JP2002508002A - 2,4,4−三置換−1,3−ジオキソラン抗菌・抗カビ剤 - Google Patents
2,4,4−三置換−1,3−ジオキソラン抗菌・抗カビ剤Info
- Publication number
- JP2002508002A JP2002508002A JP50812999A JP50812999A JP2002508002A JP 2002508002 A JP2002508002 A JP 2002508002A JP 50812999 A JP50812999 A JP 50812999A JP 50812999 A JP50812999 A JP 50812999A JP 2002508002 A JP2002508002 A JP 2002508002A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- compounds
- alkyl
- 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.)
- Granted
Links
- -1 2,4,4-trisubstituted 1,3-dioxolan Chemical class 0.000 title claims abstract description 47
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 25
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 22
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 13
- 239000003429 antifungal agent Substances 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 11
- 125000000815 N-oxide group Chemical group 0.000 claims abstract description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 26
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 12
- 230000000843 anti-fungal effect Effects 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000006091 1,3-dioxolane group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 238000007126 N-alkylation reaction Methods 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000000180 1,2-diols Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 82
- 125000003342 alkenyl group Chemical group 0.000 abstract description 3
- 125000000304 alkynyl group Chemical group 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001241 acetals Chemical class 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229930006000 Sucrose Natural products 0.000 description 10
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000005720 sucrose Substances 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 229920000858 Cyclodextrin Polymers 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 239000007921 spray Substances 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 125000005997 bromomethyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000004862 dioxolanes Chemical group 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000010419 fine particle Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
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- 239000007962 solid dispersion Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 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 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
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- 150000007513 acids Chemical class 0.000 description 4
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- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 4
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- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
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- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 2
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- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 2
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- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式(I)を有する化合物、ならびにそれらのN-オキシド形態、薬学的に許容さ れる酸付加塩または立体化学異性体形態。 式中 nは0、1、2または3であり; XはNまたはCHであり; 各R1は独立してハロ、ニトロ基、シアノ基、アミノ基、ヒドロキシ基、C1-4アル キル基、C1-4アルキルオキシ基またはトリフルオロメチル基であり; R2は水素;C3-7アルケニル基;C3-7アルキニル基、アリール基;C3-7シクロアル キル基;C1-6アルキル基もしくはヒドロキシ基、C1-4アルキルオキシ基、C3-7シ クロアルキル基またはアリールで置換したC1-6アルキル基であり; R3およびR4はそれぞれ独立して水素、C1-6アルキル基、C3-7シクロアルキル基ま たはアリール基であるか、あるいはR3とR4とが一緒になって式; 式中R5a、R5b、R5c、R5dはそれぞれ独立して水素、C1-6アルキル基またはアリー ル基であり、そしておよびアリール基はフェニル基またはハロ、ニトロ基、シア ノ基、アミノ基、ヒドロキシ基、C1-4アルキル基、C1-4アルキルオキシ基もしく はトリフルオロメチル基から選ばれた1、2または3個の置換基で置換されたフ ェニル基である、 の-R3-R4-の2価の基である。 