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WO2009000163A1 - ANTIBIOTIQUES DE TYPE 1β-MÉTHYLCARBAPÉNÈME, COMPOSITIONS PHARMACEUTIQUES ET LEUR UTILISATION - Google Patents

ANTIBIOTIQUES DE TYPE 1β-MÉTHYLCARBAPÉNÈME, COMPOSITIONS PHARMACEUTIQUES ET LEUR UTILISATION Download PDF

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Publication number
WO2009000163A1
WO2009000163A1 PCT/CN2008/001238 CN2008001238W WO2009000163A1 WO 2009000163 A1 WO2009000163 A1 WO 2009000163A1 CN 2008001238 W CN2008001238 W CN 2008001238W WO 2009000163 A1 WO2009000163 A1 WO 2009000163A1
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Prior art keywords
group
hydrogen atom
methyl
formyl
phenyl
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PCT/CN2008/001238
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English (en)
Chinese (zh)
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Zhenhua Huang
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Priority to CN2008800194777A priority Critical patent/CN101711251B/zh
Priority to JP2010513622A priority patent/JP2010531308A/ja
Publication of WO2009000163A1 publication Critical patent/WO2009000163A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention belongs to the field of antibiotic medicine, and particularly relates to an ⁇ -methyl carbapenem antibiotic, a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester, an isomer, a preparation method of the compound, a pharmaceutical composition containing the same, and Use of these compounds in the manufacture of a medicament for the treatment and/or prophylaxis of infectious diseases in mammals, including humans.
  • Background technique
  • Carbapenem antibiotics are a class of ⁇ -lactam antibiotics from the J3 ⁇ 4A ⁇ in the 1970s. Because of its broad antibacterial activity, strong antibacterial activity, and stability to ⁇ -lactamase, it is highly concerned.
  • the structure is characterized in that the sulfur at the 1 position of the penicillin core is replaced by carbon, and the 2 position has a double bond, and the 5-membered ring of penicillin and the conjugated double bond of the cephalosporin activate the ⁇ -lactam ring; The hydroxyethyl side chain is in the trans conformation.
  • the compound represented by the formula (1) is disclosed in the specification of EP 0126587.
  • the compound including the compound represented by the formula (2), that is, meropenem is used as an antibacterial agent.
  • Meropenem has been marketed in several countries and has strong activity against both Gram-positive and Gram-negative bacteria. It can be used to treat abdominal infections, skin and skin soft tissue infections, etc.; for renal dehydropeptidase I (DHP-I) Stable; but with a short half-life, administered once every 8 hours.
  • DHP-I renal dehydropeptidase I
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester or isomer,
  • R 1 represents a hydrogen atom or a protecting group
  • R 2 represents a hydrogen atom or an amino protecting group
  • R 3 represents a hydrogen atom or a lower alkyl group
  • R 4 and R s each independently represent a hydrogen atom or a lower pit group, or R 4, R s connected to form a 5-8 membered ring;
  • R 6 represents a hydrogen atom, a halogen, a H, a hydroxy group, a sulfonyl group, a sulfonyl group, which is substituted or unsubstituted by a cycline, a hydroxy group, a sulfonyl group, a decyl group, a carbamoyl group or an aminosulfonyl group.
  • n stands for 1, 2 or 3.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester or an isomer thereof And one or more pharmaceutically acceptable carriers and/or diluents.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof, a hydrolyzable ester, an isomer for use in the treatment and/or prevention of infectivity in a mammal including a human Use of the disease, or in the manufacture of a medicament for the treatment and/or prevention of an infectious disease in a mammal, including a human, especially a bacterial infectious disease which is sensitive to the compounds of the invention.
  • the compound of the present invention is a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester or an isomer,
  • R 1 represents a hydrogen atom or a protecting group
  • R 2 represents a hydrogen atom or a protecting group
  • R 3 represents a hydrogen atom or a lower alkyl group
  • R 4 and R 5 each independently represent a hydrogen atom or a lower alkyl group, or R 4, R 5 are linked to form a 5-8 membered ring;
  • R 6 represents a hydrogen atom, a halogen, a ⁇ , a hydroxy group, a sulfonyl group, a sulfonyl group, or a halogen group, a hydroxy group, a sulfonyl group, a sulfonyl group, a carbamoyl group or an aminosulfonyl group, or a Substituted lower alkyl, lower alkane Lower sulfhydrylsulfonyl, lower alkylformyl, lower alkylsulfonylamino, lower alkylamido, lower alkylcarbonyl or lower alkylcarbonyloxy;
  • ⁇ stands for 1, 2 or 3.
