EP2344499A1 - Nouveaux composes heterocycliques azotes, leur préparation et leur utilisation comme médicaments antibactériens - Google Patents
Nouveaux composes heterocycliques azotes, leur préparation et leur utilisation comme médicaments antibactériensInfo
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- EP2344499A1 EP2344499A1 EP09786093A EP09786093A EP2344499A1 EP 2344499 A1 EP2344499 A1 EP 2344499A1 EP 09786093 A EP09786093 A EP 09786093A EP 09786093 A EP09786093 A EP 09786093A EP 2344499 A1 EP2344499 A1 EP 2344499A1
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- 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
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- 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
- C07D471/02—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 two hetero rings
- C07D471/08—Bridged systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to nitrogen-containing heterocyclic compounds, their preparation and their use as antibacterial drugs.
- R 1 represents a hydrogen atom, a COOH radical, COOR, CN, (CH 2 ) n ' Rs, CONR 6 R 7 or ⁇ f'
- R is chosen from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by one or more halogen atoms or by a pyridyl radical, a -CH 2 -alkenyl radical containing in total from 3 to 9 atoms of carbon, a (poly) alkoxyalkyl group containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the nucleus of aryl or aralkyl radical being optionally substituted with an OH, NH 2 , NO 2 radical, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms or by one or more halogen atoms, R 5 is selected from the group consisting of a radical COOH, CN, OH, NH 2 , CO-NR 5 R 7 , COOR, OR,
- Re and R 7 are individually chosen from the group consisting of a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms, aryl containing from 6 to 10 carbon atoms and aralkyl containing from 7 to 11 carbon atoms and an alkyl radical containing from 1 to 6 carbon atoms substituted by a pyridyl radical, n 1 is equal to 1 or 2,
- R 3 and R 4 together form a phenyl or an aromatic heterocycle having 5 or 6 vertices containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, substituted with one or more groups R ', R' being selected from the group consisting of the radicals - (0) a - (CH 2) b - (0) a -CONR 6 R 7, - (0) a - (CH 2) b -OSO 3 H, - (0 ) a - (CH 2 ) b ⁇ SO 3 H, - (O) 3 -SO 2 R, - (O) 3 -SO 2 -CHaI 3 , - (O) 3 - (CH 2 ) b -NR 6 R 7 ,
- R 2 is selected from the group consisting of a hydrogen atom, a halogen atom and the radicals R, S (O) 1n R, OR, NHCOR, NHCOOR and NHSO 2 R, R being as defined above and m being equal to 0.1 or 2,
- X represents a divalent group -C (O) -B- connected to the nitrogen atom by the carbon atom,
- B represents a divalent group -O- (CH 2 ) n "- linked to the carbonyl by the oxygen atom, a group -NR 8 - (CH 2 ) n " - or -NR 8 -O-linked to the carbonyl by the nitrogen atom, n "is equal to 0 or 1 and Rs is chosen from the group consisting of a hydrogen atom, an OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 radical; , OY 2 , Y 3 , O-CH 2 -CH 2 -S (O) mR, SiRaRbRc and OSiRaRbRc, Ra, Rb and Rc individually representing a linear or branched alkyl radical containing 1 to 6 carbon atoms or an aryl radical containing 6 to 10 carbon atoms, and R and m being defined as above, Y is selected from the group consisting of COH radicals, COR, COOR, CONH 2
- Yi is selected from the group consisting of SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H,
- Y 2 is selected from the group consisting of PO (OH) 2 , PO (OR) 2 , PO (OH) (OR) and PO (OH) (R) radicals,
- Y 3 is selected from the group consisting of tetrazole, tetrazole radical substituted with R, squarate, NH or NR tetrazole, NH or NR tetrazole substituted with R, NHSO 2 R and NRSO 2 R, CH 2 tetrazole and CH 2 R-substituted tetrazole, R being defined as above, and n is 1 or 2, and the salts of these compounds with inorganic or organic bases or acids.
- the asymmetric carbon atoms contained in the compounds of formula (I) can independently of each other have the R, S or RS configuration and the compounds of formula (I) are therefore in the form of pure enantiomers or pure diastereoisomers or in the form of a mixture of enantiomers, especially racemates, or mixtures of diastereoisomers.
- the substituent R 1, R 2 , or R 4 taken individually on the one hand and X on the other hand can be in the cis and / or trans position with respect to the ring to which they are attached, the compounds of formula (I ) are in the form of cis isomers or trans isomers or mixtures.
- the uniqueness of the compounds of the invention lies in the fact that they exhibit excellent activity on Pseudomonas aeruginosa, a bacterial strain frequently encountered in nocosomal infections as well as in patients suffering from cystic fibrosis.
