CN101367806B - Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds - Google Patents

Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds Download PDF

Info

Publication number
CN101367806B
CN101367806B CN2008101293409A CN200810129340A CN101367806B CN 101367806 B CN101367806 B CN 101367806B CN 2008101293409 A CN2008101293409 A CN 2008101293409A CN 200810129340 A CN200810129340 A CN 200810129340A CN 101367806 B CN101367806 B CN 101367806B
Authority
CN
China
Prior art keywords
methyl
compound
pharmaceutically acceptable
salt
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN2008101293409A
Other languages
Chinese (zh)
Other versions
CN101367806A (en
Inventor
黄振华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xuanzhu Biopharmaceutical Co Ltd
Original Assignee
Shandong Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Priority to CN2008101293409A priority Critical patent/CN101367806B/en
Publication of CN101367806A publication Critical patent/CN101367806A/en
Application granted granted Critical
Publication of CN101367806B publication Critical patent/CN101367806B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a formanilide substituted sulfhydryl pyrrolidine carbapenems compound as shown in Formula (I), easily hydrolyzed ester thereof, acceptable non-toxicity salt thereof in pharmacy, isomer thereof, hydrate thereof, and hydrate of ester or salt thereof. The present invention also relates to a preparation method of the compound as shown in Formula (I), application of the compounds as active substances for medicine, in particular to the application for preparing the medicine used for treating and/or preventing infectious diseases. The R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and X are defined in details in the specification.

