CN102690242A - Carbapenem compound containing amino methenyl heterocyclic ring - Google Patents
Carbapenem compound containing amino methenyl heterocyclic ring Download PDFInfo
- Publication number
- CN102690242A CN102690242A CN2012101653114A CN201210165311A CN102690242A CN 102690242 A CN102690242 A CN 102690242A CN 2012101653114 A CN2012101653114 A CN 2012101653114A CN 201210165311 A CN201210165311 A CN 201210165311A CN 102690242 A CN102690242 A CN 102690242A
- Authority
- CN
- China
- Prior art keywords
- atom
- alkyl
- amino
- group
- sulfonyl
- 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.)
- Pending
Links
- 0 *C(c1c[s]c(S)n1)=O Chemical compound *C(c1c[s]c(S)n1)=O 0.000 description 5
- VICYTAYPKBLQFB-UHFFFAOYSA-N CCOC(C(CBr)=O)=O Chemical compound CCOC(C(CBr)=O)=O VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- WTGNEFWADGCDBI-UHFFFAOYSA-N CCOC(c1c[s]c(S)n1)=O Chemical compound CCOC(c1c[s]c(S)n1)=O WTGNEFWADGCDBI-UHFFFAOYSA-N 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 invention relates to the technical field of medicines, in particular to a carbapenem compound containing amino methenyl heterocyclic ring, which is described in the general formula (I), pharmaceutically acceptable salts of the carbapenem compound, water dissolvable esters of the carbapenem compound, an isomer of the carbapenem compound, and an intermediate of the carbapenem compound, which is described in the formula (II), in the formulae, R1, R2, R3, X, Y and A are defined in the description; the invention further relates to preparation methods of the compounds, pharmaceutical compounds containing such compounds, and applications of the compounds in preparing drugs for treating and/or preventing infective diseases.
Description
This patented claim is to be 201110035228.0 to application number, and the applying date is the dividing an application of patented claim of 2011-01-28.
1, technical field
The invention belongs to medical technical field; Be specifically related to contain ester, its isomer and the midbody of amido formyl radical heterocyclic carbapenem compounds, 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 infection.
2, background technology
Carbapenem antibiotic receives much concern by force and to β-Nei Xiananmei is stable because of its has a broad antifungal spectrum, anti-microbial activity.Be applied to clinical carbapenem antibiotic and comprised imipenum, panipenem, meropenem, ertapenem, biapenem and S-4661.
PZ-601 is the carbapenem antibiotic by the exploitation of SUMITOMO CHEMICAL Pharmaceutical Co., Ltd; Has the thyroidan structure; Antimicrobial spectrum is compared with the microbiotic in early stage with anti-microbial activity and has been obtained large increase; Staphylococcus and suis (comprising resistant organism) etc. is had better antibacterial activity, and its structural formula of PZ-601 is following:
In recent years; Because the microbiotic clinical application is too much, continuous increase, the especially methicillin-resistant staphylococcus aureus (MRSA) that causes bacterial drug resistance as in the institute with the The main pathogenic fungi of the acquired infection of community; Popular in worldwide, and clinical drug-resistant property is more and more serious.In addition, the transformation period of the carbapenem antibiotic that goes on the market at present is shorter,, about 1h, can not meet clinical needs at the intravital transformation period great majority of people.The inventor modifies on the basis of PZ-601 structure, and it is wider to have obtained antimicrobial spectrum, and anti-microbial activity is stronger, and stability is higher, and the transformation period is longer, especially positive bacteria is had very strong active one type of carbapenem compounds.
3, summary of the invention
Technical scheme of the present invention is following:
Wherein, R
1Representation carboxy or-COOR
6, described R
6Representation carboxy protection base;
R
2Represent 1～5 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, cyanic acid, nitro, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, amino-sulfonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, formamyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, by the substituted C of halogen atom
1-6Alkoxyl group, by 1～3 identical or different substituted C of the substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl, amino-sulfonyl or formamyl
1-6Alkyl;
R
3Represent Wasserstoffatoms or C
1-6Alkyl;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound or contains the alkylene of 1～6 carbon atom.
