US20020128254A1 - Crystalline 1-methylcarbapenem derivatives - Google Patents

Crystalline 1-methylcarbapenem derivatives Download PDF

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US20020128254A1
US20020128254A1 US10/034,548 US3454801A US2002128254A1 US 20020128254 A1 US20020128254 A1 US 20020128254A1 US 3454801 A US3454801 A US 3454801A US 2002128254 A1 US2002128254 A1 US 2002128254A1
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formula
compound
crystalline form
crystalline
methylcarbapenem derivative
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Isao Kawamoto
Yasuo Shimoji
Hiroshi Fukuhara
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Sankyo Co Ltd
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Sankyo Co Ltd
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Assigned to SANKYO COMPANY, LIMITED reassignment SANKYO COMPANY, LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAWAMOTO, ISAO, FUKUHARA, HIROSHI, SHIMOJI, YASUO
Publication of US20020128254A1 publication Critical patent/US20020128254A1/en
Priority to US10/351,944 priority Critical patent/US6924279B2/en
Priority to US10/407,546 priority patent/US20030232803A1/en
Priority to US10/625,317 priority patent/US7041660B2/en
Abandoned legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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

  • This invention is directed to crystalline forms of 1-methylcarbapenem derivatives or of pharmaceutically acceptable salts thereof which exhibit excellent antibiotic activity against various bacterial strains and are stable enough to keep for a long time.
  • This invention is directed compositions for the prevention or treatment of bacterial infections containing a crystalline form of the present invention as an active ingredient.
  • This invention is directed to uses of a crystalline form of the present invention in order to prepare a medicament for the prevention or treatment of bacterial infections.
  • This invention is directed to methods for the preventing or treating bacterial infections which comprise administering to a warm-blooded animal in need of such prevention or treatment an effective amount of a crystalline form of the present invention. Further this invention is directed to processes for the preparation of crystalline forms of the present invention.
  • the 1-methylcarbapenem derivative of formula (I) is disclosed in Japanese Patent Application Publication Hei-10-204086 and Hei-11-071277 and in U.S. Pat. No. 6,090,802 (corresponds to Hei-10-204086).
  • This compound (I) exhibits excellent antibiotic activity not only against Gram-positive bacterial strains but also against Gram-negative bacterial strains and can be expected to become a useful antibiotic agent.
  • the compound (I) prepared according to the Example of Japanese Patent Application Publication Hei-11-071277 (which is Example 72 of U.S. Pat. No. 6,090,802) was obtained by lyophilization as a non-crystalline powder. This powder is unstable and is a material difficult to keep for a long time.
  • This invention is directed to
  • compositions for the prevention or treatment of bacterial infections containing a crystalline form of a 1-methylcarbapenem derivative according to any one of 1 to 5 as an active ingredient,
  • Carbapenem derivatives of formula (I) are disclosed in U.S. Pat. No. 6,090,802 and Japanese Patent Application Publications Hei-10-204086 and Hei-11-071277, and exhibit potent activity against Gram-positive and Gram-negative bacterial strains.
  • Carbapenem derivatives of formula (I) can exist as pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt as used herein and in the claims is intended to include salts which are usually able to be used as medicaments.
  • the compound of formula (I) has basic groups such as a tertiary amino group and a guanidino group and can be converted to a pharmaceutically acceptable acid addition salt when treated with an appropriate acid employing conventional techniques.
  • acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as carbonates, acetates, benzoates, oxalates, maleates, fumarates, tartrates and citrates; and sulfonates such as methanesulfonates, benzenesulfonates and p-toluenesulfonates.
  • the compound of formula (I) has an acidic group such as a carboxyl group and can be converted to a pharmaceutically acceptable base addition salt when treated with an appropriate base employing conventional techniques.
