Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/06—Peri-condensed systems
• • 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 novel 7-substituted derivatives of 3-carboxy-oxadiazino-quinolones, their preparation and their application as anti-bacterial.
• R a and R b are the same or different and represent H, linear, branched or cyclic alkyl (1-6c), cycloalkyl (3-6c) -alkyl (1-6c); or still represent Rc, S (O) 2 R 0 , C (O) R., S (O) 2 Rd or C (O) R d ; or R a and R b together with the nitrogen atom form a radical R 0; Rc represents a saturated, unsaturated or aromatic ring with 5 or 6 vertices, containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted with 1 to 3 alkyl radicals (1-6c), said cycle being the case optionally connected to the NR 8 Rb nitrogen atom by a nitrogen atom or a carbon atom;
• R d represents a linear or branched (1-6c) or cyclic (3-6c) alkyl radical, optionally substituted with 1 to 4 halogens; or Rj represents R c or CHR e R c or CHR e Rd ;
• R c and R d are as defined above, R 6 represents H, OH, NH 2, NHalk (l-6c) or Naik 2 (1 -6C), or NH-acyl (l -7C) or NHR C, Rc being as defined above;
• R 2 represents: H, (CH 2 ) m -NR a R b , Rc, CHR 6 R 0 or CHR 6 Ra, Ra, Rb, Rc, Rd and R 6 being as defined above; and
• R ' 2 is H; it being understood that R 1 and R 2 can not be simultaneously H or that R 1 and R 2 or R 2 and R 1 can not be one (CH 2 ) m -NR a R b or R 0 or H and the other OH , or one H and the other NH 2 , or one H and the other (CH 2 ) n -RR a R b , R 3 and R b representing H or alkyl (1-6c) or C ( O) Ra, Rd represents un
• R 1 has the values as defined above with the exception of hydrogen and R 2 and R ' 2 represent gem dialkyl (1-6c) or alkyl (1-6c) -oxime, or R 2 and R' 2 represent respectively R 0 or R 1 and OH, NH 2 , NHRc or NHRf, R 0 and Ra being as defined above and R f being an acyl radical (1-7c);
• R 2 and R ' 2 represent together alkyl (1-6c) -oxime or represent one R 0 and the other OH, NH 2 , NHRc or NHRf, R c and R f being as defined above; n is 0 or 1;
• R 3 and R ' 3 which may be identical or different, represent H or alkyl (1-6c) optionally substituted with 1 to 3 halogens or R 3 represents a (1-6c) alkoxycarbonyl group and R' 3 represents H;
• R 4 represents methyl optionally substituted with one to three halogens
• R 5 is H, alkyl (1-6c) or arylalkyl (7-12c);
• R 6 is H, Fluorine, NO 2 , CF 3 or CN; as mixtures of enantiomers or enantiomers isolated, and their addition salts with inorganic and organic acids and their salts with inorganic or organic bases.
• the compounds of the invention exhibit remarkable antibacterial properties which make them particularly suitable for use as medicaments in both human and veterinary medicine.
• linear or branched alkyl radical (1-6c) is meant any possible radical and especially methyl, ethyl, propyl or isopropyl, butyl, isobutyl or tert-butyl; by cyclic alkyl radical (3-6c) is meant cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; an arylalkyl radical is preferably benzyl or phenethyl; halogen means fluorine, chlorine, bromine or iodine, and preferably fluorine; acyl radical (1-7c) is understood to mean any possible radical and in particular acetylpropionyl, butyryl or benzoyl.
• Rc represents a saturated ring, it is for example a pyrrolidine, piperidine, piperazine or morpholine ring.
• Rc represents an unsaturated or aromatic ring
• it is for example a pyrrole, furan, thiophene, pyrazole, triazole, tetrazole, thiazole, isothiazole, thiadiazole, imidazole, isoxazole, furazane, pyridine, pyrazine, pirimidine or pyridazine ring.
• Rc When Rc is substituted, it is particularly substituted by one or, where appropriate, two methyl radicals.
• 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 inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide or lithium hydroxide.
• ammonium or with organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, ltiistidine, N-methylglucamine.
• the subject of the invention is in particular the compounds of formula (I) as defined above, in which R 3 and R ' 3 represent H and R "represents methyl, as well as those in which R 6 represents Fluorine.
• the subject of the invention is also the compounds of formula (I) as defined above, in which one of the substituents R 1 and R 2 represents (CH 2 ) m-NRaRb in which m is 0 or 1, Rc, CHReRc or CHReRd, and the other represents H.
• one of the substituents R 1 and R 2 represents (CH 2 ) m-NRaRb in which m is 0, and the other represents H, and especially from these: those in which one of the substituents Ra or Rb represents a 5- or 6-membered aromatic ring containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted with 1 to 3 alkyl radicals (1-6c); ), said ring being optionally connected to the nitrogen atom of NR 3 R b by a nitrogen atom or a carbon atom, and the other represents H, and - those in which one of substituents Ra or Rb represents a radical C (O) Rd and the other represents H.
• the subject of the invention is also the compounds of formula (I) as defined above, in which one of the substituents R1 and R2 represents CHReRc or CHReRd and the other represents H.
