SI9500329A - Quinoxalines, process for the preparation thereof and use thereof - Google Patents
Quinoxalines, process for the preparation thereof and use thereof Download PDFInfo
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- SI9500329A SI9500329A SI9500329A SI9500329A SI9500329A SI 9500329 A SI9500329 A SI 9500329A SI 9500329 A SI9500329 A SI 9500329A SI 9500329 A SI9500329 A SI 9500329A SI 9500329 A SI9500329 A SI 9500329A
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- compounds
- cooch
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- alkoxy
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- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 17
- 150000003252 quinoxalines Chemical class 0.000 title 1
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
- 229940002612 prodrug Drugs 0.000 claims abstract description 3
- 239000000651 prodrug Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 55
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 239000011593 sulfur Substances 0.000 claims description 16
- -1 chloro, hydroxy Chemical group 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 230000003612 virological effect Effects 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000011669 selenium Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 241000725303 Human immunodeficiency virus Species 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000000451 chemical ionisation Methods 0.000 description 10
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
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- 210000004027 cell Anatomy 0.000 description 7
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 102100034343 Integrase Human genes 0.000 description 6
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000004060 metabolic process Effects 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
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- 230000037396 body weight Effects 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001885 phytohemagglutinin Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000002976 reverse transcriptase assay Methods 0.000 description 1
- FGEJJBGRIFKJTB-UHFFFAOYSA-N silylsulfanylsilane Chemical class [SiH3]S[SiH3] FGEJJBGRIFKJTB-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BDIWFCKBPZPBQT-UHFFFAOYSA-N tributyl(tributylstannylsulfanyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)S[Sn](CCCC)(CCCC)CCCC BDIWFCKBPZPBQT-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- NBTHYJWPOYZDHL-UHFFFAOYSA-N tricyclohexyl(tricyclohexylstannylsulfanyl)stannane Chemical compound C1CCCCC1[Sn](C1CCCCC1)(C1CCCCC1)S[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1 NBTHYJWPOYZDHL-UHFFFAOYSA-N 0.000 description 1
- NTCQOKPUDSWFJF-UHFFFAOYSA-N triphenyl(triphenylstannylsulfanyl)stannane Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(C=1C=CC=CC=1)S[Sn](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NTCQOKPUDSWFJF-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Dental Preparations (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Compounds Of Unknown Constitution (AREA)
Description
HOECHST AKTIENGESELLSCHAFT
Kinoksalini, postopek za njihovo pripravo in njihova uporaba
Predmet predloženega izuma so kinoksalini, postopek za njihovo pripravo in njihova uporaba kot virustatiki, zlasti za zdravljenje infekcij z virusom humane imunodeficience (HIV).
V evropski patentni prijavi EP-509398-A so opisani derivati kinoksalina za to področje uporabe.
Sedaj smo presenetljivo ugotovili, da ima skupina specialno substituiranih kinoksalinov s formulo (I) n
(D kot tudi njihovih tavtomernih oblik s splošno formulo la
kot tudi njihove fiziološko prenesljive soli ali predzdravila antivirusni učinek zlasti proti retrovirusom, kot npr. virusu humane imunodeficience (HIV).
V spojinah s formulo (I) oz. Ia pomenijo:
1) n je enako 0,1 ali 2,
R1 fluor, klor, hidroksi, (/-(/-alkoksi,
R2 (/-(/-alkil, v danem primeru substituiran s hidroksi, (/-(/-alkoksi ali (/-(/alkiltio,
R3 (/-(/-alkiloksikarbonil ali (/-(/-alkeniloksikarbonil,
X kisik, žveplo ali selen.
V prednostni skupini spojin s formulo I oz. Ia pomenijo:
2) n je enako 0,1 ali 2,
R1 fluor, klor, hidroksi, C -C -alkoksi,
R2 (/-(/-alkil, v danem primeru substituiran s hidroksi, (/-(/-alkoksi ali (/-(/ alkiltio,
R3 C, -C. -alkiloksikarbonil ali C_,-C„ -alkeniloksikarbonil,
4 2 4 7
X kisik ali žveplo.
V še enkrat prednostni skupini spojin s formulo I oz. Ia pomenijo:
3) n je enako 0 ali 1,
R1 fluor, klor, metoksi, etoksi, propoksi,
R2 metiltiometil, etil, propil, Cj-C^alkil, v danem primeru substituiran s hidroksi ali C,-C-alkoksi,
R3 C,-C.-alkiloksikarbonil ali C.-C,-alkeniloksikarbonil,
4 2 4 ’
X kisik ali žveplo.
Prav poseben pomen imajo tiste spojine s formulo I ali Ia, kot je opisano zgoraj, kjer navedeni substituenti pomenijo:
4) n je enako 0 ali 1,
R1 fluor, klor, metoksi, etoksi,
R2 metiltiometil, etil, propil, C^C^alkil, substituiran s hidroksi ali C^C^alkoksi,
R3 C,-C,-alkiloksikarbonil ali C.-C -alkeniloksikarbonil,
4 2 4 ’
X kisik ali žveplo.
Prav poseben pomen ima spojina S-4-izopropoksikarbonil-6-metoksi-3(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-tion (prim. 85). Spojine s formulama I in Ia imajo asimetričen atom ogljika v t.i. S-konfiguraciji.
Sedaj smo presenetljivo ugotovili, da imajo spojine v smislu izuma nepričakovano jasno zvišan antivirusni učinek. Nadalje smo ugotovili, da so čisti enantiomeri jasno laže topni kot pripadajoče racemne spojine. Te so pravi racemati, t.j. 1 : 1 spojine obeh enantiomerov, s posameznimi fizikalnimi lastnostmi.
Kot posledica tega se čisti enantiomeri pri živalskih poskusih jasno bolje resorbirajo po oralnem dajanju. To je bistvena predpostavka za razvoj novega zdravila.
Splošno je znano, da so posebno važni za dosego kar najbolj močnega farmakološkega ali kemoterapevtskega učinka visoki dosegljivi krvni nivoji.
Spričo dejstva, da z mnogimi potencialnimi virustatiki proti HIV zaradi njihove nizke biorazpoložljivosti po oralnem dajanju nismo mogli doseči zadostnih krvnih nivojev za preprečitev virusne replikacije, predstavljajo spojine v smislu izuma superiorno učinkovita antivirusna sredstva in torej terapevtski napredek.
Čisti enantiomeri spojin s formulama I in la se dajo z znanimi metodami ali analogno znanim metodam direktno pripraviti ali naknadno ločiti.
Spojine s formulama I in la lahko pripravimo po znanih metodah ali njihovih modifikacijah (glej npr. EP-509398-A, Rodd’s Chemistry of Carbon Compounds, S. Coffey, M. F. Ansell (izdajatelj); Elsevier, Amsterdam, 1989; Vol. IV del IJ, str. 301 do 311. Heterocyclic Compounds, R. C. Elderfield (izdajatelj); Wiley, New York, 1957; Vol. 6, str. 491 do 495).
