CN1185783A - 碳代青霉烯酯 - Google Patents
碳代青霉烯酯 Download PDFInfo
- Publication number
- CN1185783A CN1185783A CN96194191A CN96194191A CN1185783A CN 1185783 A CN1185783 A CN 1185783A CN 96194191 A CN96194191 A CN 96194191A CN 96194191 A CN96194191 A CN 96194191A CN 1185783 A CN1185783 A CN 1185783A
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- China
- Prior art keywords
- compound
- methyl
- ethyl
- methylpyrazole
- formula
- Prior art date
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- 150000002148 esters Chemical class 0.000 title description 3
- 229940041011 carbapenems Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- -1 isobutyryloxymethyl Chemical group 0.000 claims abstract description 46
- 208000035143 Bacterial infection Diseases 0.000 claims abstract 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
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- 239000000284 extract Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
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- 238000010992 reflux Methods 0.000 description 5
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- 238000005406 washing Methods 0.000 description 5
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 230000003115 biocidal effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- OLIORJQCDXKJQP-UHFFFAOYSA-N 1-(1-ethyl-5-methylpyrazol-3-yl)ethanone Chemical compound CCN1N=C(C(C)=O)C=C1C OLIORJQCDXKJQP-UHFFFAOYSA-N 0.000 description 2
- DMGJEACTEOFQPI-UHFFFAOYSA-N 1-ethyl-5-methylpyrazole-3-carboxylic acid Chemical compound CCN1N=C(C(O)=O)C=C1C DMGJEACTEOFQPI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
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- 125000003118 aryl group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- DUMHBFMURBWDPC-UHFFFAOYSA-N ethylhydrazine;oxalic acid Chemical compound CCNN.OC(=O)C(O)=O DUMHBFMURBWDPC-UHFFFAOYSA-N 0.000 description 2
