CN102106184A - 取代的哌啶子基苯基噁唑烷酮 - Google Patents
取代的哌啶子基苯基噁唑烷酮 Download PDFInfo
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- CN102106184A CN102106184A CN2007800165498A CN200780016549A CN102106184A CN 102106184 A CN102106184 A CN 102106184A CN 2007800165498 A CN2007800165498 A CN 2007800165498A CN 200780016549 A CN200780016549 A CN 200780016549A CN 102106184 A CN102106184 A CN 102106184A
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- pharmaceutically acceptable
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- DNRCUMDULWDBQC-UHFFFAOYSA-N 3-phenyl-4-piperidin-1-yl-1,3-oxazolidin-2-one Chemical class O=C1OCC(N2CCCCC2)N1C1=CC=CC=C1 DNRCUMDULWDBQC-UHFFFAOYSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 238000000034 method Methods 0.000 claims abstract description 43
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims description 23
- -1 difluoro propyl Chemical group 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
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- 241001148470 aerobic bacillus Species 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000001540 azides Chemical class 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 238000003682 fluorination reaction Methods 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
- YRYSAWZMIRQUBO-UHFFFAOYSA-N trimethylsulfoxonium Chemical compound C[S+](C)(C)=O YRYSAWZMIRQUBO-UHFFFAOYSA-N 0.000 claims description 3
- VUYQBMXVCZBVHP-UHFFFAOYSA-N 1,1-difluoroethanol Chemical compound CC(O)(F)F VUYQBMXVCZBVHP-UHFFFAOYSA-N 0.000 claims description 2
- HDBGBTNNPRCVND-UHFFFAOYSA-N 3,3,3-trifluoropropan-1-ol Chemical compound OCCC(F)(F)F HDBGBTNNPRCVND-UHFFFAOYSA-N 0.000 claims description 2
- ZFXCSCVQYQCJAT-UHFFFAOYSA-N CCN([S])CC Chemical compound CCN([S])CC ZFXCSCVQYQCJAT-UHFFFAOYSA-N 0.000 claims description 2
- COTOUBYYTMGCGA-UHFFFAOYSA-N CN(C)[S] Chemical compound CN(C)[S] COTOUBYYTMGCGA-UHFFFAOYSA-N 0.000 claims description 2
- 241000192125 Firmicutes Species 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- DFNWAJAFZZXRHY-UHFFFAOYSA-M I(=O)(=O)[O-].C[S+](=O)(C)C Chemical group I(=O)(=O)[O-].C[S+](=O)(C)C DFNWAJAFZZXRHY-UHFFFAOYSA-M 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
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- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- BNTFCVMJHBNJAR-UHFFFAOYSA-N n,n-diethyl-1,1,2,3,3,3-hexafluoropropan-1-amine Chemical compound CCN(CC)C(F)(F)C(F)C(F)(F)F BNTFCVMJHBNJAR-UHFFFAOYSA-N 0.000 claims description 2
- 229940072033 potash Drugs 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
