CN101333218B - Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds - Google Patents

Abstract

The invention relates to a formamide alkylbenzene-substituted sulfhydryl pyrrolidine carbapenem compound as shown in general formula (I), and also relates to the easy hydrolysis esters of the compound, the pharmaceutical acceptable non-toxic salts of the compound, the isomers of the compound, the hydrates of the compound, the hydrates of the esters or salts of the compound, the preparation methods for the compounds in formula (I), the purposes of the compounds as medicinal active substances and especially the applications of the compounds in the preparation of drugs for curing and/or preventing infectious diseases, as well as the drug combinations containing the compounds in formula (I). The detailed definitions of R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and n in the formula (I) are shown in the specification.

Description

Carboxamidoalkylbenzene substituted mercaptopyrrolidine carbapenem compounds

1. Technical field

The present invention relates to carboxamide alkylbenzene substituted mercaptopyrrolidine carbapenem compound, its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate, and its ester or salt The hydrate, the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the application of these compounds in the preparation of medicines for treating and/or preventing infectious diseases belong to the technical field of medicine. the

2. Background technology

Carbapenems are new broad-spectrum, enzyme-resistant and highly effective β-lactam antibiotics developed in the 1970s. In 1976, Thiamycin, the first carbapenem antibiotic, was discovered, but it was not used clinically due to its poor chemical stability. Later, the chemical structure modification of thiamycin produced a series of carbapenem derivatives. At present, such drugs that have been marketed include imipenem, panipenem, meropenem, doripenem, biapenem, ertapenem, etc. the

Its structural feature is that the sulfur at the 1-position of the penicillane core is replaced by carbon, and the 2-position has a double bond, which combines the five-membered ring of penicillin and the conjugated double bond of cephalosporin to activate the β-lactam ring; 6 The hydroxyethyl side chain is in trans conformation. the

Due to the continuous increase of bacterial resistance due to the abuse of antibiotics and the limitation of digestive tract absorption, the currently marketed carbapenems can only be administered as injections in clinical practice, and the clinical utilization is not high, and the antibacterial activity against MRSA Weak, can no longer meet the clinical needs. the

3. Contents of the invention

The present inventor has synthesized a series of carbapenem compounds through a large amount of research and practice, has strong antibacterial activity to Gram-positive and negative, aerobic and anaerobic bacteria, especially drug-resistant bacteria, good chemical stability, and innovative and superior to the closest prior art. the

Technical scheme of the present invention is as follows:

The present invention provides the compound represented by general formula (I), its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate, and the hydrate of its ester or salt:

Wherein: R ¹ represents a hydrogen atom or a carboxyl protecting group;

R ² represents a hydrogen atom or an amino protecting group;

R ³ represents a hydrogen atom or a C _1-4 alkyl group;

R ⁴ and R ⁵ are the same or different, respectively representing a hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano, nitro, trifluoromethyl, carbamoyl, or replaced by hydroxyl, amino, carboxyl, amido, sulfonic acid Group, sulfonamide group, carbamoyl substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxy;

R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a cyano group or a trifluoromethyl group;

n is an integer of 0-5. the

Preferred compounds are:

Wherein, ^R represents a hydrogen atom or a carboxyl protecting group, and the carboxyl protecting group is selected from methyl, ethyl, tert-butyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, benzoylform phenyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenylmethyl;

^R represents a hydrogen atom or an amino protecting group, and the amino protecting group is selected from methyl, ethyl, tert-butyl, benzyl, formyl, acetyl, allyloxycarbonyl, phenacyl, tert Butoxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3-acetoxypropyl or diazo;

R ³ represents a hydrogen atom, methyl, ethyl, isopropyl or tert-butyl;

R ⁴ and R ⁵ are the same or different, respectively representing a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, an amino group, a carboxyl group, a cyano group, a trifluoromethyl group, a carbamoyl group or a C _1-4 alkyl group;

R ⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group or a trifluoromethyl group;

n is an integer of 0-3. the

Further preferred compounds are:

Wherein, ^R represents a hydrogen atom or a carboxyl protecting group, and the carboxyl protecting group is selected from methyl, tert-butyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenyl methyl;

^R represents a hydrogen atom or an amino protecting group, and the amino protecting group is selected from methyl, tert-butyl, formyl, allyloxycarbonyl, tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxy benzyloxycarbonyl or diazo;

