WO1996038450A1 - Cephalosporines - Google Patents

Cephalosporines Download PDF

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Publication number
WO1996038450A1
WO1996038450A1 PCT/US1996/008928 US9608928W WO9638450A1 WO 1996038450 A1 WO1996038450 A1 WO 1996038450A1 US 9608928 W US9608928 W US 9608928W WO 9638450 A1 WO9638450 A1 WO 9638450A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
group
alkyl
compound
cephem
Prior art date
Application number
PCT/US1996/008928
Other languages
English (en)
Inventor
Burton Christensen
In-Seop Cho
Tomasz Glinka
Scott Hecker
Ving J. Lee
Zhijia J. Zhang
Original Assignee
Microcide Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/455,969 external-priority patent/US5698547A/en
Priority claimed from US08/457,673 external-priority patent/US5688786A/en
Application filed by Microcide Pharmaceuticals, Inc. filed Critical Microcide Pharmaceuticals, Inc.
Priority to AU59855/96A priority Critical patent/AU5985596A/en
Publication of WO1996038450A1 publication Critical patent/WO1996038450A1/fr

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Classifications

    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • -NR 4 R 5 ' and Z is selected from the group consisting of -CH 2 (X) m -, -C(NOR 6 )-, -CH(OR 7 )-, -C(CHC0 2 R 8 )- and -CH(NR 9 R 10 ) - ;
  • n is selected from the group consisting of 0 and 1;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl, and trialkylsilyl;
  • R 11 is selected from the group consisting of H, halogen, alkyl, hydroxyl, amino, cyano, hydroxyalkyl, carboxamidoalkyl, optionally substituted aminoalkyl or quaternary ammonium alkyl, and quaternary heteroaryliumalkyl;
  • R 17 is H or alkyl.
  • Preferred compounds include those compounds wherein R 11
  • the present invention includes methods for treating a bacterial infection in a mammal arising from bacteria resistant to ⁇ -lactam antibiotics comprising administering to a mammal suffering from such an infection a therapeutically effective amount of a compound of Structure II.
  • the present invention provides methods for using a thiolate nucleophile of the structure
  • heterocycle denotes a chain of carbon and at least one non-carbon atoms which together form one or more aromatic or non-aromatic rings having preferrably between about 6-14 atoms, such as, e.g. , furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl . These rings may be optionally substituted with one or more functional groups which are attached commonly to such rings, such as, e.g..
  • heterotricycle denotes an aromatic heterocyclic substituent as defined above which comprises three aromatic rings.
  • heterocyclecarbonyl denotes the group
  • ⁇ -lactam resistant bacteria refers to bacteria against which a ⁇ -lactam antibiotic has an minimum inhibitory concentration (MIC) greater than 32 mg/ml.
  • R 6 is selected from the group consisting of hydrogen, methyl, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroallyl and cyclopentyl
  • R 3 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-aminothiazol-4-yl, and 2-aminothiadiazol-4-yl;
  • R 13 - R 17 are H or lower alkyl .
  • R 13 -R 17 are hydrogen.
  • a suitable effective dose of the compound of the invention will be in the range of 0.1 to 1000 milligram (mg) per recipient per day, preferably in the range of 1 to 100 mg per day.
  • the desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form.
  • the compounds of the invention will be administered in amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.
  • Disposable sterile l ⁇ L loops were used to inoculate test plates, with each isolate in a designated grid on the agar plate.
  • An alternate method of inoculation involved the use of a replica plater, a device with 48 steel pins allowing the simultaneous inoculation of multiple isolates. After the spots had dried, the plates were incubated at 35-36°C for 16-20 hours. Endpoints were assessed as the minimum inhibitory concentration (MIC) of antimicrobial agent.
  • MIC minimum inhibitory concentration
  • aureus 76 (Meth R )(lac + ) >32 4 4 4 8 2 8
  • mice Groups of 5 female Swiss-Webster mice (Simonsen, Gilroy, CA) each are challenged by the intraperitoneal (IP) route with tenfold increments of a bacterial inoculum. This permits calculation of the mean lethal dose (LD 50 ) and the LD 100 .
  • mice are challenged IP with an LD 100 titer of bacteria.
