AU710158B2 - Use of quinoxalines in combination with protease inhibitors as medicaments for treating AIDS and/or HIV infections - Google Patents

Description

Use ofquinoxalines in combination withprotea inhibits amedicaments 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 (HIV) 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 S. which are elicited by other viruses, such as, for example, herpes viruses (HSV I and II) and cytomegalovirus (CMV), or O.I. which are elicited by bacteria, fungi or 15 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 HIV replication 20 (Roberts, N.A. et al., Science (1990) 248, 358 361; Lam, P.Y.S. et al., Science S(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 Le A 3 0 844 ForeigpCountries

-I-

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 and (la) I (I)

R

2 and also their tautomeric forms of the general formula Ia N X R R2 N (a)

R

R

in which 1) n is zero, 15 one, two, three or four, Le A 30 844 Foreign Countries -2the individual substituents R' are, independently of each other, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl,

C

1

-C

8 -alkyl, C- 5

-C

8 -cycloalkyl, C 1

-C

6 -alkoxy, (C 1

-C

6 -alkoxy)-(C 1

-C

4 -alkoxy), C I

C

6 -alkylthio,

CI-C

6 -alkylSUlphinyl, Ci-C 6 -alkylsulphonyl, nitro, amino, azido, C,-

C

6 -alkylamino, di(C 1

-C

6 -alkyl)amino, piperidino, morpholino, l-pyrrolidinyl, 4methylpiperazinyl, thiomorpholino, imidazolyl., triazolyl, tetazolyl,

C

1

-C

6 -aCYl,

CX-

6 -acyloxy,

C

1

-C

6 -acylamino, cyanio, carbamnoyl, carboxyl,

(C

1

-C

6 -alkyl)- Oxycarbonyl, hydroxysulphonyl or sulphamoyl, or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsuiphinyl, phenylsuiphonyl, phenoxysuiphonyl, phenylsulphonyloxy, anilinosulphonyl, phenylsuiphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five RW radicals which are independent of each other, where RW can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1

-C

6 -akl, C 3

-C

8 -cycloalkyl,

C

1

-C

6 alkoxy,

C

1

-C

6 -alkylthiio,

C

1

-C

6 -alkylsulphinyl,

CI-C

6 -alkylsulphonyl,

C

1

-C

6 alkylamino, di(CI-C 6 -alkyl)anino,

(CI-C

6 -alkyl)-oxycarbonyl, phenyl, phenoxy or 3- or 4-pyridyl, 20 R 2 and RW are identical or different and are, independently of each other, hydrogen, hydroxyl,

C

1

-C

6 -alkoxy, aryloxy, C 1

-C

6 -acyloxy, cyano, amino, C I-C 6 alkylamino, di(C 1

-C

6 -alkyl)amino, arylamino,

C

1

-C

6 -acylamino,

C

1

-C

8 -alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, *~*mercapto, hydroxyl,

CI-C

6 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

CI-C

6 alkoxy, Cl-C 6 -alkylamino, di(C 1

-C

6 -alkyl)amino,

C

1

-C

6 -alkylthio,

C,-C

6 alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; LeA 3 0844 -Foreign Counties -3 q-C 8 -alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amidno, mercapto, hydroxyl, C 1

-C

6 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

6 -alkoxy, C 1

-C

6 -alkylamino, di(C 1

-C

6 -alkyl)amino,

C

1

-C

6 -alkylthio, C 1

-C

6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -allenyl which is optionally substituted by fluorine, chlorine or hydroxyl,

CI-C

4 -alkoxy, oxo or phenyl;

C

3

-C

8 -alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, Cyano, amino, mercapto, hydroxyl, C 1

-C

6 acyloxy, benz7oyloxy, benzyloXy, phenoxy, C 1

-C

6 -alkoxy, C 1

-C

6 -alkylamino, di(C 1

-C

6 -alkyl)amino,

CI-C

6 -alkylthio, C 1

-C

6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamnoyl;

C

3

-C

8 -cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amidno, mercapto, hydroxyl, C,-C 6 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

6 -alkoxy, C 1

-C

6 -alkylamino, di(C 1

-C

6 -alkyl)amino,

C

1

-C

6 -alkylthio,

C

1

-C

6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1

-C

6 acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, Cl-C 6 -alkylamino, 25 di(CI-C 6 -alkyl)amino,

CI-C

6 -alkylthio,

C

1

-C

6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamnoyl;

(C

3

-C

8 -cycloalkyl)-(C,-C 4 -alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1

-C

6 is A30 844- ForeipnCountries -4acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, CI-C 6 -alkylamiiio di(C 1

-C

6 -alkyl)amino,

C

1

-C

6 -alkylthio,

C

1

-C

6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamoyl;

(C

3

-C

8 -cycloalkenyl)-(C 1

-C

4 -alkYl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, CI-C 6 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

6 -alkoxy, CI-C 6 -alkylanho, di(C 1

-C

6 -alkyl)amino,

C

1

-C

6 -alkylthio,

C

1

-C

6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamnoyl;

C

1

-C

6 -alkylcarbonyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl,

C

1

-C

6 acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, C 1

-C

6 -alkylanmino, di(C 1

-C

6 -alkyl)aniino,

C

1

-C

6 -alkylthio,

C

1

-C

6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl;

C

2

-C

8 -alkenylcarbonyl which is optionally substituted by fluorine, chlorine or :hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl;

(C

3

-C

8 -cycloalkyl)carbonyl which is optionally substituted by fluorine, chlorine *or hydroxyl,

C,-C

4 -alkoxy, oxo or phenyl;

(C

5

-C

8 -cycloalkenyl)carbonyl which is optionally substituted by fluorine, .*chlorine or hydroxyl, C 1

-C

4 -alkoxy, oxo or phenyl;

(C

3

-C

8 -cycloalkyl)-(Cl-C 3 alkyl)carbonyI which is optionally substituted by fluorine, chlorine or hydroxyl, C 1

-C

4 -alkoxy, oxo or phenyl;

*(C

5

C

6 cyclOalkenyl-(cl-C 3 alyl)cabonyI which is optionally substituted by fluorine, chlorine or hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; Le A 3 0 844- ForeigiCountries -5

CI-C

8 -alkyloxycarbonyl which is optionally substituted by fluorine, -chlorine, bromine, hydroxyl,

C!-C

4 -alkoxy, Ci-C 4 -alkylan-dno, di(CI-C 4 -alkyl)amj'no or

C,-C

4 -alkylthio;

Q--C

8 -alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl;

C

2

-C

8 -alkinyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

CI-C

4 -alkoxy, oxo or phenyl; Ci-C 8 -alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

CI-C

4 -alkoxy, oxo or phenyl;

C

2

-C

8 -alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; Cl-C8-alkylaminocarbonyl and di(Ci-C 8 -alkyl)aminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; pyrrolidin-1I-yl, morpholino-, piperidio-, piperazinyl- or 4 -methylpiperazin- -ly carbonyl which are optionally substituted by CI-C 4 -alkyl, Q-C 6 -alkenyl,

C

1

-C

4 acyl, oxo, thioxo, carboxyl or phenyl;

C

2

-C

8 -alkenylan'inocarbonyl and di(Ci-C 6 -alkenyl)aminocarbyjnyl which are optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; Cl-C 6 -alkeylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; LeA 30 844 -ForeinContie -6or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylIth io)th io carbonyl1, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsuiphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl which are substituted by up to five W 6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 5 C atoms and W 6 is defined as above or heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyi, (heteroarylthio)carbonyl, h e te r oarylIainno c arb on yl1 h e te r oa r yIaIkyIo x yc ar b on yl, heteroaryl(alkylthio)carbonyl or heteroarylalkylanminocarbonyl which are substituted by up to three W 6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms,

R

3 and RW are identical or different and are, independently of each other, hydrogen, or C 1

-C

8 -alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 -alkoxy, C 1

-C

4 -alkylaniino, di(C 1

-C

4 -alkyl)amino,

C

1

-C

4 -alkylthio,

C,-C

4 alkylsulphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbarnoyl; 0 0.