Preferred compound is:
Wherein, R
1Representation carboxy or-COOR
6,
Described R
6Representation carboxy protection base is selected from methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl-, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent 1～5 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Carbalkoxy, amino-sulfonyl, C
1-4Alkyl amine group alkylsulfonyl, formamyl, C
1-4Alkyl amine group formyl radical, C
1-4Alkyl amine group, by the substituted C of halogen atom
1-4Alkoxyl group, by 1～2 identical or different substituted C of the substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl, amino-sulfonyl or formamyl
1-4Alkyl;
R
3Represent Wasserstoffatoms or methyl;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound or contains the alkylene of 1～4 carbon atom.
Preferred compound is:
Wherein, R
1Representation carboxy or-COOR
6,
Described R
6Representation carboxy protection base is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, amino-sulfonyl, formamyl, by the substituted C of halogen atom
1-4Alkoxyl group, by 1 substituted C of substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl
1-4Alkyl;
R
3Represent methylidene;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound,
Preferred compound is:
Wherein, R
1Representation carboxy;
R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, fluorine atom, chlorine atom, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, amino-sulfonyl, formamyl, by the substituted C of fluorine atom
1-2Alkoxyl group, by the substituted C of fluorine atom
1-2Alkyl;
R
3Represent methylidene;
When X represents the O atomic time, Y represents CH;
When X represents the S atomic time, Y represents N atom or CH;
When X represented NH, Y represented CH; And
A represents singly-bound,
Preferred compound is:
Wherein, R
1Representation carboxy;
R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, fluorine atom, chlorine atom, carboxyl, methyl, methoxyl group, amino-sulfonyl, formamyl, difluoro-methoxy, trifluoromethoxy or trifluoromethyl;
R
3Represent methylidene;
X represents the S atom;
Y represents CH; And
A represents singly-bound,
Table 1 part of compounds of the present invention
" alkylene that contains 1～6 carbon atom " of the present invention is meant the alkylene of the straight or branched that contains 1～6 carbon atom, for example
Deng specific examples.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C according to the invention
1-6Alkyl " refer to that the hydrocarbon that contains 1～6 carbon atom partly removes a Wasserstoffatoms deutero-straight or branched or cyclic alkyl; like methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.Term " C
1-4Alkyl ", " C
1-2Alkyl " refer to the specific examples that contains 1～4,1～2 carbon atom in the above-mentioned instance.
" C according to the invention
1-6Alkoxyl group " refer to term " C
1-6Alkyl " group that is connected with other structures through Sauerstoffatom, like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Term " C
1-4Alkoxyl group ", " C
1-2Alkoxyl group " refer to term " C
1-4Alkyl ", " C
1-2Alkyl " group that is connected with other structures through Sauerstoffatom.
" C according to the invention
1-6Carbalkoxy " be C
1-6The group that alkoxyl group is connected with other structures through carbonyl is like methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, secondary butoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc.Term " C
1-4Carbalkoxy " be C
1-4The group that alkoxyl group is connected with other structures through carbonyl.
" C according to the invention
1-6The alkyl amine group alkylsulfonyl " be C
1-6The group that alkyl is connected with other structures through the amido alkylsulfonyl is like methylamino alkylsulfonyl, ethylamino alkylsulfonyl, propyl group amino-sulfonyl, sec.-propyl amino-sulfonyl, butyl amino-sulfonyl, isobutylamino alkylsulfonyl, tertiary butyl amino-sulfonyl, sec.-butyl amino-sulfonyl, amyl group amino-sulfonyl, neo-pentyl amino-sulfonyl, hexyl amino-sulfonyl etc." two (C according to the invention
1-6Alkyl) amido alkylsulfonyl " be two identical or different C
1-6The group that alkyl is connected with other structures through the amido alkylsulfonyl.Term " C
1-4The alkyl amine group alkylsulfonyl " be C
1-4The group that alkyl is connected with other structures through the amido alkylsulfonyl.
