CN1046276C - 取代羟基乙酰基哌嗪苯基唑烷酮酯及其用途 - Google Patents
取代羟基乙酰基哌嗪苯基唑烷酮酯及其用途 Download PDFInfo
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- CN1046276C CN1046276C CN94194241A CN94194241A CN1046276C CN 1046276 C CN1046276 C CN 1046276C CN 94194241 A CN94194241 A CN 94194241A CN 94194241 A CN94194241 A CN 94194241A CN 1046276 C CN1046276 C CN 1046276C
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- Prior art keywords
- methyl
- oxo
- piperazinyl
- oxazolidinyl
- kharophen
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- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
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- 239000000446 fuel Substances 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- YLNSNVGRSIOCEU-UHFFFAOYSA-N oxiran-2-ylmethyl butanoate Chemical compound CCCC(=O)OCC1CO1 YLNSNVGRSIOCEU-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了结构式Ⅰ所示的取代羟基乙酰基哌嗪苯基唑烷酮酯或其药学上可接受的盐,其中各取代基定义详见说明书。该化合物为水溶性的,可用作抗微生物剂,有效地对抗某些人和兽医学致病原,包括多重耐药的葡萄球菌、肠球菌和链球菌,以及厌氧菌和类杆菌类和梭状芽胞杆菌类,和抗酸菌如结核分支杆菌。
Description
发明领域
本发明公开了取代的羟基乙酰基哌嗪苯基噁唑烷酮的羧酸酯和磷酸酯。该化合物及其盐为水溶性的,因此它们特别适用于静脉内及口服给药以治疗微生物感染。该化合物可有效地对抗某些人和兽医学致病原,包括多重耐药的葡萄球菌、肠球菌和链球菌,以及厌氧菌如类杆菌类和梭状芽胞杆菌类,和抗酸菌如结核分支杆菌。该化合物是特别有用的,因为它可有效地对抗最后一种菌,该菌已知与人类AIDS感染有关。
技术背景
美国专利5,164,510以及相关的5,225,565和5,182,403公开了用作抗菌剂的5’-二氢吲哚基-5β-酰氨基甲基噁唑烷酮、3-(稠环取代的)苯基-5β-酰氨基甲基噁唑烷酮和3-(氮取代的)苯基-5β-酰氨基甲基噁唑烷酮。
PCT/US93/03570公开了与本发明化合物相似的羟基乙酰基二氮烯苯基噁唑烷酮,只是本发明化合物由羧酸及磷酸酯取代(即,R为-C(O)-R1,-PO3 =或-P(O)(OH)2)并且是水溶性的。
公开了各种噁唑烷酮的其他参考文献包括美国专利4,801,600;4,921,869;Gregory W.A.,et al.,J.Med.Chem.,32,1673-81(1989);Gregory W.A.,et al.,J.Med.Chem.,33,2569-78(1990);Wang C.,et al.,Tetrahedron,45,1323-26(1989);以及Brittelli,et al.,J.Med.Chm.,35,1156(1992)。
欧洲专利公开申请352,781公开了苯基和吡啶基取代的苯基恶唑烷酮。
欧洲专利公开申请316,594公开了3-取代的苯乙烯基恶唑烷酮。
欧洲专利公开申请312,000公开了苯甲基和吡啶基甲基取代的苯基恶唑烷酮。
本发明概述
R为-C(O)-R1,-PO3 =或-P(O)(OH)2;
R1为C1-6烷基,-N(R4)2,C1-6烷基-N(R4)2,-苯基-N(R4)2,-苯基NHC(O)CH2NH2,-C2H4-吗啉基,吡啶基,C1-6烷基-OH,C1-6烷基-OCH3,C1-6烷基C(O)CH3,-O-C1-6烷基-OCH3,可由C1-3烷基取代的C0-3烷基-哌嗪基,咪唑基,C1-6烷基-COOH,-C(CH2OH)2CH3;
R2和R3独立地选自氢或F,只是R2和R3中至少有一个是F;
R4独立地选自氢或C1-6烷基。
优选的本发明化合物中,R为-C(O)-R1,而R1为-CH3、-CH2N(CH3)2、-C2H4-吗啉基或-CH2OH。更优选的本发明化合物为在噁唑烷酮环C5位具有S-构型的旋光纯对映体。
进一步优选的本发明化合物中,R2和R3之一为F,而另一个为氢。
另一方面,本发明公开了一种治疗温血动物微生物感染的方法,该方法包括对需要治疗的温血动物使用有效量的上述式Ⅰ化合物。优选地,该化合物的用量为从约0.1到约100mg/kg体重/天,更优选从约3.0到约50mg/kg体重/天。
本发明的详细描述
本发明公开了定义如上的结构式Ⅰ表示的取代的-羟基乙酰基哌嗪基苯基噁唑烷酮的羧酸和磷酸酯。该化合物可用作抗微生物剂,可有效地对抗某些人和兽医学致病原,包括多重耐药的葡萄球菌、肠球菌和链球菌,以及厌氧菌如类杆菌类和梭状芽胞杆菌类,和抗酸菌如结核分支杆菌。该化合物被设计成水溶性的,以使它们可以静脉内或口服的方式使用。
关于上述定义,C1-6烷基为甲基、乙基、丙基、丁基、戊基、己基及其异构形式。
药学上可接受的盐指有助于本发明化合物给药的盐,包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、乙酸盐、丙酸盐、乳酸盐、甲磺酸盐、马来酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、2-羟基乙基磺酸盐、富马酸盐、钠盐或钾盐、铵盐等。这些盐可以为其水合物形式。
该系列中最优选的化合物应以其噁唑烷酮环C5位具有(S)-构型的旋光纯对映体的形式而被制备。更优选地,该化合物的R2和R3中仅有一个为氟。本发明化合物的水溶性大于1mg/ml,更优选大于4mg/ml。
旋光纯的物质既可通过一些不对称合成得到,也可选择性地通过(例如)由中间体胺12(如实施例1中所述)与合适的光学活性酸如二苯甲酰基酒石酸或10-樟脑磺酸形成的盐的选择性结晶而由外消旋混合物拆分,接着用碱处理而得到旋光纯的胺。
用过量的哌嗪处理商业上可获得的二氟硝基苯可得到置换产物。用甲酸铵-Pd/C试剂体系或氢-Pd/C还原硝基得到苯胺衍生物。将该苯胺衍生物保护得到双-(苄氧羰基)(CBZ)衍生物,将其在-78到-15℃用THF或乙醚中的nBuLi处理,然后加入丁酸缩水甘油酯,并将该混合物在20℃搅拌过夜,得到光学活性的5-(R)-羟基甲基噁唑烷酮。将5-(R)-羟基甲基噁唑烷酮在常规条件下甲磺酰化,得到甲磺酸酯(Mesylate),将其用叠氮化钠进行温和的置换,形成叠氮化物。在Pd/C存在下将该叠氮化物加氢还原成胺,可用乙酸酐和吡啶将该胺就地乙酰化,得到CBZ-保护的噁唑烷酮中间体,(S)-N-3-((3-氟-4-(4-(苄酯基)-1-哌嗪基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺。更优选地,氨甲基噁唑烷酮制备如下:用苯邻二甲酰亚胺基钾置换甲磺酸酯得到苯邻二甲酰亚胺,用含水甲胺处理该苯邻二甲酰亚胺得到该胺。
用Pd/C和氢将N-苄酯基脱保护,得到类似物制备的关键中间体,(S)-N-3-((3-氟-4-(1-哌嗪基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(22)。
这些化合物经肠胃外、皮肤表面及口服给药,可治疗人及其他温血动物的微生物感染。
通过使用标准及常规的技术将本发明式Ⅰ化合物与药学上可接受的固体或液体载体以及(任意地)与药学上可接受的辅助剂和赋形剂混合可制备本发明的药物组合物。固体形式的组合物包括粉末、片剂、可分散颗粒剂、胶囊、扁囊剂和栓剂。固体载体可为至少一种也可作为稀释剂、调味剂、加溶剂、润滑剂、悬浮剂、粘合剂、片剂崩解剂和色胶剂的物质。惰性固体载体包括碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、纤维素、低溶点蜡、可可脂等。液体形式组合物包括溶液、悬浮液和乳液。例如,将本发明化合物溶于水和水-丙二醇和水-聚乙二醇体系可得到溶液,其中可任选地含有合适的常用着色剂、调味剂、稳定剂和增稠剂。
优选地,使用常规技术得到含有效或适当量的活性组分、即本发明式Ⅰ化合物的单剂量形式的药物组合物。
活性组分、即本发明式Ⅰ化合物在药物组合物及其单剂量形式中的量可根据特定的用途、特定的化合物的效力、使用的浓度而有很大的不同或可被大范围地调节。通常,活性化合物的量在组合物的0.5%到90%重量的范围内。
在处理或消除温血动物的细菌感染的治疗中,该化合物或其药物组合物应该以可在被处理的动物体内获得并保持抗菌有效的浓度、即活性组分的量或血药浓度的剂量口服和/或肠胃外给药。通常,这样的活性组分抗菌有效剂量在约0.1到约100、优选约3.0到约50mg/kg体重/天的范围内。显然,该剂量可根据所治疗的对象、被处理的细菌感染的严重程度以及所使用的特定化合物而有变化。而且,显然,根据具体情况,所使用的首次剂量可被增加至较高的水平以迅速达到所需的血药浓度,或者首次剂量可小于最佳剂量,并在治疗过程中逐渐增加日剂量。如果需要,也可将日剂量分成多次给药,例如每天二到四次。
本发明式Ⅰ化合物可被肠胃外给药、即通过注射,例如,通过静脉内注射或通过其他肠胃外途径给药。肠胃外给药的药物组合物通常应含有溶于药学上可接受的液体载体(如注射用水)药学上可接受量的式Ⅰ化合物的可溶性盐(酸加成盐或碱加成盐)和可提供合适的(例如PH约为3-7的)缓冲的等渗溶液的缓冲液。合适的缓冲剂包括(例如但不限于)正磷酸三钠、碳酸氢钠、柠檬酸钠、N-甲基葡糖胺、L(+)-赖氨酸和L(+)-精氨酸。通常将足够量的式Ⅰ化合物溶于这些载体中得到浓度范围为约1mg/ml到约400mg/ml的可注射的药学上可接受的溶液。所得到的液体药物组合物以可获得上述抗菌有效的剂量给药。
由于其水溶性,本发明式Ⅰ化合物有利于以固体及液体剂型口服给药。
使用Murine Assay的方法试验体内抗微生物的活性。将使用前刚刚软化并悬浮在含4%啤酒酵母UC9213的脑心浸液中(金黄色葡萄球菌)或者悬浮在脑心浸液中(链球菌类)的细菌注射于数组雌性小鼠(每组六只18-20克重量的小鼠)的腹膜内。注射后一小时和五小时时,通过插管法口服或皮下(“Subcut”)给药,以每种药六种剂量作抗菌处理。在六天内每天观察存活情况。使用几元(Probit)分析计算基于死亡率的ED50值。将本发明化合物与作为对照的抗生素(万古霉素)比较。其数值如表1所示。
表1
实施例化合物的体内活性
实施例 | ED50mg/kg | 万古霉素ED50mg/kg(subcut.) | 途径 |
1 | 5/4 | 2 | 口服/皮下 |
2 | 9/15 | 5 | 口服/皮下 |
3 | 16/8 | 8 | 口服/皮下 |
4 | 2/2 | 2 | 口服/皮下 |
5 | 7/5 | 5 | 口服/皮下 |
6 | 2/2 | 2 | 口服/皮下 |
7 | >20/1 | 6 | 口服/皮下 |
8 | 10/6 | 5 | 口服/皮下 |
9 | 2/3 | 1 | 口服/皮下 |
10 | 1/2 | 3 | 口服/皮下 |
11 | 8/8 | 4 | 口服/皮下 |