R ³ represents methyl, isopropyl or tert-butyl;

^R4 and ^R5 are the same or different, respectively representing a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, an amino group, a carboxyl group, a cyano group, a trifluoromethyl group, a methyl group or a carbamoyl group;

R ⁶ represents a hydrogen atom or a fluorine atom;

n is 1. the

Table 1 Some compounds of the present invention

serial number R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ n 1 h h -CH ₃ h h h 1 2 h h -CH ₃ h h -F 1 3 h h -CH ₃ h -F h 1 4 h h -CH ₃ h -F -F 1 5 h h -CH ₃ h -Cl h 1 6 h h -CH ₃ h -Cl -F 1 7 h h -CH(CH ₃ ) ₂ h h h 1 8 h h -CH(CH ₃ ) ₂ h h -F 1 9 h h -CH(CH ₃ ) ₂ h -F h 1 10 h h -CH(CH ₃ ) ₂ h -F -F 1 11 h h -CH(CH ₃ ) ₂ h -Cl h 1 12 h h -CH(CH ₃ ) ₂ h -Cl -F 1 13 h h -C(CH ₃ ) ₃ h h h 1 14 h h -C(CH ₃ ) ₃ h h -F 1 15 h h -C(CH ₃ ) ₃ h -F h 1 16 h h -C(CH ₃ ) ₃ h -F -F 1

17 h h -C(CH ₃ ) ₃ h -Cl h 1 18 h h -C(CH ₃ ) ₃ h -Cl -F 1

Particularly preferred compounds are:

(4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-benzyl-2-methylpropyl-2-amino]-pyrrolidin-4-yl]thio- 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid, hereinafter referred to as compound A :

(4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-pyrrolidine-4- Base]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid , hereinafter referred to as Compound B:

The "C _1-4 alkyl" in the present invention includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.

The "halogen" mentioned in the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom. the

The "C _1-4 alkoxy" in the present invention includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

The "carboxyl protecting group" in the present invention refers to a protecting group conventionally used to replace the proton of a carboxylic acid. Examples include: methyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethylmethyl, benzyloxymethyl, phenacyl, p-bromobenzoyl Methyl, α-methylphenacyl, p-methoxyphenacyl, diacylmethyl, N-phthalimidomethyl, ethyl, 2,2,2-tris Chloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(p-nitrophenylthio)ethyl Base, 2-(p-tolylthio)ethyl, 1-methyl-1-phenethyl, allyl, tert-butyl, cyclopentyl, cyclohexyl, bis(o-nitrophenyl)methyl, 9-fluorenylmethyl, 2-(9,10-dioxo)fluorenylmethyl, diphenylmethyl, 5-diphenylthio, benzyl, 2,4,6-trimethylbenzyl , p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, piperonyl, 4-pyridylmethyl, trimethylsilyl, triethylsilyl, tert-butyl Dimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, S-tert-butyl, S-phenyl, S-2-pyridyl, N-hydroxypiperidine N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazolyl, O-acyl oxime, 2,4-dinitrophenylsulfanyl, 2-alkyl -1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-dioxane, triethylstannane , Tri-n-butylstannane; N, N'-diisopropyl hydrazide, etc. the