  • groups of 10 mice each are treated subcutaneously with two-fold increments of the test drug and an antibiotic of known efficacy in mice and humans (i.e., positive control) . Mice are observed for 72h. Those alive at 72h are considered long term survivors.
  • the total drug dose in mg/kg that protects 50% of mice in a group from death is termed the mean protective dose (PD 50 ) .
  • PD 50 s are similarly determined for several pathogens.
  • the quantitative endpoints for the new drug are then compared with those obtained with reference antibiotics.
  • Six ten-fold dilutions of inoculum suspended in 0.5 mL of sterilized 7% hog gastric mucin (Sigma) are injected IP in groups of 5 mice each. A control group of 5 mice receive mucin alone. Mice are observed for 72h. Those alive at 72h are considered long term survivors.
  • the mean lethal dose (LD 50 ) and 100% lethal dose (LD 100 ) are determined by the probit test.
  • mice are challenged IP with bacterial titers that will afford an LD 100 for the test strain.
  • SC subcutaneous route
  • Drug doses can range from 0.01 to 512 mg/kg. If the drug is poorly soluble, Tween 20 or propylene glycol will be employed to solubilize the drug. Animals are observed for 72h.
  • the 50% protective dose (PD 50 ) is calculated in mg/kg by the probit method.
  • the PD 50 is the same as the 50% effective dose (ED 50 ) and the 50% curative dose (CD 50 ) .
  • Samples of blood from the hearts of all animals that die and from half the mice that survive are cultured on brain-heart infusion agar. Animals that received a protective dosage of the test drug will be alive at 72h, although they may appear moderately ill to very ill during the observation period. Infected, placebo-treated control mice and those receiving non-effective i.e. lower dosages of the test drug will demonstrate a high rate of mortality. Most of these mice will die within 6 to 48 h. Those alive at 72h will be considered long term survivors.
  • the mixture was diluted with dichloromethane (20 mL) , and was washed with 5% aqueous sodium bicarbonate solution (20 mL) .
  • the organic layer was dried with sodium sulfate, and the solvent was removed with a rotary evaporator.
  • the residue was subjected to flash chromatography on silica gel (33% to 50% ethyl acetate/hexane) to afford 300 mg (45%) of the title compound.
  • the mixture was diluted with dichloromethane (20 mL) , and was washed with 5% aqueous sodium bicarbonate solution (20 mL) .
  • the organic layer was dried with sodium sulfate, and the solvent was removed with a rotary evaporator.
  • the residue was subjected to flash chromatography on silica gel (33% to 50% ethyl acetate/hexane) to afford 300 mg (50%) of the title compound.
  • Example 33 The procedure of Example 33 is employed, except (71?) -7- [ (phenylacetyl) amino] -3- (4-biphenylthio) -3-cephem-4-c arboxylate, benzhydryl ester is used.
  • Example 33 The procedure of Example 33 is employed, except (71?) -7- [ (phenylacetyl) amino] -3- [4- (2-imidazolyl) phenylthio] - 3
  • Example 33 The procedure of Example 33 is employed, except (71?) -7- [ (phenylacetyl) amino] -3- [3-bromo-4- (phenyl) phenylthio ] -3-cephem-4-carboxylate, benzhydryl ester is used.
  • Example 52 Using substantially the same procedure as in Example 51, the items of the following Examples 52 - 82 can similarly be prepared.
  • Example 51 The procedure of Example 51 is employed, but the reactants are 2- (iodophenythio) acetic acid and (71?) -7-amino-3- [2-iodophenylthio] -3-cephem-4-carboxylate, 4-methoxybenzyl ester.
  • Example 51 The procedure of Example 51 is employed, but the reactants are 2- (iodophenythio) acetic acid and (71?) -7-amino-3- (biphenylthio) -3-cephem-4-carboxylate, 4-methoxybenzyl ester.
  • Example 51 The procedure of Example 51 is employed, but the reactants are 2- (2-furyl) -2- (syn-methoxyimino) acetic acid and
  • Example 51 The procedure of Example 51 is employed, but the reactants are 2- (2-furyl) -2- (syn-methoxyimino) acetic acid and
  • Example 51 The procedure of Example 51 is employed, but the reactants are cyanoacetic acid and
  • EXAMPLE 82 (71?) -7- [(a- [D-4-Ethyl-2,3-dioxo-l-piperazinecarboxamido] -a-p henylacetyl)amino] -3- [dibenzofuran-3-ylthio] -3-cephem-4-carb oxylate, 4-methoxybenzyl ester
  • Example 83 Under substantially the same procedure as in Example 83, the items of the following Examples 84 - 88 are similarly prepared.
  • EXAMPLE 88 (71?) -7- [ (a- [D-4-Ethyl-2,3-dioxo-l-piperazinecarboxamido] -a-p henylacetyl)amino] -3- [4- (chloromethyl)phenylthio] -3-cephem-4 -carboxylate, 4-methoxybenzyl ester