Description

The sulfhydryl pyrrolidine carbpenem compounds that formylaniline replaces
1, technical field
The present invention relates to the hydrate of ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate and the ester or the salt of sulfhydryl pyrrolidine carbpenem compounds that formylaniline replaces, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are used to prepare the purposes of the medicine that treats and/or prevents infectious diseases, belong to medical technical field.
2, background technology
Carbapenems is the New-type wide-spectrum that grows up the seventies in 20th century, anti-enzyme, efficient β-Nei Xiananleikangshengsu.1976, find first carbapenem antibiotic---sulfomycin, but because poor chemical stability fails to be used for clinical.Afterwards sulfomycin is carried out the chemical structure transformation and produced a series of Carbpenem derivants.This similar drug that has gone on the market at present has imipenum, panipenem, meropenem, S-4661, biapenem, ertapenem etc.
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.
Because antibiotic abuse causes the continuous increase of bacterial drug resistance and the limitation that digestive tube absorbs, the carbapenems of listing clinically can only be as the injection administration at present, clinical availability is not high, and to the anti-microbial activity of MRSA a little less than, can not meet clinical needs.
3, summary of the invention
The inventor is through a large amount of research and practice, a series of carbapenem compounds have been synthesized, gram-positive and negative, aerobic and anerobe especially resistant organism are had the strong antibiotic activity, and chemical stability is good, compares with immediate prior art to have novelty and superiority.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate and the ester or the salt of compound, its facile hydrolysis shown in the general formula (I):
Figure S2008101293409D00011
Wherein: R 1, R 4Independently represent hydrogen atom or C respectively 1-4Alkyl;
R 2Expression hydrogen atom or carboxyl-protecting group;
R 3Expression hydrogen atom or amino protecting group;
R 5And R 6Identical or different, represent hydrogen atom respectively, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkyl hydroxy, C 1-4Alkylamino, C 1-4Alkyl carboxyl, C 1-4Alkylamidoalkyl, C 1-4Alkyl sulphonyl, C 1-4Alkylsulfonamido, carbamyl or C 1-4Alkylcarbamoyl group;
R 7And R 8Identical or different, represent hydrogen atom respectively, halogen atom, trifluoromethyl or C 1-4Alkyl;
X represents nitrogen-atoms, Sauerstoffatom or sulphur atom.
Preferred compound is:
In the general formula (I):
R 1, R 4Independently represent hydrogen atom or methyl respectively;
R 2Expression 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 3Expression 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 5And R 6Identical or different, represent hydrogen atom respectively, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, C 1-4Alkyl or carbamyl;
R 7And R 8Identical or different, represent hydrogen atom respectively, fluorine atom, chlorine atom, trifluoromethyl, methyl or ethyl;
X represents nitrogen-atoms or Sauerstoffatom.
Further preferred compound is:
In the general formula (I):
R 1Expression hydrogen atom or methyl;
R 2Expression 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 3Expression hydrogen atom or amino protecting group, described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tertbutyloxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
R 4The expression hydrogen atom;
R 5And R 6Identical or different, represent hydrogen atom respectively, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, methyl or carbamyl;
R 7And R 8Identical or different, represent hydrogen atom respectively, methyl or ethyl;
X represents Sauerstoffatom.
Table 1 part of compounds of the present invention
Numbering R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 X
1 H H H H H H H H O
2 H H H H H H -CH 3 -CH 3 O
3 H H H H H H -CH 2CH 3 -CH 2CH 3 O
4 H H H H H H H -CH 3 O
5 H H H H H H H -CH 2CH 3 O
6 -CH 3 H H H H H H H O
7 -CH 3 H H H H H -CH 3 -CH 3 O
8 -CH 3 H H H H H -CH 2CH 3 -CH 2CH 3 O
9 -CH 3 H H H H H H -CH 3 O
10 -CH 3 H H H H H H -CH 2CH 3 O
Particularly preferred compound is:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(N,N-DMAA-3-yl) phenyl amido]-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:
Figure S2008101293409D00031
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-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 B:
Figure S2008101293409D00032
" C of the present invention 1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.
" halogen " 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.
" C of the present invention 1-4Alkyl hydroxy " comprise methyl hydroxyl, ethyl hydroxyl, propyl hydroxy, sec.-propyl hydroxyl, butylhydroxy, tertiary butyl hydroxyl etc.
" C of the present invention 1-4Alkylamino " comprise methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, tertiary butyl amino etc.
" C of the present invention 1-4Alkyl carboxyl " comprise methyl carboxyl, ethyl carboxyl, propyl group carboxyl, sec.-propyl carboxyl, butyl carboxyl, tertiary butyl carboxyl etc.
" C of the present invention 1-4Alkylamidoalkyl " comprise formamido-, acetamido, propionamido-, Isopropamide base, amide-based small, t-butyl carboxamide base etc.
" C of the present invention 1-4Alkyl sulphonyl " comprise methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, different third alkylsulfonyl, fourth alkylsulfonyl, uncle's fourth alkylsulfonyl etc.
" C of the present invention 1-4Alkylsulfonamido " comprise methylsulfonyl amido, ethanesulfonamide group, third sulfoamido, different third sulfoamido, fourth sulfoamido, uncle's fourth sulfoamido etc.
" C of the present invention 1-4Alkylcarbamoyl group " comprise first carbamyl, second carbamyl, third carbamyl, different third carbamyl, fourth carbamyl, uncle's fourth carbamyl etc.
" carboxyl-protecting group " of the present invention is meant that routine is used for the blocking group of substituted carboxylic acid character.The example 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.
" amino protecting group " of the present invention is meant that routine is used for the blocking group of substituted-amino acid proton.The example 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; allyl group; 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.
