 25 medicament, and on the period of time and/or interval within which the administration takes place. fce A 30 844 - PUldgll Cuuiitncy -33 - WHAT WE CLAIM IS: O F§ „

1. Medicament which contains, in synergistic combination, one or more protease inhibitors selected from: a) (S)-N-[(alphaS)-alpha-[( 1 R)-2-[((3 S,4aS, 8aS)-3-(tert-butylcarbamoy l)octahydn> 2(lH)-iscKquinolinyl)-l-hydroxyethyl)phenethyl-2-quinaldamido]succinamide b) 2(R)-Benzyl-5-(2(S)-(N-tert-butylcarbameyl)-4-{3-pyricfylmdhyl)pipera2in-l-yl)-4(S)-hydroxy-N-(2(R)-hydroxyindem-1 (S)-yl)pentanamide c) N-(Quinolin-2-ylcarbonyl)-asparagine-l(S)-benzyl-3-(3-tert-butyl-l-isobutylureido)-2(R)-hydroxypropylamide d) Nl-(2R-hydroxy-3-((3-methylbutyl)methylsulphonyl)amino)-lS-(phenylmethyl)propyl)-2S-((2-quinolinylcarbonyl)aniino)butanediamide e) (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 f) (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 g) {3-[(4-Amino-benzenesulphonyl>isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid tetrahydro-furan-3-yl ester h) (3S,6R>3-{ a -Ethylbaizy l>6-{a -etl)ylphOTethyl)4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361) 0 N-[5-L-[N^2-quinolinecarbonyl>L^asparaginyl]amin()-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine -fae-A 30 S44- iMW lajBLilni !■« & - 34 intellectual property office of nx 27 JUL 1998 RECEIVED j) N-tert-buty 1-1 -[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)-y' asparaginyl]aniino]butyl-4(R)-(phenylthio)piperidine-2(S)-carboxamide k) [3,"S-(3,"R*,4",S*)]-N-[^-oxo-^-(3"-[^"-oxo-2,"-aza-3l"-phe^ylmethyl-4",-hydroxy-5,"-(2l"-N-tert-butylcarbamido)phenyl]pentyl-4"-methyl)-l, 2,3,4-tetrahydroisoquinoline 1) 2-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulphanylbutyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide m) 2H-1,4-Diazepin-2-one,hexahydro-6-hydroxy-l,3,4,7-tetrakis(phenylmethyl)-, [3S-(3.alpha, 6.beta, 7.beta)] and one or more of the quinoxalines of the general formula (I) and (la) CO and also their tautomaic forms of the general formula la in which intellectual property ofrce of n.z. 27 JUL 1398 RECEIVED -34a 1) n is zero, one, two, three or four, the individual substituents R1 are, independently of each other, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-Q-alkyl, C5-Cg-cycloalkyl, Cj-Q-alkoxy, (Q-Q-alkoxy)-(CrC4-alkoxy), CrC6-alkylthio, C,-C6-alkylsulphinyl, C,-C6-alkylsulphonyl, nitro, amino, azido, CrC6-alkylamino, diCCj-Q-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, Q-Q-acyl, CrC6-acyloxy, Q-Q-acylamino, cyano, carbamoyl, carboxyl, (C,-Q-alkyl)- riNTELLECTUAL PROPERTY umwl 1 Of N.Z. 1 27 JUL 1998 RECEIVED -34b- o p c- r- -lO uU J oxycarbonyl, hydroxysulphonyl or sulphamoyl, a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxysulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five R6 radicals which are independent of each other, where R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C,-C6-alkyl, Q-Q-cycloalkyl, Cr C6-alkoxy, C,-C6-alkylthio, C,-C6-alkylsulphinyl, C,-C6-alkylsulphonyl, CrC6-alkylamino, di(CrC6-alkyl)amino, (CpQ-alkyty-oxycarbonyl, phenyl, phenoxy or 2-, 3- or 4-pyridyl, R2 and Rs are identical or different and are, independently of each other, hydrogen, hydroxyl, C,-C6-alkoxy, aryloxy, C,-C6-acyloxy, cyano, amino, C,-C6-alkylamino, di(C,-C6-alkyl)amino, arylamino, C,-C6-acylamino, C,-C8-alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, CrC6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, cartx>xyl or carbamoyl; Q-Cg-alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, CrC6-alkylamino, di(CrC6-alkyl)amino, CrC6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; Q-Cg-allenyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; Q-Cg-alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; Cj-Cg-cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-Q-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C1-C6-alkyl)amino, CrC6-alkylthio, C,-C6-alkylsulphoriyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkyl)-(C1-C4-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C6-alkoxy, CrC6-alkylamino, di(C,-C6-alkyl)amino, CrC6-alkylthio, CrC6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkenyl)-(C|-C4-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC6-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, C,-C6-alkylthio, C ] -Chalky lsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; C,-C6-alkylcartx)nyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C6-acyloxy, benzoyloxy, benzyloxy, phsnoxy, C,-C6-alkoxy, C,-C6-alkylamino, di(C,-C6-alkyl)amino, Q-Q-alkylthio, C,-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; Q-Cg-alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C8-cycloalkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C5-C8-cycloalkenyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C8-cycloalkyl)-(Ci-C3-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, CrC4-alkoxy, oxo or phenyl; (C5-C6-cycloalkenyl)-(C,-C3-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, CrC4-alkoxy, oxo or phenyl; C,-C8-alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, CrC4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino or C,-C4-alkylthio; Q-Cg-alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, CrC4-alkoxy, oxo or phenyl; Q-Cg-alkinyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; CrCg-alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C|-C4-alkoxy, oxo or phenyl; Q-Cg-alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-Cg-alkylaminocarbonyl and di(CrCg-alkyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; pyrrolidin-l-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-l-yl-carbonyl which are optionally substituted by C,-C4-alkyl, C>-C6-alkenyl, CrC4-acyl, oxo, thioxo, carboxyl or phenyl; Q-Cg-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, Ci-C4-alkoxy, oxo or phenyl; C,-C6-alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C1-C4-alkoxy, oxo or phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, SJ f J U * arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryI(alkylthio)carbonyl which are substituted by up to five R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 5 C atoms and R6 is 5 defined as above or heteroaryl, heteroarylalkyl, heteroaiylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroaryl aminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl or 10 heteroarylalkylaminocarbonyl which are substituted by up to three R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms, R3 and R4 are identical or different and are, independently of each other, hydrogen, or C,-C8-alkyl which is optionally substituted by fluorine, 15 chlorine, hydroxyl, amino, mereapto, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, CrC4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; Q-Cg-alkenyl which is optionally substituted by fluorine or chlorine, 20 hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, 25 hydroxyl, amino, mereapto, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; l^fe A 3CHW^*Fuiugji Cuuiilnur - 39 - C3-Cg-cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; aiyl, arylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to five R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms and R5 is defined as above, R3 and R4 or R3 and R5 can, in addition, also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 8 C atoms which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C6-alkyl, Cj-Q-alkenyl, Qj-Q-alkinyl, C1-C6-acyloxy, benzoyloxy, CrC6-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur, selenium or substituted nitrogen N-R2, in which R2 can have the abovementioned meanings, with the exception of the compounds in which R3 and R4 simultaneously denote H and compounds in which R2 and R5 denote H and R3 and/or R4 denote arylalkyl and compounds in which X denotes oxygen and R2 and R5 denote hydrogen. Medicament according to Claim 1, which contains one or more of the quinoxalines of the general formula (I) and (la), in which

