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EP0977570A1 - Chinoxaline in dreier-kombination mit proteaseinhibitoren und reverse transkriptaseinhibitoren als arzneimittel zur behandlung von aids - Google Patents

Chinoxaline in dreier-kombination mit proteaseinhibitoren und reverse transkriptaseinhibitoren als arzneimittel zur behandlung von aids

Info

Publication number
EP0977570A1
EP0977570A1 EP98905297A EP98905297A EP0977570A1 EP 0977570 A1 EP0977570 A1 EP 0977570A1 EP 98905297 A EP98905297 A EP 98905297A EP 98905297 A EP98905297 A EP 98905297A EP 0977570 A1 EP0977570 A1 EP 0977570A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydroxy
alkoxy
amino
chlorine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98905297A
Other languages
German (de)
English (en)
French (fr)
Inventor
Arnold Paessens
Martin Blunck
Günter Riess
Jörg-Peter Kleim
Manfred Rösner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0977570A1 publication Critical patent/EP0977570A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the present invention relates to the use of quinoxalines in a combination of three with protease inhibitors and reverse transcriptase inhibitors as medicaments for the treatment of AIDS and / or HIV infections.
  • HIV human immunodeficiency virus
  • ARC / ALDS clinical picture various other clinical manifestations in the ARC / ALDS clinical picture are also caused by the HIV virus - in particular opportunistic infections (O.I.), caused by other viruses, such as e.g. He ⁇ esviren (HSV I and II), cytomegalovirus (CMV) or O.I., caused by bacteria, fungi or parasites.
  • O.I. opportunistic infections
  • HSV I and II He ⁇ esviren
  • CMV cytomegalovirus
  • O.I. caused by bacteria, fungi or parasites.
  • HTV belongs to the retrovirus family; One of the essential and essential enzymatic activities of these viruses in the propagation cycle is the protease (Huff, J.R .: J. Med. Chem. (1991), 34, 2305-2314). Small molecular peptide and non-peptide analogues of the natural substrates of the protease inhibit the replication of HTV (Roberts,
  • Analogs of the natural substrates of reverse transcriptase such as azidothymidine (AZT), dideoxycytidine (DDC), dideoxyinosine (DDI) and 3'-thiacytidine (Lamivudine) inhibit the replication of HIV in vitro and in vivo.
  • AZT is used, for example, to treat ARC / AIDS patients.
  • Long-term therapy for HTV-infected patients with AZT is associated with bone marrow toxicity; AZT-resistant virus isolates are also produced.
  • Intolerance such as peripheral neuropathy, has been reported by some patients treated with DDC or DDI. New inhibitors for tolerable and effective therapy are therefore necessary.
  • the now found triple combination of quinoxalines with protease inhibitors and reverse transcriptase inhibitors is new and their synergistic effect on the multiplication of HIV when used in combating AIDS or HIV infections is significantly better than the prior art.
  • the individual substituents Rl independently of one another fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 8 -alkyl, C 5 -C 8 -cycloalkyl, C r C 6 -alkoxy, (C 1 -C 6 -alkoxy) - (C 1 -C 4 -alkoxy), C r C 6 -alkylthio, C r C 6 -alkylsulfinyl, C ⁇ -C 6 -alkylsulfonyl, nitro, amino, azido, C r C 6 -alkylamino, di (C r C 6 -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl,
  • R hydrogen, Cj-C 6 alkoxy, hydroxy, picolyl, cyclopropyl or isopropenyloxycarbonyl and
  • R5 is hydrogen, hydroxy, Cj-Cg-alkoxy, aryloxy, C] -C 6 -acyloxy, cyano,
  • C 2 -C 8 alkenyl optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, C - Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, Ci-Cg-alkoxy, Ci-C ⁇ - Alkylamino, di (C ⁇ - - alkyl) amino, C ⁇ -C 6 -alkylthio, (Cj-Cg-alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;
  • C 3 -C 8 allenyl optionally substituted by fluorine, chlorine or hydroxy, -CC alkoxy, oxo, phenyl; C 3 -C 8 alkynyl, optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C Cö-
  • C ß - cycloalkyl optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, C r C 6 alkoxy, C 1 -C 6 - Alkylamino, di (C r C 6 alkyl) amino, C Cg alkylthio, C 6 -C 6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;
  • Ci-Cg-alkylcarbonyl optionally substituted with fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, Ci-Cg-acyloxy, benzoyloxy, benzyloxy, phenoxy, Ci-Cg-alkoxy, Ci-Cg-alkylamino, DKCi -Cg-alkyl) - amino -CC 6 alkylthio, C -C 6 alkylsulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;
  • (C 3 -C 8 cycloalkyl) carbonyl optionally substituted by fluorine, chlorine or hydroxy, -CC alkoxy, oxo, phenyl;