C

2

-C

8 -alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 alkoxy,

CI-C

4 -alkylamino, di(C 1

-C

4 -alkyl)arnino,

C

1

-C

4 -alkylthio,

C

1

-C

4 alkylsulphonyl, Cl-C 4 -alkylsulphiyl, carboxyl or carbamnoyl;

C

3

-C

8 -cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

CI-C

4 alkoxy, CI-C 4 -alkylanho, di(CI-C 4 alkyl)aniino,

C

1

-C

4 -alkylthio,

C

1

-C

4 alkylsulphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, Le A 3 0 844-.Foreim. Countries -7-

C,-C

4 -alkoxy, C 1

-C

4 -alkylamino, di(CI-C 4 -alkyl)amino, C 1

-C

4 -alkylthio, C 1

-C

4 alkylsulphonyl,

C-C

4 -alkylsulphinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to five

R

6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 3 C atoms and R 6 is defined as above,

R

3 and R 4 or R 3 and R 5 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-C 6 -alkyl,

C

2

C

6 -alkenyl, C2-C 6 -alkinyl, C-C 6 -acyloxy, benzoyloxy, Ci-C 6 -alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur, selenium or substituted nitrogen N-R 2 in which R 2 can have the abovementioned meanings, with the exception of the compounds in which R 3 and R 4 simultaneously denote H and compounds in which R 2 and R 5 denote H and R 3 and/or R 4 denote arylalkyl and compounds in which X denotes oxygen and R 2 and R 5 denote hydrogen, are very well suited, in combination with protease inhibitors, for use as medicaments in the control of AIDS and HIV infections.

*9 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, 2,3dimethyl-2-butenyl, 3 3 -dichloro-2-propenyl and pentadienyl groups, and the like.

Le A 30 844 ForeignCountries 8- 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 2propinyl 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, cycloaliphatic 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, butyryl, isobutyryl, pivaloyl, cyclohexanoyl and benzoyl groups.

The aryl groups mentioned in the preceding definitions are preferably aromatic groups 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, 0, S and N, where N-Z, in which Z is H or R having the respective, above-described definitions, is present in the case of a Ncontaining 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 heteroaryl groups mentioned in the preceding definitions are radicals such as 2- or 3-thienyl, 2- or 3-furyl, 3- or 4- 25 pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.

Examples of the aralkyl groups listed in the preceding definitions are benzyl, Le A 30 844 Foreign Countries 9 phenylethyl, naphthylmethyl and styryl.

The abovementioned substituents

R

1 to R 5 are preferably substituted 3 times, particularly preferably 2 times, in particular once, with the substituents which are given in each case.

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, arylalkoxycarbonyl).

Depending on the different substituents, compounds of the formulae I and Ia can possess several asymmetric carbon atoms.

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 Ia 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.

*OO*

'Pet.

S.

S *5 Le A 30 844 Foreign Countries TIhe following may, in particular, be mentioned: 1. (S)-N-[(alPhaS)-alpha-[( S,4aS,8aS)-3-(tert-butycarbamoy)ayd, 2( lH}-isoquinolinyl)-l1-hydroxyethyl)phenethyl-2-quinaldanjdolsucc ide (EP 432 695 A2) 2. 2 (R)-Beflzyl-5-(2(S).(Nertbutylcarbamoy1)4(3pydyeffyl)ppazi-y-) 4 (S)-hydroxy-N-(2(R~hydroxyindaw. 1(S)-yl)pentananmide (L-735524, EP 569 083 Al, EP 541 168 Al) is A30 844 -Foreim Countries 11 3. N-(Quinolin- 2 -ylcarbonyl)-asparagine- 1 (S)-benzyl-3-(3-tert-butyl.I 1isobutylureido)-2(R)-hydroxypropylaniide (SC 52 151, PCT WO 92/08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al)

CH

3 4. N I 2 R-hydroxy-3-((3-methylbutyI)methylsulphonyl)amino) is- (phenylmethyl)propyl)-2 2 -quinolinyicarbonyl)amino)butanediamide (AM 11 686, PCT WO 94/04492) (2S,3S,5 S)-5(N-(N-((N-methy1-N-((2-isopropy14-oxazolyl)methyl)amino)- 1,6diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/1443 6) LeA 30844 -ForeigniCountries -12yloxyacetyl)amino-3 -methylthiopropanoyl)amino.4-phenylbutanoyl).

5 dimethyl-1,3-thiazolidine-4-carboxaniide (KNI 272 Nippon Mining) H3c

CH

3

N

3

CHHN

0- CH 3H 0 ~H

OH

NHIr NH

N,

H

0 0 7. 3 4 -Amnino-benzenesulphonyl)-isobutyl-am-ino]- 1 -benzyl-2-hydroxypropyl carbamnic acid tetrahydro-fuiran-3-yl ester 0 J NH Wo 2

N

OH CH(CH 3 2 8. (3S,6R)-3-(a -Ethylbenzyl)-6-(a -ethiylphenety)4hydroxy2Hpyran2one ('11 11 478, PCT WO 9411361)

OCH

3 Le A 30 844 Foreign Countries -1 13 9. N-5L[4-unlncroy)Laprgnlain-4 3 x--hnl hexanoyl]-isoleucine (EP 601 486 A) N NH HN NHH

'A

OCH 3 0 ~NH 0 0CH 0 N-tert-butyl-l1-[2-(R)-hydroxy-4-phenyl)-3(S)- 2 -quinolinylcarbonyl) asparaginyl] amino] butyl-4(R)-(pheny Ithio)piperidine-2(S)-.carboxami de (EP 560 268 A) 0i c 11. [3 1'-oxo-l1'-(3 "-oxo-2"'-aza-3"'-phenylmethyl.4"..

"'-N-ter-t-butylcarbamido)phenyl]pentyl-4t'-methyl)- 1,2,3,4tetrahydroisoquinoline (EP 609 625 A)

CH

3

OH

Le A 30 844 Foreign Countries 14 12. 2-2Hdoy3(-yrx--ehlbezyaiO4Pe~slhnluy] decahydro-isoquinoline-3-.carboxylic acid tert-butylanMde (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA)

C

6 H

CH

3 0 ti 0 NH-C(CH 3 3 HO Ht" N OHH

H

13. 2H- 1 4 -Diazepin-2-onehexahydro-6hydoxy-. 1 3 ,4, 7 -tetrakis(phenylmethyl), [3S'-(3.alpha, 6.beta, 7.beta)] (PCT WO 94/08977) 0

N

NN

:OH

Quinoxalines of the general formulae and (la) are preferred in which 2) n is zero, one, two or three, the individual substituents RI are, independently of each other, is A30 844 -Foreim Countries -15 fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C 1

-C

4 alkyl, C 5

-C

6 -cycloalkyl,

C

1

-C

4 -alkoxy, (C 1

-C

4 -alkox4)(C-C 4 -alkoxy), C I-C 4 alkyitlio, C 1

-C

4 -alkyl-sulphinyl, Cl-C 4 -alkylsulphonyl, nitro, amino, C 1

-C

4 alkylamino, di(C 1

-C

4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4methyl-piperazinyl, thiomorpholino, inidazolyl, C 1

-C

4 -acyl, C 1

-C

4 -acyloxy, C 1

C

4 -acylamino, cyano, carbamnoyl, carboxyl,

(CI-C

4 -alkyl)-oxycarbonyl, hydroxysuiphonyl or suiphamoyl, or are a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsuiphinyl, phenylsuiphonyl, phenoxysuiphonyl, phenylsuiphonyloxy, anilinosuiphonyl, phenylsuiphonylam-ino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. radical which is substituted by up to two RW radicals which are independent of each other, where R can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C 1

