DE4320347A1 - Quinazoline derivatives and medicaments containing them - Google Patents
Quinazoline derivatives and medicaments containing themInfo
- Publication number
- DE4320347A1 DE4320347A1 DE19934320347 DE4320347A DE4320347A1 DE 4320347 A1 DE4320347 A1 DE 4320347A1 DE 19934320347 DE19934320347 DE 19934320347 DE 4320347 A DE4320347 A DE 4320347A DE 4320347 A1 DE4320347 A1 DE 4320347A1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- formula
- halogen
- alkylamino
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract 11
- 239000003814 drug Substances 0.000 title claims description 9
- -1 C1-C6-alkylmercapto Chemical group 0.000 claims abstract description 50
- 150000002367 halogens Chemical class 0.000 claims abstract description 22
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 20
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 8
- 239000000460 chlorine Chemical group 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 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 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 125000006413 ring segment Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 9
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 6
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-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 compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 5
- 208000036142 Viral infection Diseases 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000000165 tricyclic carbocycle group Chemical group 0.000 claims description 4
- 230000003612 virological effect Effects 0.000 claims description 4
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- 206010038997 Retroviral infections Diseases 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products 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
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229950000688 phenothiazine Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 3
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical group [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- ROWMQJJMCWDJDT-UHFFFAOYSA-N tribromomethane Chemical compound Br[C](Br)Br ROWMQJJMCWDJDT-UHFFFAOYSA-N 0.000 claims description 2
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 5
- 150000003246 quinazolines Chemical class 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- 206010001513 AIDS related complex Diseases 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 4
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012072 active phase Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 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 3
- 239000007788 liquid Substances 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 241000450599 DNA viruses Species 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- QIIQXSOGQOERHH-UHFFFAOYSA-N n-(2-benzoylphenyl)-2,2,2-trichloroacetamide Chemical compound ClC(Cl)(Cl)C(=O)NC1=CC=CC=C1C(=O)C1=CC=CC=C1 QIIQXSOGQOERHH-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- 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 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind Quinazolin-Derivate, Verfahren zu deren Herstellung und Arzneimittel, die diese Verbindungen enthalten.The present invention relates to quinazoline derivatives, Process for their manufacture and medicinal products containing them Connections included.
Die Erfindung betrifft Quinazolin-Derivate der Formel IThe invention relates to quinazoline derivatives of the formula I.
in der
R einen Phenylring oder einen mono-, bi- oder tricyclischen
carbocyclischen Ring mit 7-15 C-Atomen oder ein hetero
cyclisches mono-, bi- oder tricyclisches Ringsystem mit
jeweils 5 oder 6 Ringatomen bedeutet und pro Ringsystem
1-4 bzw. 1-5 Heteroatome enthalten sein können, wobei die
Heteroatome Stickstoff, Schwefel oder Sauerstoff sind,
wobei die vorgenannten Phenylringe, die mono-, bi- oder
tricyclischen carbocyclischen Ringe oder das heterocycli
sche mono-, bi- oder tricyclische Ringsystem gegebenen
falls ein- oder mehrfach substituiert ist durch C₁-C₆-
Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylmercapto, Amino, C₁-C₆-
Alkylamino, Di-C₁-C₆-alkylamino, C₁-C₆-Alkylcarbonylamino,
Hydroxy, Nitro, Halogen, Trifluormethyl oder Azido,
R¹ ein Wasserstoffatom, einen geradkettigen oder verzweigten,
gesättigten oder ungesättigten aliphatischen Rest mit 1-6
C-Atomen oder C₁-C₆-Alkoxy, C₁-C₆-Alkylmercapto, C₁-C₆-
Alkylsulfinyl, C₁-C₆-Alkylsulfonyl, Amino, C₁-C₆-Alkyl
amino, Di-C₁-C₆-Alkylamino, Sulfonamido, C₁-C₆-Alkoxycar
bonyl, Carboxy, Halogen, Hydroxy, Nitro, Cyano oder
Azido,
R² C₁-C₈-Alkyl, C₂-C₈-Alkenyl, C₃-C₈-Cycloalkyl, C₃-C₈-Cyclo
alkenyl, wobei die vorgenannten Alkyl oder Alkenylreste
gegebenenfalls mit Fluor, Chlor, Hydroxy und Mercapto
substituiert oder durch ein Sauerstoff- oder Schwefelatom
unterbrochen sein können,
R³ Wasserstoff oder eine C₁-C₆-Alkylgruppe bedeutet, die
durch ein, zwei oder drei Halogenatome substituiert sein
kann,
X ein Sauerstoff- oder Schwefelatom,
Y ein Stickstoffatom oder CR¹ bedeutet,
sowie deren Tautomere, Enantiomere, Diastereomere und physiolo
gisch verträgliche Salze.in the
R is a phenyl ring or a mono-, bi- or tricyclic carbocyclic ring with 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and 1-4 or 1- per ring system 5 heteroatoms can be contained, the heteroatoms being nitrogen, sulfur or oxygen, the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system optionally being substituted one or more times is by C₁-C₆- alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or Azido,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁- C₆-alkyl amino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆-alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,
R² C₁-C₈-alkyl, C₂-C₈-alkenyl, C₃-C₈-cycloalkyl, C₃-C₈-cyclo alkenyl, the above-mentioned alkyl or alkenyl radicals being optionally substituted with fluorine, chlorine, hydroxy and mercapto or interrupted by an oxygen or sulfur atom could be,
R³ is hydrogen or a C₁-C₆ alkyl group which can be substituted by one, two or three halogen atoms,
X is an oxygen or sulfur atom,
Y represents a nitrogen atom or CR¹,
as well as their tautomers, enantiomers, diastereomers and physiologically compatible salts.