  • C r C 8 alkyloxycarbonyl optionally substituted by fluorine, chlorine, bromine, hydroxy, alkoxy, C alkylamino, di (C 1 -C 4 alkyl) amino, C r C 4 alkylthio;
  • arylcarbonyl aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) - thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thio-carbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylsulfonyl
  • R the same or different, independently of one another hydrogen, CC 8 - alkyl, optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C 1 -C 4 -acyloxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 -alkoxy C 1 -C 4 Alkylamino, di (C r C 4 alkyl) amino, C r C 4 alkylthio, C r C 4 alkyl sulfonyl, C 1 -C 4 alkylsulfinyl, carboxy, carbamoyl;
  • C 2 -C 8 alkylene optionally substituted with fluorine or chlorine, hydroxy, amino, mercapto, C r C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy C r C 4 alkoxy, C r C 4 alkylamino, di (C r C 4 alkyl) amino, C r C 4 alkylthio, C alkyl sulfonyl, C r C alkyl sulfinyl, carboxy, carbamoyl;
  • C 3 -C 8 cycloalkyl optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C r C -acyloxy, benzoyloxy, benzyloxy, phenoxy, - -alkoxy, C 1 -C -alkylamino, DC -alkyamino, - -Alkyl-thio,--alkylsulfonyl, C 1 -C -alkylsulfinyl, carboxy, carbamoyl;
  • Arylalkyl, heteroaryl or heteroarylalkyl mean, where the alkyl radical can each contain 1 to 3 carbon atoms and R ⁇ is as defined above,
  • R ⁇ and R ⁇ can also be part of a saturated or unsaturated carbo- or heterocyclic ring with 3 to 8 carbon atoms, which optionally with
  • Carboxy, carbamoyl or phenyl can be substituted
  • X represents oxygen, sulfur, selenium or substituted nitrogen NR 2 , where R 2 can have the meanings given above
  • alkyl groups mentioned in the preceding definitions can be straight-chain or branched. Unless otherwise defined, they preferably contain 1-8, particularly preferably 1-6, in particular 1-4 C atoms. Examples are the methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl group and the like.
  • alkenyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 double bonds. Unless otherwise defined, these groups preferably contain 2-8, in particular 2-6 C-
  • Examples are the 2-propenyl, 1-methylethenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl 2,3-dimethyl-2-butenyl-3 , 3-di-chloro-2-propenyl, pentadienyl group and the like.
  • alkynyl groups mentioned in the preceding definitions can be straight-chain or branched and contain 1 to 3 triple bonds. Unless otherwise defined, they preferably contain 2-8, particularly preferably 3-6, carbon atoms. Examples are the 2-propynyl and 3-butynyl groups and the like.
  • the cycloalkyl and cycloalkenyl groups mentioned in the preceding definitions preferably contain 3-8, particularly preferably 4-6 C atoms.
  • Examples are the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl group.
  • acyl groups mentioned in the preceding definitions can be aliphatic, cycloaliphatic or aromatic. Unless otherwise defined, they preferably contain 1-8, particularly preferably 2-7, carbon atoms. Exemplary acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclohexanoyl or benzoyl group.
  • the aryl groups mentioned in the previous definitions are preferably aromatic groups with 6-14 C atoms, in particular with 6-10 C atoms, such as phenyl, naphthyl.
  • suitable heteroatoms are in particular, for example, O, S, N, where in the case of an N-containing ring saturated at this point, NZ is present, in which Z, H or R5 means with the respective definitions described above .
  • heterocyclic rings preferably have 1-13
  • heteroaromatic radicals such as 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl are suitable
  • aralkyl groups listed in the previous definitions are, for example, benzyl, phenylethyl, naphthylmethyl or styryl.
  • substituents Rl to R ⁇ are preferably 3-fold, particularly preferably 2-fold, in particular simply substituted with the substituents specified in each case.
  • compounds of the formulas I and Ia can have several asymmetric carbon atoms.
  • the invention therefore relates both to the pure stereoisomers and mixtures thereof, such as. B. the associated racemate.
  • the compounds of the formulas I and Ia can be prepared by known methods or modifications thereof (see, for example, Rodd's Chemistry of Carbon Compounds, S. Coffey, MF Ansell (editor); Elsevier, Amsterdam, 1989; Vol. IV Part IJ, Pp. 301-311. Heterocyclic Compounds, RC Elderfield (Editor); Wiley, New York, 1957; Vol. 6, pp. 491-495).