  • base addition salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; and quaternary ammonium salts such as ammonium salts.
  • the compound (I) and pharmaceutically acceptable salts thereof When allowed to stand in the air, certain forms of the compound (I) and pharmaceutically acceptable salts thereof absorb or adsorb water and can form hydrates. In certain cases forms of the compound (I) and pharmaceutically acceptable salts thereof absorb certain solvents and can form solvates.
  • the compound (I) of this invention and pharmaceutically acceptable salts thereof include such hydrates and solvates.
  • Such salts, hydrates and solvates are preferably sodium salts, hydrochlorides, sulfates, carbonates, hydrates or solvates of ethanol; most preferably carbonates, hydrates or solvates of ethanol.
  • the compound of formula (I-1) represents the 1 ⁇ 2 ethanol solvate of the 1 ⁇ 2 carbonate salt of the 1-methylcarbapenem derivative of formula (I).
  • the compound of formula (I-2) represent the 1 ⁇ 2 ethanol solvate of the 1-methylcarbapenem derivative of formula (I).
  • the compound of formula (I-3) represents the ⁇ fraction (3/2) ⁇ hydrate and 1 ⁇ 4 ethanol solvate of the 1-methylcarbapenem derivative of formula (I).
  • the crystalline forms of the present invention are solids which have regular arrangements of atoms (group of atoms) in three-dimensional structure and repeat the arrangements.
  • the crystals are different from an amorphous solid that has no such regular arrangement of atoms in a three-dimensional structure.
  • certain compounds produce a plurality of crystalline forms (polymorphic crystals) according to crystallization conditions, crystals of which are different in their three-dimensional arrangement of atoms and in physicochemical properties.
  • This invention may include each of such crystalline forms and mixtures no less than two thereof.
  • the main peaks have intensities not less than 74, which is the relative intensity when the intensity of the peak at 4.57 ⁇ is evaluated as 100.
  • the main peaks have intensities not less than 56, which is the relative intensity when the intensity of the peak at 4.91 ⁇ is evaluated as 100.
  • the main peaks have intensities not less than 48, which is the relative intensity when the intensity of the peak at 5.08 ⁇ is evaluated as 100.
  • the main peaks have intensities not less than 65, which is the relative intensity when the intensity of the peak at 7.02 ⁇ is evaluated as 100.
  • the compound of formula (I) can be prepared by the same technique as described, or by a similar procedure to that described in U.S. Pat. No. 6,090,802, Japanese Patent Application Publication Hei-10-204086 and Hei-11-071277.
  • Precipitation of the crystals begins spontaneously in the vessel, or precipitation can also begin or be accelerated by addition of crystalline seeds or by mechanical stimulations such as ultrasonic wave irradiation and scratching on the surface of the vessel.
  • Pharmaceutically acceptable salts of compound (I) are preferably hydrochlorides, sulfates and carbonates; most preferably carbonates.
  • the pharmaceutically acceptable salts can be prepared by addition of necessary amount of a desired acid or base to a solution of compound (I).
  • solutions of the compound (I) or pharmaceutically acceptable salts thereof are treated, the solutions of these compounds are usually treated between 0 and 60° C. in order to avoid decomposition of these compounds.
  • Methods of concentration of solutions of the compound (I) or pharmaceutically acceptable salts thereof are an evaporation method using a rotary evaporator under reduced or normal pressure upon heating and a concentration method using a reverse osmotic membrane.
  • the reverse osmotic membrane used in concentration of an aqueous solution can be selected from polyacrylonitrile membranes, polyvinyl alcohol membranes, polyamide membranes and cellulose acetate membranes.
  • solvents which can readily dissolve compound (I) or pharmaceutically acceptable salts thereof are water, dimethyl sulfoxide, dimethylformamide and methanol, preferably water.
  • solvents which can slightly dissolve compound (I) or pharmaceutically acceptable salts thereof are C 2 -C 4 alcohols such as ethanol, propanol and butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether and tetrahydrofuran; and esters such as methyl acetate and ethyl acetate; preferably ethanol and acetone; most preferably ethanol.
