CN101333219B

CN101333219B - Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle

Info

Publication number: CN101333219B
Application number: CN2008101293536A
Authority: CN
Inventors: 黄振华
Original assignee: Shandong Xuanzhu Pharma Co Ltd
Current assignee: Xuanzhu Biopharmaceutical Co Ltd
Priority date: 2007-06-26
Filing date: 2008-06-26
Publication date: 2010-10-13
Anticipated expiration: 2028-06-26
Also published as: CN101333219A

Abstract

The invention relates to a penem derivative containing sulfhydryl pyrrolidine formamide heterocyclic alkyl benzene as shown in general formula (I), and also relates to the easy hydrolysis esters of the derivative, the pharmaceutical acceptable non-toxic salts of the derivative, the isomers of the derivative, the hydrates of the derivative, as well as the hydrates of the esters or salts of the derivative; wherein, the detailed definitions of R1, R2, R3, R4, R5, R6, R7 and n are shown in the instruction book. The invention also relates to the preparation methods for the compounds in formula (I), the drug combinations containing the compounds in formula (I), as well as the purposes of the compounds in formula (1) as medicinal active substances, especially the applications of the compounds inthe preparation of drugs for curing and/or preventing infectious diseases.

Description

The Pennem derivates that contains mercapto pyrrolidine formamide benzene alkyl heterocycle

1, technical field

The present invention relates to contain the hydrate of ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate and ester or salt of Pennem derivates, its facile hydrolysis of mercapto pyrrolidine formamide benzene alkyl heterocycle, 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.

First listing be imipenum, gram-positive and negative, aerobic and anerobe all there is very strong activity, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with dehydropeptidase of kidney inhibitor cilastatin clinically in vivo.

Imipenum ertapenem sodium

Discover, introduce 1 Beta-methyl, can strengthen the stability of carbapenem compound DHP-I.Ertapenem for example, penicillin-binding protein had high avidity, aerophil, anerobe are had the excellent antibiotic activity, anti-wide spectrum and extended spectrum produce bacterium such as intestinal bacteria and Klebsiella Pneumoniae effect surpass the third generation and the 4th generation cynnematin.

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 Pennem derivates have been synthesized, gram-positive and negative, aerobic and anerobe especially resistant organism had the strong antibiotic activity, chemical stability is good, β-Nei Xiananmei and DHP-I had satisfactory stability, and has long post antibiotic effect (PAE), for clinical application provides new variety.Compare with immediate prior art and 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):

Wherein: R ¹Expression hydrogen atom or carboxyl-protecting group;

R ²Expression hydrogen atom or amino protecting group;

R ³Expression hydrogen atom or C _1-4Alkyl;

R ⁴, R ⁵Independently represent hydrogen atom respectively, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, carbamyl is replaced or unsubstituted C by halogen atom, hydroxyl, amino, carboxyl, amide group, sulfonic group, sulfonic acid amido, carbamyl _1-4Alkyl or C _1-4Alkoxyl group;

R ⁶Expression is selected from the heterocycle of following groups:

Wherein, R ⁸, R ⁹Independently represent hydrogen atom respectively, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, carbamyl is replaced or unsubstituted C by halogen atom, hydroxyl, amino, carboxyl, amide group, sulfonic group, sulfonic acid amido, carbamyl _1-4Alkyl or C _1-4Alkoxyl group;

R ⁷Expression hydrogen atom or C _1-4Alkyl;

N represents 0～4 integer.

Preferred compound is:

Wherein: R ¹Expression 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 ²Expression 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 ³Expression hydrogen atom or methyl;

R ⁴And R ⁵Independently represent hydrogen atom respectively, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, C _1-4Alkyl or carbamyl;

R ⁶Expression is selected from the heterocycle of following groups:

Wherein, R ⁸And R ⁹Independently represent hydrogen atom respectively, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, C _1-4Alkyl or carbamyl;

R ⁷Expression hydrogen atom or methyl;

N represents 1,2 or 3.

Further preferred compound is:

Wherein: R ¹Expression 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 ²Expression 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 ³The expression hydrogen atom;

R ⁴And R ⁵Independently represent hydrogen atom respectively, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, methyl or carbamyl;

R ⁶Expression is selected from the heterocycle of following groups:

R ⁷The expression methyl;

N represents 1 or 2.

" C of the present invention _1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.

" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.

" C of the present invention _1-4Alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy etc.

" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.

" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: methyl, ethyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.

Part of compounds of the present invention

Particularly preferred compound is:

(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compd A:

(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compd B:

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, also can make by other method:

Reaction equation:

Experimental procedure:

The preparation of step 1, compound 2

In the exsiccant reaction flask, add raw material 1, anhydrous tetrahydro furan; under nitrogen protection; add 1 in room temperature; 1-carbonyl dimidazoles (CDI); reaction, the tetrahydrofuran solution adding raw material 2 below 0 ℃ continues reaction; drip 1mol/L hydrochloric acid then; with ethyl acetate extraction, organic phase is water, saturated nacl aqueous solution washing successively, and concentrating under reduced pressure gets compound 1; compound 1 adds the hydrochloric acid of 5mol/L; stir, be adjusted to alkalescence, separate out solid with dilute alkaline soln; solid gets compound 2 with ethyl acetate-hexanaphthene mixed solution recrystallization.