K predmetu predloženega izuma spada nadalje postopek za pripravo spojin s formulama I in la, kot je spodaj razloženo pod 1) do 4), označen s tem, da
A) za pripravo spojin s formulo I z X = kisik in ostanki R1, R2 in R3, kot je definirano pri 1) do 4), spojino s formulo II,
n
pri čemer za R1 in R2 veljajo pri 1) do 4) navedene definicije, presnovimo s spojino s formulo III,
R3-Z (III) pri čemer ima R3 zgoraj pri 1) do 4) navedene pomene in je Z odhodna skupina, kot npr. klor, ali da
B) spojine s formulo I, z X = žveplo in R1, R2 in R3, kot je definirano pri 1) do 4), pripravljene z reakcijo spojine s formulo I, pri čemer je X kisik in veljajo za R1, R2 in R3 pri 1) do 4) navedene definicije, presnovimo s sredstvom za uvedbo žvepla.
Pri zgoraj navedeni metodi A) poteče presnova prednostno z alkil- ali alkenilestrom halogenmravljinčne kisline, dialkil- ali dialkilenkarbonatom ali dialkil- ali alkenilestrom piroogljikove kisline. Substituent Z v formuli III je torej primerna odhodna skupina, kot npr. klor, brom ali jod, alkoksi ali alkeniloksi ostanek ali alkoksi ali alkeniloksikarobniloksi skupina. Prednostno je Z klor.
Presnovo izvedemo smotrno v inertnem topilu. Primerni so npr. aromatski ogljikovodiki, kot toluen ali ksilen, nižji alkoholi, kot metanol, etanol ali 1-butanol, etri, kot tetrahidrofuran ali glikoldimetileter, dipolarna aprotična topila, kot N,Ndimetilformamid, N-metil-2-pirolidon, acetonitril, nitrobenzen, dimetilsulfoksid ali zmesi teh topil. Možni so tudi dvofazni sistemi z vodnimi raztopinami baz v prisotnosti katalizatorja faznega transferja, kot npr. benziltrietilamonijevega klorida.
Prisotnost primerne baze, npr. alkalijskega ali zemeljskoalkalijskega karbonata ali hidrogenkarbonata, kot natrijevega karbonata, kalcijevega karbonata ali natrijevega bikarbonata, alkalijskega ali zemeljskoalkalijskega hidroksida, kot kalijevega hidroksida ali barijevega hidroksida, alkoholata, kot natrijevega metanolata ali kalijevega terc.butilata, litijeve organske spojine, kot butillitija ali litijevega diizopropilamida, alkalijskega ali zemeljskoalkalijskega hidrida, kot natrijevega hidrida ali kalcijevega hidrida, alkalijskega fluorida, kot kalijevega fluorida, ali organske baze, kot trietilamina, piridina, 4-metilpiridina ali 4-(dimetilamino)piridina, je lahko koristna za prestrezanje kisline, ki se sprošča pri reakciji.
V mnogih primerih je koristen dodatek jodove soli, npr. kalijevega jodida. Reakcijo izvedemo običajno pri temperaturah med -10 in 160°C, prednostno pri sobni temperaturi.
Za to presnovo je treba morebitne nukleofilne substituente, kot npr. hidroksi, merkapto ali amino skupine z izjemo lege 4 v spojinah s formulo II, pred izvedbo reakcije na primeren način derivatizirati ali opremiti s spet odcepljivimi običajnimi zaščitnimi skupinami, kot so npr. acetil, benzil, tritil, tetrahidropiranil ali terc.butoksikarbonil.
Za presnovo, kot je preje opisana pri B, uporabimo prednostno kot sredstvo za uvedbo žvepla 2,4-bis(4-metoksifenil)-l,3-ditia-2,4-difosfetan-2,4-disulfid (Lawessonov reagent), bis(tricikloheksilkositrov) sulfid, bis(tri-n-butilkositrov) sulfid, bis(trifenilkositrov) sulfid, bis(trimetilsilil) sulfid ali fosforjev pentasulfid.
Reakcijo izvedemo smotrno v organskem topilu ali zmesi topil pri -10 do 120°C, prednostno pri sobni temperaturi do 60°C in po možnosti ob brezvodnih pogojih. Primerni so npr. žveploogljik, toluen, ksilen, piridin, diklormetan, 1,2-dikloretan, tetrahidrofuran, etilester ocetne kisline ali butilester ocetne kisline. Pri uporabi omenjenih kositrovih ali sililsulfidov je primerno, da izvedemo reakcijo uvedbe žvepla v prisotnosti Lewisove kisline, kot borovega triklorida.
Prisotnost karbonilne skupine v ostanku R3 v spojinah s formulo I zaradi njene majhne reaktivnosti pri tem ne moti, tako daje možna selektivna uvedba žvepla.
Kot izhodni materiali za opisane sinteze potrebni kinoksalini s splošno formulo II so znani iz literature ali jih lahko pripravimo po znanih metodah, npr. po postopkih, opisanih v evropski patentni prijavi EP-509398-A.
Nadalje spadajo k predmetu predloženega izuma spojine, kot so opisane pri 1) do 4), kot zdravila, prednostno za zdravljenje virusnih obolenj, zlasti obolenj, ki jih povzroči HIV.
Nadalje se predloženi izum nanaša na zdravila z vsebnostjo vsaj ene spojine v smislu izuma kot tudi na uporabo navedenih spojin za pripravo zdravil, prednostno za zdravljenje virusnih obolenj, zlasti za zdravljenje obolenj, kijih povzroči HIV.
Nadalje spada k predmetu predloženega izuma uporaba spojin z zgoraj navedeno formulo I oz. Ia za pripravo zdravil za zdravljenje virusnih obolenj.
Za to uporabo so prednostne zgoraj pri 1) do 4) navedene in razložene spojine.
Zdravila v smislu izuma lahko uporabimo enteralno (oralno), parenteralno (intravensko), rektalno, subkutano, intramuskularno ali lokalno (topično).
Lahko jih dajemo v obliki raztopin, praškov, (tablete, kapsule, vključno mikrokapsule), mazil (kreme ali geli) ali supozitorijev. Kot pomožne snovi za take formulacije pridejo v poštev farmacevtsko običajna tekoča ali trdna polnila in razredčila, topila, emulgatorji, drsna sredstva, sredstva za izboljšanje okusa, barvila in/ali pufrske snovi.
Kot smotrno doziranje dajemo 0,1 do 10, prednostno 0,2 do 8 mg/kg telesne teže enkrat ali večkrat dnevno. Uporabljene dozirne enote se ravnajo smotrno po vsakokratni farmakokinetiki uporabljene snovi oz. uporabljenega galenskega pripravka.
Uporabljena dozirna enota spojin v smislu izuma znaša npr. 1 do 1500 mg, prednostno 50 do 500 mg.