The "amino protecting group" in the present invention refers to a protecting group conventionally used to replace the proton of an amino acid. Examples include: methyl, ethyl, cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl, diisopropylmethyl, 9-fluorenylmethyl, 9-(2-thio)fluorenylmethyl , 2-furylmethyl, 2,2,2-trichloromethyl, 2-halomethyl, 2-iodoethyl, 2-trimethylsilylethyl, 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, 2-phosphoniumethyl, 1,1-dimethyl-3-(N,N-dimethylformamido)propane Base, 1,1-diphenyl-3-(N,N-diethylamino)propyl, 1-methyl-1-(adamantyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(4-biphenyl)ethyl, 1-methyl-1-(p-phenylazo phenyl)ethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1,1-dimethyl-2-cyanoethyl, isobutyl, tert-butyl, tert-amyl Cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 1-adamantyl, isobornyl, vinyl, allyl, cinnamyl, phenyl , 2,4,6-tri-tert-butylphenyl, m-nitrophenyl, S-phenyl, 8-quinolyl, N'-hydroxypiperidinyl, 4-(1,4-dimethylpiper Pyridyl), 4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-trimethylbenzyl, p-methoxybenzyl, p-methoxybenzyloxy Cylcarbonyl, 3,5-dimethoxybenzyl, p-decyloxybenzyl, p-nitrobenzyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyl, 3,4-dimethoxy- 6-nitrobenzyl, p-bromobenzyl, chlorobenzyl, 2,4-dichlorobenzyl, p-cyanobenzyl, o-(N,N-dimethylformamido)benzyl, m-chlorobenzyl -p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, p-(phenylazo)benzyl, p-(p-methoxyphenylazo)benzyl, 5-benzoisoxanyl Azolylmethyl, 9-anthracenylmethyl, benzhydryl, phenyl(o-nitrophenyl)methyl, bis(2-pyridyl)methyl, 1-methyl-1-(4-pyridine base) ethyl, isonicotinyl, S-benzyl, N'-piperidinylcarbonyl, N'-p-toluenesulfonylaminocarbonyl and N'-anilinothiocarbonyl carbamate; formyl, acetyl Base, acetyl-pyridinium, (N'-dithiobenzyloxycarbonylamino)acetyl, 3-phenylpropionyl, 3-(p-hydroxyphenyl)propionyl, 3-(o-nitrophenyl) Propionyl, 2-methyl-2-(o-nitrophenoxy)propionyl, 2-methyl-2-(o-benzoazophenoxy)propionyl, 4-chlorobutyryl, isobutyl Acyl, o-nitrocinnamoyl, picolyl, N'-acetylmethionyl, N'-benzoyl-phenylalkyl, benzoyl, p-phenylbenzoyl, p-methoxybenzyl Amides of acyl, o-nitrobenzoyl, o-(benzoyloxymethyl)benzoyl and p-benzoyl; phthaloyl, 2,3-diphenylmaleoyl and Cyclic imide of dithiosuccinyl; tert-butoxycarbonyl, allyl, allyloxycarbonyl, phenacyl, 3-Acetoxypropyl, 4-nitro-1-cyclohexyl-2-oxo-3-pyrrolidin-3-yl, quaternary ammonium salt, methoxymethyl, 2-chloroethoxymethyl , benzyloxymethyl, pivaloylmethyl, [1-(alkoxycarbonylamino)]-2,2,2, trifluoroethyl, [1-trifluoromethyl-1-(p-chlorophenoxy methoxy) 2,2,2,-trifluoro]ethyl, 2-tetrahydropyranyl, 2,4-dinitrophenyl, benzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, bis(p-methoxyphenyl)methyl, trityl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl, 2-pyridylmethyl Base-N'-oxide, 5-diphenylpropanyl, N', N'-dimethylaminomethylene, N'-isopropylidene, benzylidene, p-methoxybenzylidene , p-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, dibenzylidene, (5-chloro-2-hydroxyphenyl)phenylmethylene, (acylvinyl), 5,6-Dimethyl-3-oxo-1-cyclohexenyl, borane, [phenyl (chromium or tungsten pentacarbonyl)] carbonyl, copper or zinc chelate, nitro, nitroso, Oxide, diphenylphosphinyl, dimethylthiophosphinyl, diphenylthiophosphinyl, diethylphosphoryl, dibenzylphosphoryl, diphenylphosphoryl, phosphoryl, trimethylmethane Silyl group, phenylthio group, o-nitrophenylthio group, 2,4-dinitrophenylthio group, 2-nitro-4-methoxyphenylthio group, tritylthio group, benzenesulfonyl group, p- Methoxybenzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, methylsulfonyl, phenylmethylsulfonyl, p-toluenesulfonyl, trifluoromethylsulfonyl, phenacylmethylsulfonyl , Diazo group, etc. the