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- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- WZCZNEGTXVXAAS-UHFFFAOYSA-N trifluoromethanol Chemical compound OC(F)(F)F WZCZNEGTXVXAAS-UHFFFAOYSA-N 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 abstract description 17
- 230000000845 anti-microbial effect Effects 0.000 abstract description 9
- 230000000813 microbial effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000012265 solid product Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 229960003907 linezolid Drugs 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 10
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 5
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Abstract
本发明涉及某些取代的哌啶子基苯基噁唑烷酮。具体说,本发明涉及药动学曲线改善的具有抗微生物活性的双取代的哌啶子基苯基噁唑烷酮。本发明还涉及本发明化合物的制备方法、包含本发明化合物的药物组合物以及利用本发明化合物治疗或预防微生物感染的方法。
Description
发明领域
本发明涉及某些取代的哌啶子基苯基噁唑烷酮。具体说,本发明涉及药动学曲线改善的具有抗微生物活性的双取代的哌啶子基苯基噁唑烷酮。本发明还涉及本发明化合物的制备方法、包含本发明化合物的药物组合物以及利用本发明化合物治疗或预防微生物感染的方法。
发明背景
噁唑烷酮是一类新的合成抗微生物试剂。利奈唑胺是第一种用于临床的该类物质。噁唑烷酮具有抗重要的革兰氏阳性人和动物病原体的活性,这些病原体包括甲氧西林-耐药性金黄色葡萄球菌(MRSA),去甲万古霉素耐药性肠球菌(VRE)和β-内酰胺耐药性肺炎链球菌(PRSP)。噁唑烷酮还具有抗革兰氏阴性好氧菌、革兰氏阳性和革兰氏阴性厌氧菌的活性(Diekema D J等,Lancet 2001;358:1975-82)。
噁唑烷酮也存在一些限制。它们对肠杆菌科没有活性(Zhanel,GG等,Canadian Journal of Infectious Diseases,2001,12:379-390)。而且,对非典型呼吸系统病原体如肺炎支原体、人型支原体、尿素分解脲原体(Ureaplasmaurealyticium)和衣原体属的效能处于边缘范围,在呼吸道感染治疗过程中可能导致不可接受的临床效果(Diekema D.J等,Lancet 2001;358:1975-82)。
利奈唑胺以及正在开发的其潜在地后续物质的临床开发研究和应用过程中出现的其他限制是,该类化合物存在引起骨髓抑制的倾向,导致血小板减少(Kuter D J等,Pharmacotherapy,2001:21:1010-1030)。
噁唑烷酮抑制单胺氧化酶有利于该类化合物的临床应用,伴随用作肾上腺素能或5-羟色胺能试剂和选择性5-羟色胺重吸收抑制剂(Ament P W等,AmFam Physician 2002,65:663-70)。而且,由于其短半衰期,利奈唑胺的给药方案为1天2次。
存在一些描述噁唑烷酮的抗菌活性的参考文献。例如,国际申请(PCT)公开WO95/25106描述了取代的哌啶子基苯基噁唑烷酮。国际申请(PCT)公开WO96/13502描述了具有多取代的吖丁啶基或吡咯烷基部分的苯基噁唑烷酮。美国专利申请04/0063954,国际申请(PCT)公开WO04/007489和WO2004/007488描述了抗微生物应用的哌啶基苯基噁唑烷酮。吡咯烷基(Pyrrodinyl)/哌啶基苯基噁唑烷酮抗菌剂也在Kim H Y等,Bioorg.& Med.Chem.Lett.,(2003),13:2227-2230中描述。国际申请(PCT)公开WO96/35691描述了螺环和双环二嗪基(diazinyl)和卡巴肼基(carbazinyl)噁唑烷酮衍生物,环上杂原子之一是氮。二氮杂并(Diazepeno)苯基噁唑烷酮衍生物在国际申请(PCT)公开WO99/24428中描述。国际申请(PCT)公开WO02/06278描述了取代的氨基哌啶子基苯基噁唑烷酮衍生物。
国际申请(PCT)公开WO04/007488和WO04/007489描述了新的噁唑烷酮类化合物,与先前描述的利奈唑胺及文献中描述的噁唑烷酮类化合物的抑菌活性相比,其抗菌效力提高。不寻常的抗菌活性不仅表现为抗利奈唑胺-敏感菌株的活性,而且第一次能够对抗利奈唑胺耐药菌株,表明不同于核糖核蛋白常规位点的结合和/或靶向多种受体位点。国际申请(PCT)公开WO05/054234描述了体内效力提高的双取代的哌啶苯基噁唑烷酮衍生物。
本发明化合物具有改善的治疗有益的药动学曲线,可调整以开发每天一次给药的噁唑烷酮类化合物。因此,本发明化合物能够为动物提供体内保护,适合临床应用。
发明概述
一方面,提供了式-I的新的哌啶子基取代的苯基噁唑烷酮化合物及其药学上可接受的盐、药学上可接受的溶剂合物、酯、多晶型物、对映异构体或非对映异构体:
式-I
式中,
X是OH或F;和
R是CH3、-(CH2)n-CF3、-(CH2)n-CHF2,其中n是0、1或2。
另一方面,与药学上可接受的载体、赋形剂或稀释剂一起提供了适用于治疗或预防微生物感染的包含所述化合物的药物组合物。
还提供了具有同类型活性的这些化合物的对映异构体、非对映异构体、多晶型物、药学上可接受的盐和药学上可接受的溶剂合物及代谢产物,以及包含所述化合物、其代谢物、对映异构体、非对映异构体、多晶型物、溶剂合物或药学上可接受的盐与药学上可接受的载体和任选地包含赋形剂的药物组合物。
其他方面如下所述,通过这些叙述将部分地显而易见或者通过实践本发明获知。
发明详述
