HRP960070A2

HRP960070A2 - Use of quinoxaline and protease inhibitors in a composition for the treatment of aids and/or hiv infections

Info

Publication number: HRP960070A2
Application number: HR19506742.8A
Authority: HR
Inventors: Arnold Paessens; Martin Blunck; Guenther Riess; Joerg-Peter Kleim; Manfred Roesner
Original assignee: Bayer Ag
Priority date: 1995-02-27
Filing date: 1996-02-13
Publication date: 1997-10-31
Also published as: SK25196A3; CA2170222A1; CN1141196A; HU9600455D0; AR003923A1; BR9600809A; NO960775L; FI960850A; IL117247A; NZ286058A; AU4561596A; CZ57896A3; KR960030951A; EP0728481A3; AU710158B2; FI960850A0; IL117247A0; NO960775D0; ZA961516B; HUP9600455A3

Description

Predloženi izum odnosi se na upotrebu kinoksalina u kombinaciji s inhibitorima proteaze kao lijekova za liječenje AIDS-a i/ili HIV-infekcija. The proposed invention relates to the use of quinoxaline in combination with protease inhibitors as drugs for the treatment of AIDS and/or HIV-infections.

Virus humane deficijencije imuniteta (HIV) uzrokuje perzistentno-progresivnu, kroničnu bolest. HIV razara imunološki sustav (sindrom stečene slabosti imuniteta, AIDS) i središnji i periferni živčani sustav. Pored toga HI-virus također uzrokuje i mnoge druge kliničke manifestacije u ARC/AIDS slici bolesti - osobito oportunističke infekcije (O.I.), izazvane drugim virusima, kao npr. virusima herpesa (HSV I i II), citomegalovirusom (CMV) ili O.I., izazvane bakterijama, gljivicama ili parazitima. The human immunodeficiency virus (HIV) causes a persistent-progressive, chronic disease. HIV destroys the immune system (acquired immune deficiency syndrome, AIDS) and the central and peripheral nervous system. In addition, the HI-virus also causes many other clinical manifestations in the ARC/AIDS picture of the disease - especially opportunistic infections (O.I.), caused by other viruses, such as herpes viruses (HSV I and II), cytomegalovirus (CMV) or O.I., caused by bacteria, fungi or parasites.

HIV spada u porodicu retrovirusa; jedna od bitnih i u ciklusu razmnožanja esencijalne enzimatske aktivnosti tog virusa je proteaza (Huff, J.R., J. Med. Chem. (1991), 34, 2305-2314). Niskomolekulni peptidni i nepeptidni analozi prirodnih supstrata proteaze suzbijaju replikaciju HIV-a (Roberts, N.A. et al., Science (1990) 248, 358-361; Lam, P.Y.S. et al., Science (1994), 263, 380-384). HIV belongs to the family of retroviruses; one of the important and essential enzymatic activities of that virus in the reproduction cycle is protease (Huff, J.R., J. Med. Chem. (1991), 34, 2305-2314). Low molecular weight peptide and non-peptide analogs of natural protease substrates inhibit HIV replication (Roberts, N.A. et al., Science (1990) 248, 358-361; Lam, P.Y.S. et al., Science (1994), 263, 380-384).

Analozi prirodnih supstrata reverzne transkriptaze kao npr. azidotimidin (AZT), dideoksicitidin (DDC), dideoksiinosin (DDI) i 3 -tiacitidin (laraivudin) suzbijaju replikaciju HIV-a in vitro i in vivo. ATZ služi npr. za liječenje oboljelih od ARC/AIDS-a. Dugotrajnu terapiju pacijenata inficiranih s HIV-ora prati međutim markstoksičnost kostiju; zbog toga nastaju AZT-rezistentni virusni izolati. Kod nekih pacijenata, koji su bili liječeni s DDC ili DDI izvješćuje se o nepodnošljivostima kao što je npr. periferna neuropatija. Stoga su za suzbijanje za podnošljivu i učinkovitu terapiju potrebne nove tvari. Analogues of natural reverse transcriptase substrates such as azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3-thiacytidine (laraivudine) suppress HIV replication in vitro and in vivo. ATZ serves, for example, to treat patients with ARC/AIDS. However, long-term therapy of HIV-infected patients is accompanied by bone toxicity; as a result, AZT-resistant virus isolates arise. In some patients treated with DDC or DDI, side effects such as peripheral neuropathy have been reported. Therefore, new substances are needed for control for tolerable and effective therapy.

Sada pronađena kombinacija kinoksalina s inhibitorima proteaze je nova i njeno sinergističko djelovanje na razmanažanje HIV-a kod upotrebe u suzbijanju AIDS-a ili HIV-infekcija značajno je bolje od postojećeg stanja tehnike. The now found combination of quinoxaline with protease inhibitors is new and its synergistic effect on the spread of HIV when used in the suppression of AIDS or HIV-infections is significantly better than the existing state of the art.

Sada je bilo pronađeno da su kinoksalini općih formula (I) i (Ia) It has now been found that the quinoxalines of the general formulas (I) and (Ia)

[image] [image]

te njihovi tautomerni oblici opće formule Ia and their tautomeric forms of the general formula Ia

[image] [image]

u kojoj where

1) n je nula, 1) n is zero,

jedan, one,

dva, two,

tri, three,

ili četiri, or four,

pojedinačni supstituenati R1 međusobno neovisno predstavljaju the individual substituents R1 independently represent each other

fluor, klor, brom, jod, trifluormetil, trifluor-metoksi, hidroksi, C1-C8-alkil, C5-C8-cikloalkil, (C1-C6-alkoksi) - (C1-C4-alkoksi), C1-C6-alkiltio, C1-C6-alkil-sulfinil, C1-C6-alkilsulfonil, nitro, amino, azido, C1-C6-alkilamino, di(C1-C6-alkil) amino, piperidino, morfolino, 1-pirolidinil, 4-metilpiperazinil, tiomorfolino, imidazolil, triazolil, tetrazolil, C1-C6-acil, C1-C6-aciloksi, C1-C6-acilamino, cijano, karbamoil, karboksi, (C1-C6-alkil) -oksikarbonil, hidroksisulfonil, sulfamoil ili fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoro-methoxy, hydroxy, C1-C8-alkyl, C5-C8-cycloalkyl, (C1-C6-Alkoxy) - (C1-C4-Alkoxy), C1-C6-Alkylthio, C1-C6-alkyl-sulfinyl, C1-C6-alkylsulfonyl, nitro, amino, azido, C1-C6-alkylamino, di(C1-C6-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C1-C6-acyl, C1-C6-acyloxy, C1-C6-acylamino, cyano, carbamoyl, carboxy, (C1-C6-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl or

s do pet međusobno neovisnih ostatak R6 supstituirani fenil-, fenoksi-, fenoksikarbonil, feniltio-, fenilsulfinil, fenilsulfonil-, fenoksisulfonil-, fenilsulfonil-oksi-, anilinosulfonil, fenilsulfonilamino, benzoil-, 2-piridil-, 3-piridil- ili 4-piridilni ostatak, pri čemu with up to five mutually independent residues R6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein

R6 može biti fluor, klor, brom, jod, cijano, trifluormetil, trifluormetoksi, nitro, amino, azido, C1-C6-alkil, C3-C8-cikloalkil, C1-C6-alkoksi, C1-C6-alkiltio, C1-C6-alkilsulfinil, C1-C6-alkilsulfonil, C1-C6-alkilamino, di(C1-C6-alkil)amino, (C1-C6-alkil)-oksikarbonil, fenil, fenoksi, 2-, 3- ili 4-piridil, R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C1-C6-alkyl, C3-C8-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6 -alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino, (C1-C6-alkyl)-oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl,

R2 i R5, jednaki ili različiti, međusobno neovisno predstavljaju R2 and R5, the same or different, independently represent each other

vodik, hidroksi, C1-C6-alkoksi, ariloksi, C1-C6-acil-oksi, cijano, amino, C1-C6-alkilamino, di(C1-C6-alkil) amino, arilamino, C1-C6-acilamino, C1-C8-alkil, po potrebi supstituiran s fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di(C1-C6-alkil)-amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenilsulfonilom, okso, tiokso, karboksi, karbamoilom; hydrogen, hydroxy, C1-C6-Alkoxy, aryloxy, C1-C6-acyl-oxy, cyano, amino, C1-C6-alkylamino, di(C1-C6-alkyl) amino, arylamino, C1-C6-acylamino, C1- C8-alkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di( C1-C6-alkyl)-amino, C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C2-C8-alkenil, C2-C8-alkenyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di(C1-C6-alkil) -amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenilsulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C3-C8-allenil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; C3-C8-allenyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

C3-C8-alkinil, C3-C8-alkynyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di (C1-C6-alkil) -amino, C1-C6-alkiltio, C1-C6-alkilsulf onilom, fenilsulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C3-C8-cikloalkil, C3-C8-cycloalkyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di (C1-C6-alkil)-amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenilsulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C3-C8-cikloalkenil, C3-C8-cycloalkenyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di(C1-C6-alkil)-amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenil-sulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

(C3-C8-cikloalkil) - (C1-C4-alkil), (C3-C8-cycloalkyl) - (C1-C4-alkyl),

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di(C1-C6-alkil) -amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenil-sulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

(C3-C8-cikloalkenil) - (C1-C4-alkil), (C3-C8-cycloalkenyl) - (C1-C4-alkyl),

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di (C1-C6-alkil) -amino, C1-C6-alkiltio, C1-C6-alkilsulfonilom, fenil-sulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

Ci-Cg-alkilkarbonil, C1-C8-alkylcarbonyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C6-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C6-alkoksi, C1-C6-alkilamino, di(C1-C6-alkil)-amino, C1-C6-alkiltio, C1-C6-alkilsulf onilom, fenil-sulfonilom, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;

C2-C8-alkenilkarbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C8-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C3-C8-cikloalkil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C3-C8-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C8-cikloalkenil)karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C5-C8-cycloalkenyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C3-C8-cikloalkil) - (C1-C3-alkil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C3-C8-cycloalkyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cikloalkenil) - (C1-C3-alkil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C5-C6-cycloalkenyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkiloksikarbonil, po potrebi supstituiran s fluorom, klorom, bromom, hidroksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio; C1-C8-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio;