The "easily hydrolyzable ester" in the present invention can be understood as the presence of one or more carboxyl groups in formula (I) in the form of easily hydrolyzable ester groups. Examples of such esters, in conventional forms, are: lower alkanoyloxyalkyl esters, including acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl etc.; lower alkoxycarbonyloxyalkyl esters, including methoxycarbonyloxymethyl ester, 1-ethoxycarbonyloxyethyl ester and 1-isopropoxycarbonyloxyethyl ester, etc.; lower alkoxymethyl Esters, including methoxymethyl ester, 1-isopropoxymethyl ester, etc.; lower alkanoylaminomethyl esters, including formamidomethyl ester, acetamidomethyl ester, etc.; other esters can also be used, Such as benzyl ester and cyanomethyl ester. Other examples of such esters are: (2,2-dimethyl-1-oxopropoxy)methyl ester, (5-methyl-2-oxo-1,3-dioxolane En-4-yl)methyl ester, 2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester, 1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester, 1-(acetoxy)ethyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-[[(cyclohexyloxy base)carbonyl]oxy]ethyl ester and 3,3-dimethyl-2-oxobutyl ester. Particularly preferred esters are pivaloyloxymethyl ester and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester. It will be apparent to those skilled in the art that readily hydrolyzable esters of the compounds of the present invention may be formed at the free carboxyl group of the compounds. the

The "pharmaceutically acceptable non-toxic salt" in the present invention includes inorganic acid salts, organic acid salts, amino acid salts, organic alkali salts or inorganic alkali salts. Among them, inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, citric acid, fumaric acid, etc. ; Amino acids include arginine, aspartic acid, glutamic acid, etc.; organic bases include meglumine, glucosamine, trimethylamine, triethylamine, dicyclohexylamine, N, N-dibenzyl- 1,2-Ethylenediamine, etc.; inorganic bases include alkaline compounds of sodium, potassium, barium, calcium, magnesium, zinc, lithium, etc. These acid or base addition salts can be prepared according to any of the usual methods. the

The "isomers" mentioned in the present invention refer to all epimers, diastereoisomers and tautomeric forms. When a bond is represented by a wedge, this indicates that in three dimensions the bond will come out of the paper, while when a bond is shaded, this indicates that in three dimensions the bond will return into the paper. The compound represented by the general formula (I) has many stereocenters, for example, at the 4-position, 5-position, 6-position, etc.

The "hydrate" in the present invention refers to hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate and the like. The compound represented by the general formula (I), its pharmaceutically acceptable salt, and its easily hydrolyzed ester may be in the form of hydrates. Hydration can be accomplished during the preparation process or can be carried out gradually, taking advantage of the hygroscopic properties of the original anhydrous product. the

The present invention also provides a preparation method for preparing the compound shown in general formula (I), but not limited to the following preparation methods, it can also be prepared by other methods:

Reaction equation:

Experimental steps:

Step 1, preparation of compound 2

Add (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine (raw material 1) and anhydrous tetrahydrofuran into a dry reaction flask. Under the protection of nitrogen, 1,1-carbonyldiimidazole (CDI) was added at room temperature for reaction, and the tetrahydrofuran solution of raw material 2 was added below 0°C to continue the reaction. Then add 1mol/L hydrochloric acid dropwise, extract with ethyl acetate, wash the organic phase with water and saturated sodium chloride solution successively, concentrate under reduced pressure, add 3mol/L hydrochloric acid to the residue, stir, adjust to alkaline with dilute alkali solution, A solid was precipitated, and the solid was recrystallized from acetonitrile solution to obtain compound 2. the

Step 2, preparation of compound 3

In a dry reaction flask, add the acetonitrile solution of raw material 3, cool, add diisopropylethylamine and compound 2 in acetonitrile solution, and stir. After the reaction was completed, it was diluted with ethyl acetate, washed with water and saturated brine successively, and the organic layer was dried and concentrated to obtain compound 3. the

Step 3, preparation of compound 4

Dissolve compound 3 in dichloromethane, add anisole and nitromethane, add dropwise 1mol/L aluminum trichloride nitromethane solution at low temperature, stir, add water, precipitate solid, filter, filter cake Dissolve in a mixture of THF and water, add 10% palladium-carbon, stir the reaction under 5 MPa hydrogen pressure at room temperature, filter off palladium-carbon, add THF to the filtrate, separate layers, and collect the water layer. Then add 5% magnesium chloride aqueous solution to THF, let stand, separate the water layer, and repeat the operation. The aqueous phases were combined, methanol was slowly added dropwise, stirred, filtered, and the filter cake was recrystallized from water-isopropanol to obtain compound 4. the

The meanings of each substituent and n in the above reaction equation are as described above; the carboxyl group in the compound of the present invention can be protected by a carboxyl protecting group, and the nitrogen atom on the pyrrolidinyl can be protected by an amino protecting group, and the carboxyl protecting group and amino protecting groups are as previously described. the