" ester of facile hydrolysis " of the present invention can be understood as one or more carboxyl of existing in the formula (I) and exists with the form of the ester group of facile hydrolysis.The example of this class ester, the having of conventionally form: lower alkane acyloxyalkyl group ester comprises acetyl-o-methyl ester, pivalyl oxygen methyl ester, 1-acetyl 2-ethoxyethyl acetate and 1-pivalyl 2-ethoxyethyl acetate etc.; Rudimentary alkyl oxy carbonyl oxygen alkyl ester comprises the different third oxygen carbonyl oxygen base ethyl ester of methoxycarbonyl oxygen ylmethyl ester, 1-ethoxy carbonyl oxygen base ethyl ester and 1-etc.; The lower alkoxy methyl ester comprises methoxymethyl ester, the different third oxygen methyl ester of 1-etc.; Lower alkane amido methyl ester comprises formamido group methyl ester, acetylamino methyl ester etc.; Also can use other ester, as benzyl ester and cyanomethyl ester etc.Other example of this class ester also has: (2,2-dimethyl-1-oxopropoxy) methyl ester, (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester, 1-[[(1-methyl ethoxy) carbonyl] the oxygen base] ethyl ester, 1-(acetoxyl group) ethyl ester, (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl ester, 1-[[(cyclohexyloxy) carbonyl] the oxygen base] ethyl ester and 3,3-dimethyl-2-oxygen butyl ester.Particularly preferred ester is pivalyl oxygen methyl ester and (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester.It is evident that for the professional of this area the ester of facile hydrolysis can form at the free carboxy place of this compound in the body of The compounds of this invention.
" pharmaceutically acceptable non-toxic 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.
" isomer " of the present invention is meant all epimers, diastereomer 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.Compound has many three-dimensional centers shown in the general formula (I), for example on the 4-position, on the 5-position, first-class in the 6-position.
" hydrate " of the present invention is meant semihydrate, monohydrate, dihydrate, trihydrate, hexahydrate etc.The ester of compound shown in the general formula (I), its pharmaceutically acceptable non-toxic salt, its facile hydrolysis can be the form of hydrate.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 also provides the preparation method of compound shown in the preparation general formula (I), but is not limited only to following preparation method:
Reaction equation:
Figure S2008101293409D00061
Experimental procedure:
The preparation of step 1, compound 2
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine (being raw material 1), anhydrous tetrahydro furan.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles (being CDI), reaction, the acetone soln of adding raw material 2 continues reaction.Dripping hydrochloric acid then, with ethyl acetate extraction, organic phase is water, saturated nacl aqueous solution washing successively, concentrating under reduced pressure, resistates adds hydrochloric acid, stirs, and is adjusted to alkalescence with dilute alkaline soln, separate out solid, solid gets compound 2 with acetonitrile-hexanaphthene mixing solutions recrystallization.
The preparation of step 2, compound 3
Add the acetonitrile solution cooling of raw material 3 in the reaction flask, the acetonitrile solution of adding diisopropylethylamine and compound 2 stirs.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets compound 3.
The preparation of step 3, compound 4
Compound 3 is dissolved in the methylene dichloride, adds methyl-phenoxide and Nitromethane 99Min., drip the Nitromethane 99Min. solution of aluminum chloride in low temperature down, low temperature stirs down, adds entry, separates out solid, filter, filter cake is dissolved in the mixed solution of THF and water, adds palladium-charcoal, stirring reaction, filtering palladium charcoal, add THF in the filtrate, water layer is collected in layering.In THF, add magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and slowly splashes into methyl alcohol, and low temperature stirs, and filters, and the filter cake recrystallization gets compound 4.
The substituent implication of in the above reaction equation each as mentioned before.Carboxyl in the The compounds of this invention can be protected by carboxyl-protecting group, and the nitrogen-atoms on the pyrrolidyl can be protected by amino protecting group, and described carboxyl-protecting group and amino protecting group are as mentioned before.
The present invention is further claimed to comprise arbitrary compound recited above; the ester of its facile hydrolysis; its pharmaceutically acceptable non-toxic salt; its isomer; its hydrate; or the pharmaceutical composition of the hydrate of its ester or salt and one or more pharmaceutical carriers and/or thinner; wherein contain the arbitrary compound shown in the general formula (I); the ester of its facile hydrolysis; its pharmaceutically acceptable non-toxic salt; its isomer; its hydrate; or the hydrate 0.05g～5g of its ester or salt (by compound shown in the formula I) can be 0.05g as necessary active ingredient; 0.075g; 0.1g; 0.125g; 0.25g; 0.3g; 0.5g; 0.75g; 1g; 1.25g; 1.5g; 1.75g; 2g; 2.5g; 3g; 4g; 5g etc.Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment, preferred oral preparation or injection or external preparation in modes such as oral, administered parenterally or external applications.
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 add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.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.
The hydrate of the ester of the arbitrary compound shown in the further claimed general formula of the present invention (I), its facile hydrolysis, its pharmaceutically acceptable non-toxic salt, its hydrate and ester or salt is used to prepare the purposes of the medicine that treats and/or prevents infectious diseases.Carbapenem antibiotic of the present invention all has the strong antibiotic activity to clinical isolating gram-positive and negative, aerobic and anerobe, can be used for treating and/or preventing the various diseases that Mammals (comprising the people) is caused by pathogenic micro-organism, as respiratory tract infection, urinary tract infection, gynecological infection etc., also can be used for septicemia, meningitis etc.
Usually, have been found that Carbpenem derivants is nontoxic to warm-blooded animal, and this general rule also is applicable to compound of the present invention.Preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria to the mouse administration, is not observed by caused tangible toxicity symptom of The compounds of this invention or side effect.
Carbapenem compound of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has the potent anti-microbial activity of wide spectrum and shows hypotoxicity, can safety be used for the treatment of and/or to prevent various Mammalss to comprise human by the caused various diseases of sensitive organism.
(2) The compounds of this invention is when the antibacterials, and target bacteria has no particular limits, as long as The compounds of this invention shows anti-microbial activity to it, most gram-positives can be as target bacteria with negative, aerobic and anerobe.