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention porte sur des acides (7R)-7-(acylamino)-3-(arylthio)-3-cephem-4-carboxyliques d'un type nouveau ou sur leurs sels pharmaceutiquement acceptables, présentant une activité antibiotique contre un large éventail d'organismes, y compris des organismes résistants aux β-lactamines, et utiles comme antibactériens. Elle concerne également des intermédiaires d'un type nouveau utiles pour fabriquer les composés de l'invention, ainsi que des procédés nouveaux pour produire ces composés nouveaux et des composés intermédiaires.
PCT/US1996/008928 1995-05-31 1996-05-29 Cephalosporines WO1996038450A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59855/96A AU5985596A (en) 1995-05-31 1996-05-29 Cephalosporin antibiotics

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US08/455,969 US5698547A (en) 1994-04-01 1995-05-31 Cephalosporin antibiotics
US08/455,969 1995-05-31
US08/457,673 1995-06-01
US08/457,673 US5688786A (en) 1994-04-01 1995-06-01 β-lactam antibiotics
US60/005,426 1995-10-10
US542695P 1995-10-12 1995-10-12

Publications (1)

Publication Number Publication Date
WO1996038450A1 true WO1996038450A1 (fr) 1996-12-05

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ID=27357883

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US1996/008928 WO1996038450A1 (fr) 1995-05-31 1996-05-29 Cephalosporines
PCT/US1996/008141 WO1996038448A1 (fr) 1995-05-31 1996-05-31 ANTIBIOTIQUES DU TYPE β-LACTAME

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US1996/008141 WO1996038448A1 (fr) 1995-05-31 1996-05-31 ANTIBIOTIQUES DU TYPE β-LACTAME

Country Status (2)

Country Link
AU (2) AU5985596A (fr)
WO (2) WO1996038450A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021623A1 (fr) * 1999-09-22 2001-03-29 Essential Therapeutics, Inc. Antibiotiques a l'acide 7-acylamino-3-heteroarylthio-3-cephem carboxylique et promedicaments de ces derniers

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271222B1 (en) * 1998-05-28 2001-08-07 Merck & Co., Inc. Penem antibacterial compounds, compositions and methods of treatment
CN1219512C (zh) 2000-10-19 2005-09-21 阿姆拉有限公司 含奥沙培南－3－羧酸的药物组合物
EP1199077A1 (fr) * 2000-10-19 2002-04-24 Amura Limited Compositions pharmaceutiques contenant des acides oxapénème-carboxyliques stabilisées par lyophilisation avec des excipients pharmaceutiques
CN112321606B (zh) * 2020-11-04 2022-05-17 福安药业集团重庆博圣制药有限公司 头孢唑肟钠及其中间体的制备方法

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CH605998A5 (en) * 1974-08-30 1978-10-13 Ciba Geigy Ag 3-Thio-7-amino-3- and-2-cephem-4-carboxylic acids
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US4123528A (en) * 1975-11-21 1978-10-31 Merck & Co., Inc. 3-(Substituted thio) cephalosporins, derivatives and nuclear analogues thereof
US5162521A (en) * 1991-06-06 1992-11-10 Bristol-Myers Squibb Company Processes for making cephems from allenylazetidinone derivatives
WO1995026966A1 (fr) * 1994-04-01 1995-10-12 Microcide Pharmaceuticals, Inc. Cephalosporines antibiotiques

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CH605998A5 (en) * 1974-08-30 1978-10-13 Ciba Geigy Ag 3-Thio-7-amino-3- and-2-cephem-4-carboxylic acids
CH605999A5 (en) * 1974-08-30 1978-10-13 Ciba Geigy Ag 3-Thio-7-amino-3- and-2-cephem-4-carboxylic acids
US3992377A (en) * 1974-12-13 1976-11-16 Eli Lilly And Company 3-Thio-substituted cephalosporin antibiotics
US4123528A (en) * 1975-11-21 1978-10-31 Merck & Co., Inc. 3-(Substituted thio) cephalosporins, derivatives and nuclear analogues thereof
US5162521A (en) * 1991-06-06 1992-11-10 Bristol-Myers Squibb Company Processes for making cephems from allenylazetidinone derivatives
WO1995026966A1 (fr) * 1994-04-01 1995-10-12 Microcide Pharmaceuticals, Inc. Cephalosporines antibiotiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021623A1 (fr) * 1999-09-22 2001-03-29 Essential Therapeutics, Inc. Antibiotiques a l'acide 7-acylamino-3-heteroarylthio-3-cephem carboxylique et promedicaments de ces derniers

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Publication number Publication date
AU5985596A (en) 1996-12-18
WO1996038448A1 (fr) 1996-12-05
AU5958396A (en) 1996-12-18

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