C2-C8-alkeniloksikarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C8-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C8-alkiniloksikarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C8-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkiltiokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C8-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C8-alkeniltiokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C8-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C8-alkilamino- i di (C1-C8-alkil) aminokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C8-alkylamino- and di(C1-C8-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

pirolidin-1-il, morfolino-, piperidino-, piperazinil-ili 4-metilpiperazin-1-il-karbonil, po potrebi supstituiran sa C1-C4-alkilom, C2-C6-alkenilom, C1-C4-acilom, okso, tiokso, karbonil ili fenilom; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-or 4-methylpiperazin-1-yl-carbonyl, optionally substituted with C1-C4-alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo , carbonyl or phenyl;

C2-C8-alkenilamino- i di(C1-C8-alkenil) aminokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C8-alkenylamino- and di(C1-C8-alkenyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-allcilsulfonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C6-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkenilsulfonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C6-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

ili s do 5 međusobno neovisnih ostataka R6 supstistuirani aril, arilkarbonil, aril(tiokarbonil), (ariltio)karbonil, (ariltio)tiokarbonil, ariloksikarbonil, arilaminokarbonil, (arilamino)tiokarbonil, arilalkilamino-karbonil, arilsulfonil, arilalkil, arilalkenil, arilalkinil, arilalkilkarbonil, arilalkenilkarbonil, arilalkoksikarbonil, aril(alkiltio)karbonil, pri čemu alkilni ostatak može sadržavati po 1 do 5 C-atoma, a R6 je kao gore definirani, or with up to 5 mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl, (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl , arylalkenylcarbonyl, arylalkyloxycarbonyl, aryl(alkylthio)carbonyl, wherein the alkyl residue can contain 1 to 5 carbon atoms each, and R6 is as defined above,

ili s do tri međusobno neovisna ostatka R6 supstituirani heteroaril, heteroarilalkil, heteroarilalkenil, heteroarilalkilkarbonil ili heteroarilalkenilkarbonil, heteroariloksikarbonil, (heteroariltio)karbonil, heteroarilaminokarbonil, heteroarilalkiloksikarbonil, heteroaril(alkiltio)karbonil, heteroarilalkilaminokarbonil, pri čemu alkilni ostatak može sadržavati 1 do 3 ugljikova atoma, or with up to three mutually independent residues R6 substituted heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl, heteroarylalkylaminocarbonyl, wherein the alkyl residue may contain 1 to 3 carbon atoms,

R3 i R4, jednaki ili različiti, međusobno neovisno predstavljaju R3 and R4, the same or different, independently represent each other

vodik, C1-C8-alkil, po potrebi supstituiran s fluorom, klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; hydrogen, C1-C8-alkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4 -alkyl) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C2-C8-alkenil, po potrebi supstituiran s fluorom ili klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C3-C8-cikloalkil, po potrebi supstituiran s fluorom, klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di (C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C3-C8-cikloalkil, po potrebi supstituiran s fluorom ili klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C3-C8-cycloalkyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

s do pet međusobno neovisnih ostataka R6 supstituirani aril, arilalkil, heteroaril ili heteroarilalkil, pri čemu alkilni ostatak može sadržavati po 1 do 3 ugljikova atoma, a R6 je kao gore definirani, with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, whereby the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above,

R3 i R4 ili R3 i R5 mogu nadalje također biti dio zasićenog ili nezasićenog karbocikličkog ili heterocikličkog prstena s 3 do 8 ugljikovih atoma, koji po potrebi može biti supstituiran s fluorom, klorom, hidroksi, amino, C1-C6-alkilom, C2-C6-alkenilom, C2-C6-alkinilom, C1-C6-aciloksi, benzoiloksi, C1-C6-alkoksi, okso, tiokso, karboksi, karbamoilom ili fenilom; R3 and R4 or R3 and R5 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 8 carbon atoms, which can be optionally substituted with fluorine, chlorine, hydroxy, amino, C1-C6-alkyl, C2-C6 -alkenyl, C2-C6-alkynyl, C1-C6-acyloxy, benzoyloxy, C1-C6-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl;

X predstavlja kisik, sumpor, selen ili supstituirani dušik N-R2, gdje R2 može imati gore navedena značenja, X represents oxygen, sulfur, selenium or substituted nitrogen N-R2, where R2 can have the above meanings,

s izuzećem spojeva u kojima R3 i R4 istovremeno predstavljaju H i spojeva u kojima R2 i R5 predstavljaju H i R3 i/ili R4 predstavljaju arilalkil i spojeva u kojima X predstavlja kisik, a R2 i R5 su vodik, with the exception of compounds in which R3 and R4 simultaneously represent H and compounds in which R2 and R5 represent H and R3 and/or R4 represent arylalkyl and compounds in which X represents oxygen and R2 and R5 are hydrogen,

u kombinaciji s inhibitorima proteaze vrlo prikladni za upotrebu kao lijek kod suzbijanja AIDS-a i HIV-infekcija. in combination with protease inhibitors very suitable for use as a drug in the suppression of AIDS and HIV-infections.

U prethodnoj definiciji navedene alkilne skupine mogu biti ravne ili razgranate. Ako nije definirano drugačije one imaju ponajprije 1-8, s posebnom prednošću 1-6, a naročito 1-4 ugljikova atoma. To su primjerice metilna, etilna, propilna, 1-metilmetilna, butilna, 1-metilpropilna, 2-metilpropilna, 1,1-dimetiletilna i slične skupine. In the previous definition, the mentioned alkyl groups can be straight or branched. If not defined otherwise, they preferably have 1-8, with particular preference 1-6, and especially 1-4 carbon atoms. These are, for example, methyl, ethyl, propyl, 1-methylmethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and similar groups.

U prethodnoj definiciji navedene alkenilne skupine mogu biti ravne ili razgranate i sadržavati 1 do 3 dvostruke veze. Ako nije definirano drugačije one imaju ponajprije 2-8, naročito 2-6 ugljikova atoma. To su primjerice 2-propenilna, 1-metiletenilne, 2-butenilna, 3-butenilna, 2-metil-2-propenilna, 3-metil-2-butenilna, 2,3-dimetil-2-butenilna, 3,3-diklor-2-propenilna, pentadienilna i slične skupine. In the previous definition, the mentioned alkenyl groups can be straight or branched and contain 1 to 3 double bonds. If not defined otherwise, they preferably have 2-8, especially 2-6 carbon atoms. These are, for example, 2-propenyl, 1-methylethenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 3,3-dichloro -2-propenyl, pentadienyl and similar groups.

U prethodnoj definiciji navedene alkinilne skupine mogu biti ravne ili razgranate i sadržavati 1 do 3 trostruke veze. Ako nije definirano drugačije one imaju ponajprije 2-8, s posebnom prednošću 3-6 ugljikovih atoma. To su primjerice 2-propinilna i 3-butinilna i slične skupine. In the previous definition, the mentioned alkynyl groups can be straight or branched and contain 1 to 3 triple bonds. If not defined otherwise, they preferably have 2-8, with particular preference 3-6 carbon atoms. These are, for example, 2-propynyl and 3-butynyl and similar groups.

U prethodnoj definiciji navedene cikloalkilne i cikloalkenilne skupine, ako nije definirano drugačije, imaju ponajprije 3-8, s posebnom prednošću 4-6 ugljikovih atoma. To su primjerice ciklopropilna, ciklobutilna, ciklopentilna, ciklopentenilna, cikloheksilna ili cikloheksenilna skupina. In the previous definition, the mentioned cycloalkyl and cycloalkenyl groups, if not defined otherwise, preferably have 3-8, with a special advantage of 4-6 carbon atoms. These are, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.

U prethodnoj definiciji navedene acilne skupine mogu biti alifatske, cikloalifatske ili aromatske. Ako nije definirano drugačije one imaju ponajprije 1-8, s posebnom prednošću 2-7 ugljikovih atoma. Acilne skupine su primjerice formilna, acetilna, kloracetilna, trifluor-acetilna, hidroksiacetilna, propionilna, butirilna, izo-butirilna, pivaloilna, cikloheksanoilna ili benzoilna skupina. In the previous definition, the mentioned acyl groups can be aliphatic, cycloaliphatic or aromatic. If not defined otherwise, they preferably have 1-8, with particular preference 2-7 carbon atoms. Acyl groups are, for example, formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl groups.

U prethodnoj definiciji navedene arilne skupine su ponajprije aromatske skupine sa 6-14 ugljikovih atoma, naročito sa 6-10 ugljikovih atoma kao npr. fenil, naftil. In the previous definition, the mentioned aryl groups are primarily aromatic groups with 6-14 carbon atoms, especially with 6-10 carbon atoms, such as, for example, phenyl, naphthyl.

U gore navedenim heterocikličkim prstenovima, odnosno heteroarilnim skupinama kao heteroatomi dolaze u obzir na primjer 0, S, N, pri čemu u slučaju na tom mjestu zasićenog prstena, koji sadrži N, stoji N-Z, u kojem Z, H ili R5 predstavlja bilo koju od gore navedenih definicija. In the above-mentioned heterocyclic rings, i.e. heteroaryl groups, the heteroatoms are, for example, 0, S, N, in which case N-Z stands at that position of the saturated ring, which contains N, in which Z, H or R5 represents any of above definitions.

Ako nije definirano drugačije, heterociklički prstenovi imaju ponajprije 1-13 ugljikovih atoma i 1-6 heteroatoma, naročito 3-9 ugljikovih atoma i 1-4 heteroatoma. Unless otherwise defined, heterocyclic rings preferably have 1-13 carbon atoms and 1-6 heteroatoms, especially 3-9 carbon atoms and 1-4 heteroatoms.

Kao heteroarilne skupine, navedene u prethodnim definicijama, dolaze u obzir primjerice heteroaromatski ostaci kao 2- ili 3-tienil, 2- ili 3-furil, 2-, 3- ili 4-piridil, pirimidil, indolil, kinolil ili izokinolil. The heteroaryl groups mentioned in the previous definitions include, for example, heteroaromatic residues such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.

Aralkilne skupine navedene u prethodnim definicijama su primjerice benzil, feniletil, naftilmetil ili stiril. Aralkyl groups mentioned in the previous definitions are for example benzyl, phenylethyl, naphthylmethyl or styryl.

