CN101367812B - Sulfhydryl pyrrolidine formamido cyclopentene acid substituted penem derivant - Google Patents
Sulfhydryl pyrrolidine formamido cyclopentene acid substituted penem derivant Download PDFInfo
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- CN101367812B CN101367812B CN2008101293466A CN200810129346A CN101367812B CN 101367812 B CN101367812 B CN 101367812B CN 2008101293466 A CN2008101293466 A CN 2008101293466A CN 200810129346 A CN200810129346 A CN 200810129346A CN 101367812 B CN101367812 B CN 101367812B
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- Prior art keywords
- methyl
- hydrogen atom
- represent hydrogen
- compound
- acceptable salt
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- -1 Sulfhydryl pyrrolidine formamido cyclopentene Chemical compound 0.000 title claims abstract description 105
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Natural products C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 title abstract description 6
- 241001597008 Nomeidae Species 0.000 title 1
- 150000002961 penems Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 12
- 241000894006 Bacteria Species 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
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- 125000002217 penem group Chemical group 0.000 abstract 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JLZWQNRGNMXIJY-UHFFFAOYSA-N triethylstannane Chemical compound CC[SnH](CC)CC JLZWQNRGNMXIJY-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention belongs to the technical field of medicine, in particular to a penem derivative substituted by mercaptopyrrolidine formamido cyclopentene acid shown in the formula (I) and a pharmaceutically acceptable salt, an easily hydrolyzed ester, an isomer, a hydrate and a hydrate of the ester or the salt thereof: wherein, R<1>, R<2>, R<3>, R<4> and R<5> are defined in the description. The present invention also relates to preparation methods of the compounds, drug combinations and applications of the compounds in the preparation of drugs for treating and/or preventing infective diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to the hydrate of ester, its isomer, its hydrate and the ester or the salt of Pennem derivates that sulfhydryl pyrrolidine formamido cyclopentene acid replaces, its pharmacy acceptable salt, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infectious diseases.
2, background technology
Carbapenem antibiotic is the class β-Nei Xiananleikangshengsu that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
First listing be imipenum, gram-positive and negative, aerobic and anerobe all there is very strong activity, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with dehydropeptidase of kidney inhibitor cilastatin clinically in vivo.
Discover, introduce 1 Beta-methyl, can strengthen the stability of carbapenem compound DHP-I.For example meropenem is all responsive to gram positive organism, gram-negative bacteria, especially gram-negative bacteria is had very strong anti-microbial activity.
Because antibiotic abuse causes the continuous increase of bacterial drug resistance, and because the limitation that digestive tube absorbs, the carbapenems of listing clinically can only be as the injection administration at present, and clinical availability is not high.
Therefore, be badly in need of research and development and have better antibacterial activity, and have the long-acting carbapenem antibiotic of good chemical stability and DHP-I stability.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides ester, its isomer, its hydrate of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, and the hydrate of ester or salt:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group;
R
2Represent hydrogen atom or amino protecting group;
R
3Represent hydrogen atom or C
1-4Alkyl;
R
4Represent hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, carbamyl, C
1-4Alkoxyl group is replaced or unsubstituted C by halogen atom, hydroxyl, amino, carboxyl, amide group, sulfonic group, sulfonic acid amido, carbamyl
1-4Alkyl;
R
5Represent hydrogen atom or C
1-4Alkyl.
Preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
R
3Represent hydrogen atom, methyl or ethyl;
R
4Represent hydrogen atom, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, methyl, ethyl or carbamyl;
R
5Represent hydrogen atom, methyl or ethyl.
Further preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
R
3Represent hydrogen atom or methyl;
R
4Represent hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl, methyl or carbamyl;
R
5Represent hydrogen atom or methyl.
Part of compounds of the present invention
| Numbering | R 1 | R 2 | R 3 | R 4 | R 5 |
| 1 | H | H | H | H | H |
| 2 | H | H | H | H | -CH 3 |
| 3 | H | H | -CH 3 | H | H |
| 4 | H | H | -CH 3 | H | -CH 3 |
| 5 | H | -CH 3 | H | H | H |
| 6 | H | -CH 3 | H | H | -CH 3 |
| 7 | H | -CH 3 | -CH 3 | H | H |
| 8 | H | -CH 3 | -CH 3 | H | -CH 3 |
" C of the present invention
1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-4Alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: methyl, ethyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.
