JPH08500089A - Use of tricyclic pyrimidine derivatives as antiviral therapeutics - Google Patents
Use of tricyclic pyrimidine derivatives as antiviral therapeuticsInfo
- Publication number
- JPH08500089A JPH08500089A JP5519843A JP51984393A JPH08500089A JP H08500089 A JPH08500089 A JP H08500089A JP 5519843 A JP5519843 A JP 5519843A JP 51984393 A JP51984393 A JP 51984393A JP H08500089 A JPH08500089 A JP H08500089A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- alkyl
- alkylamino
- carbon atoms
- formula
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 10
- 230000000840 anti-viral effect Effects 0.000 title claims abstract description 8
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- -1 hydroxy, nitro, cyano, azido, phenyl Chemical group 0.000 claims abstract description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 27
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 20
- 150000002367 halogens Chemical class 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 15
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 13
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 4
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 4
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 125000000165 tricyclic carbocycle group Chemical group 0.000 claims description 5
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 4
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
- 150000001540 azides Chemical group 0.000 claims description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical group [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical group C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 claims description 2
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical group C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 229950000688 phenothiazine Drugs 0.000 claims description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- 125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 claims 1
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 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 abstract description 5
- 125000002837 carbocyclic group Chemical group 0.000 abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241000156724 Antirhea Species 0.000 description 9
- YHPVIBUEXBEHPV-UHFFFAOYSA-N 2,6-dihydro-1h-pyrimidin-5-one Chemical compound O=C1CNCN=C1 YHPVIBUEXBEHPV-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 6
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- 241000700605 Viruses Species 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
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- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
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- 239000013543 active substance Substances 0.000 description 4
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- 229910052801 chlorine Inorganic materials 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
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- 239000000654 additive Substances 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
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- 241001493065 dsRNA viruses Species 0.000 description 2
- AEFVLBBNSFAEDD-UHFFFAOYSA-N ethyl n-(2-benzoylphenyl)carbamate Chemical compound CCOC(=O)NC1=CC=CC=C1C(=O)C1=CC=CC=C1 AEFVLBBNSFAEDD-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- ATQUABCIJINPMX-UHFFFAOYSA-N quinazolin-5-ol Chemical compound C1=NC=C2C(O)=CC=CC2=N1 ATQUABCIJINPMX-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
(57)【要約】 本発明は、抗ウイルス作用を有する薬剤を製造するための三環式ピリミジン誘導体の新規な使用法に関する。さらに、本発明は新規なピリミジン誘導体、その製造方法および該化合物を含有する薬剤に関する。本発明は、抗ウイルス作用を有する薬剤を製造するための一般式Ｉ〔式中、Ａは炭素環または複素環を表し、Ｘは酸素または硫黄原子、もしくは基＝ＮＨ、＝Ｎ−Ｃ1−Ｃ6アルキルまたは＝Ｓ（Ｏ）2 であり、Ｙは酸素原子あるいはＮＨ−またはＣ1−Ｃ5アルキルアミノ基であり、Ｒはフェニルで置換されていてもよいｌ〜９個の炭素原子を有する脂肪族基、またはフェニル環もしくは７〜１５個の炭素原子を有する炭素環あるいは複素環系を表し、Ｒ1 は水素原子、１〜６個の炭素原子を有する脂肪族基、Ｃ1−Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト、Ｃ1−Ｃ6アルキルスルフィニル、Ｃ1−Ｃ6アルキルスルホニル、アミノ、Ｃ1−Ｃ6アルキルアミノ、ジＣ1−Ｃ6アルキルアミノ、スルホンアミド、Ｃ1−Ｃ6アルコキシカルボニル、カルボキシ、ハロゲン、ヒドロキシ、ニトロ、シアノ、アジド、フェニルまたはベンジルオキシを表し、Ｒ2 、Ｒ3 、Ｒ4 およびＲ5 は互いに独立して同一であっても異なっていてもよく、水素、Ｃ1−Ｃ6アルキル、Ｃ1−Ｃ6ヒドロキシアルキル、シアノ、カルボキシ、またはＣ1−Ｃ6アルコキシカルボニルを表し、あるいはＲ2 とＲ4 はそれらが結合している炭素原子間の追加の結合を表し、Ｒ6 は水素またはＣ1−Ｃ6アルキルを表し、そしてｍは０またはｌである〕で表される三環式ピリミジン誘導体、ならびにその互変異性体、鏡像異性体、ジアステレオマーおよび生理学的に許容される塩の使用法に関する。 (57) [Summary] The present invention relates to a novel use of a tricyclic pyrimidine derivative for producing a drug having an antiviral effect. Furthermore, the present invention relates to a novel pyrimidine derivative, a method for producing the same and a drug containing the compound. The present invention has the general formula I wherein for the manufacture of a medicament having antiviral activity, A represents a carbocyclic or heterocyclic ring, X represents an oxygen or sulfur atom or a group = NH,, = N-C 1 - C 6 alkyl or ═S (O) 2 , Y is an oxygen atom or NH— or a C 1 -C 5 alkylamino group, and R is 1 to 9 carbon atoms optionally substituted with phenyl. Represents an aliphatic group, or a phenyl ring or a carbocyclic or heterocyclic ring system having 7 to 15 carbon atoms, R 1 is a hydrogen atom, an aliphatic group having 1 to 6 carbon atoms, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, amino, C 1 -C 6 alkylamino, di C 1 -C 6 alkylamino, sulfonamide, C 1 -C 6 an alkoxycarbonyl Represents carbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R 2 , R 3 , R 4 and R 5 may be the same or different, independently of each other, hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, cyano, carboxy, or C 1 -C 6 alkoxycarbonyl, or R 2 and R 4 are additional bonds between the carbon atoms to which they are bonded. And R 6 represents hydrogen or C 1 -C 6 alkyl, and m is 0 or l], as well as tautomers, enantiomers, diastereomers thereof And the use of physiologically acceptable salts.
Description
【発明の詳細な説明】 抗ウイルス治療薬としての 三環式ピリミジン誘導体の使用 本発明は、抗ウイルス作用を有する薬剤を製造するための三環式ピリミジン誘 導体の新規な使用法に関するものである。さらに、本発明は、新規なピリミジン 誘導体、その製造方法ならびに該化合物を含有する薬剤に関するものである。 本発明は、抗ウイルス作用を有する薬剤を製造するための一般式Ｉ： で表される三環式ピリミジン誘導体、ならびにその互変異性体、鏡像異性体、ジ アステレオマーおよび生理学的に許容される塩の使用法に関するものであり、こ こで Ａは５または６個の炭素原子を有する炭素環あるいは最大４個のへテロ原子を有 する複素環を表し、その際へテロ原子は同一であっても異なっていてもよく、酸 素、窒素または硫黄を表し、所望により複素環は．１個または数個の窒素原子上 に酸素原子をもっていてもよく、Ａは所望により１個または数個の同一であ っても異なっていてもよい基Ｒ1 で置換されており； Ｘは酸素または硫黄原子、もしくは基＝ＮＨ、＝Ｎ−Ｃ1−Ｃ6アルキルまたは＝ Ｓ（Ｏ）2 であり； Ｙは酸素原子あるいはＮＨ−またはＣ1−Ｃ5アルキルアミノ基であり； Ｒはフェニルで置換されていてもよいｌ〜９個の炭素原子を有する直鎖状または 分枝鎖状の飽和もしくは不飽和脂肪族基であるか、または それはフェニル環を表し、 あるいは、それは７〜１５個の炭素原子を有する一、二または三環式炭素環、も しくはそれぞれの場合に５または６個の環原子を有する複素環式一、二または三 環系を表し、そして環系あたり１〜４個またはｌ〜５個の窒素、硫黄または酸素 のへテロ原子を含むことができ、そして上記のフェニル環、一、二または三環式 炭素環、もしくは複素環式一、二または三環系は所望によりＣ1−Ｃ6アルキル、 Ｃ1−Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト、Ｃ1−Ｃ6アルキルスルフィ ニル、Ｃ1−Ｃ6アルキルスルホニル、Ｃ2−Ｃ6アルケニル、Ｃ2−Ｃ6アルキニル 、Ｃ2−Ｃ6アルケニルオキシ、Ｃ2−Ｃ6アルケニルメルカプト、Ｃ2−Ｃ6アルキ ニルオキシ、Ｃ2−Ｃ6アルキニルメルカプト、アミノ、Ｃ1−Ｃ6アルキルアミノ 、ジＣ1−Ｃ6アルキルアミノ、Ｃ1−Ｃ6アルキルカルボニルアミノ、Ｃ1−Ｃ6ア ルキルアミノカルボニル、Ｃ1−Ｃ6アルコキシカルボニル、ヒドロキシ、ベンジ ルオキシ、フェニルメルカプト、フェニルオキシ、ニトロ、シアノ、ハロゲン、 トリフルオロメチル、アジド、ホルミルア ミノ、カルボキシ、またはフェニルでｌ回あるいは数回置換されており； Ｒ1 は水素原子、１〜６個の炭素原子を有する直鎖状または分枝鎖状の飽和もし くは不飽和脂肪族基、Ｃ1−Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト、Ｃ1 −Ｃ6アルキルスルフィニル、Ｃ1−Ｃ6アルキルスルホニル、アミノ、Ｃ1−Ｃ6 アルキルアミノ、ジＣ1−Ｃ6アルキルアミノ、スルホンアミド、Ｃ1−Ｃ6アルコ キシカルボニル、カルボキシ、ハロゲン、ヒドロキシ、ニトロ、シアノ、アジド 、フェニルまたはベンジルオキシを表し； Ｒ2 、Ｒ3 、Ｒ4 およびＲ5 は互いに独立して同一であっても異なっていてもよ く、それぞれ水素、Ｃ1−Ｃ6アルキル、Ｃ1−Ｃ6ヒドロキシアルキル、シアノ、 カルボキシ、またはＣ1−Ｃ6アルコキシカルボニルを表し、あるいはＲ2 とＲ4 はそれらが結合している炭素原子間の追加の結合を表すことができ； Ｒ6 は水素またはＣ1−Ｃ6アルキルを表し； ｍは０または１を表す。 構造的に類似した化合物（キナゾリン誘導体）が、比較的早期の欧州特許出願 明細書EP 0 530 994 に逆転写酵素の阻害剤として記載されている。特に、実施 例５Ｃ−５Ｆおよび１０１には、式ＩにおいてＡが塩素原子で置換されたフェニ ル環を表し、Ｒがシクロプロピル、シクロペンチルまたはフェニル環、あるいは プロピル基を表し、ＸおよびＹが酸素原子を表し、Ｒ1 、Ｒ2 、Ｒ3 、Ｒ5 およ びＲ6 が水素原子を表し、そしてＲ4 が水素原子またはイソプロピル基を表す化 合物の記載がある。 