CN101328178B - Penem derivates containing thiophen substituted sulfhydryl pyrrolidine - Google Patents
Penem derivates containing thiophen substituted sulfhydryl pyrrolidine Download PDFInfo
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- CN101328178B CN101328178B CN2008101248329A CN200810124832A CN101328178B CN 101328178 B CN101328178 B CN 101328178B CN 2008101248329 A CN2008101248329 A CN 2008101248329A CN 200810124832 A CN200810124832 A CN 200810124832A CN 101328178 B CN101328178 B CN 101328178B
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Abstract
The invention belongs to the medicine technical field, in particular relating to a penem derivate containing thiophene-substituted sulfhydryl pyrrolidine as shown in a general formula (1), a salt thereof acceptable in pharmacology, an easily hydrolyzed ester thereof, an isomer thereof, a hydrate thereof and a hydrate of the ester or the salt thereof, wherein R<1>, R<2>, R<3> and R<4> are defined in a specification. The invention also relates to a preparation method of the compounds, a medicine combination containing the compounds and an application of the compounds in preparing medicines usedto treat and/or prevent infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain Pennem derivates, its pharmacy acceptable salt, its facile hydrolysis of the mercapto pyrrolidine that thiophene replaces ester, its isomer, its hydrate, with and the hydrate of ester or salt, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infectious diseases.
2, background technology
Carbapenem antibiotic is the class β-Nei Xiananleikangshengsu that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
This similar drug that has gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem etc.Because antibiotic widespread use constantly increases drug-resistance of bacteria, in addition owing to the limitation of digestive tube absorption, clinically can only be as the injection administration, clinical availability is not high, can not meet clinical needs.
Therefore, need research and development the clinical infection pathogenic bacteria to be had the stable training south class microbiotic of better anti-microbial activity.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides ester, its isomer, its hydrate of the compound shown in the general formula (1), its pharmacy acceptable salt, its facile hydrolysis, with and the hydrate of ester or salt:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group;
R
2Represent hydrogen atom or amino protecting group;
R
3Represent following groups:
R
4Represent hydrogen atom or low alkyl group.
Preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
R
3Represent following groups:
R
4Represent hydrogen atom, methyl or ethyl.
Further preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Represent hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
R
3Represent following groups:
R
4Represent hydrogen atom or methyl.
" low alkyl group " of the present invention is C
1-6The alkyl of straight or branched is as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: methyl, ethyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; 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.
Table 1 part of compounds of the present invention
Further preferred compound comprises:
Chemical name: (4R, 5S, 6S)-3-[(3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-tetramethyleneimine-3-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 compound 1, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-tetramethyleneimine-3-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 compound 2, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl urea groups) methyl-thiophene-2-yl]-tetramethyleneimine-3-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 compound 3, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl thioureido) methyl-thiophene-2-yl]-tetramethyleneimine-3-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 compound 4, its structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd, reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
In the dry reaction bottle, the acetonitrile solution that adds raw material 2 is chilled to below-20 ℃, adds the acetonitrile solution of diisopropylethylamine and raw material 1,0 ℃ of stirring.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid, and promptly intermediate 1.
The preparation of step 2 The compounds of this invention
In the methylene dichloride with intermediate 1, add methyl-phenoxide and Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution that drip the 1mol/L aluminum chloride down,-40 ℃ of stirrings add entry, separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, add 10% palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, water layer is collected in layering, adds 5% magnesium chloride brine again in THF, leave standstill, divide water-yielding stratum, repetitive operation, water merges, 0 ℃ slowly splashes into methyl alcohol, filter cake acetonitrile recrystallization is filtered in-10 ℃ of stirrings, get white crystal, i.e. The compounds of this invention.
Hydrogen atom on 2 carboxyls of The compounds of this invention can be protected by carboxyl-protecting group.
R in the above reaction equation
2, R
3, R
4The group of representative as mentioned before.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl methyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; The lower alkoxycarbonyl alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound, for example at 4 carboxyl place.
Isomer of the present invention is meant its all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (1) compound has many three-dimensional centers, as on the 4-position; On the 5-position; On the 6-position.
The ester of the compound shown in the general formula (1), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.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 includes arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis ester, its isomer, its hydrate, with and the hydrate of ester or salt, with the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt thereof, Betamipron.
The present invention is further claimed to comprise arbitrary compound recited above; the ester of its facile hydrolysis; its pharmacy acceptable 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 formula (1); the ester of its facile hydrolysis; its pharmacy acceptable salt; its isomer; its hydrate; or the hydrate 0.05g～5g of its ester or salt (by compound shown in the formula 1) can be 0.05g as necessary active ingredient; 0.1g; 0.125g; 0.2g; 0.25g; 0.3g; 0.4g; 0.5g; 0.6g; 0.75g; 1g; 1.25g; 1.5g; 1.75g; 2g; 2.5g; 3g; 4g; 5g etc.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 not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Usually, have been found that carbapenems is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.With preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria, not to be noted by caused tangible poisoning aura of The compounds of this invention or side effect to the mouse administration.