一方面,提供了式I结构的化合物及其药学上可接受的盐、药学上可接受的溶剂合物、酯、多晶型物、对映异构体或非对映异构体:
式-I
式中,
X是OH或F;和
R是CH3、-(CH2)n-CF3、-(CH2)n-CHF2,其中n是0、1或2。
本发明的具体化合物是:
(5S)-N-{3-[3,5-二氟-4-(4-羟基-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺;
(5S)-N-{3-[3,5-二氟-4-(4-氟-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺;
(5S)-N-{3-[3,5-二氟-4-(4-羟基-4-(2,2,2-三氟-乙氧基甲基)-哌啶-1-基)-苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺。
本发明化合物具有适合每天一次给药的显著更好的药动学性质。例如,在狗药动学研究中,本发明化合物(5S)-N-{3-[3,5-二氟-4-(4-羟基-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺给药后一直到24小时都显示显著高于MIC值的较高的血清浓度。表明本发明化合物能够每天一次给药。
在另一方面,提供了制备式I化合物的方法。起始物质可根据本领域已知的任何方法进行制备,包括美国专利号5,668,286;美国公开2004/0063954和2005/0143421中所述的方法或有机化学合成领域普通技术人员所熟知的方法。
本文采用以下缩写:DCM表示二氯甲烷,DMAP表示4-二甲基氨基吡啶,DMF表示N,N-二甲基甲酰胺,DMSO表示二甲亚砜,EtOAc表示乙酸乙酯,TEA表示三乙胺,THF表示四氢呋喃,Ac2O表示乙酸酐,PPTS表示对甲苯磺酸吡啶鎓,PTSA表示对甲苯磺酸,LDA表示二异丙胺锂,DMAc表示二甲基乙酰胺。
化合物4是制备式I化合物的起始物质,它可通过方案1所示的一般反应步骤来制备。
方案-1
如方案-1所示,在碱如三乙胺的存在下,4-哌啶酮盐酸盐与3,4,5-三氟-硝基苯缩合形成化合物(1)。用乙二醇处理化合物(1)以保护羰基。在甲酸铵的存在下用催化量的10%Pd/C或在氯化铵的存在下用铁还原该化合物中的硝基,得到相应的氨基化合物。该氨基化合物可进一步用氯甲酸苄酯处理,得到化合物(2)。在碱如正丁基锂、二异丙胺锂、六甲基二硅氮烷锂的存在下,用R-(-)-缩水甘油基丁酸酯处理化合物(2),得到化合物(3)。在碱如三乙胺的存在下,用甲磺酰氯处理化合物(3),得到化合物(4)。
式I化合物可根据以下步骤从化合物(4)制备:
a)使化合物(4)转化为式II的化合物;
b)用合适的反应试剂将式II化合物的羰基转化为环氧化物,形成式III的化合物;
式III
c)式III的环氧化物开环,得到式I(a)或式I(b)的化合物。
采用氟化反应试剂可将式I(a)的化合物转化为式I(b)的化合物。
根据方案2和方案3所示的一般反应步骤,化合物(4)可转化为本发明式II的化合物。合成包括在C-5噁唑烷酮部分和C-4哌啶部分的转化。转化步骤可以有机化学领域的技术人员已知的任何合适的顺序进行。通常,所述步骤包括:
a)水解缩酮基团,转化成羰基;
b)将甲磺酸酯基团转化为叠氮化物;
c)将叠氮化物还原为胺;
d)胺乙酰化形成乙酰胺。
方案-2
如方案2所示,在溶剂如DMF或含水DMF或DMAc中,用叠氮化钠处理化合物(4),30-100℃的温度下保持1-48小时,使化合物(4)转化为叠氮化合物(5)。在氢源如氢气、甲酸铵或环己烯的存在下,在溶剂如甲醇、乙醇、乙酸乙酯、四氢呋喃或其混合物中,用催化剂如5%钯/碳、10%钯/碳、20%氢氧化钯/碳、铂/碳或镍处理叠氮化合物(5),0-80℃的温度下保持1-12小时,叠氮化合物(5)还原得到相应的氨基化合物。或者,在溶剂如四氢呋喃中采用反应试剂硼氢化钠-氯化钴,或在合适的溶剂中用三苯膦然后用水处理并分离游离的胺,使叠氮化合物还原为氨基化合物。在有机溶剂如氯仿、二氯甲烷、乙酸乙酯中,在碱如三乙胺或吡啶的存在下,用乙酸酐进一步处理氨基化合物,得到相应的乙酰胺基化合物(6)。在含水溶剂如含水丙酮或乙腈中,用对甲苯磺酸或对甲苯磺酸吡啶鎓(PPTS)处理化合物(6),得到式II的化合物。
或者,如方案3所示,70℃下在含水有机溶剂如丙酮中,用对甲苯磺酸或PPTS处理化合物(4),得到化合物(7)。在溶剂如DMF或含水DMF中,用叠氮化钠处理化合物(7),30-100℃的温度下保持1-48小时,甲磺酸酯基团转化为叠氮化基团,得到化合物(8)。在氢源如氢气、甲酸铵或环己烯的存在下,在溶剂如甲醇,乙醇,乙酸乙酯,四氢呋喃或其混合物中,用催化剂如5%钯/碳、10%钯/碳、20%氢氧化钯/碳、铂/碳或阮内镍处理叠氮化合物(8),在0-80℃的温度下保持1-12小时,叠氮化合物(8)还原得到相应的氨基化合物。在卤化溶剂如氯仿、二氯甲烷中,在碱如三乙胺或吡啶的存在下,用乙酸酐进一步处理氨基化合物,得到式II的化合物。
方案-3
根据方案4的反应步骤来制备式I(a)的化合物。在碱的存在下,采用合适的反应试剂,式II的化合物可转化为式III的环氧化物。在溶剂如DMSO、DMF、THF或其混合物中,在碱如氢化钠、叔丁醇钾、LDA或正丁基锂的存在下,采用碘化三甲基氧代锍或氯化三甲基氧代锍进行反应,0-85℃的温度下保持1-12小时,得到包含式III化合物的环氧化物。
在醇溶剂如甲醇、三氟甲醇、二氟乙醇、三氟乙醇、二氟丙醇或三氟丙醇中,用合适的反应试剂如醇盐(如甲醇钠)或碱(如碳酸钠、碳酸钾、叔丁醇钠或叔丁醇钾)处理式III的化合物,得到本发明式I(a)的化合物。
方案-4
如方案5所示,在有机溶剂如二氯甲烷、氯仿中,用氟化剂如三氟化二乙基氨基硫(DAST)、三氟化二甲基氨基硫、三氟化吡咯烷(pyrrolidino)硫、N,N-二乙基-1,1,2,3,3,3-六氟丙胺、N,N-二乙基-1,2,3,3,3-五氟丙烯胺、氟化氢或氟化四丁基铵处理式I(a)的化合物,-20-50℃的温度下搅拌1-24小时,得到式I(b)的化合物。
方案-5