(3) The compounds of this invention has good antibacterial activity to Staphylococcus, streptococcus, Pseudomonas aeruginosa accessory, compare clinical isolating Pseudomonas Aeruginosa medicine bacterium with immediate prior art and the Klebsiella Pneumoniae resistant organism has good especially anti-microbial activity, and MRSA is had good activity.
(4) The compounds of this invention has good chemical stability, is convenient to make clinically or pharmaceutically acceptable arbitrary formulation.
(5) The compounds of this invention has high stability to DHP-I and most β-Nei Xiananmei, can be used for β-Nei Xiananmei and produces bacterium, clinically can be individually dosed.
(6) transformation period is longer in the The compounds of this invention body, and has long post antibiotic effect, can reduce administration number of times, improves patient's tolerance.
(7) The compounds of this invention especially in its body the ester of facile hydrolysis in digestive tube, have good activity, can be through gastrointestinal administration.
(8) simple, the medicine purity height of the preparation technology of The compounds of this invention, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of the sulfhydryl pyrrolidine carbpenem compounds that formylaniline of the present invention replaces by in-vitro antibacterial experiment, but this should be interpreted as that carbapenem compound of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following is the clinical isolates strain, all buys in public institution
Gram positive organism: streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, enterococcus faecalis;
Gram-negative bacteria: escherichia coli, klebsiella pneumoniae, Proteus mirabilis, enterobacter cloacae, Pseudomonas aeruginosa, Fei Shi citric acid bacillus.
Trial-product: The compounds of this invention A, B, self-control, chemical name and structural formula are as mentioned before;
Imipenum: commercial; 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 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure S2008101293409D00101
By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A, B all have the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Figure S2008101293409D00102
By table 3 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A, B all have the excellent antibiotic activity to the clinical isolating examination gram-negative bacteria that supplies.
Above-mentioned experimental result shows that The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium, compare with immediate prior art, 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-sulfydryl-2-formyl [4-(E)-(N,N-DMAA-3-yl) phenyl amido]-1-(tertbutyloxycarbonyl) tetramethyleneimine
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 14.5g (50mmol), anhydrous tetrahydro furan 200ml.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles 9.8g (60mmol), reaction 2h, add below 0 ℃ 9.9g (52mmol) (E)-acetone soln of 3-(4-aminophenyl)-N,N-DMAA, continue reaction 1h.Drip 1mol/L hydrochloric acid 100ml then, extract with ethyl acetate (50ml * 2), organic phase is water, saturated nacl aqueous solution washing successively, concentrating under reduced pressure, and resistates adds the hydrochloric acid 200ml of 5mol/L, stir 2h, be adjusted to alkalescence with dilute alkaline soln, separate out solid, solid is with acetonitrile-hexanaphthene mixing solutions recrystallization, get solid 18.6g, yield: 88.6%.
Embodiment 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(E)-(N, N-DMAA-3-yl) phenyl amido]-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's preparation
In the reaction flask, 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 150ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 17.9g (30mmol), be chilled to below-10 ℃, add diisopropylethylamine 8ml and (2S, 4S)-4-sulfydryl-2-formyl [4-(E)-(N, N-DMAA-3-yl) phenyl amido]-the acetonitrile solution 100ml of 1-(tertbutyloxycarbonyl) tetramethyleneimine 13.4g (32mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 400ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 17.1g, yield: 74.5%.
Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(E) (N, N-DMAA-3-yl) phenyl amido]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-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)-2-formyl [4-(E)-(N, N-DMAA-3-yl) phenyl amido]-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 15.3g (20mmol) is dissolved among the methylene dichloride 100ml, adds methyl-phenoxide 20ml and Nitromethane 99Min. 30ml, in-50 ℃ of Nitromethane 99Min. solution 150ml 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 400mlTHF and water 30ml, adds 10% palladium-charcoal 5g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add 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 50ml, and-10 ℃ are stirred 1h, filters, and the filter cake recrystallization gets white crystal 5.4g, yield: 51.3%.
Molecular formula: C 26H 32N 4O 6S
Molecular weight: 528.62
Ultimate analysis: C, 58.89%; H, 6.37%; N, 10.41%; S, 5.92%
(calculate: C, 59.07%; H, 6.10%; N, 10.60%; S, 6.07%)
Embodiment 4 (2S, 4S)-preparation of 4-sulfydryl-2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-1-(tertbutyloxycarbonyl) tetramethyleneimine
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 14.5g (50mmol), (E)-3-(4-aminophenyl)-acrylamide 8.4g (52mmol), get product 17.0g, yield: 86.7%.
Embodiment 5 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-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's preparation
Concrete preparation method's reference example 2.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 17.9g (30mmol), (2S, 4S)-4-sulfydryl-2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-1-(tertbutyloxycarbonyl) tetramethyleneimine 12.1g (31mmol).Get product 15.7g, yield: 70.9%.
Embodiment 6 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 3.Throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-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 14.7g (20mmol).Get white crystal 5g, yield: 49.7%.
Molecular formula: C 24H 28N 4O 6S
Molecular weight: 500.57
Ultimate analysis: C, 57.35%; H, 5.85%; N, 11.03%; S, 6.24%
(calculate: C, 57.59%; H, 5.64%; N, 11.19%; S, 6.41%)
The preparation of embodiment 7 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Compd A 250g (in compound)
Prepare 1000 altogether
Prescription 2:
Compd B 500g (in compound)
Prepare 1000 altogether
Prescription 3:
Compd A 1000g (in compound)
Prepare 1000 altogether
Prescription 4:
Compd B 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 8 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 B 125g (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
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) The compounds of this invention A or B, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, it is an amount of to add the 2%HPMC aqueous solution, 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 (6)