Ａが置換または非置換のフェニル環を表し、そしてＸが酸素または硫黄原子あ るいは基＝ＮＨを表すいくつかの一般式Ｉの化合物もすでに文献に記載されてい る。 例えば、US 3,891,638、 US 3,812,257、 DE 21 66 380、 DE 2307 808およびDE 21 41 616には、このタイプの化合物が抗炎症作用および尿酸の排泄を向上させ る作用を有すると記載されている。 出願 JP 47036758には抗鎮痙作用を有する物質が見いだせる。 出願 DE 214 1616では該化合物は鎮痛作用を有するとされており、そして出 願US 3,329,679には中枢神経系に影響を及ぼす化合物が見いだせる。 上記の特許出願のほかに、一部の式Ｉの化合物の合成はChem.Pharm. Bull. 29 , 2135, 1981 、 Pharmazie 37, 379, 1982および薬学雑誌 90, 629, 1970にも記 載されている。 特に、一般式ＩにおいてＡが最大４個のへテロ原子を有する芳香族複素環を表 す化合物は新規であり、これまでに文献に記載されていない。 本発明の目的は、現在の技術水準より得られる既知化合物について更なる医学 的指標を見いだすことであった。さらに、本発明の目的は、薬剤の製造のために 特に薬理活性物質として使用し得る新規な三環式ピリミジン誘導体を提供するこ とであった。とりわけ、本発明の課題は、ウイルスまたはレトロウイルス感染な らびにこれらの感染によって引き起こされる疾病の治療に使用し得る薬剤を見つ けることであった。この目的は請求の範囲に規定した特徴により達成される。 本発明の化合物は価値のある薬理作用を有する。特に、それら は例えば単純へルペスウイルス、サイトメガロウイルス、乳頭腫ウイルス、水痘 −帯状庖疹ウイルスまたはエプスタイン-バーウイルスといったＤＮＡウイルス 、あるいはトガウイルス、特にレトロウイルス、例えば腫瘍ウイルスＨＴＬＶ− ＩおよびII、レンチウイルスビスナまたはヒト免疫不全ウイルスＨＩＶ−ｌおよ び２といったＲＮＡウイルスが原因で起こる感染症の治療ならびに予防に適して いる。 式Ｉの化合物は、とりわけ、持続的な全身性リンパ節症（ＰＧＬ）、進行期の エイズ関連症候群（ＡＲＣ）および完全な臨床像のエイズといったヒトにおける レトロウイルスＨＩＶ感染症の臨床的発現の治療に適しているようだ。 一般式Ｉの本発明化合物は顕著な抗ウイルス作用を有し、特にウイルスおよび レトロウイルス感染症の治療に適している。哺乳動物、とりわけヒトのウイルス 感染は広範囲にわたっている。鋭意努力しているにもかかわらず、ウイルスまた はレトロウイルスに依存する病理学的過程を原因療法的にあるいは対症療法的に 妨害する化学療法剤を以前には提供できなかった。今日、例えば後天性免疫不全 症候群（ＡＩＤＳ）、エイズ関連症候群（ＡＲＣ）およびその早期段階、へルペ ス、サイトメガロウイルス（ＣＭＶ）、インフルエンザウイルスおよび他のウイ ルス感染症といったある種のウイルス病を化学療法手段によって治すこと、また 、それらの症状を好転させることはできない。現在、例えばジドブ れている３′−アジド−３′−デオキシチミジン（ＡＺＴ）はエイズの治療に利 用できるほとんど全てである。しかし、ＡＺＴは 非常に狭い治療域と、その治療域ですでに生じる極めて強い毒性をもつ点に特徴 がある(Hirsch, M.S. (1988) J. Infec. Dis. l57, 427-431)。一般式Ｉの化合 物はこれらの欠点を示さない。それらは薬理学的に妥当な用量で細胞毒性を示す ことなく抗ウイルス的に作用する。 今回、一般式Ｉの化合物がウイルス特異的ＤＮＡおよびＲＮＡ転写のレベルで ＤＮＡおよびＲＮＡウイルスの増殖を阻止し得ることを実証することができた。 これらの物質は逆転写酵素を阻害することによってレトロウイルスの増殖に影響 を及ぼす (Proc.Natl. Acad. Sci. USA 83，1911, 1986 および Nature 325, 77 3,1987を参照のこと）。 本来の生体機能の正常なプロセスに影響を与えることなく、レトロウイルスが 原因で起こる疾病またはその症状をできる限り特異的に妨げる化学療法剤の要望 が非常に高まってきているので、前記の化合物は、レトロウイルスが病態生理学 的に、徴候的に、あるいは臨床的に関係している疾病の処置において予防または 治療上利用することができる。 式Ｉの化合物はラセミ体として、または光学活性誘導体として存在し得る。 ラセミ体の鏡像異性体への分離は、通常の溶離剤を用いる適当な光学活性相で のクロマトグラフィーにより分析的に、半調製的に、または調製的に実施するこ とができる。 適当な光学活性相は、例えば光学的に活性なポリアクリルアミドまたはポリメ タクリルアミド（一部のものはシリカゲル上にあ ロースカルバメート（例えば、Baker社／Daicel社から得られる あるいは微結晶質セルローストリアセテート（Merck社）である。 Ａの定義において、Ａは炭素環、特に直接縮合されたフェニル、シクロペンチ ル、シクロヘキシル、シクロペンテニルまたはシクロペンタジエニル環を表す。 縮合された芳香族複素環Ａは５〜６個の炭素原子を有し、これらの環原子の４個 までがへテロ原子の酸素、硫黄および／または窒素で置換され得る。例えば、次 の複素環を挙げることができる：フラン、チオフェン、ピロール、オキサゾール 、イソオキサゾール、チアゾール、ピラゾール、イミダゾール、オキサジアゾー ル、トリアゾール、ピリジン、ピリダジン、ピリミジン、またはピラジン環。複 素環Ａに窒素原子が存在する場合、相当する複素環はそのＮ−オキシドの形で存 在してもよい。環Ａは１個または数個の（好ましくは１または２個）の基Ｒ1 で 置換することができ、その際置換基Ｒ1 は同一でも異なっていてもよい。 脂肪族基ＲまたはＲ1 は１〜９個（好ましくは２〜７個）の炭素原子を有する 直鎖状または分枝鎖状のアルキル、アルケニルもしくはアルキニル基を表し、例 えばプロピル、イソプロピル、ブチル、イソブチル、ぺンチル、へキシルまたは へプチル基を表す。不飽和基としてはＣ2−Ｃ7（好ましくはＣ2−Ｃ5）アルケニ ルまたはアルキニル基、例えばアリル、ジメチルアリル、ブテニル、イソブテニ ル、ぺンテニル、またはプロピニル基が考えられる。 フェニルで置換されていてもよい脂肪族基Ｒは特にフェニル−Ｃ1−Ｃ6アルキ ル基、例えばベンジル、フェネチル、フェニルプロピル、またはフェニルブチル 基である。 基ＲまたはＲ1 がフェニル環を含む場合、それはｌ、２または３個の置換基を もつことができる。置換基は、互いに独立して、ｏ、ｍまたはｐ位に存在し得る 。 ７〜１５個の炭素原子を有する炭素環Ｒは一、二または三環系で、環あたり５ または６個の炭素原子をもつことができる。この環は飽和、不飽和、部分飽和あ るいは芳香族であり得る。例として次の環系を挙げることができる：ナフチル、 アントラセニル、フェナントレニル、フルオレニル、インデニル、インダニル、 アセナフチレニル、ノルボルニル、アダマンチル環、またはＣ3−Ｃ7シクロアル キルもしくはＣ5−Ｃ8シクロアルケニル基。さらに、この炭素環はモノまたはジ 置換されていてもよく、フェニル環の場合には置換基が互いに独立してｏまたは ｍ位に存在し得る。 基Ｒの複素環式一、二または三環系は環あたり５または６個の炭素原子を含み 、１〜４個または１〜５個の炭素原子がへテロ原子の酸素、硫黄および／または 窒素で置換され得る。環系は芳香族であっても、部分的にまたは完全に水素化さ れていてもよい。 例として次の環系を挙げることができる：ピリジン、ピリミジン、ピリダジン、 ピラジン、トリアジン、ピロール、ピラゾール、イミダゾール、トリアゾール、 チアゾール、オキサゾール、イソオキサゾール、オキサジアゾール、フラザン、 フラン、チオフェン、インドール、キノリン、イソキノリン、クマロン、チオナ フテン、ベンゾキサゾール、ベンゾチアゾール、インダゾール、べンズイ ミダゾール、ベンズトリアゾール、クロメン、フタラジン、キナゾリン、キノキ サリン、メチレンジオキシベンゼン、カルバゾール、アクリジン、フェノキサジ ン、フェノチアジン、フェナジン、またはプリン系（不飽和または芳香族の炭素 環および複素環は部分的にまたは完全に水素化することができる）。これらの複 素環が窒素原子を含む場合、相当する複素環はそのＮ−オキシドの形でも存在し 得る。さらに、複素環系はモノまたはジ置換されていてもよく、その場合、置換 基は互いに独立してｏまたはｍ位に存在することが好ましい。 Ｒは、好ましくは、非置換のフェニルを表すか、またはＣ1−Ｃ6アルキル、Ｃ1 −Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト、Ｃl−Ｃ6アルキルスルフィニ ル、Ｃ1−Ｃ6アルキルスルホニル、Ｃ2−Ｃ6アルケニル、Ｃ2−Ｃ6アルキニル、 Ｃ3−Ｃ4アルケニルオキシ、Ｃ1−Ｃ6アルキルアミノ、Ｃ1−Ｃ6ジアルキルアミ ノ、Ｃ1−Ｃ6アルキルカルボニルアミノ、Ｃ1−Ｃ6アルキルアミノカルボニル、 Ｃ1−Ｃ6アルコキシカルボニル、アミノ、ヒドロキシ、ニトロ、アジド、トリフ ルオロメチル、シアノ、またはハロゲンで１回あるいは２回置換されているフェ ニルを表し、ここで上記の脂肪族基は３個までの炭素原子を含むことが好ましい 。 炭素環Ｒは、好ましくは、ビフェニル、ナフチル、アントラセニル、インデニ ル、フルオレニル、アセナフチレニル、フェナントレニル、ノルボルニル、アダ マンチル、Ｃ3−Ｃ6シクロアルキル、Ｃ5−Ｃ8シクロアルケニルであり、ここで 炭素環はＣ1−Ｃ6アルキル、Ｃ1−Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト 、Ｃl−Ｃ6アルキルスルフィニル、Ｃ1−Ｃ6アルキルスルホニ ル、Ｃ2−Ｃ6アルケニル、Ｃ2−Ｃ6アルキニル、Ｃ3−Ｃ4アルケニルオキシ、Ｃ1 −Ｃ6アルキルアミノ、Ｃ1−Ｃ6ジアルキルアミノ、Ｃ1−Ｃ6アルキルカルボニ ルアミノ、Ｃ1−Ｃ6アルキルアミノカルボニル、Ｃl−Ｃ6アルコキシカルボニル 、アミノ、ヒドロキシ、ニトロ、アジド、トリフルオロメチル、シアノ、または ハロゲンでｌ回あるいは２回置換されていてもよく、上記の脂肪族基は３個まで の炭素原子を含むことが好ましい。 複素環系Ｒは、好ましくは、ピロール、イミダゾール、フラン、チオフェン、 ピリジン、ピリミジン、チアゾール、インドール、キノリン、イソキノリン、ク マロン、チオナフテン、ベンズイミダゾール、キナゾリン、メチレンジオキシベ ンゼン、エチレンジオキシベンゼン、カルバゾール、アクリジンおよびフェノチ アジンであり、ここで複素環はＣ1−Ｃ6アルキル、Ｃ1−Ｃ6アルコキシ、Ｃ1− Ｃ6アルキルメルカプト、Ｃ1−Ｃ6アルキルスルフィニル、Ｃ1−Ｃ6アルキルス ルホニル、Ｃ2−Ｃ6アルケニル、Ｃ2−Ｃ6アルキニル、Ｃ2−Ｃ6アルケニルオキ シ、Ｃ1−Ｃ6アルキルアミノ、Ｃ1−Ｃ6ジアルキルアミノ、Ｃ1−Ｃ6アルキルカ ルボニルアミノ、Ｃ1−Ｃ6アルキルアミノカルボニル、Ｃ1−Ｃ6アルコキシカル ボニル、アミノ、ヒドロキシ、ニトロ、アジド、トリフルオロメチル、シアノ、 またはハロゲンで１回あるいは２回置換されていてもよく、上記の脂肪族基は３ 個までの炭素原子を含むことが好ましい。 基Ｒ1 としては水素、Ｃ1−Ｃ6アルキル、Ｃ2−Ｃ4アルケニル、Ｃ2−Ｃ4アル キニル、Ｃ1−Ｃ6アルコキシ、Ｃ1−Ｃ6アルキルメルカプト、Ｃ1−Ｃ6アルキル アミノ、Ｃ1−Ｃ6アルコキシカルボ ニル、アミノ、ハロゲン、ヒドロキシ、ニトロ、シアノおよびアジドが好ましく 、上記の脂肪族基は３個までの炭素原子を含むことが好ましい。 Ｒ2 、Ｒ3 、Ｒ4 およびＲ5 として好ましい置換基は水素、Ｃ1−Ｃ3アルキル 、Ｃl−Ｃ6ヒドロキシアルキル、カルボキシ、Ｃ1−Ｃ6アルコキシカルボニルお よびシアノであり、あるいはＲ2 とＲ4 が追加の結合を形成する。 ＸおよびＹは好ましくは酸素である。ハロゲンは一般にフッ素、塩素、臭素お よびヨウ素として理解されるべきであり、フッ素、塩素および臭素が好ましい。 Ａについては特に芳香環が考慮される。好適な縮合された複素環Ａは５または ６個の環原子を有する窒素含有芳香環である。 Ｒとして好ましい基はＣ3−Ｃ5アルキル、Ｃ2−Ｃ5アルケニル、Ｃ2−Ｃ4アル キニル、べンジル、フェネチル、フェニル、（Ｃ1−Ｃ6アルキル、Ｃ1−Ｃ6アル コキシ、Ｃ1−Ｃ6アルキルメルカプト、アリル、アリルオキシ、Ｃ1−Ｃ6アルキ ルアミノ、ジＣ1−Ｃ6アルキルアミノ、アミノ、ヒドロキシ、アジド、トリフル オロメチル、シアノまたはハロゲン、あるいはフェニルでモノまたはジ置換され た）フェニル、ナフチル、アントラセニル、インデニル、アセナフチレニル、フ ェナントレニル、アダマンチル、シクロヘキシル、シクロヘキセニル、フリル、 チエニル、ピリジル、ピリミジニル、チアゾリル、インドリル、キノリニル、ベ ンズイミダゾリル、メチレンジオキシフェニル、（メチルまたはハロゲンでトリ 置換された）フェノチアジニルおよびカルバゾリル、ならびに（メチルまたはハ ロゲンでモノまたはジ置換された）上 記の炭素環もしくは複素環の誘導体である。 Ｒ1 としては水素、メチル、エチル、イソプロピル、アリル、メトキシ、エト キシ、メチルメルカプト、エチルメルカプト、メチルアミノ、メトキシカルボニ ル、エトキシカルボニル、アミノ、アジド、シアノ、ヒドロキシおよびハロゲン が特に好ましく、ハロゲンとしては特に塩素と臭素が好ましい。 Ｒ2 、Ｒ3 、Ｒ4 およびＲ5 としては水素、メチル、エチル、イソプロピルお よびシアノが特に好ましく、基Ｒ2 〜Ｒ5 のうち２個または３個は特に水素原子 を表す。Ｒ2 とＲ4 は一緒になって結合を表すこともできる。 Ａとしてはフェニル、ピロール、オキサゾール、チオフェン、フラン、イソオ キサゾール、チアゾール、イミダゾール、ピリジン、ピリダジン、ピリミジンお よびピラジン環が特に好ましい。Ａが縮合６員環を表す場合は、縮合ピリミジン 環の６員環Ａに直接結合している窒素原子に対して、６員環のパラ位（三環系の ９位）に置換基Ｒ1 （特にハロゲン原子）を有する化合物が特に好ましい。 Ｒ、Ｒ1 、Ｘおよびｍが上記の意味を有し、そしてＲ2 、Ｒ3、Ｒ4 およびＲ5 が水素、メチルまたはエチルである（好ましくは、Ｒ2 〜Ｒ5 が水素であるか 、またはＲ2 とＲ4 が追加の結合を表す）一般式Ｉの化合物が特に好ましい。 Ｒ6 としては水素またはＣ1−Ｃ3アルキルが特に好ましい。 ｍは０であることが特に好ましい。 顕著な薬理作用を有する化合物は、とりわけ、Ｒがメタ位置においてＣ1−Ｃ6 アルキル（特にメチルまたはエチル）で置換さ れたフェニル環を表し、Ｘが硫黄原子を表し、そしてＲ1 がハロゲン原子を表す 式Ｉの化合物である。 ウイルス感染を治療するための薬剤は少なくとも１種の式Ｉの化合物を含有し 、液体または固体の形態で経口的または非経口的に投与される。投与剤形として は、例えば錠剤、カプセル剤、被覆錠剤、シロップ剤、溶液剤または懸濁剤とい った通常の剤形が考えられる。注射用の媒体としては、安定剤、可溶化剤および 緩衝液のような注射液用の慣用の添加剤を含有する水を使用することが好ましい 。この種の添加剤には、例えば、酒石酸およびクエン酸緩衝液、エタノール、エ チレンジアミン四酢酸およびその無毒性塩のような錯化剤、ならびに粘度を調節 するための液体のポリエチレンオキシドのような高分子ポリマーがある。注射液 用の液体のキャリアー物質は無菌でなければならず、アンプルに分配することが 好ましい。固体のキャリアー物質には、例えば、デンプン、ラクトース、マンニ トール、メチルセルロース、タルク、高分散ケイ酸、ステアリン酸のような高分 子脂肪酸、ゼラチン、寒天、リン酸カルシウム、ステアリン酸マグネシウム、動 物性および植物性の脂肪、ポリエチレングリコールのような固体の高分子ポリマ ーなどがある。経口投与用の適当な処方物は、所望により、香料や甘味料を含む ことができる。 投与量は適用方式、種、年齢または個々の健康状態などの諸要因に左右される 。本発明による化合物は一般に０．１〜１００ｍｇ／日／ｋｇ（体重）、好まし くは０．２〜８０ｍｇ／日／ｋｇの量で投与される。１日分の投与量を２〜５回 に分けて、各回に０．５〜５００ｍｇの活性物質含量を有する錠剤１または２個 を 投与することが好ましい。また、錠剤を徐放性にすることによって１日あたりの 投与回数を１〜３回に減らすこともできる。徐放性錠剤の活性物質の含量は２〜 １０００ｍｇであり得る。活性物質を連続注入によって投与してもよく、その場 合、一般に１日あたり５〜１０００ｍｇの量が適している。 また、本発明の化合物およびその薬学的製剤は上記感染症の治療ならびに予防 のための他の薬剤と組み合わせて使用することができる。ＨＩＶ感染症およびこ の症状を伴う疾病の治療ならびに予防のために使用しうる他の薬剤の例として、 ３′−アジド−３′−デオキシチミジン、２′，３′−ジデオキシヌクレオシド 類、例えば２′，３′−ジデオキシシチジン、２′，３′−ジデオキシアデノシ ン、および２′，３′−ジデオキシイノシンまたは非環式ヌクレオシド（例：ア シクロビル）を挙げることができる。