The present invention further claims to include any compound mentioned above, its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate, or its ester or salt hydrate and a or a plurality of pharmaceutically acceptable carriers and/or diluents, containing any compound represented by general formula (I), its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, and its isomer , its hydrate, or its ester or salt hydrate 0.05g～5g (according to the compound shown in formula I) as the necessary active component, can be 0.05g, 0.075g, 0.1g, 0.125g, 0.25g, 0.3g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, etc. The above-mentioned pharmaceutical composition can be administered to patients in need of treatment by oral administration, parenteral administration or external administration, preferably oral preparations or injections or external preparations. the

For parenteral administration, it can be made into injections. Injections refer to the sterile preparations of solutions, emulsions or suspensions made of drugs for injection into the body and powders or concentrated solutions prepared or diluted into solutions or suspensions before use. Injections can be divided into injections, injections Sterile powder and concentrated solution for injection. Injections refer to sterile solution injections, emulsion injections or suspension injections made of drugs for injection into the body, which can be used for intramuscular injection, intravenous injection, intravenous drip, etc.; its specification is 1ml , 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml, etc. Among them, the large volume (generally not less than 100ml) injection for intravenous infusion is also called intravenous infusion. Sterile powder for injection refers to the sterile powder or block made of medicine that can be prepared into a clear solution or homogeneous suspension with a suitable sterile solution before use. It can be prepared with a suitable solvent for injection and then injected. , It can also be prepared by intravenous infusion and injected intravenously; the sterile powder can be prepared by solvent crystallization, spray drying or freeze drying. Concentrated solution for injection refers to a sterile concentrated solution prepared from a drug that is diluted before use for intravenous infusion. the

When made into an injection, it can be produced by conventional methods in the existing pharmaceutical field, and an aqueous solvent or a non-aqueous solvent can be selected. The most commonly used aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solutions can also be used; the commonly used non-aqueous solvent is vegetable oil, mainly soybean oil for injection, and others include ethanol, propylene glycol, and polyethylene glycol. and other aqueous solutions. When preparing injections, appropriate additives can be added according to the properties of the drug, such as osmotic pressure regulators, pH value regulators, solubilizers, fillers, antioxidants, bacteriostats, emulsifiers, suspending agents, etc. Commonly used osmotic pressure regulators include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; commonly used pH regulators include acetic acid-sodium acetate, lactic acid, citric acid, etc. acid-sodium citrate, sodium bicarbonate-sodium carbonate, etc.; commonly used solubilizers include polysorbate 80, propylene glycol, lecithin, polyoxyethylene castor oil, etc.; commonly used fillers include lactose, mannitol, sorbitol, Dextran, etc.; commonly used antioxidants are sodium sulfite, sodium bisulfite, sodium pyrosulfite, etc.; commonly used antibacterial agents are phenol, cresol, chlorobutanol, etc. Commonly used containers for injections include glass ampoules, glass bottles, plastic ampoules, and plastic bottles. the

For oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. Tablets refer to disc-shaped or special-shaped solid preparations obtained by mixing and pressing drugs and suitable excipients. Oral tablets are mainly used, and buccal tablets, sublingual tablets, buccal tablets, chewable tablets, and dispersible tablets are also available. Tablets, Soluble Tablets, Effervescent Tablets, Sustained Release Tablets, Controlled Release Tablets and Enteric Coated Tablets, etc. Capsules refer to drugs or solid preparations filled in hollow capsules or sealed in soft capsules with supplementary materials. According to their dissolution and release characteristics, they can be divided into hard capsules (commonly known as capsules), soft capsules (capsules), Sustained-release capsules, controlled-release capsules and enteric-coated capsules, etc. Pills refer to spherical or quasi-spherical solid preparations prepared by uniform mixing of drugs and suitable auxiliary materials, including dripping pills, sugar pills, small pills, etc. Granules refer to dry granular preparations with a certain particle size made of drugs and suitable excipients, which can be divided into soluble granules (commonly known as granules), suspension granules, effervescent granules, enteric-coated granules, sustained-release granules and controlled-release granules. particles etc. Oral solution refers to a drug dissolved in a suitable solvent to prepare a clear liquid preparation for oral administration. Oral suspensions refer to insoluble solid drugs, which are dispersed in liquid media and made into suspension liquid preparations for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to the concentrated sucrose aqueous solution containing the drug. the