Quinazoline-Derivate mit ähnlicher Struktur sind aus der Inter nationalen Patentanmeldung WO 93/04047 bekannt. Die dort be schriebenen Derivate sind Inhibitoren der Reversen Transkriptase und können zur Herstellung von Arzneimitteln eingesetzt werden. Außerdem sind Quinazolin-Derivate in der Patentliteratur für verschiedene medizinische Anwendungen bereits-beschrieben. Dies trifft insbesondere für solche Deri vate zu, bei denen der Rest R ein unsubstituierter Phenylring und R¹ Wasserstoff oder Chlor bedeutet. Die japanische Anmel dung JP 7214183 beschreibt in 3-Stellung substituierte China zolin-2-one mit antiinflammatorischer und analgetischer Wirkung. In der deutschen Offenlegungsschrift 2508543 werden Quinazoline als Zwischenprodukte zur Herstellung von anti depressiv wirksamen Arzneimitteln verwandt. Antidepressive, antiinflammatorische, analgetische und bakterizide Wirkung wird 3-substituierten Chinazolin-2-onen in den deutschen Offenlegun gen 2162327 und 2166327 zugeschrieben. Als Zwischenprodukte zur Herstellung von Arzneimitteln mit hypotensiver und Plättchen inhibierender Wirkung werden 3-substituierte Quinazoline in der japanischen Anmeldung JP 7844592 genannt. Die Synthese dieser Quinazolinderivate wird ausführlich in Chem. Pharm. Bull. 29, 2135, 1981 beschrieben. Eine antivirale Aktivität wurde bei diesen Derivaten bisher jedoch nicht nachgewiesen.Quinazoline derivatives with a similar structure are from the Inter national patent application WO 93/04047 known. The be there Derivatives written are reverse inhibitors Transcriptase and can be used to manufacture drugs be used. Quinazoline derivatives are also in the Patent literature for various medical applications already described. This is especially true for such deri vate zu, in which the radical R is an unsubstituted phenyl ring and R1 is hydrogen or chlorine. The Japanese application JP 7214183 describes China substituted in the 3-position zolin-2-one with anti-inflammatory and analgesic Effect. In the German Offenlegungsschrift 2508543 Quinazoline as an intermediate for the production of anti depressive drugs related. Antidepressants, anti-inflammatory, analgesic and bactericidal effect 3-substituted quinazolin-2-ones in German Offenlegun gen 2162327 and 2166327. As intermediates for Manufacture of drugs with hypotensive and platelets 3-substituted quinazolines are inhibitory in the Japanese application called JP 7844592. The synthesis of this Quinazoline derivatives is described in detail in Chem. Pharm. Bull. 29, 2135, 1981. Antiviral activity has been reported in however, these derivatives have not yet been demonstrated.
Der vorliegenden Erfindung lag die Aufgabe zugrunde, neue Quinazoline zur Herstellung von Arzneimitteln zur Verfügung zu stellen.The object of the present invention was to create new ones Quinazoline is available for the manufacture of medicines too put.
Die Verbindungen der vorliegenden Erfindung weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere besitzen sie eine antivirale Wirkung und eignen sich zur Therapie und Pro phylaxe von Infektionen, die durch DNA-Viren wie z. B. das Herpes-Simplex-Virus, das Zytomegalie-Virus, Papilloma-Viren, das Varicella-Zoster-Virus oder Epstein-Barr-Virus oder RNA- Viren wie Toga-Viren oder insbesondere Retroviren wie die Onko- Viren HTLV-I und II, sowie die Lentiviren Visna und Humanes- Immunschwäche-Virus HIV-1 und -2, verursacht werden.The compounds of the present invention have valuable pharmacological properties. In particular, they own an antiviral effect and are suitable for therapy and pro prevention of infections caused by DNA viruses such as B. that Herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA Viruses like toga viruses or especially retroviruses like the oncology HTLV-I and II viruses, as well as the lentiviruses Visna and Humanes- Immunodeficiency virus HIV-1 and -2.
Besonders geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifestationen der retroviralen HIV- Infektion beim Menschen, wie der anhaltenden, generalisierten Lymphadenopathie (PGL), dem fortgeschrittenen Stadium des AIDS- verwandten Komplex (ARC) und dem klinischen Vollbild von AIDS.The compounds of the formula I appear to be particularly suitable for Treatment of clinical manifestations of retroviral HIV Human infection, such as the persistent, generalized Lymphadenopathy (PGL), the advanced stage of AIDS related complex (ARC) and the clinical picture of AIDS.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I besitzen eine ausgeprägte antivirale Wirkung und eignen sich insbesondere zur Behandlung von viralen bzw. retroviralen Infektionen. Virale Infektionen von Säugern, insbesondere des Menschen, sind weit verbreitet. Trotz intensiver Bemühungen ist es bisher nicht gelungen, Chemotherapeutika bereitzustellen, die ursächlich oder symptomatisch mit dem viral oder retroviral bedingten Krankheitsgeschehen mit erkennbar substantiellem Erfolg interferieren. Es ist heutzutage nicht möglich, bestimm te Viruserkrankungen, wie zum Beispiel das Acquired Immune Deficiency Syndrom (AIDS), den AIDS-related-complex (ARC) und deren Vorstadien, Herpes-, Cytomegalie-Virus (CMV)-, Influenza- und andere Virusinfektionen zu heilen oder chemotherapeutisch deren Symptome günstig zu beeinflussen. Derzeit steht bei spielsweise für die Behandlung von AIDS fast ausschließlich das 3′-Azido-3′-deoxy-thymidin (AZT), bekannt als Zidovudine oder Retrovir®, zur Verfügung. AZT ist jedoch durch eine sehr enge therapeutische Breite bzw. durch bereits im therapeutischen Bereich auftretende, sehr schwere Toxizitäten charakterisiert (Hirsch, M.S. (1988) J.Infec.Dis. 157, 427-431). Die Verbindun gen der allgemeinen Formel I besitzen diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakologisch relevanten Dosen cytotoxisch zu sein.The compounds of general formula I according to the invention have a pronounced antiviral effect and are suitable especially for the treatment of viral or retroviral Infections. Viral infections in mammals, especially the People are common. Despite intensive efforts it has so far not been possible to provide chemotherapy drugs, the causal or symptomatic with the viral or retroviral conditioned illnesses with recognizable substantial Interfering Success. It is not possible these days to determine te viral diseases, such as the acquired immune Deficiency Syndrome (AIDS), the AIDS-related complex (ARC) and their pre-stages, herpes, cytomegalovirus (CMV) -, influenza and cure other viral infections or chemotherapy to influence their symptoms favorably. Is currently at for example for the treatment of AIDS almost exclusively that 3'-azido-3'-deoxy-thymidine (AZT), known as zidovudine or Retrovir®, available. AZT is, however, very tight therapeutic breadth or already in therapeutic Characterized very severe toxicities (Hirsch, M.S. (1988) J.Infec. Dis. 157, 427-431). The connection gene of the general formula I do not have these disadvantages. They have an antiviral effect without being in pharmacologically relevant doses to be cytotoxic.
Es konnte nun nachgewiesen werden, daß Verbindungen der allge meinen Formel I die Vermehrung von DNA- bzw. RNA-Viren auf der Stufe der virus spezifischen DNA- bzw. RNA-Transkription hem men. Die Substanzen können über die Inhibierung des Enzyms Reverse Transkriptase die Vermehrung von Retroviren beeinflus sen (vgl. Proc. Natl. Acad. Sci. USA 83, 1911, 1986 bzw. Nature 325, 773 1987).It has now been demonstrated that connections of the general Formula I mean the multiplication of DNA or RNA viruses on the Level of virus-specific DNA or RNA transcription hem men. The substances can inhibit the enzyme Reverse transcriptase affects retrovirus proliferation sen (see Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773 1987).
Da ein sehr großer Bedarf an Chemotherapeutica besteht, die möglichst spezifisch mit retroviral bedingten Erkrankungen oder deren Symptomen interferieren, ohne die normal ablaufenden natürlichen Körperfunktionen zu beeinflussen, könnten die genannten Verbindungen vorteilhaft prophylaktisch oder thera peutisch bei der Behandlung von Krankheiten eingesetzt werden, bei denen eine retrovirale Infektion von pathophysiologischer, symptomatischer oder klinischer Relevanz ist. Since there is a very great need for chemotherapeutics, the as specifically as possible with retroviral diseases or their symptoms interfere without the normal ones could influence natural bodily functions mentioned compounds advantageously prophylactically or thera used in the treatment of diseases in which a retroviral infection of pathophysiological, is symptomatic or clinical relevance.