12 | 12/>20 | 5 | 口服/皮下 |
13 | >20/>20 | 4 | 口服/皮下 |
14 | 3 | 2 | 口服 |
16 | 4 | 2 | 口服 |
17 | 5/2 | 2/1 | 口服/皮下 |
18 | 14/>20 | 10 | 口服/皮下 |
20 | 6/4 | 6 | 口服/皮下 |
21 | 8/13 | 3 | 口服/皮下 |
22 | >18/4 | 3 | 口服/皮下 |
23 | 2/1 | 3 | 口服/皮下 |
24 | 1 | 2 | 口服 |
25 | 8/15 | 6 | 口服/皮下 |
26 | 6/3 | 2 | 口服/皮下 |
27 | 6 | 5 | 口服 |
29 | 9 | 4 | 口服 |
表1中各实施例化合物的结构示于下表2中。
表2
实施例 | R | R2 | R3 |
1 | C(O)-C2H4-吗啉基 | H | F |
2 | C(O)-3-吡啶基 | H | F |
3 | C(O)-3-吡啶基 | F | F |
4 | C(O)-1-咪唑基 | H | F |
5 | C(O)-1-咪唑基 | F | F |
6 | C(O)OC2H4OCH3 | H | F |
7 | C(O)P-N(CH3)2Ph | H | F |
8 | C(O)p·N(CH3)2Ph | F | F |
9 | C(O)CH2N(CH3)2 | H | F |
10 | C(O)CH2N(CH3)2 | F | F |
11 | C(O)(CH2)2N(CH3)2 | H | F |
12 | C(O)(CH2)3N(CH3)2 | H | F |
13 | C(O)CH2-4-甲基-1-哌嗪基 | H | F |
14 | C(O)CH3 | F | F |
15 | C(O)C2H4C(O)OH | F | F |
16 | C(O)C2H4C(O)O-Na+ | F | F |
17 | C(O)C2H4C(O)OH | H | F |
18 | C(O)C2H4C(O)CH3 | F | F |
19 | C(O)C2H4C(O)CH3 | H | F |
20 | P(O)(OH)2 | H | F |
21 | C(O)P-NH2Ph | H | F |
22 | C(O)C(CH3)(CH2OH)2 | H | F |
23 | C(O)CH2OH | H | F |
24 | C(O)CH2OH | F | F |
25 | C(O)CH2OCH3 | H | F |
26 | C(O)C2H4-4-吗啉基 | F | F |
27 | C(O)CH2-4-吗啉基 | H | F |
28 | C(O)p[NHC(O)CH2N(CH3)2]Ph | H | F |
29 | C(O)p-NHC(O)CH2NH2 | H | F |
30 | C(O)CH3 | H | F |
实施例1:(S)-3-(4-吗啉基)丙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯
在一个3升容量的3颈烧瓶上安装机械搅拌器、温度计和氮气入口管,在其中装入45.789g(S)-N-〔〔3-氟-4-(1-哌嗪基)苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺和1.3升CH2Cl。将混合物在冰浴中冷却并在氮气氛下加入38ml三乙胺,然后经填加漏斗在35分钟内加入28ml苄氧基乙酰氯,撤去冰浴。1.5小时后,加入500ml水。将液层分离,异将有机相用500ml水洗涤。将水层用二氯甲烷萃取,并将合并的有机相干燥,浓缩,得到沉淀产物。将其收集,过滤并用二氯甲烷洗涤,得到57.48g纯的(S)-N-〔〔3-氟-4-(4-(苄氧乙酰基)-1-哌嗪基)苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺。
在一个5L烧瓶中装入29.04g该产物和2L33%二氯甲烷/甲醇(v/v),抽真空,填充氮气。将8.1g 10%钯/碳以在50ml二氯甲烷/甲醇(1∶2,v/v)中的浆状物的形式加入,并将烧瓶抽真空填充氮气,然后再抽真空并再填充氢气。将反应混合物搅拌过夜,将烧瓶抽真空并填充氮气,将该混合物用硅藻土过滤,将滤饼用33%二氯甲烷/甲醇(v/v)洗涤,浓缩,得到白色固体。将该固体通过柱色谱法(在氯仿中填充硅胶)纯化,用3-11%甲醇/氯仿梯度洗脱,得到白色泡沫状固体。将该固体置于10%甲醇/乙酸乙酯中,浓缩至干数次,得到无定形白色固体-20.448g(86.5%)(S)-N-〔〔〔3-氟-4-(4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺,mp176-177℃,(下文中称为“中间体”)。
将421mg(1.07mmol)中间体溶于21ml吡啶中。在该溶液中加入13mgDMAP、268mg(2.14mmol)3-吗啉丙酸和411mg(2.14mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐。将反应物在室温在N2气氛下搅拌15小时。之后,反应已完全,将反应物真空浓缩。通过硅胶色谱法(30g硅胶,用0.5-4%MeOH/CHCl3洗脱)将粗产物纯化两次。浓缩纯产物级分后,得到372mg(65%)玻璃状标题化合物白色固体。mp:87-90℃。水中溶解度(PH7,磷酸盐缓冲液)为36mg/ml。实施例2:(S)-烟酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯。
将251mg(0.637mmol)实施例1得到的中间体、258mg(1.35mmol)1-乙基-3-(3-二甲氨基)丙基碳化二亚胺、169mg(1.37mmol)烟酸和催化量的4-二甲氨基吡啶在5.0ml吡啶中的混合物在室温下搅拌24小时。之后,将混合物在真空下浓缩并将得到的粗产物置于二氯甲烷中,装入23.5cm×2.5cm40-63μ硅胶柱中。将柱子用乙酸乙酯、5%甲醇/乙酸乙酯、10%甲醇/乙酸乙酯和20%甲醇/乙酸乙酯(各250ml)洗脱。将适当的级分合得到300mg(94%)标题化合物,为白色泡沫状固体。此固体在80-85℃变成玻璃状油,在173-175℃熔化。水中溶解度(PH7,磷酸盐缓冲液)为0.3mg/ml,但成盐后将有更高的溶解度。实施例3:烟酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-5-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-6
按照与实施2相同的步骤,由(S)-N-〔〔3-〔3,5-二氟-4-〔4-羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(制备在实施例15中描述,以77%的收率制得标题化合物(mp=213-214℃)。水中溶解度(PH7,磷酸盐缓冲液)为0.05mg/ml,但成盐后会有更高的溶解度。实施例4:(S)-1H-咪唑-1-甲酸2-〔4-〔4-〔5〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将246mg(0.624mmol)实施例1中得到的中间体和304mg(1.875mmol)羰基二咪唑在10ml四氢呋喃中的混合物搅拌过夜。将形成的沉淀从溶液中滤出,洗涤、干燥,得到251mg(82%收率)的标题化合物(mp=188-189℃)。水中溶解度(pH7,磷酸盐缓冲液)为1.4mg/ml。实施例5:(S)-1H-咪唑-1-甲酸2-〔4-〔-4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
按照与实施例4相同的步骤,由(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基乙酰胺(制备过程在实施例15中描述)以82%的收率制得标题化合物(mp=199-200℃)。实施例6:(S)-碳酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯/2-甲氧乙基酯
向175mg(0.444mmol)实施例1中得到的中间体在5.0ml二氯甲烷中的溶液中,在0℃、氮气氛下加入0.25ml(1.79mmol)三乙胺,接着加入129mg(0.931mmol)氯甲酸2-甲氧乙基酯溶于0.5ml二氯甲烷形成的溶液。隔夜将此混合物缓慢升至室温。搅拌过夜后,加入5ml 1N HCl,将形成的溶剂层分离。将水层用二氯甲烷萃取(2×5ml)。将合并的有机相用盐水洗涤,用MgSO4干燥,然后浓缩成油状物。将此粗产物装入24cm×2.5cm 40-63μ硅胶柱中,用乙酸乙酯(300ml)、5%甲醇/乙酸乙酯、10%甲醇/乙酸乙酯、15%甲醇/乙酸乙酯和20%乙醇乙酯(各250ml)洗脱。将适当级分合并,得到170mg(77%收率)标题化合物,它为泡沫状白色固体。部分固体在沸乙酸乙酯中结晶,得到65mg(65%收率)的标题化合物固体结晶(mp=149-151℃)。水中溶解度(PH7,磷酸盐缓冲液)为2.9mg/ml。实施例7:(S)-4-二甲氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将251mg(0.637mmol)实施例1中得到的中间体、181mg(0.944mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺、181mg(1.10mmol)4-二甲基氨基苯甲酸和催化量的4二甲氨基吡啶在3.0ml吡啶中的混合物在室温下搅拌过夜。之后,再加入151mg(0.914mmol)4-二甲氨基苯甲酸,继续搅拌过夜。之后,再加入89mg(0.464mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺。将此混合物在室温下搅拌5天,然后在50℃油浴中温热1小时。然后将此反应不完全的混合物在真空下浓缩。将得到的粗产物置于二氯甲烷中,并装入24cm×2.5cm 40-63μ硅胶柱中,将此柱用乙酸乙酯(250ml)、10%甲醇/乙酸乙酯(500ml)、15%甲醇/乙酸乙酯(250ml)和20%甲醇/乙酸乙酯(500ml)洗脱。将适当的级分合并,得到95mg(41%)白色固体,将其在乙酸乙酯中研制,得到75mg(32%)标题化合物,它为白色固体(mp=210-211℃)。水中溶解度(PH7,磷酸盐缓冲液)为0.01mg/ml,但它的盐会有更高的水中溶解度。实施例8:(S)-4-二甲氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
按照实施例7的步骤,由(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(制备于实施例15中描述)以59%的收率得到标题化合物(mp=199-202℃)。水中溶解度(PH7,磷酸盐缓冲液)为0.01mg/ml,但成盐后有更高的水中溶解度。
实施例9:(S)-N,N-二甲基-甘氨酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将实施例1中得到的中间体(250mg,0.634mmol)溶于8ml无水吡啶中,然后加入乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(243mg,1.27mmol)、DMAP(16mg,0.127mmol)和N,N-二甲基甘氨酸(131mg,1.27mmol)。将此混合物在氮气氛下在室温搅拌18小时。然后在减压条件下将溶剂除去,得到胶状残余物。将残余物溶于CH2Cl2,用水和盐水洗涤。将有机相分离并用无水Na2SO4干燥,将溶液过滤并浓缩,得到一固体,在CH2Cl2/Et2O中重结晶使其纯化,分离得到220mg标题化合物,为白色固体。mp=158-159℃。水中溶解度(PH7,磷酸盐缓冲液)为150mg/ml。实施例10:(S)-N,N-二甲基甘氨酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