或者,如方案5所示,为制备式I(b)的化合物,-40到+60℃的温度下,在溶剂如二氯甲烷、氯仿中,用70%HF-吡啶处理式III的化合物,得到相应的氟衍生物。可采用有机化学领域已知的标准烷化方法进一步烷化产物,得到式I(b)的化合物,例如R是CH3,通常烷化可在氧化银的存在下用甲基碘进行。
本发明噁唑烷酮类抗微生物药剂尤其适用于治疗革兰氏阳性感染,包括多药耐药株的感染。不同于现有技术的化合物,它们对各种耐药微生物,尤其是各种粪肠球菌株具有杀菌活性。此外,它们对利奈唑胺耐药的金黄色葡萄球菌株、利奈唑胺耐药的粪肠球菌株,尤其对利奈唑胺耐药的肺炎链球菌株具有活性。这些化合物适合通过胃肠外、口服或局部给药来治疗人和其他温血动物的革兰氏阳性菌、革兰氏阴性菌、好氧菌、厌氧菌或非典型细菌感染。人和其他温血动物的感染可以是全身或局部感染。
可用本发明化合物治疗的感染的例子包括:中枢神经系统感染,外耳感染,中耳感染如急性中耳炎,硬脑膜窦感染,眼睛感染,口腔感染如牙齿、牙龈和粘膜感染,上呼吸道感染,下呼吸道感染,泌尿生殖器感染,胃肠道感染,妇科感染,败血症,骨和关节感染,皮肤和皮肤结构感染,细菌性心内膜炎,灼伤,外科手术的抗菌预防和免疫抑制患者的抗菌预防,如接受癌症化疗的患者或器官移植患者。具体说,可用本发明化合物治疗的感染性疾病是革兰氏阳性感染如骨髓炎、心内膜炎和糖尿病足。
本文所述的化合物适用于治疗或预防人和其他温血动物的革兰氏阳性或革兰氏阴性菌、好氧菌、厌氧菌或非典型细菌感染。本发明噁唑烷酮类抗微生物药剂适用于治疗革兰氏阳性感染,包括多药耐药株导致的感染。本发明化合物是有用的抗微生物试剂,能有效对抗各种人和动物的病原体,特别包括利奈唑胺耐药株。
与利奈唑胺不同,本文所述的化合物对各种耐药微生物,尤其是各种粪肠球菌株具有杀菌活性。此外,它们对利奈唑胺耐药的金黄色葡萄球菌株、利奈唑胺耐药的粪肠球菌株,尤其对利奈唑胺耐药的肺炎链球菌株具有活性。
人和其他温血动物的感染可以是全身或局部感染。通过给予处于发生细菌感染风险中的对象本发明的化合物,所述化合物可用于防止革兰氏阳性和革兰氏阴性菌、好氧菌、厌氧菌或非典型细菌导致的感染。处于发生感染风险中的对象可以是卫生保健工作者、手术患者、免疫缺陷患者等。
本发明包括一些化合物、组合物、剂型和给予人或其他动物对象这些化合物的方法。在本发明的一个实施方式中,药物组合物包含治疗有效量的本说明书中所述的本发明活性化合物、其衍生物、前药、盐或水合物以及药学上可接受的载体、稀释剂或赋形剂和任选的其他治疗成分。给予的具体化合物、组合物和剂型必须是药学上可接受的。本文所用术语"药学上可接受的"组分指符合合理效益/风险比的适用于人体和/或动物而没有过度副作用(如毒性、刺激性和过敏反应)的组分。根据本领域技术人员用于制备稳定且有效的组合物所采用的常规方法来制备药物组合物。在剂型中,本发明化合物的"治疗有效量"表示适用于任何医学治疗的具有合理的效益/风险比的用于治疗细菌感染的足够量的化合物。然而,应理解,本发明化合物和组合物总的日剂量将由主治医师决定,在合理的医疗判断范围内。任何特定患者具体的治疗效果剂量水平将取决于许多因素,包括治疗的疾病和疾病的严重性;采用的具体化合物的活性;所采用的具体化合物;患者的年龄、体重、健康状况、性别和饮食;给药时间、给药途径及采用的具体化合物的排泄速率;治疗持续时间;与采用的具体化合物联用或并行使用的药物;以及医疗领域众所周知的因素等。
出于本发明的目的,药物组合物可包含一种或多种本发明的活性化合物、其衍生物、盐、前药和/或水合物,单独给药,但通常与根据指定的给药途径和标准药学实践选择的药学载体一起给予。可使用的合适的载体包括,稀释剂或赋形剂,如填充剂、增量剂、粘合剂、软化剂、润湿剂、崩解剂、表面活性剂和润滑剂,通常根据剂型进行选择来制备药物。
化合物和组合物可通过任何合适的给药途径给予人或其他动物,这些途径包括例如,口服、直肠、阴道、胃肠外(皮下、肌肉内、静脉内)、透皮、外用等。剂型包括溶液剂、混悬剂、片剂、丸剂、粉末剂、含片、分散体、混悬剂、乳剂、溶液剂、团粒、凝胶剂、颗粒剂、胶囊、注射制剂、贴剂、软膏剂、乳膏剂、搽剂、油膏剂、扁囊剂、喷雾剂、洗剂、香波等。
本发明化合物、其衍生物、盐、前药或水合物在防止、急性或慢性控制感染或疾病中的预防或治疗剂量将取决于一种或多种因素,这些因素包括但不限于:需治疗的疾病的严重性、风险和给药途径。此外,剂量,可能地剂量频率也将根据个体患者的年龄、性别、体重和反应而变化。通常,适用于本文所述疾病的本发明化合物、其衍生物、盐、前药或水合物总的日剂量范围约为200-1500mg,单次或分次给药。在非限制性的实施方式中,日剂量范围应约为400-1200mg,单次或分次给药,最优选日剂量范围应约为500-1000mg,分次给药。胃肠外给药可以是单剂量或一直到3次分剂量,静脉内给药则可包括连续滴注。
本领域技术人员将明白,一些情况下的用量可能超出上述范围。而且,应理解,临床医师或治疗参与者知道如何以及何时根据个体患者的反应或状态或感染是否活跃或治疗是否是预防性的来中断、调整或终止治疗。术语"足以根除感染但不足以引起过度副作用的量"包括在上述剂量范围和给药频率方案内。
本发明的具体实施方式是本发明化合物的药动学曲线,从而实现每天一次的给药方案。
适合口服给药的本发明药物组合物可以是离散单元,例如胶囊、扁囊剂、片剂或喷雾剂,各自包含预定量粉末或颗粒形式、含水液体或非水液体的溶液或混悬液形式、水包油乳剂、或油包水乳剂形式的活性成分。这些组合物可通过任何药学方法制备,但所有方法都包括将活性成分与构成一种或多种必需成分的载体进行混合的步骤。通常,将活性成分与液体载体或细分的固体载体或两者均匀并充分混合来制备组合物,然后如果需要的话,使产物成形形成所需的制剂。
本发明组合物包括混悬剂、溶液剂、酏剂、气雾剂和固体剂型等组合物。下面一般描述的载体是口服固体制剂(如粉末剂、胶囊和片剂)中常用的载体,相对于口服液体制剂,更优选口服固体制剂。最优选的口服固体制剂是片剂和胶囊。