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- 125000005843 halogen group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 239000002245 particle Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
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Abstract
一种式(Ⅰ)的化合物,其中R选自:异丁酰氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、和苯甲酰氧基甲基。该化合物用于治疗细菌感染。
Description
本发明涉及一种新的抗菌化合物,其制备方法,包含这种化合物的药物组合物和兽药组合物,以及它们在抗菌治疗中的应用。
碳代青霉烯如化合物(A)亚胺培南(imipenem)具有潜在的广谱抗菌活性(见US3950357和US4194047;Merck and Co.)。但是,这种碳代青霉烯在肾的脱氢肽酶-1(DHP-1)作用下会发生水解,这限制了其在化疗中的应用。就亚胺培南而言,该问题可以通过同时给药DHP-1抑制剂而得以解决。
通过对碳代青霉烯核进行化学改性可以提高其对DHP-1的稳定性,例如,可在化合物(B)基本青霉烯(meropenem)中引入1β-甲基取代基,(见Shih D.H.等,杂环,1984,21,29和Sunagawa M.等,抗菌素杂志,1990,43,519)。近来,已发展到引入1β-氨基烷基取代基(见EP 0433759,Bristo1-Meyers Squibb)。
改善DHP-1稳定性的其它研究是采用了2-碳取代的碳代青霉烯,例如,2-芳基、2-杂芳基、2-芳香杂环的碳代青霉烯(US4543257,US6260627,US4962101,US4978659,EP014493,EP0414489,EP0010316和EP0030032,Merck&Co)和2-(取代)甲基碳代青霉烯(Schmidt等,J.Antibiotics,41,1988,780)。
UK专利1593524(Merck&Co.)公开了一系列的5-元杂芳基碳代青霉烯衍生物,包括二唑基和四唑基化合物。但是,就吡唑基衍生物而言,杂环化合物会通过C-4位置与碳代青霉烯结合。
其它在2-位引入的结构改进包括取代的乙烯基-C(Ra)=CHRb,其中例如,Ra为氢或甲基,Rb为氢或低级烷基(EP0330108;Fujisawa)或Ra和Rh选自氢、低级烷基、氨基羰基、低级烷氧基、氰基、硝基和低级烷氧羰基(EP0430037,Banyu Pharmaceutical Co.)。但是,在缺乏1β-甲基取代基的情况下,这种修饰并不能提高对DHP-1的稳定性。
本发明特别优选的化合物是:
异丁酰氧基甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]碳代青霉-2-烯-3-羧酸酯;
(5-甲基-2-氧代-1,3-二氧杂环戊烯-3-基)甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]碳代青霉-2-烯-3-羧酸酯和
苯甲酰氧基甲基(5R,6S)2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]碳代青霉-2-烯-3-羧酸酯。
由于本发明的每一个碳代青霉烯化合物要被用于药物组合物,当然其基本上以纯的形式提供,例如纯度至少50%,更适宜纯度至少为75%,优选至少为95%(%以wt/wt为基准)。化合物的不纯制剂可被用于制备药物组合物的更纯制剂。本发明的每一个化合物优选尽可能以结晶形式得到。
当本发明的每一个化合物由有机溶剂进行结晶或重结晶时,结晶的溶剂可存在于结晶产品中。本发明包括这种溶剂化物。类似地,本发明的化合物可从含水的溶剂中结晶或重结晶。在这种情形下,本发明包括化学计量的水合物。
可以按照本领域公知的制备其它抗菌素的方法,将本发明的碳代青霉烯抗菌化合物配制成用于人药或兽药的常规给药方式,因此,本发明包括含本发明抗菌化合物及可药用载体或赋形剂的药物组合物。该组合物可配制成任何适宜的给药方式,例如口服给药、非肠道给药或局部给药,优选采用口服给药。该组合物可制成片剂、胶囊剂、粉剂、颗粒剂、锭剂、霜膏或液体制剂,如口服杀菌非肠道溶液或悬浮液。口服给药的片剂和胶囊剂可为单位剂量制剂形式,可包含常规的赋形剂,如粘合剂,例如阿拉伯糖浆、明胶、山梨醇、黄耆胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;成片润滑剂,例如硬脂酸镁、滑石、聚乙二醇或二氧化硅;崩解剂,例如马铃薯淀粉;或可接受的润湿剂如十二烷基硫酸钠。