- the compounds of the invention have been active on models of animal infection, including strains usually resistant to commonly used antibiotics.
- the compounds of the invention are capable of counteracting the main resistance mechanisms of bacteria such as ⁇ -lactamases, efflux pumps and porin mutations.
- the compounds of the invention are compounds corresponding to the above formula, in which R 2 represents a hydrogen atom, X represents a divalent group C (O) NRs in which Rs is a radical OYi, Yi being a radical SO 3 H, and especially containing the particular combination of substituents Ri, R 3 , R 4 following:
- R 1 represents an alkyl radical substituted by an amino radical and R 3 and R 4 together form a nitrogenous heterocycle with a 5-membered aromatic character substituted with a group comprising or consisting of a polar substituent of amino type or aromatic heterocyclic amine or carboxy.
- R 1 represents a radical (CH 2 ) D -NHa, n being equal to 1 or 2;
- R 2 represents a hydrogen atom;
- R 3 and R 4 together form a nitrogenous heterocycle with a 5-membered aromatic character containing 1, 2 or 3 nitrogen atoms, substituted on this nitrogen atom or on one of these nitrogen atoms by a group (CH 2 m ⁇ (C (O)) P -Rs where m is 0, 1, 2 or 3, where p is 0 or 1 and R 5 is hydroxy, in which case p is 1, or amino group, alkyl (Ci-Ce) or dialkyl (Ci-Cg) amino, or a nitrogenous heterocycle with aromatic character at 5 or 6 vertices containing 1 or 2 nitrogen atoms and, if appropriate, an oxygen atom or sulfur; it being understood that when the subgroup (C (O)) p -R 5 forms a carboxy, amino or (C 1 -C e) alkyl or dialkyl (C
- heterocycle with aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms is meant those selected from the following list, the two bonds symbolizing the junction with the nitrogenous ring formed by R 3 and R 4 :
- nitrogenous heterocycle with aromatic character with 5 or 6 vertices containing 1 or 2 nitrogen atoms and, if appropriate, 1 atom of oxygen or sulfur is meant those of the type represented above, or an oxazole or thiazole ring , or a six-membered ring of pyridine, pyrazine, pyrimidine or pyridazine type, the heterocycle being attached to the chain or to the heterocycle formed by R 3 and R 4 by a nitrogen atom or a carbon atom.
- 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, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesul
- 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 hydroxide or with organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris
- mineral bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide
- organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris
- (hydroxymethyl) aminomethane ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine, or phosphonium salts, such as alkylphosphonium, arylphosphonium, alkylarylphosphonium, alkenylarylphosphonium or quaternary ammonium salts such as tetra n-butylammonium salt.
- phosphonium salts such as alkylphosphonium, arylphosphonium, alkylarylphosphonium, alkenylarylphosphonium or quaternary ammonium salts such as tetra n-butylammonium salt.
- the asymmetric carbon atoms contained in the compounds of formula (I) can independently of each other have the R, S or RS configuration and the compounds of formula (I) are therefore in the form of pure enantiomers or pure diastereoisomers or in the form of a mixture of enantiomers, especially racemates, or mixtures of diastereoisomers.
- the substituent Ri on the one hand and the chain -C (O) -N (OSO 3 H) - on the other hand can be in the cis and / or trans position with respect to the cycle on which they are attached, the Compounds of formula (I) are in the form of cis isomers or trans isomers or mixtures.
- the invention particularly relates to the compounds in which R 3 and R 4 together form a substituted pyrazolyl heterocycle.
- the subject of the invention is in particular those in which R x is a group (CH 2 J n -NH 2 , n being equal to 1 and the heterocycle formed by R 3 and R 4 is substituted by a group (CH2) m- (C (O)) P -Rs as defined above, and more particularly among these, those in which R 5 represents an amino, alkyl (C 1 -C 6 ) or dialkyl group; (Ci-C 6 ) amino, m and p being as defined above.