此物质用与实施例9相同的方法制备,但原料为(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(制备在实施例15中描述),mp=171-172℃。水中溶解度(PH7,磷酸盐缓冲液)为4.2mg/ml。实施例11:(S)-3-(二甲氨基)丙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将3-(二甲氨基)丙酸甲酯12.0g,15.2mmol)用NaOH(18.2mmol,1.ON溶液)回流处理2小时,使其水解成为酸。将此溶液用冰浴冷却到0℃,并且用1.0NHCl(18.2mmol)处理。将此溶液冻干成为蜡状固体,无需任何纯化将在以后使用。
将实施例1得到的中间体(400mg,1.02mmol)溶解于10ml无水吡啶中,将此溶液用3-(二甲氨基)丙酸(粗料,239mg,2.04mmol)、乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐(391mg,2.04mmol)和DMAP(25mg,0.204mmol)处理。此混合物在室温、氮气氛下搅拌2.5天。之后将此反应混合物在减压下浓缩,得到固体状残余物,将此残余物混入CH2Cl2中,形成淤浆状物,然后用水和盐水洗涤。将澄清的油相分离,并用无水Na2SO4干燥,将此无水溶液过滤,浓缩至胶状,用CH2Cl2/Et2O重结晶纯化,分离出296mg预期产物,它为暗白色固体。mp=136-137℃。实施例12:(S)-4-(二甲氨基)丁酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将实施例1中得到的中间体(400mg,1.01mmol)溶于10ml无水吡啶中,此溶液用4-(二甲氨基)丁酸盐酸盐(341mg,2.03mmol)、乙基-3-(3-二甲氨基丙基)碳化二亚胺(389mg、2.03mmol)和DMAP(248mg,2.03mmol)处理。将此混合物在室温、N2下搅拌40小时,之后将反应混合物在减压条件下浓缩,得到胶状残余物。将此残余物溶于CH2Cl2中,随后用水和盐水洗涤。分离油相,用无水Na2SO4干燥,过滤,浓缩,得到玻璃状残余物,于CH2Cl2/Et2O中重结晶纯化。分离得到178mg预期产物,它为白色固体。mp=69-71℃。水中溶解度(PH7,磷酸盐缓冲液)为34.6mg/ml。实施例13:(S)-(4-甲基-1-哌嗪基)乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氨代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将实施例1中得到的中间体(400mg,1.01mmol)溶于12ml无水CH2Cl2中,并将此溶液在冰浴中冷却到0℃。然后加入无水吡啶(92mg,1.16mmol),接着用注射器滴加入氯乙酰氯(131mg,1.16mmol)。30分钟后,将混合物加热到微沸回流1小时。将反应物冷却,加入分液漏斗中,同时加入CH2Cl2。将溶液用1%盐酸、水和盐水洗涤。将有机相用无水Na2SO4干燥。过滤并浓缩成为泡沫状物体,通过在CH2Cl2/Et2O中重结晶来纯化。分离得到407mg中间体的氯乙酸酯,mp=173-174℃。
将此氯乙酸酯中间体(303mg,0.643mmol)溶解于7ml无水CH3CN中,并将此溶液在冰浴中冷却到0℃。然后加入N-甲基哌嗪(258mg,2.57mmol),并将混合物在0℃下搅拌1小时,接着在室温温热3小时,之后,TLC检测显示起始物已耗尽。将反应混合物加入分液漏斗中,同时加入CH2Cl2。将此溶液用水和盐水洗涤,有机相用无水Na2SO4干燥。过滤并浓缩,得到玻璃状残余物,通过在CH2Cl2/Et2O中重结晶来纯化。分离得到198mg期望产物,它为白色固体。mp=128-129℃,水中溶解度(PH7,磷酸盐缓冲液)为79.1mg/ml。实施例14:(S)-乙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1哌嗪基)-2-氧代乙基酯
将二氟哌嗪噁唑烷酮的三氟乙酸盐(在实施例15中制备)(0.454g,0.969mmol)和碳酸钾10.159g,2.27mmol)溶于3ml二氯甲烷中制成溶液,将此溶液在氮气氛下冷却到0℃。然后用注射器在3分钟内滴加入乙酸基乙酰氯(0.125ml,1.16mmol)。将此溶液逐渐升至室温,并搅拌48小时。由于存在有残余的起始物,因而再加入乙酰氧基乙酰氯(0.1ml,0.93mmol),并将反应混合物再搅拌2.5小时。然后将反应混合物过滤并蒸馏,得到0.371g粗产物,然后在硅胶柱上纯化(40-63μ,2.5×24cm,用5%甲醇/乙酸乙酯装柱并洗脱,收集15ml级分),得到0.107g(24%)预期产物,它为白色固体,mp193-195℃,同时得到0.096g(28%收率)二氟哌嗪噁唑烷酮游离碱。水中溶解度(PH7,磷酸盐缓冲液)为1.6mg/ml。实施例15:(S)-琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯
第1部分表示本发明的二氟代中间体的制备步骤。第一部分:(a)三氟甲磺酸2,6-二氟-4-硝基苯酯。
将2,6-二氟-4-硝基苯酚(31.55g,180.19mmol)同CH2Cl2(300ml)和吡啶(29.15ml,360.38mmol)合并,将得到的浆状物在冰浴中冷却到0℃,然后在45分钟内滴加入三氟甲磺酸酐(31.8ml,189.2mmol)。将反应物在0℃下搅拌2小时,然后放入冰箱(5℃)过夜。用TLC(15%EtOAc/己烷,UV短波)测定反应完全后,将混合物在减压下浓缩,然后用H2O(50ml)和EtOAc(50ml)处理。再将此混合物用EtOAc(100ml)移至分液漏斗中,然后用1NHCl洗涤直至洗出液为酸性(2×100ml)。将水相用EtOAc(2×200ml)反萃取。将EtOAc萃取液合并,然后再用1NHCl(400ml)洗涤,再用盐水洗涤1次(400ml)。将有机相用无水Na2SO4干燥,过滤并浓缩,得到54.092g金红色油状物。虽然该油状物用NMR检测时是纯的,但仍将其与另外两次操作的粗产物合并,将其用以5%EtOAc填充的硅胶(550g)色谱提纯,用5%EtOAc和10%EtOAc各2L洗脱,得到浅黄色油状标题化合物,总收率为95%,HRM5(M+)(C7H2F5NO5S):计算值306.9574,实测值306.9590。(b)1-(叔丁氧基羰基)-4-(2,6-二氟-4-硝基苯基)哌嗪将三氟甲磺酸2,6-二氟-4-硝基苯酯(55g,179mmol)溶于无水DMF中(275ml),用1-(叔丁氧羰基)哌嗪(45.71g,250mmol)处理。得到的亮黄色溶液在加入N,N-二异丙基乙胺(47ml,269mmol)后变为桔黄色。此反应物在N2下加热回流15小时。用TLC(30%EtOAc/己烷,UV短波)测定反应完全后,将此混合物浓缩至干,并和另一反应粗产物合并纯化。将粗产物溶于热CH2Cl2中(420ml,一些与产物无关的物质不溶解)然后在三个不同的柱子上用色谱法纯化(2个柱子装750g硅胶,用CH2Cl2装180ml粗产物,并用1%,5%EtOAc/CH2Cl2各1L洗脱;另一个柱子用CH2Cl2填充250g硅胶,装60ml化合物,并用2.5%和5%EtOAc/CH2Cl2洗脱)得到收率为87%的标题化合物,它为桔黄色固体,HRM5(M+)(C15H19F2N3O4):计算值343.1343,实测值343.1358。(c)1-(叔丁氧基羰基)-4-〔2,6-二氟-4-(苄氧羰基)氨基苯基〕哌嗪
在2L烧瓶中,将1-(叔丁氧羰基)-4-(2,6-二氟-4-硝基苯基)哌嗪(44.7g,130mmol)溶于20%THF/MeOH(600ml)中。在冰浴冷却下,分批加入甲酸铵(41g,651mmol),接着加入10%pd-C(1.12g,2.5重量%)。添加完毕后撤去冰浴,烧瓶微微变热,黄色消失。1.5小时后用TLC(30%EtOAc/己烷,UV短波)测定反应已完全。将反应混合物用硅藻土过滤(用500ml MeOH洗涤滤饼)。将滤液减压浓缩得到一固体,用1L EtOAc和500ml H2O处理。将液层分离,然后将有机层再用H2O(500ml)洗涤,再用盐水(500ml)洗涤一次。将水相用EtOAc(2×300ml)反萃取。将合并的有机萃取液用无水Na2SO4干燥。过滤、浓缩得到黄色固体(40.8g),将其在N2下立刻溶于无水DMF(500ml)中,并用(冰/MeOH浴)冷却到-20℃。将此溶液用N,N-二甲基苯胺(20.6mL,163mmol)处理,接着滴加入氯甲酸苄酯(21.5mL,143mmol)。将冰浴消耗过夜。用TLC(30%EtOAc/己烷,UV短波)测定反应已完全,然后将混合物浓缩成黄色油状物,溶于1L EtOAc中,然后用H2O(500ml)和盐水(500mL)洗涤。水相用EtOAc(2×300mL)反萃取。将合并的有机相萃取液用无水Na2SO4干燥,过滤、浓缩,得到黄色油状物。将粗产物在热EtOAc/己烷中重结晶,得到39.11g(67%)标题化合物,它为浅黄色结晶固体,mp171-172℃。(d)〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲醇
将1-(叔丁氧基羰基)-4-(2,6-二氟-4-(苄氧基羰基)氨基苯基)哌嗪(14.05g,31mmol)溶于无水THF(150ml)中,然后冷却至-78℃(干冰/丙酮)。然后向反应物中在25分钟内滴加入n-BuLi(21.6mL,35mmol)。将反应物在-78℃搅拌30分钟,然后在7分钟内滴加入(R)-(-)-丁酸缩水甘油酯(4.89mL,35mmol)。将此反应物在-78℃维持15分钟,然后撤去冰浴。使反应物缓慢温热至室温过夜。用TLC(5%MeOH/CHCl3,UV短波)测定反应已完全。将反应混合物用500mL CH2Cl2稀释,然后用H2O(3×300mL)和盐水(300mL)洗涤。水相用CH2Cl2(3×400mL)反萃取。将合并的有机萃取液用无水Na2SO4干燥,过滤并浓缩,得到奶黄色固体。将粗产物在热EtOAc/己烷中重结晶纯化,得到11.063g(85%)标题化合物,它为白色固体。mp164-166℃。(e)对甲苯磺酸〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕酯
将〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲醇(24.2g,59mmol)溶于吡啶中,并冷却至0℃(冰浴)。加入新重结晶的对甲苯磺酰氯(13.4g,70mmol),将反应物在N2气氛下在0℃搅拌2.5小时。然后塞好烧瓶,置于冰箱(5℃)中过夜,反应混合物变成淡粉色浆状物。用TLC测出显示仍残留有一些醇,在反应物中再加入对甲苯磺酰氯(1.12g,5.85mmol)、催化剂4-(二甲氨基)吡啶和20mL无水CH2Cl2(以便于搅拌)。0℃下搅拌4小时后,用TLC(5%MeOH/CHCl3,UV短波)测出反应已完全。将该混合物加到750ml冰水,通过抽吸过滤漏斗得到预期产物,用水(1L)和乙醚(500mL)洗涤,在真空下干燥后,得到29.921g(90%)标题化合物,它为白色固体,mp150.5-151.5℃。