Die Trennung der Racemate in die Enantiomeren kann analytisch, semipräparativ und präparativ chromatographisch auf geeigneten optisch aktiven Phasen mit gängigen Elutionsmitteln durchge führt werden.The separation of the racemates into the enantiomers can be carried out analytically, semi-preparative and preparative chromatographic on suitable optically active phases with common eluents leads.
Als optisch aktive Phasen eignen sich beispielsweise optisch aktive Polyacrylamide oder Polymethacrylamide, z. T. auch an Kieselgel (z. B. ChiraSpher® von Merck, Chiralpak® OT/OP von Baker), Celluloseester/-carbamate (z. B. Chiracel® OB/OY von Baker/Daicel), Phasen auf Cyclodextrin- oder Kronenether basis (z. B. Crownpak® von Daicel) oder mikrokristallines Cellulosetriacetat (Merck).Optically active phases are, for example, optically suitable active polyacrylamides or polymethacrylamides, e.g. T. also on Silica gel (e.g. ChiraSpher® from Merck, Chiralpak® OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel® OB / OY from Baker / Daicel), phases on cyclodextrin or crown ether base (e.g. Crownpak® from Daicel) or microcrystalline Cellulose triacetate (Merck).
Ein carbocyclischer Ring R mit 7-15 C-Atomen kann mono-, bi- oder tricyclisch sein und pro Ring jeweils 5 oder 6 C-Atome aufweisen. Dieser Ring kann gesättigt, ungesättigt, teilweise gesättigt oder aromatisch sein. Beispielhaft genannt seien die folgenden Ringsysteme: der Naphthyl-, Anthracenyl-, Phenanthre nyl-, Flourenyl-, Indenyl-, Acenaphthylenyl-, Norbornyl-, Adamantylring oder eine C₃-C₇-Cycloalkyl- oder C₅-C₈-Cycloalke nylgruppe. Der carbocyclische Ring kann darüberhinaus mono- oder disubstituiert sein, wobei die Substituenten unabhängig voneinander bevorzugt in o- oder m-Stellung stehen können.A carbocyclic ring R with 7-15 C atoms can be mono-, bi- or be tricyclic and 5 or 6 carbon atoms per ring exhibit. This ring can be saturated, unsaturated, partial be saturated or aromatic. Examples include those following ring systems: the naphthyl, anthracenyl, phenanthre nyl, flourenyl, indenyl, acenaphthylenyl, norbornyl, Adamantyl ring or a C₃-C₇ cycloalkyl or C₅-C₈ cycloalke nyl group. The carbocyclic ring can also be mono- or be disubstituted, the substituents being independent can preferably be in the o- or m-position.
Die heterocylischen mono-, bi- oder tricyclischen Ringsysteme des Restes R enthalten pro Ring 5 oder 6 Kohlenstoffatome, wobei 1-4 bzw. 1-5 C-Atome durch die Heteroatome Sauerstoff, Schwefel und/oder Stickstoff ersetzt sein können. Die Ring systeme können aromatisch, partiell oder vollständig hydriert sein. Beispielhaft genannt seien die folgenden Ringsysteme: das Pyridin-, Pyrimidin-, Pyridazin-, Pyrazin-, Triazin-, Pyrrol-, Pyrazol-, Imidazol-, Triazol-, Thiazol-, Oxazol-, Isoxazol-, Oxadiazol-, Furazan-, Furan- , Thiophen-, Indol-, Chinolin-, Isochinolin-, Cumaron-, Thionaphthen-, Benzoxazol-, Benzthia zol-, Indazol-, Benzimidazol-, Benztriazol-, Chromen-, Phthala zin-, Chinazolin-, Chinoxalin-, Methylendioxybenzol-, Carbazol-, Acridin-, Phenoxazin-, Phenothiazin-, Phenazin- oder Purinsystem, wobei die ungesättigten bzw. aromatischen Carbo- und Heterocyclen partiell oder vollständig hydriert sein kön nen. Das heterocyclische Ringsystem kann darüberhinaus mono- oder disubstituiert sein, wobei die Substituenten unabhängig voneinander bevorzugt in o- oder m-Stellung stehen können.The heterocyclic mono-, bi- or tricyclic ring systems of the radical R contain 5 or 6 carbon atoms per ring, where 1-4 or 1-5 carbon atoms through the heteroatoms oxygen, Sulfur and / or nitrogen can be replaced. The ring systems can be aromatic, partially or fully hydrogenated his. The following ring systems may be mentioned as examples: Pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, Pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, Oxadiazole, furazane, furan, thiophene, indole, quinoline, Isoquinoline, coumarone, thionaphthene, benzoxazole, benzthia zole, indazole, benzimidazole, benzotriazole, chromene, phthalate tin, quinazoline, quinoxaline, methylenedioxybenzene, Carbazole, acridine, phenoxazine, phenothiazine, phenazine or Purine system, the unsaturated or aromatic carbo- and heterocycles can be partially or fully hydrogenated nen. The heterocyclic ring system can also be mono- or be disubstituted, the substituents being independent can preferably be in the o- or m-position.
R bedeutet bevorzugt unsubstituiertes Phenyl oder Phenyl ein- oder zweifach substituiert durch C₁-C₃-Alkyl, C₁-C₃-Alkoxy, C₁- C₃-Alkylmercapto, C₁-C₃-Alkylamino, C₁-C₃-Dialkylamino-, C₁-C₃- Alkylcarbonylamino, Amino, Hydroxy, Nitro, Azido, Tri fluormethyl oder Halogen, wobei die zuvor genannten aliphati schen Reste bevorzugt bis zu 3 Kohlenstoffatomen enthalten.R preferably denotes unsubstituted phenyl or phenyl mono- or substituted twice by C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁- C₃-alkylmercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino-, C₁-C₃- Alkylcarbonylamino, amino, hydroxy, nitro, azido, tri fluoromethyl or halogen, the aforementioned aliphati rule radicals preferably contain up to 3 carbon atoms.