Spojine v smislu izuma lahko dajemo tudi v kombinaciji z drugimi antivirusnimi sredstvi, kot so npr. nukleozidni analogi, proteazni inhibitorji ali adsorpcijski inhibitorji, imunostimulanti, interferoni, interlevkini in faktorji, ki stimulirajo kolonijo (npr. GM-CSF, G-CSF, M-CSF).
S čistimi enantiomeri so mišljene take spojine, v katerih znaša enantiomerno razmerje vsaj 95:5, prednostno najmanj 97:3.
Predloženi izum podrobneje pojasnjujemo z naslednjimi primeri kot tudi z vsebino patentnih zahtevkov.
Primer 1:
N-(5-fluor-2-nitrofenil)-S-metil-L-cistein
16,2 g (-)-S-metil-L-cisteina (0,1 mol) suspendiramo v zmesi 120 ml vode in 120 ml acetona v bučki s štirimi vratovi pod N2> Ob mešanju hitro dodamo 30,4 ml (22,2 g) trietilamina (0,22 molov). V nastajajočo rumeno raztopino ob nadaljnjem mešanju dodamo 15,9 g 2,4-difluornitrobenzena (0,1 mol).
Ob mešanju segrevamo 7,5 ur do refluksa (oranžno obarvana raztopina), na rotacijskem uparjalniku odstranimo aceton pod zmanjšanim tlakom, vodni ostanek prevedemo v lij ločnik in 2x ekstrahiramo z okoli 50 ml metil-terc.butiletra (MTBeter). Ta ekstrakt obstoji pretežno iz 2,4-difluomitrobenzena in ga zavržemo. Vodno fazo prevedemo v bučko s štirimi vratovi, dodamo 150 ml MTB etra in ob hlajenju (<25°C) naravnamo z okoli 25 ml 38%-ne žveplove kisline na pH 1. Mešamo, dokler ne dobimo bistrih faz. Etrsko fazo odločimo in vodno fazo še enkrat ekstrahiramo s 50 ml MTB etra.
Ekstrakte posušimo nad natrijevim sulfatom in uparimo na rotacijskem uparjalniku. Dobitek 27 g rumenega olja, ki se hitro strdi, tal. 147°C (iz vode/metanola).
MS: kemična ionizacija, (M + H)+ = 275
| Analiza: | izrač. | ugot. |
| C | 43,8 % | 43,8 % |
| H | 4,0% | 4,1% |
| N | 10,2 % | 10,0 % |
| S | 11,7 % | 11,3 %. |
Primer 2:
N-(5-metoksi-2-nitrofenil)-S-metil-L-cistein g N-(5-fluor-2-nitrofenil-S-metil-L-cisteina (0,1 mol) iz primera 1 raztopimo v bučki s štirimi vratovi v 150 ml abs. metanola in ob dobrem mešanju, pod argonom in ob hlajenju s pomočjo kopeli ledu v 20 minutah po deležih dodamo 14,4 g 95%-nega natrijevega metilata (0,25 molov). Ob mešanju segrevamo 2 uri do refluksa. Reakcija je končana po DC kontroli.
Glavno količino metanola odstranimo na rotacijskem uparjalniku pod zmanjšanim tlakom. Ostanku dodamo 200 ml ledene vode, z okoli 25 ml 38%-ne žveplove kisline naravnamo na pH 1 in pomešamo s 150 ml MTB etra. Etrsko fazo odločimo in vodno fazo še enkrat ekstrahiramo s 30 ml MTB etra in rotacijsko uparimo pod zmanjšanim tlakom.
Dobitek: 21,5 g rjavordečega olja, ki počasi kristalizira.
MS: kemična ionizacija, (M + H)+ = 287
HPLC: 99,3 % S-enantiomera
| Analiza: | izrač. | ugot. |
| C | 46,2 % | 47,3 % |
| H | 4,9% | 5,6% |
| N | 9,8% | 9,1% |
| S | 11,1 % | 10,6 %. |
Primer 3:
S-6-metoksi-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-on
20,7 g spojine iz primera 2 (0,065 molov) raztopimo v 250 ml metanola in pod argonom hidriramo z 0,5 ml ledocta in okoli 20 g Raneyevega niklja pri normalnem tlaku pri sobni temperaturi. Ko se po DC ne da ugotoviti več izhodnega materiala, se hidriranje konča. Nastavek odsesamo pod dušikovim pokrovom in naknadno izperemo s 100 ml metanola.
Ostanek na filtru skupaj s katalizatorjem mešamo pod dušikovim pokrovom z dimetilformamidom (DMF) pri 45 do 50°C in nato ponovno odsesamo preko bistrilnega sloja. DMF raztopino, ki vsebuje produkt, pustimo takoj dotekati ob mešanju v 11 ledene vode, ki smo ji dodali 2 g askorbinske kisline kot antioksidanta. Produkt se pri tem obori v obliki svetlorumenih kristalov. Odsesamo, izperemo z okoli 2 1 vode, nato s 500 ml etanola in nato s 300 ml pentana ter sušimo nad fosforjevim pentoksidom.
Dobitek 10,8 g, nadaljnjih 1,3 g lahko dobimo s koncentriranjem filtrata. Tal. 186 do 187°C, rumeno sivkasta trdna snov
Ή-NMR (200 MHz, d6-DMSO): δ = 2,08 (s, 3 H, SCH3), 2,75 (dg^, 2 H, -CH2-S), 3,65 (s, 3 H, MeO), 3,95 (m, 1 H, CH), 6,05 (š. s, NH), 6,1 - 6,7 (m, 3 H, aromati), 10,15 (s, 1 H, amid).
MS: kemična ionizacija, (M + H)+ = 239
HPLC: čistota 97,5 %, 98,2% S-enantiomera
| Optična rotacija: [a]22D = | -42°C (c = 1 v ac | |
| Analiza: | izrač. | ugot. |
| C | 55,5 % | 55,2 % |
| H | 5,9% | 5,8% |
| N | 11,8 % | 11,7 % |
| S | 13,4 % | 13,3 %. |
Na analogen procesni način dobimo:
Primer 4:
S-6-etoksi-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-on
Iz spojine primera 1 z litijevim etilatom v etanolu ter redukcijo in sklenitvijo obroča analogno primeru 2.
MS: kemična ionizacija, (M + H)+ = 253
Ή-NMR (200 MHz, d6-DMSO): etoksi skupina δ = 1,27 (t, 3 H), 3,87 (q, 2 H)
Primer 5:
S-3-(metiltiometil)-6-propoksi-3,4-dihidrokinoksalin-2(lH)-on
Iz spojine primera 1 z natrijevim propilatom v propanolu. Tal. smola,
MS: kemična ionizacija, (M + H)+ = 267
Ή-NMR (200 MHz, d6-DMSO): propoksi skupina δ = 0,95 (t, 3 H), 1,67 (q, 2 H), 3,79 (t,2H)
Primer 6:
S-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-on
Pri uporabi 2-fluornitrobenzena namesto 2,4-difluornitrobenzena v primeru 1 Tal. 109°C, MS: kemična ionizacija, (M + H)+ = 208
Primer 7:
S-6-fluor-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-on
Pri direktni nadaljnji uporabi spojine iz primera 1 v redukcijski reakciji in reakciji sklenitve obroča po primeru 3.