可根据常规制药的公知方法对片剂包衣。口服液体制剂例如可以为含水或含油的悬浮液、溶液、乳液、糖浆或酏剂,或者可为干产品,使用时再用水或其它适宜的溶媒进行重配。这种液体制剂可包含常规的添加剂如悬浮剂,例如山梨醇、甲基纤维素、葡萄糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝胶或氢化食用脂肪;乳化剂,例如卵磷脂、脱水山梨醇单油酸酯或阿糖;非水溶媒(可包括食用油),例如杏仁油、油脂、甘油、丙二醇或乙醇;防腐剂,例如对羟基苯甲酸甲酯或丙酯或山梨酸;如果需要的话,还可包含常规的香味剂或着色剂。栓剂可包含常规的栓剂基质,如可可脂或其它甘油。
对于非肠道给药,采用化合物和菌溶媒(优选水)制备液体单位剂量形式。根据所用的溶媒和浓度,化合物可悬浮或溶解于溶媒中。制备溶液时,化合物可溶解于注射用水中并进行无菌过滤,再充入适宜的管形瓶或安瓿中,密封。优选将试剂如局麻剂、防腐剂和缓冲剂溶解于溶媒中。为了增强稳定性,可以充入管形瓶中后进行冷冻,真空除去水。然后干的冷冻干燥粉末密封在管形瓶中,并附一个注射水的管瓶以在使用前进行配制。除了化合物是悬浮在溶媒中而非溶解于其中以及不能通过过滤来杀菌外,非肠道悬浮液以基本相同的方式制备。在悬浮于无菌溶媒中之前,可使化合物与环氧乙烷接触来对化合物杀菌。优选在组合物中包含表面活性剂或润湿剂以便利化合物的分散。
根据给药方式的不同,组合物可以包含0.1-99.5%(重量),优选10-60%的活性物质。当组合物为单位剂量时,每一单位优选包含50-500mg的活性成分。所用剂量根据给药的途径和频率不同,对于成人患者(体重为70kg)治疗的剂量优选为100mg-12g/天,例如1500mg/天。该剂量相应于约1.5-170mg/kg天。剂量适宜为1-6g/天。
适宜的每日剂量在24小时内分几次给本发明的化合物。通常,250mg一天分四次给药,但是,实际上,患者最适宜的给药剂量和频率将根据患者的年龄、体重和反应而变化,医生可随机地选择剂量的大小以及不同的给药频率。这种剂量方案也属于本发明范围之内。
当本发明的任一种化合物以上述剂量给药时,未发现毒性反应。
本发明也包括治疗人和动物细菌感染的方法,该方法包括给药治疗有效量的本发明式(I)的抗菌化合物。
另一方面,本发明也提供了式(I)化合物在生产治疗细菌感染药物方面的应用。
本发明式(I)的化合物对于广谱格兰氏阳性和格兰氏阴性菌均有活性,可用于治疗各种细菌感染,包括免疫缺陷患者。
在许多其它的应用中,本发明的化合物还可用于治疗人体皮肤、软组织、呼吸道和尿道感染,也可用于治疗牛乳腺炎。
本发明的抗菌活性化合物的特殊优点是,它们对于β-内酰胺酶稳定,因此,可对产生β-内酰胺酶的生物体有效。
本发明还提供了一种制备R为异丁酰氧基甲基或苯甲酰氧基甲基的式(I)化合物的方法,该方法包括用式XCH2OCOCHMe2或XCH2OCOC6H5的化合处理R为碱金属阳离子的相应的式(I)化合物,其中X为离去基团如卤原子,更优选为溴或碘。
该反应通常在0-60℃(例如室温)及惰性气氛(例如氩气氛)下,在适宜的溶剂中进行,溶剂如N-甲基吡咯烷-2-酮。其它适宜的溶剂体系包括N,N′-二甲基甲酰胺和N,N′-二甲基乙酰胺。
本发明还提供了一种制备式(I)化合物的方法,其中R为(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基,该方法包括用下式的化合物处理R为碱金属阳离子的相应的式(I)化合物,其中,X为离去基团,如卤原子,优选溴或碘。
该反应通常在0-60℃(例如室温)下,在适宜的有机溶剂(如N-甲基吡咯烷-2-酮)中,在适宜的酸结合剂(如2,6二甲基吡啶)存在下进行。其它适宜的酸结合剂包括吡啶和二异丙基乙基胺。其它适宜的溶剂包括N,N′-二甲基甲酰胺和N,N′-二甲基乙酰胺。
在PCT/GB94/02347及下面的制备1中描述了R是碱金属阳离子特别是钠的式(I)化合物。
式I的化合物CH2OCOCHMe2(异丁酸碘甲酯)和苯甲酸碘甲酯可通过Finkelstein反应由相应的氯化物制备,该反应是本领域技术人员公知的。
异丁酸氯甲酯和苯甲酸氯甲酯可通过分别用氯代硫酸氯代甲酯来酯化异丁酸或苯甲酸制得(Binderup等,Synthetic Commun.,14(9),857-864(1984))。下述实施例用于进一步说明本发明。
一般性指示:溶液采用无水硫酸镁进行干燥,溶剂使用旋转蒸发器经减压蒸发除去。硅胶柱色谱采用Merck硅胶60,粒径<0.063mm。实施例1异丁酰氧基甲基-(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]碳代青霉-2-烯-3-羧酸酯