Gore navedeni supstituienti R1 do R5 su ponajprije trostruko, s posebnom prednošću dvostruko, a naročito jednostruko supstituirani s bilo kojim navedenim supstituentom. The above-mentioned substituents R1 to R5 are preferably triply, with particular preference doubly, and especially singly substituted with any given substituent.

Za dotične sastavljene definicije složenih supstituenata (kao npr. ariloksikarbonil) također su od prednosti pojedinačni supstituenti opisani prethodno kao oni s posebnom prednošću. For the respective composite definitions of complex substituents (such as, for example, aryloxycarbonyl), the single substituents described above are also advantageous.

Ovisno o različitim supstituentima spojevi formule I i Ia mogu imati više asimetričnih ugljikovih atoma. Depending on the different substituents, the compounds of formula I and Ia can have more asymmetric carbon atoms.

Predmet izuma su stoga također čisti stereoizomeri kao također i njihove smjese, kao npr. pripadni racemat. The subject of the invention is therefore also pure stereoisomers as well as their mixtures, such as, for example, the corresponding racemate.

Čisti stereoizomeri spojeva formula I i Ia mogu se proizvesti izravno ili naknadno rastaviti po poznatim metodama ili analogno poznatim metodama. Pure stereoisomers of the compounds of formulas I and Ia can be produced directly or subsequently separated by known methods or analogously known methods.

U okviru izuma inhibitori proteaze su poznati strukturno različiti analozi peptida, koji su prikladni za liječenje bolesti induciranih s retrovirusom. Within the scope of the invention, protease inhibitors are known structurally different peptide analogs, which are suitable for the treatment of retrovirus-induced diseases.

Posebno se navode: In particular, the following are mentioned:

1. (S) -N-[(alfa) S) -alfa[(1R) -[((3S, 4aS, 8aS) -3- (terc.butil-karbamoil)oktahidro-2-(1H)-izokinolinil)-1-hidroksi-etil)fenetil-2-kinaldaraido]-sukcinamid (EP 432 695 A2) 1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S, 4aS, 8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldaraido]-succinamide (EP 432 695 A2)

[image] [image]

2. 2(R)-benzil-5-(2(S)-N-terc.butilkarbamoil)-4-(3-piridilmetil)piperazin-1-il)-4(S)-hidroksi-N-(2(R)-hidroksiindan-1(S)pentanamid 2. 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-Hydroxyindan-1(S)pentanamide

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

[image] [image]

3. N-(kinolin-2-il-karbonil)-asparagin-1(S)-benzil-3-(3-terc.butil-1-izobutilureido-2(R)-hidroksipropilamid (SC 52 151, PCT WO 92/08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92/08700 A1) 3. N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide (SC 52 151, PCT WO 92 /08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92/08700 A1)

[image] [image]

4. N1-(2R-hidroksi-3-((3-metilbutil)metilsulfonil)amino-1S-(fenilmetil)propil)-2S-((2-kinolilkarbonil)amino)-butandiamid (AM 11 686, PCT WO 94/04492) 4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide (AM 11 686, PCT WO 94/ 04492)

[image] [image]

5. (2S,3S,5S)-5(N-(N-((N-metil-N-((2-izopropil-4-oksazolil)metil)amino)-karbonil)valinil)amino)-2-(N-((5-tiazolil)metoksikarbonil)amino)-1,6-difenil-3-hidroksiheksan (A 84 538, PCT W0 94/14436) 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)-1,6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436)

[image] [image]

6. (R)-N-terc.butil-3-((2S,3S)-2-hidroksi-3-N-((R)-2-N-(izokinolil-5-il-oksiacetil)amino-3-metiltio-propanoil)amino-4-fenilbutanoil)-5,5-dimetil-1,3-tiazolidin-4-karboksamid (KNI 272/Nippon Mining) 6. (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI 272/Nippon Mining)

[image] [image]

7. Tetrahidrofuran-3-il-ester {3-[(4-amino-benzen-sulfonil)-izobutil-amino]-1-benzil-2-hidroksi -propil}-karbaminske kiseline 7. Tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid

[image] [image]

8. (3S, 6R) -3- (α-etilbenzil)-6-(α-etilfenetil)-4-hidroksi-2H-piran-2-oni (VB 11 47 8, PCT WO 9411361) 8. (3S, 6R) -3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one (VB 11 47 8, PCT WO 9411361)

[image] [image]

9. N-[5-L-[N- (2-kinolinkarbonil) -L-asparaginil]amino-(4R,3S) -epoksi-6-fenil-heksanoil]-izoleucin (EP 601 486 A) 9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine (EP 601 486 A)

[image] [image]

10. N-terc.butil-1-[2-(R)-hidroksi-4-fenil)-3(S)-[[N-(2-kinolinilkarbonil)asparaginil]amino]butil-4(R)-(fenil-tio)piperidin-2(S)-karboksamid (EP 560 268 A) 10. N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide (EP 560 268 A)

[image] [image]

11. [3"'S-(3"'R*,4"'s*)]-N-[1'-okso-(3"[1'"-okso-2"'-aza-3'"-fenilmetil-4'"-hidroksi-5'"-(2'"-N-terc. butilkarbamido)fenil]pentil-4" -metil) -1, 2, 3, 4-tetrahidro-izo-kinolin (EP 609 625 A) 11. [3"'S-(3"'R*,4"'s*)]-N-[1'-oxo-(3"[1'"-oxo-2"'-aza-3'" -phenylmethyl-4'"-hydroxy-5'"-(2'"-N-tert.butylcarbamido)phenyl]pentyl-4"-methyl)-1, 2, 3, 4-tetrahydro-iso-quinoline (EP 609 625 A)

[image] [image]

12. Terc.butilamid 2-[2-hidroksi-3-(3-hidroksi-2-metil-benzoilamino)-4-fenilsulfanil-butil]-dekahidro-izo-kinolin-3-karboksilne kiseline (AG 1343 Agouron Pharmaceutics Inc., San Diego USA) 12. Tert.butylamide 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid (AG 1343 Agouron Pharmaceutics Inc. , San Diego USA)

[image] [image]

13. 2H-1,4-diazepin-2-on,heksahidro-6-hidroksi-1,3,4,7-tetrakis(fenilmetil)-[3S-(3.alfa., 6.beta.,7.beta,)] (PCT WO 94/08977) 13. 2H-1,4-diazepin-2-one,hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S-(3.alpha., 6.beta.,7.beta) ,)] (PCT WO 94/08977)

[image] [image]

Kinoksalini općih formula (I) i (Ia) kojima se daje prednost jesu oni Preferred quinoxalines of the general formulas (I) and (Ia) are those

u kojima in which

2) n je nula, 2) n is zero,

jedan, one,

dva, two,

ili tri, or three,

fluor, klor, brom, trifluormetil, trifluormetoksi, hidroksi, C1-C4-alkil, C5-C6-cikloalkil, C1-C4-alkoksi, (C1-C4-alkoksi) - (C1-C4-alkoksi), C1-C4-alkiltio, C1-C4-alkil-sulfinil, C1-C4-alkilsulfonil, nitro, amino, C1-C4-alkil-amino, di (C1-C4-alkil) amino, piperidino, morfolino, 1-pirolidinil, 4-metil-piperazinil, tiomorfolino, imidazolil, C1-C4-acil, C1-C4-aciloksi, C1-C4-acilamino, cijano, karbamoil, karboksi, (C1-C4-alkil)-oksikarbonil, hidroksi-sulfonil, sulfamoil Fluorine, Chlorine, Bromine, Trifluoromethyl, Trifluoromethoxy, Hydroxy, C1-C4-Alkyl, C5-C6-Cycloalkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4- alkylthio, C1-C4-alkyl-sulfinyl, C1-C4-alkylsulfonyl, nitro, amino, C1-C4-alkyl-amino, di (C1-C4-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl- piperazinyl, thiomorpholino, imidazolyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl, carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxy-sulfonyl, sulfamoyl

ili or

s do da međusobno neovisna ostatka R6 supstituirani fenil-, fenoksi-, fenoksikarbonil, feniltio-, fenilsulfinil, fenilsulfonil-, fenoksisulfonil-, fenilsulfonil-oksi-, anilinosulfonil, fenilsulfonilamino, benzoil-, 2-piridilni-, 3-piridilni- ili 4-piridilni ostatak, pri čemu s to that mutually independent residues R 6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein

R6 može biti R6 can be

fluor, klor, brom, cijano, trifluormetil, nitro, amino, C1-C4-alkil, C3-C7-cikloalkil, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-alkilsulf inil, C1-C6-alkilsulfonil, C1-C6-alkilamino, di(C1-C4-alkil)-amino, (C1-C6-alkil)-oksi-karbonil, fenil, fenoksi, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1-C4-alkyl, C3-C7-cycloalkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfinyl, C1-C6-alkylsulfonyl , C1-C6-alkylamino, di(C1-C4-alkyl)-amino, (C1-C6-alkyl)-oxy-carbonyl, phenyl, phenoxy,

R2 je vodik, a R5 predstavlja R2 is hydrogen and R5 represents

vodik, hidroksi, cijano, amino, hydrogen, hydroxy, cyano, amino,

C1-C6-alkil, C1-C6-alkyl,

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil)-amino, C1-C4-alkiltio, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

C2-C8-alkenil, C2-C8-alkenyl,

po potrebi supstituiran s if necessary substituted with

C3-C8-allenil, C3-C8-allenyl,

C3-C8-alkinil, C3-C8-alkynyl,

po potrebi supstituiran s if necessary substituted with

C3-C8-cikloalkil, C3-C8-cycloalkyl,

po potrebi supstituiran s if necessary substituted with

C3-C8-cikloalkenil, C3-C8-cycloalkenyl,

po potrebi supstituiran s if necessary substituted with

(C3-C8-cikloalkil) - (C1-C2-alkil), (C3-C8-cycloalkyl) - (C1-C2-alkyl),

po potrebi supstituiran s if necessary substituted with

fluorom, klorom, bromom, jodom, cijano, amino, merkapto, hidroksi, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di (C1-C4-alkil)-amino, C1-C4-alkiltio, okso, tiokso, karboksi, karbamoilom; fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl;