因为其给药方便,片剂和胶囊代表了最常优选的口服剂型,其中采用了固体药用载体。合适的载体的例子包括:赋形剂如乳糖、白糖、氯化钠、葡萄糖溶液、尿素、淀粉、碳酸钙、高岭土、晶体纤维素和硅酸;粘合剂如水、乙醇、丙醇、单糖浆、葡萄糖、淀粉溶液、明胶溶液、羧甲基纤维素、虫胶、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮;崩解剂如干燥淀粉、藻酸钠、琼脂粉末、昆布粉末、碳酸氢钠、碳酸钙、吐温(聚氧乙烯去水山梨糖醇的脂肪酸酯)、月桂硫酸钠、硬脂酸甘油一酯、淀粉和乳糖;崩解抑制剂如白糖、硬脂酸甘油酯、可可豆脂和氢化油;吸收促进剂如季铵碱和月桂硫酸钠;润湿剂如甘油和淀粉;吸收剂如淀粉、乳糖、高岭土、膨润土和胶体硅酸;润滑剂如纯化滑石粉、硬脂酸盐、硼酸粉末、聚乙二醇和固体聚乙二醇。
需要时可对片剂进行包衣,制成糖包衣片、明胶包衣片、肠衣片、薄膜包衣片或包含两层或多层的片剂。
需要时,可通过标准含水或非水技术对片剂进行包衣。在将药物组合物模制成丸的过程中,可使用许多本领域已知的常规载体。合适的载体的例子是赋形剂如葡萄糖、乳糖、淀粉、可可豆脂、硬化植物油、高岭土和滑石粉;粘合剂如阿拉伯胶粉末、黄芪胶粉末、明胶和乙醇;和崩解剂如昆布和琼脂。
理想地,每个口服剂型包含约200-1500毫克活性成分。最优选地,片剂、扁囊剂或胶囊包含以下三种剂量之一,约200毫克、约400毫克或约600毫克的活性成分。
在将药物组合物模制成栓剂的过程中,可采用许多本领域已知的载体。合适的载体的例子包括:聚乙二醇、可可豆脂、高级醇、明胶和半合成甘油酯。
第二种优选的方法是采用胃肠外剂型的胃肠外给药,包括肌内,静脉内或皮下给药。采用的胃肠外剂型可以是直接使用的剂型或者临用前用适合胃肠外剂型的溶液稀释的剂型。
如果将药物组合物配制成注射用制剂,在将药物组合物配制成溶液或混悬液的过程中,可使用所有本领域常用的稀释剂。合适的稀释剂的例子是水、乙醇、聚丙二醇、乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和去水山梨糖醇酯。可将氯化钠,葡萄糖或甘油掺入治疗剂。
第三种优选的给药途径是局部应用,非常适合乳膏、软膏、香波、洗剂、丸衣粉等。通常,局部应用剂型中本发明化合物的有效量占组合物总重量约0.1-10%w/w。优选地,本发明化合物的有效量占组合物总重量约1%w/w。
局部应用时,可以非喷雾形式、粘稠到半固体或固体形式使用,包含与局部应用相容的载体且动态粘度优选大于水。合适的制剂包括但不限于:溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、粉末剂、搽剂、油膏剂、气雾剂等,需要时可进行灭菌或与辅助试剂如防腐剂、抗氧化剂、稳定剂、润湿剂、影响渗透压的缓冲液或盐等混合。对于局部应用,合适的还有可喷射的气雾剂,其中活性成分优选与固体或液体惰性载体材料组合。
除上述常用剂型之外,本发明化合物也可通过控释方式和/或递送装置进行给药,如美国专利3,845,770;3,916,899;3,536,809;3,598,123和4,008,719中所述;这些专利的内容被纳入本文作为参考。
本发明的非限制性实施方式是式I的本发明化合物的储存稳定的组合物制剂。这种稳定组合物优选采用选择性稳定剂进行制备。各种稳定剂是药物组合物制备领域的技术人员已知的。尤其适合制备式I的本发明化合物的储存稳定的组合物的稳定剂包括乙二胺四乙酸二钠(EDTA),氨丁三醇,环糊精如γ-环糊精,羟基-丙基-γ-环糊精。抗微生物药物组合物可还包含常规溶解助剂、缓冲液、疼痛-缓解剂和防腐剂以及任选的着色剂、芳香剂、调味剂、甜味剂和其他药物。
本发明的优点是,与利奈唑胺相比化合物具有有益的安全性优点,具体是本发明化合物不会引起骨髓抑制或降低了骨髓抑制的可能。已知骨髓抑制是噁唑烷酮类抗微生物试剂典型的类别特异性毒理学特征。
虽然以具体实施方式的形式描述了本发明,某些改进和等价形式是本领域技术人员所明白的,且包括在本发明的范围内。下面的实施例阐述了本发明化合物的制备方法,仅以实施例的方式提供,而不是限制本发明化合物的范围。
实施例-1:1-(2,6-二氟-4-硝基苯基)-哌啶-4-酮
搅拌下,在3,4,5-三氟硝基苯(3.894g,0.022mol)和4-哌啶酮盐酸盐一水合物(3.072g,0.020mol)的氯仿(24ml)混合液中,加入三乙胺(8.3ml,0.06mol)。将所得混合液在70℃下加热和搅拌7小时。反应完全后(TLC),减压蒸发溶剂,用水(10ml)稀释残留物。过滤分离的固体,用水(8ml)、然后用己烷(5ml)洗涤,得到黄色结晶状固体产物4.8g,产率94%。熔点:130-132℃;MS:M+1=257(MH+100%);M.F.:C11H10F2N2O3
实施例-2:[4-(1,4-二氧杂(dioxa)-8-氮杂-螺[4.5]癸-8-基)-3,5-二氟-苯基]-
氨基甲酸苄基酯
搅拌下,在实施例-1化合物(5.632g,0.022mol)的甲苯(40ml)混合液中,加入乙二醇(2.48g,0.040mol)和对甲苯磺酸一水合物(0.988g,0.0052mol)。将该反应混合物在110-120℃下加热,共沸除去水。反应完全后,用碳酸氢钠溶液中和内容物(约12ml)。分离各层,将甲苯层装入圆底烧瓶中。将Pd/C(10%,1g)加入甲苯层中,将内容物在氢气气氛下搅拌24小时。反应完全后,滤去催化剂,用氯仿(10ml)洗涤。将滤液装载到圆底烧瓶中,加入碳酸氢钠(5.04g,0.06mol)得到悬浮液。搅拌下,在10分钟的时间内将氯甲酸苄酯(50%的甲苯溶液,9ml,0.026mol)加入到悬浮液中。将该反应混合物再搅拌1小时。反应完全后,过滤固体,用氯仿(10ml)洗涤。真空浓缩滤出液,加入己烷(10ml)得到固体产物。将固体过滤并在70-80℃下真空干燥,得到灰白色产物7.2g,产率81%。
熔点:126-128℃;MS:M+1=405(MH+100%);M.F.:C21H22F2N2O4
实施例-3:5(R)-3-[4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3,5-二氟苯基]-5-(羟
甲基)-1,3-噁唑烷-2-酮