- the invention particularly relates to the compounds described later in the experimental part and in particular those whose names follow: trans-8- (aminomethyl) -2-carbamoyl-4,8 dihydro-5- (sulphooxy) -4, 7-methano-7H-pyrazolo [3, 4-e] [1/3] diazepin-6 (5H) -one, trans 8- (aminomethyl) -2-dimethylcarbamoyl 4,8-dihydro-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin-6 (5H) -one, trans-8- (aminomethyl) -2-methylcarbamoyl-4, 8-dihydro-5- (sulphooxy) -4, 7-methano-7H-pyrazolo [3, 4-e] [1/3] diazepin-6 (5H) -one, trans 8 - (Aminomethyl)
- Another subject of the invention is a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is treated: in which R 'i represents a radical R 1 in which the nitrogen atom is protected, R 2 is as defined above, R' 3 and R ' 4 together form a nitrogenous heterocycle with a 5-membered aromatic character containing 1, 2 or 3 nitrogen atoms and P represents a protecting group of the hydroxyl radical, in the presence of a base, with a compound of formula (III):
- R ' 1 , R 2 and P are as defined above and R'' 3 and R'' 4 together form a nitrogenous heterocycle with a 5-membered aromatic character as defined above for R 3 and R 4 , substituted by a group (CH 2 ) m - (C (O)) p -R ' 5 , m, p and R' 5 being as defined above, then deprotects the hydroxyl radical and subjects the compound obtained to a sulfation reaction by action of SO 3 complexed, then, where appropriate, subjects the compound obtained to one or more of the following reactions, in an appropriate sequence: deprotection of the amine and, where appropriate, carboxy function (s) present, salification, ion exchange, resolution or separation of diastereoisomers .
- the prior protection of the amine at R 'i and R' 5 is in particular carried out in the form of benzyl or tritylated derivatives, in the form of carbamates, especially of allyl, benzyl, phenyl or tertbutyl, or else in the form of derivatives.
- silyl derivatives such as tertbutyl dimethyl, trimethyl, triphenyl or diphenylterbutyl-silyl derivatives, or else phenylsulfonylalkyl or cyanoalkyl derivatives.
- Deprotection can be performed by various methods known to those skilled in the art, depending on the nature of the protecting group.
- the deprotection can be carried out by various methods known to those skilled in the art, for example by saponification, acid hydrolysis, hydrogenolysis or cleavage using soluble complexes of Palladium 0.
- the base in the presence of which the compounds of formulas (II) and (III) are reacted can for example be an alkaline carbonate but other bases known to those skilled in the art can be used.
- 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 O, hydrolysis in an acidic medium or, for the silylated derivatives, treatment with tetrabutylammonium fluoride.
- saponification hydrogenolysis
- cleavage with soluble complexes of Palladium O hydrolysis in an acidic medium or, for the silylated derivatives, treatment with tetrabutylammonium fluoride.
- (III) is carried out in the form of mesylate or tosylate, under conditions known to those skilled in the art.
- the sulfation reaction is carried out by the action of SO 3 complexes such as SC 3 -pyridine or SO 3 -dimethylformamide, by operating in pyridine or in dimethylformamide, the salt formed, for example the pyridine salt, which can then be exchanged. for example by a salt of another amine, a quaternary ammonium or an alkali metal.
- SO 3 complexes such as SC 3 -pyridine or SO 3 -dimethylformamide
- 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 amine salt and in particular pyridine obtained during the action of the S0 3 -amine complex and the other salts are obtained from this amine salt. It can in particular operate by ion exchange resin.
- the separation of enantiomers and diastereoisomers can be carried out according to the techniques known to those skilled in the art, in particular chromatography, on chiral phase or otherwise. Examples of usable conditions are also described in the application WO 04/052891 or in the application WO 02/100860.
- the compounds of formula (I) wherein m is 0, p is 1 and R 5 is R '5, R' 5 is an amino group, alkyl (Ci-Cg) or di (Ci-Ce ) amino, can also be obtained by a process characterized in that a compound of formula (II) as defined above, in the presence of a base, is treated with diphosgene and then with an amine of formula
- the base used during the action of diphosgene may especially be a tertiary amine such as triethylamine
- R 5 represents a heterocycle
- the compounds of formula (I) in which R 5 represents a heterocycle may be obtained by the various reactions known to those skilled in the art to form the CN bonds and in particular by palladium or copper catalysis such as that described in one of the examples below
- the compounds of general formula (I) have excellent antibiotic activity on Pseudomonas aeruginosa as well as models of animal infection with strains resistant to antibacterial agents commonly used. This remarkable and unexpected antibiotic activity was not observed for the compounds described in application WO 04/052891 and in particular for the structurally similar compounds. This is illustrated below.
- respiratory tract infections eg acute pneumonia or chronic lower tract infections
- blood infections eg septicemia, acute or chronic urinary tract infections
- auditory system infections eg, malignant otitis externa, or chronic suppurative otitis
- those of the skin and soft tissues eg dermatitis, infected wounds, folliculitis, pyoderma, relapsing forms of acne, eyes, for example corneal ulcer, those of the nervous system, including meningitis and abscesses of the brain
- cardiac infections such as endocarditis, bone and joint infections such as stenoarticular pyoarthrosis, vertebral osteomyelitis, pubic symphysitis
- gastrointestinal tract infections such as necrotizing enterocolitis and peri-rectal infections .