1. compound shown in the formula (I) or its pharmaceutically acceptable non-toxic salt:
Figure FSB00000168073700011
Wherein: R 1The expression methyl;
R 2The expression hydrogen atom;
R 3The expression hydrogen atom;
R 4The expression hydrogen atom;
R 5And R 6Represent hydrogen atom respectively;
R 7And R 8Identical or different, represent hydrogen atom respectively, methyl or ethyl;
X represents Sauerstoffatom.
2. compound as claimed in claim 1 or its pharmaceutically acceptable non-toxic salt, described compound is selected from:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(N,N-DMAA-3-yl) phenyl amido]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, perhaps
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(E)-(acrylamide-3-yl) phenyl amido]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid.
3. each described compound of claim 1～2 or its pharmaceutically acceptable non-toxic salt, its pharmaceutically acceptable non-toxic salt is inorganic acid salt, organic acid salt, organic alkali salt or inorganic base salts.
4. the pharmaceutical composition that comprises each described compound of claim 1～2 or its pharmaceutically acceptable non-toxic salt and one or more pharmaceutical carriers and/or thinner.
5. pharmaceutical composition as claimed in claim 4, it is for clinically or pharmaceutically acceptable arbitrary formulation.
6. each described compound of claim 1～2 or its pharmaceutically acceptable non-toxic salt are used to prepare the purposes of the medicine that treats and/or prevents infectious diseases.
CN2008101293409A 2007-06-28 2008-06-28 Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds Active CN101367806B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008101293409A CN101367806B (en) 2007-06-28 2008-06-28 Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN200710015000.9 2007-06-28
CN200710015000 2007-06-28
CN2008101293409A CN101367806B (en) 2007-06-28 2008-06-28 Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds

Publications (2)

Publication Number Publication Date
CN101367806A CN101367806A (en) 2009-02-18
CN101367806B true CN101367806B (en) 2010-11-17

Family

ID=40411831

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2008101293409A Active CN101367806B (en) 2007-06-28 2008-06-28 Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds

Country Status (1)

Country Link
CN (1) CN101367806B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1225636A (en) * 1996-07-12 1999-08-11 麦克公司 Process for synthesizing carbapenem atnibiotics
WO2002053566A1 (en) * 2000-12-27 2002-07-11 Sumitomo Pharmaceuticals Company, Limited Novel carbapenem compounds
WO2002094829A1 (en) * 2001-05-21 2002-11-28 Kyoto Pharmaceutical Industries, Ltd. Carbapenem compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1225636A (en) * 1996-07-12 1999-08-11 麦克公司 Process for synthesizing carbapenem atnibiotics
WO2002053566A1 (en) * 2000-12-27 2002-07-11 Sumitomo Pharmaceuticals Company, Limited Novel carbapenem compounds
WO2002094829A1 (en) * 2001-05-21 2002-11-28 Kyoto Pharmaceutical Industries, Ltd. Carbapenem compound

Also Published As

Publication number Publication date
CN101367806A (en) 2009-02-18

Similar Documents

Publication Publication Date Title
CN101372489B (en) Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl
CN101333218B (en) Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds
CN101362760B (en) 1beta-methyl carbapenem compound
CN101525336B (en) Carbapenem compound containing substituted formohydrazide group
CN101367806B (en) Formyl aniline substituted sulfhydryl pyrrolidine carbpenem compounds
CN101367815B (en) Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound
CN101367804B (en) Penem derivant containing adamantane
CN101362763B (en) Carbapenem derivates containing sulfhydryl pyrrolidine
CN101333219B (en) Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle
CN101357917B (en) Carbapenem compound containing formyl hydrazino
CN101367805B (en) Formyl guanidino substituted sulfhydryl pyrrolidine carbpenem compounds
CN101367812B (en) Sulfhydryl pyrrolidine formamido cyclopentene acid substituted penem derivant
CN101357916B (en) Penem compound containing dihydroimidazole formamido
CN101367817B (en) Carbpenem compound containing cyclohexenone formamido group
CN101367807B (en) Sulfhydryl pyrrolidine formamido pyridine substituted penem derivant
CN101367816B (en) Carbpenem derivants
CN101367811B (en) Carbon substituted penems antibiotics
CN101328179B (en) Sulfhydryl pyrrolidine penem derivates containing oxo aza ring
CN101367810A (en) Novel carbpenem antibiotic
CN101367809B (en) Penem derivant containing sulfhydryl pyrrolidine formhydrazide
CN101357919B (en) Penem derivative containing sulfhydryl formamide benzenesulfonyl pyrrolidine
CN101357918A (en) Penem derivative containing isothioureido sulfhydryl pyrrolidine
CN101343272B (en) Carbpenem compound containing cyclohexane
CN101343271B (en) Penem derivant containing isoxazole alkyl ketone
CN101372488A (en) Novel carbapenem compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20190103

Address after: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee after: Hainan Xuanzhu Pharmaceutical Technology Co., Ltd.

Address before: 250101 No. 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province

Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd.

TR01 Transfer of patent right
CP03 Change of name, title or address

Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507

Patentee after: Xuanzhu Biotechnology Co., Ltd

Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee before: Hainan Xuanzhu Pharma Co.,Ltd.

CP03 Change of name, title or address
CP01 Change in the name or title of a patent holder

Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province

Patentee after: Xuanzhu Biotechnology Co.,Ltd.

Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province

Patentee before: Xuanzhu Biotechnology Co.,Ltd.

CP01 Change in the name or title of a patent holder