(f)甲磺酸〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕酯
将〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲醇(3.831g,9.27mmol)溶于CH2Cl2(40mL)中,冷却至0℃,并在N2气氛下用三乙胺(1.74g,2.4ml,17.22mmol)处理。在1分钟内缓慢加入甲磺酰氯(1.48g,1mL,12.92mmol)。半小时后用TLC分析(2%丙酮/CH2Cl2)表明反应已完全,将反应混合物用CH2Cl2(200ml)稀释,用水(3×50mL)和盐水(50ml)洗涤,用Na2SO4干燥,过滤,在真空下干燥,得到灰白色固体标题化合物,HRMS(M+)(C20H27F2N3O7S):计算值491.1538,实测值491.1543。(g)〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕叠氮化物
将对甲苯磺酸〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕酯(29.661g,52mmol)溶于无水DMF(125ML)中,然后在室温下用固体NaN3(10.19g,156mmol)处理。将反应物加热到60℃计3小时,然后在N2气氛下自然冷却到室温过夜,用TLC法(30%EtOAc/己烷,跑两次,UV短波)测定到反应已完全。将反应混合物在真空下浓缩,得到乳白色固体。将此粗产物溶于600mL EtOAc中,然后用H2O(2×500mL)和盐水(500mL)洗涤,水相再用EtOAc(2×400mL)反萃取,将合并的有机萃取液用无水Na2SO4干燥,过滤并在真空下浓缩,得到22.41g(91%)标题化合物,它为浅黄色固体,mp115-117℃。
使用基本相同的条件,相应的甲磺酸酯转变成相同的叠氮化物。(h)N-〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺
将〔〔3-〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕叠氮化物(22.4g,51mmol)溶于1L EtOAc中,然后在N2气氛下脱气3次。接着加入10%Pd-C(4.48g,20%重量),换成H2(用气球)前再脱气三次(用N2)。3小时后,用TLC(20%MeOH/CHCl3,UV短波)测定反应已完全。此时加入吡啶(8.26mL,102mmol),随后用醋酐(9.64mL,102mmol)处理。将反应混合物在室温下搅拌过夜。用TLC(20Me OH/C2HCl3/UV短波)测定反应已完全。将该混合物用硅藻土过滤(滤饼用EtOAc500mL洗涤),将滤液浓缩至近600mL,用H2O(2×500mL)和盐水(500mL)洗涤。将水相用EtOAc(2×500mL)反萃取,将合并的有机萃取液用无水Na2SO4干燥,过滤并浓缩,得到黄色固体。将此粗产物在热CHCl3和己烷中重结晶,得到19.167g(83%)标题二氟化合物,它为白色固体,mp177-179℃第二部分:将(S)-N-〔〔3,〔3,5-二氟-4-〔4-(叔丁氧羰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(7.1g,15.6mmol)溶于CH2Cl2(20ml)中,然后加入冷的三氟乙酸溶液(24mL)。将该反应物在N2气氛下在0℃搅拌15分钟,然后撤去冰浴。在室温下搅拌2小时后,用TLC(10%MeOH/CHCl3,UV短波)测得此反应已完全。将此溶液在真空下蒸干,得到棕色胶质固体。将此固体溶于30%H2O/丙酮中,然后分批加入NaHCO3(7.87g,93.7mmol)处理。将此反应物在室温下搅拌20分钟,然后将此三氟乙酸酯用在4分钟内滴加的苄氧乙酰氯(3.70mL,23.4mmol)处理。将此反应混合物在室温下、在N2气氛下搅拌过夜。将此反应混合物用EtOAc(400mL)移至分液漏斗中,然后用水(3×250mL)、饱和NaHCO3(250mL)和盐水(250mL)洗涤。水相用EtOAc和CH2Cl2反萃取,将有机层用无水Na2SO4干燥,过滤、浓缩,得到黄色固体。将此固体吸收于硅胶(25g)上,用硅胶色谱法(200gSG)纯化。用溶于10%CH3CN/CHCl3中的1-4%的甲醇梯度来洗脱,得到5.85g(75%)(S)-N-〔〔3-〔3,5-二氟-4-〔4-(苄氧乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺,它为白色固体,熔点172-173℃。
随后,将(S)-N-〔〔3-〔3,5-二氟-4-〔4-(苄氧乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(3.84g,7.6mmol)溶于热10%EtOAc/MeOH(150mL)中。在N2气氛下脱气三次后,加入Pearlman催化剂(384mg,10%重量)。再将溶液脱气,然后氢气置换。将反应液在室温下搅拌4.5小时。此刻用TLC法(10%MeOH/CHCl3,UV短波)测定表明反应已完全。将溶液用硅藻土过滤,用EtOAc(250ml)洗涤滤饼,将滤液减压浓缩,得到白色固体。将此产物以硅胶(150g)色谱法纯化,以溶于10%CH3CN/CHCl3中的1-6、10%的甲醇梯度洗脱,得到3.078g(98%)(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺,它为白色固体,熔点160.5-162.5℃。
称取上述制备的产物(0.247g,0.599mmol)、琥珀酐(0.092g,0.919mmol)和4-二甲氨基吡啶(0.024g,0.196mmol)置于火焰烤干的烧瓶中。加入吡啶(10ml),并将此溶液置于氮气氛中,搅拌24小时后反应仍未完全,于是再加入琥珀酐(0.096g,0.959mmol)。将反应混合物在室温下再搅拌2小时,然后加热回流35分钟。将溶液通过球管到球管(bulb to bulb)的蒸馏得到粗产物,为胶状油。向粗产物中加入水(35ml)和二氯甲烷(65ml)。将液层分离,将有机相用饱和碳酸氢钠(35ml)萃取。将水层用3M盐酸酸化,然后用乙酸乙酯3×35ml萃取。将有机层合并,用MgSO4干燥,蒸干,得到预期产物,为白色固体(0.169g),仍有微量琥珀酸杂染。由于收率低,所以将水层用饱和碳酸氢钠碱化,用二氯甲烷(30ml)萃取。将水层再用3M盐酸酸化,用乙酸乙酯(3×35ml)萃取。将有机相蒸干,得到0.161g白色固体,其中含有预期产物和乙酸以及琥珀酸。将第一批产物在甲醇中重结晶得到0.120g(39%)白色固体,mp143-144℃。将第二批产物先经过柱色谱法纯化(硅胶,40×63μ,2ml移液吸管,用5%甲醇/乙酸乙酯装柱,用乙酸乙酯、5%和20%甲醇/乙酸乙酯洗脱,收集2ml流出液),然后在甲醇和氯仿中重结晶,得到另外0.078g(25%)预期产物,它为白色固体。水中溶解度(PH7,磷酸盐缓冲液)为12.3mg/ml。实施例16:(S)-琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯,钠盐
将实施例15的产物溶于1ml 0.14M碳酸氢钠和5ml水中。然后将该溶液冷冻并凉干,得到0.032g(41%)白色胶状预期产物。实施例17:(S)-琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯
将实施例1中得到的中间体(0.267g,0.677mmol)的吡啶溶液(5ml)、琥珀酐(0.075g,0.749mmol)和4-二甲氨基吡啶在氮气氛下搅拌6天。虽经TLC法测试表明仍有噁唑烷存在,但将反应物处理,在高真空中将吡啶蒸去,将残余物置于乙酸乙酯(15ml)和饱和碳酸氢钠(35ml)中。将液层分离,将水层用3M盐酸酸化到PH为1,然后用乙酸乙酯(5×15ml)萃取。将萃取液合并,用MgSO4干燥,蒸干,得到0.135g微粉色固体。由于收率低,将水层再用乙酸乙酯(5×15ml)萃取,将萃取液用MgSO4干燥,蒸干,得到0.177g白色固体。将此两种固体合并并进行上述处理,以提纯此物质。即,将此固体溶于10ml饱和碳酸氢钠和15ml乙酸乙酯中。将液层分离,将水相用3M盐酸酸化,用乙酸乙酯(5×10ml)萃取。将有机相用MgSO4干燥,蒸干,得到预期产物(0.130g,39%),它为白色固体,mp67-70℃。水中溶解度(pH7,磷酸盐缓冲液)为28mg/ml。实施例18:(S)-4-氧代-戊酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙酯
称取(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(制备在实施例15中描述)(0.178g,0.432mmol)、乙基-3-(3-二甲氨基)丙基碳化二亚胺盐酸盐(0.161g,0.839mmol)和4-二甲氨基吡啶(0.007g,0.057mmol),置于火焰干燥过的烧瓶中。加入吡啶(3mL),然后将系统置于氮气氛下,加入乙酰丙酸(0.07ml,0.683mmol)。搅拌5天后,在高真空下蒸去吡啶,得到粗产物,它为黄色油。将该粗产物在高效硅胶柱上精制(硅胶,40×63μ,2ml移液吸管,用乙酸乙酯装柱,用二氯甲烷、乙酸乙酯和5%甲醇/乙酸乙酯洗脱,收集1ml流出液)。通过第二根柱子使质量再提高(mp,硅胶,40×63μ,1.5×27cm,用乙酸乙酯填装,用乙酸乙酯和5%甲醇/乙酸乙酯洗脱,收集20ml流出液),得到白色固体,仍轻微量杂质。将此固体在乙酸乙酯中重结晶,得到0.152g(69%)预期产物,它为白色固体,mp130-133℃。水中溶解度(PH7,磷酸盐缓冲液)为1.2mg/ml。实施例19:(S)-4-氧代-戊酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基单酯
称取实施例1中得到的中间体(0.100g,0.253mmol)、乙基-3-(3-二甲氨基)丙基碳化亚二胺盐酸盐(0.091g、0.475mmol)和4-二甲氨基吡啶(0.005g,0.041mmol),置于火焰干燥过的烧瓶中。加入吡啶(3ml)和乙酰丙酸(0.04ml,0.391mmol),并将系统置于氮气氛下。搅拌2天后,在高真空下将吡啶蒸去,将残余物在硅胶柱上纯化(40×63μ,1.5×25cm,用乙酰乙酯装柱,用二氯甲烷和甲醇加料,用乙酸乙酯和5%甲醇/乙酸乙酯洗脱,收集15ml流出液),得到0.136g预期产物,在乙酸乙酯中重结晶,得到0.074g(59%)预期产物,为白色固体,mp135.5-138℃。水中溶解度(PH7,磷酸盐缓冲液)为2.29mg/ml。实施例20:(S)-磷酸2-(4-(4-(5-((-乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯
将实施例1中得到的中间体(200mg,0.51mmol)溶于无水乙腈(20mL)中,在氮气氛下冷却,用1H-四唑(Aldrich)处理并搅拌。在另一烧瓶中,将N,N-二乙基氨基磷酸二苄基酯(483mg,152mmol)溶于7ml无水乙腈中,并通过套管移至上述反应混合物中,搅拌20小时。将烧瓶在冰浴中冷却30分钟,将混合物用间-氯过苯甲酸处理。5分钟后,将冰浴撤去,将混合物搅拌1.5小时,之后将混合物冷却到0℃,以15mg亚硫酸钠于10mL PH7缓冲液中的溶液处理。将该混合物用二氯甲烷稀释,用水和饱和亚硫酸钠溶液萃取。将有机层用Na2SO4干燥,在真空下浓缩,得到无色油状物。将其用径向展开色谱法精制(以二氯甲烷-甲醇体系洗脱),得到250mg(75%)中间体-磷酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯/二苄酯它为白包硬泡沫,TLC∶Rf=0.51(20∶1二氯甲烷-甲醇)。高分辨质谱(C32H36FN4O8P):计算值655.2333,实测值655.2347。