-C

4 alkyl, C 3

-C

7 -cycloalkyl,

C,-C

4 -alkoxy, C 1

-C

4 -alkylthio, C 1

-C

4 -alkyl-sulphinyl,

C

1 I

:C

4 -alkylsulphonyl,

C

1

-C

4 -alkylamino, di(C 1

-C

4 -alkyl)-amino,

(C

1

-C

4 -alkyl)oxycarbonyl, phenyl or phenoxy,

R

2 is hydrogen and W is hydrogen, hydroxyl, cyano, amino, Cj-C 6 -alkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 :acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

4 -alkoxy, C 1

-C

4 -alkylamino, di(C 1

-C

4 -alkyl)amino,

CI-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; Q2-C 8 -alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1

-C

4 Le A 3 0 844 -ForeigiCountries 16acyloxy, benzoyloxy, benzyloxy, phenoxy, Ci-C 4 -alkoxy, C 1

-C

4 -alkylaimino, di(C 1

-C

4 -alkyl)amino,

C,-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl;

C

3

-C

8 -allenyl, Q3-C 8 -alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl,

C

1

-C

4 acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 -alkoxy,

CI-C

4 -alkylamino, di(C 1

-C

4 -alkyl)aniino,

CI-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, Mercapto, hydroxyl,

C

1

-C

4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1

-C

4 -alkoxy, Cl-C 4 -alkylan-fio, di(C 1

-C

4 -alkyl)anho,

C

1

-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl;

C

3

-C

8 -cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl,

CI-C

4 acyloxy, benzoyloxy, benzyloxy, phenoxy,

CI-C

4 -alkoxy, C 1

-C

4 -alkylamino, di(C 1

-C

4 alkyl)an-ino,

CI-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl;

(C

3

-C

8 -cycloalkyl)-(Cl-c2.alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C,-C 4 000000acyloxY, benzoyloxy, benzyloxy, phenoxy, C 1

-C

4 -alkoxy, Cl-C 4 -alkylamino, di(CI-C 4 -alkyl)amino,

C

1

-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl;

(C

3

-C

8 -cycloalkenyl).(C 1 -Q,-alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, Cyano, amino, mercapto, hydroxyl,

C

1

-C

4 acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 -alkoxy, C 1

-C

4 -alkylamino, Le A30 844 -ForeipnCountries 17di(C 1

-C

4 -alkyl)ano,

CI-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl; Cl-C 6 -alkylcarbonyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl,

C

1

-C

4 acyloxy, benzoyloxy, benzyloxy, phenoxy,

CI-C

4 -alkoxy, Ci-C 4 -alkylan-ino, di(CI-C 4 -alkyl)amino,

C

1

-C

4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl;

C

2

-C

6 -alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl;

(C

3

-C

6 -cyclOal)carbnyl which is optionally substituted by fluorine, chlorine or hydroxyl,

CI-C

4 -alkoxy, oxo or phenyl;

(C

5

-C

6 -cycloalkenyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; (C-6CColy)(C-2aklcroy which is optionally substituted by fluorine, chlorine or hydroxyl,

CI-C

4 -alkoxy, oxo or phenyl; (C-6ccoley C-2aklcroy which is optionally substituted by fluorine, chlorine or hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; Ci-C 6 -alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl,

CI-C

4 -alkoxy, CI-C 4 -alkylaimino, di(C 1

-C

4 -alkyl)amino or

C,-C

4 -alkylthio;

C

2

-C

6 -alkenyloxycarbonyl which is optionally substituted by fluorine, chlorine, to 0.

hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl;

C

2

-C

6 -alkinyloxycarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; Le A30 844 -ForeiW Countries -18-

C

1

-C

6 -alkylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; Q2-C 6 -alkenylthiocarbonyl which is Optionally substituted by fluorine, chlorine, hydiroxyl,

CI-C

4 -alkoxy, oxo or phenyl; Ci-C 6 -alkYlaminocarbonyl and di(CI-C 6 -alkYl)aMinocaribOnyl Which are optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl; pyrrolidin- 1 -yl or morpholino-, piperidino-, piperazinyl- or 4 -methylpiperazin_ 1yl-carbonyl;

C

2

-C

6 -alkenylaniinocarbonyl and di(CI-C 6 -alkenyl)anminocarbonyl which are optionally substituted by fluorine, chlorine, hydroxyl,

C

1

-C

4 -alkoxy, oxo or phenyl;

C

1

-C

4 -alkylsulphonyl which is Optionally substituted by fluorine, chlorine, hydroxyl, C 1

-C

4 -alkoxy, oxo or phenyl;

CI-C

4 -alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C 1

-C

4 -alkoxy, oxo or phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, *(ar yIt h io) t h iocarb o nyl1 aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl. which are substituted by up to three RW radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 5 C atoms and RW is defined as above or 1- or 2-naphthylmethyl, 3- or 4-picolyl, 2- or 3-futylmethyl, 2- or 3thienylmethyl, 2- or 3 -pyrrolylmethyl, 3- or 4 -pyridylcarbonyl, 2- or 3- LA 30 844 -ForeiwinCountie 19furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 3- or 4picolyloxycarbonyl, 2- or 3 -fuirylmethyloxycarbonyl or 2- or 3thienylmethyloxycarbonyl which are substituted by up to two W 6 radicals which are independent of each other, and

R

3 and Wi are identical or different and are, independently of each other, hydrogen,

CI-C

6 -alkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 -alkoxy,

C

1

-C

4 alkylamino, di(C 1

-C

4 -alkyl)amino,

CI-C

4 -alkylthio, Cl-C 4 -alkylsulphonyl,

C

1

-C

4 alkylsuiphinyl, carboxyl or carbamoyl;

C

2

-C

8 -alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 alkoxy, C,-C 4 -alkylan'ino, di(C 1

-C

4 -alkyl)amino,

C,-C

4 -alkylthio,

C

1

-C

4 9 9alkylsuiphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, mercapto,

C

1

-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C!-C

4 alkoxy,

C

1

-C

4 -alkylan-ino, di(CI-C 4 -alkyl)amino,

C,-C

4 -alkylthio,

C,-C

4 alkylsuiphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbamoyl;

C

3

-C

8 -cycloalkenyl which is optionally substituted by fluorine or chlorine, :hydroxyl, amino, mercapto,

CI-C

4 -acyloxy, benzoyloxy, benzyloxy, phenoxy,

C

1

-C

4 -alkoxy,

CI-C

4 -alkylamino, di(C 1

-C

4 -alkyl)amino,

C,-C

4 -alkylthio,

C

1

-C

4 alkylsulphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbamoyl; or aryl, axylalkyl, heteroaryl or heteroarylalkyl which are substituted by up to three Wi radicals which are independent of each other, and where the alkyl raical can in each case connfrom Ito 3C aomsand W is defmed a Le A30 844 -Foreim Countre above, RW and RW 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, CI-C 4 -alkyl, Q2-C 4 -alkenyl, Q2-C 4 -alkinyl, C 1

-C

4 -acyloxy, benzoyloxy,

C,-C

4 -alkoxy, oxo, thioxo, carboxyl, carbamnoyl or phenyl, X denotes oxygen, sulphur or selenium optionally in an isomeric form, in combination with protease inhibitors of the group: 1. (S)-N-II(alphaS)-alpha-[(