  • the compound of the present invention is a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester, an isomer, wherein
  • R 1 represents a hydrogen atom or a protecting group
  • R 2 represents a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom or a lower alkyl group
  • R 4 and R 5 each independently represent a hydrogen atom or a lower alkyl group, or R 4 and R 5 are bonded to form a 5-7 membered ring;
  • R 6 represents a hydrogen atom, a quinone, a hydroxy group, a decanoyl group, a ⁇ sulfonyl group, a lower alkyl group substituted or unsubstituted with a halogen, a lower alkoxy group, a methyl group, a methylsulfonamide group or an ethyl amide. base;
  • ⁇ stands for 1 or 2.
  • the compound of the present invention is a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester, an isomer, wherein
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom, a fluorenyl group or an ethyl group
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group or an ethyl group, or R 4 and R 5 are bonded to form a 5-7 membered ring;
  • R 6 represents a hydrogen atom, a fluorine atom, a decanoyl group, a sulfonyl group, or a lower alkyl group substituted or unsubstituted with a halogen;
  • the compound of the present invention is a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester, an isomer, wherein
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom or a methyl group
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group or an ethyl group, or R 4 and R 5 are bonded to form a 5-7 membered ring;
  • R 6 is selected from a hydrogen atom, a fluorine atom, an amino group, a carbamoyl group, an aminosulfonyl group, or a lower alkyl group substituted or unsubstituted with a fluorine atom;
  • n stands for 2.
  • the compound of the present invention is a compound of the formula (I), a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester, an isomer, wherein
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group or an ethyl group, or R 4 and R 5 are bonded to form a 5-7 membered ring;
  • R 6 represents a hydrogen atom, a fluorine atom, , a sulfonyl group, a sulfonyl group, a methyl group or a trifluoromethyl group;
  • the compound of the invention is selected from the group consisting of: (4R, 5S, 6S)-3-[(2S,4S)-2-formyl[2-(3,4-dimethoxy) -phenyl-1-yl) fluorenyl-ethylamino I-pyrrolidin-4-yl Ithio-6-[(lR)sodium hydroxyethyl H-methyl-7-oxydiazabicyclo-[3 , 2,01hept-2-ene-2-carboxylic acid, abbreviated as compound 1, the structural formula is as follows:
  • the compound B obtained in the above step is dissolved in dichloromethane, phenyl ether and nitrodecane are added, a solution of aluminum trichloride in nitromethane is added dropwise, stirred, water is added, a solid is precipitated, and the filter cake is dissolved.
  • a solution of aluminum trichloride in nitromethane is added dropwise, stirred, water is added, a solid is precipitated, and the filter cake is dissolved.
  • To a mixture of THF and water 10% palladium-carbon was added, and the reaction was stirred under a hydrogen pressure of 5 MPa at room temperature. Palladium on carbon was filtered off, THF was added to the filtrate, and the layers were separated, and the aqueous layer was collected. Further, an aqueous magnesium chloride solution was added to the THF, and the mixture was allowed to stand, and the aqueous layer was separated, and the operation was repeated once.
  • the aqueous phases are combined, and the methanol
  • the groups represented by R 3 , R 4 , R 5 and R 6 and the value represented by n are as described above, the carboxyl group in the compound C may be protected by a carboxyl group, and the hydrogen atom on the nitrogen atom may be The amino protecting group is protected by the compound of the formula (I).
  • the "halogen atom” in the present invention is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the "lower alkyl group” of the present invention is a linear or branched alkyl group such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a sec-butyl group, a pentyl group. , New amyl, hexyl, etc.
  • the "lower alkoxy group of the present invention which is a C straight or branched alkoxy group, includes a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group.