本発明の化合物と他の薬剤は、それぞれの ケースに応じて、相乗作用が達成されるように、別々に、同時に、所望により単 一の処方物としてまたは２つの処方物として、あるいは異なる回数で投与するこ とができる。 本発明による一般式Ｉの化合物は、一般式II： 〔式中、Ａ、Ｒ、Ｒ1 およびＲ6 は上記の意味を有し、Ｒ7 は容 易に切断できる基、例えばＣＣ１3 、ＣＦ3 、ＯＲ8 またはＮＲ8Ｒ9 を表し、 ここでＲ8 およびＲ9 は同一でも異なっていてもよく、例えばＣ1−Ｃ6アルキル 、置換または非置換のフェニル、フェニルアルキル、へタリールまたはへタリー ルアルキルを表す〕の化合物と、一般式III ： 〔式中、Ｒ2 、Ｒ3 、Ｒ4 、Ｒ5 およびｍは上記の意味を有する〕の置換または 非置換の化合物とを、適当な不活性溶媒中で室温ないし還流温度で、場合により 触媒量の酸（例えばｐ−トルエンスルホン酸）または塩基（例えば水酸化カリウ ム）の存在下に反応させることにより公知の方法に従って製造し、所望により、 その後、式Ｉの化合物を他の式Ｉの化合物に変換し、続いてクロマトグラフィー または再結晶により精製する。ラセミ体は適当な光学活性相（例えばセルロース トリアセテート）でのクロマトグラフィーにより対掌体に分離することができる 。 式Ｉの化合物の他の式Ｉの化合物への変換は、例えば、Ｘ＝Ｓである三環式ピ リミジン誘導体の製造に関係している。Ｘ＝Ｓである化合物は、Ｘが酸素原子で ある式Ｉの化合物を硫黄基含有化合物（例えばLawesson試薬）と反応させること により製造される。 Ｘ＝ＮＨである式Ｉの化合物は、Ｘが酸素原子である式Ｉの化合物を、まずＰ ＯＣ１3のような塩素化試薬を使ってクロルイミンを製造し、これをアンモニア で処理して変換することにより製造される。 Ｒ2 とＲ4 が追加の結合を表す一般式Ｉの化合物は、Ｒ2 、Ｒ3 、Ｒ4 または Ｒ5 がカルボン酸（例えば酢酸）またはスルホン酸（例えばトルエンスルホン酸 ）でエステル化されたヒドロキシーメチル基を表す一般式Ｉの化合物を５０〜２ ００℃で加圧下に、必要ならば不活性溶媒中でイミダゾールや水酸化ナトリウム のような塩基の存在下に、加熱することによって製造される。 出発物質として用いられる一般式IIの化合物は、文献に記載された方法に従っ てアシル化によりアミノベンゾフェノン誘導体から得られる。置換または非置換 の２−アミノベンゾフェノン誘導体は、David A.Walshにより記載された方法（S ynthesis, 677,1980）を用いて製造することが好ましい。 実施例で述べる化合物および請求の範囲で規定した置換基のすべての意味の組 合せから誘導される化合物のほかに、ラセミ混合物または光学活性体つまり純粋 なＲおよびＳ鏡像体として存在しうる下記の式Ｉの化合物が本発明の範囲内で考 えられる： １． 10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-オン ２． 10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-チオン ３． 10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-イミン ４． 6-メチル-10b-フェニル-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン ５． 9-クロロ-l0b-フェニル-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c］ キナゾリン-5-オン ６． 9-メチル-10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン ７． 9-メトキシ-l0b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c ]キナゾリン-5-オン ８． 10-クロロ-l0b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン ９． 10-ニトロ-10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン 10． 7-メチル-10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン 11． 8-メチル-10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン 12． 10b-(3-メチルフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン 13． 10b-(3-クロロフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5-オン 14． 10b-(4-メトキシフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2- c]キナゾリン-5-オン 15． 10b-(2,3-ジメチルフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3, 2-c]キナゾリン-5-オン 16． 10b-(3,5-ジメチルフェニル)-2,3,6,10b-テトラヒドロ-5H- オキサゾロ[3,2-c]キナゾリン-5-オン 17． 10b-(1-ナフチル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾ リン-5-オン 18． 10b-(4-インダニル)-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナ ゾリン-5-オン 19. 10b-(2-アミノ-5-メチルフェニル）-2,3,6,l0b-テトラヒドロ-5H-オキサゾ ロ[3,2-c]キナゾリン-5-オン 20． 10b-(6-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2 -c]キナゾリン-5-オン 21． 10b-(4-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2 -c]キナゾリン-5-オン 22． 10b-チエニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-オン 23． 10b-フラニル-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-オン 24． 11b-フェニル-3,4,7,llb-テトラヒドロ-2H,6H-[1,3]オキサジノ[3,2-c]キ ナゾリン-6-オン 25． 10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c]ピリド[2,3 -e] ピリミジン-5-オン 26． 10b-(3-メチルフェニル）-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c ] ピリド[2,3-e] ピリミジン-5-オン 27． 10b-(3-クロロフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] ピリド[2,3-e] ピリミジン-5-オン 28． 10b-(6-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2 -c] ピリド[2,3-e] ピリミジン-5-オン 29． 10b-(4-メチル-2-ピリジル)-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2 -c]ピリド[2,3-e] ピリミジン-5-オン 30． 3-エトキシカルボニル-l0b-フェニル-2,3,6,l0b-テトラヒドロ-5H-オキサ ゾロ[3,2-c] ピリド[2,3-e] ピリミジン-5-オン 31． 3-ヒドロキシメチル-10b-フェニル-2,3,6,l0b-テトラヒドロ-5H-オキサゾ ロ[3,2-c] ピリド[2,3-e] ピリミジン-5-オン 32． 10b-フェニル-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c] ピリド[3, 4-e] ピリミジン-5-オン 33． 10b-(3-エチルフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] ピリド[3,4-e] ピリミジン-5-オン 34． 10b-(3-ニトロフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] ピリド[3,4-e]ピリミジン-5-オン 35． 10b-(6-メチル-2-ピリジル)-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2 -c] ピリド[3,4-e] ピリミジン-5-オン 36． 10b-メチル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c] ピリド[3,4- e] ピリミジン-5-オン 37． 9b-フェニル-2,3,6,9b-テトラヒドロ-5H-オキサゾロ[3,2-c]チエノ[2,3-e ] ピリミジン-5-オン 38． 9b-(3-メチルフェニル)-2,3,6,9b-テトラヒドロ-5H-オキサゾロ[3,2-c]チ エノ[2,3-e] ピリミジン-5-オン 39． 9b-(3,5-ジクロロフェニル）-2,3,6,9b-テトラヒドロ-5H-オキサゾロ[3,2 -c]チエノ[2,3-e] ピリミジン-5-オン 40． 9b-フェニル-2,3,6,9b-テトラヒドロ-5H-オキサゾロ[3,2- c]フラノ[2,3-e] ピリミジン-5-オン 41． 9b-(4-メチル-2-ピリジル)-2,3,6,9b-テトラヒドロ-5H-オキサゾロ[3,2-c ]フラノ[2,3-e] ピリミジン-5-オン 42. 10b-フェニル-6,10-ジヒドロ-5H-オキサゾロ[3,2-c]キナゾリン-5-オン 43． 10b-(3-メチルフェニル)-6,10-ジヒドロ-5H-オキサゾロ[3,2-c]キナゾリ ン-5-オン 44． 3-メチル-10b-フェニル-6,10-ジヒドロ-5H-オキサゾロ[3,2-c]キナゾリン -5-オン 45． 10b-(3-メチルフェニル)-6,10-ジヒドロ-5H-オキサゾロ[3,2-c]ピリド[2, 3-e] ピリミジン-5-オン 46． 3-メチル-l0b-(3-メチルフェニル)-6,10-ジヒドロ-5H-オキサゾロ[3,2-c] ピリド[2,3-e] ピリミジン-5-オン la． 10b-フェニル-2,3,6,l0b-テトラヒドロ−イミダゾ[1,2-c]キナゾリン-5(1 H)-オン 2a． 10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナゾリン-5(1 H)-チオン 3a． 10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[l,2-c] キナゾリン-5(1H)-イミン 4a． 6-メチル-10b-フェニル-2,3,6,l0b-テトラヒドロ−イミダゾ[l,2-c]キナ ゾリン-5(1H)-オン 5a． 9-クロロ-l0b-フェニル-2,3,6,l0b-テトラヒドロ−イミダゾ[l,2-c]キナ ゾリン-5(1H)-オン 6a． 9-メチル-10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[l,2-c]キナ ゾリン-5(1H)-オン 7a． 9-メトキシ-10b-フェニル-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2-c ]キナゾリン-5(1H)-オン 8a． 10-クロロ-10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナ ゾリン-5(1H)-オン 9a． 10-ニトロ-10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナ ゾリン-5(1H)-オン 10a. 7-メチル-l0b-フェニル-2,3,6,l0b-テトラヒドロ−イミダゾ[1,2-c]キナ ゾリン-5(1H)-オン 11a. 8-メチル-10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナ ゾリン-5(1H)-オン 12a. 10b-(3-メチルフェニル)-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2-c] キナゾリン-5(1H)-オン 13a. 10b-(3-クロロフェニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナ ゾリン-5(1H)-オン 14a. 10b-(4-メトキシフェニル)-2,3,6,l0b-テトラヒドロ-5H-オキサゾロ[3,2- c]キナゾリン-5(1H)-オン 15a. 10b-(2,3-ジメチルフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3, 2-c]キナゾリン-5(1H)-オン 16a. 10b-(3,5-ジメチルフェニル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3, 2-c]キナゾリン-5(1H)-オン 17a. 10b-(1-ナフチル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナゾリン -5(1H)-オン 18a. 10b-(4-インダニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナゾリ ン-5(1H)-オン l9a. 10b-(2-アミノ-5-メチルフェニル)-2,3,6,10b-テトラヒド ロ−イミダゾ[1,2-c]キナゾリン-5(1H)-オン 20a. 10b-(6-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2 -c］キナゾリン-5(1H)-オン 21a. 10b-(4-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ-5H-オキサゾロ[3,2 -c]キナゾリン-5(1H)-オン 22a. 10b-チエニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナゾリン-5(1 H)-オン 23a. 10b-フラニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]キナゾリン-5(1 H)-オン 24a. 11b-フェニル-1,2,3,4,7,11b-ヘキサヒドロ-6H-ピリミド[1,2-c]キナゾリ ン-6-オン 25a. 10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c]ピリド[2,3-e] ピリミジン-5(1H)-オン 26a. 10b-(3-メチルフェニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピ リド[2,3-e] ピリミジン-5(1H)-オン 27a. 10b-(3-クロロフェニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピ リド[2,3-e] ピリミジン-5(1H)-オン 28a. 10b-(6-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピリド[2,3-e] ピリミジン-5(1H)-オン 29a. 10b-(4-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピリド[2,3-e] ピリミジン-5(1H)-オン 30a. 3-エトキシカルボニル-10b-フェニル-2,3,6,10b-テトラヒドロ−イミダゾ [1,2-c] ピリド[2,3-e] ピリミジン-5(1H)-オン 31a. 3-ヒドロキシメチル-10b-フェニル-2,3,6,10b-テトラヒド ロ−イミダゾ[1,2-c] ピリド[2,3-e]ピリミジン-5(1H)-オン 32a. 10b-フェニル-2,3,6,10b−テトラヒドロ−イミダゾ[l,2-c]ピリド[3,4-e] ピリミジン-5(1H)-オン 33a. 10b-(3-エチルフェニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピ リド[3,4-e] ピリミジン-5(1H)-オン 34a. 10b-(3-ニトロフェニル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピ リド[3,4-e] ピリミジン-5(1H)-オン 35a. 10b-(6-メチル-2-ピリジル)-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピリド[3,4-e] ピリミジン-5(1H)-オン 36a. 10b-メチル-2,3,6,10b-テトラヒドロ−イミダゾ[1,2-c] ピリド[3,4-e] ピリミジン-5(1H)-オン 37a. 9b-フェニル-2,3,6,9b-テトラヒドロ−イミダゾ[1,2-c]チエノ[2,3-e] ピ リミジン-5(1H)-オン 38a. 9b-(3-メチルフェニル)-2,3,6,9b-テトラヒドロ−イミダゾ[1,2-c]チエノ [2,3-e] ピリミジン-5(1H)-オン 39a. 9b-(3,5-ジクロロフェニル)-2,3,6,9b-テトラヒドロ−イミダゾ[1,2-c]チ エノ[2,3-e] ピリミジン-5(1H)-オン 40a. 9b-フェニル-2,3,6,9b-テトラヒドロ−イミダゾ[1,2-c]フラノ[2,3-e] ピ リミジン-5(1H)-オン 41a. 9b-(4-メチル-2-ピリジル)-2,3,6,9b-テトラヒドロ−イミダゾ[1,2-c]フ ラノ[2,3-e] ピリミジン-5(1H)-オン 42a. 10b-フェニル-6,10-ジヒドロ−イミダゾ[1,2-c]キナゾリン-5(1H)-オン 43a. 10b-(3-メチルフェニル)-6,10-ジヒドロ−イミダゾ[1,2- c]キナゾリン-5(1H)-オン 44a. 3-メチル-10b-フェニル-6,10-ジヒドロ−イミダゾ[1,2-c]キナゾリン-5(1 H)-オン 45a. 10b-(3-メチルフェニル)-6,10-ジヒドロ−イミダゾ[1,2-c] ピリド[2,3-e ] ピリミジン-5(1H)-オン 46a. 3-メチル-10b-(3-メチルフェニル)-6,10-ジヒドロ-5H-オキサゾロ[3,2-c] ピリド[2,3-e]ピリミジン-5(1H)-オン実施例１ 10b-フェニル-2,3,6,10-テトラヒドロ-5H-オキサゾロ[3,2-c]キナゾリン-5-オン ａ）トルエン125 ml中の2-アミノベンゾフェノン 10 ｇ (50.7mmol)およびピ リジン4.9 mlに、10℃で攪拌しながらトルエン25ml中のエチルクロロホルメート 5.8 ml (60.8mmol)を滴下した。 １時間後、混合物を水とともに３回振とうし、有機相を分離し、乾燥し、蒸発さ せた。得られた油をイソヘキサンでこすって固化させ、結晶を吸引濾過した。 融点73〜75℃の2-エトキシカルボニルアミノベンゾフェノン12.3ｇが得られた 。 ｂ）2-エトキシカルボニルアミノベンゾフェノン 5ｇ (18.6mmol)、エタノー ルアミン 2.3 ｇ (37.1 mmol)およびp-トルエンスルホン酸 0.5 ｇをジメチルホ ルムアミド(DMF) 100 ml中で140℃にて窒素下に52時間加熱した。次に、DMF を 蒸留により除き、残留物を水に溶解し、ジクロロメタンとともに振とうして２回 抽出した。有機相を乾燥して蒸発させ、残留物をシリカゲルによるクロマトグラ フィー（移動溶媒： イソヘキサン：酢酸エチル７：３）にかけた。目的画分を 蒸発させ、残留物をエタノールから再結晶したところ融点193〜196℃の表題化合 物 3.2 ｇが得られた。実施例２ 11b-(4-メチル-2-ピリジル)-3,4,7,llb-テトラヒドロ-2H,6H-[1,3]オキサジノ[3 ,2-c]キナゾリン-6-オン 実施例１と同様にして、1-エトキシカルボニルアミノ-2-(4-メチル-2-ピリジ ノイル）べンゼンと3-ヒドロキシ-1-プロパンアミンから融点 の表題化合物を 得た。実施例３ 実施例１と同様にして、1-エトキシカルボニルアミノ-2-(3-メチルベンゾイル ）ピリジンおよびエチレンジアミンから融点の表題化合物を得た。実施例４ 逆転写酵素（ＲＴ）の阻害 スクリーニング試験系は、遺伝子工学的手法により大腸菌で発現させたＨＩＶ −１由来の精製ＲＴ、鋳型として隣接プライマー結合部位を有するＨＩＶ−ＬＴ Ｒのin vitro転写物のような開始複合体の成分、およびプライマーとしてプライ マー結合部位に相補的な18 merオリゴヌクレオチドを含むものであった。［3Ｈ ］-チミジン-5'-三リン酸の取り込みはβ−カウンターでの計測により測定した 。 試験した実施例１〜３の化合物に関して、およそ０．０１〜１０μＭの逆転写 酵素（ＨＩＶ−ＲＴ）阻害のＩＣ50値が測定された。Detailed Description of the Invention As an antiviral therapeutic agent Use of tricyclic pyrimidine derivatives The present invention provides a tricyclic pyrimidine derivative for producing a drug having an antiviral effect. It concerns new uses of conductors. Furthermore, the present invention provides a novel pyrimidine The present invention relates to a derivative, a method for producing the derivative, and a drug containing the compound. The present invention relates to the general formula I for preparing a drug having an antiviral effect: A tricyclic pyrimidine derivative represented by and its tautomers, enantiomers, dimers It relates to the use of stereomers and physiologically acceptable salts. Here A has a carbocycle having 5 or 6 carbon atoms or a maximum of 4 heteroatoms. Represents a heterocycle in which the heteroatoms may be the same or different and Represents a hydrogen, nitrogen or sulfur, optionally a heterocycle. On one or several nitrogen atoms Optionally have an oxygen atom, A is optionally one or several identical Groups R which may be different or different1 Has been replaced with; X is an oxygen or sulfur atom, or a group = NH, = NC1-C6Alkyl or = S (O)2 And Y is an oxygen atom or NH- or C1-CFiveAn alkylamino group; R is a straight chain having 1 to 9 carbon atoms optionally substituted with phenyl or A branched or saturated aliphatic group, or It represents a phenyl ring, Alternatively, it is a mono-, bi- or tricyclic carbocycle having 7 to 15 carbon atoms, also Or in each case a heterocyclic mono-, di- or tricyclic having 5 or 6 ring atoms Representing a ring system, and 1 to 4 or 1 to 5 nitrogen, sulfur or oxygen per ring system Heteroatoms of any of the above and may include a phenyl ring, mono-, bi- or tricyclic as described above. Carbocyclic or heterocyclic mono-, bi- or tricyclic ring systems may optionally be C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkyl mercapto, C1-C6Alkyl sulfi Nil, C1-C6Alkylsulfonyl, C2-C6Alkenyl, C2-C6Alkynyl , C2-C6Alkenyloxy, C2-C6Alkenyl mercapto, C2-C6Archi Nyloxy, C2-C6Alkynyl mercapto, amino, C1-C6Alkylamino , The C1-C6Alkylamino, C1-C6Alkylcarbonylamino, C1-C6A Ruquil aminocarbonyl, C1-C6Alkoxycarbonyl, hydroxy, benzyl Luoxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, Trifluoromethyl, azide, formyla Substituted one or more times with mino, carboxy, or phenyl; R1 Is a hydrogen atom, straight or branched chain saturated having 1 to 6 carbon atoms Ku unsaturated unsaturated aliphatic group, C1-C6Alkoxy, C1-C6Alkyl mercapto, C1 -C6Alkylsulfinyl, C1-C6Alkylsulfonyl, amino, C1-C6 Alkylamino, di-C1-C6Alkylamino, sulfonamide, C1-C6Arco Xycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azide Represents phenyl or benzyloxy; R2 , R3 , RFour And RFive May independently be the same or different Respectively hydrogen and C1-C6Alkyl, C1-C6Hydroxyalkyl, cyano, Carboxy or C1-C6Represents alkoxycarbonyl, or R2 And RFour Can represent an additional bond between the carbon atoms to which they are attached; R6 Is hydrogen or C1-C6Represents alkyl; m represents 0 or 1. A structurally similar compound (quinazoline derivative) was applied for a relatively early European patent application It is described in the specification EP 0 530 994 as an inhibitor of reverse transcriptase. In particular Examples 5C-5F and 101 include phenyls in which A in formula I is replaced by a chlorine atom. Represents a ring and R is a cyclopropyl, cyclopentyl or phenyl ring, or Represents a propyl group, X and Y represent an oxygen atom, and R1 , R2 , R3 , RFive And And R6 Represents a hydrogen atom, and RFour Represents a hydrogen atom or an isopropyl group There is a description of the compound. A represents a substituted or unsubstituted phenyl ring, and X is an oxygen or sulfur atom. Some compounds of general formula I in which the radical = NH is also described in the literature. It For example, US 3,891,638, US 3,812,257, DE 21 66 380, DE 2307 808 and DE 21 41 616 showed that this type of compound improves anti-inflammatory activity and excretion of uric acid. It is described as having an action. In application JP 47036758 a substance with an antispasmodic action can be found. In application DE 214 1616 the compound is said to have an analgesic effect and In US Pat. No. 3,329,679 compounds are found which affect the central nervous system. In addition to the above patent applications, the synthesis of some compounds of Formula I is described in Chem. Pharm. Bull.29 , 2135, 1981, Pharmazie37, 379, 1982 and Pharmaceutical Journals90, Also written in 629, 1970 It is listed. In particular, in the general formula I, A represents an aromatic heterocycle having up to 4 heteroatoms. The compounds are new and have not previously been described in the literature. The object of the present invention is to improve the medical properties of known compounds obtained from the state of the art. It was to find the target index. Furthermore, the object of the present invention is for the manufacture of a medicament. In particular, a novel tricyclic pyrimidine derivative that can be used as a pharmacologically active substance is provided. It was. Among other things, the subject of the present invention is to prevent viral or retroviral infections. Finding drugs that can be used to treat diseases caused by these infections in Ravi Was to kick. This object is achieved by the features defined in the claims. The compounds of the present invention have valuable pharmacological actions. Especially those Are, for example, herpes simplex virus, cytomegalovirus, papilloma virus, chickenpox -A DNA virus such as herpes