Tal. 149°C, MS: kemična ionizacija, (M + H)+ = 243
Primer 8:
S-6-klor-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)-on
Pri uporabi 2,4-diklornitrobenzena namesto 2,4-difluornitrobenzena v primeru 1 in z natrijevim hidroksidom in glikolmonometiletrom pri temperaturi refluksa.
Tal. 149°C, MS: kemična ionizacija, (M + H)+ = 243
Na procesni način, analogen primerom 1 do 8, lahko npr. pri uporabi drugih amino kislin dobimo ustrezne spojine s formulo II, v katerih -substituent uporabljene amino kisline postane substituent R2 v formuli II:
Tabela 1
| Primer št. | Rln | R2 | Tal. °C |
| 9 | H (n = 0) | C2H5 | olje |
| 10 | H (n = 0) | C3H7 | smola |
| 11 | H (n = 0) | c4h9 | olje |
| 12 | H (n = 0) | ho-ch2 | 82 |
| 13 | 6-CI | C2H5 | 120 |
| 14 | 6-CI | C3H7 | 75 - 77 |
| 15 | 6-CI | c4h9 | olje |
| 16 | 6-F | C2H5 | 93 |
| 17 | 6-F | C3H7 | smola |
| 18 | 6-F | H0-CH2 | 134 |
| 19 | 6-CH3 0 | c2h5 | olje |
| 20 | 6-CH3 0 | C3H7 | 138 |
| 21 | 6-CH3 0 | c4h9 | |
| 22 | 6-CH3 0 | ho-ch2 | 125 razp. |
| 23 | 6-CH3 0 | CH3 CH(OH)- | 156 |
| 24 | 6-CH3 0 | ch3 o-ch2 | 167 |
(nadaljevanje)
| 25 | 6-C2H5 O | c2h5 | |
| 26 | 6-C2H5 O | C3H7 | |
| 27 | 6-C2H5 O | ch3 o-ch2 | |
| 28 | 6-C3H7 0 | ^2^5 | |
| 28a . | 6-OH | CH3SCH2 | 146 |
Primer 29:
S-4-izopropoksikarbonil-6-metoksi-3-(metiltiometil)-3,4-dihidrokinoksalin-2-(lH)-on
11,9 g (0,05 molov) spojine primera 3 suspendiramo pod dušikom v 300 ml metilenklorida. Ob mešanju kot bazo hitro dodamo 7,0 g 4-metilpiridina (0,075 molov). Nato dokapavamo 30 minut pri sobni temperaturi 60 ml 1 molarne raztopine izopropilestra klormravljinčne kisline v toluenu (0,06 molov). Pri tem gre suspenzija počasi v raztopino. Po DC kontroli je reakcija končana po 4 do 6 urah pri sobni temperaturi. Raztopino nakisamo z 2n žveplovo kislino, organsko fazo odločimo, vodno fazo še enkrat ekstrahiramo s 50 ml metilenklorida. Po uparjenju topila pod zmanjšanim tlakom ostane poltrden produkt, ki ga prekristaliziramo ob mešanju iz diizopropiletra.
Dobitek 15,0 g, tal. 115°C.
Ή-NMR (200 MHz, d6-DMSO): δ = 1,3 (2d, J = 7 Hz, 6H, 2 izopropil-CH3), 2,1 (s, 3 H, SCH3), 2,35 + 2,7 (dqAB, 2 H, -CH2-S), 3,73 (s, 3 H, MeO), 4,87 (q, 1 H, CH), 4,97 (m, J = 7 Hz, 1 H, izopropil-CH), 6,7 - 7,25 (m, 3 H, aromati), 10,65 (s, 1 H, amid).
| MS: kemična ionizacija, (M + H)+ = 325 | ||
| HPLC: čistota 98%, 99,9 % S-enantiomera | ||
| Optična rotacija: [a]22D = 39° (c = | 1 v metanolu) | |
| Analiza: | izrač. | ugot. |
| C | 55,6 % | 55,5 % |
| H | 6,2% | 5,8% |
| N | 8,6% | 8,4% |
| S | 9,8% | 9,7 %. |
Na procesni način, analogen primeru 29, lahko npr. pri uporabi spojin s formulo II, kot so navedene npr. v primerih 3 do 28, s presnovo z ustreznimi spojinami s formulo III naslednje spojine s formulo I z X = O:
Tabela 2
| Primer št. | R1n | R2 | R3 | Tal.°C |
| 30 | H (n = 0) | c2h5 | COOCH(CH3)2 | 163 |
| 31 | H (n = 0) | C3H7 | COOCH(CH3)2 | 117 |
| 32 | H (n = 0) | c4h9 | COOCH(CH3)2 | 120 |
| 33 | H (n = 0) | ho-ch2 | C00CH(CH3)2 | |
| 34 | H (n = 0) | ch3sch2 | COOCH(CH3)2 | 119 |
| 35 | 6-CI | c2h5 | COOCH(CH3)2. | 145-147 |
| 36 | 6-CI | C3H7 | COOCH{CH3)2 |
| Primer št. | R1n | R2 | R3 | Tal.°C |
| 37 | 6-CI | c4h9 | COOCH(CH3)2 | |
| 38 | 6-CI | ch3sch2 | COOCH(CH3)2 | 105 |
| 39 | 6-F | C2H5 | COOCH(CH3)2 | 123 - 125 |
| 40 | 6-F | C3H7 | COOCH(CH3)2 | 110 |
| 41 | 6-F | c4h9 | COOCH(CH3)2 | |
| 42 | 6-F | ch3sch2 | COOCH(CH3)2 | 136 |
| 43 | 6-CH3 0 | c2h5 | COOCH(CH3)2 | olje |
| 44 | 6-CH3 0 | C3H7 | COOCH(CH3)2 | 153 |
| 45 | 6-CH3 0 | c4h9 | COOCH(CH3)2 | |
| 46 | 6-CH3 0 | ho-ch2 | COOCH(CH3)2 | smola |
| 47 | 6-CH3 0 | CH3 CH(OH)- | COOCH(CH3)2 | smola |