  • the "lower alkylsulfonyl group" of the present invention is a C"alkylsulfonyl group, and includes a sulfonamide & an ethanesulfonyl group.
  • the "lower alkyl group formyl group” of the present invention is an alkyl group formyl group, and includes a methyl formyl group, an ethyl group J ⁇ , and the like.
  • the "lower alkylsulfonyl group” of the present invention is a C alkylsulfonyl group, and includes a methylsulfonylamino group, an ethylsulfonylamino group and the like.
  • the “lower alkyl sulfonate group” of the present invention is a C "alkyl amide group, and includes acetylamino group, propionylamino group and the like.
  • the “amino protecting group” as used in the present invention refers to a protecting group conventionally used for substituting an amino acid proton.
  • Examples of such a group include: mercapto, ethyl, cyclopropylmethyl, 1-methyl-1-cyclopropane Methyl, diisopropylmethyl, 9-fluorenylmethyl, 9-(2-thio)fluorenylmethyl, 2-furanmethyl, 2,2,2-trichloromethyl, 2-halomethyl , 2-iodoethyl, 2-trimethylsilylethyl,
  • the "carboxy protecting group” as used in the present invention refers to a protecting group conventionally used for substituting a proton of a carboxylic acid.
  • examples of such groups include: methoxymethyl, guanidinomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethylmethyl, benzyloxymethyl, benzoylmethyl, p-bromobenzoyl Methyl, ⁇ -mercaptobenzoyl hydrazino, p-methoxyphenacyl, diacyl fluorenyl, fluorenyl-phthalimido, ethyl, 2,2,2-trichloro Ethyl, 2-haloethyl, ⁇ -chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(p-nitro ⁇ yl)ethyl , 2-(p-methyl)ethyl, 1-fluorenyl-1-
  • the pharmaceutically acceptable salt of the present invention is an organic acid salt, an inorganic acid salt, an organic alkali salt or an inorganic alkali salt, wherein the organic acid includes acetic acid, trifluoroacetic acid, methanesulfonic acid, terephthalic acid, maleic acid, Succinic acid, tartaric acid, citric acid, fumaric acid, etc.; inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic bases include meglumine, glucosamine, etc.; inorganic bases include sodium, potassium, barium, calcium , alkaline compounds of magnesium, zinc, and lithium.
  • the organic acid includes acetic acid, trifluoroacetic acid, methanesulfonic acid, terephthalic acid, maleic acid, Succinic acid, tartaric acid, citric acid, fumaric acid, etc.
  • inorganic acids include hydrochloric acid, hydrobromic acid,
  • pharmaceutically acceptable salts of the compounds of the present invention can be formed at the free carboxyl groups of the compounds, and can be prepared by conventional methods.
  • Preferred pharmaceutically acceptable salts are the sodium and potassium salts, for example (4R, 5S, 6S)-3-[(2S,4S)-2-formyl
  • the readily hydrolyzable ester of the present invention is a compound which is present in the form of an ester group which is susceptible to hydrolysis.
  • These esters may be conventional, including lower alkanoyloxyalkyl esters such as pivaloyloxymethyl ester, 1-pivaloyloxyethyl ester; lower oxycarbonyloxyalkyl esters such as methoxycarbonyl oxygen Methyl ester, 1-ethoxyoxetyloxyethyl ester, 1-isopropyloxycarbonyloxyethyl ester; lower steryl ester, such as methoxymethyl ester; lactone ester, benzofuranone Ester, thiobenzofuranone ester; lower alkanoyl methyl ester, such as acetyl methyl ester.
  • esters such as: benzyl esters and methyl esters can also be used.
  • Other examples of such esters are: (2,2-dimethyl-1-oxopropyl)methyl ester; (1RS)-1-acetyl Oxyethyl ester; 2-[(2-methylpropenyl) 1-2-pentenyl ester; 1-[[(1-methylethylcarbonyl) oxy-I ethyl ester; isopropoxy oxyethyl ester; (5-Mercapto-2-oxo-1,3-dioxole-4-yl)methyl ester; 1-[[(cyclohexane 1 ⁇ )]oxy]ethyl ester; 3-Dimethyl-2-oxobutyl ester It will be apparent to those skilled in the art that the readily hydrolyzable ester of the compound of the invention can be formed at the free carboxyl group of the compound and can be prepared by conventional methods.