When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. Commonly used fillers include starch, powdered sugar, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc.; commonly used binders include sodium carboxymethylcellulose, PVP -K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.; commonly used disintegrants include dry starch, crospovidone, croscarboxyl Sodium methyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc.; common lubricants include magnesium stearate, talc, sodium lauryl sulfate, micronized silica gel, etc. the

The present invention further claims that any compound represented by general formula (I), its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its hydrate, or the hydrate of its ester or salt are used for the preparation of therapeutic and /or the use of drugs for the prevention of infectious diseases. The carboxamide alkylbenzene-substituted mercaptopyrrolidine carbapenem compound of the present invention has strong antibacterial activity against clinically isolated Gram-positive and negative, aerobic and anaerobic bacteria, and can be used to treat and/or prevent mammals (including human) Various diseases caused by pathogenic microorganisms, such as respiratory tract infection, urinary tract infection, gynecological infection, etc., can also be used for sepsis, meningitis, etc. the

In general, carbapenem derivatives have been found to be nontoxic to warm-blooded animals, and this general rule applies to the compounds of the present invention. The preferred compound of the present invention was administered to the mice in an excess dose required to prevent bacterial infection, and no obvious toxic symptoms or side effects caused by the compound of the present invention were observed. the

Compared with the closest prior art, the carbapenem compound of the present invention has the following advantages:

(1) The compound of the present invention has broad-spectrum potent antibacterial activity and low toxicity, and can be safely used to treat and/or prevent various diseases caused by sensitive bacteria in various mammals, including humans. the

(2) When the compounds of the present invention are used as antibacterial drugs, the target bacteria are not particularly limited, as long as the compounds of the present invention show antibacterial activity, most Gram-positive and negative, aerobic and anaerobic bacteria can be used as targets bacteria. the

(3) The compound of the present invention has good antibacterial activity against Staphylococcus, Streptococcus and Pseudomonas aeruginosa. the

(4) The compound of the present invention has good chemical stability and is convenient to be made into any clinically or pharmaceutically acceptable dosage form. the

(5) The compound of the present invention has high stability to DHP-I and most β-lactamases, can be used in β-lactamase-producing bacteria, and can be administered alone clinically. the

(6) The compound of the present invention has longer post-antibiotic effect, long-lasting antibacterial effect and convenient administration. . the

(7) The compounds of the present invention, especially their easily hydrolyzed esters have excellent activity in the digestive tract and can be administered through the gastrointestinal tract. the

(8) The preparation process of the compound of the present invention is simple, the drug has high purity, high yield and stable quality, and is easy to carry out large-scale industrial production. the

The beneficial effects of the carbamidoalkylbenzene-substituted mercaptopyrrolidine carbapenem compound of the present invention are further described below through in vitro antibacterial experiments, but this should not be interpreted as that the penem compound of the present invention only has the following beneficial effects. the

Experimental example The in vitro antibacterial activity of the compound of the present invention

Tested strains: the following clinical isolates were purchased from public institutions

Gram-positive bacteria: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis;

Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa, Citrobacter fischeri. the

testing sample:

Compounds A and B of the present invention are self-made, and their chemical names and structural formulas are as described above;

Imipenem: commercially available; Meropenem: commercially available. the

Experiment method: agar dilution method, refer to "Pharmacological Test Methodology" P1659-1660, People's Medical Publishing House, editor-in-chief: Xu Shuyun, etc., edition: August 1982, first edition, January 2002, third edition, fifth printing. the

Experimental results and conclusions:

Table 2 The compound of the present invention is to the antibacterial activity of clinical separation Gram-positive bacteria

It can be seen from the experimental results in Table 2 that, compared with imipenem and meropenem, compounds A and B of the present invention have good antibacterial activity against clinically isolated Gram-positive bacteria tested. the

Table 3 The compound of the present invention is to the antibacterial activity of clinical isolation Gram-negative bacteria

It can be seen from the experimental results in Table 3 that, compared with imipenem and meropenem, compounds A and B of the present invention have good antibacterial activity against clinically isolated Gram-negative bacteria tested. the

Above-mentioned experimental result shows, compound of the present invention all has potent antibacterial action to Gram-positive bacteria, negative bacteria, compared with the closest prior art, antibacterial activity is equal or better, and antibacterial spectrum is wide, has good clinical efficacy. application potential. the