Carbocyclische Ringe R sind bevorzugt Biphenyl, Naphthyl, Anthracenyl, Indenyl, Fluorenyl, Acenaphthylenyl, Phenanthre nyl, Norbornyl, Adamantyl, C₃-C₆-Cycloalkyl, C₅-C₈-Cycloalke nyl, wobei die carbocyclischen Ringe ein- oder zweifach substituiert sein können durch C₁-C₃-Alkyl, C₁-C₃-Alkoxy, C₁- C₃-Alkylmercapto, C₁-C₃ -Alkylamino, C₁-C₃ -Dialkylamino-, C₁-C₃- Alkylcarbonylamino, Amino, Hydroxy, Nitro, Azido, Tri fluormethyl oder Halogen, wobei die zuvor genannten aliphati schen Reste bevorzugt bis zu 3 Kohlenstoffatomen enthalten.Carbocyclic rings R are preferably biphenyl, naphthyl, Anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthre nyl, norbornyl, adamantyl, C₃-C₆-cycloalkyl, C₅-C₈-cycloalke nyl, the carbocyclic rings being one or two can be substituted by C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁- C₃-alkyl mercapto, C₁-C₃-alkylamino, C₁-C₃-dialkylamino-, C₁-C₃- Alkylcarbonylamino, amino, hydroxy, nitro, azido, tri fluoromethyl or halogen, the aforementioned aliphati rule radicals preferably contain up to 3 carbon atoms.
Heterocyclische Ringsysteme R sind bevorzugt Pyrrol, Imidazol, Furan, Thiophen, Pyridin, Pyrimidin, Thiazol, Triazin, Indol, Chinolin, Isochinolin, Cumaron, Thionaphthen, Benzimidazol, Chinazolin, Methylendioxybenzol, Ethylendioxybenzol, Carbazol, Acridin und Phenothiazin, wobei die heterocyclischen Ringe ein- oder zweifach substituiert sein können durch C₁-C₃-Alkyl, C₁- C₃-Alkoxy, C₁-C₃-Alkylmercapto, C₁-C₃-Alkylamino, C₁-C₃-Di alkylamino-, C₁-C₃-Alkylcarbonylamino, Amino, Hydroxy, Nitro, Azido, Trifluormethyl oder Halogen.Heterocyclic ring systems R are preferably pyrrole, imidazole, Furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, Quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, Quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, Acridine and phenothiazine, with the heterocyclic rings or can be substituted twice by C₁-C₃-alkyl, C₁- C₃-alkoxy, C₁-C₃-alkyl mercapto, C₁-C₃-alkylamino, C₁-C₃-di alkylamino, C₁-C₃ alkylcarbonylamino, amino, hydroxy, nitro, Azido, trifluoromethyl or halogen.
Für den Rest R¹ ist Wasserstoff, C₁-C₃-Alkyl, C₂-C₄-Alkenyl, C₂-C₄-Alkinyl, C₁-C₃-Alkoxy, C₁-C₃-Alkylmercapto, C₁-C₃-Alkyl amino, C₁-C₃ Alkoxycarbonyl, Amino, Halogen, Hydroxy, Nitro, Cyano und Azido bevorzugt. For the rest R¹ is hydrogen, C₁-C₃-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkyl amino, C₁-C₃ alkoxycarbonyl, amino, halogen, hydroxy, nitro, Cyano and azido preferred.
Bevorzugt für R² sind C₁-C₃-Alkyl, C₁-C₃-Hydroxyalkyl, C₁-C₃- Alkylthiomethyl-, C₁-C₃-Alkylthioethyl, C₁-C₃-Alkylthioethyl, C₁-C₃-Alkylthiopropyl, C₁-C₃-Alkoxymethyl, C₁-C₃-Alkoxyethyl und C₁-C₃-Alkoxypropyl.Preferred for R² are C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃- Alkylthiomethyl, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthioethyl, C₁-C₃-alkylthiopropyl, C₁-C₃-alkoxymethyl, C₁-C₃-alkoxyethyl and C₁-C₃ alkoxypropyl.
R³ bedeutet insbesondere eine Alkylgruppe mit bis zu 4 C-Atomen, die geradkettig oder verzweigt sein kann, vorzugs weise eine Methyl-, Ethyl-, Propyl- oder Butylgruppe, wobei die Alkylgruppe an einem oder mehreren C-Atomen durch ein, zwei oder drei Halogenatome substituiert ist und insgesamt bis zu drei Halogensubstituenten vorhanden sein können. Halogenatome sind insbesondere das Fluor-, Chlor- oder Bromatom. Besonders bevorzugt kommt die Trifluormethyl- und Trichlormethylgruppe in Frage.R³ means in particular an alkyl group with up to 4 C atoms, which can be straight-chain or branched, preferred have a methyl, ethyl, propyl or butyl group, the Alkyl group on one or more carbon atoms by one or two or three halogen atoms is substituted and in total up to three halogen substituents may be present. Halogen atoms are in particular the fluorine, chlorine or bromine atom. Especially the trifluoromethyl and trichloromethyl groups are preferred Question.
X ist bevorzugt Sauerstoff.X is preferably oxygen.
Unter Halogen ist allgemein Fluor, Chlor, Brom und Iod zu verstehen, bevorzugt Fluor, Chlor und Brom.Halogen generally includes fluorine, chlorine, bromine and iodine understand, preferably fluorine, chlorine and bromine.
Y ist bevorzugt ein Stickstoffatom oder die Gruppe CH.Y is preferably a nitrogen atom or the group CH.
Besonders bevorzugte Reste für R sind Phenyl, durch C₁-C₃- Alkyl, C₁-C₃-Alkoxy, C₁-C₃-Alkylmercapto, C₁-C₃-Alkylamino, Di- C₁-C₃-alkylamino, Amino, Hydroxy, Azido, Trifluormethyl oder Halogen mono- oder disubstituiertes Phenyl bzw. durch Methyl oder Halogen trisubstituiertes Phenyl, Naphthyl, Anthracenyl, Indenyl, Acenaphthylenyl, Phenanthrenyl, Adamantyl, Cyclohexyl, Cyclohexenyl, Furyl, Thienyl, Pyridyl, Pyrimidinyl, Thiazolyl, Indolyl, Chinolinyl, Benzimidazolyl, Methylendioxyphenyl, Carbazolyl und Phenothiazinyl und durch Methyl oder Halogen mono- oder disubstituierte Derivate der vorgenannten carbo cyclischen oder heterocyclischen Ringe.Particularly preferred radicals for R are phenyl, by C₁-C₃- Alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylmercapto, C₁-C₃-alkylamino, di- C₁-C₃-alkylamino, amino, hydroxy, azido, trifluoromethyl or Halogen mono- or disubstituted phenyl or by methyl or halogen trisubstituted phenyl, naphthyl, anthracenyl, Indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, Cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, Indolyl, quinolinyl, benzimidazolyl, methylenedioxyphenyl, Carbazolyl and phenothiazinyl and by methyl or halogen mono- or disubstituted derivatives of the aforementioned carbo cyclic or heterocyclic rings.
Für R¹ ist besonders bevorzugt Wasserstoff, Methyl, Ethyl, Isopropyl, Allyl, Methoxy, Ethoxy, Methylmercapto, Ethylmer capto, Methylamino, Methoxycarbonyl, Ethoxycarbonyl, Amino, Azido, Cyano, Hydroxy und Halogen, wobei Chlor und Brom für Halogen bevorzugt in Frage kommen.R 1 is particularly preferably hydrogen, methyl, ethyl, Isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmer capto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, Azido, Cyano, Hydroxy and Halogen, whereby chlorine and bromine for Halogen is preferred.