| 48 | 6-CH3 0 | ch3 o-ch2 | COOCH(CH3)2 | 98 |
| 49 | 6-C2H5 0 | c2h5 | COOCH(CH3)2 | |
| 50 | 6-C2H5 0 | C3H7 | COOCH(CH3)2 | |
| 51 | 6-C2H5 0 | ch3 o-ch2 | COOCH(CH3)2 | |
| 52 | 6-C2H5 0 | ch3sch2 | COOCH(CH3)2 | 112 |
| 53 | 6-C3H7 0 | C2H5 | COOCH{CH3)2 | |
| 54 | 6-C3H7 0 | CH3SCH2 | COOCH(CH3)2 | 105 |
| Primer št. | Rln | R2 | R3 | Tal.°C |
| 55 | H (n = 0) | c2h5 | cooc :ch3)=ch2 | |
| 56 | H (n = 0) | ch3sch2 | COOC' (CH3)=CH2 | |
| 57 | 6-CI | C2H5 | COOC' (CH3) = CH2 | 143 |
| 58 | 6-CI | c2h5 | cooch2ch=ch2 | 122-124 |
| 59 | 6-CI | ch3sch2 | COOC' (CH3)=CH2 | 182 |
| 60 | 6-CI | ch3sch2 | cooc3h7 | 68 |
| 61 | 6-CI | ch3sch2 | cooc2h5 | 143 |
| 62 | 6-F | c2h5 | COOC, ;(CH3)=CH2 | 125 |
| 63 | 6-F | c3h7 | COOC (CH3)=CH2 | |
| 64 | 6-F | ch3sch2 | COOC: i(CH3) = CH2 | |
| 65 | 6-CH3 0 | c2h5 | COOC.1(CH3)=CH2 | |
| 66 | 6-CH3 0 | c3h7 | cooc:<(Ch3) = ch2 | |
| 67 | 6-CH3 0 | ch3 o-ch2 | COOC (CH3)=CH2 | |
| 68 | 6-CH3 0 | ch3sch2 | COOC» (CH3)=CH2 | 152 |
| 69 | 6-CH3 0 | ch3sch2 | COOCH2CH(CH3)-C2H5 | |
| 70 | 6-C2H5 0 | C2H5 | COOC' (CH3)=CH2 | |
| 71 | 6-C2H5 0 | C3H7 | COOC (CH3)=CH2 | |
| 72 | 6-C2H5 0 | ch3 o-ch2 | COOC '{CH3)=CH2 | |
| 73 | 6-C2H5 0 | ch3sch2 | cooc: (ch3)=ch2 | |
| 74 | H (n = 0) | C2H5 | cooc2h5 | |
| 75 | H (n = 0) | C3H7 | cooc2h5 | |
| 76 | H (n = 0) | ch3sch2 | cooc2h5 | |
| 77 | 6-CI | C2H5 | cooc2h5 |
| Primer št. | Rl n | R2 | R3 | Tal.-c |
| 78 | 6-F | c2h5 | cooc2h5 | |
| 79 | 6-F | ch3sch2 | C00C,H. | |
| 80 | 6-CH3 0 | c2h5 | cooc2h5 | |
| 81 | 6-CH3 0 | ch3 o-ch2 | cooc2h5 | |
| 82 | 6-CH3 0 | ch3s-ch2 | cooc2h5 | |
| 83 | 6-C2H5 0 | c2h5 | cooc2h5 | |
| 84 | 6-C2H5 0 | ck3 s-ck2 | cooc2h5 | |
| 84a | 6-OH | ch3sch2 | COOCH(CH3)2 | 182 |
| 84b | 6-OH | c2K5 | C00CH(CH3)2 | 201 |
| 84c | 6-C1 | ch3 | cooc2h5 | 151 |
| 84d | 6-C1 | COOC(CH3)=CH2 | 158 | |
| 84e | 6-C1 | ch3sch2 | cooc2h5 | 143 |
| 84f | 6-C1 | ch3sch2 | cooc3h7 | 68 |
| 84g | 6-CH30 | ch3sch2 | C00CH(CH3)-c2h5 | 86 |
| 84h | 6-CK30 | ch3sch2 | COOCH2CH(CH3)2 | 60 |
| 84 i | 6-F | ch3 | C00CH(CH3)2 | 151 |
| 84j | 6-F | c2h5 | C00CH(CH3)-C2H5 | smola |
| 84k | 6-F | c2h5 | COOCHg | 50 |
| 841 | 6-F | c2K5 | cooc.hq 4 9 | 92 |
| 84m | 6-F | c2h5 | COOCH2CH(CH3)2 | 90 |
| 84n | 6-F | ch2oh | COOCH(CH3)2 | smola |
| 84o | 6-F | ch3och2 | COOCH(CH3)2 | 114 |
Primer 85:
S-4-izopropoksikarbonil-6-metoksi-3-(metiltiometil)-3,4-dihidrokinoksalin-2(lH)tion
16,1 g spojine iz primera 29 (0,05 molov) raztopimo v 200 ml suhega dimetoksietana, ob argonu in mešanju dodamo 13 g fino uprašenega fosforjevega pentasulfida (0,06 molov) in mešamo pri sobni temperaturi. Po 24 urah presnova še ni popolna, tako da naknadno dodamo še 4 g fosforjevega pentasulfida. Po 24 urah pri sobni temperaturi mešamo še 3 ure pri 30°C. Za odločenje trdnih snovi odsesamo preko bistrilnega sloja in še izperemo z dimetoksietanom. Zbrane filtrate uparimo pod zmanjšanim tlakom. Preostalo temno olje prevzamemo v 250 ml MTB etra in mešamo z 200 ml nasičene raztopine natrijevega hidrogenkarbonata. Faze ločimo, vodno fazo še enkrat ekstrahiramo z 20 ml MTB etra. Organske ekstrakte posušimo nad magnezijevim sulfatom ali natrijevim sulfatom in rotacijsko uparimo.
Preostalo rumeno rjavo olje vroče raztopimo v 30 ml diizopropiletra. Kristalizira pri ohlajenju ob mešanju. Izločene kristale izperemo z malo diizopropiletra in n-pentana in posušimo v eksikatorju.
Dobitek 91,4 g, tal. 103°C.
Ή-NMR (200 MHz, dfi-DMSO): δ = 1,27 (2d, J - 7 Hz, 6H, 2 izopropil-CH3), 2,1 (s, 3 H, SCH3), 2,34 + 2,79 (dqAB, 2 H, -CH2-S), 3,75 (s, 3 H, MeO), 4,97 (m, J = 7 Hz, 1 H, izopropil-CH), 5,25 (q, 1 H, CH), 6,75 - 7,3 (m, 3 H, aromati), 12,73 (s, 1 H, tioamid).