S,

4 aS,8aS)-3-(tert-butylcarbamoyl)octaydo 2(1 H}-isoquinolinyl)-l1-hydroxyethyl)phenethyl-2-quinaldamdo] succinande 2. 2()Bny--2S 1 etbtlabaol--3prdlmty~ieai--yl)- 4. 4 (S)-hydroxy-N-(2(R)..hydroxyindern 1(S)-yl)pentanamide 3. N-(Quinolin-2-ylcarbonyl)..asparagine 1 (S)-benzyl-3-(3-tert-butyl.. 1 9isobutylureido)-2(R)-hydroxypropylamde 4. Ni 2-yrxy3(3mthluy~etyslhny mn)iS- 5. (2S,3 S,5S)5N(- -ehlN(2ioroy--xzllmty~mn) S lvliy~mn)--N(5thaoy~etoyabny~mn) 1,6diphenyl-3-hydroxyhexane S@ 20 6. (R)-N-tert-butyl-3-((2S,3

S)-

2 -hydroxy-3-N-((R)-2-.N-(isoquinolin.5yloxyacetyl)amino-3-methylthiopropanoyl)amino-.4phenylbutanoyl)-5, dimethyl- 1 3 -thiazolidine-4-carboxmnide Le A 30 844 Foreign Countries 21 7. 3 4 -Amino-benzenesulphonyl)-isobutyl-aino]. 1-benzyl-2-hydroxypropyl carbamic acid tetrahydro-ftuan-3-yl ester 8. (3S,6R)-3-(a -Ethylbenzyl)-6-(a -ethylphenethy)4hydroxy-2Hpya-2-one

(VB

11 478, PCT WO 9411361) 9. N-5L[-2qioieabnl--saaiy~nio(FS-px--hnl hexanoyl]-isoleucine N-tert-butyl- hdoy4penl-()[N(-uioiycroy) asparaginyl]aninojbutyb4(R}.phenyltho)piperdife.2(S)carboxamid 11. 1 1 t -oxo-2"'-aza-3 "'-phenylmethyl-4"'hydroxy-5" 2 "-N-tert-butylarbamido)phenyllpentyl4"-methyl)- 1,2,3,4tetrahydroisoquinoline 12. 2-2Hdoy3(-yrx--ehlbnolmn)4peyslhnluy] decahydro-isoquinoline.3-carboxylic acid tert-butylamide :13. 2H- 1 4 -Diazepin-2-one,hexahydro6hydrox.. 1 3 4 ,7-tetrakis(phenylmethyl)-, [3S-(3.alpha, 6.beta, 7.beta)] for use as medicamnents in the treatment of AIDS and/or FIIV infections.

Quinoxalines of the general formulae and (la) are particularly preferred in which n is zero, 20 one or two, the individual substituents R' are, independently of each other, Le A 3 0844 -Foreian.Countries, -22fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, C 1

-C

4 -alkyi, C,_C 4 alkoxy, (Ci-C 4 -alkoxy)-(C 1

-C

2 -alkoxy), cl-C 4 -alkylthio, nitro, amino, C 1

-C

4 alkylamino, di(C 1

-C

4 -alkyl)amino, piperidino, morpholino, 1-pyrrolidinyl, 4methylpiperazinyl, C ,-C 4 -acyl, CI-C 4 -acyloxy,

C

1

-C

4 -acylamino, cyano, carbamnoyl, carboxyl, (C I-C 4 -alkyl)-oxycarbonyl, hydroxysuiphonyl or suiphamoyl, or are a phenyl, phenoxy, phenylthio, phenylsuiphonyl, phenoxysuiphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two W 6 radicals which are independent of each other, where W{ can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C 1

-C

4 alkyl, CI-C 4 -alkoxy, (C 1

-C

4 -alkyl)-oxycarbonyl, phenyl or phenoxy, P3 is hydrogen and RW is

CI-C

6 -alkYl which is optionally substituted by C 1

-C

4 -alkoxy or C 1

-C

4 -alkylthio; C2-C 6 -alkenyl, which is optionally substituted by oxo;

C

3

-C

6 -allenyl,

C

3

-C

8 -alkinyl, in particular 2-butinyl;

C

3

-C

6 -cycloalkyl;

C

5

-C

6 -CYCloalkenyl; Le A30 844 -Foreign Countties -23-

(C

3

-C

6 -cycloalkyl)-(C 1

-C

2 -alkyl), in particular cyclopropylmethyl, which is optionally substituted by C 1

-C

4 -alkyl;

(C

3

-C

6 -cycloalkenyl)-(C 1

-C

2 -alkyl), in particular cyclohexenylmnethyl;

C

1

-C

6 -alkylcarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, benzyloxy, phenoxy,

CI-C

4 -alkoxy,

C

1

-C

4 -alkylamio, Cl-C 4 -alkenylamino, di(C 1

-C

4 alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4 -methylpiperazini1yi or

C

1

-C

4 -alkylthio; Q2-C 6 -alkenylcarbonyl;

CI-C

6 -alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl,

CI-C

4 -alkoxy, C 1

-C

4 -alkcylamino, di(CI-C 4 -alkyl)amino or

C

1

-C

4 -alkylthio;

C

2

-C

6 -alkenyloxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl;

C

2 C-alkinyloxycarbonyl, in particular propinyloxycarbonyl or butinyloxycarbonyl;

C

1

-C

6 -alkylthiocarbonyl;

CX-

6 -alkenylthiocarbonyl, in particular allylthiocarbonyl;

C

1

-C

6 -alkylaminocarbonyl and di(CI-C 6 -alkyl)anlinocarbonyl; 9 20 pyrrolidin-1I-yl or morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-lI- 9. yl-carbonyl; q-C 6 -alkenylaminocarbonyl and di(C 1

-C

6 -alkenyl)aniinocarbonyl; Le A 30844 -Foreign-Countries -24- Cl-C 4 -alkylsulphonyl;

C,-C

4 -alkenylsulphonyl; or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsuiphonyl, arylalkyl, in particular benzyl, phenylethyl, aiylalkenyl, arylalkylcarbonyl, aiylalkoxycarbonyl or aryl(alkylthio)carbonyl which are substituted by up to two RW radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 3 C atoms and W 6 is defined as above or 1- or 2-naphthylmethyl, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3thienylmethyl, 2- or 3-pyrrolylmnethyl, 3- or 4-pyridylcarbonyl, 2- or 3furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 3- or 4picolyloxycarbonyl, 2- or 3 -fturylmethyloxycarbonyl or 2- or 3thienylmethyloxycaronyl which are substituted by up to two W( radicals which are independent of each other, and

R

3 and W 4 are identical or different and are, independently of each other, hydrogen, 20

C,-C

4 -alkyl :which Is optionally substituted by hydroxyl, mercapto, C 1

-C

4 -alkoxy, C 1

-C

4 alkylthio, C 1

-C

4 -alkylsulphonyl,

C

1

-C

4 -alkylsulphinyl, carboxyl or carbamoyl; q-C 6 -alkenyl, aryl, benzyl, thienyl or thienylmethyl which are substituted by up to two R radicals which are independent of each other and where RI is defined as above, Le A 30 844 Foreign Countries 25 RW and W 4 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 optionally in an isomeric form in combination with protease inhibitors of the group: 2(1 H)-isoquinolinyl)-l-yrxet1 hnthl2qinlaiosucnmd 2. 2()Bny--2S 1 etbtlabaol--3prdlmty~ieai--yl)- 4 (S)-hydroxy-N-(2(R)-hyclroxyindem.. 1(S)-yl)pentanamjde 3. N-(Quinolin-2-ylcarbonyl).asparagine- 1(S)-benzyl-3-(3-tert-butyl 1isobutylureido)-2(R)hydroxypropylrnde 4. N I 1(Rhdoy3(3mtybty~ehlupoy~mn) Scarbonyl)valinyl)amino)-.2.(N((5-.thiazolyl)methoxycarbonyl)amjfl 0 )-16 diphenyl-3-hydroxyhexane 6. (R)-N-tert-butyl-3-((2S,3