- the subject of the present invention is therefore also, as medicaments and in particular antibiotic medicaments, the compounds of formula (I) as defined above, in free form and in the form of zwitterions and salts with bases and acids. inorganic or organic pharmaceutically acceptable.
- the invention particularly relates, as medicaments, compounds wherein R 3 and R 4 together form a substituted pyrazolyl heterocycle.
- the invention more particularly relates, as medicaments, to the compounds in which R 1 is a (CH 2 ) D -NH 2 group , n being equal to 1 and the heterocycle formed by R 3 and R 4 is substituted with a group (CH 2 ) m - (C (O)) p - R 5 as defined above, and more particularly among these, those in which R 5 represents an amino group, alkyl (C 1 -C 6 ) or dialkyl (C 1 -C e) amino, m and p being as defined above.
- the subject of the invention is, as a medicament, the compounds whose names follow: trans-8- (aminomethyl) -2-carbamoyl-4,8-dihydro-5- (4-sulfooxy) -7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin-6 (5H) -one, trans-8- (aminomethyl) -2-dimethylcarbamoyl-4,8-dimethylcarbamoyl; dihydro-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin-6 (5H) -one, trans-8- (aminomethyl) -2-methylcarbamoyl- 4,8-Dihydro-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-e] [1,3] diazepin-6 (5H) -one, trans-8- (amino
- compositions containing, as active principle, at least one of the compounds according to the invention as defined above.
- These 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.
- excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles.
- compositions may especially be in the form of a lyophilizate intended to be dissolved extemporaneously in a suitable vehicle, for example sterile, pyrogen-free water.
- the dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It may be, for example, between 0.250 g and 10 g per day, orally in humans, with the product described in Example 1, 4 or 5, or between 0.25 g and 10 g per day intramuscularly or intravenously.
- the products of formula (I) can also be used as disinfectants for surgical instruments.
- 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. 1 equivalent of azide is added if necessary for the conversion to be 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 and then concentrated under reduced pressure to give the expected azide as a yellow oil.
- the intermediate is reacted, under nitrogen, in absolute ethanol (17.5 ml), then di-tert-butyl dicarbonate (1.38 g, 6.34 mmol), triethylsilane (1.38 ml, 8.64 mmol) are added successively and palladium hydroxide on carbon 10% (52 mg). After one night at room temperature, the reaction mixture is filtered and concentrated to give a crude yellow oil. This crude is purified by chromatography on a silica column (gradient eluent CH 2 Cl 2 / MeOH 100/0 to 95/5 by 1%) to yield the expected compound (1.36g, 3.40mmol, 34%) as a white solid.
- the derivative obtained in Stage C (94 mg, 0.212 mmol) is dissolved in dimethylformamide (0.3 mL) and dichloromethane (0.9 mL), then 10% palladium on carbon at 50% water (68 mg, 0.032%). mmol) is added. After empty purge / nitrogen, the reaction mixture is placed under an atmosphere of hydrogen until the starting material is removed by HPLC. The mixture is then concentrated under vacuum and then coevaporated with anhydrous dichloromethane, finally dried under reduced pressure in the presence of P 2 O 5 for 2 h to give the expected debenzylated intermediate.
- the debenzylated derivative is taken up in anhydrous pyridine (O. ⁇ mL) in the presence of the pyridine / trioxide sulfide complex (68 mg, 0.425 mmol).
- the reaction mixture is then stirred at ambient temperature until complete conversion to HPLC and then evaporated to dryness after treatment with the addition of water.
- the crude reaction product is chromatographed on a silica column (gradient eluent CH 2 Cl 2 / MeOH 100/0 to 80/20 by 5%) to give the expected product (50 mg, 0.093 mmol, 43%) in the form of a white solid. .
- MS (ES (-)): m / z [M "] 431
- Stage F Sodium salt and trifluoroacetate salt of trans-8- (aminomethyl) -2-carbamoyl-4,8-dihydro-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3,4-e] [ 1,3] diazepin-6 (5H) -one
- a solution of trifluoroacetic acid (2.4mL) in dichloromethane (2.4mL) is added dropwise to a solution of the sodium salt obtained in stage E (42mg, 0.092mmol ) in dichloromethane (1.2mL) under nitrogen and cooled to 0 ° C. The reaction is stirred for 1h at room temperature.