4. Specific implementation

The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. The auxiliary materials of each dosage form in the following examples can be replaced with pharmaceutically acceptable auxiliary materials, or decreased or increased. the

Example 1 Preparation of (2S, 4S)-4-mercapto-2-formyl [N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrolidine

14.5 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 150 ml of anhydrous tetrahydrofuran were added to a dry reaction flask. Under the protection of nitrogen, 13g (80mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 0.5h, and 8.3g (51mmol) of N-benzyl-2-methylpropyl-2-amine was added below 0°C. Tetrahydrofuran solution 100ml, continue to react for 1h. Then 60ml of 1mol/L hydrochloric acid was added dropwise, extracted with ethyl acetate (100ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added 150ml of 3mol/L hydrochloric acid, stirred for 2h, and The dilute alkali solution was adjusted to be alkaline, and a solid was precipitated, which was recrystallized from an acetonitrile solution to obtain 16.1 g of a solid, with a yield of 82.1%. the

Example 2 (2S, 4S)-4-mercapto-2-formyl [N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrole Preparation of alkane

Refer to Example 1 for the specific preparation method. Cast (2S, 4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine 14.5g (50mmol), N-(4-fluorobenzyl)-2-methylpropyl- 2-amine 9.2 g (51 mmol). 16.3 g of the product was obtained, yield: 79.3%. the

Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl )pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept 2-ene - Preparation of p-nitrobenzyl 2-carboxylate

In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 11.9g (20mmol) in 120ml of acetonitrile solution, cooled to below -10°C, add 5ml of diisopropylethylamine and (2S, 4S)-4-mercapto-2-formyl [N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrolidine 8.6g (22mmol) Acetonitrile solution 80ml, stirred at 0°C for 15h. After the reaction was completed, 300 ml of ethyl acetate was added to dilute, washed with water and saturated brine in sequence, the organic layer was dried and concentrated to obtain 10.1 g of solid, yield: 68.3%. the

Example 4 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-1- (tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0 Preparation of ]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester

Refer to Example 3 for the specific preparation method. Cast (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3, 2,0] Hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 11.9g (20mmol), (2S,4S)-4-mercapto-2-formyl[N-(4-fluorobenzyl)- 9.0 g (22 mmol) of 2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrolidine. 10.7 g of the product was obtained, yield: 71.0%. the

Example 5 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-benzyl-2-methylpropyl-2-amino]-pyrrolidin-4-yl] Thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (ie Preparation of Compound A)

(4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrole Alkyl-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene- 7.5g (10mmol) of p-nitrobenzyl 2-carboxylate was dissolved in 50ml of dichloromethane, 10ml of anisole and 20ml of nitromethane were added, and 1mol/L of nitrobenzyl chloride was added dropwise at -50°C. 100ml of methane solution, stirred at -40°C for 2h, added 200ml of water, precipitated solid, filtered, dissolved the filter cake in a mixture of 400ml of THF and 30ml of water, added 2g of 10% palladium-carbon, stirred at room temperature for 2h under hydrogen pressure of 5MPa, Palladium carbon was filtered off, THF150ml was added to the filtrate, the layers were separated, and the water layer was collected. Add 20 ml of 5% magnesium chloride aqueous solution to THF, let it stand still, separate the water layer, and repeat the operation once. The aqueous phases were combined, 30ml of methanol was slowly added dropwise at 0°C, stirred at -10°C for 1 hour, filtered, and the filter cake was recrystallized from water-isopropanol to obtain 2.6g of white crystals, yield: 51.5%. the

Molecular formula: C ₂₆ H ₃₅ N ₃ O ₅ S

Molecular weight: 501.64

Elemental analysis: C, 62.11%; H, 7.25%; N, 8.12%; S, 6.16%

(Calculation: C, 62.25%; H, 7.03%; N, 8.38%; S, 6.39%)

Example 6 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-pyrrolidine -4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2 - Preparation of carboxylic acid (i.e. compound B)

For the specific preparation method, refer to Example 5. Cast (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-1-(tert Butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]heptane 7.6 g (10 mmol) of p-nitrobenzyl 2-ene-2-carboxylate. 2.5 g of the target product was obtained, yield: 48.9%. the