(C3-C8-cikloalkenil) - (C1-C2-alkil), (C3-C8-cycloalkenyl) - (C1-C2-alkyl),

po potrebi supstituiran s if necessary substituted with

C1-C6-alkilkarbonil, C1-C6-alkylcarbonyl,

po potrebi supstituiran s if necessary substituted with

C2-C6-alkenilkarbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C6-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C3-C6-cikloalkil)karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C3-C6-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cikloalkenil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C5-C6-cycloalkenyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C3-C6-cikloalkil) - (C1-C2-alkil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C3-C6-cycloalkyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

(C5-C6-cikloalkenil) - (C1-C2-alkil) karbonil, po potrebi supstituiran s fluorom, klorom ili hidroksi, C1-C4-alkoksi, okso, fenilom; (C5-C6-cycloalkenyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkiloksikarbonil, po potrebi supstituiran s fluorom, klorom, bromom, hidroksi, C1-C4-alkoksi, C1-C4-alkilamino, di (C1-C4-alkil) amino, C1-C4-alkiltio; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio;

C2-C6-alkeniloksikarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C6-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C6-alkiniloksikarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C6-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkiltiokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C6-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C2-C6-alkeniltiokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C6-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C6-alkilamino- i di(C1-C6-alkil) aminokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C6-alkylamino- and di(C1-C6-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

pirolidin-1-il, morfolino-, piperidino-, piperazinil-ili 4-metilpiperazin-1-il-karbonil; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl;

C2-C6-alkenilamino- i di(C1-C6-alkenil)aminokarbonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C4-alkilsulfonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C4-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

C1-C4-alkenilsulfonil, po potrebi supstituiran s fluorom, klorom, hidroksi, C1-C4-alkoksi, okso, fenilom; C1-C4-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl;

ili s do tri međusobno neovisna ostataka R6 supstistuirani aril, arilkarbonil, aril(tiokarbonil), (ariltio)karbonil), (ariltio)tiokarbonil, ariloksikarbonil, arilaminokarbonil, (arilamino)tiokarbonil, arilalkilamino-karbonil, arilsulfonil, arilalkil, arilalkenil, aril-alkinil, arilalkilkarbonil, arilalkenilkarbonil, aril-(alkiltio)karbonil, arilalkoksikarbonil, pri čemu alkilni ostatak može sadržavati po 1 do 5 C-atoma, a R6 je kao gore definirani, or with up to three mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl- alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-(alkylthio)carbonyl, arylalkyloxycarbonyl, wherein the alkyl residue may contain 1 to 5 C-atoms each, and R6 is as defined above,

ili s do dva međusobno neovisna ostatka R6 supstituirani 1- ili 2-naftilmetil, 2-, 3- ili 4-pikolil, 2- ili 3-furilmetil, 2- ili 3-tienilmetil, 2- ili 3-pirolilmetil, or with up to two mutually independent residues R6 substituted 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl,

2-, 3- ili 4-piridilkarbonil, 2- ili 3-furilkarbonil, 2- ili 3-tienilkarbonil, 2- ili 3-tienilacetil, 2-, 3- ili 4-pikoliloksikarbonil, 2- ili 3-furilmetoksikarbonil, 2-ili 3-tienilmetiloksikarbonil, 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl,

i and

vodik, hydrogen,

C1-C6-alkil, C1-C6-alkyl,

po potrebi supstituiran s fluorom, klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) -amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino, C1- C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C2-C8-alkenil, po potrebi supstituiran s fluorom ili klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil)amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl )amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C3-C8-cikloalkil, po potrebi supstituiran s fluorom, klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilora, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C3-C8-cikloalkenil, po potrebi supstituiran s fluorom ili klorom, hidroksi amino, merkapto, C1-C4-aciloksi, benzoiloksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

s do tri međusobno neovisna ostatka R6 supstituirani aril, arilalkil, heteroaril ili heteroarilalkil, pri čemu alkilni ostatak može sadržavati po 1 do 3 ugljikova atoma, a R6 je kao gore definirani, with up to three mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above,

R3 i R4 mogu nadalje također biti R3 and R4 can furthermore also be

dio zasićenog ili nezasićenog karbocikličkog ili heterocikličkog prstena s 3 do 7 ugljikovih atoma, koji po potrebi može biti supstituiran s fluorom, klorom, hidroksi, amino, C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinilom, C1-C4-aciloksi, benzoiloksi, C1-C4-alkoksi, okso, tiokso, karboksi, karbamoilom ili fenilom, part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 7 carbon atoms, which can be substituted with fluorine, chlorine, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-acyloxy, benzoyloxy, C1-C4-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl,

X predstavlja kisik, sumpor, selen, po potrebi u jednom izomernom obliku, u kombinaciji s inhibitorima proteaze niza: X represents oxygen, sulfur, selenium, if necessary in one isomeric form, in combination with protease inhibitors of the series:

1. (S)-N-[(alfa)S)-alfa[(1R)-[((3S,4aS,8aS)-3-(terc.butil-karbamoil)oktahidro-2-(1H)-izokinolinil)-1-hidroksi-etil)fenetil-2-kinaldamido]-sukcinamid, 1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide,

2. 2(R)-benzil-5-(2(S)-N-terc.butilkarbamoil)-4-(3-piridilmetil)piperazin-1-il)-4(S)-hidroksi-N-(2(R)-hidroksiindan-1(S)pentanamid, 2. 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-hydroxyindan-1(S)pentanamide,

3. N-(kinolin-2-il-karbonil)-asparagin-1(S)-benzil-3-(3-terc.butil-1-izobutilureido-2(R)-hidroksipropilamid, 3. N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide,

4. N1-(2R-hidroksi-3-((3-metilbutil)metilsulfonil)amino-1S-(fenilmetil)propil)-2S-((2-kinolilkarbonil) amino)-butandiamid, 4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide,

5. (2S,3S,5S)-5(N-(N-((N-metil-N-((2-izopropil-4-oksazolil)metil)amino)-karbonil)valinil)amino)-2-(N-((5-tiazolil)metoksikarbonil)amino)-1,6-difenil-3-hidroksiheksan, 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)-1,6-diphenyl-3-hydroxyhexane,

6. (R)-N-terc.butil-3-((2s,3s)-2-hidroksi-3-N-((R)-2-N-izokinolil-5-il-oksiacetil)amino-3-metiltio-propanoil)-amino-4-fenilbutanoil)-5,5-dimetil-1,3-tiazolidin-4-karboksamid, 6. (R)-N-tert.butyl-3-((2s,3s)-2-hydroxy-3-N-((R)-2-N-isoquinolyl-5-yl-oxyacetyl)amino-3- methylthio-propanoyl)-amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

7. tetrahidrofuran-3-il-ester{3-[(4-amino-benzen-sulfonil)-izobutil-amino]-1-benzil-2-hidroksi-propil}-karbaminske kiseline, 7. tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid,

8. (3S, 6R)-3-(α-etilbenzil)-6-(α-etilfenetil)-4-hidroksi-2H-piran-2-on, 8. (3S, 6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one,

9. N-[5-L-[N-(2-kinolinkarbonil)-L-asparaginil]amino-(4R, 3S)-epoksi-6-fenil-heksanoil]-izoleucin, 9. N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R, 3S)-epoxy-6-phenyl-hexanoyl]-isoleucine,

10. N-terc.butil-1-[2-(R)-hidroksi-4-fenil)-3(S)-[[N-(2-kinolinilkarbonil)asparaginil]amino]butil-4(R)-(fenil-tio)piperidin-2(S)-karboksamid, 10. N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3(S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide,

11. [3"'S-(3"'R*,4"'S*)]-N-[1'-okso-(3"[1'"-okso-2'"-aza-3'"-fenilmetil-4"'-hidroksi-5"'-(2"'-N-terc. butilkarbamido)fenil]pentil-4''-metil)-1,2,3,4-tetrahidro-izo-kinolin, 11. [3"'S-(3"'R*,4"'S*)]-N-[1'-oxo-(3"[1'"-oxo-2'"-aza-3'" -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4''-methyl)-1,2,3,4-tetrahydro-iso-quinoline,

12. terc.butilamid 2-[2-hidroksi-3-(3-hidroksi-2-metil-benzoilamino)-4-fenilsulfanil-butil]-dekahidro-izo-kinolin-3-karboksilne kiseline, 12. 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid tert.butylamide,

13. 2H-1,4-diazepin-2-on, heksahidro-6-hidroksi-1,3,4,7-tetrakis(fenilmetil)- [3S'-(3.alfa., 6.beta., 7.beta,)], 13. 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S'-(3.alpha., 6.beta., 7. beta,)],

za upotrebu kao lijeka kod liječanja AIDS- odnosno HIV-infekcija. for use as a medicine in the treatment of AIDS- or HIV-infections.