MS: kemična ionizacija, (M -I- H)+ = 341 HPLC: čistota 99,6 %, 99,4% S-enantiomera Optična rotacija: [a]22D = 18° (c = 1 v metanolu)
| Analiza: | izrač. | ugot. |
| C | 52,9 % | 52,9 % |
| H | 5,9% | 5,3% |
| N | 8,4% | 8,3% |
| S | 18,8 % | 18,6 % |
Na procesni način, analogen primeru 85, lahko npr. pri uporabi spojin s formulo I z X = O, kot so navedene npr. v primerih 30 do 84, s presnovo z ustreznimi sredstvi za uvedbo žvepla dobimo naslednje spojine s formulo I z X = S:
Tabela 3
| Primer št. | Rln | R2 | R3 | Tal.°C |
| 86 | H (n = 0) | C2H5 | COOCH(CH3)2 | 114 |
| 87 | H (n = 0) | C3H7 | COOCH(CH3)2 | 128 |
| 88 | H (n = 0) | C4Hg | COOCH(CH3)2 | 78 |
| 89 | H (n = 0) | ho-ch2 | COOCH(CH3)2 | |
| 90 | H (n = 0) | ch3sch2 | COOCH(CH3)2 | olje |
| 91 | 6-CI | C2H5 | COOCH(CH3)2 | 161 |
| 92 | 6-Cl | C3H7 | COOCH(CH3)2 | |
| 93 | 6-CI | c4h9 | COOCH(CH3)2 | |
| 94 | 6-CI | ch3sch2 | COOCH(CH3)2 | 124 |
| 95 | 6-F | c2h5 | COOCH(CH3)2 | 93 ' |
| 96 | 6-F | C3H7 | COOCH(CH3)2 | 60 |
| 97 | 6-F | c4h9 | COOCH(CH3)2 | |
| 98 | 6-F | ch3sch2 | COOCH{CH3)2 | 122 |
| 99 | 6-CH3 0 | c2h5 | COOCH(CH3)2 | 74 |
| 100 | 6-CH3 0 | C3H7 | COOCH(CH3}2 | 140 |
| 101 | 6-CH3 0 | c4h9 | COOCH(CH3)2 | |
| 102 | 6-CH3 0 | ho-ch2 | COOCH(CH3)2 |
| Primer št. | R1n | R2 | R3 | Tal.°C |
| 103 | 6-CH3 0 | CH3 CH(OH)- | COOCH(CH3)2 | |
| 104 | 6-CH3 0 | ch3 o-ch2 | COOCH(CH3)2 | 137 |
| 105 | 6-C2H5 0 | c2h5 | COOCH(CH3)2 | |
| 106 | 6-C2H5 0 | C3H7 | COOCH(CH3)2 | |
| 107 | 6-C2H5 0 | ch3 o-ch2 | COOCH(CH3)2 | |
| 108 | 6-C2H5 0 | ch3sch2 | COOCH(CH3)2 | olje |
| 109 | 6-C3H7 0 | c2h5 | COOCH(CH3)2 | |
| 110 | 6-C3H7 0 | ch3sch2 | COOCH(CH3)2 | smola |
| Primer št. | R2 | R3 | Tal.°C | |
| 111 | H (n = 0) | c2h5 | COOC (CH3)=CH2 | |
| 112 | H (n = 0) | ch3sch2 | COOC ,(CH3)=CH2 | |
| 113 | 6-CI | c2h5 | COOC j(CH3)=CH2 | 170 |
| 114 | 6-CI | c2h5 | cooch2ch=ch2 | 123 |
| 115 | 6-CI | ch3sch2 | COOC ,(CH3)=CH2 | 128 |
| 116 | 6-CI | ch3sch2 | cooc3h7 | |
| 117 | 6-CI | ch3sch2 | cooc2h5 | |
| 118 | 6-F | c2h5 | COOC, (CH3)=CH2 | |
| 119 | 6-F | C3H7 | cooc :ch3)=ch2 | |
| 120 | 6-F | ch3sch2 | COOC· (CH3)=CH2 | |
| 121 | 6-CH3 0 | c2h5 | COOC !(CH3)=CH2 |
| Primer št. | H | R2 | R3 | Tal.°C |
| 122 | 6-CH3 0 | C3H7 | COOCi (CH3)=CH2 | |
| 123 | 6-CH3 0 | ch3 o-ch2 | COOC (CH3)=CH2 | |
| 124 | 6-CH3 0 | ch3sch2 | COOC (CH3)=CH2 | 152 |
| 125 | 6-CH3 0 | ch3sch2 | COOCH2CH(CH3)-C2H5 | |
| 126 | 6-C2H5 0 | ^2^5 | COOC (CH3)=CH2 | |
| 127 | 6-C2H5 0 | C3H7 | COOC (CH3)=CH2 | |
| 128 | 6-C2H5 0 | ch3 o-ch2 | COOC ,{CH3)=CH2 | |
| 129 | 6-C2H5 0 | ch3sch2 | cooc :{ch3)=ch2 | |
| 130 | H (n = 0) | c2h5 | cooc2h5 | |
| 131 | H (n = 0) | C3H7 | cooc2h5 | |
| 132 | H (n = 0) | ch3sch2 | cooc2h5 | |
| 133 | 6-CI | c2h5 | cooc2h5 | |
| 134 | 6-F | c2h5 | cooc2h5 | smola |
| 135 | 6-F | ch3sch2 | cooc2h5 | |
| 136 | 6-CH3 0 | c2h5 | cooc2h5 | |
| 137 | 6-CH3 0 | ch3 o-ch2 | cooc2h5 | |
| 138 | 6-CH3 0 | ch3sch2 | cooc2h5 | |
| 139 | 6-C2H5 0 | c2h5 | cooc2h5 | |
| 140 | 6-C2H5 0 | ch3sch2 | cooc2h5 |
| Primer št. | R1 n | R2 | R3 | Tal.’C |
| 140a | 6-0H | ch3sch2 | C00CH(CH3)2 | 113 |
| 140b | 6-OH | c2h5 | COOCH(CH3)2 | smola |
| 140c | 6-C1 | CH3 | cooch2ch=ch2 | 144 |
| 140d | 6-C1 | CH3 | C00C(CH3)=CH2 | 149 |
| 140e | 6-C1 | C4H9 | COOC(CH3)=CH2 | 132 |
| 140f | 6-CH30 | ck3sch2 | C00CH(CH3)-C2H5 | 60 |
| 140g | 6-CH30 | ch3sch2 | C00CH2CH(CH3)2 | 89 |
| 140h | 6-F | c2K5 | cooch3 | 146 |
| 140i | 6-F | C2 H5 | cooc.hq 4 9 | 103 |
| 140j | 6-F | C2K5 | COOCH2CH(CH3)2 | smola |
| 140k | 6-F | C2H5 | COOCH(CH3)-C2Hs | 51 |
| 1401 | 6-F | ch3ock2 | C00CH(CH3)2 | 143 |
Testi učinkovitosti:
Testiranje preparatov proti HIV v celični kulturi
Opis metod:
Medij: RMPI, pH 6,8
Kompleten medij vsebuje dodatno 20% fetalnega telečjega seruma in 40 IU/ml rekombinantnega interlevkina 2.
Celice:
Iz sveže krvi krvodajalca s pomočjo FicollR-gradientnega centrifugiranja izolirane limfocite gojimo ob dodatku 2 g/ml fitohemaglutinina (Wellcome) v kompletnem mediju 36 ur pri 37°C pod 5% CO2. Celice po dodatku 10% DMSO pri celični gostoti 5 χ 106 zamrznemo in skladiščimo v tekočem dušiku. Za poskus celice odtajamo, izperemo v RPMI mediju in gojimo v kompletnem mediju 3 do 4 dni.