Further preferred compound is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compd A, structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following preparation method:
Reaction equation:
Reactions steps:
The preparation of step 1 compound 1
Add raw material 1 in the exsiccant reaction flask, anhydrous tetrahydro furan is under nitrogen protection; add 1 in room temperature; 1-carbonyl dimidazoles (CDI) reaction, low temperature adds the tetrahydrofuran solution of raw material 2, continues reaction; dripping hydrochloric acid is an amount of then; with ethyl acetate extraction, organic phase is water, saturated nacl aqueous solution washing successively, concentrating under reduced pressure; solid gets compound 1 with the ethanolic soln recrystallization.
The preparation of step 2 compound 2
The dichloromethane solution that in reaction flask, adds compound 1, the ice bath cooling, the adding triethylamine is an amount of, stirs the back and drips (Boc)
2The dichloromethane solution of O stirs, and adds entry under the frozen water cooling, divide water-yielding stratum, water layer is used dichloromethane extraction again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds hydrochloric acid, stir, be adjusted to alkalescence, separate out solid with dilute alkaline soln, solid gets compound 2 with the acetonitrile recrystallization.
The preparation of step 3 compound 3
In the dry reaction bottle, add the acetonitrile solution of raw material 3, cooling, the acetonitrile solution of adding diisopropylethylamine and compound 2, low temperature stirs, and after reaction finishes, adds the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets compound 3.
The preparation of step 4 compound 4
Compound 3 is dissolved in the methylene dichloride, adds methyl-phenoxide and Nitromethane 99Min., low temperature drips the Nitromethane 99Min. solution of aluminum chloride, stir, add entry, separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, adding palladium-charcoal is an amount of, stirring reaction under the room temperature hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, layering, collect water layer, in THF, add magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation, water merges, and slowly splashes into methyl alcohol, stir, filter, the filter cake recrystallization promptly gets compound 4.
R in the above reaction equation
3, R
4, R
5The representative group as mentioned before, the carboxyl in the compound 4 can be protected by carboxyl-protecting group, the hydrogen atom on the nitrogen-atoms can be protected by amino protecting group.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises inorganic acid salt, organic acid salt, amino acid salts, organic alkali salt or inorganic base salts.Wherein mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.; Organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid etc.; Amino acid comprises arginine, aspartic acid, L-glutamic acid etc.; Organic bases comprises meglumine, glucosamine, Trimethylamine, triethylamine, dicyclohexylamine, N, N-dibenzyl-1 etc.; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium etc.These acid or base addition salt can be according to any universal method preparations.
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetyl-o-methyl ester, pivalyl oxygen methyl ester, 1-acetyl 2-ethoxyethyl acetate and 1-pivalyl 2-ethoxyethyl acetate; Rudimentary alkyl oxy carbonyl oxygen alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, the different third oxygen ketonic oxygen ethyl ester of 1-; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane amido methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester; The 1-[[(1-methyl ethoxy) carbonyl] the oxygen base] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound.
Isomer of the present invention is meant its all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has many three-dimensional centers, as on the 4-position; On the 5-position; On the 6-position.
Hydrate of the present invention is meant semihydrate, monohydrate, dihydrate, trihydrate, hexahydrate etc.The ester of compound, its pharmacy acceptable salt, its facile hydrolysis can be the form of hydrate shown in the general formula (I).Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients, as with the pharmaceutical composition of cilastatin or its sodium salt, Betamipron etc.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.05g～5g shown in the general formula (I) of physiology significant quantity, can be 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g etc.
The ester of The compounds of this invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate, with and the hydrate of ester or salt, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Usually, have been found that carbapenems is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.With preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria, not to be noted by caused tangible poisoning aura of The compounds of this invention or side effect to the mouse administration.
The present invention also provide Pennem derivates of the present invention preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Pennem derivates of the present invention all has better antibacterial activity to gram-positive microorganism and negative bacterium, aerophil and anerobe and hospital clinical pathogenic bacteria such as Pseudomonas aeruginosa and acinetobacter bacterium, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
The Pennem derivates that sulfhydryl pyrrolidine formamido cyclopentene acid of the present invention replaces is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) The compounds of this invention has a broad antifungal spectrum all has better antibacterial activity to gram-positive microorganism and negative bacterium, aerophil and anerobe and hospital clinical pathogenic bacteria;
(3) The compounds of this invention has high stability to β-Nei Xiananmei and DHP-I, can be used for β-Nei Xiananmei and produces bacterium, and do not need to share with other medicines;
(4) The compounds of this invention preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of the Pennem derivates that sulfhydryl pyrrolidine formamido cyclopentene acid of the present invention replaces by in-vitro antibacterial experiment, but this should be interpreted as that Pennem derivates of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For the examination bacterial classification: below be the clinical isolates strain, purchase in public institution.