Naročitu prednost daje se kinoksalinima općih formula (I) i (a) u kojima Particular preference is given to quinoxalines of the general formulas (I) and (a) in which

n je nula, n is zero,

jedan, one,

ili dva, or two,

fluor, klor, brom, trifluormetil, hidroksi, C1-C4-alkil, C1-C4-alkoksi, (C1-C4-alkoksi) - (C1-C4-alkoksi), C1-C4-alkiltio, nitro, amino, C1-C4-alkilamino, di(C1-C4-alkil)-amino, piperidino, morfolino, 1-pirolidinil, 4-metil-piperazinil, C1-C4-acil, C1-C4-aciloksi, C1-C4-acilamino, cijano, karbamoil, karboksi, (C1-C4-alkil)-oksikarbonil, hidroksisulfonil, sulfamoil Fluorine, Chlorine, Bromine, Trifluoromethyl, Hydroxy, C1-C4-Alkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4-Alkylthio, Nitro, Amino, C1- C4-alkylamino, di(C1-C4-alkyl)-amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl , carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl

ili or

s do dva međusobno neovisna ostatka R6 supstituirani fenil-, fenoksi-, feniltio-, fenilsulfinil, fenilsulfonil-, fenoksisulfonil-, benzoil-, 2-piridilni, 3-piridilni ili 4-piridilni ostatak, with up to two mutually independent residues R6 substituted phenyl-, phenoxy-, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, benzoyl-, 2-pyridyl, 3-pyridyl or 4-pyridyl residue,

pri čemu whereby

R6 može biti R6 can be

fluor, klor, brom, cijano, trifluormetil, nitro, amino, C1-C4-alkil, C1-C4-alkoksi, (C1-C4-alkil) oksi-karbonil, fenil, fenoksi, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1-C4-alkyl, C1-C4-alkoxy, (C1-C4-alkyl) oxy-carbonyl, phenyl, phenoxy,

R2 je vodik, a R5 je R2 is hydrogen and R5 is

C1-C6-alkil, C1-C6-alkyl,

po potrebi supstituiran s C1-C4-alkoksi ili C1-C4-alkiltio; optionally substituted with C1-C4-Alkoxy or C1-C4-Alkylthio;

C2-C6-alkenil, C2-C6-alkenyl,

po potrebi supstituiran s okso; optionally substituted with oxo;

C3-C6-allenil; C3-C6-allenyl;

C3-C8-alkinil, osobito 2-butinil; C3-C8-alkynyl, especially 2-butynyl;

C3-C6-cikloalkil, C3-C6-cycloalkyl,

C5-C6-cikloalkenil; C5-C6-cycloalkenyl;

(C3-C6-cikloalkil) - (C1-C2-alkil), osobito ciklopropil-metil, po potrebi supstituiran sa C1-C4-alkilom; (C3-C6-cycloalkyl) - (C1-C2-alkyl), especially cyclopropyl-methyl, optionally substituted with C1-C4-alkyl;

(C3-C6-cikloalkenil) - (C1-C2-alkil) , osobito ciklo-heksilmetil; (C3-C6-cycloalkenyl) - (C1-C2-alkyl), especially cyclohexylmethyl;

C1-C6-alkilkarbonil, C1-C6-alkylcarbonyl,

po potrebi supstituiran s fluorom, klorom, hidroksi, benziloksi, fenoksi, C1-C4-alkoksi, C1-C4-alkilamino, C1-C4-alkenilamino, di(C1-C4-alkil)-amino, 1-pirolidinil, piperidino, morfolino, 4-metilpiperazin-1-il, C1-C4-alkiltio; optionally substituted with fluorine, chlorine, hydroxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkenylamino, di(C1-C4-alkyl)-amino, 1-pyrrolidinyl, piperidino, morpholino , 4-methylpiperazin-1-yl, C1-C4-alkylthio;

C2-C6-alkenilkarbonil; C2-C6-alkenylcarbonyl;

C1-C6-alkiloksikarbonil, po potrebi supstituiran s fluorom, klorom, bromom, hidroksi, C1-C4-alkoksi, C1-C4-alkilamino, di(C1-C4-alkil) amino, C1-C4-alkiltio; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl) amino, C1-C4-alkylthio;

C2-C6-alkeniloksikarbonil, osobito viniloksikarbonil, alliloksikarbonil, izopropeniloksikarbonil, buteniloksi-karbonil, penteniloksikarbonil; C2-C6-alkenyloxycarbonyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl;

C2-C6-alkiniloksikarbonil, osobito propiniloksi-karbonil, butiniloksikarbonil; C2-C6-alkynyloxycarbonyl, especially propynyloxycarbonyl, butynyloxycarbonyl;

C1-C6-alkiltiokarbonil; C1-C6-alkylthiocarbonyl;

C2-C6-alkeniltiokarbonil, osobito alliltiokarbonil; C2-C6-alkenylthiocarbonyl, especially allylthiocarbonyl;

C1-C6-alkilamino- i di(C1-C6-alkil) aminokarbonil; C1-C6-alkylamino- and di(C1-C6-alkyl)aminocarbonyl;

pirolidin-1l-il, morfolino-, piperidino-, piperazinil-ili 4-metilpiperazin-1-il-karbonil; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl;

C2-C6-alkenilamino- i di(C1-C6-alkenil) aminokarbonil; C2-C6-alkenylamino- and di(C1-C6-alkenyl) aminocarbonyl;

C1-C4-alkilsulfonil; C1-C4-alkylsulfonyl;

C1-C4-alkenilsulfonil; C1-C4-alkenylsulfonyl;

ili s do dva međusobno neovisna ostataka R6 supstistuirani aril, osobito fenil, or with up to two mutually independent residues R6 substituted aryl, especially phenyl,

arilkarbonil, osobito benzoil, (ariltio)karbonil, ariloksikarbonil, arilaminokarbonil, (arilamino)tio-karbonil, arilalkilaminokarbonil, arilsulfonil, arylcarbonyl, especially benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl,

arilalkil, osobito benzoil, feniletil, arilalkenil, arilalkilkarbonil, arilalkoskikarbonil, aril(alkiltio)-karbonil, pri čemu alkilni ostatak može sadržavti po 1 do 3 C-atoma, a R6 je kao gore definirani, arylalkyl, especially benzoyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkylcarbonyl, aryl(alkylthio)-carbonyl, wherein the alkyl residue may contain 1 to 3 C-atoms each, and R6 is as defined above,

I AND

vodik, hydrogen,

C1-C4-alkil, C1-C4-alkyl,

po potrebi supstituiran s hidroksi amino, merkapto, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-alkilsulfonilom, C1-C4-alkilsulfinilom, karboksi, karbamoilom; optionally substituted with hydroxy amino, mercapto, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl;

C2-C6-alkenil, C2-C6-alkenyl,

s do dva međusobno neovisna ostataka R6 supstituirani aril, benzil, tienil ili tienilmetil, pri čemu R6 je kao gore definirani, with up to two mutually independent residues R6 substituted aryl, benzyl, thienyl or thienylmethyl, wherein R6 is as defined above,

R3 i R4 mogu također biti R3 and R4 can also be

dio zasićenog ili nezasićenog karbocikličkog ili heterocikličkog prstena s 3 do 6 ugljikovih atoma, koji po potrebi mogu biti supstituirani s okso ili tiokso i part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 carbon atoms, which can be substituted with oxo or thioxo if necessary and

X predstavlja kisik ili sumpor po potrebi u jednom izomernom obliku, u kombinaciji s inhibitorima proteaze niza: X represents oxygen or sulfur as needed in one isomeric form, in combination with protease inhibitors of the series:

1. (S)-N-[(alfa)S)-alfa[(lR)-[((3S,4aS,8aS)-3-(terc.butil-karbamoil)oktahidro-2-(1H)-izokinolinil)-1-hidroksi-etil)fenetil-2-kinaldamido]-sukcinamid, 1. (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide,

4. N1-(2R-hidroksi-3-((3-metilbutil)metilsulfonil)amino-1S-(fenilmetil)propil)-2S-((2-kinolilkarbonil)amino)-butandiamid, 4. N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)amino)-butanediamide,

6. (R)-N-terc.butil-3-((2S,3S)-2-hidroksi-3-N-((R)-2-N-(izokinolil-5-il-oksiacetil)amino-3-metiltio-propanoil)-amino-4-fenilbutanoil)-5,5-dimetil-1,3-tiazolidin-4-karboksamid, 6. (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)-amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

8. (3S,6R)-3-(α-etilbenzil)-6-(α-etilfenetil)-4-hidroksi-2H-piran-2-on, 8. (3S,6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one,

11. [3"' S-(3"' R*, 4"' S*)]-N-[1'-okso-(3"[1"'-okso-2'"-aza-3"'-fenilmetil-4"'-hidroksi-5"'-(2"'-N-terc. butilkarbamido)fenil]pentil-4"-metil)-1,2,3,4-tetrahidro-izo-kinolin, 11. [3"' S-(3"' R*, 4"' S*)]-N-[1'-oxo-(3"[1"'-oxo-2'"-aza-3"' -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4"-methyl)-1,2,3,4-tetrahydro-iso-quinoline,

12. tercbutilamid 2-[2-hidroksi-3-(3-hidroksi-2-metil-benzoilamino)-4-fenilsulfanil-butil]-dekahidro-izo-kinolin-3-karboksilne kiseline, 12. tertbutylamide 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid,

za upotrebu kao lijek kod liječanja AIDS- odnosno HIV-infekcija. for use as a medicine in the treatment of AIDS- or HIV-infections.

Posve naročitu prednost daje se kombinaciji S-4-izopropoksikarbonil-6-metoksi-3-(metiltio-metil)-3, 4-dihidro-kinoksazolin-2(1H)-tiona formule (A) Particular preference is given to the combination of S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3, 4-dihydro-quinoxazoline-2(1H)-thione of the formula (A)

[image] [image]

i (S) -N-[(alfa)S)-alfa[(1R)-2-[((3S,4aS,8aS)-3-(terc.butil-karbaraoil)oktahidro-2-(1H)-izokinolinil)-1-hidroksietil)-fenetil-2-kinaldamido]-sukcinaraida (Sakvinavir) formule (B) and (S)-N-[(alpha)S)-alpha[(1R)-2-[((3S,4aS,8aS)-3-(tert.butyl-carbaraoyl)octahydro-2-(1H)-isoquinolinyl )-1-hydroxyethyl)-phenethyl-2-quinaldamido]-succinaride (Saquinavir) of formula (B)

[image] [image]

za upotrebu pri suzbijanju AIDS-a odnosno HIV-infekcija. for use in the suppression of AIDS or HIV-infections.

Kinoksalini općih formula (I) i (Ia) su poznati [usporedi EP 509 398 A1]. Također su poznati navedeni inhibitori proteaze [usporedi EP 432 695 A2, EP 569 083 A1, EP 541 168 A1, PCT WO 92/08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92/08700 A1, PCT WO 94/04492, PCT WO 94/14436, PCT WO 94/11361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977]. Quinoxalines of the general formulas (I) and (Ia) are known [compare EP 509 398 A1]. Said protease inhibitors are also known [compare EP 432 695 A2, EP 569 083 A1, EP 541 168 A1, PCT WO 92/08688 A1, WO 92/08699 A1, WO 92/08698 A1, WO 92/08701 A1, WO 92 /08700 A1, PCT WO 94/04492, PCT WO 94/14436, PCT WO 94/11361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977].