" C according to the invention
1-6The alkyl amine group formyl radical " be C
1-6The group that alkyl is connected with other structures through the amido formyl radical is like methyl amido formyl radical, ethyl amido formyl radical, propyl group amido formyl radical, sec.-propyl amido formyl radical, butyl amido formyl radical, isobutyl-amido formyl radical, tertiary butyl amido formyl radical, sec.-butyl amido formyl radical, amyl group amido formyl radical, neo-pentyl amido formyl radical, hexyl amido formyl radical etc." two (C according to the invention
1-6Alkyl) amido formyl radical " be two identical or different C
1-6The group that alkyl is connected with other structures through the amido formyl radical.Term " C
1-4The alkyl amine group formyl radical " be C
1-4The group that alkyl is connected with other structures through the amido formyl radical.
" C according to the invention
1-6Alkyl amine group " be C
1-6The group that alkyl is connected with other structures through amido is like methyl amido, ethyl amido, propyl group amido, sec.-propyl amido, butyl amido, isobutyl-amido, tertiary butyl amido, sec.-butyl amido, pentyloxy amido, neo-pentyl amido, hexyloxy amido etc." two (C according to the invention
1-6Alkyl) amido " be two identical or different C
1-6The group that alkyl is connected with other structures through amido.Term " C
1-4Alkyl amine group " be C
1-4The group that alkyl is connected with other structures through amido.
" carboxyl-protecting group " according to the invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methyl, methoxymethyl, first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl-, to bromobenzene formyl methyl, Alpha-Methyl phenacyl-, to methoxybenzoyl methyl, diacyl methyl, N-phthalimidomethyl, ethyl, 2; 2; 2-three chloroethyls, 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, 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, sec.-propyl dimetylsilyl, phenyl dimetylsilyl, the S-tertiary butyl, S-phenyl, 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; 3-oxazoline, 4-alkyl-5-oxo-1; 3-oxazolidine, 5-alkyl-4-oxo-1,3-diox, triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
The present invention further requires to protect the preparation method of the said compound of general formula (I).
The preparation method of general formula of the present invention (I) compound comprises ester or its isomer that makes compound, its pharmacy acceptable salt, its facile hydrolysis shown in the general formula (II); Ester or its isomer generation nucleophilic substitution reaction with compound shown in the general formula (III), its pharmacy acceptable salt, its facile hydrolysis
Wherein, R
1, R
2, R
3, X, Y and A such as preamble definition, L representes leavings group.
Above-mentioned " leavings group " be meant in the nucleophilic substitution reaction from one than atom that breaks away from the macromole or functional group, for example can be halogens such as chlorine, bromine, iodine; Three halogenated methoxies such as trichlorine methoxyl group; Lower alkane such as mesyloxy, ethanesulfonyloxy group sulfonyloxy; Halo lower alkane sulfonyloxies such as trifluoro-methanesulfonyl oxy, five fluorine ethanesulfonyloxy groups; Arylsulfonyloxies such as phenylsulfonyloxy, tolysulfonyl oxygen base, p-nitrophenyl sulfonyloxy; Perhaps aryl phosphorus acyloxy such as diphenylphosphine acyloxy.Preferred diaryl phosphorus acyloxy, more preferably diphenylphosphine acyloxy (O-P (=O) (Oph)
2).
Above-claimed cpd of the present invention can adopt method and/or known other technology of those of ordinary skills of describing in the following flow process to synthesize, but is not limited only to following method.
Reactions step:
The preparation of step 1 compound a
Raw material 1 is soluble in water, add NaOH then, reaction finishes, and then reaction mixture is extracted with MTBE, and water layer is used the HCl acidifying, filters to obtain first product.Filtrating is used ethyl acetate extraction, and dry concentrating obtains second batch of product.Merge two batches of products, obtain compound a after the vacuum-drying.
The preparation of step 2 compound c
Compound a is dissolved among the anhydrous THF, dropwise adds isopropyl chlorocarbonate and Et then
3N, stirring reaction with the reaction solution cooling, adds raw material 2, and the temperature with reaction solution rises to room temperature again, stirred overnight.Solids removed by filtration joins water in the filtrating, uses ethyl acetate extraction, and vacuum-drying obtains bullion, and column chromatography purification obtains compound c.
The preparation of step 3 compound d
Compound c is dissolved among the anhydrous THF, adds LiOH solution then, stirring finishes up to reaction.Then reaction mixture extracts with MTBE, and water layer use the HCl acidifying, filters and obtains solid, washs with ETHYLE ACETATE, and vacuum-drying obtains compound d.