  • pivaloyloxymethyl ester isopropoxycarbonyl oxyethyl ester and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester
  • Ithio-6-[(lR)-l-hydroxyethyl-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2- Alkene-2-carboxylic acid pivaloyloxymethyl ester (referred to as compound 5 pivaloyloxymethyl ester).
  • the isomers of the present invention refer to all of their epimeric, diastereomeric, and tautomeric forms.
  • a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will return to the paper in three dimensions.
  • the compound of formula (I) has many stereocenters, including at the 4-position, at the 5-position, at the 6-position, and the like.
  • the present invention further encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds, a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester or isomer, and other pharmaceutically active ingredients, such as cilastatin and its sodium salt, Milon.
  • the compounds of the present invention, pharmaceutically acceptable salts, hydrolyzable esters or isomers thereof are usually formulated into a pharmaceutical composition for administration with one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition of the present invention can be formulated into any clinically or pharmaceutically acceptable form by any means known in the art, and administered orally, parenterally, rectally or via pulmonary administration to such a treatment in need thereof. patient.
  • it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • a suitable filler, a binder, a disintegrant, a lubricant or the like may be added.
  • parenteral administration it can be prepared as an injection, including injection, sterile powder for injection and concentrated injection. Solution.
  • the injection it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be made into an inhalant or a spray.
  • Each unit of the preparation contains a physiologically effective amount of 0.01 g to 10 g of the compound represented by the formula (I), which may be 0.01 g, 0.05 g, 0.1 g, 0.125 g, 0.2 g, 0.25 g, 0.3 g, 0.4 g, 0.5. g, 0.6 g, 0.75 g, lg, 1.25 g, 1.5 g, 1.75 g, 2 g, 2.5 g, 3 g, 4 g, 5 g, lO, and the like.
  • physiologically effective amount is meant an amount of a compound which, when administered to an animal for the treatment and/or prevention of said disease, is sufficient to effect treatment and/or prevention of the disease.
  • the compound of the present invention has excellent antibacterial activity against Gram-positive and negative, aerobic and anaerobic bacteria and has an unexpectedly long half-life and is stable to P-lactamase and DHP-I, and can be safely used.
  • Treatment and/or prevention of various mammals includes various diseases caused by pathogenic microorganisms in humans, such as respiratory infections and urinary tract infections.
  • carbapenems have been found to be non-toxic to warm-blooded animals, and this general rule is also applicable to the compounds of the invention.
  • the compounds of the present invention are administered to mice in an excess dose required to treat bacterial infections without noticeable signs of toxicity or side effects caused by the compounds of the present invention.
  • 6-(N-tert-butoxyethylamino)-2,3-dioxabenzoyl chloride 6-(2-ethylamino)-2,3-dimethylHS ⁇ benzene was added. 6.8 g (30 mmol) of citric acid in 100 mL of dichloromethane and 8 mL of triethylamine were cooled to 0-5 in a water bath. C, 100 mL of 21.8 g (31 mmol) of dichloromethane solution of di-tert-butyl dicarbonate was added dropwise, and the mixture was stirred at room temperature for 3 h.
  • the mixture is washed successively with water and saturated brine, and the organic layer is dried, and then, the mixture is dried in a 3 ⁇ 4 V reaction flask, and 10 ml of SOCl 2 is added dropwise at room temperature, and the reaction is stirred for 2 hours, then the temperature is raised to reflux for 2 hours, and the reaction is stopped, followed by 1 N sodium hydroxide solution and water. After washing with saturated brine, the organic layer was dried and concentrated under reduced pressure to remove most of the dichloromethane.
  • reaction solution is poured into an appropriate amount of water, adjusted to pH 8 ⁇ 9 with cold sodium hydroxide solution, extracted with ethyl acetate several times, combined organic layer, washed with water, dried, and the solvent is recovered under reduced pressure to obtain 2-(2- Nitro-4,5-di-diethylenedioxy-phenyl-1-yl)-ethylamine was used directly in the next step.
