JP5511824B2 - 環状アミドキシムまたは環状アミドラゾン基を有する新規なオキサゾリジノン誘導体及びこれを含む医薬組成物 - Google Patents
環状アミドキシムまたは環状アミドラゾン基を有する新規なオキサゾリジノン誘導体及びこれを含む医薬組成物 Download PDFInfo
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- JP5511824B2 JP5511824B2 JP2011527752A JP2011527752A JP5511824B2 JP 5511824 B2 JP5511824 B2 JP 5511824B2 JP 2011527752 A JP2011527752 A JP 2011527752A JP 2011527752 A JP2011527752 A JP 2011527752A JP 5511824 B2 JP5511824 B2 JP 5511824B2
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title description 43
- 125000004122 cyclic group Chemical group 0.000 title description 16
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 204
- 239000000126 substance Substances 0.000 claims description 74
- -1 amino, hydroxy Chemical group 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 33
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 239000003242 anti bacterial agent Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229940088710 antibiotic agent Drugs 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 9
- 150000004677 hydrates Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
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- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 15
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 229940032049 enterococcus faecalis Drugs 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 9
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 8
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 8
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- SJURCIWIZZIIDD-BMQYTIHCSA-N C([ClH]([2H])([2H])[2H])(Cl)(Cl)[2H] Chemical compound C([ClH]([2H])([2H])[2H])(Cl)(Cl)[2H] SJURCIWIZZIIDD-BMQYTIHCSA-N 0.000 description 6
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- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- UAIJRGWLKLRQAH-CURYUGHLSA-L disodium;[(5r)-3-[3-fluoro-4-[6-(2-methyltetrazol-5-yl)pyridin-3-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl phosphate Chemical compound [Na+].[Na+].CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP([O-])([O-])=O)C2)=O)F)=N1 UAIJRGWLKLRQAH-CURYUGHLSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