The preparation of step 4 Verbindung
Compound d is dissolved in the acetonitrile, adds diisopropyl ethyl amine (DIPEA), mixture becomes clarification, then adds raw material 3, finishes up to reaction.Mixture is cooled to room temperature, obtains Verbindung through column chromatography purification.
The preparation of step 5 compound f
Verbindung is dissolved in THF, adds Pd/C and water, feed H2, under room temperature and atmosphere of hydrogen, stir, finish up to reaction.Remove by filter Pd/C, filtrating extracts with MTBE.The aqueous solution is with preparation HPLC (under the neutrallty condition) purifying, and lyophilize obtains compound f.
In the reaction equation, R
2, R
3, X, Y and A such as preamble definition.
The present invention further requires to protect the midbody of compound in the preparation process shown in the general formula (I), i.e. the ester of the compound shown in the general formula (II), its pharmacy acceptable salt, its facile hydrolysis or its isomer, wherein, R
2, X, Y and A such as preamble definition.
" pharmacy acceptable salt " of the above-mentioned arbitrary compound of the present invention comprises an alkali metal salt, like sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is like calcium salt, magnesium salts etc.; Other metal-salts are like aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is like ammonium salt; Organic alkali salt; Like uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-NMG salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) amido methane salt; Halogen acid salt is like hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is like nitrate salt, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulphonate is like mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is like benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is like acetate, malate, fumarate, SUMATRIPTAN SUCCINATE, Citrate trianion, tartrate, oxalate, PHENRAMINE MALEATE etc.; Amino acid salts is like glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
" ester of facile hydrolysis " of the above-mentioned arbitrary compound of the present invention be meant those can be in human body hydrolysis generate the pharmaceutically acceptable ester of parent compound.It is obvious that for the professional of this area, and the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy or the hydroxyl place of this compound, can make through ordinary method.
" isomer " of the above-mentioned arbitrary compound of the present invention comprises that all differences are to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this was illustrated in three-dimensional this key of going up and will comes out from paper, and when a key was shade, this was illustrated in three-dimensional this key of going up and will returns in the paper.Formula (I) compound has many three-dimensional centers, be included on the 4-position, on the 5-position, first-class in the 6-position.
The present invention further requires to protect the ester that comprises arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and other active pharmaceutical ingredients, like cilastatin and sodium salt, CS-443 etc.
The present invention also comprises ester or its isomer of above-mentioned arbitrary compound, its pharmacy acceptable salt, its facile hydrolysis; Can be mixed with clinically or pharmaceutically acceptable arbitrary formulation with mode known in the art, be applied to the patient who needs this treatment with oral, parenteral, rectum or through modes such as lung administrations.When being used for oral administration, can be made into conventional solid preparation, like tablet, capsule, pill, granule etc.; Also can be made into oral liquid, like oral solution, oral suspensions, syrup etc.When processing oral prepns, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When processing injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.When being used for rectal administration, can be made into suppository etc.Be used for when the lung administration, can be made into inhalation or sprays etc.Contain the compound 0.01g～10g shown in the formula (I) of physiology significant quantity in the per unit preparation, can be 0.01g, 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, 10g etc.
The present invention also provides The compounds of this invention to be used for treating and/or preventing the purposes of the medicine of infection in preparation.The compounds of this invention all has better antibacterial activity to gram positive organism, can be used for treating and/or preventing the various diseases that is caused by pathogenic micro-organism, like respiratory tract infection and urinary tract infection.
The compounds of this invention 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 be treated and/or prevented various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safe being used to;
(2) The compounds of this invention has better antibacterial activity to gram-positive;
(3) The compounds of this invention is stable to β-Nei Xiananmei and DHP-I, can single medicine administration;
(4) The compounds of this invention has long transformation period and post antibiotic effect, and anti-microbial effect is lasting, and medication is convenient;
(5) The compounds of this invention preparation technology is simple, and medicine purity is high, high, the steady quality of yield, is easy to carry out large-scale commercial prodn.
Below further set forth the beneficial effect of The compounds of this invention through antibacterial experiment in external and the body, but should this be interpreted as that The compounds of this invention only has following beneficial effect.
