EP2344500A1 - Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments - Google Patents

Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments

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Publication number
EP2344500A1
EP2344500A1 EP09786281A EP09786281A EP2344500A1 EP 2344500 A1 EP2344500 A1 EP 2344500A1 EP 09786281 A EP09786281 A EP 09786281A EP 09786281 A EP09786281 A EP 09786281A EP 2344500 A1 EP2344500 A1 EP 2344500A1
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EP
European Patent Office
Prior art keywords
compound
antibacterial
methano
trans
diazepin
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.)
Withdrawn
Application number
EP09786281A
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German (de)
English (en)
French (fr)
Inventor
Premavathy Levasseur
John Lee Pace
Kenneth Coleman
John Lowther
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Novexel SA
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Novexel SA
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Publication date
Application filed by Novexel SA filed Critical Novexel SA
Publication of EP2344500A1 publication Critical patent/EP2344500A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the combination of antibacterial nitrogen heterocyclic compounds with other antibacterial compounds and their use as medicaments.
  • beta lactams mention may be made of carbapenems such as: Imipenem, Meropenem, Ertapenem and the compound known under the name PZ-601;
  • Cephalosporins such as cefazolin, cefepime, cefotaxime,
  • Ticarcillin Ticarcillin / Clavulanate and Penicillin.
  • examples of glycylcycline and tetracycline include Doxycycline, Minocycline, Tetracycline and Tigecycline.
  • Quinolones As examples of Quinolones, ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin and Ofloxacin may be mentioned.
  • Macrolide and Ketolide include Azithromycin, Clarithromycin, Roxythromycin and Telithromycin.
  • polymyxin As examples of polymyxin, mention may be made of Colistin and Polymyxin B. Other antibacterial compounds such as Fosfomycin and the combination may also be mentioned.
  • alkyl radical containing from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, and butyl, pentyl or hexyl linear or branched.
  • alkenyl radical containing from 2 to 6 carbon atoms is meant in particular the allyl radical and the linear or branched butenyl, pentenyl and hexenyl radicals.
  • Heterocycle with aromatic character especially means those selected from the following list, the two bonds symbolizing the junction with the nitrogenous ring (R 3 R 4):
  • acid salts of the products of formula (I) mention may be made, inter alia, of those formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acids, or with organic acids such as formic acid. , acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane and ethanesulphonic acids, arylsulfonic acids such as benzene and paratoluenesulphonic acids.
  • mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acids
  • organic acids such as formic acid.
  • base salts of the products of formula (I) mention may be made, inter alia, of those formed with mineral bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium or with organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine , picoline, dicyclohexylamine, morpholine, benzylamine, procaline, lysine, arginine, histidine, N-methylglucamine, or phosphonium salts, such as alkylphosphonium, arylphosphonium, alkylarylphosphonium, alkenylarylphosphonium or quaternary ammonium salts such as tetra-n-butylammonium salt.
  • mineral bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium
  • organic bases
  • the subject of the invention is in particular those containing compounds of formula (I) in which R 3 and R 4 together form an optionally substituted pyrazolyl or triazolyl heterocycle.
  • the subject of the invention is in particular those containing compounds in which R1 is chosen from the group consisting of (CH 2 ) H -NH 2 groups and
  • the subject of the invention is more particularly those containing compounds in which R 1 represents a radical (CHa) n -NH 2 or (CH 2 ) n -NHCH 3 , n being as defined previously and R 3 and R4 together form a pyrazolyl ring substituted by a (C 1 -C 6 ) alkyl radical.
  • the subject of the invention is particularly those containing a compound of formula (I) chosen from: trans-8- (aminomethyl) -4,8-dihydro-1-methyl-5- (sulfooxy) -4 7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin- ⁇ (5H) -one, trans-8- (aminomethyl) -4,8-dihydro-5- (sulfooxy) -4- , 7-methano-7H-pyrazolo [3, 4-e] [I 1 3] diazepin- ⁇ (5H) -one, - trans 8- (methylaminomethyl) -4, 8-dihydro-5- (sulphooxy) -
  • the subject of the invention is in particular those containing antibacterial compounds chosen from beta-lactams or penicillins if necessary combined with beta lactamase inhibitors, and polymyxins.