  • Methyldioxy-phenyl-1-yl)-ethylamine further added dropwise 5 g of sodium nitrite in 12 mL of aqueous solution, allowed to stand, filtered, washed twice with a small amount of methanol-diethyl ether (2:1), drained, at 45 Pyrolysis is carried out around e C, then ethyl acetate is added, and after vigorous stirring, the insoluble solids are removed by filtration and dissolved. The liquid was transferred to the reaction flask and the temperature was lowered to 10. 10 mL of concentrated hydrochloric acid was added under C and stirred for about 1 h. The solution was concentrated under reduced pressure, and the residue was crystallised from EtOAc EtOAc (EtOAc)
  • (2S,4S)-4-Mercapto-2-formyl yl 2-(3,4-linked trimethylenedioxy-phenyl small group)-Ethylamine-1-(tert-butoxy-pyrrole) Preparation of bismuth Using a procedure similar to that described in Example 6, (2S,4S)-4-acetylthio (tert-butoxycarbonyl)pyrrolidine 14.5 g (50 mmol), 2-(3,4-linked trimethylene) H ⁇ -phenyl-1-yl)-ethylamine 17.4 g (90 mmol) gave a solid 16.2 g, yield: 76.8%.
  • Example 20 (4R,5S,6S)-3-K2S,4S)-2-Formyl "2-(3,4-methylenediphenyl-1-yl)-ethylamino-tert-butoxycarbonyl)pyrrole Alkyl-4-yl 1 thio-6-[(lR)-l-hydroxyethyl b 4-methyl-7-oxo-1-azabicyclo-[3,2,01hept-2-ene-2 - Preparation of p-nitrobenzyl carboxylate
  • Example 24 (4R,5S,6S)-3-i(2S,4S)-2-Formyl yl 2-(3,4-linked trimethylenedioxy-phenyl-1-yl)-ethylamine 1 Small (tert-butoxycarbonyl)pyrrolidin-4-yl 1thio-6-K1R) small hydroxyethyl 1-4-methyl-7-oxo-1-azabicyclo43,2,01 hept-2- Preparation of p-nitrobenzyl ester of ene-2-carboxylic acid
  • Example 25 (4R,5S,6S)-3-i(2S,4S)-2-formyl "2-(3,4-linked trimethylenedioxy-5-J>sulfonyl-benzene-1 -yl)-ethylaminodibu: U-tert-butoxypyrrolidine-4-ylsulfanyl-6-K1RV1-hydroxyethyl1-4-fluorenyl-7-oxoazabicyclo-[3,2, Preparation of nicotyl benzyl ester of 01 hept-2-ene-2-carboxylic acid
  • Example 30 (4R,5S,6S)-3-[(2S,4SV2-formyl[2-(3,4-methylenedi-Il-phenyl-1-yl)-ethylamino-1-pyrrolidine) 4-yl 1 thio-6-inR)-l-hydroxyethyl 1-4-methyl-7-oxo-1-azabicyclo43,2,01hept-2-ene-2-carboxylic acid ( Preparation of compound 5)
  • Example 35 WR, 5S, 6S)-34i2S, 4S)-2-formyl [2-(3,4-linked trimethylenedioxy-5-J ⁇ sulfonyl-phenyl-1-yl)-B Amino 1-pyrrolidin-4-yl 1 thio-6-[aR)-l-hydroxyethyl b 4-methyl-7-oxoazabicyclo-[3,2,01hept-2-ene Preparation of 2-carboxylic acid (compound 10)
  • Example 36 i4R,5S,6S)-3-K2S,4SV2-formyl[2-(3,4-dimethyl-I-phenyl-1-yl)-ethylaminopyrrolidine-4-yl 1 thio Base-6-[(lR)-l-hydroxyethyl 4-methyl-7-oxo-1-aza Preparation of Bicyclo-[3,2,01hept-2-ene-2-carboxylate (Compound 2 Sodium Salt) Preparation of (4R,5S,6S)-3-[(2S,4S)-2-Formyl[ 2-(3,4-Dimethoxy-phenyl-1-yl)-ethylaminopyrrolidin-4-yl]thio-6-[(lR)-l-hydroxyethyl]-4-A 5.2-oxo-1-azabicyclo-[3,2,0]hept-2-ene-2-carboxylic acid 5.2 g (10 mmol) was dissolved in 20 mL of
  • Example 38 Preparation of a sterile powder needle of a compound of the invention
  • Compound 1 2500g prepared a total of 1000 ⁇ Department 2:
  • a total of 1000 bottles, rubber stoppers and liquid containers for use in production, equipment and equipment for cleaning, sterilizing and depyrogenation were prepared.