将来自制备例1的产物(200mg,0.61mmol)溶解于N-甲基吡咯烷-2-酮(2ml)中。在室温及氩气氛下,向该溶液中加入异丁酰氧基甲基碘(360mg,1.6mmol)的N-甲基吡咯烷-2-酮(0.5ml)溶液,0.5小时后,反应混合物用乙酸乙酯(15ml)稀释,用水(3×15ml)、5%硫代硫酸钠溶液(15ml)和饱和盐水(15ml)洗涤。有机层经干燥(硫酸钠)后,浓缩成一种油,将其用硅胶色谱纯化(用丙酮/甲苯梯度混合物洗脱),产生浅黄色固体;由乙醚进行重结晶得到标题化合物,为浅黄色微针状结晶(100mg,40%),m.p.107-8℃;(实验值:M+,405.1899.C20H27N3O6理论值M 405.1900);νmax(CHCl3)3458,3019,1772and 1734cm-1;δH(CDCl3)1.19(6H,d,J7.1Hz),1.36(3H,d,J6.1Hz),1.40(3H,t,J7.2Hz),1.76(1H,d,J4.9Hz),2.29(3H,s),2.62(1H,septet,J7.1Hz),3.18(1H,dd,J2.7,6.5Hz),3.30(1H,dd,J9.0,18.8Hz),3.64(1H,dd,J9.8,18.8Hz),4.08(2H,q,J7.2Hz),4.16-4.30(2H,m),5.92(1H,d,J5.6Hz),5.98(1H,d,J5.6Hz)和7.02(1H,s).实施例2(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基(5R,6S)-6-[(R)-1-羟乙基]-2(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸酯
将(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)-碳代青霉-2-烯-3-羧酸钠(300mg)的N-甲基吡咯烷酮(4ml)溶液用2,6-二甲基吡啶(约30mg)处理,随后,再用4-溴甲基-5-甲基-1,3-二氧杂环戊二烯-2-酮(290mg)[F.Sakamoto,S.Ikeda和G.Tsukamoto,Chem.Pharm Bull.32,(6),2241-2248(1984)]的四氢呋喃(1ml)溶液处理。将混合物搅拌1.25小时。加入乙酸乙酯和水,将两层分开。水层用乙酸乙酯再次萃取,合并乙酸乙酯层,用水洗涤,再用饱和盐水溶液洗涤,然后干燥(硫酸镁)。过滤后的溶液在冰箱中过夜贮存,然后蒸发,并用硅胶(230-400目ASTM)(2.5×12cm柱)进行色谱处理,载于CH2Cl2/己烷上,用乙酸乙酯洗脱。合并包含产物的馏分并蒸发,得到无色固体,将其用丙酮重结晶,得到(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基(5R,6S)-6-[(R)-1-羟乙基]-2-[1-乙基-5-甲基吡唑-3-基]碳代青霉-2-烯-3-羧酸酯,m.p.148-151℃;νmax(CH2Cl2)3605,2975,1823,1776,1737(sh),1721,1598,1546,1314,1231,and 1182cm-1;λmax(EtOH/nm325(ε/dm3mol-1cm-114,654),260.5(ε/dm3mol-1cm-13404);δ(CDCl3)1.36(3H,d,J6.2Hz),1.40(3H,t,Jca.7.3Hz),1.76(1H,d,J4.9Hz),2.21(3H,s),2.30(3H,s),3.19(1H,dd,J2.7&6.5Hz),3.31(1H,dd,UJ9.0&18.7Hz),3.61(1H,dd,J9.9&18.7Hz),4.08(2H,q,J7.3Hz),4.16-4.30(2H,m),5.00&5.07(2H,ABq,J13.9Hz),6.88(1H,s)ppm;实验值(EIms)m/z417(m+)实施例3苯甲酰氧基甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]碳代青霉2烯-3-羧酸酯