  • the invention particularly relates to those containing antibacterial compounds selected from Tobramycin, Meropenem, Aztreonam, Cefepime,
  • the compounds of formula (I) may be prepared by a process comprising: a) a step in which a compound of formula (II) is reacted with a carbonylation agent, if appropriate in the presence of a base :
  • R ' ! represents a radical CN, COOH protected, COOR or (CH 2 J n R ' 5 ,
  • R ' 5 is a protected OH, CN NH 2 or protected NHR, protected CO 2 H, CO 2 R n, R, R 3 and R 4 are as defined above, the aminoalkyl substituent optionally present on the heterocycle formed by R 3 and R 4 being then optionally protected,
  • ZH represents a protected group -NHOH, in order to obtain an intermediate compound of formula (III):
  • R'i, R 3 and R 4 have the same meanings as above and either X x is a hydrogen atom or a protecting group and X2 represents a group -Z-CO-X 3 , X 3 representing the remainder of the carbonylation agent, ie X 2 is a -ZH group and X1 represents a CO-X 3 group , X 3 being defined as above; b) a step during which the intermediate obtained previously is cyclized in the presence of a base; c) where appropriate, step a) is preceded and / or step b) is followed by one or more of the following reactions, in an appropriate order:
  • the carbonylation agent it is possible to use a reagent such as phosgene, diphosgene, triphosgene, an aryl chloroformate such as phenyl or p-nitrophenyl chloroformate, an aralkyl chloroformate such as benzyl chloroformate. an alkyl or alkenyl chloroformate such as methyl or allyl chloroformate, an alkyl dicarbonate such as tert-butyl dicarbonate, carbonyl diimidazole and mixtures thereof, disphosgene being preferred.
  • a reagent such as phosgene, diphosgene, triphosgene, an aryl chloroformate such as phenyl or p-nitrophenyl chloroformate, an aralkyl chloroformate such as benzyl chloroformate.
  • an alkyl or alkenyl chloroformate such as methyl or allyl chloroformate
  • the reaction is preferably carried out in the presence of a base or a mixture of bases which neutralises the acid formed.
  • a base or a mixture of bases which neutralises the acid formed.
  • It can especially be an amine such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine.
  • the product of formula II is used in the form of an acid salt, for example a hydrochloride or a trifluoroacetate.
  • step b it is also possible to use the amines, or the hydrides, alkoxides, amides or carbonates of alkali or alkaline-earth metals.
  • the amines can be chosen for example from the list above.
  • hydride can be used in particular sodium hydride or potassium.
  • alkali metal alcoholate potassium t-butoxide is preferably used.
  • alkali metal amide can be used in particular lithium bis (trimethylsilyl) amide.
  • carbonate it is possible to use carbonate or sodium bicarbonate or potassium.
  • the intermediate of formula III can be obtained in the form of an acid salt generated during the carbonylation reaction and in particular a hydrochloride. It is then implemented in the cyclization reaction in this form.
  • the cyclization is carried out without isolation of the intermediate of formula III.
  • the reactions mentioned in step c) are generally conventional reactions, well known to those skilled in the art. Examples of conditions used are described in application WO 02/100860 or in application 04/052891.
  • the reactive functions that should be protected, if necessary, are the carboxylic acid, amine, amide, hydroxyl and hydroxylamine functions.
  • the protection of the acid function is especially carried out in the form of alkyl esters, allyl esters, benzyl, benzhydryl or p-nitrobenzyl.
  • Deprotection is carried out by saponification, acid hydrolysis, hydrogenolysis, or cleavage using soluble complexes of Palladium O. Examples of these protections and deprotections are provided in application WO 02/100860.