Nastavek:
Testne preparate raztopimo v koncentraciji 16,7 mg/ml v DMSO in v kompletnem mediju razredčimo na 1 mg/ml.
0,4 ml medija predložimo v Multiwell skledice s 24 vdolbinami. Po dodatku 0,1 ml raztopljenega preparata v gornjo vrsto skledice proizvedemo s prenašanjem vsakokrat 0,1 ml geometrično vrsto razredčenja. Kontrole brez preparata vsebujejo vsakokrat 0,4 ml kompletnega medija z 0,5 % DMSO.
Limfocitne kulture s številom celic 5 χ 105 celic/ml inficiramo z dodatkom 1/50 volumna supernatanta iz limfocitnih kultur, inficiranih s HIV. Titer teh supernatantov kultur določimo z razredčenjem končne točke z 1 - 5 χ 106 infektivnih enot/ml. Po 30 minutah inkubacije pri 37°C inficirane limfocite odcentrifugiramo in spet prevzamemo v enakem volumnu medija. Od te celične suspenzije damo vsakokrat 0,6 ml v vse vdolbine testne plošče. Nastavke inkubiramo 3 dni pri 37°C.
Ovrednotenje:
Inficirane celične kulture preiskujemo pod mikroskopom na prisotnost celic velikank, ki kažejo na aktivno razmnoževanje virusov v kulturi. Najmanjšo koncentracijo preparata, pri kateri ne nastopijo celice velikanke, določimo kot zaviralno koncentracijo proti HIV. Za kontrolo določimo supernatante iz plošč kultur s pomočjo HlV-antigenskega testa ustrezno podatkom proizvajalca (Organon) na prisotnost HIV antigena.
Rezultati:
Tabela 4:
| Spojina | test T-celične kulture |
| primera | MHK EC50 (ng/ml) |
| St. | |
| 29 | <8 |
| 30 | <40 |
| 31 | 50 |
| 34 | <1 |
| 35 | <80 |
| 38 | <1 |
52 54
61 68
99
100
108
110
113
114
115 124
62 78 84 i 84j 841 84o
98 <8 <1 <80 <8 <40 <8 <8 <1 <5
0,8
1,6
1,6 <8 <80 <80
| 104 | 8 |
| 134 | 8 |
| 140a | 40 |
| 140b | <80 |
| 140c | 40 |
| 140d | 10 |
| 140f | 8 |
| 140g | 40 |
| 140h | 10 |
| 140i | 10 |
| 140j | 10 |
| 140k | 8 |
| 1401 | 8 |
Preiskava snovi na zaviranje HlV-reverzne transkriptaze
Aktivnost reverzne transkriptaze (RT) določimo s pomočjo testa Scintillation Proximity Assay (SPA).
Reagenčni komplet za RT-SPA smo dobili pri Amersham/Buchler (Braunschvveig). Encim RT (kloniran iz HIV in E. coli) je izviral iz firme HT-Biotechnology Ltd, Cambridge, Velika Britanija).
Nastavek:
Test smo izvedli po priročniku metod proizvajalca Amershama - z naslednjimi modifikacijami:
pufru za test smo dodali goveji serumski albumin do končne koncentracije 0,5 mg/ml test smo izvedli v Eppendorfovih reakcijskih posodah z volumnom nastavka 100 μ1
RT koncentrat proizvajalca (5000 U/ml) smo razredčili v Tris-HCl pufru 20 mM; pH 7,2; 30 % glicerina na aktivnost 15 U/ml inkubacijski čas za nastavke znaša 60 min (37°C) po ustavitvi reakcije in razvijanju s suspenzijo biserov smo transferirali 130 μΐ nastavka v 4,5 ml Tris-HCl pufra, 10 mM; pH 7,4; 0,15 M NaCl in določili aktivnost tricija v /3-števcu.
Test snovi
Za predtest inhibitorske aktivnosti smo snovi raztopili v DMSO (osnovna raztopina c = 1 mg/ml) in testirali v razredčenju v DMSO ΙΟ'1, ΙΟ'2,10'3, itd.
Za določitev vrednosti IC50 smo inhibotorske osnovne raztopine v Tris-HCl pufru, 50 mM, pH 8, nadalje razredčevali in testirali v primernih koncentracijah.
Iz grafične predstave RT aktivnosti proti log Cjnh smo določili koncentracijo, ki pripada 50 %-nemu zaviranju encima.
Rezultate preiskave kaže tabela 5.
Tabela 5:
Spojina test reverzne transkriptaze primera IC5Q (ng/ml) št.
38 52
61 68
87
94
10-100
10-100
10-100
10-100
10-100
10-100
| 99 | 11 |
| 100 | 16 |
| 108 | 8 |
| 110 | 10-100 |
| 113 | 6 |
| 114 | 7 |
| 115 | 10 |
| 125 | 15 |
| 39 | 20 |
| 40 | 10-100 |
| 62 | 92 |
| 78 | 80 |
| 84g | 118 |
| 84 i | 170 |
| 84j | 87 |
| 841 | 150 |
| 96 | 16 |
| 98 | 12 |
| 104 | 35 |
| 134 | 3 |
| 140a | 93 |
| 140b | 70 |
| 140c | 110 |
| 140d | 27 |
| 140f | 19 |
| 140g | 17 |
| 140h | 8 |
| 140i | 22 |
| 140 j | 15 |
| 140k | 16 |
| 1401 | 22 |
Za
Claims (9)
1. Spojine s formulo I in la kot tudi njihove fiziološko prenesljive soli in predzdravila, pri čemer v formulah I in la pomenijo n je enako 0,1 ali 2,
R1 fluor, klor, hidroksi, Cj-C^-alkoksi,
R2 Cj-C^alkil, v danem primeru substituiran s hidroksi, Cj-C^alkoksi ali Cj-C^ alkiltio,
R3 C-C,-alkiloksikarbonil ali C.-C-alkeniloksikarbonil,
10 2 0 1
X kisik, žveplo ali selen.
2. Spojine s formulo I oz. Ia po zahtevku 1, označene s tem, da substituenti v navedenih formulah pomenijo:
nje enako 0,1 ali 2,
R1 fluor, klor, hidroksi, C^C^alkoksi,
R2 Cj-C^-alkil, v danem primeru substituiran s hidroksi, Cj-Cj-alkoksi ali Cj-C429 alkiltio,
R3 C,-C,-alkiloksikarbonil ali CL-C -alkeniloksikarbonil,
1 4 2 4 ’
X kisik ali žveplo.
3. Spojine s formulo I oz. Ia po zahtevkih 1 ali 2, označene s tem, da substituenti v navedenih formulah pomenijo:
n je enako 0 ali 1,
R1 fluor, klor, metoksi, etoksi, propoksi,
R2 metiltiometil, etil, propil, C1-C2-alkil, v danem primeru substituiran s hidroksi ali C.-C-alkoksi,
1 4 1
R3 C,-C,-alkiloksikarbonil ali CL-C -alkeniloksikarbonil,
1 4 2 4 ’
X kisik ali žveplo.