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- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- KGVPNLBXJKTABS-UHFFFAOYSA-N hymexazol Chemical compound CC1=CC(O)=NO1 KGVPNLBXJKTABS-UHFFFAOYSA-N 0.000 description 1
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
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- WBGPDYJIPNTOIB-UHFFFAOYSA-N n,n-dibenzylethanamine Chemical compound C=1C=CC=CC=1CN(CC)CC1=CC=CC=C1 WBGPDYJIPNTOIB-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
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- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 description 1
- HLZDTEQPACMNJR-UHFFFAOYSA-N tert-butyl 2-amino-1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CSC(N)=N1 HLZDTEQPACMNJR-UHFFFAOYSA-N 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Yは−O−または−N(R2)−であり;
R2は水素、シアノ、(C1−C6)アルキル、(C3−C6)シクロアルキル、−(CH2)mOC(=O)R11、−(CH2)mC(=O)R12、−(CH2)mC(=S)R12または−SO2R13であり、前記R2のアルキルは(C2−C6)アルケニル、(C2−C6)アルキニル、ハロゲン、ハロ(C1−C6)アルキル、(C1−C6)アルキル(C2−C6)アルキニル、ヒドロキシ、(C3−C6)シクロアルキル及びシアノからなる群から選ばれた一つ以上の置換基によってさらに置換され得;
R11乃至R13は互いに独立的に、水素、(C1−C6)アルキル、(C1−C6)アルコキシ、アミノ、(C3−C6)シクロアルキル、(C2−C6)アルケニル、(C2−C6)アルキニルまたは(C1−C6)アルキルカルボニルであり、前記R11乃至R13のアルキル、アルコキシまたはアミノはハロゲン、アミノ、ヒドロキシ、シアノ、(C1−C6)アルキル、(C1−C6)アルキルカルボニルオキシ及びヒドロキシ(C1−C6)アルキルから選ばれた一つ以上の置換基によってさらに置換され得;
mは0〜2の整数であり;
X1及びX2は互いに独立的に、水素またはフッ素であり;
Pは−O−または−NH−であるか、または下記構造の5員の芳香族複素環であり;
Qは水素、−C(=O)R3、−C(=S)R4、−C(=O)NR5R6または−C(=S)NR5R6であるか、または下記構造から選ばれる5員の芳香族複素環であり;
R3及びR4は互いに独立的に、水素、(C1−C6)アルキル、(C1−C6)アルコキシ、(C3−C6)シクロアルキル、(C2−C6)アルケニルまたは(C2−C6)アルキニルであり;
R5及びR6は互いに独立的に、水素、(C1−C6)アルキル、(C3−C6)シクロアルキルまたは(C2−C6)アルケニルであり;
R7は水素、ハロゲン、(C1−C6)アルキルまたは(C3−C6)シクロアルキルであり;
前記R3乃至R7のアルキルは、ヒドロキシ、シアノ、ハロゲン、(C1−C6)アルキルカルボニルオキシ及びアミノからなる群から選ばれた一つ以上の置換基によってさらに置換され得る。)
R11乃至R13は互いに独立的に、水素、(C1−C6)アルキル、(C1−C6)アルコキシ、アミノ、(C3−C6)シクロアルキルまたは(C1−C6)アルキルカルボニルであり、前記R11乃至R13のアルキル、アルコキシまたはアミノはハロゲン、アミノ、ヒドロキシ、シアノ、(C1−C6)アルキル、(C1−C6)アルキルカルボニルオキシ及びヒドロキシ(C1−C6)アルキルから選ばれた一つ以上の置換基によってさらに置換され得;
mは0〜2の整数であり;
Pは−O−または−NH−であるか、または下記構造の5員の芳香族複素環であり;
Qは水素、−C(=O)R3、−C(=S)R4、−C(=O)NR5R6または−C(=S)NR5R6であるか、または下記構造から選ばれる5員の芳香族複素環であり;
R3及びR4は互いに独立的に、水素、(C1−C6)アルキルまたは(C1−C6)アルコキシであり;
R5及びR6は互いに独立的に、水素または(C1−C6)アルキルであり;
前記R3乃至R6のアルキルは、ヒドロキシ、シアノ、ハロゲン、(C1−C6)アルキルカルボニルオキシ及びアミノからなる群から選ばれた一つ以上の置換基によってさらに置換され得る。)
a)文献[Design of Prodrugs、edited by H. Bundgaard、(Elsevier、1985)及びMethods in Enzymology、Vol.42、P.309−396、edited by K.Widder、et al.(Academic Press、1985)];