zoster virus or Epstein-Barr virus , Or togaviruses, especially retroviruses, such as the oncovirus HTLV- I and II, lentivirus visna or human immunodeficiency virus HIV-1 and Suitable for treatment and prevention of infectious diseases caused by RNA viruses such as There is. The compounds of formula I are especially suitable for persistent systemic lymphadenopathy (PGL), advanced stage In humans, such as AIDS-related syndrome (ARC) and AIDS with a complete clinical picture It appears to be suitable for treating the clinical manifestations of retroviral HIV infection. The compounds of the invention of the general formula I have a pronounced antiviral action, in particular viral and Suitable for treating retroviral infections. Mammalian, especially human viruses Infection is widespread. Despite strenuous efforts, viruses and Causes retroviral pathological processes causatively or symptomatically Previously, interfering chemotherapeutic agents could not be provided. Today, for example, acquired immunodeficiency Syndrome (AIDS), AIDS-related syndrome (ARC) and its early stages, HELP , Cytomegalovirus (CMV), influenza virus and other viruses To cure certain viral diseases such as Rus infectious disease by chemotherapy, , Those symptoms cannot be improved. Currently, for example, Zidob The currently used 3'-azido-3'-deoxythymidine (AZT) is useful for the treatment of AIDS. Almost everything you can use. However, AZT Characterized by a very narrow therapeutic range and the extremely strong toxicity that already occurs in that therapeutic range (Hirsch, M.S. (1988) J. Infec. Dis.l57, 427-431). Compound of general formula I The objects do not show these drawbacks. They are cytotoxic at pharmacologically relevant doses Acts antivirally without. This time, the compounds of general formula I were detected at the level of virus-specific DNA and RNA transcription It was possible to demonstrate that it is able to block the growth of DNA and RNA viruses. These substances affect the growth of retroviruses by inhibiting reverse transcriptase Affect (Proc. Natl. Acad. Sci. USA83,1911, 1986 and Nature325, 77 3, 1987). Retroviruses can be used without affecting the normal process of the original biological function. Demand for chemotherapeutic agents that interfere as specifically as possible with the underlying disease or its symptoms The retroviruses have been shown to be , Preventive or in the treatment of symptomatically or clinically relevant diseases It can be used therapeutically. The compounds of formula I can exist as racemates or as optically active derivatives. Separation of racemates into enantiomers can be carried out in the appropriate optically active phase using conventional eluents. Chromatographically, analytically, semi-preparatively, or preparatively. You can Suitable optically active phases are, for example, optically active polyacrylamides or polymers. Tacrylamide (some on silica gel) Loose carbamates (eg obtained from Baker / Daicel) Alternatively, it is microcrystalline cellulose triacetate (Merck). In the definition of A, A is carbocycle, especially directly fused phenyl, cyclopentyl Represents a cyclohexyl, cyclopentenyl or cyclopentadienyl ring. The fused aromatic heterocycle A has 5 to 6 carbon atoms and has 4 of these ring atoms. Up to can be replaced by the heteroatoms oxygen, sulfur and / or nitrogen. For example, Can be mentioned as heterocycles: furan, thiophene, pyrrole, oxazole , Isoxazole, thiazole, pyrazole, imidazole, oxadiazo Ring, triazole, pyridine, pyridazine, pyrimidine, or pyrazine ring. Compound If a nitrogen atom is present in the prime ring A, the corresponding heterocycle exists in its N-oxide form. May be present. Ring A is one or several (preferably 1 or 2) groups R1 so Can be substituted, in which case the substituent R1 May be the same or different. Aliphatic group R or R1 Has 1 to 9 (preferably 2 to 7) carbon atoms Represents a linear or branched alkyl, alkenyl or alkynyl group, examples For example propyl, isopropyl, butyl, isobutyl, pentyl, hexyl or Represents a heptyl group. C as an unsaturated group2-C7(Preferably C2-CFive) Archeni Or alkynyl groups such as allyl, dimethylallyl, butenyl, isobutenyl It may be a ru, pentenyl, or propynyl group. Aliphatic radicals R optionally substituted by phenyl are especially phenyl-C1-C6Archi Group such as benzyl, phenethyl, phenylpropyl, or phenylbutyl Group. Group R or R1 When contains a phenyl ring, it contains 1, 2 or 3 substituents. You can have it. The substituents may, independently of one another, be in the o, m or p position. . Carbocycles R having 7 to 15 carbon atoms are mono-, bi- or tricyclic ring systems, with 5 per ring. Or it can have 6 carbon atoms. This ring is saturated, unsaturated, or partially saturated. Rui can be aromatic. The following ring systems may be mentioned by way of example: naphthyl, Anthracenyl, phenanthrenyl, fluorenyl, indenyl, indanyl, Acenaphthylenyl, norbornyl, adamantyl ring, or C3-C7Cycloal Kill or CFive-C8A cycloalkenyl group. Furthermore, this carbocycle is mono- or di- It may be substituted, and in the case of a phenyl ring, the substituents are independently o or It can be in the m position. The heterocyclic mono-, di- or tricyclic ring system of the group R contains 5 or 6 carbon atoms per ring , 1 to 4 or 1 to 5 carbon atoms are heteroatoms oxygen, sulfur and / or It can be replaced by nitrogen. Even if the ring system is aromatic, it may be partially or fully hydrogenated. It may be. The following ring systems may be mentioned by way of example: pyridine, pyrimidine, pyridazine, Pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, Thiazole, oxazole, isoxazole, oxadiazole, furazan, Furan, thiophene, indole, quinoline, isoquinoline, coumarone, thiona Futhene, benzoxazole, benzothiazole, indazole, benzi Midazole, benztriazole, chromene, phthalazine, quinazoline, quinoki Sarin, methylenedioxybenzene, carbazole, acridine, phenoxazi , Phenothiazine, phenazine, or purine (unsaturated or aromatic carbon The rings and heterocycles can be partially or fully hydrogenated). These compound If the prime ring contains a nitrogen atom, the corresponding heterocycle also exists in its N-oxide form. obtain. Further, the heterocyclic ring system may be mono- or di-substituted, in which case the substitution The groups are preferably present in the o or m position independently of one another. R preferably represents unsubstituted phenyl or C1-C6Alkyl, C1 -C6Alkoxy, C1-C6Alkyl mercapto, Cl-C6Alkylsulfini Le, C1-C6Alkylsulfonyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-CFourAlkenyloxy, C1-C6Alkylamino, C1-C6Dialkylami No, C1-C6Alkylcarbonylamino, C1-C6Alkylaminocarbonyl, C1-C6Alkoxycarbonyl, amino, hydroxy, nitro, azide, trif Phenyl substituted once or twice with luoromethyl, cyano, or halogen Represents nyl, in which the abovementioned aliphatic groups preferably contain up to 3 carbon atoms. . Carbocycle R is preferably biphenyl, naphthyl, anthracenyl, indenyl. Le, fluorenyl, acenaphthylenyl, phenanthrenyl, norbornyl, ada Manchill, C3-C6Cycloalkyl, CFive-C8Is cycloalkenyl, where Carbocycle is C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkyl mercapto , Cl-C6Alkylsulfinyl, C1-C6Alkyl sulfoni Le, C2-C6Alkenyl, C2-C6Alkynyl, C3-CFourAlkenyloxy, C1 -C6Alkylamino, C1-C6Dialkylamino, C1-C6Alkyl Carboni Lumino, C1-C6Alkylaminocarbonyl, Cl-C6Alkoxy carbonyl , Amino, hydroxy, nitro, azide, trifluoromethyl, cyano, or It may be substituted once or twice with halogen, and the number of the above aliphatic groups is up to 