Gram positive organism: MSSA (MSSA) 18 strains, methicillin-resistant staphylococcus aureus (MRSA) 11 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 19 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 13 strains, responsive streptococcus pneumoniae (PSSP) 25 strains of penicillin, penicillin resistance streptococcus pneumoniae (PRSP) 15 strains, streptococcus pyogenes 20 strains, enterococcus faecalis 15 strains;
Gram-negative bacteria: hemophilus influenzae 12 strains, escherichia coli 18 strains, klepsiella pneumoniae 20 strains, Proteus mirabilis 16 strains, enterobacter cloacae 17 strains, Pseudomonas aeruginosa 17 strains; Grain-negative anerobe: bacteroides fragilis 7 strains.
Trial-product:
Preferred compound A of the present invention, self-control, its chemical name and structural formula are as mentioned before;
Imipenum, meropenem: commercial.
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 1 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A all has the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A comprises that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.
Above-mentioned experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (2S, 4S)-preparation of 4-acetylthio-2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-tetramethyleneimine
In the exsiccant reaction flask, add (2S; 4S)-4-acetylthio-2-carboxyl-tetramethyleneimine 9.5g (50mmol); anhydrous tetrahydro furan 150ml; under nitrogen protection; add 1 in room temperature; 1-carbonyl dimidazoles 13g (80mmol), reaction 0.5h is at the tetrahydrofuran solution 100ml that adds 4-amino cyclopentyl-2-olefin(e) acid 7.6g (60mmol) below 0 ℃; continue reaction 0.5h; drip 1mol/L hydrochloric acid 60ml then, extract with ethyl acetate (100ml * 2), organic phase is water successively; the saturated nacl aqueous solution washing; concentrating under reduced pressure; solid gets product 11.6g, yield: 77.6% with the ethanolic soln recrystallization.
Embodiment 2 (2S, 4S)-4-sulfydryl-2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-1-tertbutyloxycarbonyl tetramethyleneimine
Preparation
In reaction flask, add (2S, 4S)-the dichloromethane solution 100ml of 4-acetylthio-2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-tetramethyleneimine 9.0g (30mmol), ice bath is chilled under 5 ℃, adds triethylamine 12ml, stirs the back and drips 15g (Boc)
2The dichloromethane solution 100ml of O stirs 1h, and the frozen water cooling adds 100ml water down, divide water-yielding stratum, water layer is used the dichloromethane extraction of 50ml * 3 again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds the hydrochloric acid 100ml of 3mol/L, stirs 2h, is adjusted to alkalescence with dilute alkaline soln, separate out solid, solid gets product 9.3g, yield: 87.1% with the ethyl hydrazine recrystallization.
Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-1-tertbutyloxycarbonyl pyrroles
Alkane-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's system
Be equipped with
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] the acetonitrile solution 120ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol) is chilled to below-10 ℃, adds diisopropylethylamine 5ml and (2S, 4S)-the acetonitrile solution 80ml of 4-sulfydryl-2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-1-tertbutyloxycarbonyl tetramethyleneimine 7.5g (21mmol), 0 ℃ is stirred 15h, after reaction finishes, adds ethyl acetate 300ml dilution, water successively, the saturated salt washing, the organic layer drying, concentrate, get product 10.2g, yield: 72.7%.
Embodiment 4 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-tetramethyleneimine-4-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-1-tertbutyloxycarbonyl tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.0g (10mmol) is dissolved in the 50ml methylene dichloride, add methyl-phenoxide 10ml and Nitromethane 99Min. 40ml, in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down ,-40 ℃ are stirred 2h, add entry 200ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 400ml THF and water 30ml, add 10% palladium-charcoal 2g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF150ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 30ml, and-10 ℃ are stirred 1h, filters, and the filter cake recrystallization gets target product 2.1g, yield: 45.6%.