  • amines, heterocyclic nitrogens and amides is in particular carried out, as the case may be, in the form of benzylated or tritylated derivatives, in the form of carbamates, especially of allyl, benzyl, phenyl or tertbutyl, or else in the form of silylated derivatives.
  • silylated derivatives such as tertbutyl dimethyl, trimethyl, triphenyl or diphenyl tert-butylsilyl derivatives, or phenylsulfonylalkyl or cyanoalkyl derivatives.
  • Deprotection is carried out, according to the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or with the aid of soluble complexes of Palladium O, by action of an acid, or by the action of fluoride.
  • tetrabutylammonium or strong bases such as sodium hydride or potassium t-butoxide.
  • the hydroxylamine protection is carried out in particular in the form of benzyl or allyl ethers.
  • the cleavage of the ethers is carried out by hydrogenolysis or with the aid of soluble complexes of Palladium O.
  • the protection of alcohols and phenols is carried out conventionally in the form of ethers, esters or carbonates.
  • the ethers may be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silylated ethers, for example derivatives thereof. silylated above.
  • the esters may be any cleavable ester known to those skilled in the art and preferably acetate, propionate or benzoate or p-nitrobenzoate.
  • the carbonates may be, for example, methyl, tert-butyl, allyl, benzyl or p-nitrobenzyl carbonates.
  • the deprotection is carried out by means known to those skilled in the art, in particular saponification, hydrogenolysis, cleavage with soluble complexes of palladium-0, hydrolysis in an acidic medium or, for the silylated derivatives, the treatment with tetrabutylammonium fluoride.
  • the sulphation reaction is carried out by action of S0 3 complex amines such as SO 3 -pyridine or SO 3 - dimethylformamide, operating in pyridine, the salt formed, for example the pyridine salt, can then be exchanged for example by a salt of another amine, a quaternary ammonium or an alkali metal.
  • S0 3 complex amines such as SO 3 -pyridine or SO 3 - dimethylformamide
  • the alkylation reaction is carried out by action on the hydroxylated derivatives, the enolates of esters or ketones, the amines or the heterocyclic nitrogens, as the case may be, of an alkyl sulphate or of an alkyl halide or substituted alkyl, in particular with a free or esterified carboxy radical.
  • Alkylation reactions can also be carried out by reductive amination.
  • Salification with acids is optionally carried out by adding an acid in the soluble phase to the compound.
  • Salification with the bases of the sulphooxy function can be carried out using the pyridinium salt obtained during the action of the S ⁇ 3 -pyridine complex and the other salts are obtained from this pyridinium salt.
  • the carbamoylation reaction may be carried out by the use of a chloroformate or a Boc-ON type reagent and then an amine or, where appropriate, ammonia.
  • the introduction of an azido group may be carried out for example by the action of sodium azide on a mesylate intermediate or by Mitsunobu type reactions.
  • the reduction of an azide group can be carried out by the action of trialkyl or triarylphosphine.
  • the separation of enantiomers and diastereoisomers can be carried out according to the techniques known to those skilled in the art, in particular chromatography.
  • compounds of formula (I) can be obtained by methods which initially use a compound of formula (II) in which R ' 1 , R 3 , R 4 and HZ have the values which directly lead to (without transformation) to those of the compounds that we wish to prepare. If appropriate, those of these values which contain reactive functions as mentioned above are then protected, the deprotection occurring at the end of the cyclization step b or at any other convenient time in the synthesis. The protections and deprotections are then carried out as described above.
  • the compound of formula (II) can be obtained by a process according to which a compound of formula (IV) is treated:
  • the compound of formula (II) may also be obtained by a process according to which a compound of formula (IV) as defined above is treated with hydroxylamine protected at the level of hydroxy to obtain a compound of formula (VII ):
  • A, R ', R 3 , R 4 , n "and ZH are defined as above, which is treated, if appropriate, with a deprotecting agent of the appropriate nitrogen atom.
  • Nitrogen is one of those mentioned above.
  • the reducing agent is in particular an alkaline borohydride.