The present invention also provide Pennem derivates that the present invention contains the mercapto pyrrolidine that thiophene replaces preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Pennem derivates of the present invention all has better antibacterial activity to gram-positive microorganism, Gram-negative bacteria, aerophil, anerobe and hospital clinical pathogenic bacteria, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Pennem derivates of the present invention compared with prior art has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can by safety be used for the treatment of and/or to prevent various Mammalss (as mouse, rat, rabbit, dog, cat, ox, pig etc.) to comprise human by the caused various diseases of germ, as pulmonary infection and urinary tract infections etc.;
(2) The compounds of this invention has a broad antifungal spectrum all has better antibacterial activity to Gram-positive and negative bacterium, aerobic and anerobe and hospital clinical pathogenic bacteria;
(3) The compounds of this invention has high stability to β-Nei Xiananmei and DHP-I, can be used for β-Nei Xiananmei and produces bacterium, and do not need to share with other medicines.
(4) The compounds of this invention has good antibacterial activity to clinical drug-resistant bacterium MRSA.
(5) The compounds of this invention preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect that contains the Pennem derivates of the mercapto pyrrolidine that thiophene replaces of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the southern antibiotics of training 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 clinical isolates strain
Gram positive organism: MSSA (MSSA) 22 strains, methicillin-resistant staphylococcus aureus (MRSA) 17 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 20 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 18 strains, responsive streptococcus pneumoniae (PSSP) 21 strains of penicillin, penicillin resistance streptococcus pneumoniae (PRSP) 18 strains, streptococcus pyogenes 16 strains, enterococcus faecalis 15 strains;
Gram-negative bacteria: hemophilus influenzae 19 strains, escherichia coli 25 strains, klepsiella pneumoniae 27 strains, Proteus mirabilis 15 strains, enterobacter cloacae 16 strains, Pseudomonas aeruginosa 22 strains; Grain-negative anerobe: bacteroides fragilis 8 strains.
Trial-product:
Preferred compound 1-4 of the present invention, self-control, its chemical name and structural formula are as mentioned before;
Imipenum, meropenem: commercial.
Experimental technique: agar dilution.
Experimental result and conclusion:
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 2 experimental result as seen, compare with meropenem with imipenum, preferred compound 1-4 of the present invention all has 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
By table 3 experimental result as seen, compare with meropenem with imipenum, preferred compound 1-4 of the present invention comprises that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.
Above-mentioned experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-system of N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine
Be equipped with
In reaction flask, add (3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-the methylene dichloride 200ml solution ice bath of 3-sulfydryl-tetramethyleneimine 29.3g (100mmol) is chilled under 5 ℃, adds triethylamine 20ml, drips 33g (Boc) after stirring 5min
2The methylene dichloride 100ml solution of O (150mmol) stirs 1h, and the frozen water cooling adds 300ml water down, divide water-yielding stratum, water layer is used the dichloromethane extraction of 100ml * 3 again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, solid 32.3g, yield: 82.2%.
Embodiment 2 (3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine
Preparation
With reference to embodiment 1 operation, throw (3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-3-sulfydryl-tetramethyleneimine 31.4g (100mmol), get product 33.1g, yield: 79.8%.
Embodiment 3 (3S)-5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl urea groups] methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-mercapto
The preparation of base-tetramethyleneimine
With reference to embodiment 1 operation, throw (3S)-5-[5-(2-amino-ethyl urea groups) methyl-thiophene-2-yl]-3-sulfydryl-tetramethyleneimine 30.0g (100mmol), get product 40.3g, yield: 80.4%.
Embodiment 4 (3S)-5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl thioureido] methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-
The preparation of sulfydryl-tetramethyleneimine
With reference to embodiment 1 operation, throw (3S)-5-[5-(2-amino-ethyl thioureido) methyl-thiophene-2-yl]-3-sulfydryl-tetramethyleneimine 31.7g (100mmol), get product 43.3g, yield: 83.7%.
Embodiment 5 (4R, 5S, 6S)-3-[(3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-tetramethyleneimine
-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's system
Be equipped with
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the acetonitrile 400ml solution of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol) is chilled to below-20 ℃, add diisopropylethylamine 16ml and (3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-the acetonitrile 200ml solution of N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine 27.5g (70mmol), 0 ℃ is stirred 24h, after reaction finishes, adds ethyl acetate 600ml dilution, water successively, the saturated salt washing, the organic layer drying, concentrate, get solid 32.2g, yield: 72.8%.
Embodiment 6 (4R, 5S, 6S)-3-[(3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-pyrrole
Cough up alkane-3-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
Preparation
Concrete preparation method's reference example 5.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 35.8g (60mmol), (3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine 29g (70mmol), get product 31.8g, yield: 69.8%.
Embodiment 7 (4R, 5S, 6S)-3-[(3S)-and 5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl urea groups] methyl-thiophene-2-yl]-uncle N-
Butoxy carbonyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation to the nitrobenzyl ester
Concrete preparation method's reference example 5.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 35.8g (60mmol), (3S)-and 5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl urea groups] methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine 35g (70mmol), get product 33.7g, yield: 66.4%.