The preparation of step 2, compound 3

In the dry reaction bottle, add the acetonitrile solution of raw material 3, be chilled to below-20 ℃, add the acetonitrile solution of diisopropylethylamine and compound 2,0 ℃ of stirring after reaction finishes, adds 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., in-50 ℃ of Nitromethane 99Min. solution that drip the 1mol/L aluminum chloride down,-30 ℃ 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, layering, collect water layer, in THF, add 5% magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation, water merges, and 0 ℃ slowly splashes into methyl alcohol,-10 ℃ of stirrings, filter, filter cake water-Virahol recrystallization gets compound 4.

Each substituting group in above reaction equation and the step and the implication of n are as mentioned before.Carboxyl in the compound 4 can be protected by carboxyl-protecting group, 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.

" 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, its pharmacy acceptable salt, its facile hydrolysis can be the form of hydrate shown in the general formula (I).Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.

The present invention is further claimed to comprise arbitrary compound recited above; the ester of its facile hydrolysis; its pharmaceutically acceptable non-toxic salt; its isomer; its hydrate; and the pharmaceutical composition of the hydrate of 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, can be 0.05g; 0.1g; 0.125g; 0.2g; 0.25g; 0.3g; 0.4g; 0.5g; 0.6g; 0.75g; 1g; 1.25g; 1.5g; 1.75g; 2g; 2.5g; 3 g; 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.The Pennem derivates that contains mercapto pyrrolidine formamide benzene alkyl heterocycle 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.

The Pennem derivates that contains mercapto pyrrolidine formamide benzene alkyl heterocycle 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 belongs to Staphylococcus, streptococcus, Pseudomonas aeruginosa, 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) 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.

(7) 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 present invention by in-vitro antibacterial experiment and contain the beneficial effect of the Pennem derivates of mercapto pyrrolidine formamide benzene alkyl heterocycle, 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 the examination bacterial classification: below be the clinical isolates strain, purchase in public institution.

Gram positive organism: MSSA (MSSA) 19 strains, methicillin-resistant staphylococcus aureus (MRSA) 13 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 18 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 10 strains, responsive streptococcus pneumoniae (PSSP) 22 strains of penicillin, penicillin resistance streptococcus pneumoniae (PRSP) 18 strains, streptococcus pyogenes 21 strains, enterococcus faecalis 13 strains;

Gram-negative bacteria: hemophilus influenzae 13 strains, escherichia coli 22 strains, klepsiella pneumoniae 21 strains, Proteus mirabilis 15 strains, enterobacter cloacae 12 strains, Pseudomonas aeruginosa 15 strains; Grain-negative anerobe: bacteroides fragilis 7 strains.

Trial-product:

Preferred compound A of the present invention and compd B, self-control, its chemical name and structural formula are as mentioned before;

Imipenum, meropenem: commercial.

Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.

Experimental result and conclusion:

Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism

By table 1 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A and compd B all have the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.

Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria

By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention A and compd B comprise that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.

Above-mentioned experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.

4, embodiment

The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.

Embodiment 1 (2S, 4S)-4-sulfydryl-2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine Preparation

In the exsiccant reaction flask, add (2S; 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 5.8g (20mmol); anhydrous tetrahydro furan 100ml; under nitrogen protection; add 1 in room temperature; 1-carbonyl dimidazoles 4.9g (30mmol), reaction 1h is at the tetrahydrofuran solution 100ml that adds 4-(pyridin-4-yl) methyl-aniline 7.4g (40mmol) below 0 ℃; continue reaction 0.5h; drip 1mol/L hydrochloric acid 40ml then, extract with ethyl acetate (50ml * 2), organic phase is water successively; the saturated nacl aqueous solution washing; concentrating under reduced pressure; resistates adds the hydrochloric acid 100ml of 5mol/L, stirs 2h, is adjusted to alkalescence with dilute alkaline soln; separate out solid; solid gets solid 6.9g, yield: 83.4% with ethyl acetate-hexanaphthene mixed solution recrystallization.

Embodiment 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) pyrrole Cough up alkane-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 Preparation

In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1 R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the acetonitrile solution 120ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), be chilled to below-10 ℃, add diisopropylethylamine 5ml and (2S, 4S)-and the acetonitrile solution 80ml of 4-sulfydryl-2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 9.1g (22mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 300ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 11.7g, yield: 77.1%.

Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid

Will (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.6g (10mmol) is dissolved in the 50ml methylene dichloride, add methyl-phenoxide 10ml and Nitromethane 99Min. 20ml, in-50 ℃ of Nitromethane 99Min. solution 100ml 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 THF 400ml and water 30ml, add 10% palladium-charcoal 2g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF 150ml, layering in the filtrate, collect water layer, in THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time, water merges, and 0 ℃ slowly splashes into methyl alcohol 30ml, and-10 ℃ are stirred 1h, filter, filter cake water-Virahol recrystallization gets white crystal 2.5g, yield: 48.6%.

Molecular formula: C ₂₇H ₃₀N ₄O ₅S

Molecular weight: 522.62

Ultimate analysis:

Measured value: C, 61.89%; H, 5.98%; N, 10.55%; S, 6.01%

Theoretical value: C, 62.05%; H, 5.79%; N, 10.72%; S, 6.14%

Embodiment 4 (2S, 4S)-4-sulfydryl-2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-1-(uncle's fourth oxygen Carbonyl) preparation of tetramethyleneimine

Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 9.6g (20mmol), 4-(1,1-diketo-thiomorpholine-4-yl) methyl-aniline 9.6g (40mmol), get product 7.4g, yield: 78.9%.

Embodiment 5 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenylamino Base]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] heptan-2- Alkene-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 11.9g (20mmol), (2S, 4S)-[4-(1 for 4-sulfydryl-2-formyl, 1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 10.3g (22mmol), get product 11.8g, yield: 72.3%.

Embodiment 6 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-pyrrole Cough up alkane-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)-2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 8.1g (10mmol) gets white crystal 2.5g, yield: 43.1%.

Molecular formula: C ₂₆H ₃₄N ₄O ₇S ₂

Molecular weight: 578.7

Ultimate analysis:

Measured value: C, 53.78%; H, 6.15%; N, 9.47%; S, 11.22%

Theoretical value: C, 53.96%; H, 5.92%; N, 9.68%; S, 11.08%

The preparation of embodiment 7 The compounds of this invention aseptic powder injections

1, prescription:

Prescription 1:

Any one 250g (in compound) in compd A, the B or derivatives thereof

Prepare 1000 altogether

Prescription 2:

Any one 500g (in compound) in compd A, the B or derivatives thereof

Prepare 1000 altogether

Prescription 3:

Any one 1000g (in compound) in compd A, the B or derivatives thereof

Prepare 1000 altogether

Prescription 4:

Any one 2000g (in compound) in compd A, the B 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 8 The compounds of this invention tablets

1, prescription:

Prescription 1:

Any one 250g (in compound) in compd A, the B 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 compd A, the B 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 compd A, the B 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

1. compound shown in the formula (I) or its pharmaceutically acceptable non-toxic salt:

Wherein: R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

R ³Expression hydrogen atom or C _1-4Alkyl;

R ⁴, R ⁵Independently represent hydrogen atom or C respectively _1-4Alkyl;

R ⁶Expression is selected from the heterocycle of following groups:

Wherein, R ⁸, R ⁹Independently represent hydrogen atom or C respectively _1-4Alkyl;

R ⁷Expression hydrogen atom or C _1-4Alkyl;

N represents 0～4 integer.

2. compound as claimed in claim 1 or its pharmaceutically acceptable non-toxic salt:

Wherein: R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

R ³Expression hydrogen atom or methyl;

R ⁴And R ⁵Independently represent hydrogen atom or C respectively _1-4Alkyl;

R ⁶Expression is selected from the heterocycle of following groups:

Wherein, R ⁸And R ⁹Independently represent hydrogen atom or C respectively _1-4Alkyl;

R ⁷Expression hydrogen atom or methyl;

N represents 1,2 or 3.

3. compound as claimed in claim 2 or its pharmaceutically acceptable non-toxic salt:

Wherein: R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

R ³The expression hydrogen atom;

R ⁴And R ⁵Independently represent hydrogen atom or methyl respectively;

R ⁶Expression is selected from the heterocycle of following groups:

R ⁷The expression methyl;

N represents 1 or 2.

4. compound as claimed in claim 3 or its pharmaceutically acceptable non-toxic salt, described compound is selected from:

(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(pyridin-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, or

(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid.

5. each described compound of claim 1～4 or its pharmaceutically acceptable non-toxic salt, its pharmaceutically acceptable non-toxic salt is inorganic acid salt, organic acid salt, amino acid salts, organic alkali salt or inorganic base salts.

6. the pharmaceutical composition that comprises each described compound of claim 1～4 or its pharmaceutically acceptable non-toxic salt and one or more pharmaceutical carriers and/or thinner.

7. pharmaceutical composition as claimed in claim 6 wherein contains each described compound of claim 1～4 or its pharmaceutically acceptable non-toxic salt 0.05g～5g as essential active ingredient.

8. pharmaceutical composition as claimed in claim 6, this pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.

9. each described compound of claim 1～4 or its pharmaceutically acceptable non-toxic salt are used to prepare the purposes of the medicine that treats and/or prevents infectious diseases.