  • the leaving group is in particular a sulphonate, for example a mesylate or a tosylate, obtained by the action of corresponding sulphonyl chloride in the presence of a base, or a halogen, more particularly chlorine, bromine or iodine, obtained for example by the action of thionyl chloride or P (C 6 H 5 ) 3 CBr 4 or PBr 3 or, in the case of an iodine atom, by the action of an alkaline iodide on a sulfonate.
  • the deprotection agent is in particular one of those mentioned above.
  • synergistic combinations according to the invention suitable for use as medicaments, in particular in the treatment of severe Pseudomonas and Enterobacteriaceae infections, in particular nosocomial infections and, in general, major infections in subjects at risk.
  • These may include respiratory tract infections, eg acute pneumonia or chronic lower respiratory tract infections, blood infections, eg septicemia, acute or chronic urinary tract infections, systemic infections.
  • the subject of the invention is, as medicaments, those containing compounds of formula (I) in which R 3 and R 4 together form an optionally substituted pyrazolyl or triazolyl heterocycle, and of these, those in which R 1 is selected from the group consisting of (CH 2 ) n -NH 2 and (CH 2 ) n "NHCH 3 groups , n being as defined above, the heterocycle formed by R 3 and R 4 is substituted by an alkyl radical (C 1 -C 6 ).
  • the invention more particularly relates, as medicaments, those containing compounds in which R 1 represents a radical (CH 2 ) n -NH 2 or (CH 2 ) n ⁇ NHCH 3 , n being as defined above and R 3 and R 4 together form a pyrazolyl ring substituted with a (C 1 -C 6 ) alkyl radical.
  • the subject of the invention is, as a medicament, those containing at least one of the compounds whose names follow: trans-8- (aminomethyl) -4,8-dihydro-1-methyl- 5- (Sulfooxy) -7,7-methano-7H-pyrazolo [3,4-e] [1,3] diazepine
  • the subject of the invention is, in particular, as medicaments, those containing antibacterial compounds chosen from aminoglycosides, beta- lactams, penicillins where appropriate combined with beta lactamase inhibitors, and polymyxins.
  • the invention also relates to pharmaceutical compositions containing as active ingredients, a synergistic combination as defined above.
  • compositions may be administered orally, rectally, parenterally, in particular intramuscular, or locally by topical application to the skin and mucous membranes.
  • compositions according to the invention can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, single or coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • These compositions may in particular be in the form of a lyophilizate intended to be dissolved extemporaneously in a suitable vehicle, for example sterile, pyrogen-free water.
  • compositions according to the invention thus comprise at least two active principles, and these can be administered simultaneously, separately or in a staggered manner over time.
  • they can present in the form of a "kit", allowing the administration of a compound of general formula (I) and that of another antibacterial compound separately.
  • the dose of compound of formula (I) administered varies according to the level and nature of the condition treated, the subject, the route of administration and the other antibacterial product considered. It may be, for example, between 0.25 g and 10 g per day, orally in humans, with the product described in Example 1 or between 0.25 g and 10 g per day per day. intramuscular or intravenous route.
  • the dose in the other antibacterial compound is also variable depending on the condition being treated, the subject, the route of administration and the product under consideration, but usually follows the usual doses prescribed by the pratitians, for example as described in Vidal reference publication.
  • This dose can be up to 10 g per day or more. Nevertheless, as a result of the potentiation provided by the compounds of general formula (I) to the other antibacterial compounds, the doses thereof in the combination can be reduced compared with standard doses.
  • the combinations according to the invention can also be used as disinfectants for surgical instruments.
  • the following examples illustrate the preparation of compounds of formula (I).
  • the other antibacterial compounds are known and commercial.
  • a solution of O-benzylhydroxylamine in dichloromethane is freshly prepared from O-benzylhydroxylamine hydrochloride (25.4 g, 160.6 mmol, 5eq).
  • O-Benzylhydroxylamine hydrochloride is dissolved in a mixture of dichloromethane (100 ml) and water (50 ml).
