EP0131611A1 - AGENTS ANTIBACTERIENS DE $g(b)-LACTAME - Google Patents

AGENTS ANTIBACTERIENS DE $g(b)-LACTAME

Info

Publication number
EP0131611A1
EP0131611A1 EP84900522A EP84900522A EP0131611A1 EP 0131611 A1 EP0131611 A1 EP 0131611A1 EP 84900522 A EP84900522 A EP 84900522A EP 84900522 A EP84900522 A EP 84900522A EP 0131611 A1 EP0131611 A1 EP 0131611A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
compound
acid
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP84900522A
Other languages
German (de)
English (en)
Inventor
Peter Henry Milner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0131611A1 publication Critical patent/EP0131611A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the compounds of the present invention may contain both an amino group and/or a carboxyl group and may, therefore, exist as the zwitterion or may form salts with suitable acids or bases.
  • the formamido group can exist in two preferred conformations, those wherein the hydrogen atoms of the -NH-CHO are, cis- or trans-, of which the cisconformation normally predominates.
  • the ⁇ -lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutial compositions. Although the purity of intermediate compounds of the present invention is less critical it will readily be understood that the substantially pure form is preferred as for the ⁇ -lactam antibiotic compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
  • R 14 represents hydrogen, C 1-6 alkyl, substituted alkyl, aryl, or aralkyl
  • R 15 and R 16 are the same or different and represent hydrogen, C 1-6 alkyl, substituted alkyl, halogen, amino, hydroxy or
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • the present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of this invention.
  • the antibiotic compounds of the present invention are active against a broad range of gram positive and gram negative bacteria, in particular they are useful for treatment of respiratory tract and urinary tract infections in humans and mastitis in cattle.
  • a particular advantage of the antibacterially active compounds of this invention is their stability to ⁇ -lactamase enzymes and they are therefore effective against ⁇ -lactamase producing organisms.
  • Suitable formylating agents include mixed anhydrides such as formic acetic anhydride.
  • the reaction may suitably be carried out in a temperature in the range -50°C to 30oC in aprotic solvent such as, for example, dichloromethane, chloroform, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide, or dimethylsulphoxide, in the presence of a tertiary base.
  • a preferred tertiary base employed in the reaction is a base of the pyridine type, such as pyridine, lutidine or picoline.
  • R 19 is C 1-6 alkyl, aryl or benzyl; with anhydrous ammonia , an ammonium salt or an amine of the formula (XII)
  • Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
  • Acylation with an acid halide may be affected in the presence of an acid binding agent for example, tertiary amine (such as triethylamine, pyridine or dimethylaniline), an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
  • the oxirane is preferably a (C 1-6 )1,2-alkylene oxide - such as ethylene oxide or propylene oxide.
  • the thiol HetSH may be reacted as the free compound or a salt with an alkali metal such as sodium or potassium.
  • This reaction is desirably conducted in a solvent.
  • a solvent for example, use can be made of water, or organic solvents inert to the starting compounds, such as dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, 1,2-dichloroethane, acetonitrile, dimethylsulfoxide or tetrahydrofuran, or mixtures thereof.
  • the reaction temperature and time depend, among other factors, upon the starting compounds and solvent to be employed but generally the reaction is carried out at a selected temperature within the range of 0 to 100°C for a selected time of a few hours to several days.
  • the reaction is desirably conducted between pH 3 and 7.
  • Example 1 illustrates the preparation and use of the compounds of the present invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

Composé de formule (I) ou son sel, dans laquelle R1 et R3 représentent indépendamment un groupe hydrolysable in vivo, ou R1 et R3 forment ensemble un groupe hydrolysable in vivo, à condition que R1 et R3 ne représentent pas tous deux un alkyle-carbonyle C1-6; R7 est un hydroxyle, un groupe acide carboxylique ou un alkyle ou phényle inférieur, l'ester de tolyle ou d'indanyle de ceux-ci, un groupe amino ou un groupe amino substitué; R2 représente l'hydrogène ou un groupe de protection carboxyle pouvant être aisément enlevé; Y représente (II), où Y1 représente l'oxygène, le soufre ou -CH2- et Z représente l'hydrogène, l'halogène, ou un groupe organique tel qu'un alkoxy C1-4, -CH2Q ou -CH=CH-Q dans lesquels Q représente l'hydrogène, l'halogène, un groupe hydroxy, mercapto, cyano, carboxy, carbamoyloxy, un ester carboxylique, un alkoxy C1-4, un acyloxy, un aryle, un hétérocyclyle lié par un carbone, un groupe hétérocyclylthio ou un azote contenant un groupe hétérocyclique lié par l'azote.
EP84900522A 1983-01-21 1984-01-19 AGENTS ANTIBACTERIENS DE $g(b)-LACTAME Ceased EP0131611A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8301694 1983-01-21
GB838301694A GB8301694D0 (en) 1983-01-21 1983-01-21 Beta-lactam antibacterial agents

Publications (1)

Publication Number Publication Date
EP0131611A1 true EP0131611A1 (fr) 1985-01-23

Family

ID=10536717

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84900522A Ceased EP0131611A1 (fr) 1983-01-21 1984-01-19 AGENTS ANTIBACTERIENS DE $g(b)-LACTAME

Country Status (4)

Country Link
EP (1) EP0131611A1 (fr)
JP (1) JPS60500497A (fr)
GB (1) GB8301694D0 (fr)
WO (1) WO1984002911A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL83549A (en) * 1987-08-16 1992-08-18 Yossi Matias Video scrambling apparatus and method based on space filling curves
CA2702257C (fr) 2007-10-09 2016-07-12 Sopharmia, Inc. Inhibiteurs de beta-lactamase a large spectre
US9975905B2 (en) 2013-03-12 2018-05-22 Gladius Pharmaceuticals Corporation Derivatized 3-styryl-cephalosporins

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2119363B (en) * 1981-05-22 1984-08-08 Beecham Group Plc Penicillanic acid derivatives
DE3278878D1 (en) * 1981-07-25 1988-09-15 Beecham Group Plc Beta-lactam antibacterial agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8402911A1 *

Also Published As

Publication number Publication date
GB8301694D0 (en) 1983-02-23
WO1984002911A1 (fr) 1984-08-02
JPS60500497A (ja) 1985-04-11

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Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19840828

AK Designated contracting states

Designated state(s): CH DE FR GB LI NL

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19871001

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MILNER, PETER, HENRY