The antimicrobial spectrum and the antibacterial activity in vitro of experimental example 1 The compounds of this invention 1
Supply the examination bacterial classification: below be the clinical isolates strain, purchase in public institution.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), CN-S (CNS), streptococcus pyogenes, streptococcus pneumoniae.
Trial-product: part of compounds 1 of the present invention, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound;
Vancomyein: commercial; PZ-601: self-control, structural formula such as preamble are said.
Experimental technique: agar dilution, with reference to " pharmacological experimental 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:
The antibacterial activity in vitro of table 2 The compounds of this invention 1
Visible by table 2, The compounds of this invention to the activity of strains tested and contrast medicine quite or comparison stronger according to medicine, compare with the contrast medicine and to have obvious improvement.
The antimicrobial spectrum and the antibacterial activity in vitro of experimental example 2 The compounds of this invention 20
Supply the examination bacterial classification: below be the clinical isolates strain, purchase in public institution.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), enterococcus faecalis, streptococcus pyogenes, streptococcus pneumoniae.
Trial-product:
The compounds of this invention 20, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound;
Ertapenem and meropenem: commercial.
Experimental technique: agar dilution, with reference to " pharmacological experimental 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:
The antibacterial activity in vitro of table 3 The compounds of this invention 20
Visible by table 3, quite perhaps comparison is stronger according to medicine with the contrast medicine for the activity of 20 pairs of strains testeds of The compounds of this invention, compares with the contrast medicine to have obvious improvement.
4, embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.
Embodiment 1 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(3-amino-sulfonyl phenyl amido formyl radical) thiophene
Azoles-2-base sulfenyl]-preparation of 1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 1)
The preparation of step 1 2-thyroidan-4-carboxylic acid, ethyl ester
With the 3-ethyl bromide acetone (220g 1.13mol) is dissolved in the ethanol (2L), add ammonium dithiocarbamate (123g, 1.12mol).Reaction mixture at room temperature stirred 2.5 hours, then refluxed 1 hour, was cooled to room temperature, and reaction mixture is joined in the trash ice, added water (2L), with ETHYLE ACETATE (500mL*3) extraction, used anhydrous Na
2SO
4Drying, vacuum concentration obtains bullion, and column chromatography purification obtains 2-thyroidan-4-carboxylic acid, ethyl ester (89.15g, 42.1%).
The preparation of step 2 2-thyroidan-4-carboxylic acid
((2N, 23.8mL 47.6mmol), reacted 2 hours, detected 2-thyroidan-4-carboxylic acid, ethyl ester reaction up to TLC and finished to add NaOH at 0～5 ° for 4.52g, 23.89mmol) water-soluble (10mL) with step 1 products therefrom.Then reaction mixture is with MTBE (30mL*3) extraction, and water layer is acidified to pH=1～2 with 2N HCl, filters and obtains first product.Filtrating is with ETHYLE ACETATE (30mL*3) extraction, and dry concentrating obtains second batch of product.Merge two batches of products, obtain 2-thyroidan-4-carboxylic acid (3.81g, 98.9%) after the vacuum-drying.
The preparation of step 3 4-[(3-amino-sulfonyl) phenyl amido formyl radical]-2-[(isopropoxy carbonyl) sulfenyl] thiazole
Throw step 2 products therefrom (4.5g 28mmol) is dissolved in anhydrous THF (60mL), under-78 ℃, dropwise add isopropyl chlorocarbonate (7.5g, 61.5mmol) with Et3N (6.15g, 61.5mmol) ,-20～0 ℃ of stirring 2 hours down.Reaction solution is cooled to again-78 ℃, (4.82g 28mmol), rises to room temperature, stirred overnight with the temperature of reaction solution to add the 3-aminobenzene sulfonamide.Solids removed by filtration, (50mL) joins in the filtrating with water, extracts with ETHYLE ACETATE (50mL*3); Vacuum-drying obtains bullion; Column chromatography purification gets solid product 4-[(3-amino-sulfonyl) phenyl amido formyl radical]-2-[(isopropoxy carbonyl) sulfenyl] thiazole (7.25g, 64.5%).