  • a 2N sodium hydroxide solution (85 ml, 176.66 mmol) is added at 0 ° C. After 10 min of contact and decantation, the organic phase is dried over magnesium sulfate for 45 min and then concentrated to half volume. The addition of this solution to the mesylate prepared above is at -78 ° C dropwise over 1 hour.
  • reaction mixture is stirred while allowing the temperature to rise gradually to ambient temperature. It is treated by addition of water (200 ml) and the medium is diluted with dichloromethane (100 ml), stirred, decanted and then the aqueous phase is re-extracted with dichloromethane. The organic phase is washed with saturated NaCl solution (200 ml), dried and then concentrated to dryness. A white amorphous powder is recovered, which after chromatography delivers the expected derivative B (8.25 g, 66%).
  • the mixture is stirred for 2 h, treated with water (200 ml), stirred, decanted.
  • the organic phase is washed with water (2 ⁇ 200 ml) and then with saturated NaCl solution (1 ⁇ 200 ml), dried over MgSO 4 and then concentrated to dryness.
  • a suspension of 60 g of DOWEX 50WX8 resin in 2N sodium hydroxide solution (300 ml) is stirred for one hour and then poured onto a chromatographed column.
  • the product is eluted with demineralized water to a neutral pH, and then the column is conditioned with a 90/10 water / THF mixture.
  • the derivative H (0.49 g, 1.01 mmol) is dissolved in a minimum of water, deposited on the column, then eluted with a water / THF 90/10 mixture.
  • the fractions containing the substrate are combined and frozen.
  • the frozen solution is lyophilized to yield the expected product (0.44 g, 1.03 mmol, 100%).
  • reaction mixture After stirring overnight at room temperature, the reaction mixture is treated with an aqueous solution of 10% NaH 2 PO 4.
  • Step B trans [[4,5,6,8-tetrahydro-6-oxo-5- (phenylmethoxy) -4,7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin-8 -yl] methyl] - carbamate • 1, 1-dimethyl the alcohol obtained in step A of example 2 (1.73 g, 5.76 mmol) is dissolved in anhydrous pyridine (35 mL) under nitrogen at 0 0 C. Then methanesulfonyl chloride (1.78 mL, 23 mmol) was added dropwise.
  • reaction mixture After stirring for 2 hours at room temperature, the reaction mixture is treated with a saturated aqueous solution of ammonium chloride (100 ml) and then extracted with ethyl acetate. The combined organic phases are then washed 5 times with a saturated aqueous solution of ammonium chloride, dried over sodium sulfate, filtered and then concentrated in vacuo to give the expected dimesylated derivative in the form of a yellow oil.
  • the dimesylated intermediate is dissolved in anhydrous dimethylformamide (45 ml), under nitrogen, in the presence of sodium azide (1.12 g, 17.3 mmol).
  • the reaction mixture is heated at 70 ° C. for 24 hours. If necessary 1 eq. Azide is added so that the conversion is complete.
  • the reaction is complete, the mixture is treated with a 10% aqueous solution of NaH 2 PO 4 (100 mL) and then extracted with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and then concentrated in vacuo to give the expected azide as a yellow oil.
  • Stage D pyridinium salt of trans [[1-tert-butoxycarbamate-4,5,6,8-tetrahydro-6-oxo-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-de] e] [1,3] diazepin-8-yl] methyl] -carbamate 1,1-dimethyl
  • a suspension of 6 g of DOWEX 50WX8 resin in a 2N sodium hydroxide solution (30 mL) is stirred at room temperature for 1 h, then poured onto a column to be chromatographed. After rinsing with H 2 O until neutral pH, the column is conditioned with a THF / H 2 O 10/90 mixture.
  • the derivative obtained in Step D of Example 2 (47 mg, 0.08 mmol) is dissolved in a minimum of methanol and then deposited on the column. After elution with a THF / H 2 O 10/90 mixture, the fractions containing the expected product are combined, frozen and then lyophilized to yield the expected sodium salt.