40℃下,在实施例-2化合物(7.19g,0.0178mol)的无水四氢呋喃(THF)(45ml)混合液中,氮气气氛下10分钟内加入用己烷配制的正丁基锂(1.6M,13.1ml,0.021mol)。将内容物在40℃下再搅拌1小时,在15分钟内逐渐加入R-(-)-缩水甘油基丁酸酯(2.6g,0.018mol)。将该反应混合物搅拌1小时,反应完全后,将甲醇(4.75ml)、甲醇钠(0.15g,0.0028mol)和水(0.5ml)加入烧瓶中。将内容物再搅拌0.5小时,加入饱和氯化铵溶液(20ml)。用乙酸乙酯(2X20ml)萃取内容物,真空蒸发有机层,得到稠厚的残留物。将甲苯(12ml)加入残留物中,得到固体产物,过滤并用甲苯(4ml)洗涤。将残留物在50-60℃下减压干燥,得到灰白色固体产物3.5g,产率53%。
熔点:152-154℃;MS:M+1=371,(MH+100%);M.F.:C17H20F2N2O5
实施例-4:(5R)-{3-[4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3,5-二氟苯基]-2-氧
代-噁唑烷-5-基甲基}-甲磺酸酯
搅拌下,在实施例-3化合物(3.44g,0.0093mol)的二氯甲烷(23ml)混合液中,加入三乙胺(2.5ml,0.018mol)。室温下10分钟内向该溶液中加入甲磺酰氯(1.385g,0.0121mol),将该反应混合物再搅拌2小时。反应完全后,40℃下真空蒸发内容物,得到油状残留物。向残留物中加入水(10ml),真空除去痕量二氯甲烷。用额外的水(5ml)洗涤残留物,70℃下减压干燥,得到白色固体产物3.95g,产率95%。
熔点:144-146℃;MS:M+1=449(MH+100%);M.F.:C18H22F2N2O7S
实施例-5:(5R)-3-[4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3,5-二氟苯基]-5-(叠
氮基甲基)-噁唑烷-2-酮
搅拌下,在实施例-4化合物(4.166g,0.0093mol)的N,N-二甲基甲酰胺(8ml)溶液中,加入叠氮化钠(1.82g,0.028mol)。将该反应混合物逐渐加热,在70℃的温度下保持8小时。反应完全后,使内容物冷却至20-25℃,缓慢倒入冷却水(50ml)中。过滤所得固体产物,用水(10ml)洗涤,室温下干燥,得到灰白色固体产物3.48g,产率96%。
熔点=叠氮化物未检测;MS:M+1=396(MH+100%);M.F.:C17H19F2N5O4
实施例-6:(5S)-N-{3-[4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3,5-氟苯基]-噁唑
烷-2-氧代-噁唑烷-5-基甲基}-乙酰胺
在实施例-5化合物(3.673g,0.0093mol)的THF(23ml)溶液中,30分钟的时间内加入硼氢化钠(1.21g,0.032mol)和氯化钴(0.547g,0.0023mol)。室温下将该反应混合物搅拌2小时。反应完全后,使内容物滤过助滤床并用THF(5ml)洗涤滤床。将滤液合并,60-70℃下真空浓缩,得到油状产物。向该油状产物中加入乙酸乙酯(20ml)得到澄清溶液,使其滤过助滤床并用乙酸乙酯(5ml)洗涤滤床。用水(20ml)洗涤合并的滤液,有机层在硫酸钠上干燥。向上述有机层中加入三乙胺(3.2ml,0.023mol),室温下15分钟的时间内逐渐加入乙酸酐(1.7g,0.0166mol)。将该反应混合物搅拌2小时。反应完全后,真空蒸发内容物,得到残留物。残留物中加水(20ml),真空除去痕量的乙酸乙酯。将所得固体产物过滤并用水(5ml)洗涤。将残留物在室温下干燥,得到白色固体产物2.29g,两步的产率60%
熔点:218-220℃;MS:M+1=412(MH+100%);M.F.:C19H23F2N3O5
实施例-7:(5R)-{3-[3,5-二氟-4-(4-氧代哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-甲磺酸酯
搅拌下将实施例-4的化合物(17g,0.035mol)加入到水(100ml)和丙酮(200ml)的混合液中。向该搅拌的混合液中加入对甲苯磺酸一水合物(0.067mol),将内容物加热并在70℃下维持3.5小时。反应完全后,使内容物冷却至30℃,用碳酸氢钠中和至pH7-7.5。60-65℃下真空除去丙酮,得到粘稠物质。向该物质中加入水(25ml),使内容物冷却至5-10℃。将所得固体产物过滤,用水(10ml)洗涤并在80-85℃下减压干燥,得到白色固体产物14g,产率91%。
熔点:152℃;MS:M+1=405(MH+100%);M.F.:C16H18F2N2O6S
实施例-8:(5R)-{3-[3,5-二氟-4-(4-氧代哌啶-1-基)苯基]-5-(叠氮基甲基)-噁唑烷-2-酮
搅拌下,在实施例-7化合物(3.01g,0.0093mol)的N,N-二甲基甲酰胺(8ml)溶液中,加入叠氮化钠(1.82g,0.028mol)。将该反应混合物逐渐加热并在70℃的温度下保持8小时.反应完全后,使内容物冷却至20-25℃,缓慢倒入冷却水(50ml)中。将所得固体产物过滤,用水(10ml)洗涤,残留物在室温下干燥,得到灰白色固体产物。湿润产物无需干燥用于下一反应。
MS:M+1=398;M.F.:C17H21F2N5O4
实施例-9:(5S)-N-{3-[3,5-二氟-4-(4-氧代哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺
方法A:搅拌下,将实施例-6(2.8g,0.0068mol)加入水(34.5ml)和丙酮(23ml)的混合液中。将对甲苯磺酸一水合物(2.47g,0.013mol)加入搅拌的混合液中,加热内容物并在70℃的温度下保持3小时。反应完全后(TLC),将内容物冷却至30-35℃,用碳酸氢钠(约1.2g)中和至pH7-7.5。减压浓缩反应混合物,得到稠厚物质。向该物质中加入水(25ml),使内容物冷却至5-10℃,过滤分离的固体,用额外的水(10ml)洗涤残留物。残留物在80-85℃下减压干燥,得到白色固体产物1.64g,产率66%。
M.P.:132-134℃;MS:M+1=368(MH+,100%);M.F.:C17H19F2N3O4