  • C 2 -C 4 alcohols such as ethanol, propanol and butanol
  • ketones such as acetone and methyl ethyl ketone
  • ethers such as diethyl ether and tetrahydrofuran
  • esters such as methyl acetate and ethyl acetate; preferably ethanol and acetone; most preferably ethanol.
  • the starting compound (I) which is isolated as a lyophilized powder can be used.
  • a crude reaction solution containing compound (I) can also be used because it is possible to purify by crystallization.
  • Supersaturation can be accomplished by concentration of an aqueous solution of compound (I) at between 30 and 60° to a saturated aqueous solution, followed by gradually cooling to between 0 and 10° C. or accomplished by gradual addition of an appropriate solvent which can slightly dissolve compound (I) or pharmaceutically acceptable salts thereof, such as ethanol or acetone, to the saturated aqueous solution, if necessary, followed by cooling.
  • an appropriate solvent which can slightly dissolve compound (I) or pharmaceutically acceptable salts thereof, such as ethanol or acetone
  • Crystalline forms of this invention preferably precipitate when aqueous solutions of compound (I) or pharmaceutically acceptable salts are concentrated, if necessary, followed by the addition of a solvent which can slightly dissolve these compounds, followed by cooling. More preferably crystals of this invention precipitate when aqueous solutions of compound (I) or pharmaceutically acceptable salts thereof are concentrated, if necessary, followed by the addition of ethanol or acetone and then cooling.
  • the preferred crystalline form of compound (I-1) precipitates when an aqueous solution of compound (I) is concentrated, followed by saturation with carbon dioxide, addition of ethanol and cooling;
  • the preferred crystalline form of compound (I-2) precipitates when an aqueous solution of compound (I) is concentrated, followed by the addition of ethanol and by cooling (preferably by irradiation with ultrasonic waves);
  • the preferred crystalline form of compound (I) precipitates when an aqueous solution of compound (I) is concentrated, followed by cooling;
  • the preferred crystalline form of compound (I-3) precipitates when an aqueous solution of compound (I) is concentrated, followed by addition of ethanol and by cooling.
  • the precipitated crystals are isolated, for example, by filtration, centrifugation or decantation. If necessary, the isolated crystals can be washed with an appropriate solvent. Preferably the crystals are washed at first with the solvent which is used in crystallization, and then washed with a solvent such as ethanol, acetone, and ether.
  • a solvent such as ethanol, acetone, and ether.
  • the isolated crystals are dried at between 10 and 50° C., preferably at between 20 and 30° C. until the weight of the crystals become constant. If necessary, they may be dried in the presence of drying agents such as silica gel and calcium chloride under reduced pressure.
  • the crystalline forms of this invention exhibit a wide spectrum of antibiotic activity and potent antibacterial activities against Gram-positive and Gram-negative strains and anerobic bacteria, as well as bacteria producing cephalosporinase.
  • the antibacterial activities of the crystals of this invention were determined by the agar-plate dilution method, they exhibited potent antibacterial activities against various bacteria, for example, Gram-positive strains such as Staphylococcus aureus , methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus and the like; Gram-negative strains such as Escherichia coli, Bacillus dysenteriae, Klebsiella pneumoniae, Proteus vulgaris, Serratia, Enterobacteriaceae, Pseudomonas aeruginosa and the like; and anerobic bacteria such as bacteroides fragilis.
  • the crystalline forms of this invention exhibited potent antibacterial activity against Helicobacter pylori
  • excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ starch, dextrin and carboxymethylstarch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and internally-cross-linked sodium carboxymethylcellulose; arabic gum; dextran; pululan; silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate, and sulfate derivatives such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol
  • starch derivatives such as corn starch, potato starch, ⁇ starch, dextrin and carboxymethylstarch