  • the sodium salt is taken up in anhydrous dichloromethane (1.04 mL) under nitrogen and then cooled to 0 ° C. A solution of trifluoroacetic acid / anhydrous dichloromethane 1/1 (2.04 mL) is added dropwise. The reaction mixture is then stirred at room temperature for 45 minutes. After evaporation to dryness and then co-evaporation with anhydrous dichloromethane, the compound is taken up in water ( ⁇ 2 mL) and then frozen and lyophilized to give the expected salt (16 mg, 0.030 mmol, 36%) as a yellow powder. blade.
  • Example 3 Sodium salt and trifluoroacetate salt of trans [[8- (methylamnomethyl) -4,8-dihydro-1-methyl-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-de] e] [1,3] diazepin-6 (5H) -one
  • Step A Iodide of trans [[[4,5,6,8-tetrahydro-1-methyl-6-oxo-5-
  • Step B trans 8- (methylaminomethyl) -4,8-dihydro-1- methyl-5-
  • the reaction medium is stirred at 55 ° C. for 3 h 30 min. After cooling to room temperature, the medium The reaction is saturated with sodium chloride in the presence of ethyl acetate (25 mL). The aqueous phase is extracted with ethyl acetate (3x25 mL). The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure to give a yellow oil (0.26 g).
  • the crude reaction product is purified by chromatography on a silica column (100% dichloromethane eluent and then gradient with 2% to 10% methanol) to give the expected derivative (0.084 g, 0.256 mmol, 26%).
  • the aqueous phase is extracted with dichloromethane (3 ⁇ 20 mL).
  • the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure to give an amorphous white powder (157 mg).
  • the crude reaction product is chromatographed on a silica column (100% dichloromethane eluent and then gradient with 20% to 30% ethyl acetate) to give the expected derivative (0.068 g, 0.159 mmol, 60%).
  • Step H of Example 1 the salt obtained in Step D of Example 3 (0.045 g, 0.090 mmol), DOWEX 50WX8 resin (30 g) and 2N sodium hydroxide (150 mL) lead to expected sodium salt (0.039 g, 0.090 mmol, 100%).
  • composition for injection containing:
  • Aim The in vitro bactericidal activity of the antibiotic is measured by demonstrating the lowest concentration that allows the survival of 0.001% of bacteria after a given single time and over time.
  • the products to be tested are weighed and solubilized, and the mother solution obtained is then diluted in medium according to concentrations to be tested, knowing that each dilution will be introduced under 0.5ml in a total volume of 20ml is a final dilution to 1/40.
  • the Minimum Inhibitory Concentrations (MICs) of the test products are determined beforehand.
  • Each flask is inoculated with 1 ml of the shaking culture or dilution, the initial inoculum to be 1x10 6 cfu / ml. • The different antibiotic solutions are added in a volume of 0.5 ml and 0.5 ml of medium in the control flask.
  • Bactericidal effect 3 log reduction compared to the initial inoculum.
  • PETERSON LR SHANHOLTZER CJ. Tests for bactericidal effects of antimicrobials agents: technical performance and clinical relevance. Clin. Microb. Rev. , 1992, 5, 420-432
  • MICs are determined on a microplate:
  • Ciprofloxacin / CIPRO 1 ⁇ g / mL
  • the MICs are determined in a volume of 10 mL - Bactericidal conditions (exponential bacterial growth): - CAZ: 8 ⁇ g / mL
  • the bactericidal activities shown on plates 1 to 3 in the appendix are evaluated after 48 hours, either for the product of example 1 alone, or for a combination. They show a total absence of bacterial regrowth after 48 hours for combinations.
  • MIC minimum inhibitory concentrations
  • the purpose of the study is to determine the concentration of a compound A, necessary to reduce the MIC of a compound B by one-half, one-quarter, one-eighth, one-sixteenth and 'a thirty second against strains of enterobacteriaceae and non-enterobacteriaceae species resistant to compound B.