4. Spojine s formulo I oz. Ia po zahtevkih 1 do 3, označene s tem, da substituenti v navedenih formulah pomenijo:
nje enako 0 ali 1,
R1 fluor, klor, metoksi, etoksi,
R2 metiltiometil, etil, propil, Cj-C^alkil, substituiran s hidroksi ali C1-C4-alkoksi, R3 C1-C4-alkiloksikarbonil ali C2-C4-alkeniloksikarbonil,
X kisik ali žveplo.
5. Postopek za pripravo spojin s formulo I oz. Ia po zahtevku 1, označen s tem, da
A) za pripravo spojin s formulo I z X = kisik in ostanki R1, R2 in R3, kot je definirano v zahtevkih 1 do 4, spojino s formulo II,
H pri čemer za R1 in R2 veljajo v zahtevkih 1 do 4 navedene definicije, presnovimo s spojino s formulo III,
R3-Z (III) pri čemer ima R3 zgoraj v zahtevkih 1 do 4 navedene pomene in je Z odhodna skupina, kot npr. klor, ali da
B) spojine s formulo I, z X = žveplo in R1, R2 in R3, kot je definirano v zahtevkih 1 do 4, pripravljene z reakcijo spojine s formulo I, pri čemer je X kisik in veljajo za R1, R2 in R3 v zahtevkih 1 do 4 navedene definicije, presnovimo s sredstvom za uvedbo žvepla.
6. Spojine s formulo I oz. Ia po enem ali več od zahtevkov 1 do 4 za uporabo kot zdravila.
7. Zdravila, označena s tem, da vsebujejo učinkovito količino vsaj ene spojine s formulo I oz. Ia po enem ali več od zahtevkov 1 do 4,
8. Postopek za pripravo zdravila po zahtevku 7, označen s tem, da učinkovito količino spojine s formulo I oz. Ia z običajnimi farmacevtskimi pomožnimi snovmi spravimo v primerno dajalno obliko.
9. Uporaba spojin s formulo I oz. Ia po enem ali več od zahtevkov 1 do 4 za pripravo zdravil za zdravljenje virusnih obolenj.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4437406A DE4437406A1 (de) | 1994-10-19 | 1994-10-19 | Chinoxaline, Verfahren zu ihrer Herstellung und ihre Verwendung |
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|---|---|
| SI9500329A true SI9500329A (en) | 1996-04-30 |
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| SI9500329A SI9500329A (en) | 1994-10-19 | 1995-10-19 | Quinoxalines, process for the preparation thereof and use thereof |
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| US (1) | US5723461A (sl) |
| EP (1) | EP0708093B1 (sl) |
| JP (1) | JPH08225544A (sl) |
| KR (1) | KR960014108A (sl) |
| CN (1) | CN1094930C (sl) |
| AT (1) | ATE198747T1 (sl) |
| AU (1) | AU708293B2 (sl) |
| BR (1) | BR9504456A (sl) |
| CA (1) | CA2160859A1 (sl) |
| CZ (1) | CZ271295A3 (sl) |
| DE (2) | DE4437406A1 (sl) |
| DK (1) | DK0708093T3 (sl) |
| ES (1) | ES2154311T3 (sl) |
| FI (1) | FI954946L (sl) |
| GR (1) | GR3035673T3 (sl) |
| HK (1) | HK1011988A1 (sl) |
| HR (1) | HRP950524B1 (sl) |
| HU (1) | HUT73485A (sl) |
| IL (1) | IL115641A0 (sl) |
| MY (1) | MY132057A (sl) |
| NO (1) | NO306615B1 (sl) |
| NZ (1) | NZ280258A (sl) |
| PL (1) | PL184860B1 (sl) |
| PT (1) | PT708093E (sl) |
| SI (1) | SI9500329A (sl) |
| SK (1) | SK128495A3 (sl) |
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| US6369057B1 (en) * | 1991-04-15 | 2002-04-09 | Aventis Pharma Deutschland Gmbh | Quinoxalines, processes for their preparation and their use |
| US6015800A (en) * | 1997-09-03 | 2000-01-18 | Warner-Lambert Company | Substituted quinoxaline-2-ones as glutamate receptor antagonists |
| WO1999025327A2 (en) * | 1997-11-14 | 1999-05-27 | Warner-Lambert Company | Small molecule intervention in hiv-1 replication |
| GB9901795D0 (en) * | 1999-01-28 | 1999-03-17 | Glaxo Group Ltd | Chemical compounds |
| GB9911887D0 (en) * | 1999-05-21 | 1999-07-21 | Glaxo Group Ltd | Methods and medicaments for post exposure prophylaxis of an hiv infection |
| WO2002087500A2 (en) * | 2001-04-27 | 2002-11-07 | Newbiotics, Inc. | Viral enzyme activated prototoxophores and use of same to treat viral infections |
| WO2005018531A2 (fr) * | 2003-08-26 | 2005-03-03 | 'chemical Diversity Research Institute', Ltd. | Compositions pharmaceutiques, composes azo-heterocycliques et procedes de fabrication et d'utilisation correspondants |
| US7351709B2 (en) * | 2004-06-09 | 2008-04-01 | Wyeth | Estrogen receptor ligands |
| BR112014026703B1 (pt) | 2012-04-24 | 2022-10-25 | Vertex Pharmaceuticals Incorporated | Inibidores de dna-pk e seus usos, composição farmacêutica e seus usos, e método de sensibilização de uma célula |
| HRP20211855T1 (hr) | 2013-03-12 | 2022-03-04 | Vertex Pharmaceuticals Incorporated | Inhibitori dnk-pk |
| LT3424920T (lt) | 2013-10-17 | 2020-08-10 | Vertex Pharmaceuticals Incorporated | (s)-n-metil-8-(1-((2`-metil-[4,5`-bipirimidin]-6-il)amino)propan-2-il)chinolin-4-karboksamido ir jo deuterintų darinių, kaip dnr-pk inhibitorių, bendri kristalai |
| KR20190062485A (ko) | 2016-09-27 | 2019-06-05 | 버텍스 파마슈티칼스 인코포레이티드 | Dna-손상제 및 dna-pk 저해제의 조합을 사용한 암 치료 방법 |
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| EP0509398B1 (de) * | 1991-04-15 | 2001-09-19 | Aventis Pharma Deutschland GmbH | Chinoxaline, Verfahren zu ihrer Herstellung und ihre Verwendung |
| DE4342024A1 (de) * | 1993-12-09 | 1995-06-14 | Hoechst Ag | Kombinationspräparate, enthaltend ein Chinoxalin und ein Nukleosid |
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1994
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- 1995-10-12 AT AT95116094T patent/ATE198747T1/de not_active IP Right Cessation
- 1995-10-12 EP EP95116094A patent/EP0708093B1/de not_active Expired - Lifetime
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