b)文献[A Textbook of Drug Design and Development、edited by Krogsgaard−Larsen and H.Bundgaard、Chapter 5「Design and Application of Prodrugs」、by H.Bundgaard P.113−191(1991)];
c)文献[H.Bundgaard、Advanced Drug Delivery Reviews、8、1−38(1992)];
d)文献[H.Bundgaard、et al.、Journal of Pharmaceutical Sciences、77、285(1988)];及び
e)文献[N.Kakeya、et al.、Chem Pharm Bull、32、692(1984)]
などの文献を参照することができる。
前記実施例1乃至106で合成したオキサゾリジノン誘導体の抗菌力を確認するために、試験管内の活性検査を下記のような方法で行った。
メチシリン感受性黄色ブドウ球菌(MSSA、methicillin susceptible staphylococcus aureus)、メチシリン耐性黄色ブドウ球菌(MRSA、methicillin resistant staphylococcus aureus)、バンコマイシン耐性腸球菌(VRE、Vancomycin resistant Enterococci)、バンコマイシン−リネゾリド耐性エンテロコッカス‐フェカーリス(VLRE、Vancomycin−Linezolid Resistant Enterococcus Faecalis)、ヘモフィルス‐インフルエンゼ(Haemophilus Influenzae)とモラクセラ(moraxella)など、総14個の菌株(S.aureus、S.aureusMR、S.epidermidis、S.epidermidisMR、E.faecalis、E.faecalisVanA、E.faecalisVanA LR、E.faeciumVanA、E.faecium、E.coli、P.aeruginosa、K.pneumoniae、H.influenzae、M.catarrhalis)を用いて抗菌力を測定し、そのうちもっとも重要な二つの菌株であるメチシリン耐性黄色ブドウ球菌(MRSA、methicillin resistant Staphylococcus aureus)とバンコマイシン−リネゾリド耐性エンテロコッカス‐フェカーリス(VLRE、Vancomycin−Linezolid Resistant Enterococcus faecalis)の結果を表1に示した。
試験物質(実施例1乃至106で合成した本発明によるオキサゾリジノン誘導体化合物1乃至106)を10240ug/mLの濃度でDMSOに溶かした後、2倍(fold)ずつ希釈し、殺菌された3次蒸溜水で20倍(fold)希釈した。抗菌試験時の最終濃度は最高128ug/mL、最低0.0625ug/mLであり、賦形剤として用いられたDMSOの濃度は最終的に2.5%(V/V)であった。対照物質としてはPharmacia&Upjohn社のリネゾリド(化学式B)の化合物を用いて、抗菌活性を比較してその結果を下記表1に示した。
1)MTT方法を用いた細胞毒性測定法
MTT方法は、哺乳動物の細胞生存と細胞増殖を定量する発色法である。生きている細胞のミトコンドリア膜に存在するコハク酸脱水素酵素(succinate dehydrogenase)がMTTを還元させて青色のホルマザン(formazan)反応物を生成する。この方法は細胞の呼吸を測定するものであり、生成されたホルマザンの量は培養液内に生きている細胞の数と比例的な関係を有する。本試験では米国のATCC社で購入したChinese Ovary Cell(CHO−K1)を用いた。継代培養中のCHO細胞をtrypsin−EDTA溶液で処理して培養容器で分離させた後、96 well microplateに5000個ずつシーディングした。37℃、5% CO2インキュベーターで24時間培養した後、前記実施例で合成した本発明によるオキサゾリジノン誘導体を7つの多様な濃度勾配で処理した。37℃、5% CO2インキュベーターでさらに48時間培養した後、5mg/mLのMTT溶液を15uLずつ入れ、37℃、5% CO2インキュベーターで2時間程度反応させた。2時間後、細胞培養培地を捨てて100uLのDMSO溶液を各wellに加えた。Microplateを30分撹拌した後、Spectramax plus 190 plate reader(Molecular Devices、USA)を用いて550nmでの吸光度を測定した。化合物を処理しない対照群に対する化合物処理群の吸光度の減少は、生きている細胞の減少を示し、化合物の細胞毒性程度を測定することができる。本発明による化合物のCC50値は多様な濃度勾配下での吸光度を対照群に対する百分率に換算した後、Erithacus Software社で購入したGraFit(version 5.0.12)統計処理プログラムを用いて細胞増殖を50%減少させる濃度で求めた。