Molecular formula: C
21H
27N
3O
7S
Molecular weight: 465.22
Ultimate analysis:
Measured value: C, 54.10%; H, 5.96%; N, 8.89%; S, 6.73%
Theoretical value: C, 54.18%; H, 5.85%; N, 9.03%; S, 6.89%
The preparation of embodiment 5 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Compd A 250g (in compound)
Prepare 1000 altogether
Prescription 2:
Compd A 500g (in compound)
Prepare 1000 altogether
Prescription 3:
Compd A 1000g (in compound)
Prepare 1000 altogether
Prescription 4:
Compd A 2000g (in compound)
Prepare 1000 altogether
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time;
(3) jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention tablets
1, prescription:
Prescription 1:
Compd A 250g (in compound)
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Compd A 125g (in compound)
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose v 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
(2) take by weighing raw material and auxiliary material according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) compd A, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
(5) cross 20 mesh sieve system particles.
(6) particle is dried under 60 ℃ condition.
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
(8) sampling, the work in-process chemical examination.
(9) the sheet weight sheet of determining according to chemical examination.
(10) finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2Represent hydrogen atom;
R
3Represent hydrogen atom or C
1-4Alkyl;
R
4Represent hydrogen atom, halogen atom, hydroxyl, amino or C
1-4Alkyl;
R
5Represent hydrogen atom or C
1-4Alkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2Represent hydrogen atom;
R
3Represent hydrogen atom, methyl or ethyl;
R
4Represent hydrogen atom, fluorine atom, chlorine atom, hydroxyl, amino, methyl or ethyl;
R
5Represent hydrogen atom, methyl or ethyl.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2Represent hydrogen atom;
R
3Represent hydrogen atom or methyl;
R
4Represent hydrogen atom, fluorine atom, chlorine atom or methyl;
R
5Represent hydrogen atom or methyl.
4. compound as claimed in claim 3 is (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [2-thiazolinyl-cyclopentyl formic acid-4-yl] amino-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, and pharmacy acceptable salt.
5. as each described compound of claim 1～4, its pharmacy acceptable salt is inorganic acid salt, organic acid salt, amino acid salts, organic alkali salt or inorganic base salts.
6. the pharmaceutical composition that comprises each described compound of claim 1～4 or its pharmacy acceptable salt and one or more pharmaceutical carriers.
7. pharmaceutical composition as claimed in claim 6, it is pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 6 contains each described compound of claim 1～4 or its pharmacy acceptable salt 0.05g～5g as essential activeconstituents.
9. each described compound of claim 1～4 or its pharmacy acceptable salt are in the application that is used for preparing the medicine that treats and/or prevents the infectious diseases that gram-positive microorganism, Gram-negative bacteria cause.
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Citations (5)
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|---|---|---|---|---|
| WO1993019070A1 (en) * | 1992-03-26 | 1993-09-30 | Zeneca Limited | Carbapenem derivatives as antibiotics and intermediates thereof |
| EP0551993B1 (en) * | 1992-01-10 | 1996-07-10 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
| CN1486316A (en) * | 2000-11-20 | 2004-03-31 | ������������ʽ���� | Processes for the preparation of carbapenem-type antibacterial agents |
| US20040176351A1 (en) * | 2001-09-26 | 2004-09-09 | Raymond Cvetovich | Process for making carbapenem compounds |
| CN1752074A (en) * | 2005-10-20 | 2006-03-29 | 上海交通大学 | Intermediate N-protection-(2S,4S)-2-[(3-hydroxyl carbonyl)-phenyl amino formyl)]-pyrrolidine-4-thio alcohol of ertabeinan |
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2008
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0551993B1 (en) * | 1992-01-10 | 1996-07-10 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
| WO1993019070A1 (en) * | 1992-03-26 | 1993-09-30 | Zeneca Limited | Carbapenem derivatives as antibiotics and intermediates thereof |
| CN1486316A (en) * | 2000-11-20 | 2004-03-31 | ������������ʽ���� | Processes for the preparation of carbapenem-type antibacterial agents |
| US20040176351A1 (en) * | 2001-09-26 | 2004-09-09 | Raymond Cvetovich | Process for making carbapenem compounds |
| CN1752074A (en) * | 2005-10-20 | 2006-03-29 | 上海交通大学 | Intermediate N-protection-(2S,4S)-2-[(3-hydroxyl carbonyl)-phenyl amino formyl)]-pyrrolidine-4-thio alcohol of ertabeinan |
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| Makoto Sunagawa,et al.Structural Features Resulting in Convulsive Activity of Carbapenem Compounds:Effect of C-2 Side Chain.the journal of antibiotics.1995,48(5),第408-416页. * |
| 孔漫.碳青霉烯类抗生素的研究进展.中国新药杂志.2003,12(9),第700-703页. * |
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