随后,将上步得到的中间体(350mg,0.54mmol)溶于5mL甲醇中,形成透明的无色溶液,它含有少量不溶的无定形固体物。将此溶液在大气压下以100mg 10%钯-碳和氢气处理16小时。将此混合物用硅藻土过滤,用甲醇洗涤滤饼,在真空下浓缩,得到硬泡沫。将此产物用水溶解,过滤、冻干,得到白色固体,mp119-122℃,水中溶解度(PH7,磷酸盐缓冲液)为25.7mg/ml。实施例21:(S)-4-氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将956mg(2.426mmol)实施例1中得到的中间体和0.7ml(5.03mmol)三乙胺于20ml二氯甲烷中形成混合物,一次加入固体状553mg(2.980mmol)4-硝基苯甲酰氯。将此混合物在室温下搅拌21.5小时。此刻加入10ml 1N HCl,并将液层分离。将水层用二氯甲烷(4×10mL)萃取;将合并的有机层用盐水洗涤,干燥(MgSO4),在真空中浓缩。将得到的泡沫状固体置于二氯甲烷中,装于24cm×2.5cm 40-63μ硅胶柱上,以乙酸乙酯(250ml)、10%甲醇/乙酸乙酯(250ml)、20%甲醇/乙酸乙酯(250ml)和10%甲醇/二氯甲烷(250ml)洗脱。将适当的级分合并,得到1.082g 4-硝基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯(S)它为黄色固体,收率82%(mp=222-224℃)。
随后,将845mg(1.555mmol)此产物和460mg 10%钯-碳置于100ml甲醇/二氯甲烷(1∶1)中,在氢气氛(从气球)下搅拌2小时。然后将混合物用硅藻土过滤,将滤饼用70ml-甲醇/二氯甲烷(1∶1)洗涤。将滤液在真空中浓缩,得到765mg(96%粗收率)泡沫状固体。将550mg此固体置于二氯甲烷中,并装于9cm×2.5cm 70-230目硅胶柱上。用500mL 10%甲醇/乙酸乙酯洗脱。将合并级分部分浓缩后,有沉淀折出。用抽滤将沉淀收集,得到352mg白色固体。浓缩滤液再得到29mg此化合物。浓缩终滤液得到165mg标题化合物,为玻璃状固体。过硅胶柱共得到546mg标题化合物(收率99%),此白色固体在110℃-115℃变为玻璃状固体,在>215℃时为自由流动的液态。水中溶解度(PH7,磷酸盐缓冲液)为0.03mg/ml,成盐后会更高。实施例22:(S)-2,2-二(羟甲基)丙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将183mg(0.46mmol)实施例1中得到的中间体和146mg(0.46mmol)2,2-二(苄氧甲基)丙酸于5mL吡啶中的溶液,在氮气氛中搅拌下加入98mg(0.51mmol)1-乙基-3-(3-二甲氨丙基)碳化二亚胺和57mg(0.46mmol)二甲氨基吡啶。72小时后,将溶剂在真空中蒸去,得到黄色油状物。将其用硅胶色谱法纯化(用二氯甲烷-甲醇体系洗脱)。此过程得到82mg(26%)白色硬泡沫固体。TLC∶Rf=0.59(20∶1二氯甲烷-甲醇)
在氮气氛下,将此产物160mg(0.23mmol)溶于7mL甲醇中,用50mg 10%钯-碳和常压氢气处理。16小时后,将此混合物用硅藻土过滤,在真空中浓缩,得到无色油状物。将此产物用径向色谱法纯化(以二氯甲烷-甲醇体系洗脱),得到99mg(85%)预期产物,为白色硬泡沫固体。TLC∶Rf=0.26(20∶1二氯甲烷-甲醇)水中溶解度(PH7,磷酸盐缓冲液)为13mg/ml。实施例23:(S)-羟基乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
在0℃下,向200mg(0.508mmol)U-100592(实施例1)、149mg(1.47mmol,0.205mL)和5mL二氯甲烷混合物中滴加入苄氧基乙酰氯。将反应物缓慢升至室温。搅拌5小时后,加入5mL 1N HCl,将形成的液层分离。将水层用二氯甲烷(3×5mL)萃取。将合并的有机相用盐水洗涤,干燥(MgSO4),然后过滤、浓缩,得到白色固体。将此粗产物溶于少量二氯甲烷和甲醇中,装于22cm×2.5cm 40-63μ的硅胶柱上。用乙酸乙酯、2%甲醇/乙酸乙酯、4%甲醇/乙酸乙酯、6%甲醇/乙酸乙酯、8%甲醇/乙酸乙酯和10%甲醇/乙酸乙酯(各250mL)洗脱。将适当的级分合并,得到120mg(44%)苄氧基乙酸2-〔4-〔4-〔5(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯(S);为白色固体(mp=146-148℃)。
将此产物170mg(0.314mmol)、15mL甲醇、3mL二氯甲烷和100mg 10%钯催化剂混合。将此反应烧瓶用氢气抽真空3次,并在氢气下搅拌过夜。将此反应物用滤器真空滤,除去钯催化剂,浓缩,得到130mg(93%收率)标题化合物(mp=105-107℃)。水中溶解度(PH7,磷酸盐缓冲液)为4.2mg/ml。实施例24:羟基乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
按与实施例23相同的步骤,用(S)-N-〔3-〔3,5-二氟-4-〔4-(羟乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(制备在实施例15中描述)来制备苄氧乙酸2-〔4-〔4-〔5〔(乙酰氨基)甲基〕-2-氧代-3-恶唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯(S),收率为62%(mp=155-157℃)。按与实施例23相同的步骤,由苄氧基乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯(S)来制备标题化合物,收率为76%(mp=106-108℃)。实施例25:(S)-甲氧基乙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-二氟苯基)-1-哌嗪基)-2-氧代乙基酯
将(S)-N-〔〔3-〔3-氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰胺(263mg,0.67mmol)混入无水CH2Cl2(10mL)中,用冰浴冷却到0℃,加入吡啶(0.216mL,2.67mmol)后溶液成均相。接着,加入甲氧基乙酰氯(0.064mL,0.69mmol)。将反应物在0℃搅拌30分钟后撤去冰浴。1小时后,用TLC法(10%MeOH/CHCl3,UV短波)测定表明反应已完全。将反应混合液用CH2Cl2(100mL)稀释,并用1N HCl/盐水(各50mL)、饱和NaHCO3/盐水(各50mL)和盐水(100mL)洗涤。将各水相再用CH2Cl2(2×25mL)反萃取。将有机层合并,用无水Na2SO4干燥,过滤,减压浓缩,得到桔黄色固体。此固体用硅胶(35g)色谱法纯化(用在10%CH3CN/CHCl3中的1-5%MeOH梯度洗脱),得到桔黄色固体。将后得到的固体溶于少量的CH2Cl2/MeOH中使其重结晶,然后用乙醚研制,得到158mg(51%)标题化合物,为灰白色固体,mp147-148℃,水中溶解度(PH7,磷酸盐缓冲液)为6.4mg/ml。实施例26:(S)-3-(N-吗啉基)丙酸2-(4-(4-(5-((乙酰氨基)甲基)-2氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基酯
将(S)-N-〔〔3-〔3,5-二氟-4-〔4-(羟基乙酰基)-1-哌嗪基〕苯基〕-2-氧代-5-噁唑烷基〕甲基〕乙酰氨(制备于实施例15中描述)250mg(0.607mmol)溶于10mL吡啶中。在该溶液中加入13mg DMAP/192mg(1.21mmol)3-(N-吗啉基)丙酸和232mg(1.21mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺盐酸盐。将此反应在室温、N2气氛中搅拌15小时。这时反应已完全,在真空下浓缩。将粗产物用硅胶色谱法纯化(10g硅胶,用1-4%MeOH/CHCl3洗脱)。回收的产物(367mg)含有少量脲类副产物。将250mg此产物再通过径向色谱法(用1-66%MeOH/CHCl3洗脱)纯化。浓缩后,得到210mg分析纯产物,为玻璃状白色固体。回收得到(92%)玻璃状白色标题化合物。mp:139-142℃。
FTIR(mull):cm-13450(br),1754,1665,1514,1450,1247,1120,1032,836,元素分析:计算值C25H33F2N6O7·1/3 H2O:C,53.66;H,6.02;N,12.52.实测值C,53.66;H,6.01;N,12.55.水中溶解度(pH7,磷酸盐缓冲液)8.2mg/ml.
MS(EI):m/z(rel.int.)553[M+](1),478(7),229(19),158(17),100(66),56(53),43(100).[α]=-7°(c=9.67,CHCl3).实施例27:(S)-(4-吗啉基)乙酸2-(4-(4-(5-((乙酰氨基)-甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯
将140mg(0.272mmol)U-103676于3mL无水乙腈中的溶液用52mg(0.598mmol)吗啉搅拌处理18小时。将此混合物用二氯甲烷稀释,然后用水萃取,得到一灰白色固体。将此物质用硅胶色谱法纯化(用甲醇-二氯甲烷洗脱),得到115mg(81%)预期产物,它为白色固体。TLC∶Rf=0.33(20∶1二氯甲烷-甲醇)。高分辨质谱(C24H32FN5O7):计算值521.2286,实测值521.2288。水中溶解度(PH7,磷酸盐缓冲液)为55.3mg/mL。实施例28:(S)-4-N-(N,N-二甲基甘氨酰基)氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将204mg(0.398mmol)实施例21中得到的标题化合物、催化量(<10mg)的4-二甲氨基吡啶(DMAP)、156mg(0.814mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺和147mg(1.05mmol)N,N-二甲基甘氨酸在2.5ml吡啶中混合,在室温下搅拌过夜。将此混合物在真空下浓缩。将得到的粗产物用5ml饱和碳酸氢钠水溶液和20ml水处理,然后用二氯甲烷萃取(4×20ml)。将有机层合并,用盐水洗涤,干燥(MgSO4),然后用23cm×2.5cm,40-63μ硅胶柱纯化(用5%甲醇/二氯甲烷(1L)洗脱),得到175mg(74%)预期化合物,为泡沫状固体。将来自不同份的泡沫状固体用10%甲醇/乙酸乙酯研制,得到白色固体,mp=180-182℃。水中溶解度(PH7,磷酸盐缓冲液)为0.09mg/ml,成盐时会更高。实施例29:(S)-4-N-(甘氨酰基)氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)-甲基-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