  • protease inhibitors stand for known structurally different peptide analogs which are suitable for the treatment of retrovirus-induced diseases.
  • PCT WO 95/20384 AI PCT WO 95/009614 AI [ABBOTT (ritonavir) ABT-538]
  • reverse transcriptase inhibitors stand for different nucleosides. Zidovudine (Retrovir) (AZT) and didanosine are preferred (DDI), dideoxycytidine (DDC), lamivudine (Epivir, 3-TC ®), stavudine (d4T), BW 935U83, BW 1592U89. ; especially zidovudine and epivir.
  • the nucleosides mentioned can be prepared by generally known methods (cf. Merck Index, 11th edition Rahway, NJ 1989, Drugs 45 (4), 488 ff., 45 (5), 637 ff., 1993, Drugs 44 (4th ), 656 ff., 1992, Clin. Pharmacol. Ther. 55, No. 2, 198, 1994,
  • Retrovir is particularly preferred.
  • n zero, one or two
  • Rl independently of one another fluorine, chlorine, bromine, trifluoromethyl, hydroxy
  • Ci- -alkylthio nitro, amino, C r C 4 -alkylamino, di (C 1 -C -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C r C 4 -acyl, C r C - Acyloxy, C r C 4 acylamino, cyano, carbamoyl, carboxy, (C 1 -C alkyl) oxycarbonyl, hydroxysulfonyl, sulfamoyl
  • R 2 is hydrogen
  • R5 C j -Cg alkyl optionally substituted with fluorine, chlorine, hydroxy,
  • C 1 -C 4 acyloxy benzoyloxy, benzyloxy, phenoxy, C 1 -C alkoxy, C 1 -C 4 alkylamino, di (C 4 -C 4 alkyl) amino, C 1 -C alkylthio, oxo, thioxo, carboxy, carbamoyl ;
  • C 3 -C cycloalkenyl optionally substituted with fluorine, chlorine, hydroxy, - alkyl, - acyloxy, benzoyloxy, benzyloxy, phenoxy, C r C 4 alkoxy, C r C 4 alkylamino, di (C r C 4 alkyl) amino, C r C 4 alkyl thio, oxo, thioxo, carboxy, carbamoyl;
  • C Cg-alkylcarbonyl optionally substituted with fluorine, chlorine, hydroxy, C 1 -C 4 -alkyl, C ⁇ -acyloxy " , benzoyloxy, benzyloxy, phenoxy, C r C -alkoxy, C r C -alkylamino, C ⁇ C- ⁇ Alkenylamino, di (C 1 -C 4 alkyl) amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-l-yl, C r C alkylthio, oxo, thioxo, carboxy, carbamoyl;
  • C 1 -C 6 alkyloxycarbonyl optionally substituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 -alkylthio;
  • arylcarbonyl or aryl, arylcarbonyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, substituted by up to two mutually independent radicals R6,
  • R ⁇ and R ⁇ are the same or different, independently of one another hydrogen
  • C j -C 4 alkyl optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C j -C acyloxy, benzoyloxy, phenoxy, C r C 4 alkoxy, C 1 -C 4 alkylamino, Di (C r C 4 alkyl) amino, C r C 4 alkylthio, C r C 4 alkyl sulfonyl, C 1 -C alkyl sulfinyl, carboxy, carbamoyl; C 2 -C 6 alkenyl, optionally substituted with fluorine or chlorine;
  • C 3 -C 6 cycloalkyl optionally substituted with fluorine, chlorine, hydroxy, amino, mercapto, C r C 4 acyloxy, benzoyloxy, benzyloxy, phenoxy, C r C 4 alkoxy, C r C 4 alkylamino, di ( C r C 4 alkyl) amino, C r C 4 alkyl thio, C 1 -C 4 alkylsulfonyl, C 1 -C alkylsulfinyl, carboxy, carbamoyl;
  • R3 and R ⁇ can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 C atoms, which may optionally contain fluorine, chlorine, hydroxy, amino, Cj- acyloxy, benzoyloxy, Cj-Calk- oxy, oxo, thioxo, carboxy, carbamoyl can be substituted, and
  • X oxygen or sulfur
  • n zero, one or two
  • Rl independently of one another fluorine, chlorine, bromine, trifluoromethyl, hydroxy, C r C 4 alkyl, C r C 4 alkoxy, (C r C 4 alkoxy) - (C r C 2 alkoxy), C r C 4 - Alkylthio, nitro, amino, C 1 -C 4 -alkylamino, di (C ! -C 4 -alkyl) amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, C r C 4 -acyl,
  • R 6 fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, C 1 -C 4 alkyl, C r C 4 alkoxy, (- -alkyoxycarbonyl, phenyl, phenoxy
  • R 2 is hydrogen
  • R 5 Cj- alkyl optionally substituted with Cj- alkoxy or C r C 4 -
  • Ci-Cg-alkylcarbonyl optionally substituted with fluorine, chlorine, hydroxy, benzyloxy, phenoxy, C -alkoxy, C 1 -C -alkylamino, CC 4 - Alkenylamino, di (C r C 4 alkyl) amino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-l-yl, CC alkylthio;