S)-

2 -hydroxy-3-N-((R)2N-.(isoquinolin-5 yloxyacetyl)amino-3 -methylthiopropanoyl)amino4phenylbutanoyl)-5,5- **dimethyl- 1,3 zldii--aroa- Le A 30844 -Foreim Countries -26- 7. 3 4 -Amnino-benzenesulphonyl)isoutyl.amino]-l-benzyl- 2 -hydroxypropyl carbamnic acid tetrahydro-furan-3-yl ester 8. (3S,6R)-3-(cc-Ethylbenzyl)-6-(a -ethylphenethyl)4hydroxy2H-pyran2-on

(VB

11 478, PCT WO 9411361) 9. N-5L[-2qioiexoy)Lapraiy~mn-4,3)Tx--hnl hexanoyl]-isoleucine N-tert-butyl- 1 hdoy4penl-()[N(-uioiyeroy asaaiy~mn~uy-()(hnyti~ieiie2S-abxmd 11. 1 '-oxo- 1 1l"'-oxo- 2 "'-aza-3"-phenylmethyl.4"'.

hydroxy-5"'-(2" '-N-tert-butylcarbamido)phenyl]penyl-4rmethyl)- 1,2,3,4tetrahydroisoquinoline 12. 2-2Hdoy3(-yrx--ehlbnolmn)4peyslhnluy] decahydroisoquinoine3aroxylc acid tert-butylamide :13. 2H-- 1 4 -Diazepin-2-one,hexahydro-6hydroxy.. 1 3 4 ,7-tetrakis(phenylmethyl)..

15 [3S-(3.alpha, 6.beta, 7.beta)] for use as medicaments in the treatment of AIDS and/or I-ITV infections.

The combination which is very particularly preferred for use in the control of AIDS and/or FHV infections is that of S-4-isopropoxycarbonyl6methoxy3.methylthiomethyl)-3,4-dihydroquinoxaolin-2( 1 H)-thione of the formula (A) U A 30 844 -Forim Counries -27- NH S

H

3 C-O N CH J (A)

H

3 C

CH

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

H

NH (B) 0

OH

0 NH2

NH-C(CH)

The quinoxalines of the general formulae and (Ia) 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 the monotherapy using the individual compounds, in the treatment of retrovirus- :i induced, in particular, however, HIV-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 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, Le A 30 844 Foreign Countries 28 it is known that the use of these combinations results in synergistic toxicity [cf.

M.N. Prichard et al.; Antimicrob. Agents Chemotherapy (1991), 35, 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 development of resistant virus isolates.

The invention deals with the combination of two classes of compound of the HIV reverse transcriptase and the HIV 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 HIV.

HIV 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 ug/ml) and interleukin-2 (40 U/ml) in RPMI J 15 1640 containing 20% foetal calf serum. For infection with the infectious HIV, 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 0 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 x 105 cells per ml. 1 x 10 4 cells which had been infected in this manner were pipetted into each of the wells of 96-well microtitre S*p lates.

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.

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 Le A 30 8 4 4 Foreign Countries -29above (cell control). Only HIV infected cells (virus control) in growth medium were added to the second vertical row of the microtitre plate. The 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 plate, from which the test substances were further diluted in doubling-dilution steps pl 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 pl of the previously prepared HIV-infected cells (see above) were then added to each of these remaining wells. This resulted in test concentrations being covered within approximately the 10-50-fold range above and below the IC 50 concentrations.

The test mixtures were incubated at 37 0 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 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 96well plate and screened for HIV-specific antigen in an HIV-specific ELISA test (Vironostika HIV antigen, Organon Teknika).

SThe inhibition values were converted into per cent inhibition values in accordance S 20 with the cut-off values from corresponding cell controls, virus controls or internal test controls, and the IC 5 0 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 values were determined for each combination (Prichard, M.N. et al., Antimicrob.

Agents Chemoth. (1993), 37, 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 saquinavir together with the example of the formula (A) Le A 30 844 Foreign Countries 30 Example of fonnula 50 25 12 nM Saquinavir (B) nM 0 0 0 0 0 0 12 0 0 0 6 0 0 0 3 0 0 0 1.5 0.7 13 32 30 16 29 49 20 3 37 40 0 0 32 57 23 0 27 0 0 0 o o o o oo o o r eooo r o o* Synergistic activity is obtained for the combinations within the concentration window of 0.7 6 nM for the example of the formula and 6 50 nM for the protease inhibitor 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).

20 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: The treatment and prophylaxis of retroviral infections in humans.

Le A 30 844 Foreign Countries 31 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.

For the treatment or the prophylaxis of an HTLV-I or HTLV-II infection.

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) 15 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- Le A 30 844 Foreign Countries 32 toxic, inert, pharmaceutically suitable carrier substances, contain one or more compounds of the formulae (Ia) in combination with one of the given protease inhibitors, or which consist of one or more active compounds of the formulae (Ia) and the protease inhibitors, and also processes for producing these preparations, in particular the combination of the test compounds.

The active compounds of the formulae and 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 by weight, of the total mixture.

The above-listed pharmaceutical preparations can also contain further pharmaceutical active compounds in addition to the compounds of the formulae (Ia) 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 substance(s).

;i 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 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 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 •00 of the disease, on the nature of the preparation and the administration of the medicament, and on the period of time and/or interval within which the administration takes place.

0eo tae0p0e Le A 30 844 Foreign Countries 33 p PAWPDOCS\KDF\SPECS\584143SPED0C 23/7/99 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

S S S S. SS*

S

S S

S.

S.

S

S

*SSS

S S S S 555S S S S S

S.

S

555

S

S

S.

S

S

*5 *5 55

S

6 P:\WPDOCS\KDF\SPECS\584I43.SPE.DOC 23/7/99 The claims defining the invention are as follows: 1. A medicament which contains, in combination, one or more protease inhibitors selected from the group consisting of 1. [(al phaS) -a Ipha-[( IlR) 2 S, 4aS, 8aS)- 3 (tert b utylIcarb amoyl1) oct ahy dro- 2 1 is oq u in o I mny 2. 2 -B e n zy-5 (N et btbuItarlbam a1) 4 3 pyridylmethyl)piperzin-1 -yl)-(S~hydrox-N-(2Rhydroxyindm 1(S)yI)pentanamide 3. N-(Quinolin-2-ylcarbony)sparagine- 1 (S)-benzy-3-(3-tert-btyl..I 1isobutylureido)-2(R)-hydroxypropyaide 4. Ni I -2-yrx--(-ehluymehlupoyain)l

S-

**(phenylethy)pro pyI)2-(2quinlincrbnyl1amnyo)bneaid 2 S, 3 S, 5S5-(N e thyhy-N- l(2- ((2op py 4 Sn. thiazolyl)methoxycarbonyl)amnoy..1 6 -dipheny-3-hydroxyheane 6. (R--etbtl3(2,S)- 2 -hydroxy-3.N-((R).2N..(isoquinolin.s..

yl* ()-N-erttylmn-3-mtylhopoan(2aio4-hnyb,3ol)55 7. 3 3- 4 -Amino-benzenesulphonyl)-isobutyI -amino] -I -benzyl1-2hydroxypropy1}-carbamic acid tetrahydro-firan-3.yl ester 8. (3 cc-Ethylbenzyl) 6- ethylphenethy)-4hydroy2j{pyan-2 one (VB 11 478, PCT WO09411361)

Claims (5)