方法B:在1升帕尔反应器中加入乙酸乙酯120ml、吡啶(2.76ml,0.034mol)、实施例-8(12g,0.034mol)、乙酸酐(3.6ml,0.038mol)和1.2g10%Pd/C(50%湿润),混合物在200psi下氢化。反应完全后(4小时,TLC监测),将反应混合物过滤通过滤床。用氯仿(50ml)洗涤残留物。将合并的滤液减压浓缩。用乙醚(50ml)搅拌残留的半固体,轻轻倒出醚层。用50ml蒸馏水搅拌残留的固体30分钟。过滤分离的固体,用蒸馏水洗涤,减压干燥得到白色固体产物7.5g,产率82%。
熔点:132-134℃;MS:M+1=368(MH+,100%);M.F.:C17H19F2N3O4
实施例-10:(5S)-N-{3-[4-(1-氧杂-6-氮杂螺[2.5]辛-6-基)-3,5-二氟苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺
室温下,在氯化三甲基氧化锍(0.67g,0.0052mol)的THF(13ml)溶液中,加入叔丁醇钾(0.617g,0.0055mol),将内容物回流4-5小时。1分钟内将实施例-7(1.6g,0.0044mol)分批加入该回流的混合液中。将反应混合物再回流2小时。反应完全后(TLC),减压蒸发THF,得到稠厚的残留物。残留物中加水(20ml),充分搅拌,过滤分离的固体,用水(5ml)洗涤。60-70℃下减压干燥残留物,得到白色固体产物1.57g,产率94%。
熔点:160-162℃;MS:M+1=382(MH+,100%);M.F:C18H21F2N3O4
实施例-11:(5S)-N-{3-[3,5-二氟-4-(4-羟基-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺
室温搅拌下,将实施例-10(54.86g,0.144mol)悬浮在甲醇(1100ml)中。搅拌下,2分钟内向上述悬浮液中少量加入金属钠(4g,0.174mol)。将反应混合物加热至40-42℃,在该温度下搅拌约40小时。反应完全后(TLC),减压蒸发溶剂,得到稠厚浆液。搅拌下,向所得稠厚浆液中逐渐加入水(1100ml)。加入完成后,通过加入足量的冰醋酸将含水悬浮液的pH调节至7。过滤分离的固体,并用水洗涤残留物。所得固体在硅胶柱上通过色谱法进一步纯化,得到白色固体产物32.7g,产率55%。
熔点:173-174℃;MS:M+1=414(MH+,100%);M.F.:C19H25F2N3O5
1H-NMR(400MHz,CDCl3):δ7.0-7.1(m,2H,Ar-H),6.0(t,1H,NH),4.70-4.80(m,1H),4.00(t,1H),3.70-3.75(m,2H),3.5-3.7(m,1H),3.43(s,3H,OCH3),3.37-3.42(m,2H),3.30(s,2H,-OCH2),3.0-3.05(m,2H),2.22(bs,1H,-OH),2.04(s,3H,COCH3),1.70-1.75(m,4H)
实施例-12:(5S)-N-{3-[3,5-二氟-4-(4-氟-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺
在实施例-11(0.475g,1.15mmol)的二氯甲烷(10ml)溶液中加入DAST(0.232g,1.44mmol),0℃下搅拌8小时。蒸发溶剂,通过柱色谱法纯化残留物,得到白色固体产物50mg,产率10%。
MS:(M+1)=416;(MH+,100%);M.F.:C19H24F3N3O4
实施例-13:(5S)-N-{3-[3,5-二氟-4-(4-羟基-4-(2,2,2-三氟-乙氧基甲基)-哌啶-1-基)-苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺
在实施例-10(2.75mmol)的2,2,2-三氟乙醇(10mL)溶液中加入K2CO3(4.40mmol),将所得混合液在25℃下搅拌18小时。蒸发溶剂,将残留物悬浮在水(10mL)中,充分搅拌,用乙酸乙酯萃取(2x25mL)。浓缩萃取物,残留物在硅胶柱上纯化,得到白色固体产物,产率58%。
熔点182-184℃;MS(M+1)=482.1(MH+,100%);M.F.=C20H24F5N3O5
生物试验实施例-1
大致根据WO95/25106、US5,668,286和EP 0 750 618 B1所述确定试验化合物的体外MIC方法。
MIC测试方法
将在胰蛋白酶大豆肉汤(Tryptic Soya broth)中培养过夜的MRSA-032生物体稀释在MH肉汤(Mueller Hinton Broth)中,得到与MacFarland管0.5标准相匹配的光密度。将培养物以1:10进一步稀释在MH肉汤中。采用Denley多点接种法,将104个细胞接种到含2倍试验化合物稀释液的MH琼脂(Difco)上。将平板在35℃下孵育24小时,记录MIC结果。MIC的定义是抑制测试生物体的最低药物浓度。本发明化合物的MIC结构如表1所示。
表-1:实施例11的MIC
生物体 | MIC(mcg/ml) |
金黄色葡萄球菌ATCC25923 | 2 |
金黄色葡萄球菌ATCC29213 | 2 |
金黄色葡萄球菌Smith | 2 |
金黄色葡萄球菌STA-014 | 4 |
金黄色葡萄球菌MRSA-032 | 4 |
金黄色葡萄球菌Mu-50VISA | 2 |
表皮葡萄球菌STE-118 | 1 |
表皮葡萄球菌STE-110MRSE | 1 |
粪肠球菌ATCC29212 | 2 |
粪肠球菌Efe-406VRE | 4 |
屎肠球菌Efa-303 | 4 |
屎肠球菌Efa-332VRE | 2 |
肺炎链球菌ATCC49619 | 2 |
肺炎链球菌ATCC6303 | 2 |
酿脓链球菌ATCC25147 | 2 |
无乳链球菌ATCC13813 | 2 |
链球菌F型ATCC12392 | 2 |
链球菌G型ATCC12394 | 2 |
链球菌B型ATCC12386 | 2 |
链球菌C型ATCC12388 | 2 |
生物试验实施例-2
在狗中进行口服(15mg/kg p.o)药动学研究。在时间点0、0.08(不是口服)、0.25、0.50、1.0、1.5、2.0、3.0、4.0、5.0、6.0、8.0、10.0、12.0和24.0小时收集血样。为便于静脉给药和收集血样,在狗头侧静脉内植入插管。血样分离得到的血清用于HPLC-基分析。