  • C 1 -C 4 -alkyloxycarbonyl optionally substituted by fluorine, chlorine, bromine, hydroxy, - -alkoxy, C 1 -C 4 -alkylamino, di (C r C 4 -alkyl) - amino, - -alkylthio;
  • C 2 -C 6 alkenyloxycarbonyl especially vinyloxy carbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl;
  • C r C 4 alkenylsulfonyl or aryl substituted with up to two independent radicals, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylaminocarbonyl, arylsulfonyl, arylalkyl, in particular
  • alkyl radical can contain 1 to 3 carbon atoms and R ⁇ is as defined above
  • R ⁇ and R ⁇ the same or different, independently of one another hydrogen, C - alkyl, optionally substituted with hydroxy, mercapto, -CC alkoxy,
  • R3 and R ⁇ can also be part of a saturated or unsaturated carbo- or heterocyclic ring with 3 to 6 carbon atoms, which can optionally be substituted with oxo or thioxo and
  • X oxygen or sulfur
  • Retrovir Retrovir
  • Epivir for use in combating AIDS and HIV infections.
  • the quinoxalines of the general formulas (I) and (Ia) are known [cf. EP 509 398 AI; EP 708 093; EP 657 166].
  • the protease inhibitors listed above are also known [cf. EP 432 695 A2, EP 569 083 AI, EP 541 168 AI, PCT WO 92/08688 AI, WO 92/08699 AI, WO 92/08698 AI, WO 92/08701 AI, WO 92/08700 AI, PCT WO 94/04492, PCT WO 94/14436, PCT WO 9411361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977].
  • the use of the combination of these compounds offers advantages in the treatment of retrovirus-induced - but especially HIV-induced diseases - compared to monotherapy or combinations of two with the individual compounds.
  • the advantageous and superior use of the combination of these compounds for the treatment of AIDS or HIV infections results primarily from the synergistic antiviral activity, but also from the unchanged tolerance of the substances in combination in the area of toxicity at 50 % of the cells survive - compared to the Tox-50 of the individual components. It is known for other combinations - e.g. AZT in combination with ganciclovir that synergistic toxicity occurs when a combination is used [cf. M.N. Prichard et al. ; Antimicrobial. Agents Chemotherapy (1991), 35, 1060-1065].
  • the use of the triple combination of the substances results in a reduced effective dose for the treatment.
  • the use of the triple combination reduces the likelihood of developing resistant virus isolates.
  • the invention relates to the combination of three classes of compounds of HIV reverse transcriptase inhibitors and HIV protease for the prevention and treatment of infections with HIV, and for the treatment of HIV-induced diseases such as AIDS Related Complex (ARC) or AIDS. HIV infection in cell culture
  • the HIV test was carried out with modifications according to the method of Pauwels et al. [see. Journal of Virological Methods 20, (1988), 309-321].
  • PBL normal human blood lymphocytes
  • RPMI 1640 20% fetal calf serum with phythema agglutinin (90 ⁇ glm ⁇ ) and interleukin-2 (40 U / ml).
  • phythema agglutinin 90 ⁇ glm ⁇
  • interleukin-2 40 U / ml
  • PBLs were pelleted and the cell pellet was then suspended in 1 ml of HIV virus solution for adsorption and incubated for 1 hour at 37 ° C.
  • the virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium so that 1 ⁇ 10 ⁇ cells per ml were set.
  • the cells infected in this way were pipetted into 1 ⁇ 10 4 cells / well into the wells of 96-well microtiter plates.
  • H9 cells were used for the antiviral tests.
  • test titration checkerboard titration
  • the first vertical row of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as described above (cell control).
  • the second vertical row of the microtiter plate only received HIV-infected cells (virus control) in growth medium.