- Step C of Example 1 the use of the derivative obtained in Step B of Example 1 (200 mg, 0.501 mmol), dichloromethane (2 ⁇ mL), triethylamine (140 ⁇ L, 100 mmol), Diphosgene (91 ⁇ L, 0.751 mmol) and dimethylamine (40% aqueous, 0.634 mL, 5.0 mmol) give, after chromatography on a silica column (eluent CH 2 Cl 2 / MeOH 99/1), the expected derivative (170 mg, 0.361mmol, 72%) as a beige solid.
- Step D of Example 1 use of the derivative obtained in Step A (160 mg, 0.350 mmol), dimethylformamide (0.5 ⁇ mol), dichloromethane (1.52 ml), palladium 10% on charcoal at 50% water (112mg, 0.052mmol) and hydrogenation during 2.hl5 lead to the expected debenzylated intermediate.
- Trimethylphosphine (IM solution in tetrahydrofuran, 748 ⁇ L, 0.75 mmol) is added at 0 ° C. to a solution of the azide obtained above (320 mg, 0.575 mmol) in tetrahydrofuran (2.5 mL) and toluene (2.5 mL). .
- This solution is stirred for 2 hours at room temperature, then cooled to 0 ° C. and a solution of BOC-ON (21 mg, 0.86 mmol) in tetrahydrofuran (2 ml) is added.
- the solution is stirred at room temperature for 1 h, then hydrolysed by adding a saturated solution of NaHCO 3 and then extracted with ethyl acetate.
- the combined organic phases are dried and concentrated.
- the residue is purified by chromatography on a silica column (gradient cyclohexane / ethyl acetate 60/40 to 30/70) to provide the expected derivative (220mg, 0.41mmol, 70%).
- Step A of Example 1 the implementation of the N 2 -substituted ester obtained in Step A of Example 4 (623 mg, 1.32 mmol), NaBH 4 (300 mg, 7.92 mmol), of tetrahydrofuran (13 mL) and methanol (13 mL) at 0 ° C. conducted, after chromatography on a silica column (gradient eluent CH 2 Cl 2 / MeOH 98/2 to 90/10) to the expected derivative (250 mg, 0.58 mmol, 43%). %).
- Stage C Sodium salt and trifluoroacetate of trans-8- (aminomethyl) -2- (2-aminoethyl) -4,8-dihydro-5- (sulfooxy) -4,7-methano-7H-pyrazolo [3 , 4-e] [1,3] diazepin-6 (5H) -one
- Step D of Example 1 the use of the compound obtained in Stage B (85 mg, 0.157 mmol) in a mixture dimethylformamide / dichloromethane (1/3, 2mL) and Pd / C (50% H 2 O, 30mg) gives the expected debenzylated derivative.
- Example 6 Sodium salt and trifluoroacetate salt of trans-8- (aminomethyl) -2- (2-pyridinyl) -4,8-dihydro-5- (sulfooxy) -4,1-methano-7H-pyrazolo [3, 4-e] [1,3] diazepin-6 (5H) -one
- Step D of Example 1 the use of the derivative obtained in Step A (90 mg, 0.189 mmol), a mixture of dimethylformamide / dichloromethane 1/3 (2.OmL) and palladium 10% on charcoal at 50% water (36mg) conducted after 3 days under hydrogen to the expected debenzylated intermediate.
- the use of the debenzylated intermediate, pyridine (0.73mL) and pyridine / trioxide sulphide complex (60 Da, 0.378 mmol) leads, after chromatography on a silica column (eluent CH 2 Cl 2 / MeOH 90/10). , the expected derivative (63mg).
- the crude is then taken up in pyridine (0.73 ml), under nitrogen, in the presence of SU 3 / pyridine complex (60 mg, 0.378 mmol).
- the reaction mixture is then stirred at room temperature until complete conversion to HPLC (72h). After treatment with the addition of H 2 O, the mixture is filtered and then evaporated to dryness.
- the crude product thus obtained is purified by chromatography on silica (eluent CH 2 Cl 2 / MeOH 90/10). The product is thus obtained pure (63 mg).
- a suspension of 8.5 g of DOWEX 50WX8 resin in a 2N sodium hydroxide solution (43 ml) is stirred for 1 h and then poured onto a chromatography column.
- the column is conditioned with demineralised water until neutral pH.
- the derivative obtained (63 mg) is dissolved in a minimum of methanol and water, deposited on the column, then eluted with H 2 O.
- the fractions containing the substrate are combined, frozen and lyophilized to yield the expected sodium salt (55 mg). , 0.112mmol, 60%) as a yellow powder.
- the expected product is thus obtained (117 mg).
- a suspension of 20 g of DOWEX 50WX8 resin in a 2N sodium hydroxide solution (10OmL) is stirred for 1 h and then poured onto a chromatography column.
- the column is conditioned with demineralised water until neutral pH.