2. ) n is zero, one, two or three, the individual substituents R1 are, independently of each other, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C,-C4-alkyl, Cg-Cg-cycloalkyl, CrC4-alkoxy, (C,-C4-alkoxy)-(CrCr alkoxy), Q-Q-alkylthio, C,-C4-alkyl-sulphinyl, CrC4-alkylsulphonyl, nitro, amino, C,-C4-alkylamino, di(CrC4-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, thiomorpholino, imidazolyl, CrC4-acyl, C,-C4-acyloxy, CrC4-acylamino, cyano, carbamoyl, carboxyl, (CrC4-alkyl)-oxycarbonyl, hydroxysulphonyl or sulphamoyl, or are a phenyl, phenoxy, phenoxy carbonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenoxy-sulphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two R6 radicals which are independent of each other, where R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, Q-Q-cycloalkyl, C,-C4-alkoxy, C,-C4-alkylthio, C,-C4-alkyl-sulphinyl, C,-C4-alkylsulphonyl, C,-C4-alkylamino, di(C,-C4-alkyl)-amino, (C,-C4-alkyl)-oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is hydrogen, hydroxyl, cyano, amino, C,-C6-alkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Cj-Cg-alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C rC4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-allenyl, Q-Cg-alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C3-C8-cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C3-C8-cycloalkyl)-(CrC2-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C;-C4-alkyl)amino, CrC4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; (Q-Q-cycloalkenylXCpQ-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; C,-C6-alkylcarbonyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mereapto, hydroxyl, CrC4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, CrC4-alkylamino, di(C, -C4-alky l)amino, C,-C4-alkylthio, oxo, thioxo, carboxyl or carbamoyl; Q-Q-alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C6-cycloalkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C5-C6-cycloalkenyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; (C3-C6-cycloalkyl)-(CrC2-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; 4 • • 28 80 58 (C5-C6-cycloalkenyl)-(CrC2-alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkyloxycarbonyl which is optionally substituted by fluorine, 5 chlorine, bromine, hydroxyl, Ct-C4-alkoxy, CrC4-alkylamino, di(C,-C4- alkyl)amino or C,-C4-alkylthio; CVC6-alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; Cj-Q-alkinyloxycarbonyl which is optionally substituted by fluorine, 10 chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C6-alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; Q-Cg-alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, CrC4-alkoxy, oxo or phenyl; C,-C6-alkylaminocarbonyl and di(C,-C6-alkyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, CrC4-alkoxy, oxo or phenyl; pyrrolidin-l-yl or morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1 -yl-carbonyl; 20 Q-Q-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; C,-C4-alkylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, CrC4-alkoxy, oxo or phenyl: 1 CUUliliics' -44- Ci-C4-alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C4-alkoxy, oxo or phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, aiylalkenylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl which are substituted by up to three R6 radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 5 C atoms and R6 is defined as above or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2-or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3-or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl or 2- or 3-thienylmethyloxycarbonyl which are substituted by up to two R6 radicals which are independent of each other, R3 and R4 are identical or different and are, independently of each other, hydrogen, C,-C6-alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(CrC4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C2-C8-alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino, C,-C4- alkylthio, CrC4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-Cg-cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; C3-C8-cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mereapto, C,-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, CrC4-alkoxy, CrC4-alkylamino, di(C,-C4-alkyl)amino, C,-C4-alkylthio, C,-C4-alkylsulphonyl, C,-C4-alkylsulphinyl, carboxyl or carbamoyl; or aryl, arylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to three R6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms and R6 is defined as above, R3 and R4 can, in addition, also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 7 C atoms which can optionally be substituted by fluorine, chlorine, hydroxyl, amino, C,-C4-alkyl, Q-Q-alkenyl, Q-Q-alkinyl, C,-C4-acyloxy, benzoyloxy, CrC4-alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur or selenium optionally in an isomeric form. Medicament according to Claim 1, which contains one or more quinoxalines of the general formulae (I) and (la), in which n is zero, one or two, the individual substituents R1 are, independently of each other, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C,-C4-alkyl, C,-C4-alkoxy, (C,-C4-alkoxy)-(C,-C2-alkoxy), C,-C4-alkylthio, nitro, amino, C,-C4-alkylamino, di(CrC4-alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C,-C4-acyl, CrC4-acyloxy, C,-C4-acylamino, cyano, carbamoyl, carboxyl, (C,-C4-alkyl)-oxycarbonyi, hydroxysulphonyl or sulphamoyl, are a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two R6 radicals which are independent of each other, where R5 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C,-C4-alkyl, C,-C4-alkoxy, (CrC4-alkyl)-oxycarbonyl, phenyl or phenoxy, R2 is hydrogen and R5 is C,-C6-alkyl which is optionally substituted by C,-C4-alkoxy or C,-C4-alkylthio; Cj-Q-alkenyl, which is optionally substituted by oxo; C3-C6-allenyl, C 0 V 'J . C3-Cg-alkinyl, in particular 2-butinyl; C3-C6-cycloalkyl; C5-C6-cycloalkenyl; (C3-C6-cycloalkyl)-(Ci-C2-alkyl), in particular cyclopropylmethyl, which is optionally substituted by CrC4-alkyl; (Q-Q-cycloalkenylHCrCj-alkyl), in particular cyclohexenylmethyl; C ,-C6-alky lcarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy, C,-C4-alkoxy, C,-C4-alkylamino, C,-C4-alkenylamino, di(C,-C4-alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl or C,-C4-alkylthio; Q-Q-alkeny lcarbonyl; C, -C6-alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, C,-C4-alkoxy, C,-C4-alkylamino, di(C,-C4-alkyl)amino or C,-C4-alkylthio; C2-C6-alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; C2-C6-alkinyloxycarbonyl, in particular propinyloxycarbonyl or butiny loxycarbonyl; CrC6-alkylthiocarbonyl; Q-Q-alkenylthiocarbonyl, in particular allylthiocaibonyl; C,-C6-alkylaminocarbonyl and di(C,-C6-alkyl)aminocarbonyl; pyrrolidin-l-yl or morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-l-yl-carbonyl; C^-Q-alkenylaminocarbonyl and di(C,-C6-alkenyl)aminocarbonyl; CrC4-alkylsulphonyl; C,-C4-alkenylsulphonyl; or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl which are substituted by up to two R6 radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to

3. C atoms and R6 is defined as above or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2-or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 2-, 3-or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl or 2- or 3-thienylmethyloxycaronyl which are substituted by up to two R6 radicals which are independent of each other, and R3 and R4 are identical or different and are, independently of each other, n hydrogen, <" & fh f) ^ C,-C4-alkyl U which is optionally substituted by hydroxyl, mereapto, C,-C4-alkoxy, CrC4-alkylthio, CrC4-alkylsulphonyl, C,-C4-alkyIsulphinyI, carboxyl or 5 carbamoyl; Q-Q-alkenyl, aryl, benzyl, thienyl or thienylmethyl which are substituted by up to two R6 radicals which are independent of each other and where R6 is defined as above, 10 R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring having from 3 to 6 C atoms which can optionally be substituted by oxo or thioxo, and X denotes oxygen or sulphur 15 optionally in an isomeric form.

4. Medicament according to Claims 1 to 3, which contains, as protease inhibitor, (S)-N-[(alphaS)-alpha-[(1 R)-2-[((3 S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydr o-2(l H)-isoquinolinyl)-l -20 hydroxyethyl)phenethyl-2-quinaldamido]succinamide » asicnsiiJKtniiti - 56 intellectual pflopfflty ofrce of nz 2 7 JUL 1998 RECEIVED

5. Medicament which contains, in synergistic combination, S-4-isopropoxycaibonyl-6-methoxy-3 -(methylthio-methyl)-3,4-dihydroquinoxazolin-2( 1 H)-thione of the formula (A) h3c-o NH (A) 10 and (S)-N-[(alphaS)-alpha-[( 1 R)-2-[((3 S,4aS,8aS)-3-(tert-butylcarbamoyl)-octahydro-2( 1 H)-isoquinolinyl)-1 -hydroxyethy l)phenethy 1-2-quinaldamido]-succinamide (Saquinavir) of the formula (B) (B). intellectual property ofrce of nz 2 7 JUL 1998 RECEIVED Ll A. 30 014 ■ffum'njii -51 - / o p c. 0 5 8

6. A medicament according to claim 1 or claim 5 substantially as herein described or exemplified.