Für R² sind Methyl, Ethyl und Isopropyl besonders bevorzugt.For R², methyl, ethyl and isopropyl are particularly preferred.
Insbesondere bevorzugt sind Verbindungen der allgemeinen Formel I, in denen R, R¹, X und Y, die oben angegebene Bedeu tung haben und R² Methyl oder Ethyl ist.Compounds of the general are particularly preferred Formula I in which R, R¹, X and Y have the meaning given above tion and R² is methyl or ethyl.
Für R³ ist insbesondere Trichlormethyl bevorzugt.Trichloromethyl is particularly preferred for R³.
Die Arzneimittel enthalten mindestens eine Verbindung der Formel I zur Behandlung von viralen Infektionen und können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Hierbei kommen die üblichen Applikationsformen in Frage, wie beispielsweise Tabletten, Kapseln, Drag´es, Sirupe, Lösungen oder Suspensionen. Als Injektionsmedium kommt vorzugs weise Wasser zur Anwendung, das die bei Injektionslösungen üblichen Zusätze wie Stabilisierungsmittel, Lösungsvermittler und Puffer enthält. Derartige Zusätze sind z. B. Tartrat- und Zitratpuffer, Ethanol, Komplexbildner, wie Ethylen-diamintetra essigsäure und deren nichttoxischen Salze, hochmolekulare Polymere, wie flüssiges Polyethylenoxid zur Viskositätsregulie rung. Flüssige Trägerstoffe für Injektionslösungen müssen steril sein und werden vorzugsweise in Ampullen abgefüllt. Feste Trägerstoffe sind beispielsweise Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, höher molekulare Fettsäuren, wie Stearinsäure, Gelatine, Agar-Agar, Calziumphosphat, Magnesiumstearat, tierische und pflanzliche Fette, feste hochmolekulare Polymere, wie Polyethylenglykole, etc. Für orale Applikationen geeignete Zubereitungen können gewünschtenfalls Geschmacks- oder Süßstoffe enthalten.The medicinal products contain at least one compound of Formula I for the treatment of viral infections and can be used in liquid or solid form applied enterally or parenterally become. The usual forms of application come into play here Question such as tablets, capsules, drag'es, syrups, Solutions or suspensions. Preference is given as the injection medium wise water to use, which is the case with injection solutions usual additives such as stabilizers, solubilizers and contains buffers. Such additives are e.g. B. tartrate and Citrate buffer, ethanol, complexing agents, such as ethylene diamine tetra acetic acid and its non-toxic salts, high molecular weight Polymers such as liquid polyethylene oxide for viscosity control tion. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, Methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar, Calcium phosphate, magnesium stearate, animal and vegetable Fat, solid, high molecular weight polymers, such as polyethylene glycols, etc. Suitable preparations for oral applications if desired contain flavorings or sweeteners.
Die Dosierung kann von verschiedenen Faktoren, wie Applika tionsweise, Spezies, Alter oder individuellem Zustand abhängen. Die erfindungsgemäßen Verbindungen werden üblicherweise in Mengen von 0,1-100 mg, vorzugsweise 0,2-80 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tages dosis auf 2-5 Applikationen zu verteilen, wobei bei jeder Applikation 1-2 Tabletten mit einem Wirkstoffgehalt von 0,5-500 mg verabreicht werden. Die Tabletten können auch retardiert sein, wodurch sich die Anzahl der Applikationen pro Tag auf 1-3 vermindert. Der Wirkstoffgehalt der retardierten Tabletten kann 2-1000 mg betragen. Der Wirkstoff kann auch durch Dauer infusion gegeben werden, wobei die Mengen von 5-1000 mg pro Tag normalerweise ausreichen.The dosage can depend on various factors, such as appliques manner, species, age or individual condition. The compounds according to the invention are usually described in Amounts of 0.1-100 mg, preferably 0.2-80 mg per day and applied per kg body weight. It is preferred the day distribute dose over 2-5 applications, with each Application 1-2 tablets with an active ingredient content of 0.5-500 mg can be administered. The tablets can also be delayed be, which brings the number of applications per day to 1-3 reduced. The active substance content of the prolonged-release tablets can Amount to 2-1000 mg. The active ingredient can also last through be given infusion, the amounts of 5-1000 mg per Day is usually sufficient.
Die Verbindungen der vorliegenden Erfindung und ihre pharmazeu tischen Zubereitungen können auch in Kombination mit anderen Arzneimitteln zur Behandlung und Prophylaxe der oben genannten Infektionen eingesetzt werden. Beispiele dieser weiteren Arz neimittel beinhalten Mittel, die zur Behandlung und Prophylaxe von HIV-Infektionen oder diese Krankheit begleitende Erkrankun gen einsetzbar sind wie 3′-Azido-3′desoxythymidin, 2′,3′-Dide soxynukleoside wie z. B. 2′,3′-Didesoxycytidin, 2′,3′- Didesoxyadenosin und 2′,3 ′-Didesoxyinosin, acyclische Nukleosi de (z. B. Acyclovir), Interferone wie z. B. alpha-Interferon, renale Ausscheidungs-Inhibitoren wie z. B. Probenicid, Nukleo sid-Transport-Inhibitoren wie z. B. Dipyridamol, als auch Immunmodulatoren wie z. B. Interleukin II oder Stimulierungs- Faktoren wie z. B. der Granulocyten-Makrophagen-Kolonie Faktor. Die Verbindungen der vorliegenden Erfindung und das andere Arzneimittel können jeweils einzeln, gleichzeitig, gegebenen falls in einer einzigen oder zwei getrennten Formulierungen oder zu unterschiedlichen Zeiten verabreicht werden, so daß ein synergistischer Effekt erreicht wird.The compounds of the present invention and their pharmazeu Table preparations can also be used in combination with others Medicines for the treatment and prophylaxis of the above Infections are used. Examples of these other medic neimittmittel include agents used for treatment and prophylaxis HIV infection or disease accompanying this disease gene can be used like 3'-azido-3'deoxythymidine, 2 ', 3'-dide soxynucleosides such as B. 2 ', 3'-dideoxycytidine, 2', 3'- Dideoxyadenosine and 2 ′, 3 ′ -dideoxyinosine, acyclic nucleosi de (e.g. acyclovir), interferons such as e.g. B. alpha interferon, renal excretion inhibitors such as B. probenicid, nucleo sid transport inhibitors such as B. dipyridamole, as well Immunomodulators such as B. Interleukin II or stimulation Factors such as B. the granulocyte-macrophage colony factor. The compounds of the present invention and the other Medicines can be given individually, at the same time if in a single or two separate formulations or administered at different times, so that a synergistic effect is achieved.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I werden nach literaturbekannten Verfahren (Chem. Pharm. Bull. 29, 2135, 1981 oder Heterocycles 29, 1317, 1989) hergestellt, indem man Verbindungen der allgemeinen Formel IIThe compounds of general formula I according to the invention are based on methods known from the literature (Chem. Pharm. Bull. 29, 2135, 1981 or Heterocycles 29, 1317, 1989), by using compounds of the general formula II
in der R und R¹ die oben angegebene Bedeutung haben und R³, C₁-₆-Alkyl, CBr₃, CCl₃ oder CF₃ sein kann, mit einem Amin der allgemeinen Formel IIIin which R and R¹ have the meaning given above and R³, C₁-₆-alkyl, CBr₃, CCl₃ or CF₃ can be with an amine general formula III
H₂N-R² III,H₂N-R² III,
in der R² die oben angegebene Bedeutung hat, in einem geeigne ten inerten Lösungsmittel bei Raumtemperatur bis Rückflußtempe ratur evtl. in Gegenwart katalytischer Mengen Säure, z. B. p- Toluolsulfonsäure oder Salzsäure umsetzt und gegebenenfalls anschließend Verbindungen der Formel I in andere Verbindungen der Formel I nachträglich umwandelt und anschließend chromato graphisch bzw. durch Umkristallisation reinigt. Racemate können durch Chromatographie an geeigneten optisch aktiven Phasen, z. B. Cellulosetriacetat, in die Antipoden getrennt werden.in which R² has the meaning given above, in a suitable ten inert solvent at room temperature to reflux temperature temperature in the presence of catalytic amounts of acid, e.g. B. p- Toluene sulfonic acid or hydrochloric acid and optionally then compounds of the formula I into other compounds of the formula I subsequently converted and then chromato cleaned graphically or by recrystallization. Racemate can by chromatography on suitable optically active phases, e.g. B. cellulose triacetate, are separated into the antipodes.