步骤1:将100mg(0.195mmol)实施例21的标题化合物、243mg(1.27mmol)1-乙基-3-(3-二甲氨基丙基)碳化二亚胺和269mg(1.29mmol)N-CBZ-甘氨酸的混合物于4.0mL吡啶中与催化量(<10mg)4-二甲氨基吡啶(DMAP)在室温下一起搅拌过夜。将此混合物在真空中浓缩,并将得到的粗产物于23cm×2.5cm,40-63μ硅胶柱纯化(用甲醇∶二氯甲烷梯度(500ml 2.5%MeOH/CH2Cl2、500ML5%MeOH/CH2Cl2、500ML 10%MeOH/CH2Cl2)洗脱,得到135mg(99%)4-N-(N-苄氧羰基甘氨酰基)氨基苯甲酸2-〔4-〔4-〔5-〔乙酰氨基)甲基〕-2-氧代-3-恶唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯(S)为白色固体。元素分析:计算值:C,59.65;H,5.29;N,11.93。实测值:C,59.73;H,5.35;N,11.54。
步骤2:将此产物275mg(0.391mmol)和置于75ml甲醇和55ml二氯甲烷中的170mg 10%钯-碳混合,在氢气氛(气球)下搅拌过夜。将此混合物用硅藻土过滤,滤液在真空中浓缩。在温水浴中,将得到的固体用甲醇研制,然后冷却,将固体抽滤收集,得到211mg(95%收率)预期产物,为灰白色固体(mp:240℃,分解)。水中溶解度(PH7,磷酸盐缓冲液)为9.8mg/ml。实施例30:(S)-乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯
将519mg实施例1的中间体在2.5ml无水乙酐和10ml吡啶中的混合物在室温下搅拌2小时。将混合物在真空中浓缩,得到白色固体。将其用24.5×2.5cm,40-63μ硅胶柱纯化,用500ml10%甲醇/乙酸乙酯和400ml 15%甲醇/乙酸乙酯洗脱(25ml级分)。将适当的级分合并,在真空下浓缩,得到540mg(94%)标题化合物,为白色泡沫状固体。将此固体用15ml 10%甲醇/乙酸乙酯研制,抽滤收集固体,真空干燥,得到436mg(76%)标题化合物,为白色细粉(mp=199-201℃)。
Claims (9)
2.如权利要求1的化合物,其中R为-C(O)R1,R1如权利要求1所定义。
3.权利要求2的化合物,其中R1为-CH3、-CH2N(CH3)2、
-C2H1-吗啉基或-CH2OH。
4.权利要求1的化合物,其中R为-P(O)(OH)2。
5.权利要求1的化合物,其中R为-PO3 =。
6.权利要求1的化合物,其中该化合物为在噁唑烷酮环C5位具有S-构型的旋光纯的对映体。
7.权利要求1的化合物,其中R2和R3之一为F,而另一个为氢。
8.权利要求1的化合物,其中该化合物为:
1)3-(4-吗啉基)丙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
2)烟酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S);
3)烟酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S);
4)1H-咪唑-1-甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S);
5)1H-咪唑-1-甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S);
6)碳酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯/2-甲氧乙基酯,(S);
7)4-二甲氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
8)4-二甲氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
9)N,N-二甲基甘氨酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
10)N,N-二甲基甘氨酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
11)3-(二甲氨基)丙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
12)4-(二甲氨基)丁酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
13)(4-甲基-1-哌嗪基)乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
14)乙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S)-;
15)琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯,(S);
16)琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯,钠盐(S);
17)琥珀酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基单酯,(S);
18)4-氧代-戊酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
19)4-氧代-戊酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基单酯,(S);
20)磷酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
21)4-氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌噻基〕-2-氧代乙基酯,(S)-;
22)2,2-双(羟甲基)丙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
23)羟基乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S);
24)羟基乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2,6-二氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
25)甲氧基乙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
26)3-(N-吗啉基)丙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2,6-二氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
27)(4-吗啉基)乙酸2-(4-(4-(5-((乙酰氨基)甲基)-2-氧代-3-噁唑烷基)-2-氟苯基)-1-哌嗪基)-2-氧代乙基酯,(S);
28)4-N-(N,N-二甲基甘氨酰基)氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;
29)4-N-(甘氨酰基)氨基苯甲酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-;或
30)乙酸2-〔4-〔4-〔5-〔(乙酰氨基)甲基〕-2-氧代-3-噁唑烷基〕-2-氟苯基〕-1-哌嗪基〕-2-氧代乙基酯,(S)-。
9.权利要求1的式Ⅰ化合物制备用于治疗温血动物微生物感染的药物的用途。
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Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX9703543A (es) * | 1994-11-15 | 1997-08-30 | Upjohn Co | Antibacterianos de oxazina biciclica y oxazolidinona tiazina. |
DE69631347T2 (de) * | 1995-09-15 | 2004-10-07 | Upjohn Co | Aminoaryl oxazolidinone n-oxide |
ZA969622B (en) * | 1995-12-13 | 1998-05-15 | Upjohn Co | Oxazolidinone antibacterial agents having a six-membered heteroaromatic ring. |
GB9601666D0 (en) * | 1996-01-27 | 1996-03-27 | Zeneca Ltd | Chemical compounds |
GB9702213D0 (en) | 1996-02-24 | 1997-03-26 | Zeneca Ltd | Chemical compounds |
MY116093A (en) * | 1996-02-26 | 2003-11-28 | Upjohn Co | Azolyl piperazinyl phenyl oxazolidinone antimicrobials |
GB9609919D0 (en) | 1996-05-11 | 1996-07-17 | Zeneca Ltd | Chemical compounds |
GB9614236D0 (en) * | 1996-07-06 | 1996-09-04 | Zeneca Ltd | Chemical compounds |
GB9614238D0 (en) * | 1996-07-06 | 1996-09-04 | Zeneca Ltd | Chemical compounds |
GB9717807D0 (en) * | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
GB9717804D0 (en) | 1997-08-22 | 1997-10-29 | Zeneca Ltd | Chemical compounds |
DK1030852T3 (da) * | 1997-11-12 | 2003-12-22 | Upjohn Co | Oxazolidinonderivater og farmaceutiske præparater |
US6040306A (en) * | 1997-11-18 | 2000-03-21 | Pharmacia & Upjohn Company | Method of treating psoriasis, arthritis and reducing the toxicity of cancer chemotherapy |
AU780197B2 (en) * | 1997-11-18 | 2005-03-10 | Pharmacia & Upjohn Company | Method of treating psoriasis, arthritis and reducing the toxicity of cancer chemotherapy |
WO1999025344A1 (en) * | 1997-11-18 | 1999-05-27 | Pharmacia & Upjohn Company | Use of oxazolidinone derivatives for treating psoriasis, arthritis and reducing the toxicity of cancer chemotherapy |