  • This technique consists in titrating the compound A, an inhibitor, in a series of dilutions (2 in 2) arranged horizontally on a microplate, while at the same time assaying the compound B in a series of dilutions arranged vertically. The plate is then inoculated with the bacterial strain and the bacteria are allowed to grow overnight. Each well on the chessboard of the microplate contains a different combination of concentrations of the inhibitor and the antibacterial compound, which allows a total determination of any synergy between the two components.
  • FIC Fractional Inhibitory Concentration
  • (A) is the concentration of compound A in a well corresponding to the lowest concentration of this growth inhibiting compound in the row. when the well also contains compound B (MIC A ) is the lowest concentration of compound A alone that inhibits growth.
  • FIC A is the "Fractional Inhibitory Concentration" of compound A.

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EP09786281A 2008-10-10 2009-09-29 Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments Withdrawn EP2344500A1 (fr)

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FR0805618A FR2936951B1 (fr) 2008-10-10 2008-10-10 Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments
PCT/IB2009/006992 WO2010041112A1 (fr) 2008-10-10 2009-09-29 Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments

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AU2011333305B2 (en) 2010-11-25 2017-06-22 Allecra Therapeutics Gmbh Compounds and their use
US9505761B2 (en) 2011-12-02 2016-11-29 Fedora Pharmaceuticals Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
US8796257B2 (en) 2011-12-02 2014-08-05 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and β-lactamase inhibitors
AR090539A1 (es) 2012-04-02 2014-11-19 Astrazeneca Ab COMPUESTOS INHIBIDORES DE b LACTAMASA
UA111925C2 (uk) 2012-12-11 2016-06-24 Федора Фармасьютікалз Інк. БІЦИКЛІЧНІ СПОЛУКИ ТА ЇХ ВИКОРИСТАННЯ ЯК АНТИБАКТЕРІАЛЬНИХ АГЕНТІВ ТА ІНГІБІТОРІВ β-ЛАКТАМАЗИ
GB201305277D0 (en) * 2013-03-22 2013-05-01 Helperby Therapeutics Ltd Novel combination and use
WO2015052682A1 (en) 2013-10-11 2015-04-16 Wockhardt Limited Nitrogen containing compounds and their use
RS58429B1 (sr) * 2014-11-17 2019-04-30 Entasis Therapeutics Ltd Kombinovana terapija za lečenje rezistentnih bakterijskih infekcija
CN114591223A (zh) 2016-09-16 2022-06-07 恩塔西斯治疗有限公司 β-内酰胺酶抑制剂化合物
JOP20190061A1 (ar) 2016-09-28 2019-03-26 Novartis Ag مثبطات بيتا-لاكتاماز
TWI791018B (zh) 2017-05-08 2023-02-01 美商安特西醫療公司 治療細菌感染之化合物及方法
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FR2936951B1 (fr) 2010-12-03
JP2012505196A (ja) 2012-03-01
FR2936951A1 (fr) 2010-04-16
AU2009302153A1 (en) 2010-04-15
ECSP11010973A (es) 2011-06-30
AR073771A1 (es) 2010-12-01
PE20110392A1 (es) 2011-06-11
CA2740035A1 (fr) 2010-04-15
MX2011003812A (es) 2011-07-29
BRPI0919812A2 (pt) 2015-12-22
WO2010041112A1 (fr) 2010-04-15
ZA201102498B (en) 2013-07-25
PA8845401A1 (es) 2010-05-26
CN102216301B (zh) 2014-12-10
CN102216301A (zh) 2011-10-12
IL212180A0 (en) 2011-06-30
UY32168A (es) 2010-04-30
NZ592165A (en) 2012-12-21
US20100092443A1 (en) 2010-04-15
TW201026697A (en) 2010-07-16
CL2011000783A1 (es) 2012-07-06
EA201170532A1 (ru) 2011-12-30
BRPI0919812A8 (pt) 2016-11-01
CO6361930A2 (es) 2012-01-20
KR20110067148A (ko) 2011-06-21

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