リネゾリドはモノアミン酸化酵素(monoamine oxidase)に対して非選択的、可逆的阻害剤として作用すると知られており、アドレナリン作用性(adrenergic)あるいはセロトニン作用性(serotonergic)薬物と作用する可能性がある。前記実施例で合成した本発明によるオキサゾリジノン誘導体のmonoamine oxiase(MAO)A型とB型に対する活性阻害を測定した。MAO−GLO assay kitを米国Promega社で購入し、MAO A型とB型酵素は米国Sigma−Aldrich社で購入した。MAO酵素が基質のアミン基(amine)に作用して生じたアルデヒド(aldehyde)反応物からルシフェリンメチルエステル(luciferin methyl ester)が生成される。これに、ルシフェリン検出試薬(luciferin detection reagent)を加えてMAO酵素反応を非活性させる。同一試薬に入っているエステル分解酵素(esterase)とルシフェリン分解酵素(luciferase)はルシフェリン(luciferin)を酸化させて光(light)を生成し、この発光を測定してMAO酵素の活性を測定した。発光はLEADseeker(Amershan Bioscience、Sweden)を用いて測定した。この際、本発明による化合物は3.9〜500uMの化合物存在下でMAO活性を測定した後、化合物を処理しない対照群の活性に対する阻害程度を比較した。対照物質としてはリネゾリド(Linezolid)を用いた。本発明による化学式1の化合物のMAOに対する阻害活性を測定する時、酵素活性を50%阻害する化学式1の化合物の濃度、即ち、IC50値(これは阻害定数Kiに係る)を測定して評価することができる。加水分解の相対速度(阻害されない対照群と比較)に対する化学式1の化合物の濃度のログをプロッティングした後、基質加水分解の速度を50%減少させる阻害剤の濃度を求めることができる。
Ki=IC50/{1+([S]/Km)}
上述したように、本発明の新規なオキサゾリジノン誘導体は、MRSAを含む耐性菌に対する抗菌スペクトラムが広く、毒性が低く、対照物質であるリネゾリドに比べて、極めて低い濃度で既存抗生剤に対して耐性を有する黄色ブドウ球菌とエンテロコッカス‐フェカーリスなどに強い抗菌力を示し、特に、リネゾリド耐性エンテロコッカス‐フェカーリスに対して優れた抗菌力を示すため、次世代オキサゾリジノン系抗生剤として有用に用いられることができる。また、本発明の環状アミドキシムまたは環状アミドラゾン基を含むオキサゾリジノン誘導体は、既存の公知された化合物より水に対する溶解度が高いため、経口投与用あるいは注射剤としての開発が容易である。
Claims (7)
- 下記化学式1で表されるオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
[化学式1]
R1は水素、(C1−C6)アルキル、または(C3−C6)シクロアルキルであり;
Yは−O−または−N(R2)−であり;
R2は水素、シアノ、(C1−C6)アルキル、(C3−C6)シクロアルキル、−(CH2)mOC(=O)R11、−(CH2)mC(=O)R12、−(CH2)mC(=S)R12または−SO2R13であり、前記R2のアルキルは(C2−C6)アルケニル、(C2−C6)アルキニル、ハロゲン、ハロ(C1−C6)アルキル、(C1−C6)アルキル(C2−C6)アルキニル、ヒドロキシ、(C3−C6)シクロアルキル及びシアノからなる群から選ばれた一または二つ以上の置換基によってさらに置換され得;
R11乃至R13は互いに独立的に、水素、(C1−C6)アルキル、(C1−C6)アルコキシ、アミノ、(C3−C6)シクロアルキル、(C2−C6)アルケニル、(C2−C6)アルキニルまたは(C1−C6)アルキルカルボニルであり、前記R11乃至R13のアルキル、アルコキシまたはアミノはハロゲン、アミノ、ヒドロキシ、シアノ、(C1−C6)アルキル、(C1−C6)アルキルカルボニルオキシ及びヒドロキシ(C1−C6)アルキルから選ばれた一または二つ以上の置換基によってさらに置換され得;
mは0〜2の整数であり;
X1及びX2は互いに独立的に、水素またはフッ素であり;
Pは−O−または−NH−であるか、または下記構造の5員の芳香族複素環であり;
R5及びR6は互いに独立的に、水素、(C1−C6)アルキル、(C3−C6)シクロアルキルまたは(C2−C6)アルケニルであり;
R7は水素、ハロゲン、(C1−C6)アルキルまたは(C3−C6)シクロアルキルであり;
前記R3乃至R7のアルキルは、ヒドロキシ、シアノ、ハロゲン、(C1−C6)アルキルカルボニルオキシ及びアミノからなる群から選ばれた一または二つ以上の置換基によってさらに置換され得る。) - 下記化学式2または3で表される請求項1に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
[化学式2]
- 下記化学式4乃至6で表される請求項2に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