采用Water’s OASIS HLB药筒,通过固相萃取技术萃取血清样品。采用HPLC-二极管阵列检测系统进行分析。制备的样品在YMC-AM反相柱(150x4.6mm ID;5μm)上色谱纯化,采用恒组成流动相醋酸盐缓冲液(50mmol醋酸铵,pH6.6)乙腈,66:34%v/v(对于本发明的代表性化合物),流速1ml/分钟,λ最大254nm下测定。独立制备的分析用标准品和质量控制样品与未知样品组一起进行分析。
表2:0-24小时的血清浓度
时间点(小时) | 实施例-11 |
0.0 | 0.0 |
0.25 | 4.14 |
0.5 | 5.41 |
1.0 | 8.76 |
2.0 | 11.42 |
3.0 | 10.97 |
4.0 | 10.37 |
5.0 | 8.81 |
6.0 | 7.28±2.14 |
8.0 | 5.82±1.58 |
10.0 | 4.50±1.03 |
12.0 | 3.47±1.25 |
24.0 | 2.19±1.91 |
结果:给药后,一直到24小时的血清浓度高于MIC值。
Claims (16)
2.选自以下的化合物:
(5S)-N-{3-[3,5-二氟-4-(4-羟基-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺;
(5S)-N-{3-[3,5-二氟-4-(4-氟-(4-甲氧基甲基)-哌啶-1-基)苯基]-2-氧代-噁唑烷-5-基甲基}-乙酰胺;
(5S)-N-{3-[3,5-二氟-4-(4-羟基-4-(2,2,2-三氟-乙氧基甲基)-哌啶-1-基)-苯基]-2-氧代-噁唑烷-5-基甲基)-乙酰胺。
3.一种药物组合物,其包含治疗有效量的如权利要求1或2所述的化合物以及任选的药学上可接受的载体、赋形剂或稀释剂。
5.如权利要求4所述的方法,其特征在于,所述微生物感染是革兰氏阳性菌、革兰氏阴性菌、好氧菌、厌氧菌或非典型细菌引起的。
6.一种治疗或预防动物或人微生物感染的方法,所述方法包括给予所述动物或人如权利要求3所述的药物组合物。
8.如权利要求7所述的方法,其特征在于,化合物(4)转化为式II的化合物的过程包括任何合适的反应顺序的以下步骤:
a)水解缩酮基团,转化成羰基;
b)将甲磺酸酯基团转化为叠氮化物;
c)将叠氮化物还原为胺;
d)胺乙酰化形成乙酰胺。
9.如权利要求7所述的方法,其特征在于,所述合适的反应试剂是碘化三甲基氧代锍或氯化三甲基氧代锍。
10.如权利要求7所述的方法,其特征在于,在碱存在下,用醇盐或醇使所述环氧化物开环,形成式I(a)的化合物。
11.如权利要求7所述的方法,其特征在于,用70%HF-吡啶使所述环氧化物开环,然后烷基化,形成式I(b)的化合物。
12.如权利要求10所述的方法,其特征在于,所述醇盐是甲醇钠。
13.如权利要求10所述的方法,其特征在于,所述醇是甲醇、三氟甲醇、二氟乙醇、三氟乙醇、二氟丙醇或三氟丙醇。
14.如权利要求10所述的方法,其特征在于,所述碱是碳酸钠、碳酸钾、叔丁醇钠或叔丁醇钾。
15.如权利要求7所述的方法,所述方法还包括用氟化试剂将式I(a)化合物转化为式I(b)化合物。
16.如权利要求15所述的方法,其特征在于,所述氟化试剂是三氟化二乙基氨基硫、三氟化二甲基氨基硫、三氟化吡咯烷硫、N,N-二乙基-1,1,2,3,3,3-六氟丙胺、N,N-二乙基-1,2,3,3,3-五氟丙烯胺、氟化氢或氟化四丁基铵。
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2008
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1143961A (zh) * | 1994-03-15 | 1997-02-26 | 法玛西雅厄普约翰公司 | 噁唑烷酮衍生物和含有它们的药物组合物 |
US20050143421A1 (en) * | 2003-09-08 | 2005-06-30 | Wockhardt Limited | Substituted piperidino phenyloxazolidinones having antimicrobial activity with improved in vivo efficacy |
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EP2018792A4 (en) | 2012-12-05 |
WO2007132314A2 (en) | 2007-11-22 |
RU2008148319A (ru) | 2010-06-20 |
US8217058B2 (en) | 2012-07-10 |
EP2018792A2 (en) | 2009-01-28 |
ZA200809724B (en) | 2011-10-26 |
US20100056581A1 (en) | 2010-03-04 |
MX2008013371A (es) | 2009-02-06 |
CA2651634A1 (en) | 2007-11-22 |
CN102106184B (zh) | 2014-04-09 |
BRPI0712535A2 (pt) | 2012-09-04 |
AU2007251289A1 (en) | 2007-11-22 |
KR101345445B1 (ko) | 2013-12-27 |
EP2018792B1 (en) | 2015-09-16 |
CA2651634C (en) | 2013-07-30 |
JP2009536939A (ja) | 2009-10-22 |
ES2556183T3 (es) | 2016-01-13 |
WO2007132314A3 (en) | 2011-07-14 |
KR20090028699A (ko) | 2009-03-19 |
JP5313126B2 (ja) | 2013-10-09 |
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