Molecular formula: C ₂₆ H ₃₄ FN ₃ O ₅ S

Molecular weight: 519.63

Elemental analysis: C, 60.21%; H, 6.86%; F, 3.23; N, 8.01%; S, 6.09%

(Calculation: C, 60.10%; H, 6.60%; F, 3.66; N, 8.09%; S, 6.17%) 

Example 7 Preparation of sterile powder injection of compound of the present invention

1. Prescription:

Prescription 1:

Compound A 250g (calculated as compound)

A total of 1000 sticks were prepared

Prescription 2:

Compound B 500g (calculated as compound)

A total of 1000 sticks were prepared

Prescription 3:

Compound A 1000g (calculated as compound)

A total of 1000 sticks were prepared

Prescription 4:

Compound B 2000g (compound)

A total of 1000 sticks were prepared

2. Preparation process:

(1) Aseptically treat the antibiotic glass bottles and rubber stoppers used in the preparation;

(2) Weigh the raw materials according to the prescription (feeding after conversion), put the sterile powder in the filling machine for subpackaging, and check the filling volume at any time;

(3) Stoppering, capping, full inspection of finished products, packaging and storage. the

Embodiment 8 The preparation of compound tablet of the present invention

1. Prescription:

Prescription 1:

Compound A 250g (calculated as compound)

Pregelatinized starch 50g

Low-substituted hydroxypropyl cellulose 40g

Microcrystalline Cellulose 40g

2% HPMC aqueous solution Appropriate amount

Micropowder silica gel 4.0g

Magnesium stearate 4.0g

Sodium starch glycolate 2.0g

A total of 1000 pieces were prepared

Prescription 2:

Compound B 125g (calculated as compound)

Pregelatinized starch 50g

Low-substituted hydroxypropyl cellulose 40g

Microcrystalline Cellulose 40g

2% HPMC aqueous solution Appropriate amount

Micropowder silica gel 4.0g

Magnesium stearate 4.0g

Sodium starch glycolate 2.0g

A total of 1000 pieces were prepared

2. Preparation process:

(1) Pulverize the raw materials and pass through a 100-mesh sieve, and pass the remaining auxiliary materials through a 100-mesh sieve respectively, and set aside;

(2) Weigh the raw materials and auxiliary materials according to the prescription quantity;

(3) Hypromellose is dissolved in water to make a 2% aqueous solution for subsequent use;

(4) Mix compound A or B of the present invention, pregelatinized starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose evenly, add an appropriate amount of 2% HPMC aqueous solution, and stir evenly to make a suitable soft material;

(5) cross 20 mesh sieves to make granules;

(6) The particles are dried at 60°C;

(7) Add magnesium stearate, micropowder silica gel and carboxymethyl starch sodium to the dried granules, pass through a 18-mesh sieve for granulation, and mix well;

(8) Sampling and testing of semi-finished products;

(9) Press the tablet according to the weight determined by the test;

(10) Full inspection of finished products, packaging and storage. the

Claims (9)

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

Wherein: R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

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

R ⁴And R ⁵Identical or different, represent hydrogen atom or C respectively _1-4Alkyl;

R ⁶The expression hydrogen atom, halogen atom, hydroxyl, amino, cyano group or trifluoromethyl;

N is 1.

2. compound as claimed in claim 1 and pharmaceutically acceptable non-toxic salt thereof:

Wherein, R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

R ³The expression methyl, ethyl, the sec.-propyl or the tertiary butyl;

R ⁴And R ⁵Represent hydrogen atom respectively;

R ⁶The expression hydrogen atom, fluorine atom, chlorine atom, cyano group or trifluoromethyl;

N is 1.

3. compound as claimed in claim 2 and pharmaceutically acceptable non-toxic salt thereof:

Wherein, R ¹The expression hydrogen atom;

R ²The expression hydrogen atom;

R ³Expression methyl, sec.-propyl or the tertiary butyl;

R ⁴And R ⁵Represent hydrogen atom respectively;

R ⁶Expression hydrogen atom or fluorine atom;

N is 1.

4. compound as claimed in claim 3 and pharmacy acceptable salt thereof, described compound is selected from:

(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [N-benzyl-2-methyl-propyl-2-amido]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, perhaps

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

5. each described compound and pharmacy acceptable salt thereof of claim 1～4, 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 is for clinically or pharmaceutically acceptable arbitrary formulation.

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