Upotreba kombinacije ovih spojeva kod liječenja bolesti induciranih retrovirusom - a osobito bolesti induciranih HIV-om - nudi prednosti u usporedbi s monoterapijom s pojedinačnim spojevima. Korisna i nadmoćna upotreba kombinacije ovih spojeva za liječenje AIDS- i HIV-infekcija proizlazi uglavnom iz sinergističke antivirusne učinkovitosti, ali dodatno također i iz nepromijenjene podnošljivosti tvari u kombinaciji u području toksičnosti, kod koje preživljava 50% stanica - u usporedbi s Tox-50 pojedinačnih komponenata. Za ostale kombinacije poznato je - npr. AZT u kombinaciji s Ganciclovirom, da upotrebu kombinacije prati sinergistička toksičnost [usporedi M.N. Prichard et al., Antimicrob. Agents Chemotherapiy (1991), 35, 1060-1065]. The use of a combination of these compounds in the treatment of retrovirus-induced diseases - and particularly HIV-induced diseases - offers advantages compared to monotherapy with individual compounds. The beneficial and superior use of the combination of these compounds for the treatment of AIDS- and HIV-infections derives mainly from the synergistic antiviral efficacy, but additionally also from the unchanged tolerability of the substances in combination in the area of toxicity, where 50% of the cells survive - compared to Tox-50 individually components. For other combinations, it is known - for example, AZT in combination with Ganciclovir, that the use of the combination is accompanied by synergistic toxicity [compare M.N. Prichard et al., Antimicrob. Agents Chemotherapy (1991), 35, 1060-1065].

Smanjena učinkovita doza, koja proizlazi iz upotrebe kombinacije tvari za liječenje, ograničava prema tome vjerojatnost tvorbe rezistentnih virusnih izolata. The reduced effective dose, resulting from the use of a combination of treatment substances, therefore limits the likelihood of the formation of resistant viral isolates.

Izum obraduje kombinaciju dvaju razreda spojeva HIV reverznih transkriptaza i HIV-proteaza za prevenciju i liječenje infekcija s HIV-om, te za liječenje bolesti induciranih HIV-om kao AIDS Related Complex (ARC) ili AIDS. The invention provides a combination of two classes of HIV reverse transcriptase and HIV protease compounds for the prevention and treatment of HIV infections, and for the treatment of HIV-induced diseases such as AIDS Related Complex (ARC) or AIDS.

HIV-infekcija u staničnoj kulturi HIV infection in cell culture

HIV-test bio je proveden po metodi Pauwelsa et al., [usporedi Journal of Virological Methods 20, (1988), 309-321]. The HIV test was performed according to the method of Pauwels et al., [compare Journal of Virological Methods 20, (1988), 309-321].

Normalni ljudski krvni limfociti (PBL s) bili koncentrirani preko Ficoll-Hypaque i stimulirani u RPMI 1640, 20% fetalnog telećeg seruma s fitemaglutininom (90 μg/ml) i interleukinom-2 (40 U/ml). Za infekciju s infektivnim HIV-om PBL S su peletirani, i stanična peleta je bila na kraju suspendirana u 1 ml HI-otopine virusa za apsorpciju i inkubirana 1 sat pri 37°C. Normal human blood lymphocytes (PBL s) were concentrated over Ficoll-Hypaque and stimulated in RPMI 1640, 20% fetal calf serum with phytomagglutinin (90 μg/ml) and interleukin-2 (40 U/ml). For infection with infectious HIV, PBL S were pelleted, and the cell pellet was finally suspended in 1 ml HI-absorbing virus solution and incubated for 1 hour at 37°C.

Virusna apsorpcijska otopina bila je centrifugirana, a inficirana stanična peleta preuzeta je u medij za rast, tako da se je uspostavilo 1x105 stanica po ml. Tako inficirane stanice pipetirane su k 1x104 stanica/jamici u jamice mikrotitarske ploče s 96 jamica. The viral absorption solution was centrifuged, and the infected cell pellet was taken up in the growth medium, so that 1x105 cells per ml were established. Thus infected cells were pipetted at 1x104 cells/well into the wells of a 96-well microtiter plate.

Alternativno umjesto PBL’ za antivirusna ispitivanja upotrijebljene su H9 stanice. Alternatively, instead of PBL', H9 cells were used for antiviral tests.

Ispitivanje kombiniranog djelovanja ispitnih tvari bilo je provedeno titracijom šahovskog polja (Chequerboard-titration). The test of the combined action of the test substances was carried out by titration of the checkerboard (Chequerboard-titration).

Prvi okomiti niz mikrotitarske ploče sadržavao je samo sredstvo za rast i stanice koje nisu bile inficirane, ali su inače bile obrađene potpuno jednako kako je gore opisano (stanična kontrola). Drugi okomiti niz mikrotitarske ploče sadržavao je sam HIV-inficirane stanice (virusna kontrola) u sredstvu za rast. Preostale jamice sadržavale su spojeve prema izumu - same ili u odgovarajućim kombinacijama - u različitim koncentracijama, polazeći od jamica trećeg okomitog niza mikrotitarske ploče, od koje su se ispitne tvari dalje razređivale u dva stupnja (50 μl volumena po jamici). Za kombinaciju su bila pripremljena razređenja 2. tvari na odvojenoj 96 mikrotitarskoj ploči i na kraju su dopipetirane na prvu pripremljenu ploču. K tome je bilo dodano po 100 μl pripremljenih HIV-inficiranih stanica (vidi gore). Time su bile pokrivene ispitne koncentracije u području pribl. 10-50-struko iznad i ispod koncentracija IC50. The first vertical row of the microtiter plate contained only growth medium and cells that were not infected, but were otherwise treated exactly as described above (cell control). The second vertical row of the microtiter plate contained HIV-infected cells alone (viral control) in the growth medium. The remaining wells contained the compounds according to the invention - alone or in appropriate combinations - in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were further diluted in two stages (50 μl volume per well). For the combination, dilutions of the 2nd substance were prepared on a separate 96 microtitre plate and at the end they were pipetted onto the first prepared plate. To this was added 100 μl of prepared HIV-infected cells (see above). This covered test concentrations in the area of approx. 10-50-fold above and below IC50 concentrations.

Ispitne tvari inkubirane su pri 37°C tako dugo dok se je u neobrađenoj virusnoj kontroli mikroskopski mogla vidjeti tvorba sinticija na stanicama domaćinima tipična za HIV (između trećeg i šestog dana nakon infekcije). Pod tim uvjetima ispitivanja u neobrađenoj virusnoj kontroli nastalo je otprilike 20 - 50 sinticija, dok neobrađene stanične kontrole nisu imale ni jednu sinticiju. The test substances were incubated at 37°C until the formation of syncytia on host cells typical of HIV could be seen microscopically in the untreated viral control (between the third and sixth day after infection). Under these test conditions, approximately 20 - 50 syncytiums were formed in the untreated viral control, while untreated cell controls did not have a single syncytium.

Zatim je ostatak 96-jamične ploče bio pobran i istražen HIV-specifičnim ELISA-testora glede HIV-specifičnih antigena (Vironostika HIV Antigen, Organon Tehnika). Then the rest of the 96-well plate was collected and investigated with an HIV-specific ELISA-tester for HIV-specific antigens (Vironostika HIV Antigen, Organon Tehnika).

Vrijednosti suzbijanja bile su preračunate sukladno Cutt-Off-vrijednosti iz odgovarajuće stanične, odnosno virusne kontrole, odnosno inertnih ispitnih kontrola u postocima (%)-vrijednosti suzbijanja, a IC50-vrijednosti bile su oredene kao koncentracije obrađenih i inficiranih stanica, kod koje je obradom sa spojevima bilo suzbijeno 50% virus-specifičnih antigena. Za analizu sinergističke učinkovitosti bile su određene diferentne vrijednosti izračunatih i izmjerenih vrijednosti suzbijanja svake kombinacije (Prichard. M.N. et al., Antimicrob. Agents Chemoth. (1993), 37. 540-545). Suppression values were recalculated in accordance with the cut-off value from the corresponding cell, i.e. virus control, i.e. inert test controls in percentage (%)-suppression value, and the IC50-values were ordered as concentrations of treated and infected cells, where the treatment with the compounds, 50% of virus-specific antigens were suppressed. For the analysis of synergistic efficiency, the different values of the calculated and measured suppression values of each combination were determined (Prichard. M.N. et al., Antimicrob. Agents Chemoth. (1993), 37. 540-545).

Diferentna vrijednost > nule znači da se pojavljuje sinergistički učinak. Dobiveni su primjerice slijedeći rezultati: A differential value > zero means that a synergistic effect occurs. For example, the following results were obtained:

Tablica 1. Tablica diferentnih vrijednosti za proračunati i izmjereni učinak Sakvinavira (B) s primjerom formule (A). Table 1. Table of different values for the calculated and measured effect of Saquinavir (B) with an example of formula (A).

[image] [image]

U koncentracijskom oknu 0,7 - 6 Nm primjera formule (A) sa 6 - 50 nM inhibitora proteaze (B) dobivena je sinergistička učinkovitost kombinacije. In the concentration range 0.7 - 6 Nm of the example of the formula (A) with 6 - 50 nM of the protease inhibitor (B) a synergistic efficiency of the combination was obtained.

Za mjerenje sinergističke toksičnosti spojeva bile su ispitane koncentracije tvari na Tox-50 vrijednost pojedinačnog spoja i istražene mikroskopski glede stanično toksičnih svojstva, odnosno provedeno je vitalno obojenje pomoću Trypan-plavog. Ni jedna od ispitanih kombinacija nije pokazala sinergističku toksičnost. To measure the synergistic toxicity of the compounds, substance concentrations were tested for the Tox-50 value of the individual compound and examined microscopically for cellular toxic properties, i.e. vital staining was performed using Trypan blue. None of the tested combinations showed synergistic toxicity.

Iznenađujuće je bilo nađeno, da se je upotrebom kombinacije spojeva postiglo sinergističko djelovanje na HIV. To je primjerice bilo pokazano proučavanjem kombinacije derivata kinoksalina sa Sakvinavirom (tablica 1). Surprisingly, it was found that a synergistic effect on HIV was achieved by using a combination of compounds. This was demonstrated, for example, by studying the combination of quinoxaline derivatives with Saquinavir (table 1).