将来自制备例1的产物(200mg,0.61mmol)溶解于N-甲基吡咯烷-2-酮(2ml)中。在室温及氩气氛下,向该溶液中加入苯甲酰氧基甲基碘(336mg,1.28mmol)的N-甲基吡咯烷-2-酮(0.5ml)溶液,0.5小时后,反应混合物用乙酸乙酯(15ml)稀释,用水(3×15ml)、5%硫代硫酸钠溶液(15ml)和饱和盐水(15ml)洗涤。有机层经干燥(硫酸钠)后,浓缩成一种油,将其用硅胶色谱纯化(用丙酮/甲苯梯度混合物洗脱),产生浅黄色固体;由丙酮/乙醚进行重结晶得到标题化合物,为白色固体(143mg,53%),m.p.131-4℃;(实验值:M+,4391743.C22H25N3O6理论值M439.1743);νmax(CHCl3)3021,1740,1602,1452和1440cm-1;δH(CDCl3)1.34(6H,m),1.70(1H,d,J4.9Hz),2.25(3H,s),3.19(1H,dd,J2.4,6.3Hz),3.30(1H,dd,J8.8,18.8Hz),3.64(1H,dd,J10.1,18.8Hz),4.07(2H,q,J7.2Hz),4.18-4.31(2H,m),6.20(2H,s),7.42-7.48(2H,m),7.56-7.61(1H,m),and8.10(2H,d,J7.1Hz)ppm制备例1(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸钠(a)1-乙基-5-甲基吡唑-3羧酸乙酯
将草酸N-乙基肼(12g)的冰醋酸(100ml)溶液在冰浴中冷却,用2,4-二氧杂戊酸乙酯(11.24mmol)处理。添加完成后,在室温下搅拌混合物;约45分钟后,将混合物升温以使不溶解的草酸乙基肼溶解。将混合物再搅拌2小时,然后,将其倒入水(约300ml)/乙酸乙酯(约700ml)中,边搅拌边小心加入碳酸钾,直至pH呈中性。分离后,水层用乙酸乙酯再次萃取。合并后的乙酸乙酯萃取相用硫酸镁干燥,除去溶剂,得到一种油。经硅胶色谱处理(用CH2Cl2/己烷装柱,乙酸乙酯/己烷混合物(2∶8-1∶1)梯度洗脱),得到1-乙基-5-甲基吡唑-3-羧酸乙酯油(13.2g);νmax(CH2Cl2)1717,1446,1389,and 1219cm-1;δ(CDCl3)1.38(3H,t,J7.2Hz),1.42(3H,t,J7.3Hz),2.30(3H,s),4.17(2H,q,J7.3Hz),4.38(2H,q,J7.1Hz),6.55(1H,s);(实验值m/z182.1055.C9H14N2O2理论值m/z182.1055).(b)1-乙基-5-甲基吡唑-3-羧酸
1-乙基-5-甲基吡唑-3羧酸乙酯(10.93g)的乙醇(70ml)溶液用KOH(3.69g)处理,再用水(30ml)处理,在回流下搅拌并加热混合物6小时。用旋转蒸发器除去乙醇,加入乙酸乙酯/水。将混合物的pH值调节至3.0,将两层分开。水层用乙酸乙酯再次萃取。合并后的乙酸乙酯层用过量的碳酸氢钠水溶液萃取。将碳酸氢钠萃取相倒入过量的酸中,将pH值调节至3,向溶液中加入氯化钠。再次用乙酸乙酯萃取混合物,合并后的萃取相用硫酸镁干燥,蒸发。残余物用乙醚研制,得到固体酸(5.65g);νmax(CH2Cl2)2754,2598,1698,1498,1464,1387,and 1233cm-1;δ(CDCl3)1.40(3H,t,J7.3Hz),2.32(3H,s),4.19(2H,q,J7.3Hz),6.61(1H,s)ppm;(实验值m/z 154.0740.C7H10N2O2理论值m/z 154.0742).(c)N-甲氧基-N-甲基-1-乙基-5-甲基吡唑-3-羧酰胺
将包含N,N-二甲基甲酰胺(0.26ml)的无水二氯甲烷(100ml)中的1-乙基-5-甲基吡唑-3-羧酸乙酯在冰浴中冷却,用滴加进去草酰氯(3.27ml)的二氯甲烷(25ml)溶液进行处理。冷却下搅拌混合物25分钟,当观察到气体逸出时,使其升温至室温。10分钟后,通过真空蒸发除去溶剂,加入甲苯并除去(2次)以确保除去所有残余的HCl和草酰氯。将形成的酰氯溶解于无水二氯甲烷中,再用N,O-二甲基羟基胺盐酸盐(3.61g)处理。将混合物在冰浴中冷却,用吡啶(6.0ml)处理。然后,将混合物在室温下搅拌1.5小时,用乙醚(100ml)稀释,用盐水洗涤。有机层用硫酸镁干燥,蒸发得到一种油。将其用硅胶色谱处理(负载于二氯甲烷上,用乙酸乙酯/己烷混合物洗脱,在蒸发出必需的馏分后,得到异羟肟酸酯(hydroxamate)(5.2g)固体;νmax(CH2Cl2)2982,2937,1641,1489,1445,1379,and 975cm-1;δ(CDCl3)1.43(3H,t,J7.3Hz),2.29(3H,s),3.42(3H,s),3.76(3H,s,),4.13(2H,q,J7.3Hz),6.49(1H,s);(实验值m/z 197.1164.C9H15N3O2理论值m/z 197.1164).(d)3-乙酰基-1-乙基-5-甲基吡唑