3. It is preferable to include the carbon atom of The heterocyclic system R is preferably pyrrole, imidazole, furan, thiophene, Pyridine, pyrimidine, thiazole, indole, quinoline, isoquinoline, c Malon, thionaphthene, benzimidazole, quinazoline, methylenedioxybe Benzene, ethylenedioxybenzene, carbazole, acridine and phenothi Is an azine, where the heterocycle is C1-C6Alkyl, C1-C6Alkoxy, C1− C6Alkyl mercapto, C1-C6Alkylsulfinyl, C1-C6Alkyls Lefonil, C2-C6Alkenyl, C2-C6Alkynyl, C2-C6Alkenyl oki Si, C1-C6Alkylamino, C1-C6Dialkylamino, C1-C6Alkyr Lubonylamino, C1-C6Alkylaminocarbonyl, C1-C6Alkoxycar Bonyl, amino, hydroxy, nitro, azide, trifluoromethyl, cyano, Alternatively, it may be substituted once or twice with halogen, and the above aliphatic group is 3 It preferably contains up to 4 carbon atoms. Group R1 As hydrogen, C1-C6Alkyl, C2-CFourAlkenyl, C2-CFourAl Quinyl, C1-C6Alkoxy, C1-C6Alkyl mercapto, C1-C6Alkyl Amino, C1-C6Alkoxy carbo Nyl, amino, halogen, hydroxy, nitro, cyano and azide are preferred , The above aliphatic groups preferably contain up to 3 carbon atoms. R2 , R3 , RFour And RFive And preferred substituents are hydrogen and C1-C3Alkyl , Cl-C6Hydroxyalkyl, carboxy, C1-C6Alkoxycarbonyl And cyano, or R2 And RFour Form additional bonds. X and Y are preferably oxygen. Halogen is generally fluorine, chlorine or bromine. And iodine, with fluorine, chlorine and bromine being preferred. Aromatic rings are especially considered for A. A preferred fused heterocycle A is 5 or It is a nitrogen-containing aromatic ring having 6 ring atoms. The preferred group as R is C3-CFiveAlkyl, C2-CFiveAlkenyl, C2-CFourAl Quinyl, benzyl, phenethyl, phenyl, (C1-C6Alkyl, C1-C6Al Coxy, C1-C6Alkyl mercapto, allyl, allyloxy, C1-C6Archi Lumino, di C1-C6Alkylamino, amino, hydroxy, azide, triflu Mono- or di-substituted with oromethyl, cyano or halogen, or phenyl ) Phenyl, naphthyl, anthracenyl, indenyl, acenaphthylenyl, phenyl Enanthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, Thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, beta Imidazolyl, methylenedioxyphenyl, (tris with methyl or halogen) (Substituted) phenothiazinyl and carbazolyl, and (methyl or ha On (mono or di substituted with a rogen) It is a derivative of the above carbocycle or heterocycle. R1 Is hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, eth Xy, methyl mercapto, ethyl mercapto, methylamino, methoxycarboni , Ethoxycarbonyl, amino, azide, cyano, hydroxy and halogen Is particularly preferable, and as halogen, chlorine and bromine are particularly preferable. R2 , R3 , RFour And RFive Is hydrogen, methyl, ethyl, isopropyl or And cyano are particularly preferred, the radical R2 ~ RFive 2 or 3 of them are especially hydrogen atoms Represents R2 And RFour Can also together represent a bond. As A, phenyl, pyrrole, oxazole, thiophene, furan, isoo Xazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine And pyrazine ring are particularly preferred. When A represents a condensed 6-membered ring, condensed pyrimidine The 6-membered para position (tricyclic ring system) with respect to the nitrogen atom directly bonded to the 6-membered ring A of the ring. Substituent R at the 9-position)1 A compound having (particularly a halogen atom) is particularly preferable. R, R1 , X and m have the meanings given above, and R2 , R3, RFour And RFive Is hydrogen, methyl or ethyl (preferably R2 ~ RFive Is hydrogen , Or R2 And RFour (Wherein represents an additional bond) compounds of general formula I are particularly preferred. R6 As hydrogen or C1-C3Alkyl is particularly preferred. It is particularly preferable that m is 0. Compounds having a pronounced pharmacological action are especially those in which R is C in the meta position.1-C6 Substituted with alkyl (especially methyl or ethyl) Represents a phenyl ring, X represents a sulfur atom, and R1 Represents a halogen atom It is a compound of formula I. Agents for treating viral infections contain at least one compound of formula I , Orally or parenterally in liquid or solid form. As a dosage form Refers to, for example, tablets, capsules, coated tablets, syrups, solutions or suspensions. The usual dosage forms are possible. Injectable vehicles include stabilizers, solubilizers and It is preferable to use water containing conventional additives for injection solutions such as buffer solutions . Additives of this type include, for example, tartaric acid and citrate buffers, ethanol, ethanol. Complexing agents such as tolylenediaminetetraacetic acid and its non-toxic salts, and viscosity control There are high molecular weight polymers such as liquid polyethylene oxide to do so. Injection solution The liquid carrier material must be sterile and can be dispensed in ampoules. preferable. Solid carrier materials include, for example, starch, lactose, mannitol. High content such as tall, methyl cellulose, talc, highly dispersed silicic acid, stearic acid Child fatty acid, gelatin, agar, calcium phosphate, magnesium stearate, kinetics Physical and vegetable fats, solid polymeric polymers such as polyethylene glycol There are such things. Suitable formulations for oral administration optionally include flavors and sweeteners be able to. Dosage depends on various factors such as mode of application, species, age or individual health status . The compounds according to the invention are generally 0.1-100 mg / day / kg body weight, preferably Or, it is administered in an amount of 0.2 to 80 mg / day / kg. 2 to 5 times daily dose 1 or 2 tablets with 0.5-500 mg active substance content each time, divided into To It is preferable to administer. In addition, by making the tablet sustained-release The number of administrations can be reduced to 1 to 3 times. The content of the active substance in the sustained-release tablet is 2 to It can be 1000 mg. The active substance may be administered by continuous infusion, in situ. In general, amounts of 5 to 1000 mg per day are generally suitable. In addition, the compound of the present invention and its pharmaceutical preparation are useful for treating and preventing the above-mentioned infectious diseases. Can be used in combination with other drugs for. HIV infection and this Examples of other drugs that can be used for the treatment and prevention of diseases associated with 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleoside Such as 2 ', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine And a 2 ', 3'-dideoxyinosine or acyclic nucleoside (eg, a Cyclovir). The compound of the present invention and the other drug are Depending on the case, so that a synergistic effect is achieved, separately, simultaneously, and if desired, Can be administered as one formulation or as two formulations or at different times You can The compounds of general formula I according to the invention have the general formula II: [In the formula, A, R, R1 And R6 Has the above meaning, R7 Is Cleavable groups, eg CC13 , CF3 , OR8 Or NR8R9 Represents Where R8 And R9 May be the same or different, eg C1-C6Alkyl , Substituted or unsubstituted phenyl, phenylalkyl, hetaryl or hetary A compound of formula III: [In the formula, R2 , R3 , RFour , RFive And m have the meanings given above] or Unsubstituted compound at room temperature to reflux temperature in a suitable inert solvent, optionally Catalytic amounts of acid (eg p-toluenesulfonic acid) or base (eg potassium hydroxide) Produced in accordance with a known method by reacting in the presence of The compound of formula I is then converted to another compound of