  • binders include excipients as described above; gelatin; polyvinylpyrrolidone; and macrogol.
  • lubricants include talc; stearic acid; metal stearate derivatives such as calcium stearate and magnesium stearate; colloidal silica; bee gum; waxes such as bee's wax and spermaceti; boric acid; glycol; carboxylic acid derivatives such as fumaric acid and adipic acid; sodium carboxylate derivatives such as sodium benzoate; sulfate derivatives such as sodium sulfate; leucine; lauryl sulfate derivatives such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid derivatives such as silicic acid anhydride and silicic acid hydrate; and starch derivatives as described for the excipients.
  • corrigents include sweetening, souring and flavoring agents all of which are usually used.
  • topical anaesthetic agents examples include lidocaine hydrochloride, and mepivacaine hydrochloride.
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates the diffraction angle as the value 2 ⁇ .
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates the diffraction angle as the value 2 ⁇ .
  • Elemental analysis calculated for C 23 H 35 N 7 O 6 S ⁇ 1 ⁇ 4C 2 H 6 O ⁇ fraction (3/2) ⁇ H 2 O Cal.: C 48.99%; H 6.91%; N 17.02%; S 5.56%;
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates the diffraction angle as the value 2 ⁇ .
  • N,N-dimethylformamide 10 ml
  • N,N-diisopropylethylamine (0.63 ml)
  • 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate 541 mg
  • to the reaction mixture was added 1% aqueous sodium hydrogencarbonate solution.
  • the resulting precipitate was filtered, washed with water and dried.
  • Example 1 The crystalline compounds obtained in Example 1, 2, 4 and 5 were kept for about 2 months in a desiccator at 40° C. and 75% relative humidity and in a desiccator at 60° C. in which silica gel was placed, respectively.
  • the remaining percentages of these compounds were calculated from the remaining amount of them and show in Tables 1-4. TABLE 1 Stability in desiccator at 40° C.
  • the MIC ( ⁇ g/ml), the lowest concentration of antibiotic which inhibits growth of the test bacterial strain, was determined by the agar-plate dilution method.
  • the crystalline compounds obtained in Example 1, 2, 4 and 5 of this invention were evaluated against various bacterial strains by determining the MIC of each compound with respect to each strain. Table 5 illustrates the result of such experiments.
  • Example 1 The crystalline compound obtained in Example 1 (250 mg) is used to fill a vial and shielded with a stopper under sterile conditions.
  • Pharmaceutical additives known to those skilled in the art such as a local anaesthetic agent, for example, lidocaine hydrochloride can be added to the vial, if necessary.
  • the sterile solid compositions can be dissolved in an injectable medium such as water for injection immediately before use.
  • FIG. 1 shows the powder diffraction pattern of crystalline (1R,5S,6S)-2-[(2S,4S)-2-[(3 S)-3-(2-guanidinoacetylamino)pyrrolidin-1-ylcarbonyl]-1-methylpyrrolidin-4-ylthio]-6-[(1 R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic Acid ⁇ 1 ⁇ 2 Carbonate ⁇ 1 ⁇ 2 Ethanol (I-1).
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates diffraction angle as the value 2 ⁇ .
  • FIG. 2 shows the x-ray powder diffraction pattern of crystalline (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-3-(2-guanidinoacetylamino)pyrrolidin-1-ylcarbonyl]-1-methyl-pyrrolidin-4-ylthiol-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid ⁇ 1 ⁇ 2 ethanol (I-2).
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates diffraction angle as the value 2 ⁇ .
  • FIG. 3 shows the x-ray powder diffraction pattern of (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-3-(2-guanidinoacetylamino)pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio]-6-[(1 R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid (I).
  • the vertical axis of the x-ray powder diffraction pattern indicates the diffraction intensity in units of counts/second (CPS).
  • the horizontal axis indicates diffraction angle as the value 2 ⁇ .
  • FIG. 4 shows the x-ray powder diffraction pattern of crystalline (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-3-(2-guanidinoacetylamino)pyrrolidin-1-ylcarbonyl]-1-methyl-pyrrolidin-4-ylthio]-6-[(l R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid ⁇ 1 ⁇ 4 ethanol ⁇ fraction (3/2) ⁇ hydrate (I-3).