于无水四氢呋喃(60ml)中的N-甲氧基-N-甲基-1-乙基-5-甲基吡唑-3-羧酰胺(3.12g)在冰浴中冷却,用3.0M的溴甲基镁的乙醚(11.08ml)溶液处理。搅拌1.5小时后,将混合物倒入于冰浴中甲醇(100ml)和5M盐酸水溶液(10ml)的混合物中。然后,将混合物蒸发减少体积,用二氯甲烷、水和饱和盐水的混合物处理。分离后,水层再用二氯甲烷萃取。将合并后的二氯甲烷萃取液干燥(硫酸镁),蒸发得到一种油(2.26g),静置后固化;νmax(CH2Cl2)1680,1446,1425,1380,1324,1208,and 945cm-1;δ(CDCl3)1.44(3H,t,J7.3Hz),2.30(3H,s),2.53(3H,s)4.13(2H,q,J7.3Hz,),6.51(1H,s);(Found m/z 152.0949,C8H12N2O requires m/z 152.090).(e)(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]氮杂环丁-2-酮
在氩气氛下,将无水四氢呋喃(THF)(150ml)中的3-乙酰基-1-乙基-5-甲基吡唑(3.51g)于丙酮/固体二氧化碳浴中冷却,然后用1M的双(三甲基甲硅烷基)酰胺锂(50ml)的溶液处理。将混合物搅拌45分钟,然后在掩蔽下或氩气氛下,加入(3R,4R)4-乙酰氧基3-[(1R)-1-叔丁基二甲基甲硅烷基氧基乙基]氮杂环丁酮(6.6g)。然后在冷却下搅拌混合物3.5小时。随后加入饱和氯化铵水溶液,再加入乙酸乙酯,将混合物升温至室温。加入少量水,将两层分开,水层用乙酸乙酯再次萃取。合并后的乙酸乙酯层用饱和盐水洗涤,干燥,蒸发。经硅胶色谱处理(用乙酸乙酯/己烷混合物洗脱)得到标题化合物(3.65g),νmax(CH2Cl2)3411,1761,1678,1376,1151,and 838cm-1;δ(CDCl3)0.064(6H,s),0.86(9H,s),1.20(3H,d,J6.3Hz),1.44(3H,t,J7.3Hz),2.31(3H,s),2.89(1H,dd,J1.8&4.9Hz),3.15(1H,dd,J10.0&17.1Hz),3.50(1H,dd,J3.5&17.0Hz),4.06-4.25(4H,m),6.11(1H,s),6.53(1H,s).(实验值m/z379.2296.C19H33N3O3Si理论值m/z379.2291).(f)(2R和2S)-2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]-2-氧代氮杂环丁烷基}-2-羟基乙酸烯丙酯
在氩气氛下,在Dean and Stark装置中,回流加热于甲苯(100ml)中的(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]氮杂环丁-2-酮(3.6g)和乙醛酸烯丙酯水合物(1.66g),加热3.5小时。反应混合物的T.l.c.表明,反应几乎完成,再加入更多的乙醛酸烯丙酯水合物(190mg),将混合物继续加热回流45分钟。将混合物冷却,除去甲苯,得到粗的(2R和2S)-2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]-2-氧代氮杂环丁烷基}-2-羟基乙酸烯丙酯,它可用于下一步骤;νmax(CH2Cl2)3681,3518,1758,1676,1448,1376,1326,1209,1148,1092,954,和836cm-1;δ(CDCl3)inter alia 0.035(s),0.061(s)(together 6H,),0.858(s),0.865(s)(together 9H),1.21(d,J6.2Hz),1.24(d,J6.2Hz),(together 3H),1.44(3H,t,J7.2Hz),2.31(3H,s),2.95-3.00(1H,m),3.25-3.64(2H,m),6.53(s),6.56(s)ppm.(g)(2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]-2氧代氮杂环丁烷基}-2-(三正丁基正膦亚基(phosphoranylidene))乙酸烯丙酯