  • the raw materials and auxiliary materials were weighed according to the prescription, and the auxiliary materials were added with 80% water for injection. Stir and dissolve; then add 0.05% of the needle with activated carbon, stir for 15min, filter, decarbonize, add the raw materials to the solution, stir to dissolve, determine and adjust the pH value of the solution, add water for injection to the full amount, constant volume;
  • the liquid is finely filtered through a 0.22 ⁇ microporous membrane to check the clarity and semi-finished product inspection; the liquid is divided into the vial, half-plugged, freeze-dried, plugged, and tied; the finished product is inspected and packaged into the warehouse.
  • Preparation process The raw materials are pulverized through a 100 mesh sieve, and the other auxiliary materials are passed through a 100 mesh sieve separately for use; the raw materials and auxiliary materials are weighed according to the prescription amount; the compound of the present invention, pregelatinized starch/starch, and low substituted hydroxypropyl fiber are used.
  • Prime if any, microcrystalline cellulose is mixed evenly, add appropriate amount of HPMC 7J solution, stir evenly, make suitable soft material; sieve through 20 mesh; granules are dried under 60 conditions; dry granules are added to hard Magnesium citrate, micro-silica gel, sieved through 18 mesh, uniform mixing; sampling, semi-finished product test; tablet weight-pressed according to the test; finished product inspection, package library.
  • beneficial effects of the compounds of the present invention are further illustrated by the in vitro antibacterial experiments and animal pharmacokinetics of some of the compounds of the present invention.
  • Other compounds of the present invention have the same beneficial effects as some of the compounds of the present invention listed in the test, but should not be used. It is understood that the compounds of the invention have only the following beneficial effects.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • Gram-negative bacteria large vein Escherichia coli (ESBLs), Klebsiella pneumoniae, Pseudomonas aeruginosa.
  • Test article Compound 1-11 of the present invention, homemade; comparator: meropenem (injection) Use meropenem).
  • Agar dilution method refer to "Pharmacological Test Methodology" P1659-1660, People's Health Publishing House, Editor-in-Chief: Xu Shuyun, etc., edition: August 1982, first edition, January 2002, third edition, fifth edition .
  • the compounds of the present invention have high antibacterial activity against clinical isolates, which is comparable to or slightly higher than that of meropenem.
  • Test article The compound of the invention 2, 4, 5, 10, homemade.
  • Control drug meropenem (meropenem for injection), commercially available.
  • Warfarin White powder, purity 99%, batch number 0072-8501, provided by Shanghai Drug Inspection Institute.
  • Drug preparation Prepared before administration, dissolved in physiological saline to a final concentration of 5 mg/mL for intravenous injection.
  • Test animals male SD rats; body weight 200 ⁇ 250 grams; Source: Shanghai Slack Laboratory Animals Co., Ltd.
  • Mass spectrometry ⁇ h Scanning mode positive ion multiple reaction monitoring (MRM); ion source: electrospray (ESI); Nebulize gas: 8L/min; Curtain gas: 8L/min; Collision gas: 4L/min; Ionspray voltage: 4500v; Temperature: 400. C / 500 o C.
  • MRM positive ion multiple reaction monitoring
  • ion source electrospray (ESI)
  • Nebulize gas 8L/min
  • Curtain gas 8L/min
  • Collision gas 4L/min
  • Ionspray voltage 4500v
  • Temperature 400. C / 500 o C.