formula I, followed by chromatography Alternatively, it is purified by recrystallization. The racemate is a suitable optically active phase (eg cellulose Can be separated into enantiomers by chromatography with triacetate) . Conversion of a compound of formula I to another compound of formula I is accomplished, for example, by a tricyclic pi where X = S. It is concerned with the production of limidine derivatives. In the compound where X = S, X is an oxygen atom. Reacting certain compounds of formula I with compounds containing sulfur groups (eg Lawesson's reagent) Manufactured by. A compound of formula I wherein X = NH is prepared by first adding a compound of formula I wherein X is an oxygen atom to P OC13A chlorinating reagent such as It is manufactured by processing with and converting. R2 And RFour Compounds of general formula I in which R represents an additional bond are2 , R3 , RFour Or RFive Is carboxylic acid (eg acetic acid) or sulfonic acid (eg toluenesulfonic acid) ) A compound of general formula I, which represents a hydroxy-methyl group esterified with Imidazole or sodium hydroxide under pressure at 00 ° C, if necessary in an inert solvent. Manufactured by heating in the presence of a base such as. The compounds of general formula II used as starting materials follow the methods described in the literature. It is obtained from an aminobenzophenone derivative by acylation. Replaced or not replaced 2-aminobenzophenone derivatives of the method described by David A. Walsh (S synthesis, 677, 1980). A set of all meanings of the compounds mentioned in the examples and the substituents defined in the claims In addition to compounds derived from combination, racemic mixtures or optically active forms, i.e. pure Within the scope of the present invention are compounds of formula I below which may exist as different R and S enantiomers. available: 1. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazoline -5-on 2. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazoline -5-Thion 3. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazoline -5-imine 4. 6-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 5. 9-chloro-l0b-phenyl-2,3,6, l0b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 6. 9-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 7. 9-Methoxy-l0b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c ] Quinazoline-5-on 8. 10-Chloro-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 9. 10-Nitro-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on Ten. 7-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 11. 8-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 12. 10b- (3-Methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 13. 10b- (3-chlorophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5-on 14. 10b- (4-Methoxyphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2- c] quinazolin-5-one 15． 10b- (2,3-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3, 2-c] quinazolin-5-one 16. 10b- (3,5-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H- Oxazolo [3,2-c] quinazolin-5-one 17． 10b- (1-naphthyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazo Phosphorus-5-on 18. 10b- (4-Indanyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quina Zolin-5-on 19. 10b- (2-amino-5-methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazo B [3,2-c] quinazolin-5-one 20. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] quinazolin-5-one twenty one. 10b- (4-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] quinazolin-5-one twenty two. 10b-thienyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazoline -5-on twenty three. 10b-furanyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] quinazoline -5-on twenty four. 11b-phenyl-3,4,7, llb-tetrahydro-2H, 6H- [1,3] oxazino [3,2-c] ki Nazolin-6-on twenty five. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido [2,3 -e] Pyrimidin-5-one 26. 10b- (3-Methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c ] Pyrido [2,3-e] pyrimidin-5-one 27. 10b- (3-chlorophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Pyrido [2,3-e] pyrimidin-5-one 28. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] pyrido [2,3-e] pyrimidin-5-one 29. 10b- (4-methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] pyrido [2,3-e] pyrimidin-5-one 30. 3-Ethoxycarbonyl-l0b-phenyl-2,3,6, l0b-tetrahydro-5H-oxa Zoro [3,2-c] pyrido [2,3-e] pyrimidin-5-one 31. 3-hydroxymethyl-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazo B [3,2-c] pyrido [2,3-e] pyrimidin-5-one 32. 10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido [3, 4-e] Pyrimidin-5-one 33. 10b- (3-Ethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Pyrido [3,4-e] pyrimidin-5-one 34. 10b- (3-Nitrophenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Pyrido [3,4-e] pyrimidin-5-one 35. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] pyrido [3,4-e] pyrimidin-5-one 36. 10b-Methyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] pyrido [3,4- e] Pyrimidin-5-one 37. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c] thieno [2,3-e ] Pyrimidine-5-on 38. 9b- (3-Methylphenyl) -2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c] thio Eno [2,3-e] pyrimidin-5-one 39. 9b- (3,5-dichlorophenyl) -2,3,6,9b-tetrahydro-5H-oxazolo [3,2 -c] Thieno [2,3-e] pyrimidin-5-one 40. 9b-phenyl-2,3,6,9b-tetrahydro-5H-oxazolo [3,2- c] Furano [2,3-e] pyrimidin-5-one 41. 9b- (4-Methyl-2-pyridyl) -2,3,6,9b-tetrahydro-5H-oxazolo [3,2-c ] Furano [2,3-e] pyrimidin-5-one 42. 10b-Phenyl-6,10-dihydro-5H-oxazolo [3,2-c] quinazolin-5-one 43. 10b- (3-Methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] quinazoli -5-on 44. 3-Methyl-10b-phenyl-6,10-dihydro-5H-oxazolo [3,2-c] quinazoline -5-on 45. 10b- (3-methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] pyrido [2, 3-e] Pyrimidin-5-one 46. 3-Methyl-10b- (3-methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] Pyrido [2,3-e] pyrimidin-5-one la. 10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoline-5 (1 H) -On 2a. 10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoline-5 (1 H) -Thion 3a. 10b-phenyl-2,3,6,10b-tetrahydro-imidazo [l, 2-c] Quinazoline-5 (1H) -imine 4a. 6-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [l, 2-c] quina Zolin-5 (1H) -on 5a. 9-chloro-l0b-phenyl-2,3,6, l0b-tetrahydro-imidazo [l, 2-c] quina Zolin-5 (1H) -on 6a. 9-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [l, 2-c] quina Zolin-5 (1H) -on 7a. 9-Methoxy-10b-phenyl-2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c ] Quinazoline-5 (1H) -on 8a. 10-Chloro-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quina Zolin-5 (1H) -on 9a. 10-Nitro-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quina Zolin-5 (1H) -on 10a. 7-Methyl-l0b-phenyl-2,3,6, l0b-tetrahydro-imidazo [1,2-c] quina Zolin-5 (1H) -on 11a. 8-Methyl-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quina Zolin-5 (1H) -on 12a. 10b- (3-Methylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2-c] Quinazoline-5 (1H) -on 13a. 10b- (3-chlorophenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] quina Zolin-5 (1H) -on 14a.10b- (4-Methoxyphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2- c] quinazoline-5 (1H) -one 15a.10b- (2,3-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3, 2-c] quinazoline-5 (1H) -one 16a.10b- (3,5-Dimethylphenyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3, 2-c] quinazoline-5 (1H) -one 17a. 10b- (1-naphthyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoline -5 (1H) -on 18a. 10b- (4-Indanyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoli -5 (1H) -on l9a. 10b- (2-amino-5-methylphenyl) -2,3,6,10b-tetrahydr Lo-imidazo [1,2-c] quinazoline-5 (1H) -one 20a.10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] Quinazoline-5 (1H) -on 21a.10b- (4-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-5H-oxazolo [3,2 -c] quinazoline-5 (1H) -one 22a. 10b-thienyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoline-5 (1 H) -On 23a. 10b-furanyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] quinazoline-5 (1 H) -On 24a. 11b-Phenyl-1,2,3,4,7,11b-hexahydro-6H-pyrimido [1,2-c] quinazoli N-6-on 25a. 10b-Phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] pyrido [2,3-e] Pyrimidine-5 (1H) -one 26a. 10b- (3-Methylphenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] py Lido [2,3-e] pyrimidin-5 (1H) -one 27a. 10b- (3-Chlorophenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] py Lido [2,3-e] pyrimidin-5 (1H) -one 28a. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] Pyrido [2,3-e] pyrimidin-5 (1H) -one 29a. 10b- (4-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] Pyrido [2,3-e] pyrimidin-5 (1H) -one 30a. 3-Ethoxycarbonyl-10b-phenyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one 31a. 3-Hydroxymethyl-10b-phenyl-2,3,6,10b-tetrahydr Loimidazo [1,2-c] pyrido [2,3-e] pyrimidin-5 (1H) -one 32a. 10b-Phenyl-2,3,6,10b-tetrahydro-imidazo [l, 2-c] pyrido [3,4-e] Pyrimidine-5 (1H) -one 33a. 10b- (3-Ethylphenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] py Lido [3,4-e] pyrimidin-5 (1H) -one 34a. 10b- (3-Nitrophenyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] py Lido [3,4-e] pyrimidin-5 (1H) -one 35a. 10b- (6-Methyl-2-pyridyl) -2,3,6,10b-tetrahydro-imidazo [1,2-c] Pyrido [3,4-e] pyrimidin-5 (1H) -one 36a. 10b-Methyl-2,3,6,10b-tetrahydro-imidazo [1,2-c] pyrido [3,4-e] Pyrimidine-5 (1H) -one 37a. 9b-Phenyl-2,3,6,9b-tetrahydro-imidazo [1,2-c] thieno [2,3-e] pi Limidine-5 (1H) -on 38a. 9b- (3-Methylphenyl) -2,3,6,9b-tetrahydro-imidazo [1,2-c] thieno [2,3-e] Pyrimidin-5 (1H) -one 39a. 9b- (3,5-dichlorophenyl) -2,3,6,9b-tetrahydro-imidazo [1,2-c] thio Eno [2,3-e] pyrimidin-5 (1H) -one 40a. 9b-phenyl-2,3,6,9b-tetrahydro-imidazo [1,2-c] furano [2,3-e] pi Limidine-5 (1H) -on 41a. 9b- (4-Methyl-2-pyridyl) -2,3,6,9b-tetrahydro-imidazo [1,2-c] fu Rano [2,3-e] pyrimidin-5 (1H) -one 42a. 10b-Phenyl-6,10-dihydro-imidazo [1,2-c] quinazolin-5 (1H) -one 43a.10b- (3-Methylphenyl) -6,10-dihydro-imidazo [1,2- c] quinazoline-5 (1H) -one 44a. 3-Methyl-10b-phenyl-6,10-dihydro-imidazo [1,2-c] quinazoline-5 (1 H) -On 45a. 10b- (3-Methylphenyl) -6,10-dihydro-imidazo [1,2-c] pyrido [2,3-e ] Pyrimidine-5 (1H) -one 46a. 3-Methyl-10b- (3-methylphenyl) -6,10-dihydro-5H-oxazolo [3,2-c] Pyrido [2,3-e] pyrimidin-5 (1H) -oneExample 1 10b-Phenyl-2,3,6,10-tetrahydro-5H-oxazolo[3,2-c] quinazolin-5-one a) 10 g (50.7 mmol) of 2-aminobenzophenone in 125 ml of toluene and To 4.9 ml of lysine, ethyl chloroformate in 25 ml of toluene with stirring at 10 ° C. 5.8 ml (60.8 mmol) was added dropwise. After 1 hour, the mixture was shaken 3 times with water, the organic phase was separated, dried and evaporated. I let you. The oil obtained was rubbed with isohexane to solidify and the crystals were suction filtered. 12.3 g of 2-ethoxycarbonylaminobenzophenone having a melting point of 73-75 ° C was obtained. . b) 2-ethoxycarbonylaminobenzophenone 5 g (18.6 mmol), ethanol Ruamine 2.3 g (37.1 mmol) and p-toluenesulfonic acid 0.5 g Heat in 100 ml of Lumamide (DMF) at 140 ° C. under nitrogen for 52 hours. Then DMF Remove by distillation, dissolve residue in water, shake with dichloromethane twice. Extracted. The organic phase is dried and evaporated and the residue chromatographed on silica gel. Pee (mobile solvent: isohexane: ethyl acetate 7: 3). The target fraction Evaporation and recrystallization of the residue from ethanol gave the title compound, mp 193-196 ° C. 3.2 g of product was obtained.Example 2 11b- (4-methyl-2-pyridyl) -3,4,7, llb-tetrahydro-2H, 6H-[1,3] Oxazino [3 , 2-c] quinazolin-6-one In the same manner as in Example 1, 1-ethoxycarbonylamino-2- (4-methyl-2-pyridyl (Noyl) benzen and 3-hydroxy-1-propanamine Obtained.Example 3 In the same manner as in Example 1, 1-ethoxycarbonylamino-2- (3-methylbenzoyl) ) The title compound with melting point was obtained from pyridine and ethylenediamine.Example 4 Inhibition of reverse transcriptase (RT) The screening test system is HIV expressed in E. coli by a genetic engineering method. -1-derived purified RT, HIV-LT having adjacent primer binding sites as template Components of the initiation complex, such as the R in vitro transcript, and ply as a primer It contained an 18 mer oligonucleotide complementary to the mer binding site. [3H ] -Thymidine-5'-triphosphate uptake was measured by β-counter counting . Approximately 0.01-10 μM reverse transcription for the compounds of Examples 1-3 tested Enzyme (HIV-RT) inhibition IC50The value was measured.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ Ｃ０７Ｄ 487/04 １４４ 7019−4Ｃ 491/147 7019−4Ｃ 495/14 Ｄ 9165−4Ｃ 498/04 (72)発明者 ケニク，バーンハルト ドイツ連邦共和国 ディー―8137 ベルク ３ ドュエルバークシュトラーセ 28番 地 (72)発明者 レサー，ウルリケ ドイツ連邦共和国 ディー―8000 ミュン ヘン 70 スティフツボーゲン 64番地─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 6 Identification number Internal reference number FI C07D 487/04 144 7019-4C 491/147 7019-4C 495/14 D 9165-4C 498/04 (72) Invention Kenik, Bernhard, Germany Dee-8137 Berg 3, Germany 28 Dürbergstraße 28 (72) Inventor Lesser, Ulrike, Germany Dee 8000 München 70 Stiftsbogen 64
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4214829A DE4214829A1 (en) | 1992-05-10 | 1992-05-10 | Use of tricyclic pyrimidine derivatives as antiviral drugs |
| DE4214829.4 | 1992-05-10 | ||
| PCT/EP1993/001124 WO1993023405A1 (en) | 1992-05-10 | 1993-05-07 | Use of tricyclic pyrimidine derivatives as anti-viral medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH08500089A true JPH08500089A (en) | 1996-01-09 |
Family
ID=6458212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5519843A Pending JPH08500089A (en) | 1992-05-10 | 1993-05-07 | Use of tricyclic pyrimidine derivatives as antiviral therapeutics |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0640087A1 (en) |
| JP (1) | JPH08500089A (en) |
| AU (1) | AU4065493A (en) |
| CA (1) | CA2134218A1 (en) |
| DE (1) | DE4214829A1 (en) |
| WO (1) | WO1993023405A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA986932A (en) * | 1970-08-27 | 1976-04-06 | Shigeho Inaba | Process for preparing quinazoline derivatives |
| DE4108395A1 (en) * | 1991-03-15 | 1993-01-28 | Boehringer Mannheim Gmbh | USE OF OXAZOLO- (2,3-A) ISOINDOL AND IMIDAZO (2,1-A) ISOINDOL DERIVATIVES AS ANTIVIRAL MEDICAMENTS AND NEW OXAZOLO (2,3-A) ISOINDOL DERIVATIVES |
| IL102764A0 (en) * | 1991-08-16 | 1993-01-31 | Merck & Co Inc | Quinazoline derivatives,and pharmaceutical compositions containing them |
-
1992
- 1992-05-10 DE DE4214829A patent/DE4214829A1/en not_active Withdrawn
-
1993
- 1993-05-07 WO PCT/EP1993/001124 patent/WO1993023405A1/en not_active Ceased
- 1993-05-07 EP EP93909920A patent/EP0640087A1/en not_active Withdrawn
- 1993-05-07 JP JP5519843A patent/JPH08500089A/en active Pending
- 1993-05-07 CA CA002134218A patent/CA2134218A1/en not_active Abandoned
- 1993-05-07 AU AU40654/93A patent/AU4065493A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0640087A1 (en) | 1995-03-01 |
| AU4065493A (en) | 1993-12-13 |
| DE4214829A1 (en) | 1993-11-11 |
| WO1993023405A1 (en) | 1993-11-25 |
| CA2134218A1 (en) | 1993-11-11 |
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