将无水THE(125ml)中的(2R和2S)-2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-叔丁基二甲基甲硅烷基氧基乙基]-2-氧代氮杂环丁烷基}-2羟基乙酸烯丙酯(来自上述步骤的粗产物)在氩气氛下冷却至-20℃,用2,6-二甲基吡啶(1.98ml)处理,再用亚硫酰氯(1.24ml)处理。将混合物在-20℃下搅拌30分钟,使其升温至室温,过滤,用THF(20ml)洗涤残余物。滤液通过真空蒸发,加入甲苯(70ml)真空除去,残余油真空干燥。然后,在氩气氛下,将油吸收于1,4-二氧杂环己烷(40ml)中,用三正丁基膦(3.11ml)处理。混合物继续搅拌1小时。然后,加入2,6-二甲基吡啶(1.59ml),混合物再搅拌30分钟。用乙酸乙酯稀释混合物,用水再用盐水洗涤,干燥(硫酸镁)。除去乙酸乙酯后,粗产物经硅胶色谱处理(洗脱液为乙酸乙酯/己烷混合物),得到正膦,它可用于下一步骤。(h)(2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]-3-[(R)-1-羟乙基]-2-氧代氮杂环丁烷基}-2-(三正丁基正膦亚基))乙酸烯丙酯
上述步骤制备的正膦溶于1,4二氧杂环己烷(60ml)中,用5M的HCl(20ml)处理。1小时后,小心地用约40ml的饱和碳酸氢钠水溶液进行处理,再用固体碳酸氢钠进行处理,直至pH呈微碱性。加入饱和盐水,混合物用乙酸乙酯萃取两次。合并后的萃取液用硫酸镁干燥,蒸发。残余物经硅胶色谱处理(用乙酸乙酯/己烷混合物洗脱),得到羟基化合物(2.6g);νmax(CH2Cl2)3454,1741,1667,1606,1448,1403,1379,1155,1087,953,and 811cm-1;(i)(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸烯丙酯
将包含氢醌(20mg)于甲苯(120ml)中的(2-{(3S,4R)-4-[(1-乙基-5-甲基吡唑-3-基)羰基甲基]3-[(R)-1-羟乙基]-2-氧代氮杂环丁烷基}-2-(三正丁基正膦亚基))乙酸烯丙酯在氩气氛下加热回流4小时,放置64小时,然后再加热回流2小时。将混合物冷却,然后负载于硅胶(粒径为0.040-0.063mm)柱上(45×12cm),用乙酸乙酯/己烷混合物以1∶1;6∶4;7∶3;8∶2;9∶1洗脱(每次250ml),再用乙酸乙酯洗脱。得到碳代青霉烯(436mg);νmax(CH2Cl2)3604,2976,1774,1716,1600,1546,1311,1189cm-1;λmax(EtOH)/nm 321.5(ε/dm3mol-1cm114,856),δ(CDCl3)1.36(3,J6.3Hz),1.39(t,J7.3Hz)(together 5H),1.80(1H,d,J5.0Hz),2.28(3H,s),3.19(1H,dd J2.7&6.7Hz),3.28(1H,dd,J9.0&18.6Hz),3.60(1H,dd,J9.9&18.5Hz),4.08(2H,q,J7.3Hz),4.16-4.30(2H,m),4.68-4.90(2H,m),5.27(1H,m,approxd,J ca12Hz),5.46(m,approx d,J ca.17Hz),5.93-6.08(1H,m),7.00(1H,s)ppm;[实验值m/z 345.1693.C18H23N3O4理论值m/z 345.1689].(j)(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸钠
在氩气氛下,将二氯甲烷(3ml)和乙酸乙酯(3ml)中的(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸烯丙酯(267mg)用2-乙基己酸钠(183mg)处理,再用三苯膦(24mg)处理,再用四(三苯膦)钯(0)(35mg)处理,将混合物搅拌45分钟。加入乙醚(100ml),搅拌90分钟后,将混合物离心分离。残余的固体在氩气流中干燥,然后置于一个干燥器中。然后,将固体吸收于包含氯化钠的水中,并在DIAIONHp20SS树脂进行色谱处理,用水洗脱,再用1%、2%、3%水/THF混合物洗脱。通过HPLC检测馏分,合并包含产物的馏分,减少其体积,冷冻干燥,得到(5R,6S)-6-[(R)-1-羟乙基]-2-(1-乙基-5-甲基吡唑-3-基)碳代青霉-2-烯-3-羧酸钠固体(168mg);νmax(KBr)1761,1608,1577,1381,1225cm-1;λmax(H2O)/nm 298(ε/dm3mol-1cm-18,531);δ(D2O)1.26(d,J ca.6Hz),1.27(d,J ca.7Hz)(together 5H),2.23(3H,s),3.17(2H,approx d,J ca.9Hz),3.44(1H,dd,J 2.9&6.0Hz),4.04(2H,q,J 7.3Hz),4.15-4.25(2H,m),6.41(1H,s)ppm.