Kombinacije prema izumu služe za liječenje i profilaksu bolesti izazvanih retrovirusima u humanoj medicini i veterini. The combinations according to the invention serve for the treatment and prophylaxis of diseases caused by retroviruses in human medicine and veterinary medicine.

Kao područja indikacija u humanoj medicini mogu se primjerice navesti: The areas of indication in human medicine can be mentioned, for example:

1.) liječenje i profilaksa ljudskih retrovirusnih infekcija, 1.) treatment and prophylaxis of human retroviral infections,

2.) liječenje ili profilaksa bolesti uzrokovanih virusom HIV I (virus humane imunodeficijencije; ranije zvan HTLV III/LAV) (AIDS) i njihovih popratnih stanja kao ARC (AIDS related complex) i LAS (sindrom limfadenopatije), te slabosti imuniteta i encefalopatije izazvane tim virusom, 2.) treatment or prophylaxis of diseases caused by the HIV I virus (human immunodeficiency virus; previously called HTLV III/LAV) (AIDS) and their accompanying conditions such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome), as well as immune weakness and encephalopathy caused that virus,

3.) liječenje ili profilaksa HTLV-I ili HTLV-II infekcije, 3.) treatment or prophylaxis of HTLV-I or HTLV-II infection,

4.) liječenje ili profilaksa stanja AIDS-carrier (stanje prijenosnika AIDS-a). 4.) treatment or prophylaxis of the AIDS-carrier condition.

Kao indikacije u veterini mogu se primjerice navesti infekcije s: Indications in veterinary medicine include, for example, infections with:

a) Maedivisna (kod ovaca i koza), a) Maedivisna (in sheep and goats),

b) progresivnim pneumo virusom (PPV) (kod ovaca i koza), b) progressive pneumovirus (PPV) (in sheep and goats),

c) caprine arthritis ancephalitis virusom (kod ovaca i koza), c) caprine arthritis encephalitis virus (in sheep and goats),

d) Zwoegerziektovim virusom (kod ovaca), d) Zwoegerziekt virus (in sheep),

e) infektoznim virusom anemije (konja), e) infectious anemia virus (horse),

f) infekcije uzrokovane virusom mačje leukemije, f) infections caused by feline leukemia virus,

g) infekcije uzrokovane virusom mačje imunodeficijencije (FIV), g) infections caused by feline immunodeficiency virus (FIV),

h) infekcije uzrokovane virusom majmunske imunodeficijencije (SIV). h) infections caused by simian immunodeficiency virus (SIV).

Ponajprije, to je područje indikacija u humanoj medicini navedeno gore pod točkama 2, 3 i 4. First of all, it is the area of indications in human medicine mentioned above under points 2, 3 and 4.

U predloženi izum spadaju farmaceutski pripravci, koji pored netoksične, inertne farmaceutski prikladne noseće tvari sadrže jedan ili više spojeva formula (I)/(Ia) u kombinaciji s jednim od navedenih inhibitora proteaze ili koji se sastoje od jedne ili više aktivnih tvari formula (I)/(Ia) i inhibitora proteaze, te postuci za proizvodnju tih pripremaka, osobito kombinacija ispitnih spojeva. The proposed invention includes pharmaceutical preparations, which, in addition to a non-toxic, inert pharmaceutically suitable carrier substance, contain one or more compounds of the formulas (I)/(Ia) in combination with one of the mentioned protease inhibitors or which consist of one or more active substances of the formulas (I )/(Ia) and protease inhibitors, and procedures for the production of these preparations, especially combinations of test compounds.

Aktivne tvari formula (I) i (Ia) i inhibitori proteaze u gore navedenim farmaceutskim pripremcima moraju biti prisutni ponajprije u koncentraciji od pribl. 0,1 do 99,5 mas. %, naročito od pribl. 0,5 do 95 mas. % ukupne smjese. Active substances of formulas (I) and (Ia) and protease inhibitors in the above-mentioned pharmaceutical preparations must be present primarily in a concentration of approx. 0.1 to 99.5 wt. %, especially from approx. 0.5 to 95 wt. % of the total mixture.

Osim spojeva formula (I) i (Ia) gore navedeni farmaceutski pripremci u kombinaciji s jednim od gore navedenih inhibitora proteaze mogu sadržavati također i daljnje farmaceutske učinkovite tvari. In addition to the compounds of formulas (I) and (Ia), the above-mentioned pharmaceutical preparations in combination with one of the above-mentioned protease inhibitors may also contain further pharmaceutical active substances.

Proizvodnja gore navedenih farmaceutskih pripremaka vrši se na uobičajen način po poznatim metodama, npr. miješanjem jedne ili više aktivnih tvari s jednom ili više nosećih tvari. The production of the above-mentioned pharmaceutical preparations is carried out in the usual way by known methods, for example by mixing one or more active substances with one or more carrier substances.

Za postizanje željenog rezultata, kako u humanoj medicini, tako također i u veterini pokazalo se je općenito korisnim dati jednu ili više aktivnih tvari ukupnom količinom od pribl. 0,5 do pribl. 500, ponajprije 1 do 100 mg/kg tjelesne težine svaka 24 sata. Pojedinačno davanje sadrži jednu ili više aktivnih tvari količinom od pribl. 1 do pribl. 80, naročito 1 do 30 mg/kg tjelesne težine. Međutim, može ipak biti potrebno odstupiti od navedenog doziranja, i to ovisno o vrsti i tjelesnoj težini liječenog pacijenta, vrsti i težini blesti, vrsti pripremka i aplikaciji lijeka, te o vremenskom razmaku, odnosno inetrvalu u kojem se daje lijek. In order to achieve the desired result, both in human medicine and also in veterinary medicine, it has generally been shown to be useful to give one or more active substances in a total amount of approx. 0.5 to approx. 500, preferably 1 to 100 mg/kg of body weight every 24 hours. A single dose contains one or more active substances in an amount of approx. 1 to approx. 80, especially 1 to 30 mg/kg of body weight. However, it may still be necessary to deviate from the stated dosage, depending on the type and body weight of the treated patient, the type and severity of the rash, the type of preparation and application of the drug, and the time interval, i.e., the interval in which the drug is administered.

Claims

1. A drug containing in combination one or more protease inhibitors and one or more quinoxalines of the general formulas (I) and (Ia) [image] and their tautomeric forms of the general formula Ia [image] indicated by that 1) n is zero, one, two, three, or four, individual substituents R1 represent independently of each other fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxy, C1-C8-alkyl, C5-C8-cycloalkyl, C1-C6-alkoxy, (C1-C6-Alkoxy) - (C1-C4-Alkoxy), C1-C6-alkylthio, C1-C66-alkylsulfinyl, C1-C6-alkylsulfonyl, nitro, amino, azido, C1-C6-alkylamino, di(C1-C6-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4- methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, C1-C6-acyl, C1-C6-acyl-oxy, C1-C6-acylamino, cyano, carbamoyl, carboxy, (C1-C6-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfaroyl or with up to five mutually independent residues R6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or a 4-pyridyl residue, whereby R6 can be fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, C1-C6-alkyl, C3-C8-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6 -alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylamino, di(C1-C6-alkyl)amino, (C1-C6-alkyl)-oxycarbonyl, phenyl, phenoxy, 2-, 3- or 4-pyridyl, R2 and R5, the same or different, independently represent each other hydrogen, hydroxy, C1-C6-Alkoxy, aryloxy, C1-C6-acyl-oxy, cyano, amino, C1-C6-alkylamino, di(C1-C6-alkyl) amino, arylamino, C1-C6-acylamino, C1- C8-alkyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di( C1-C6-alkyl)-amino, C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C2-C8-alkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C3-C8-allenyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C3-C8-alkynyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkyl) - (C1-C4-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkenyl) - (C1-C4-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydrocny, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C1-C6-alkylcarbonyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C6-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C6-alkoxy, C1-C6-alkylamino, di(C1-C6-alkyl)-amino , C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C2-C8-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C8-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C8-cycloalkenyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C8-cycloalkyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C8-cycloalkenyl) - (C1-C3-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C8-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C8-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C8-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C8-alkylamino- and di(C1-C8-alkyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl-or 4-methylpiperazin-1-yl-carbonyl, optionally substituted with C1-C4-alkyl, C2-C6-alkenyl, C1-C4-acyl, oxo, thioxo , carboxy, or phenyl; C2-C8-alkenylamino- and di(C1-C8-alkenyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; or with up to 5 mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl- alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-alkoxycarbonyl, aryl(alkylthio)carbonyl, wherein the alkyl residue can contain 1 to 5 C-atoms each, and R6 is as defined above, or with up to three mutually independent radicals R6 substituted heteroaryl, heteroarylalkyl, heteroaryl-alkenyl, heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl, (heteroarylthio)carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl(alkylthio)carbonyl, heteroarylalkylaminocarbonyl, wherein the alkyl residue may contain 1 to 3 carbon atoms, R3 and R4, the same or different, independently represent each other hydrogen, C1-C8-alkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4 -alkyl) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C2-C8-alkyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, -hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4- alkyl) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, whereby the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above, R3 and R4 or R3 and R5 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 8 carbon atoms, which can be optionally substituted with fluorine, chlorine, hydroxy, amino, C1-C6-alkyl, C2-C6 -alkenyl, C2-C6-alkynyl, C1-C6-acyloxy, benzoyloxy, C1-C6-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl; X represents oxygen, sulfur, selenium or substituted nitrogen N-R2, where R2 can have the above meanings, with the exception of compounds in which R3 and R4 simultaneously represent H and compounds in which R2 and R5 represent H, with R3 and/or R4 representing arylalkyl and compounds in which X represents oxygen and R2 and R5 are hydrogen.