1. 9. N-5L[-2q oieabnl-asaaiylmn-4,Soy6 PhenYl-hexanoyl]-isoleucine N-tert-butYl-l2R yrxy4pey)3S)[N(-unliyeroy) asParagflYlaflif~lObutY1R)4Phenythio)piperdne2(S),j, 4 xide
2. 11. 1 "'-oxo- 2 1 "-aza-31"'-phenylmethyl- 4 "'-hydroxy-5"(2'N-ertbutycarbamdo)phenylpeltyl-4nmehyl)- 1 ,2,3,4-tctrahydroisoquinoline
3. 12. 2 2 Hydroxy- 3-(3 -hydroxy-2-methyl..benzoyl am ino)- 4 phenylsulphanybuty1]-dcahydro-isoqunoine3-carbxyljc acid tert- butylamide
4. 13. 2H- 1 4 -Diazepin-2-one,hexahydro-6hydroxy-.1,3,4,7- teraisphnymeh l) [S-3.lp 6.beta, 7.beta)]. and one or more quinoxalines selected from the general formula (I) R2 R and their tautomeric forms of the general formula (Ia) RR in which n i zro ntiw zro onre or four th iniida susiun 'ae nepnetyo ahohr fl oie choie rmnioie9*furmtyl rfurmtoy hydrxyl two-ly ,C -C -y lak l C -6ak x -6ak x *C -4ak x .9C -lyti ,C -ly slp iy C -6 alyslhnl niraio 9.o IC akla io iC-6 heiniidual subsitntsR i darel, ieenely oefa o ter, -6ayC- hydroxy, C-C-alylO, C 8 cCakylY C 1 c-alkoXY, (C-C 6 -alx)- 37 oxycarbonyl, hydroxysuiphonyl or suiphamnoyl, or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulphinyl, phenylsuphonyl, phenoxysuphonyl, phenylsulphonyloxy, anilinosulphonyl, phenyisulphonyiamno 0 benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to five RW radicals which are independent of each other, where W 6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C 1 -C 6 -alkyl, C 3 -C8-cycloalkyl, C,- C 6 -alkoxy, C 1 -C 6 -alkylthio, Ci-C 6 -alklIsulphinyl, CX- 6 -alkylsulphonyl, C 1 -C 6 -allcylamino, di(Ci-C 6 -allcyl)amino, (C 1 -C6-alkyl)-.oxycarbonyl, .phenyl, Phnx or 3- or 4-pyridyl, *R 2 R 2 and W( are identical or different and are, independently of each other, hydrogen, hydroxyl, C 1 -C 6 -alkoxy, aryloxy, C 1 -C 6 -acyloxy, cyano, amino, C 1 6 -alkylamnino, di(C 1 -C 6 -alkyl)miiio, arylamino, C,-C 6 acylamino, CI-C 8 -alkyl, optionally substituted by fluorine, chlorine, bromneiodine, cynamino, mercapto, hydroxyl, ci-C 6 -acyloxy, benzoyloxy, benlzyloxy, phenoxy, C 1 -C 6 -alkOxY, CX- 6 -alkylarnino, di(C 1 20 C 6 -akl)amjno, C 1 -C 6 -alkylthio, Ci-C 6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamnoyl; C 2 -C 8 -alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 6 -alkoxy, C 1 -C 6 alkylamino, di(CI-C 6 -alkyl)amno, Cl-C 6 -alkylthjoC 1 -C 6 -alkylsulphonyl, <J\L1 38 phenylsuiphonyl, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -allenyl which is optionally substituted by fluorine, chlorine or hydiroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; C 3 -C 8 -alkinyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, Cl-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, Cl-C 6 -alkoxy, CI-C 6 alkylamino, di(C 1 -C 6 -alky)an-ino, C 1 -C 6 -alkylthio, Ci-C 6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamnoyl; C 3 -Cg-cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoYloxy, berizyloxy, phenoxy, C 1 -C 6 -alkoxy, C,-C 6 alkylamino, di(C 1 -C 6 -alkyl)aino, C 1 -C 6 -alkylthio, CI-C 6 -alkylsulphonyl, 15 phenylsuiphonyl, oxo, thioxo, carboxyl or carbamnoyl; C 3 -C 8 -cycloalkenyl which is optionally substituted by woo* fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, CI-C 6 -acyloxy, benzyloxy, benZYlOXY, hX, CI-C 6 -alkoxy, C-6 alkylamino, di(CI-C 6 -allcyl)amino, C 1 -C 6 -alkylthio, CI-C 6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamnoyl; #0 .0 (C 3 -C 8 -cycloalkyl)-(C 1 C 4 .alkyl) which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 6 -alkoxy, Cl-C 6 alkylamino, di(C,-C 6 -alkyl)amino, C 1 -C 6 -alkylthio, Cl-C 6 -alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; (C 3 -C8-CYCloalkenyl)-(C 1 .C 4 alyl) 39 which is Optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amnino, mercapto, hydroxyl, C 1 -C 6 -acyloxy, benzoyloxy, benzyloxy, Phenoxy, Cj-C 6 -alkocy, C,-C 6 alkylamino, di(C 1 -C 6 -akl)amino, C 1 -C 6 -alkylthio, C I-C6-alkylsulphonyl, phenylsulphonyl, oxo, thioxo, carboxyl or carbamoyl; CI-C 6 -alkylcarbonyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C-C 6 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 6 -alkoxy, C-C 6 ailylamino, di(C 1 -C 6 -alkyl)aino C 1 -C 6 -alkylthio, Cr-C 6 -alkylsulphonyl, phenylsuiphonyl, oxo, thioxo, carboxyl or carbamoyl; C 2 -C8-alkenylcarbonyl which is optionally substituted by, fluorine, chlorine Or hydroxyl, CX- 4 -alkoxy, oxo or phenyl; which is optionally substituted by fluorine, 15chlorine Or hydroxyl, Ci-C 4 -alkoxy, oxo or phenyl; *by fluorine, clrn rhdoyC-4akxooo hnl (Cs-C6-cycloalkenyl-C C-lyl)cairyjny1 which is optionallysutite susiue furnchlorine or hydroxyl, C,-C 4 -alkoxy, oxo orphn; CI. -C-alkyloxcarbonyl which is optionally substituted loie byhlorine, corine hydroxyl, C 1 -C 4 -alkoxy, oxo kylior henyl;4 substy~aitute by fline, ckylhlorieo yrxl 1 4 ak ,ooo 40 C 2 -C 8 .alkenyloxycarby-nyj which is optionally substituted by -fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; C 2 -C8-alkinyloxycarbonyl which is optionally substituted by fluoine, chlorine, hydroxyl, Cl-C 4 -alkoxy, oxo or phenyl; Cl-Cg-alkylthiocarbOnYl which is optionally substituted by fluorine, chlorine, hydroxyl, C 1 -Calkoxy, oxo or phenyl; C-2CgsakenyltiocYarnbnyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-Calkoxy, oxo or phenyl; Ci-Cg-alkyaminocarbonyj and di(CIjCs-allcyj)ami ocaiionyl which are optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; 000 0 pyrrolidin-l-yl, morpholino-, piperidino-, piperzinyl- or 4- 9 methylpiperazin- 1 -yl-carbonyl which are optionally substituted by C 1 -C 4 0 alkyl, q-C 6 -alkenyl, C 1 -C 4 -acyl, oxo, thioxo, carboxyl or phenyl; *0 15 q_8aknl~n~r~y and diC-6aknl~mncroy which are Optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; Cl-.6 alkrl.ulphonjl which is optionally sbtuedbyfloie chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; CI-C 6 -alkenylsulPhonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbony I, (arylamino)thiocarbonyl, arylalkylaminocarbonyi, arylsuiphonyl, 41 arylalkyl, axylalkenyl, arylalknyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or aryl(alkyitio)cabonyl which are substituted by UP to five W 6 radicals which are independent of each other, and where the alkyl radical can in each case contain from 1 to 5 C atom and R 6 is defied as above or heteroaryl, heteroaxylalkyl, heteroarylalkenyl, heteroarylalkylcabonyi or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl or heteroarylalkylaminocabonyl which are substituted by up to three W( radicals which are independent of each other, and where the alkyl radical can in each case contain from I to 3 C atoms, R 3 and R! are identical or different and are, independently of each other, hydrogen, or CI-C 8 -alkyl which is optionally substituted by fluorine, 15 chlorine, hydroxyl, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Ci-C 4 -alkylaniino, di(C 1 -C 4 alkyl)amino, C,-C 4 -aklthio, C 1 -C 4 -alkylsulphonyl, C, -C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 2 -C 8 -alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Ci-C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, CI-C 4 alkylthio, CI-C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamoyl; *C 3 -C 8 -cycoalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Ci-C 4 -alkylanmino, di(CI-C 4 -alkyl)amino, CI-C 4 alkylthio, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamoyl; 42 C 3 -C 8 -cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Cl-C 4 -alkylamino, di(C 1 -C 4 alkyl)amino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulphonyl, Cl-C 4 -alkylsulphinyl, carboxyl or carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylallcyl which are substituted by up to five W 6 radicals which are independent of each other, and where the alkyl radical can in each case contain from Ilto 3 C atoms and is defined as above, W3 and RW or R? and RI 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, CX- 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, CX- 6 -acyloxy, benzoyloxy, C,-C 6 -alkoxy, oxo, thioxo, carboxyl, carbamnoyl or phenyl, .0SX denotes oxygen, sulphur, selenium or substituted nitrogen N-R 2 in which W3 can have the abovementioned meanings, with the exception of the compounds in which W{ and W 4 simultaneously denote H and compounds in which RW and RW denote H and W3 and/or W( denote arylalkyl and compounds in which X denotes oxygen and W3 and W3 denote hydrogen. :0 2. A medicament according to Claim 1, wherein the one or more quinoxalines are 0selected from the general fomuae() and (1) in which n is zero, one, two or three, 43 the individual substituents R' are, independently of each other, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, hydroxyl, C[-C 4 -alkyl, C 5 -C 6 -cycloalkl, CI-C 4 -alkoxy, (Cl-C 4 -alkoxy}-(C 1 -C 4 alkoxy), Cl-C 4 -alkylthio, C 1 -C 4 -alkyl-sulphinyl, C 1 -C 4 -alkylsulphonyl, nitro, amino, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, piperidino, morpholino, 1 -pyrrolidinyl, 4 -methyl-piperazinyl, thiomorpholino, iilidazolyl, C 1 -C 4 -acyl, C 1 -C 4 -acyloxy, C 1 -C 4 -acylamino, cyano, carbamoyl, carboxyl, (CI-C 4 -alkyl)-oxycarb-onyl, hydroxysuiphonyl or sulphamoyl, or are a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsuiphinyl, phenylsuiphonyl, phenoxy-sulphonyl, phenyl suiphonyloxy, anilinosuiphonyl, phenylsuiphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two R 6 radicals which are independent of each other, where R can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, am-ino, C 1 -C 4 -alkYl, C 3 -C7rcycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 alkyl-suiphinyl, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)- S 20 amino, (CI-C 4 -alkyl)-oxycarbonyl, phenyl or phenoxy, 0.. P3 is hydrogen and W 5 is hydrogen;, hydroxyl, cyano, amidno, C,-C,-alkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C 1 -C 4 alkylarnino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl 44 or carbamnoyl; C2-C 8 -alkenyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 4 -aCYloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C,-C 4 alkylamino, di(C 1 -C 4 -alkyl)amino, Ci-C 4 -alkyltliio, oxo, thioxo, carboxyl or carbamoyl; C 3 -C 8 -allenyl, q-C 8 -alldnyl, which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, Ci-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 -alkoxy, C,-C 4 alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; 15 C 3 -C 8 -cycloalkyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 -alkoxy, C 1 -C 4 alkylamino, di(CI-C 4 -alkyl)aniino, CI-C 4 -alkyhthio, oxo, thioxo, carboxyl or carbamnoyl; C 3 -C 8 -cycloalkenyl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 -alkoxy, C,-C 4 alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamnoyl; 45 which is optionally substituted by fluorine, chlorine, bromine, iodine, cyan, amino, mercapto, hydroxyl, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C 1 -C 4 alkylamino, di(CI-C 4 -alkyl)amno, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; (C-8C~~tey)(Iqakl which is optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxyl, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Cl-C 4 alkylamino, di(CI-C 4 -alkyl)anino, C 1 -C 4 -alkylthio, oxo, thioxo, carboxyl or carbamoyl; CI-C 6 -alkylcarbonyl which is optionally substituted by fuorie, hlornebromneiodine, cyano, amino, mercapto, hydroxy, I -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C 1 -C 4 alkylan-ino, di(C,-C 4 -alkyl)aminoC-4aklho oxo, UUUAo, croy or carbamoyl; B a q-C 6 -alkenylcarbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; o. :6-Ylaly~aroy which is opinlysubstituted b loie (C-6ccol.nlcroy whc sopinlysusiue by fluorine, chlorine Or hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; (C5-C 6 -cycloalken-(,-lyl)carbonyI which is optionally substituted loie byfunchlorine or hydroxyl, C X 4 -alkoxy, oxo or phenyl; 46 (C 5 -C 6 -cycloalkenyl)-(C 1 -C 2 -alkyl)carbonyl which is optionally substituted by fluorine, chlorine or hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; CI-C 6 -alkyloxycarbonyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylam-ino, di(C 1 -C 4 alkyl)amino or CI-C 4 -alkylthio; C 2 -C 6 -alkenyloxycar-bonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; C 2 -C 6 -alkinyloxyvcarb~onyl which is optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; CI-C 6 -alkylthiocar-bonyl which is optionally substituted by fluorine, 'low. chlorine, hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; C 2 -C 6 -alkenylthiocarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C,-C 4 -alkoxy, oxo or phenyl; Ci-C 6 -alkYlaiinocarbonyl and di(CI-C 6 -alkyl)aminocarbonyl which are ,optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo *or phenyl; pyrrolidin- 1-yl or morpholino-, piperidino-, piperazinyl- or 4- a methylpiperazin- 1-yl-carbonyl; C 2 -C 6 -alkenylaniinocarbyjnyl and di(Ci-C 6 -alkenyl)a-ijnocariyjnyl which are optionally substituted by fluorine, chlorine, hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; C,-C 4 -alkylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, CI-C 4 -alkoxy, oxo or phenyl; 47 C 1 -C 4 -alkenylsulphonyl which is optionally substituted by fluorine, chlorine, hydroxyl, C 1 -C 4 -alkoxy, oxo or phenyl; or aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamnino)thiocarbonyl, arylalkylamninocarbonyl, arylsuiphonyl, arylalkyl, arylalkenyl, arylalkinyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl(alkylthio)carbonyl or arylalkoxycarbonyl which are substituted by up to three RW radicals which are independent of each other and where thealkyl radical can in each casecntain from I to 5C atoms andRW is defined as above or 1- or 2-naphthylmethyl, 3- or 4-picolyl, 2- or 3-finylmethyl, 2- or 3-thienylmethyl, 2- or 3 -pyrrolylmethyl, 3- or 4 -pyridylcarbonyl, 2- or 3-fuirylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 3- or 4 -picolyloxycarbonyl, 2- or 3 -furylmethyloxycarbonyl or 2- or 3- 15 thienylmethyloxycarbonyl which are substituted by up to two W( radicals which are independent of each other, 0**a and 4. 