Die nachträgliche Umwandlung von Verbindungen der Formel I in andere Verbindungen der Formel I betreffen z. B. die Herstellung von Verbindungen mit R³ gleich Wasserstoff. Diese Verbindungen werden z. B. hergestellt aus Verbindungen der Formel I mit R² = Trihalogenmethyl durch Reaktion mit einem Reduktionsmittel wie z. B. NaBH₄ oder LiAlH₄ in einem inerten Lösungsmittel bei Temperaturen zwischen -20°C und 150°C.The subsequent conversion of compounds of formula I into other compounds of formula I relate to e.g. B. the manufacture of compounds with R³ equal to hydrogen. These connections z. B. prepared from compounds of formula I with R² = Trihalomethyl by reaction with a reducing agent such as e.g. B. NaBH₄ or LiAlH₄ in an inert solvent Temperatures between -20 ° C and 150 ° C.
Verbindungen der allgemeinen Formel I mit X=S werden herge stellt durch Umsetzung von Verbindungen der Formel I, in der X ein Sauerstoffatom bedeutet, mit schwefelgruppenübertragenden Verbindungen, wie z. B. Lawesson′s Reagenz. Compounds of the general formula I with X = S are obtained represents by reacting compounds of formula I in which X means an oxygen atom with sulfur group transferring Connections such as B. Lawesson's reagent.
Die als Ausgangsmaterial verwendeten Verbindungen der allgemei nen Formel II werden nach literaturbekannten Verfahren aus Aminobenzophenon-Derivaten durch Acylierung gewonnen. Die substituierten oder unsubstituierten 2-Aminobenzophenon-Deriva te lassen sich vorteilhaft nach den von David A. Walsh be schriebenen Verfahren (Synthesis, 677, 1980) herstellen.The compounds of the general used as starting material NEN Formula II are based on methods known from the literature Aminobenzophenone derivatives obtained by acylation. The substituted or unsubstituted 2-aminobenzophenone derivatives te can be advantageous according to those of David A. Walsh produce the written method (Synthesis, 677, 1980).
Im Sinne der vorliegenden Erfindung kommen außer den in den Beispielen genannten Verbindungen und der durch Kombination aller in den Ansprüchen genannten Bedeutungen der Substituenten die folgenden Verbindungen der Formel in Frage, die als racemi schen Gemische oder in optisch aktiver Form bzw. als reine R- und S-Enantiomere vorliegen können:For the purposes of the present invention come in addition to the in Examples mentioned compounds and the combination all the meanings of the substituents mentioned in the claims the following compounds of the formula in question as racemi mixtures or in optically active form or as pure R- and S enantiomers can be present:
1. 3-Ethyl-4-phenyl-3,4-dihydroquinazolin-2(1H)on
2. 3-Ethyl-4-phenyl-3,4-dihydroguinazolin-2(1H)thion
3. 3-Ethyl-4-(3-methylphenyl)-3,4-dihydroguinazolin-2(1H)on
4. 3-Ethyl-4-(3-chlorphenyl)-3,4-dihydroguinazolin-2(1H)on
5. 3-Ethyl-4-(4-methoxyphenyl)-3,4-dihydroguinazolin-2(1H)on
6. 3-Ethyl-4-(2,3-dimethylphenyl)-3,4-dihydroquinazolin-
2(1H)on
7. 3-Ethyl-4-(3,5-dimethylphenyl)-3,4-dihydroquinazolin-
2(1H)on
8. 3-Ethyl-4-(1-naphthyl)-3,4-dihydroguinazolin-2(1H)on
9. 3-Ethyl-4-(4-indonyl)-3,4-dihydroguinazolin-2(1H)on
10. 3-Ethyl-4-(2-amino-5-methylphenyl)-3,4-dihydroguinazolin-
2(1H)on
11. 3-Ethyl-4-(3,5-dichlorphenyl)-3,4-dihydroguinazolin-
2(1H)on
12. 3-Ethyl-4-(6-methyl-2-pyridyl)-3,4-dihydroguinazolin-
2(1H)on
13. 3-Ethyl-4-(4-methyl-2-pyridiyl)-3,4-dihydroguinazolin-
2(1H)on
14. 3-Ethyl-4-(2-thienyl)-3,4-dihydroquinazolin-2(1H)on
15. 3-Ethyl-4-(2-furanyl)-3,4-dihydroquinazolin-2(1H)on
16. 3-Ethyl-4-phenyl-6-chlor-3,4-dihydroguinazolin-2(1H)on
17. 3-Ethyl-4-phenyl-6-methyl-3,4-dihydroguinazolin-2(1H)on
18. 3-Ethyl-4-phenyl-6-methoxy-3,4-dihydroguinazolin-2(1H)on
19. 3-Ethyl-4-phenyl-5-chlor-3,4-dihydroquinazolin-2(1H)on
20. 3-Ethyl-4-phenyl-5-nitro-3,4-dihydroguinazolin-2(1H)on
21. 3-Ethyl-4-phenyl-8-methyl-3,4-dihydroguinazolin-2(1H)on
22. 3-Ethyl-4-phenyl-7-methyl-3,4-dihydroguinazolin-2(1H)on
23. 3-Ethyl-4-phenyl-3,4-dihydropyrido[3,2-b]pyrimidin-
2(1H)on
24. 3-Ethyl-4-(3-methylphenyl)-3,4-dihydropyrido[3,2-
b]pyrimidin-2(1H)on
25. 3-Ethyl-4-(3-chlorphenyl)-3,4-dihydropyrido[3,2-
b]pyrimidin-2(1H)on
26. 3-Ethyl-4-(6-methyl-2-pyridyl)-3,4-dihydropyrido[3,2-