- the derivative obtained (117 mg, 0.233 mmol) is dissolved in a minimum of water, deposited on the column, then eluted with H 2 O.
- the fractions containing the substrate are combined, frozen and freeze-dried to conduct with the expected sodium salt ( ⁇ mg, 0.12 ⁇ mmol, 35%) in the form of a white powder.
- Step B of Example 7 the compound obtained in Step A (188 mg, 0.411 mmol) is hydrogenated and then sulfated in the presence of SO 3 / pyridine complex (131 mg, 0.823 mmol) in pyridine (1.58 mL), under nitrogen, at room temperature for 4 days.
- the gross product obtained is purified by chromatography on silica (gradient eluent CH 2 Cl 2 / MeOH / NH 4 OH 80/20/1) to yield the expected product (23 mg, 0.044 mmol, 11%) in the form of a mixture of N 1 isomers / N2 in a ratio of about 1/2.
- composition for injection comprising:
- dilutions method in liquid medium A series of tubes are prepared in which the same amount of sterile nutrient medium is distributed, increasing amounts of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain. . After incubation for 24 hours in an oven at 37 0 C, inhibition of growth is assessed by transillumination, which allows to determine the minimum inhibitory concentrations (MIC) expressed in ⁇ g / ml.
- MIC minimum inhibitory concentrations
- the products of Examples 1 to 8 are thus tested in comparison with the products of Examples 7, 9, 11 and 45 of Application WO 04/052891.
- the products of the present application are very active on Pseudomonas aeruginosa, which is absolutely not the case for comparison products.
- the difference in activity on Pseudomonas aeruginosa between the products of the invention and the closest products of the prior art is according to the products in a range of 16 to more than 500.
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14188601.0A EP2845855A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composés hétérocycliques azotés, leur préparation et leur utilisation comme médicaments antibactériens |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0805472A FR2936798B1 (fr) | 2008-10-03 | 2008-10-03 | Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens. |
PCT/IB2009/006433 WO2010038115A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composes heterocycliques azotes, leur préparation et leur utilisation comme médicaments antibactériens |
Related Child Applications (1)
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EP14188601.0A Division EP2845855A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composés hétérocycliques azotés, leur préparation et leur utilisation comme médicaments antibactériens |
Publications (1)
Publication Number | Publication Date |
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EP2344499A1 true EP2344499A1 (fr) | 2011-07-20 |
Family
ID=40548019
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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EP14188601.0A Withdrawn EP2845855A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composés hétérocycliques azotés, leur préparation et leur utilisation comme médicaments antibactériens |
EP09786093A Withdrawn EP2344499A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composes heterocycliques azotes, leur préparation et leur utilisation comme médicaments antibactériens |
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EP14188601.0A Withdrawn EP2845855A1 (fr) | 2008-10-03 | 2009-08-03 | Nouveaux composés hétérocycliques azotés, leur préparation et leur utilisation comme médicaments antibactériens |
Country Status (18)
Country | Link |
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US (1) | US8067435B2 (fr) |
EP (2) | EP2845855A1 (fr) |
JP (1) | JP5555240B2 (fr) |
KR (1) | KR20110067137A (fr) |
CN (1) | CN102203094B (fr) |
AU (1) | AU2009299511A1 (fr) |
BR (1) | BRPI0919810A8 (fr) |
CA (1) | CA2739503A1 (fr) |
CL (1) | CL2011000729A1 (fr) |
CO (1) | CO6361957A2 (fr) |
EA (1) | EA021799B1 (fr) |