2. The drug according to claim 1, characterized in that it contains one or more quinoxalines of the general formulas (I) and (Ia) in which 2) n is zero, one, two, or three, the individual substituents R1 independently represent each other Fluorine, Chlorine, Bromine, Trifluoromethyl, Trifluoromethoxy, Hydroxy, C1-C4-Alkyl, C5-C6-Cycloalkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4- alkylthio, C1-C4-alkyl-sulfinyl, C1-C4-alkylsulfonyl, nitro, amino, C1-C4-alkyl-amino, di (C1-C4-alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl- piperazinyl, thiomorpholino, imidazolyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl, carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxy-sulfonyl, sulfamoyl or s to that mutually independent residues R 6 substituted phenyl-, phenoxy-, phenoxycarbonyl, phenylthio-, phenylsulfinyl, phenylsulfonyl-, phenoxysulfonyl-, phenylsulfonyl-oxy-, anilinosulfonyl, phenylsulfonylamino, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4 -pyridyl residue, wherein R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1-C4-alkyl, C3-C7-cycloalkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfinyl, C1-C6-alkylsulfonyl , C1-C6-alkylamino, di(C1-C4-alkyl)-amino, (C1-C6-alkyl)-oxy-carbonyl, phenyl, phenoxy, R2 is hydrogen and R5 represents hydrogen, hydroxy, cyano, amino, C1-C6-alkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C2-C8-alkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-allenyl, C3-C8-alkynyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C3-C8-cycloalkenyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkyl) - (C1-C2-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di (C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; (C3-C8-cycloalkenyl) - (C1-C2-alkyl), if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C1-C6-alkylcarbonyl, if necessary substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino , C1-C4-alkylthio, oxo, thioxo, carboxy, carbamoyl; C2-C6-alkenylcarbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C6-cycloalkyl)carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C3-C6-cycloalkyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; (C5-C6-cycloalkenyl) - (C1-C2-alkyl) carbonyl, optionally substituted with fluorine, chlorine or hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C6-alkenyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C6-alkynyloxycarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C2-C6-alkenylthiocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C6-alkylamino- and di(C1-C6-alkyl) aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl; C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C4-alkylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; C1-C4-alkenylsulfonyl, optionally substituted with fluorine, chlorine, hydroxy, C1-C4-alkoxy, oxo, phenyl; or with up to three mutually independent residues R6 substituted aryl, arylcarbonyl, aryl(thiocarbonyl), (arylthio)carbonyl), (arylthio)thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thiocarbonyl, arylalkylamino-carbonyl, arylsulfonyl, arylalkyl, arylalkenyl, aryl-alkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, aryl-( alkylthio)carbonyl, arylalkyloxycarbonyl, wherein the alkyl residue can contain 1 to 5 C-atoms each, and R6 is as defined above, or with up to two mutually independent radicals R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, and R3 and R4, the same or different, independently represent each other hydrogen, C1-C6-alkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl)-amino, C1- C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C2-C8-alkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl )amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C3-C8-cycloalkyl, optionally substituted with fluorine, chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; C3-C8-cycloalkenyl, optionally substituted with fluorine or chlorine, hydroxy amino, mercapto, C1-C4-acyloxy, benzoyloxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, di(C1-C4-alkyl ) amino, C1-C4-alkylthio, C1-C4-alkylsulfonyl, C1-C4-alkylsulfinyl, carboxy, carbamoyl; with up to five mutually independent residues R6 substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein the alkyl residue can contain 1 to 3 carbon atoms each, and R6 is as defined above R3 and R4 can furthermore also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 7 carbon atoms, which can be substituted with fluorine, chlorine, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-acyloxy, benzoyloxy, C1-C4-alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl; X represents oxygen, sulfur, selenium, if necessary in one isomeric form.

3. The drug according to claim 1, characterized in that it contains one or more quinoxalines of the general formulas (I) and (Ia) in which n is zero, one, or two, individual substituents R1 independently of each other can be Fluorine, Chlorine, Bromine, Trifluoromethyl, Hydroxy, C1-C4-Alkyl, C1-C4-Alkoxy, (C1-C4-Alkoxy) - (C1-C4-Alkoxy), C1-C4-Alkylthio, Nitro, Amino, C1- C4-alkylamino, di (C1-C4-alkyl)-amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, C1-C4-acyl, C1-C4-acyloxy, C1-C4-acylamino, cyano, carbamoyl , carboxy, (C1-C4-alkyl)-oxycarbonyl, hydroxysulfonyl, sulfamoyl or one with up to two mutually independent residues R6 substituted phenyl-, phenoxy-, phenylthio-, phenylsulfinyl, phenoxysulfonyl-, benzoyl-, 2-pyridyl-, 3-pyridyl- or 4-pyridyl residue, whereby R6 can be fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C1-C4-alkyl, C1-C4-alkoxy, (C1-C4-alkyl)-oxycarbonyl, phenyl, phenoxy, R2 is hydrogen and R5 is C1-C6-alkyl, optionally substituted with C1-C4-Alkoxy or C1-C4-Alkylthio; C2-C6-alkenyl, optionally substituted with oxo, C3-C6-allenyl, C3-C8-alkynyl, especially 2-butynyl; C3-C6-cycloalkyl, C5-C6-cycloalkenyl; (C3-C6-cycloalkyl) - (C1-C2-alkyl), especially cyclopropyl-methyl, optionally substituted with Cx-Ct-alkyl; (C3-C6-cycloalkenyl) - (C1-C2-alkyl), especially cyclohexylmethyl; C1-C6-alkylcarbonyl, optionally substituted with fluorine, chlorine, hydroxy, benzyloxy, phenoxy, C1-C4-alkoxy, C1-C4-alkylamino, C1-C4-alkenylamino, di(C1-C4-alkyl)amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl, C1-C4-alkylthio; C2-C6-alkenylcarbonyl; C1-C6-alkyloxycarbonyl, optionally substituted with fluorine, chlorine, bromine, hydroxy, C1-C4-alkoxy, C1-C4-alkylamirio, di(C1-C4-alkyl)amino, C1-C4-alkylthio; C2-C6-alkenyloxycarbonyl, especially vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; C2-C6-alkynyloxycarbonyl, especially propynyloxycarbonyl, butynyloxycarbonyl; C1-C6-alkylthiocarbonyl; C2-C6-alkenylthiocarbonyl, especially allylthiocarbonyl; C1-C6-alkylamino- and di(C1-C6-alkyl!) aminocarbonyl; pyrrolidin-1-yl, morpholino-, piperidino-, piperazinyl- or 4-methylpiperazin-1-yl-carbonyl; C2-C6-alkenylamino- and di(C1-C6-alkenyl)aminocarbonyl; C1-C4-alkylsulfonyl; C1-C4-alkenylsulfonyl; or with up to two mutually independent residues R6 substituted aryl, especially phenyl, arylcarbonyl, especially benzoyl, (arylthio)carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino)thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, especially benzyl, phenylethyl, arylalkenyl, arylalkylcarbonyl, arylalkylcarbonyl, aryl(alkylthio)-carbonyl, wherein the alkyl residue can contain 1 to 3 C-atoms each, and R6 is as defined above, or with up to two mutually independent radicals R6 substituted 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-furylmethoxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, and R3 and R4, the same or different, independently represent each other hydrogen, C1-C4-alkyl, optionally substituted with hydroxy amino, mercapto, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylsulfinyl, carboxy, carbamoyl; C2-C6-alkenyl, with two mutually independent residues R6 substituted aryl, benzyl, thienyl or thienylmethyl, where R6 is as defined above, R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 carbon atoms, which can be substituted with oxo or thioxo if necessary and X represents oxygen or sulfur as needed in one isomeric form.

4. The drug, according to claims 1 to 3, characterized by the fact that as a protease inhibitor it contains one or more compounds from the group 1) (S)-N-[(alpha)S)-alpha[(1R)-[((3S,4aS,8aS)-3-(tert.butyl-carbamoyl)octahydro-2-(1H)-isoquinolinyl) -1-hydroxy-ethyl)phenethyl-2-quinaldamido]-succinamide, 2) 2(R)-benzyl-5-(2(S)-N-tert.butylcarbamoyl)-4-(3-pyridylmethyl)piperazin-1-yl)-4(S)-hydroxy-N-(2( R)-hydroxyindem-1(S)-yl)pentanamide, 3) N-(quinolin-2-yl-carbonyl)-asparagine-1(S)-benzyl-3-(3-tert.butyl-1-isobutylureido-2(R)-hydroxypropylamide, 4) N1-(2R-hydroxy-3-((3-methylbutyl)methylsulfonyl)amino-1S-(phenylmethyl)propyl)-2S-((2-quinolylcarbonyl)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)-1,6-diphenyl-3-hydroxyhexane, 6) (R)-N-tert.butyl-3-((2S,3S)-2-hydroxy-3-N-((R)-2-N-(isoquinolyl-5-yl-oxyacetyl)amino-3 -methylthio-propanoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, 7) tetrahydrofuran-3-yl-ester {3-[(4-amino-benzene-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid, 8) (3S, 6R)-3-(α-ethylbenzyl)-6-(α-ethylphenethyl)-4-hydroxy-2H-pyran-2-one, 9) N-[5-L-[N-(2-quinolinecarbonyl)-L-asparaginyl]amino-(4R,3S)-epoxy-6-phenyl-hexanoyl]-isoleucine, 10) N-tert.butyl-1-[2-(R)-hydroxy-4-phenyl)-3 (S)-[[N-(2-quinolinylcarbonyl)asparaginyl]amino]butyl-4(R)-( phenyl-thio)piperidine-2(S)-carboxamide, 11) [3"'S-(3"'R*,4"'S*)]-N-[1'-oxo-(3"[1"'-oxo-2"'-aza-3"' -phenylmethyl-4"'-hydroxy-5"'-(2"'-N-tert.butylcarbamido)phenyl]pentyl-4-methyl)-1,2,3,4-tetrahydro-iso-quinoline, 12) 2-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenylsulfanyl-butyl]-decahydro-iso-quinoline-3-carboxylic acid tert.butylamide, 13) 2H-1,4-diazepin-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis(phenylmethyl)-[3S'-(3.alpha., 6.beta.,7. beta,)].

5. Medicine, characterized by the fact that it contains a combination of S-4-isopropoxy-carbonyl-6-methoxy-3-(methylthio-methyl)-3, 4-dihydro-quinoxaline-2(1H)-thione of formula (A) [image] and (S)-N-[(alpha)S)-alpha[(1R)-[((3S, 4aS, 8aS)-3-(tert.butyl-carbamoyl)octa-hydro-2-(1H)-isoquinolinyl )-1-hydroxyethyl)-phenethyl-2-quinaldamido]-succinamide (Saquinavir) of formula (B) [image]