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US10/034,548 1999-07-06 2001-12-28 Crystalline 1-methylcarbapenem derivatives Abandoned US20020128254A1 (en)

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Application Number Priority Date Filing Date Title
US10/351,944 US6924279B2 (en) 1999-07-06 2003-01-27 Crystalline 1-methylcarbapenem derivatives
US10/407,546 US20030232803A1 (en) 1999-07-06 2003-04-03 Crystalline 1-methylcarbapenem derivatives
US10/625,317 US7041660B2 (en) 1999-07-06 2003-07-23 Crystalline 1-methylcarbapenem derivatives

Applications Claiming Priority (3)

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JP19136899 1999-07-06
JPHEI-11-191368 1999-07-06
PCT/JP2000/004496 WO2001002401A1 (fr) 1999-07-06 2000-07-06 Composes de 1-methylcarbapenem cristallin

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US10/351,944 Division US6924279B2 (en) 1999-07-06 2003-01-27 Crystalline 1-methylcarbapenem derivatives
US10/407,546 Continuation US20030232803A1 (en) 1999-07-06 2003-04-03 Crystalline 1-methylcarbapenem derivatives

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Cited By (8)

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WO2003027067A2 (en) 2001-09-26 2003-04-03 Merck & Co., Inc. Process for making carbapenem compounds
US6596751B2 (en) 1999-04-06 2003-07-22 Sankyo Company Limited α-substituted carboxylic acid derivatives
US6887992B2 (en) * 1999-09-30 2005-05-03 Otsuka Kagaku Kabushiki Kaisha 3-cephem derivative crystal
US20060189592A1 (en) * 2003-08-25 2006-08-24 Sankyo Company, Limited Crystal of 1-methylcarbapenem compound
US20080139805A1 (en) * 2005-03-22 2008-06-12 Daiichi Sankyo Company, Limited Process for producing carbapenem derivative having a 1-alkylpyrrolidine structure
US20080227768A1 (en) * 2005-05-13 2008-09-18 Makoto Michida Crystal of 1-Methylcarbapenem Compound
US20110054168A1 (en) * 2008-01-17 2011-03-03 Ayumu Kurimoto Method for preparing adenine compound
HRP20040264B1 (en) * 2001-09-26 2012-07-31 Merck@Sharp@@@Dohme@Corp Process for making carbapenem compounds

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7041660B2 (en) * 1999-07-06 2006-05-09 Sankyo Company, Limited Crystalline 1-methylcarbapenem derivatives
WO2001097851A2 (en) 2000-06-21 2001-12-27 Cubist Pharmaceuticals, Inc. Compositions and methods to improve the oral absorption of antimicrobial agents
KR100451672B1 (ko) * 2001-06-05 2004-10-08 한미약품 주식회사 결정성 세프디니르 산부가염, 이의 제조방법 및 이를이용한 세프디니르의 제조방법
WO2003016312A1 (fr) * 2001-08-13 2003-02-27 Eisai Co., Ltd. Procede de preparation d'antibiotiques a base de carbapenem
ITMI20012364A1 (it) * 2001-11-09 2003-05-09 Antibioticos Spa Processo di sintesi della cefixima via alchil-o arilsolfonati
JP2005097278A (ja) * 2003-08-25 2005-04-14 Sankyo Co Ltd １−メチルカルバペネム化合物の結晶
ES2370829T3 (es) * 2004-06-02 2011-12-23 Sandoz Ag Producto intermedio de meropenem en forma cristalina.
AU2006242535B2 (en) 2005-04-29 2012-08-09 Merck Sharp & Dohme Corp. Therapeutic compositions
CN101328179B (zh) * 2007-06-15 2011-01-12 山东轩竹医药科技有限公司 含有氧代氮杂环的巯基吡咯烷培南衍生物
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