Embodiment 8 (4R, 5S, 6S)-3-[(3S)-5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl thioureido]
Methyl-thiophene-2-yl]-N-
Tertbutyloxycarbonyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic
Acid is to the preparation of nitrobenzyl ester
Concrete preparation method's reference example 5.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 35.8g (60mmol), (3S)-and 5-[5-[2-(tertbutyloxycarbonyl) amino-ethyl thioureido] methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-3-sulfydryl-tetramethyleneimine 36.2g (70mmol), get product 34.7g, yield: 67.1%.
Embodiment 9 (4R, 5S, 6S)-3-[(3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Will (4R, 5S, 6S)-3-[(3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] in the 200ml methylene dichloride of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 29.5g (40mmol), adds methyl-phenoxide 20ml and Nitromethane 99Min. 30ml, in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down,-40 ℃ are stirred 2h, add entry 500ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 1000mlTHF and water 60ml, add 10% palladium-charcoal 8g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF300ml in the filtrate, water layer is collected in layering, adds 5% magnesium chloride brine 80ml again in THF, leave standstill, divide water-yielding stratum, repetitive operation 1 time, water merges, 0 ℃ slowly splashes into methyl alcohol 100ml,-10 ℃ are stirred 1h, filter filter cake acetonitrile recrystallization, get white crystal 7.5g, yield: 37.3%.
Molecular formula: C
19H
26N
4O
6S
3
Molecular weight: 502.63
Ultimate analysis: measured value: C, 45.12%; H, 5.47%; N, 11.26%; S, 18.08%
Theoretical value: C, 45.40%; H, 5.21%; N, 11.15%; S, 19.14%
Embodiment 10 (4R, 5S, 6S)-3-[(3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 9.Throw (4R, 5S, 6S)-3-[(3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-tetramethyleneimine-3-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 30.4g (40mmol), get target product 7.5g, yield: 35.6%.
Molecular formula: C
22H
29N
5O
6S
2
Molecular weight: 523.63
Ultimate analysis: measured value: C, 50.19%; H, 5.72%; N, 13.11%; S, 12.02%
Theoretical value: C, 50.46%; H, 5.58%; N, 13.37%; S, 12.25%
Embodiment 11 (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl urea groups) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 9.Throw (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl urea groups) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-tetramethyleneimine-3-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 33.8g (40mmol), get target product 7.0g, yield: 34.1%.
Molecular formula: C
22H
31N
5O
5S
2
Molecular weight: 509.64
Ultimate analysis: measured value: C, 51.67%; H, 6.35%; N, 13.58%; S, 12.41%
Theoretical value: C, 51.85%; H, 6.13%; N, 13.74%; S, 12.58%
Embodiment 12 (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl thioureido) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 9.Throw (4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl thioureido) methyl-thiophene-2-yl]-N-tertbutyloxycarbonyl-tetramethyleneimine-3-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 34.4g (40mmol), get target product 6.8g, yield: 32.4%.
Molecular formula: C
22H
31N
5O
4S
3
Molecular weight: 525.71
Ultimate analysis: measured value: C, 50.14%; H, 6.04%; N, 13.18%; S, 18.13%
Theoretical value: C, 50.26%; H, 5.94%; N, 13.32%; S, 18.30%
The preparation of embodiment 13 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
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 14 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
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:
Any one 125g (in compound) in the The compounds of this invention 1-4 or derivatives thereof
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) with in the The compounds of this invention 1-4 or derivatives thereof any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, 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 (8)
1. the compound shown in the general formula (1) or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2Represent hydrogen atom;
R
3Represent following groups:
R
4Represent hydrogen atom or C
1-6The straight or branched alkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2Represent hydrogen atom;
R
3Represent following groups:
R
4Represent hydrogen atom, methyl or ethyl.
3. compound as claimed in claim 2 or its pharmacy acceptable salt is characterized in that being selected from:
(4R, 5S, 6S)-3-[(3S)-5-[5-(aminosulfonyl amino) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-5-[5-(2-urea groups-kharophen) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl urea groups) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, or
(4R, 5S, 6S)-3-[(3S)-5-[5-(2-amino-ethyl thioureido) methyl-thiophene-2-yl]-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid.
4. each described compound of claim 1～3 or its pharmacy acceptable salt, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid is selected from acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid is selected from hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases is selected from meglumine, glucosamine; Mineral alkali is selected from the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
5. the pharmaceutical composition that comprises each described compound of claim 1～3 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
6. pharmaceutical composition as claimed in claim 5, this pharmaceutical composition are pharmaceutically acceptable arbitrary formulation.
7. pharmaceutical composition as claimed in claim 5, this pharmaceutical composition contain each described compound of claim 1～4 or its pharmacy acceptable salt 0.05g～5g as essential activeconstituents.
8. each described compound of claim 1～3 or its pharmacy acceptable salt are in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
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| WO2002040482A1 (en) * | 2000-11-20 | 2002-05-23 | Sankyo Company, Limited | Process for producing carbapenem-type antibacterial |
| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
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