2.nが1または2であり、そして各R1が独立してハロである請求項1記載の化 合物。 3.R3およびR4が独立して水素またはC1-6アルキル基であるか、あるいはR3とR4 とが式(a)、(b)、(c)、(d)または(e)の2価の基-R3-R4-を形成する請求項1また は2記載の化合物。 4.R2がC3-7シクロアルキル基またはC1-6アルキル基である請求項1から3のい ずれかに記載の化合物。 5.1,3-ジオキソラン環の置換基がシス配置である請求項1から4のいずれかに 記載の化合物。 6.1,3-ジオキソラン環の4-位に結合するフェニル環が2,4-ジフルオロフェニル 環であり;R3とR4とがR5a、R5b、R5cまたR5dが水素である式(c)の2価の基-R3-R4 -を形成し;そしてR2がメチル基、エチル基、プロピル基、ブチル基、1-メチル エチル基または1-メチルプロピル基である請求項1から5のいずれかに記載の化 合物。 7.請求項1から6のいずれかに記載の化合物の医薬としての使用。 8.菌・カビ感染症の治療の為の医薬の製造に請求項1から6のいずれかに記載 の化合物の使用。 9.薬学的に許容される担体、および請求項1から6のいずれかに記載の化合物 の治療的有効量を有効成分としてなる薬学的組成物。 10.請求項1に記載の化合物の製法に於いて、 a)式(III)の適当に置換されたフェノールを式(II)のアルキル化剤で、適当な塩 基の存在下に、適当な反応に不活性の溶媒中で、任意に不活性雰囲気中でO-アル キル化し、 式中Wは適当な反応性脱離基を、またn、X、R1からR4は請求項1に定義され たとおりである b)式(V)のアセタールを式(IV)の1,2-ジオールに依り反応剤を適当な反応に不活 性の溶媒中で、適当な酸触媒の存在下にかき混ぜてアセタール変換させ、 式中Rはアルキル基または両R基が一緒になって2価のアルカンジイル基を形成す ることもでき、そしてn、X、R1からR4は請求項1に定義されたとおりである; c)式(VI)または(IX)の中間体を、それぞれ式(VII)または(VIII)のアミンと、場 合によって、反応に不活性の溶媒中および任意に塩基の存在下に環化させ; 式中Wは適当な反応性脱離基を表し、またn、X、R1からR4は請求項1に定義さ れるとおりである; d)式(X)の化合物を式R2-W(XI)のアルキル化剤でN-アルキル化し、 式中Wは適当な反応性脱離基を表し、n、X、R1からR4は請求項1に定義るとおり である; e)中間体(XVII)とイソシアナートR2-N=C=Oとを反応に不活性の溶媒中で反応させ 、式(I-a)の化合物を得て; 式中n、X、R1からR3は請求項1に定義されるとおりである; f)式(XVIII)の中間体と中間体NHR2R4'とを、ここで、Lは適当な脱離基であり、 そしてn、X、R1からR3は請求項1に定義されたとおりであり、R4'が水素、C1-6 アルキル基、C3-7シクロアルキル基およびアリール基として定義される、を、反 応に不活性の溶媒中および適当な塩基の存在下に反応させ;式中R2の反応性アミ ノ基が存在する場合は保護基Pで保護し、また次いでもし必要なら公知の脱保護 技法を用いて脱保護し;式(I-b)の化合物を得て;また、もし所望なら式(I)の化合物をお互いにその他の公知の変換方法に従って ;また更に所望なら酸で処理して治療的に有効な非毒性の酸付加塩に変換し;ま たは逆に酸付加塩形態をアルカリで処理して遊離塩基に変換し;またもし所望な らその立体化学的異性体形態またはN-オキシド形態を製造することを特徴とする 請求項1に記載の化合物の製造方法。 11.請求項1に記載の式(I)の化合物と他の抗菌・抗カビ化合物との組み合わ せ物。 12.医薬として使用するための請求項11に記載の組み合わせ物。 13.抗菌・抗カビ治療に於ける同時、別個または逐次的使用の為の組み合わせ 製剤として、(a)請求項1に記載の式(I)の化合物、および(b)その他の抗菌・抗 カビ化合物を含有する製品。 14.薬学的に許容される担体、および有効成分として(a)請求項1に記載の式( I)の化合物、および(b)その他の抗菌・抗カビ化合物を含んでなる薬学的組成物 。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP97202161.2 | 1997-07-11 | ||
EP97202161 | 1997-07-11 | ||
PCT/EP1998/004194 WO1999002523A1 (en) | 1997-07-11 | 1998-07-07 | 2,4,4-trisubstituted-1,3-dioxolane antifungals |
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JP2010000239A Pending JP2010132666A (ja) | 1997-07-11 | 2010-01-04 | 2,2,4−三置換−1,3−ジオキソラン抗菌・抗カビ剤 |
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JP (2) | JP4473350B2 (ja) |
CN (1) | CN100343249C (ja) |
UA (1) | UA63954C2 (ja) |
ZA (1) | ZA986155B (ja) |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4619931A (en) * | 1983-02-28 | 1986-10-28 | Janssen Pharmaceutica, N.V. | [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles |
CA1292472C (en) * | 1985-12-03 | 1991-11-26 | Alfonsus Guilielmus Knaeps | Derivatives of ¬¬4-¬4-(4-phenyl-1-piperazinyl)- phenoxymethyl|-1,3-dioxolan-2-yl|methyl|-1h-imidazoles and 1h-1,2,4-triazoles |
US4788190A (en) * | 1986-12-24 | 1988-11-29 | Schering Corporation | 2,4,4-tri- and 2,2,4,4-tetra substituted-1,3-dioxolane antifungal, antiallergy compounds |
ATE186540T1 (de) * | 1994-01-24 | 1999-11-15 | Janssen Pharmaceutica Nv | Wasserlösliche azol-antifungus |
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1998
- 1998-07-07 CN CNB988069830A patent/CN100343249C/zh not_active Expired - Lifetime
- 1998-07-07 JP JP50812999A patent/JP4473350B2/ja not_active Expired - Lifetime
- 1998-07-07 UA UA99126609A patent/UA63954C2/uk unknown
- 1998-07-10 ZA ZA9806155A patent/ZA986155B/xx unknown
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ZA986155B (en) | 2000-01-10 |
JP4473350B2 (ja) | 2010-06-02 |
JP2010132666A (ja) | 2010-06-17 |
UA63954C2 (en) | 2004-02-16 |
CN1262684A (zh) | 2000-08-09 |
CN100343249C (zh) | 2007-10-17 |
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