The preparation of step 4 2-sulfydryl-4-(3-amino-sulfonyl) phenyl amido formyl thiazole
(7.39g 18.4mmol) is dissolved among the THF (19mL), adds LiOH (2N down at 0 ℃ to throw step 3 products therefrom; 19mL; 38mmol), stir, detect 4-[(3-amino-sulfonyl) phenyl amido formyl radical]-2-[(isopropoxy carbonyl) sulfenyl] thiazole reaction up to TLC and finish.Then reaction mixture is with MTBE (25mL*3) extraction, and water layer is acidified to pH=1～2 with 2N HCl, filtration and obtain solid; Wash with ETHYLE ACETATE (30mL); Vacuum-drying gets solid product 2-sulfydryl-N-(3-amino-sulfonyl phenyl) thiazole-4-carboxamide (2.87g, 49.5%).
Step 5 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(3-amino-sulfonyl phenyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0.] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
(2.87g 9.11mmol), is dissolved in the acetonitrile (90mL) to throw step 4 products therefrom; Adding diisopropyl ethyl amine (DIPEA) (2.35g, 18.22mmol), mixture becomes clarification; Then add (4R; 5R, 6S)-3-(two phenoxys) phosphorus acyloxy-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (5.54g, 9.11mmol); Reaction mixture finishes up to the reaction of 2-sulfydryl-N-(3-amino-sulfonyl phenyl) thiazole-4-carboxamide 60-65 ℃ of reaction down.Be cooled to room temperature; Column chromatography purification; Get solid product (4R; 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(3-amino-sulfonyl phenyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0.] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (1.35g, 22.0%).
The preparation of step 6 compound 1
(1.51g 2.24mmol) is dissolved in THF (50mL), adds Pd/C (1.5g) and water (30mL) to throw step 5 products therefrom; Join in the hydrogenation still; Feed hydrogen, stirring at room detects (4R up to TLC; 5S; 6S)-and 6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(3-amino-sulfonyl phenyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0.] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy reaction finishes, and removes by filter Pd/C, and filtrating extracts with MTBE (30mL*3).Water layer is with preparation HPLC (under the neutrallty condition) purifying, and lyophilize obtains compound 1 (0.40g, 34.0%).
Molecular formula: C
20H
20N
4O
7S
3Molecular weight: 524.59
1H-NMR(400MHz，DMSO-d
6)：δ0.917(3H，d)，1.080(3H，d)，3.140(1H，dd)，3.243(1H，m)，3.885(1H，m)，4.096(1H，dd)，4.999(1H，d)，7.342(2H，s)，7.473(2H，m)，7.932(1H，d)，8.442(2H，s)，10.609(1H，s).
The preparation of step 7 compound 1 sodium salt
(1.51g 2.29mmol) is dissolved in THF (50mL), adds NaHCO with step 5 products therefrom
3(192mg, 2.29mmol), Pd/C (1.5g) and water (30mL).Feed H
2, stirring at room detects raw material reaction up to TLC and finishes.Remove by filter Pd/C, filtrating extracts with MTBE (30mL*3).The aqueous solution is with preparation HPLC (under the neutrallty condition) purifying, and lyophilize obtains compound 1 sodium salt (0.42g, 33.5%).
Embodiment 2 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(4-amino-sulfonyl benzyl amido formyl radical) thiophene
Azoles-2-base sulfenyl]-preparation of the preparation (compound 20) of 1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
Step 1～2 are with step 1～2 of embodiment 1.
The preparation of step 34-[(4-amino-sulfonyl) benzyl amido formyl radical]-2-sec.-propyl oxygen carbonyl sulfhydryl thiazole
With isopropyl chlorocarbonate (57g, 465mmol) in the time of-10 ℃, be added dropwise to 2-trityl thyroidan-4-carboxylic acid (30g, 186mmol) and triethylamine (47.1g, in two chlorine solution 465mmol), insulated and stirred 3h.Reaction solution is cooled to again-10 ℃, add sulfanilamide (37.9g, 154mmol) with triethylamine (38.9g, in dichloromethane solution 385mmol), controlled temperature stirs 18h, with washing, organic phase is used anhydrous Na
2SO
4Drying is revolved dried bullion (20.4g, 31.9%).