DK1304107T3 (da) * | 1997-11-18 | 2005-08-22 | Pharmacia & Upjohn Co Llc | Anvendelse af oxozolidinonderivater til behandling af psoriasis |
GB9725244D0 (en) | 1997-11-29 | 1998-01-28 | Zeneca Ltd | Chemical compounds |
BR9907183A (pt) | 1998-01-23 | 2003-06-10 | Versicor Inc | Colet neas combinatórias de oxazolidinona, composições e processos de preparação |
US6562844B2 (en) | 1998-01-23 | 2003-05-13 | Pharmacia & Upjohn Company | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
US7002020B1 (en) | 1998-01-23 | 2006-02-21 | Pharmacia & Upjohn Company | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
JP2002503655A (ja) * | 1998-02-13 | 2002-02-05 | ファルマシア・アンド・アップジョン・カンパニー | 抗菌剤として有用な置換アミノフェニルイソオキサゾリン誘導体 |
AU753988B2 (en) | 1998-06-05 | 2002-10-31 | Astrazeneca Ab | Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them |
MY122454A (en) * | 1998-06-05 | 2006-04-29 | Upjohn Co | Use of oxazolidinones for the preparation of a medicament for transdermal delivery |
CN1305374A (zh) * | 1998-07-14 | 2001-07-25 | 法玛西雅厄普约翰美国公司 | 治疗眼部感染的噁唑烷酮 |
AR020660A1 (es) * | 1998-09-30 | 2002-05-22 | Alcon Lab Inc | Composiciones antibioticas para el tratamiento de ojos, oidos y nariz |
JP2002535680A (ja) | 1999-01-27 | 2002-10-22 | ファルマシア・アンド・アップジョン・カンパニー | 延長因子p活性モジュレーターのアッセイ方法 |
GB9928568D0 (en) | 1999-12-03 | 2000-02-02 | Zeneca Ltd | Chemical compounds |
PE20010851A1 (es) * | 1999-12-14 | 2001-08-17 | Upjohn Co | Esteres del acido benzoico de oxazolidinonas que tienen un substituyente hidroxiacetilpiperazina |
US6642238B2 (en) | 2000-02-10 | 2003-11-04 | Pharmacia And Upjohn Company | Oxazolidinone thioamides with piperazine amide substituents |
GB0009803D0 (en) * | 2000-04-25 | 2000-06-07 | Astrazeneca Ab | Chemical compounds |
HUP0301562A2 (hu) | 2000-06-05 | 2003-12-29 | Dong A Pharm. Co., Ltd. | Új oxazolidinonszármazékok és eljárás ezek előállítására, ezeket tartalmazó gyógyszerkészítmények |
US6734307B2 (en) * | 2000-07-17 | 2004-05-11 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
PE20020300A1 (es) * | 2000-08-22 | 2002-05-10 | Pharmacia Corp | Composicion de solucion de un farmaco antibiotico a base de oxazolidinona con mejoramiento de la carga de farmaco |
PE20020578A1 (es) | 2000-10-10 | 2002-08-14 | Upjohn Co | Una composicion de antibiotico topico para el tratamiento de infecciones oculares |
US6861433B2 (en) | 2000-12-15 | 2005-03-01 | Pharmacia & Upjohn Company | Oxazolidinone photoaffinity probes |
EP1409464A4 (en) * | 2001-07-16 | 2005-11-02 | Ranbaxy Lab Ltd | OXAZOLIDINONE DERIVATIVES AS POTENTIAL ANTIMICROBIALS |
US6956040B2 (en) | 2001-07-16 | 2005-10-18 | Ranbaxy Laboratories Limited | Oxazolidinone piperazinyl derivatives as potential antimicrobials |
TW200302095A (en) * | 2002-01-25 | 2003-08-01 | Upjohn Co | Oxazolidinone cotherapy |
BR0307898A (pt) * | 2002-02-22 | 2004-12-07 | Pharmacia Corp | Formulações de droga antibiótica oftálmica contendo um composto de ciclodextrina e cloreto de cetil piridìnio |
US7141588B2 (en) * | 2002-02-25 | 2006-11-28 | Pfizer, Inc. | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
AR038536A1 (es) * | 2002-02-25 | 2005-01-19 | Upjohn Co | N-aril-2-oxazolidinona-5- carboxamidas y sus derivados |
JP2005527575A (ja) * | 2002-03-29 | 2005-09-15 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | 糖尿病性足病変感染を治療するためのオキサゾリジノンの非経口、静脈内および経口投与 |
WO2004014897A1 (en) * | 2002-08-12 | 2004-02-19 | Pharmacia & Upjohn Company Llc | N-aryl-2-oxazolidinones and their derivatives |
AU2003253141A1 (en) * | 2002-08-22 | 2004-03-11 | Orchid Chemicals And Pharmaceuticals Ltd | Novel antibacterial agents |
WO2004026848A1 (en) * | 2002-09-20 | 2004-04-01 | Lupin Limited | Oxazolidinone derivatives, process for their preperation and their use as antimycobacterial agents |
AR042086A1 (es) | 2002-11-21 | 2005-06-08 | Upjohn Co | N-aril-2- oxazolidinon -5- carboxamidas y sus derivados, usados como agentes antibacterianos |
AU2002357561A1 (en) * | 2002-12-30 | 2004-07-22 | Nanjing Chang'ao Pharmaceutical Science And Technology Limited Company | Oxazolidine derivative, methods of preparation and uses |
US20040170686A1 (en) * | 2003-01-31 | 2004-09-02 | Fredrickson Jennifer K. | Suspension vehicle for coated drug particles |
EP1594494A1 (en) * | 2003-02-07 | 2005-11-16 | Warner-Lambert Company LLC | Oxazolidinone derivatives n-substituted by a bicyclic ring, for use as antibacterial agents |
JP2006516991A (ja) * | 2003-02-07 | 2006-07-13 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | 抗菌剤 |
US20040191326A1 (en) * | 2003-03-31 | 2004-09-30 | Reo Joseph P. | Taste-masking vehicle for coated oxazolidinone particles |
US20040204463A1 (en) * | 2003-04-01 | 2004-10-14 | Harris Christina Renee | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
EP1660488A1 (en) * | 2003-08-25 | 2006-05-31 | Warner-Lambert Company LLC | Novel antimicrobial aryloxazolidinone compounds |
US7304050B2 (en) * | 2003-09-16 | 2007-12-04 | Pfizer Inc. | Antibacterial agents |
KR100854211B1 (ko) | 2003-12-18 | 2008-08-26 | 동아제약주식회사 | 신규한 옥사졸리디논 유도체, 그의 제조방법 및 이를유효성분으로 하는 항생제용 약학 조성물 |
WO2008061954A1 (en) * | 2006-11-23 | 2008-05-29 | Agfa Graphics Nv | Novel co-initiators |