Claims (9)
1.一种式(I)的化合物:其中,R选自:异丁酰氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基和苯甲酰氧基甲基。
2.异丁酰氧基甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]-碳代青霉-2-烯-3-羧酸酯。
3.(5-甲基2-氧代-1,3-二氧杂环戊烯-4-基)甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]-碳代青霉-2-烯-3-羧酸酯。
4.苯甲酰氧基甲基(5R,6S)-2-[1-乙基-5-甲基吡唑-3-基]-6-[(1R)-1-羟乙基]-碳代青霉-2-烯-3-羧酸酯。
5.一种药物组合物,它包含上述任一项权利要求所述的化合物和药物可接受的载体或赋形剂。
6.一种治疗人体和动物细菌感染的方法,该方法包括给药治疗有效量的上述权利要求1-4任一项的化合物。
7.权利要求1-4任一项的化合物在生产治疗细菌感染药物中的应用。
8.一种制备R为异丁酰氧基甲基或苯甲酰氧基甲基的式(I)化合物的方法,该方法包括用式XCH2OCOCHMe2或XCH2OCOC6H5的化合物处理R为碱金属阳离子的相应的式(I)化合物,其中X为离去基团。
9.一种制备如上权利要求1式(I)化合物的方法,其中R为(5-甲基-2-氧代-1,3-二氧杂环戊烯4-基)甲基,该方法包括用下式的化合物处理R为碱金属阳离子的相应的式(I)化合物,其中,X为离去基团。
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Application Number | Priority Date | Filing Date | Title |
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GBGB9508957.9A GB9508957D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
GB9508956.1 | 1995-05-03 | ||
GBGB9508956.1A GB9508956D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
GB9508955.3 | 1995-05-03 | ||
GB9508957.9 | 1995-05-03 | ||
GBGB9508955.3A GB9508955D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
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CA (1) | CA2217990A1 (zh) |
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HU (1) | HUP9801066A3 (zh) |
IL (1) | IL118092A0 (zh) |
MA (1) | MA23853A1 (zh) |
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OA (1) | OA10632A (zh) |
PE (1) | PE50697A1 (zh) |
PL (1) | PL323141A1 (zh) |
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WO2013157583A1 (ja) * | 2012-04-18 | 2013-10-24 | 大日本住友製薬株式会社 | 新規カルバペネム化合物 |
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CA1212105A (en) * | 1980-04-30 | 1986-09-30 | Shoji Ikeda | Ampicillin esters and production thereof |
WO1995005380A1 (fr) * | 1993-08-18 | 1995-02-23 | Sankyo Company, Limited | Derives cristallins de carbapenem |
CA2175054C (en) * | 1993-10-29 | 2005-07-12 | Steven Coulton | 2-(pyrazol-3-yl)carbapenem derivatives |
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BG102014A (en) | 1998-11-30 |
PL323141A1 (en) | 1998-03-16 |
NO974994D0 (no) | 1997-10-30 |
CA2217990A1 (en) | 1996-11-07 |
MX9708421A (es) | 1998-02-28 |
CZ347597A3 (cs) | 1998-08-12 |
EA199700293A1 (ru) | 1998-06-25 |
OA10632A (en) | 2002-09-16 |
KR19990008355A (ko) | 1999-01-25 |
WO1996034868A1 (en) | 1996-11-07 |
NO974994L (no) | 1997-10-30 |
PE50697A1 (es) | 1997-12-18 |
AU5813996A (en) | 1996-11-21 |
BR9608313A (pt) | 1999-01-26 |
HUP9801066A2 (hu) | 1998-08-28 |
IL118092A0 (en) | 1996-09-12 |
JPH11504910A (ja) | 1999-05-11 |
HUP9801066A3 (en) | 1999-01-28 |
EP0823910A1 (en) | 1998-02-18 |
MA23853A1 (fr) | 1996-12-31 |
TR199701286T1 (xx) | 1998-02-21 |
AR005416A1 (es) | 1999-06-23 |
SK146497A3 (en) | 1998-05-06 |
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