[化学式4]
R2は水素、シアノ、(C1−C6)アルキル、(C3−C6)シクロアルキル、−(CH2)mOC(=O)R11、−(CH2)mC(=O)R12、−(CH2)mC(=S)R12または−SO2R13であり、前記R2のアルキルは(C2−C6)アルケニル、(C2−C6)アルキニル、ハロゲン、ハロ(C1−C6)アルキル、(C1−C6)アルキル(C2−C6)アルキニル、ヒドロキシ、(C3−C6)シクロアルキル及びシアノからなる群から選ばれた一または二つ以上の置換基によってさらに置換され得;
R11乃至R13は互いに独立的に、水素、(C1−C6)アルキル、(C1−C6)アルコキシ、アミノ、(C3−C6)シクロアルキルまたは(C1−C6)アルキルカルボニルであり、前記R11乃至R13のアルキル、アルコキシまたはアミノはハロゲン、アミノ、ヒドロキシ、シアノ、(C1−C6)アルキル、(C1−C6)アルキルカルボニルオキシ及びヒドロキシ(C1−C6)アルキルから選ばれた一または二つ以上の置換基によってさらに置換され得;
mは0〜2の整数であり;
Pは−O−または−NH−であるか、または下記構造の5員の芳香族複素環であり;
R5及びR6は互いに独立的に、水素または(C1−C6)アルキルであり;
前記R3乃至R6のアルキルは、ヒドロキシ、シアノ、ハロゲン、(C1−C6)アルキルカルボニルオキシ及びアミノからなる群から選ばれた一または二つ以上の置換基によってさらに置換され得る。) - 下記化学式7乃至9で表される請求項2に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
[化学式7]
Pは−O−または−NH−であるか、または下記構造の5員の芳香族複素環であり;
R5及びR6は互いに独立的に、水素または(C1−C6)アルキルであり;
前記R3乃至R6のアルキルは、ヒドロキシ、シアノ、ハロゲン、(C1−C6)アルキルカルボニルオキシ及びアミノからなる群から選ばれた一または二つ以上の置換基によってさらに置換され得る。) - 下記化合物から選ばれることを特徴とする請求項3に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
- 下記化合物から選ばれることを特徴とする請求項4に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩。
- 請求項1乃至6の何れか一項に記載のオキサゾリジノン誘導体、その水和物、その溶媒和物、またはそれらの薬学的に許容される塩を有効成分とする抗生剤用医薬組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
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US10583668B2 (en) | 2018-08-07 | 2020-03-10 | Markem-Imaje Corporation | Symbol grouping and striping for wide field matrix laser marking |
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BRPI0918964A2 (pt) | 2015-12-01 |
CA2737299C (en) | 2014-04-01 |
MX2011003118A (es) | 2011-07-20 |
RU2011116164A (ru) | 2012-10-27 |
EP2331529B1 (en) | 2014-11-05 |
KR20100034522A (ko) | 2010-04-01 |
BRPI0918964B1 (pt) | 2021-08-03 |
AU2009297294B2 (en) | 2013-10-31 |
US20110178293A1 (en) | 2011-07-21 |
AU2009297294A1 (en) | 2010-04-01 |
CN102171207A (zh) | 2011-08-31 |
WO2010036000A2 (en) | 2010-04-01 |
EP2331529A2 (en) | 2011-06-15 |
KR101023174B1 (ko) | 2011-03-18 |
EP2331529A4 (en) | 2011-10-19 |
CA2737299A1 (en) | 2010-04-01 |
RU2468023C1 (ru) | 2012-11-27 |
CN102171207B (zh) | 2014-04-16 |
ZA201101894B (en) | 2012-07-25 |
JP2012503599A (ja) | 2012-02-09 |
ES2526120T3 (es) | 2015-01-07 |
US8242113B2 (en) | 2012-08-14 |
WO2010036000A3 (en) | 2010-07-15 |
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