Synthesizing of step 4 2-sulfydryl-4-(4-amino-sulfonyl benzyl amido formyl radical) thiazole
(20.4g 49mmol) is dissolved in methyl alcohol, and (3.9g 98mmol), stirs 3h, and reaction solution revolves dried, and with the dilution of hydration ETHYLE ACETATE, organic phase is used anhydrous Na to add NaOH under the room temperature with 4-[(4-amino-sulfonyl) benzyl amido formyl radical]-2-sec.-propyl oxygen carbonyl sulfhydryl thiazole
2SO
4Drying is revolved dried bullion (14.8g, 91.8%).
Step 5 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(4-amino-sulfonyl benzyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With 2-sulfydryl-4-(4-amino-sulfonyl benzyl amido formyl radical) thiazole (10g, 30.4mmol) and MAP (18g 30.4mmol) adds among the DMF, drips triethylamine (5g; 49.5mmol), be warming up to 60 ℃, stir 3h; In the reaction solution impouring water, use ethyl acetate extraction, organic phase is used anhydrous Na
2SO
4Drying is revolved dried bullion (9.2g, 45.1%).
Step 6 (4R, 5S, 6S)-preparation of 6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(4-amino-sulfonyl benzyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
With (4R; 5S; 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[4-(4-amino-sulfonyl benzyl amido formyl radical) thiazol-2-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (9.2g; 13.7mmol) and Pd/C (5g) adding THF and buffering solution (150mL, V
THF: V
Buffer=7: in the mixed solution 3), in autoclave 30 ℃-35 ℃, hydrogen pressure is 4Mpa, hydrogenation 40min, and reaction finishes, and filters Pd/C, with the mixed solution (V of THF and deionized water
THF: V
Water=2: 3) wash, use ETHYLE ACETATE (50ml * 3) to wash again, liquid phase is with preparation liquid phase purifying, and freeze-drying gets white solid (0.065g, 0.8%).
Molecular formula: C
21H
22N
4O
7S
3Molecular weight: 538.62LC-MS:539 (M+H)
+
1H-NMR(400MHz，d
6-DMSO)：δ0.93(d，3H)，δ1.12(d，3H)，δ3.14(dd，1H)，δ3.22(dd，1H)，δ3.91(s，1H)，δ4.09(dd，1H)，δ4.48(dd，2H)，δ4.98(s，1H)，δ7.30(s，2H)，δ7.47(d，2H)，δ7.76(d，2H)，δ8.25(s，1H)，δ9.18(t，1H).
With reference to aforesaid method, also prepared following compound:
Table 4 part of compounds of the present invention
Claims (6)
1. the ester of the compound shown in the formula (II), its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein, R
2Represent 1～5 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, cyanic acid, nitro, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, amino-sulfonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, formamyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, by the substituted C of halogen atom
1-6Alkoxyl group, by 1～3 identical or different substituted C of the substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl, amino-sulfonyl or formamyl
1-6Alkyl;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound or contains the alkylene of 1～6 carbon atom.
2. the ester of compound as claimed in claim 1, its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein, R
2Represent 1～5 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Carbalkoxy, amino-sulfonyl, C
1-4Alkyl amine group alkylsulfonyl, formamyl, C
1-4Alkyl amine group formyl radical, C
1-4Alkyl amine group, by the substituted C of halogen atom
1-4Alkoxyl group, by 1～2 identical or different substituted C of the substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl, amino-sulfonyl or formamyl
1-4Alkyl;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound or contains the alkylene of 1～4 carbon atom.