EP1925609A1 (en) * | 2006-11-23 | 2008-05-28 | Agfa Graphics N.V. | Novel-co-initiators |
KR101023174B1 (ko) * | 2008-09-24 | 2011-03-18 | 주식회사 레고켐 바이오사이언스 | 사이클릭 아미독심 또는 사이클릭 아미드라존 기를 가지는 신규한 옥사졸리디논 유도체 및 이를 함유하는 의약 조성물 |
KR101674146B1 (ko) | 2008-10-10 | 2016-11-08 | 머크 샤프 앤드 돔 코포레이션 | 옥사졸리디논 및 이를 포함하는 조성물을 제조하는 방법 |
CA2751392C (en) | 2009-02-03 | 2017-03-28 | Trius Therapeutics, Inc. | Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate |
WO2010103281A1 (en) * | 2009-03-13 | 2010-09-16 | Sun Chemical B.V. | Cyclic carbamate compounds useful in energy-curable compositions |
US8580767B2 (en) | 2009-05-28 | 2013-11-12 | Trius Therapeutics, Inc. | Oxazolidinone containing dimer compounds, compositions and methods to make and use |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0352781A2 (en) * | 1988-07-29 | 1990-01-31 | The Du Pont Merck Pharmaceutical Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
WO1993009103A1 (en) * | 1991-11-01 | 1993-05-13 | The Upjohn Company | Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents |
WO1993023384A1 (en) * | 1992-05-08 | 1993-11-25 | The Upjohn Company | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4801600A (en) * | 1987-10-09 | 1989-01-31 | E. I. Du Pont De Nemours And Company | Aminomethyl oxooxazolidinyl cycloalkylbenzene derivatives useful as antibacterial agents |
US4921869A (en) * | 1987-10-09 | 1990-05-01 | E. I. Du Pont De Nemours And Company | Aminomethyl oxooxazolidinyl cycloalkylbenzene derivatives useful as antibacterial agents |
CA1320730C (en) * | 1987-10-16 | 1993-07-27 | The Du Pont Merck Pharmaceutical Company | Aminomethyl oxooxazolidinyl aroylbenzene derivatives useful as antibacterial agents |
EP0316594B1 (en) * | 1987-10-21 | 1993-09-29 | The Du Pont Merck Pharmaceutical Company | Aminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents |
US5164510A (en) * | 1988-09-15 | 1992-11-17 | The Upjohn Company | 5'Indolinyl-5β-amidomethyloxazolidin-2-ones |
US5225565A (en) * | 1988-09-15 | 1993-07-06 | The Upjohn Company | Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones |
US5182403A (en) * | 1988-09-15 | 1993-01-26 | The Upjohn Company | Substituted 3(5'indazolyl) oxazolidin-2-ones |
-
1994
- 1994-09-27 CA CA002174107A patent/CA2174107C/en not_active Expired - Fee Related
- 1994-09-27 CN CN94194241A patent/CN1046276C/zh not_active Expired - Fee Related
- 1994-09-27 KR KR1019960702714A patent/KR100312903B1/ko not_active IP Right Cessation
- 1994-09-27 WO PCT/US1994/010582 patent/WO1995014684A1/en active IP Right Grant
- 1994-09-27 JP JP51504895A patent/JP3698724B2/ja not_active Expired - Fee Related
- 1994-09-27 US US08/640,899 patent/US5652238A/en not_active Expired - Fee Related
- 1994-09-27 DE DE69419523T patent/DE69419523T2/de not_active Expired - Fee Related
- 1994-09-27 AU AU80103/94A patent/AU698699B2/en not_active Ceased
- 1994-09-27 EP EP94931278A patent/EP0730591B1/en not_active Expired - Lifetime
- 1994-09-27 AT AT94931278T patent/ATE182142T1/de not_active IP Right Cessation
- 1994-09-27 DK DK94931278T patent/DK0730591T3/da active
- 1994-09-27 NZ NZ274966A patent/NZ274966A/en unknown
- 1994-09-27 ES ES94931278T patent/ES2133588T3/es not_active Expired - Lifetime
- 1994-10-07 ZA ZA947885A patent/ZA947885B/xx unknown
- 1994-10-10 IL IL11121594A patent/IL111215A0/xx unknown
- 1994-10-13 TW TW083109509A patent/TW427987B/zh not_active IP Right Cessation
- 1994-11-17 CO CO94052446A patent/CO4290433A1/es unknown
- 1994-11-17 PE PE1994254930A patent/PE22896A1/es not_active Application Discontinuation
-
1999
- 1999-10-07 GR GR990402509T patent/GR3031420T3/el unknown
-
2000
- 2000-07-14 LV LVP-00-91A patent/LV12538B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0352781A2 (en) * | 1988-07-29 | 1990-01-31 | The Du Pont Merck Pharmaceutical Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
WO1993009103A1 (en) * | 1991-11-01 | 1993-05-13 | The Upjohn Company | Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents |
WO1993023384A1 (en) * | 1992-05-08 | 1993-11-25 | The Upjohn Company | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
Also Published As
Publication number | Publication date |
---|---|
AU698699B2 (en) | 1998-11-05 |
DK0730591T3 (da) | 2000-01-31 |
CA2174107C (en) | 2005-04-12 |
DE69419523T2 (de) | 1999-11-25 |
KR960705818A (ko) | 1996-11-08 |
ATE182142T1 (de) | 1999-07-15 |
LV12538B (en) | 2000-12-20 |
JPH09505582A (ja) | 1997-06-03 |
ZA947885B (en) | 1996-04-09 |
LV12538A (en) | 2000-10-20 |
TW427987B (en) | 2001-04-01 |
EP0730591B1 (en) | 1999-07-14 |
ES2133588T3 (es) | 1999-09-16 |
NZ274966A (en) | 1998-01-26 |
GR3031420T3 (en) | 2000-01-31 |
WO1995014684A1 (en) | 1995-06-01 |
DE69419523D1 (en) | 1999-08-19 |
CN1135752A (zh) | 1996-11-13 |
CA2174107A1 (en) | 1995-06-01 |
CO4290433A1 (es) | 1996-04-17 |
IL111215A0 (en) | 1994-12-29 |
JP3698724B2 (ja) | 2005-09-21 |
KR100312903B1 (ko) | 2002-02-28 |
AU8010394A (en) | 1995-06-13 |
EP0730591A1 (en) | 1996-09-11 |
US5652238A (en) | 1997-07-29 |
PE22896A1 (es) | 1996-06-07 |
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