  • the other wells contained the compounds according to the invention - alone or in appropriate combinations - in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were further diluted in steps of two (50 ⁇ l volume per well). For the combination, dilutions of the second substance were made on a separate 96-well microtiter plate and then pipetted onto the prepared first plate.
  • the the third compound was presented in a fixed concentration, so that, for example, 4 dilution stages (corresponding to 4 test batches) of the 3rd inhibitor were tested. In each case 100 ⁇ l of the prepared HIV-infected cells were added (see above). This covered test concentrations of the three inhibitors in the range of approx. 10 - 50 times above and below the IC5Q concentrations of the individual compounds.
  • test batches were incubated at 37 ° C. until, in the untreated virus control, the syncytia formation typical of HIV on the host cell (between days 3 and 8 after infection) was microscopically detectable. Under the test conditions, the untreated virus control resulted in about 20-50 syncytia, while the untreated cell control showed no syncytia.
  • the supernatants from the 96-well plate were then harvested and examined for HIV-specific antigen in an HIV-specific ELISA test (Vironostika HIV
  • the inhibition values were calculated according to the cut-off values from the corresponding cell or Virus controls or internal test controls are converted into percent (%) inhibition values, and the IC50 values were determined as the concentrations of the treated and infected cells at which 50% of the virus-specific antigen was suppressed by the treatment with the compounds.
  • the difference values between calculated and measured inhibition values of the combinations were determined (Prichard, M.N. et al., Antimicrob. Agents Chemoth. (1993), 37, 540-545).
  • the combination of three surprisingly shows synergistic activity in concentration ranges in which no antiviral effect is observed by single treatment or double combination.
  • 0.5 nM retrovir and 0.1 nM retrovir in combination with 0.1 to about 10 nM of quinoxaline and about 70 to 6 nM indinavir and 0.2 to 6 nM of quinoxaline each have about 10 to 50 nM indinavir has a strong synergistic effect.
  • Examples include the combination of retrovir with S-4-isopropoxycarbonyl-6-methoxy-3- (methylthio-methyl) -3,4-dihydro-quinoxazoline-
  • Combination of the compounds has a synergistic effect on HIV. This has been demonstrated by three combination studies of the quinoxaline derivative with indinavir and retrovir.
  • triple combinations according to the invention are used for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.
  • Areas of indication in human medicine include:
  • HIV I human immunodeficiency virus
  • HTLV III / LAV human immunodeficiency virus
  • AIDS AIDS and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) as well as the immune deficiency and encephalopathy caused by this virus. 3.) The treatment or prophylaxis of an HTLV-I or HTLV-II infection.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formulas (I) / (Ia) in combination with a protease inhibitor and a reserve transcriptase inhibitor or which consist of one or more active ingredients of the Formulas (I) / (Ia), the protease inhibitor and the
  • Reverse transcriptase inhibitor exist, as well as processes for the preparation of these preparations, in particular the combination of the test compounds.
  • Preparations are present in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).
  • the active ingredient (s) in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight per 24 hours in the form of several single doses to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight.

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EP98905297A 1997-01-29 1998-01-15 Chinoxaline in dreier-kombination mit proteaseinhibitoren und reverse transkriptaseinhibitoren als arzneimittel zur behandlung von aids Withdrawn EP0977570A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19703131A DE19703131A1 (de) 1997-01-29 1997-01-29 Verwendung von Chinoxalin in Dreier-Kombination mit Protease-Inhibitoren und Reverse Transkriptaseinhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen
DE19703131 1997-01-29
PCT/EP1998/000197 WO1998032442A1 (de) 1997-01-29 1998-01-15 Chinoxaline in dreier-kombination mit proteaseinhibitoren und reverse transkriptaseinhibitoren als arzneimittel zur behandlung von aids

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EP0977570A1 true EP0977570A1 (de) 2000-02-09

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ZA98679B (en) 1998-08-05
JP2001511124A (ja) 2001-08-07
IL130877A0 (en) 2001-01-28
NO993670L (no) 1999-09-10
CN1251525A (zh) 2000-04-26
NO993670D0 (no) 1999-07-28
AU6094098A (en) 1998-08-18
AR011094A1 (es) 2000-08-02
SK99899A3 (en) 2000-03-13
WO1998032442A1 (de) 1998-07-30
BR9807523A (pt) 2000-03-21
PL334770A1 (en) 2000-03-13
CA2278773A1 (en) 1998-07-30
DE19703131A1 (de) 1998-07-30
ID22414A (id) 1999-10-14
KR20000070543A (ko) 2000-11-25

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