3. the ester of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein, R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, halogen atom, hydroxyl, amino, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, amino-sulfonyl, formamyl, by the substituted C of halogen atom
1-4Alkoxyl group, by 1 substituted C of substituting group that is selected from halogen atom, hydroxyl, amino, carboxyl
1-4Alkyl;
X represents the O atom, S atom or NH;
Y represents N atom or CH; And
A represents singly-bound,
4. the ester of compound as claimed in claim 3, its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein, R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, fluorine atom, chlorine atom, carboxyl, C
1-4Alkyl, C
1-4Alkoxyl group, amino-sulfonyl, formamyl, by the substituted C of fluorine atom
1-2Alkoxyl group, by the substituted C of fluorine atom
1-2Alkyl;
When X represents the O atomic time, Y represents CH;
When X represents the S atomic time, Y represents N atom or CH;
When X represented NH, Y represented CH; And
A represents singly-bound,
5. the ester of compound as claimed in claim 4, its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein, R
2Represent 1～2 identical or different substituting group, said substituting group is selected from Wasserstoffatoms, fluorine atom, chlorine atom, carboxyl, methyl, methoxyl group, amino-sulfonyl, formamyl, difluoro-methoxy, trifluoromethoxy or trifluoromethyl;
X represents the S atom;
Y represents CH; And
A represents singly-bound,
6. the ester of compound as claimed in claim 5, its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101653114A CN102690242A (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amino methenyl heterocyclic ring |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010123692.0 | 2010-02-11 | ||
| CN201010123692 | 2010-02-11 | ||
| CN2012101653114A CN102690242A (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amino methenyl heterocyclic ring |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100352280A Division CN102153555B (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amido formacyl heterocycle |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102690242A true CN102690242A (en) | 2012-09-26 |
Family
ID=44435265
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101653114A Pending CN102690242A (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amino methenyl heterocyclic ring |
| CN2011100352280A Active CN102153555B (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amido formacyl heterocycle |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100352280A Active CN102153555B (en) | 2010-02-11 | 2011-01-28 | Carbapenem compound containing amido formacyl heterocycle |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN102690242A (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101328177B (en) * | 2007-06-15 | 2011-02-09 | 山东轩竹医药科技有限公司 | Nitrogen heterocyclic ring vinyl substituted sulfhydryl heterocycle carbpenem compounds |
| CN101328176B (en) * | 2007-06-15 | 2010-12-15 | 山东轩竹医药科技有限公司 | Tetrahydrochysene pyrimidine vinyl substituted sulfhydryl heterocycle carbpenem compounds |
| EP2177522B1 (en) * | 2007-06-28 | 2013-09-04 | XuanZhu Pharma Co., Ltd. | Novel carbapenem derivatives |
-
2011
- 2011-01-28 CN CN2012101653114A patent/CN102690242A/en active Pending
- 2011-01-28 CN CN2011100352280A patent/CN102153555B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN102153555B (en) | 2013-03-27 |
| CN102153555A (en) | 2011-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9162974B2 (en) | Process for the preparation of vorinostat | |
| ES2942259T3 (en) | Carboxylic acid compound, method for preparing the same and use thereof | |
| JP2006523195A (en) | Pleuromutilin derivative, its production and use | |
| DK144763B (en) | ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES | |
| JPS6259709B2 (en) | ||
| AU2022201724B9 (en) | Macrocyclic broad spectrum antibiotics | |
| JPS61207388A (en) | Beta-lactam compound | |
| EP1538150B1 (en) | Novel pleuromutilin derivatives | |
| WO1999057121A1 (en) | Carbapenem derivatives, utilization thereof and intermediate compounds of the same | |
| CN102153555B (en) | Carbapenem compound containing amido formacyl heterocycle | |
| JPS61215395A (en) | Beta-lactam antibiotic | |
| WO1998034936A1 (en) | Carbapenem compounds, use thereof, and intermediate compounds of the same | |
| WO2002094829A1 (en) | Carbapenem compound | |
| JPH03204883A (en) | Cephalosporin compound, production thereof and use thereof | |
| EP4289842A1 (en) | Phenyldihydropyrimidine compound and use thereof | |
| KR0177844B1 (en) | Antibacterial penem compounds | |
| JPS62126189A (en) | Novel cephalosporin derivative and antimicrobial agent containing said derivative | |
| CN102584827B (en) | Containing the carbapenem compounds of sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine | |
| CN102443014B (en) | 3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor | |
| JPH0812676A (en) | 2-((pyridyl-substituted)thio)-carbapenem derivative | |
| JPS58128387A (en) | Novel beta-lactam compound, manufacture and use | |
| JP3274855B2 (en) | Antibacterial penem compounds | |
| JPH0812675A (en) | 2-((4-halogen-substituted phenyl)thio)-carbapenem derivative | |
| KR101458494B1 (en) | New arylsulfonylimidazolone derivatives and an anti-cancer pharmaceutical composition comprising the same | |
| CN101817837A (en) | Carbapenem derivative containing azabicyclo |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120926 |