b]pyrimidin-2(1H)on
27. 3-Ethyl-4-(4-methyl-2-pyridyl)-3,4-dihydropyrido[3,2-
b]pyrimidin-2(1H)on
28. 3-Ethyl-4-methyl-4-phenyl-3,4-dihydroguinazolin-2(1H)on
29. 3-Ethyl-4-trichlormethyl-4-phenyl-3,4-dihydroguinazolin-
2(1H)on
30. 3-Ethyl-4-trifluormethyl-4-phenyl-3,4-dihydroquinazolin-
2(1H)on
31. 3-Methyl-4-phenyl-3,4-dihydroquinazolin-2(1H)on
32. 3-Methylthioethyl-4-phenyl-3,4-dihydroguinazolin-2(1H)on
33. 3-(2-Hydroxypropyl)-4-phenyl-3,4-dihydroguinazolin-
2(1H)on
34. 3-Allyl-4-phenyl-3,4-dihydroguinazolin-2(1H)on
35. 3-Cyclopropyl-4-phenyl-3,4-dihydroguinazolin-2(1H)on
36. 3-(1-Cyclopentyl)-4-phenyl-3,4-dihydroquinazolin-2(1H)on
37. 3-(3-Chlorpropyl)-4-phenyl-3,4-dihydroquinazolin-2(1H)on
38. 3-(Ethoxyethyl)-4-phenyl-3,4-dihydroguinazolin-2(1H)on1. 3-ethyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
2. 3-ethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) thione
3. 3-ethyl-4- (3-methylphenyl) -3,4-dihydroguinazolin-2 (1H) one
4. 3-ethyl-4- (3-chlorophenyl) -3,4-dihydroguinazolin-2 (1H) one
5. 3-ethyl-4- (4-methoxyphenyl) -3,4-dihydroguinazolin-2 (1H) one
6. 3-ethyl-4- (2,3-dimethylphenyl) -3,4-dihydroquinazolin-2 (1H) one
7. 3-ethyl-4- (3,5-dimethylphenyl) -3,4-dihydroquinazolin-2 (1H) one
8. 3-ethyl-4- (1-naphthyl) -3,4-dihydroguinazolin-2 (1H) one
9. 3-ethyl-4- (4-indonyl) -3,4-dihydroguinazolin-2 (1H) one
10. 3-ethyl-4- (2-amino-5-methylphenyl) -3,4-dihydroguinazolin-2 (1H) one
11. 3-Ethyl-4- (3,5-dichlorophenyl) -3,4-dihydroguinazolin-2 (1H) one
12. 3-ethyl-4- (6-methyl-2-pyridyl) -3,4-dihydroguinazolin-2 (1H) one
13. 3-Ethyl-4- (4-methyl-2-pyridiyl) -3,4-dihydroguinazolin-2 (1H) one
14. 3-Ethyl-4- (2-thienyl) -3,4-dihydroquinazolin-2 (1H) one
15. 3-Ethyl-4- (2-furanyl) -3,4-dihydroquinazolin-2 (1H) one
16. 3-Ethyl-4-phenyl-6-chloro-3,4-dihydroguinazolin-2 (1H) one
17. 3-ethyl-4-phenyl-6-methyl-3,4-dihydroguinazolin-2 (1H) one
18. 3-ethyl-4-phenyl-6-methoxy-3,4-dihydroguinazolin-2 (1H) one
19. 3-ethyl-4-phenyl-5-chloro-3,4-dihydroquinazolin-2 (1H) one
20. 3-ethyl-4-phenyl-5-nitro-3,4-dihydroguinazolin-2 (1H) one
21. 3-Ethyl-4-phenyl-8-methyl-3,4-dihydroguinazolin-2 (1H) one
22. 3-Ethyl-4-phenyl-7-methyl-3,4-dihydroguinazolin-2 (1H) one
23. 3-ethyl-4-phenyl-3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
24. 3-Ethyl-4- (3-methylphenyl) -3,4-dihydropyrido [3,2- b] pyrimidin-2 (1H) one
25. 3-Ethyl-4- (3-chlorophenyl) -3,4-dihydropyrido [3,2- b] pyrimidin-2 (1H) one
26. 3-ethyl-4- (6-methyl-2-pyridyl) -3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
27. 3-Ethyl-4- (4-methyl-2-pyridyl) -3,4-dihydropyrido [3,2-b] pyrimidin-2 (1H) one
28. 3-ethyl-4-methyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
29. 3-ethyl-4-trichloromethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
30. 3-ethyl-4-trifluoromethyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
31. 3-Methyl-4-phenyl-3,4-dihydroquinazolin-2 (1H) one
32. 3-Methylthioethyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
33. 3- (2-hydroxypropyl) -4-phenyl-3,4-dihydroguinazolin-2 (1H) one
34. 3-Allyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
35. 3-Cyclopropyl-4-phenyl-3,4-dihydroguinazolin-2 (1H) one
36. 3- (1-Cyclopentyl) -4-phenyl-3,4-dihydroquinazolin-2 (1H) one
37. 3- (3-Chloropropyl) -4-phenyl-3,4-dihydroquinazolin-2 (1H) one
38. 3- (Ethoxyethyl) -4-phenyl-3,4-dihydroguinazolin-2 (1H) one
-
a) Zu 5 g (25 mmol) 2-Aminobenzophenon in 50 ml Toluol und
2.2 ml Pyridin tropft man 3.1 ml (27.5 mmol) Trichlorace
tylchlorid in 10 ml Toluol bei 10°C unter Rühren. Nach
einer Stunde wird der Ansatz 3 × mit Wasser geschüttelt,
die organische Phase abgetrennt, getrocknet und einge
dampft. Das erhaltene Öl wird mit Isohexan angerieben und
die Kristalle abgesaugt.
Man erhält 7.7 g 2-Trichloracetylaminobenzophenon vom Smp. 103-105°C.a) To 5 g (25 mmol) of 2-aminobenzophenone in 50 ml of toluene and 2.2 ml of pyridine are added dropwise 3.1 ml (27.5 mmol) of trichloroacetyl chloride in 10 ml of toluene at 10 ° C. with stirring. After one hour, the mixture is shaken 3 × with water, the organic phase is separated off, dried and evaporated. The oil obtained is rubbed with isohexane and the crystals are filtered off with suction.