EC (1) | ECSP11010946A (fr) |
FR (1) | FR2936798B1 (fr) |
IL (1) | IL212059A0 (fr) |
MX (1) | MX2011003573A (fr) |
PE (1) | PE20110845A1 (fr) |
WO (1) | WO2010038115A1 (fr) |
ZA (1) | ZA201102429B (fr) |
Families Citing this family (19)
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US8772490B2 (en) | 2010-12-22 | 2014-07-08 | Meiji Seika Pharma Co., Ltd. | Optically active diazabicyclooctane derivatives and process for preparing the same |
JP5677634B2 (ja) | 2011-08-30 | 2015-02-25 | ウォックハート リミテッド | 1,6−ジアザビシクロ[3,2,1]オクタン−7−オン誘導体および細菌感染の処置におけるそれらの使用 |
RU2569307C1 (ru) * | 2011-09-13 | 2015-11-20 | Вокхардт Лимитед | Азотсодержащие соединения и их применение |
KR20150003777A (ko) * | 2012-03-30 | 2015-01-09 | 큐비스트 파마슈티컬즈 인코포레이티드 | 이속사졸 β-락타마제 억제제 |
AR090539A1 (es) | 2012-04-02 | 2014-11-19 | Astrazeneca Ab | COMPUESTOS INHIBIDORES DE b LACTAMASA |
AR091222A1 (es) * | 2012-05-30 | 2015-01-21 | Meiji Seika Pharma Co Ltd | INHIBIDOR DE b-LACTAMASA Y PROCESO PARA PREPARARLO |
ES2672100T3 (es) * | 2012-08-25 | 2018-06-12 | Wockhardt Limited | Derivados de 1,6-diazabiciclo[3,2,1]octano-7-ona y su uso en el tratamiento de infecciones bacterianas |
BR112016006246B8 (pt) | 2013-09-24 | 2021-10-05 | Meiji Seika Pharma Co Ltd | Processos de produção de derivados de diazabiciclo-octano e compostos intermediários dos mesmos |
EP3613740A1 (fr) | 2013-10-08 | 2020-02-26 | Meiji Seika Pharma Co., Ltd. | Procédé de production d'un dérivé de diazabicyclooctane |
MX2016004509A (es) * | 2013-10-11 | 2016-10-28 | Wockhardt Ltd | Compuestos que contienen nitrogeno y su uso. |
TWI690317B (zh) | 2014-11-17 | 2020-04-11 | 英商安特西醫療有限公司 | 用於治療抗藥性細菌感染之組合療法 |
JP6779787B2 (ja) | 2014-12-05 | 2020-11-04 | Meiji Seikaファルマ株式会社 | ジアザビシクロオクタン誘導体の結晶及び安定な凍結乾燥製剤の製造法 |
EP3075733A1 (fr) * | 2015-03-31 | 2016-10-05 | Mutabilis | Nouveaux composés hétérocycliques et leur utilisation dans la prévention ou le traitement d'infections bactériennes |
WO2016156348A1 (fr) * | 2015-03-31 | 2016-10-06 | Mutabilis | Nouveaux composés hétérocycliques et utilisation de ceux-ci pour prévenir ou traiter des infections bactériennes |
CA2980395A1 (fr) | 2015-04-03 | 2016-10-06 | Mutabilis | Composes heterocycliques et leur utilisation dans la prevention ou le traitement d'infections bacteriennes |
WO2017055922A1 (fr) | 2015-10-02 | 2017-04-06 | Legochem Biosciences, Inc. | Compositions et méthodes pour inhiber la bêta-lactamase |
PL3512851T3 (pl) | 2016-09-16 | 2022-11-14 | Entasis Therapeutics Limited | Związki stanowiące inhibitory beta-laktamazy |
CN110709081B (zh) | 2017-05-08 | 2023-09-22 | 恩塔西斯治疗公司 | 用于治疗细菌感染的化合物及方法 |
EP3604315A1 (fr) | 2018-07-30 | 2020-02-05 | Mutabilis | Nouveaux composés hétérocycliques et leur utilisation dans la prévention ou le traitement d'infections bactériennes |
Family Cites Families (18)
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CN1264837C (zh) | 1997-09-15 | 2006-07-19 | 普罗克特和甘保尔公司 | 喹诺酮抗微生物剂、其组合物和应用 |
US6387928B1 (en) | 1997-09-15 | 2002-05-14 | The Procter & Gamble Co. | Antimicrobial quinolones, their compositions and uses |
FR2812635B1 (fr) * | 2000-08-01 | 2002-10-11 | Aventis Pharma Sa | Nouveaux composes heterocycliques, preparation et utilisation comme medicaments notamment comme anti- bacteriens |
PL363323A1 (en) | 2000-12-14 | 2004-11-15 | The Procter & Gamble Company | Antimicrobial quinolones |
AU3089302A (en) | 2000-12-14 | 2002-06-24 | Procter & Gamble | Antimicrobial 2-pyridones, their compositions and uses |
FR2825705B1 (fr) * | 2001-06-08 | 2005-05-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens |
FR2833596B1 (fr) | 2001-12-14 | 2005-02-18 | Aventis Pharma Sa | Procede de preparation de derives d'echinocandine |
FR2835186B1 (fr) | 2002-01-28 | 2006-10-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, actifs comme inhibiteurs de beta-lactamases |
US6900224B2 (en) | 2002-07-31 | 2005-05-31 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