1(3and 14are identical or different and are, independently of each other, hydrogen, CI-C 6 -alkYl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)aniino, C 1 -C 4 -alkylthio, C 1 -C 4 alkylsuiphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbam-oyl; C 2 -C 8 -alkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amidno, mercapto, CI-C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, CI-C 4 -alkoxy, C,-C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, C 1 -C 4 48 alkylthio, Cl-C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamoyl; C 3 -C 8 -cycloalkyl which is optionally substituted by fluorine, chlorine, hydroxyl, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, Cl-C 4 -alkylamino, di(C 1 -C 4 -alkyl)aniino, C 1 -C 4 alkylthio, C,-C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamnoyl; C 3 -Cg-cycloalkenyl which is optionally substituted by fluorine or chlorine, hydroxyl, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, di(C 1 -C 4 alkyl~amino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulphonyl, C,-C 4 -alkylsulphinyl, carboxyl or carbamoyl; or aryl, arylalkyl, heteroaryl or heteroarylalkyl which are substituted by 9 a up to three W 6 radicals which are independent of each other, and where alkyl radical can in each case contain from I to 3 C atoms and R 6 is defined as above, R 3 and W 4 can, in addition, also be a apart 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 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkinyl, C 1 C 4 -acyloxy, benzoyloxy, C 1 -C 4 -alkoxy, oxo, thioxo, carboxyl, carbamoyl or phenyl, X denotes oxygen, sulphur or selenium optionally in an isomeric form. 3. A medicament according to Claim 1, wherein the one or more quinoxalines are selected from the general formulae and (Ia), -49 in which n is zero, one or two, the individual substituents R' are, independently of each other, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, CI-C 4 -alkyl, -C 1 C 4 -alkoxy, (C 1 -C 4 -alkoxy)-(C-C,-alkor)' C 1 -C 4 -alkylthio, nitro, amino, Ci-C 4 -allcylamino, di(C 1 -C 4 -alkyl)an-fino, piperidino, morpholino, 1_ pyrrolidinyl, 4 -methylpiperazinyl, C 1 -C 4 -acyl, CI-C 4 -acyloxy, C 1 -C 4 acylamino, cyano, carbamnoyl, Carboxyl, (CI-C 4 -alkyl)-oxycarbonyl, hydroxysuiphonyl or sulphamnoyl, or are a phenyl, phenoxy, phenylthio, phenylsulphonyl, phenoxysulphonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical which is substituted by up to two W 6 radicals which are independent of each other, where RW can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 -alkoxy, (CI-C 4 -alkyl)-oxycarbonyl, phenyl or pheoy R 2 is hydrogen and WY is CI-C 6 -alkyl which is optionally substituted by C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio; q-C 6 -alkenyl, which is optionally substituted by oxo; C 3 -C 6 -allenyl, C 3 -C 8 -alkinyl, in particular 2-butinyl; C 3 -C 6 -cycloalkyl; C 5 -C 6 -cycloalkenyl; (C 3 -C 6 -CccoalkYl)-(C-C 2 .alky1), in particular cyclopropylmnethyl, which is optionally substituted by C 1 -C 4 -alkyl; (C 3 -C 6 -cycloalkenyl)-(c,..qC..alkyl), in particular cyclohexenylmethyl; C 1 -C 6 -alkylcarbonyl which is optionally substituted by fluorine, chlorine, hydroxyl, 10 benzyloxy, phenoxy, C 1 C-alkoxy, C 1 C-alkylamino, C- 4 *9-C 9IC C- alkenylamino, di(C 1 -C 4 -alkyl)amino, 1-pyrrolidinyl, piperidino, 9 morpholino, 4 -methylpiperazin- 1-yl or C 1 -C 4 -alkylthio; Q2-C 6 -alkenylcarbonyl; CrC 6 -alkyloxycarbonyl which is optionally substituted by fluorine, 9. 15chlorine, bromine, hydroxyl, CX- 4 -alkoxy, C 1 -C 4 -alkylarnino, di(C 1 -C 4 alkyl)amino or C 1 -C 4 -alkylthio; -2 akeyoxcrbn in particular vinyloxycarbonyl, 9 99 allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl or pentenyloxycarbonyl; Cq-C 6 -akinyloxycarbonyl, in particular propinyloxycarbonyl or butinyloxycarbonyl; Cl-C 6 -alkylthiocarbonyl; 51 C 2 -C 6 -alkenylthiocarbonyl, in particular allthiocarbonyl; C 1 -C 6 -alkYlaMinocarbonyl and di(C 1 -C 6 -alky1)aninocarbony; pyrrolidin-1-yl Or morpholino-, piperidino-, piperazinyl- or 4- methylpiperazin- 1-yl-carbonyl; C 2 -C 6 -alkenylamlinocarbonyl and di(Ci-C 6 -alkenyl)aniinocarbonyl; C 1 -C 4 -alkylsulphonyl; Cl-C 4 -alkenylsulphonyl; or aryl, in particular phenyl, axylcarbonyl, in particular benzoyl, (arylthio)carbonyi, aryloxycarbonyl, 10 arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsuiphonyl, :arylalkyl, in particular benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl or aryl(alkylthio)carbonyl which are substituted by up to two W 6 radicals which are independent of each other and where the alkyl radical can in each case contain from 1 to 3 C atoms and W 6 is defined as above or 1- or 2-naphthylmethyl, 3- or 4-picolyl, 2- or 3-fuirylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 3- or 4-pyridylcarbonyl, 2- 9 or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-thienylacetyl, 3- *9 20 or 4 -picolyloxycarbonyl, 2- or 3 -fiuylmethyloxycarbonyl or 2- or 3- thienylmethyloxycaronyl which are substituted by up to two RW radicals which are independent of each other, and RW and W( are identical or different and are, independently of each other, 52 hydrogen, C 1 -C 4 -alk which is optionally substituted by hydroxyl, mercapto, CI-C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphinyl, carboxyl or carbamnoyl; C 2 -C 6 -alkenyl, aryl, benzyl, thienyl or thienylmnethyl which are substituted by up to two R 6 radicals which are independent of each other and where W 6 is defined as above, W 3 and Wcan 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 optionally in an isomeric form.
5. 53- a a a a a a. a a.. a a a C. 4. A medicament which contains, in combination SA4-isopropoxycarbonyl6meffioxy-3 (methylthio-methyl)y3 4 -dihydroquinoxazolin-2()-t.hjifl of the formula (A) H 3 -O 'N H S H 0 -K- 0 (A) H 3 C 1, CH 3 and (S)-N.{(alphaS).alpha.[( lR)- 2 -[((3S4aS,8aS)3(tebutylabmoyl)- octahydro-2( 1 H)-isoquinolinyl)- I-hydroxyethyl)phenethyI..2.quinldamido]- succinanide, (Saquiavir) of the formula (B) NH H CI I, I o= NH 2 IH NH-C(CH 3 )3 54 P.\WPDOCS\KDF\SPECS\584143.SPE.DOC 23/7/99 A medicament which comprises one or more protease inhibitors and one or more quinoxalines as defined in any one of claims 1 to 4 substantially as hereinbefore described with reference to the examples. 6. A method for the treatment of AIDS and/or HIV infection which comprises administering to a subject in need of such treatment a medicament according to any one of claims 1 to 5, optionally in association with one or more pharmaceutically acceptable carriers, and/or excipients. 7. A method for the treatment of retroviral diseases which comprises administering to a subject in need of such treatment one or more protease inhibitors and one or more quinoxalines as defined in claim 1. 8. Use of one or more protease inhibitors as claimed in claim 1 in combination with one or more quinoxalines of general formulae and (la) as defined in claim 1 in the preparation of a medicament for the treatment of retroviral diseases. S 9. A method for the preparation of a medicament of anyone of claims 1 to 5, which method comprises the step of bringing one or more protease inhibitors as claimed in claim 1 in association with one or more quinoxalines of general formulae and (Ia) as defined in 9..9 claim 1, optionally together with one or more pharmaceutically acceptable carriers and/or o 9 9' excipients. DATED this 23rd day of July, 1999 BAYER AKTIENGESELLSCHAFT By its Patent Attorneys DAVIES COLLISON CAVE Use of gudinoaie in COMbInatin mhpaeihbti eia i fotnwafng AIDS and/o r HIV inffections A bs tr a ct The present invention relates to the use of quinoxalines in combination with protease inhibitors as medicaments for treating AIDS and/or MIV infections. L* LU A 30 844 Foreig Cuntries