  • Standard curve and quality control sample preparation Accurately weigh the appropriate amount of test sample, and prepare a stock solution with a concentration of 2.60m g /mL with ultrapure water. The stock solution was diluted with methanol to obtain a series of working solutions having concentrations of 25,000, 5000, 2500, 500, 250 and 50 ng/mL. Take 100 ⁇ L of plasma and add 20 ⁇ of the above working solution to obtain calibration solutions at concentrations of 5000, 1000, 500, 100, 50 and 10 ng/mL. In the same way, quality control sample solutions with concentrations of 4000, 800 and 20 ng/mL can be prepared, analyzed, chromatograms and standard curves.
  • Sample processing method Take plasma sample lOO L, add 20 ⁇ acetonitrile, 200 ⁇ 200ng/mL Warfarin acetonitrile solution; lmin, centrifuge at 15000rpm for 5min. Take the supernatant ⁇ , 3 ⁇ for LC/MS/MS injection analysis.
  • Dosing concentration The prepared drug is tested by HPLC and compared with the standard. The concentration accuracy to the intravenous administration solution was 103.2%.
  • the plasma drug concentration was calculated to be 0 below the detection limit (10 ng/ml), and the pharmacokinetic parameters were calculated from the non-compartmental model in Winnonlin Professional 5.2 pharmacokinetic software.
  • Pharmacokinetics The pharmacokinetic parameters and the time curve of the drug were calculated according to the drug concentration in plasma at each time point.
  • the plasma half-life (t 1/2 ) of each compound is shown in the table below.
  • the plasma half-life of the compounds of the invention in rats (intravenously) is significantly longer than that of meropenem.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Communicable Diseases (AREA)
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  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés antibiotiques de type 1β-méthylcarbapénème de formule (1), leurs sels pharmaceutiquement acceptables, des esters hydrolysable in vivo, des isomères, leurs préparations ou leurs compositions, ou leur utilisation dans la fabrication de médicaments qui préviennent et/ou traitent des maladies infectieuses chez les mammifères, notamment les êtres humains.
PCT/CN2008/001238 2007-06-26 2008-06-26 ANTIBIOTIQUES DE TYPE 1β-MÉTHYLCARBAPÉNÈME, COMPOSITIONS PHARMACEUTIQUES ET LEUR UTILISATION Ceased WO2009000163A1 (fr)

Priority Applications (2)

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CN2008800194777A CN101711251B (zh) 2007-06-26 2008-06-26 1β-甲基碳青霉烯抗生素及其药物组合物和用途
JP2010513622A JP2010531308A (ja) 2007-06-26 2008-06-26 １β−メチルカルバペネム系抗生物質、薬剤組成物およびその用途

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CNA2007100166079A CN101333217A (zh) 2007-06-26 2007-06-26 1-甲基碳青霉烯抗生素
CN200710016607.9 2007-06-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110160177A1 (en) * 2009-12-31 2011-06-30 Zhenhua Huang Novel carbapenem derivatives
US8722896B2 (en) 2008-12-17 2014-05-13 The Regents Of The University Of California Prokineticin receptor antagonists and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817837A (zh) * 2009-02-13 2010-09-01 山东轩竹医药科技有限公司 含有氮杂双环的碳青霉烯衍生物

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EP0126587A1 (fr) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carboxyle thio-pyrrolidinyle-bêta-lactame et leur préparation
CN1066657A (zh) * 1991-04-08 1992-12-02 帝国化学工业公司 抗菌化合物
US5554606A (en) * 1990-03-12 1996-09-10 Zeneca Limited Antibiotic compounds

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EP0126587A1 (fr) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Dérivés de carboxyle thio-pyrrolidinyle-bêta-lactame et leur préparation
US5554606A (en) * 1990-03-12 1996-09-10 Zeneca Limited Antibiotic compounds
CN1066657A (zh) * 1991-04-08 1992-12-02 帝国化学工业公司 抗菌化合物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8722896B2 (en) 2008-12-17 2014-05-13 The Regents Of The University Of California Prokineticin receptor antagonists and uses thereof
US20110160177A1 (en) * 2009-12-31 2011-06-30 Zhenhua Huang Novel carbapenem derivatives
US8318716B2 (en) * 2009-12-31 2012-11-27 Kbp Biosciences Co., Ltd. Carbapenem derivatives

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