7.7 g of 2-trichloroacetylaminobenzophenone with a melting point of 103-105 ° C. are obtained. - b) 1 g (2.9 mmol) 2-Trichloracetylaminobenzophenon, 1.6 g (11.7 mmol) Triethylamin und 1.84 g (23.4 mmol) Ethylamin- Hydrochlorid, werden in 5 ml DMSO 24 Stunden unter Stick stoff gerührt. Anschließend wird mit Wasser verdünnt und die Kristalle abgesaugt. Nach Umkristallisierung erhält man 0.7 g der Titelverbindung vom Smp. 223-225°C.b) 1 g (2.9 mmol) 2-trichloroacetylaminobenzophenone, 1.6 g (11.7 mmol) triethylamine and 1.84 g (23.4 mmol) ethylamine Hydrochloride, stick in 5 ml of DMSO for 24 hours stuff stirred. Then it is diluted with water and the crystals are suctioned off. Obtained after recrystallization 0.7 g of the title compound of mp. 223-225 ° C.
Analog Beispiel 1 erhält man die folgenden Produkte:The following products are obtained analogously to Example 1:
1.4 g (3.8 mmol) der in Beispiel 1 erhaltenen Verbindung wurde in 20 ml DMF gelöst und bei 25°C mit 0.3 g (7.6 mmol) NaBH₄ versetzt. Nach 16 Stunden wurde mit Wasser verdünnt, vorsichtig mit 2 N HCl versetzt und der Niederschlag abgesaugt. Man erhält 0.85 g der Titelverbindung vom Smp. 170-172°C. 1.4 g (3.8 mmol) of the compound obtained in Example 1 was dissolved in 20 ml DMF and at 25 ° C with 0.3 g (7.6 mmol) NaBH₄ transferred. After 16 hours it was diluted with water, carefully treated with 2 N HCl and the precipitate is suction filtered. You get 0.85 g of the title compound of mp 170-172 ° C.
Analog Beispiel 3 erhält man die folgenden Produkte:The following products are obtained analogously to Example 3:
0.5 g (1.9 mmol) der in Beispiel 3 erhaltenen Verbindung wurde mit 0.75 g (1.9 mmol) Lawessons-Reagenz in 25 ml Toluol bei 90°C gerührt. Nach 4 und 8 Stunden wurde nochmals die gleiche Menge Lawessons-Reagenz zugesetzt. Nach 24 Stunden wurde das Toluol mit Wasser gewaschen, getrocknet, eingedampft und der Rückstand über Kieselgel (Laufmittel: 60% Isohexan-40% Essig ester) gereinigt. Nach Eindampfen der gewünschten Fraktionen wurde der Rückstand aus Ethanol kristallisiert. Man erhält 110 mg der Titelverbindung vom Smp. 160-62°C.0.5 g (1.9 mmol) of the compound obtained in Example 3 was with 0.75 g (1.9 mmol) of Lawesson's reagent in 25 ml of toluene 90 ° C stirred. After 4 and 8 hours the same thing happened again Amount of Lawessons reagent added. After 24 hours it was Washed toluene with water, dried, evaporated and the Residue on silica gel (mobile phase: 60% isohexane-40% vinegar ester) cleaned. After evaporating the desired fractions the residue was crystallized from ethanol. You get 110 mg of the title compound of mp 160-62 ° C.
Analog Beispiel 5 erhält man die folgenden Produkte:The following products are obtained analogously to Example 5:
Claims (11)
R einen Phenylring oder einen mono-, bi- oder tricyclischen carbocyclischen Ring mit 7-15 C-Atomen oder ein hetero cyclisches mono-, bi- oder tricyclisches Ringsystem mit jeweils 5 oder 6 Ringatomen bedeutet und pro Ringsystem 1-4 bzw. 1-5 Heteroatome enthalten sein können, wobei die Heteroatome Stickstoff, Schwefel oder Sauerstoff sind, wobei die vorgenannten Phenylringe, die mono-, bi- oder tricyclischen carbocyclischen Ringe oder das heterocycli sche mono-, bi- oder tricyclische Ringsystem gegebenen falls ein- oder mehrfach substituiert ist durch C₁-C₆- Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylmercapto, Amino, C₁-C₆- Alkylamino, Di-C₁-C₆-alkylamino, C₁-C₆-Alkylcarbonyl amino, Hydroxy, Nitro, Halogen, Trifluormethyl oder Azido,
R¹ ein Wasserstoffatom, einen geradkettigen oder verzweig ten, gesättigten oder ungesättigten aliphatischen Rest mit 1-6 C-Atomen oder C₁-C₆-Alkoxy, C₁-C₆-Alkylmercapto, C₁-C₆-Alkylsulfinyl, C₁-C₆-Alkylsulfonyl, Amino, C₁-C₆- Alkylamino, Di-C₁-C₆-Alkylamino, Sulfonamido, C₁-C₆- Alkoxycarbonyl, Carboxy, Halogen, Hydroxy, Nitro, Cyano oder Azido,
R² C₁-C₈-Alkyl, C₂-C₈-Alkenyl, C₃-C₈-Cycloalkyl, C₃-C₈- Cycloalkenyl, wobei die vorgenannten Alkyl oder Alkenyl reste gegebenenfalls mit Fluor, Chlor, Hydroxy und Mercapto substituiert oder durch ein Sauerstoff- oder Schwefelatom unterbrochen sein können,
R³ Wasserstoff oder eine C₁-C₆-Alkylgruppe bedeutet, die durch ein, zwei oder drei Halogenatome substituiert sein kann,
X ein Sauerstoff- oder Schwefelatom,
Y ein Stickstoffatom oder CR¹ bedeutet,
sowie deren Tautomere, Enantiomere, Diastereomere und physiologisch verträgliche Salze.1. Quinazoline derivatives of the formula I. in the
R is a phenyl ring or a mono-, bi- or tricyclic carbocyclic ring with 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and 1-4 or 1- per ring system 5 heteroatoms can be contained, the heteroatoms being nitrogen, sulfur or oxygen, the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring system optionally being substituted one or more times is by C₁-C₆- alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonyl amino, hydroxy, nitro, halogen, trifluoromethyl or azido,
R¹ is a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms or C₁-C₆-alkoxy, C₁-C₆-alkylmercapto, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, amino, C₁ -C₆- alkylamino, di-C₁-C₆-alkylamino, sulfonamido, C₁-C₆- alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano or azido,
R² C₁-C₈-alkyl, C₂-C₈-alkenyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, where the aforementioned alkyl or alkenyl radicals are optionally substituted with fluorine, chlorine, hydroxy and mercapto or interrupted by an oxygen or sulfur atom could be,
R³ is hydrogen or a C₁-C₆ alkyl group which can be substituted by one, two or three halogen atoms,
X is an oxygen or sulfur atom,
Y represents a nitrogen atom or CR¹,
as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19934320347 DE4320347A1 (en) | 1993-06-19 | 1993-06-19 | Quinazoline derivatives and medicaments containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19934320347 DE4320347A1 (en) | 1993-06-19 | 1993-06-19 | Quinazoline derivatives and medicaments containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4320347A1 true DE4320347A1 (en) | 1994-12-22 |
Family
ID=6490703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19934320347 Withdrawn DE4320347A1 (en) | 1993-06-19 | 1993-06-19 | Quinazoline derivatives and medicaments containing them |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE4320347A1 (en) |
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1993
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