FR2844273B1 (fr) | 2002-09-05 | 2008-04-04 | Aventis Pharma Sa | Nouveaux composes heterocycliques, procede et intermediaires de preparation et utilisation comme medicament, notamment comme inhibiteurs de beta-lactamases et anti-bacteriens. |
FR2844270B1 (fr) | 2002-09-11 | 2006-05-19 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, leur procede et intermediaires de preparation et les compositions qui les contiennent |
FR2844268B1 (fr) | 2002-09-11 | 2004-10-22 | Aventis Pharma Sa | Derives de la quinolyl propyl piperidine, leurs procedes et intermediaires de preparation et les compositions qui les contiennent |
FR2848210B1 (fr) * | 2002-12-06 | 2007-10-19 | Aventis Pharma Sa | Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens et inhibiteurs de beta-lactamases |
US7439253B2 (en) | 2002-12-06 | 2008-10-21 | Novexel | Heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors |
US7232833B2 (en) | 2003-03-28 | 2007-06-19 | Novexel | 4-substituted quinoline derivatives, method and intermediates for their preparation and pharmaceutical compositions containing them |
US7449481B2 (en) | 2004-04-13 | 2008-11-11 | Cephalon, Inc. | Thio-substituted biaryl-methanesulfinyl derivatives |
FR2914923B1 (fr) * | 2007-04-12 | 2013-06-14 | Novexel | Nouveaux composes heterocycliques azotes,leur preparation et leur utilisation comme medicaments antibacteriens. |
FR2937034B1 (fr) * | 2008-10-10 | 2012-11-23 | Novexel | Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens |
-
2008
- 2008-10-03 FR FR0805472A patent/FR2936798B1/fr not_active Expired - Fee Related
-
2009
- 2009-08-03 CN CN200980141781.3A patent/CN102203094B/zh not_active Expired - Fee Related
- 2009-08-03 BR BRPI0919810A patent/BRPI0919810A8/pt not_active IP Right Cessation
- 2009-08-03 JP JP2011529643A patent/JP5555240B2/ja not_active Expired - Fee Related
- 2009-08-03 PE PE2011000827A patent/PE20110845A1/es not_active Application Discontinuation
- 2009-08-03 WO PCT/IB2009/006433 patent/WO2010038115A1/fr active Application Filing
- 2009-08-03 CA CA2739503A patent/CA2739503A1/fr not_active Abandoned
- 2009-08-03 MX MX2011003573A patent/MX2011003573A/es active IP Right Grant
- 2009-08-03 EP EP14188601.0A patent/EP2845855A1/fr not_active Withdrawn
- 2009-08-03 EA EA201170522A patent/EA021799B1/ru not_active IP Right Cessation
- 2009-08-03 KR KR1020117009615A patent/KR20110067137A/ko not_active Application Discontinuation
- 2009-08-03 EP EP09786093A patent/EP2344499A1/fr not_active Withdrawn
- 2009-08-03 AU AU2009299511A patent/AU2009299511A1/en not_active Abandoned
- 2009-08-05 US US12/536,096 patent/US8067435B2/en not_active Expired - Fee Related
-
2011
- 2011-03-30 ZA ZA2011/02429A patent/ZA201102429B/en unknown
- 2011-03-31 IL IL212059A patent/IL212059A0/en unknown
- 2011-04-01 EC EC2011010946A patent/ECSP11010946A/es unknown
- 2011-04-01 CL CL2011000729A patent/CL2011000729A1/es unknown
- 2011-04-01 CO CO11040684A patent/CO6361957A2/es active IP Right Grant
Non-Patent Citations (1)
Title |
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See references of WO2010038115A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP5555240B2 (ja) | 2014-07-23 |
CL2011000729A1 (es) | 2012-07-06 |
IL212059A0 (en) | 2011-06-30 |
FR2936798B1 (fr) | 2012-09-28 |
KR20110067137A (ko) | 2011-06-21 |
EP2845855A1 (fr) | 2015-03-11 |
WO2010038115A1 (fr) | 2010-04-08 |
US8067435B2 (en) | 2011-11-29 |
EA201170522A1 (ru) | 2011-12-30 |
EA021799B1 (ru) | 2015-09-30 |
CA2739503A1 (fr) | 2010-04-08 |
ZA201102429B (en) | 2012-05-30 |
BRPI0919810A8 (pt) | 2017-12-12 |
MX2011003573A (es) | 2011-08-12 |
FR2936798A1 (fr) | 2010-04-09 |
AU2009299511A1 (en) | 2010-04-08 |
JP2012504593A (ja) | 2012-02-23 |
BRPI0919810A2 (pt) | 2017-10-31 |
CN102203094A (zh) | 2011-09-28 |
US20100087648A1 (en) | 2010-04-08 |
PE20110845A1 (es) | 2011-11-17 |
CN102203094B (zh) | 2014-04-02 |
CO6361957A2 (es) | 2012-01-20 |
ECSP11010946A (es) | 2011-05-31 |
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