• the subject of the invention is in particular the compounds of formula (I) as defined above, in which R 1 represents OH or NH 2 and R 2 and R ' 2 represent gem dialkyl (1-6c), as well as those in which R 1 represents hydrogen or - (CH 2 ) m -NR a R b and R 2 and R ' 2 represent alkyl (1-6c) oxime.
• the compounds of the invention can be prepared by a process characterized in that a compound of formula (II) is treated:
• R 3 , R ' 3 , R 4 and R 6 are as defined above and R' 5 has the values of R 5 defined above or represents another group protecting the carboxylic function, with a compound of formula ( HI):
• R 1, R 2 , R ' 2 and n are defined as above, in the presence of a base, and then, where appropriate, eliminates the protective group or groups present.
• the base used is preferably a tertiary amine, for example triethylamine, N-methyl morpholine or DBU.
• R ' 5 represents a protective group, it may especially be a (1-6c) alkyl, an alkenyl (2-6c), or an arylalkyl (7-14c).
• R ' 5 may especially be a (1-6c) alkyl, an alkenyl (2-6c), or an arylalkyl (7-14c).
• R 2 and R ' 2 represent alkyl (1-C) -oxime
• R 2 and R ' 2 represent alkyl (1-C) -oxime
• the operation is carried out for example by the action of an alkoxylamine chloride, in the presence of a base, in particular an alkaline carbonate or bicarbonate, dissolved in an alkanol or in an alkanol-tetrahydrofuran-water mixture.
• a base in particular an alkaline carbonate or bicarbonate
• the compound of formula (IV) can be prepared from the corresponding alcohol, for example by a Swern type oxidation reaction, in the presence of oxalyl chloride, dimethylsulfoxide and a base, for example an amine such as triethylamine.
• the operation is carried out for example in the presence of an alkali metal alcoholate, dissolved in a solvent such as toluene.
• HaI is preferably chlorine or bromine.
• R 1 or R 2 represents a - (CH 2 ) m -NRaRb radical in which Ra or Rb or Ra and Rb represent C (O) Rc or C (O) Rd
• R 1 or R 2 represents a - (CH 2 ) m -NRaRb radical in which Ra or Rb or Ra and Rb represent C (O) Rc or C (O) Rd
• Rc-COOH or Rd-COOH (IX) by peptide coupling reaction in the presence of EDCI / HOBt in solution in a solvent such as DMF, or by the action of a corresponding acid halide or its corresponding anhydride, in presence of a base, for example an amine such as triethylamine, in a solvent such as dichloromethane, followed by deprotection of the cyclic nitrogen.
• R or R2 represents a radical (CH 2) m-NRaRb wherein Ra and Rb or Ra and Rb S (O) 2 R c or S (O) 2RD
• R or R2 represents a radical (CH 2) m-NRaRb wherein Ra and Rb or Ra and Rb S (O) 2 R c or S (O) 2RD
• a compound of formula (V) as defined above by the action of a corresponding alkylsulphonic acid anhydride, in the presence of a base, for example an amine such as triethylamine, in a solvent such as dichloromethane, followed by deprotection of the cyclic nitrogen.
• the compound of formula (III) in which R 1 or R 2 represents a - (CH 2 ) m -NRaRb radical in which one of Ra and Rb represents H and the other represents a radical Rc of 4,5-dihydro- thiazol-2-yl may be prepared starting from a compound of formula (V) as defined above, by the action of thiocarbonylimidazole, to obtain the corresponding thiocyanate which is treated with 2-chloroethyl amine, or its hydrochloride in the presence of a base, for example triethylamine, followed by deprotection of the cyclic nitrogen.
• a base for example triethylamine
• NRaRb in which Ra and Rb together form a radical Rc may be prepared either starting from a compound of formula (VI) as defined above, by the action of a compound H-Rc, H being attached to an atom of of the Rc ring, in the presence of diethylazadicarboxylate and triphenylphosphine, in the THF, or starting from a reactive derivative of the hydroxy of the compound of formula (VI), in particular a mesylate, by the action of the same H-Rc compound, in the presence of sodium hydride in DMF, followed by deprotection of cyclic nitrogen.
• R or R2 represents a radical - (CH 2) m NR a R b wherein m is 0 and Ra and Rb together form a type of Rc radical [1,2,3] - triazol -1-yl may also be prepared starting from a compound of formula (X):
• the compound of formula (III) in which R1 or R2 represents an Rc radical of 1H-tetrazol-5-yl type may also be prepared starting from a reactive derivative of hydroxy of the compound of formula (VII), in particular a mesylate, by the action of tetrabutylammonium cyanide in acetonitrile, to obtain the corresponding cyano derivative, which is treated with sodium azide in the presence of a base, for example an amine such as triethylamine, in a solvent such as toluene, followed by deprotection of the cyclic nitrogen.
• a base for example an amine such as triethylamine
• the compound of formula (III), where appropriate in protected form, in which R1 represents H and R2 and R'2 respectively represent Rd and OH, NH2 or NHRf may be prepared by methods known to those skilled in the art and in particular by the method described by Britton et al., WO0644454, or by Matsumoto et al., US4649144, or by Giordanetto et al., WO0711284, or by Hossain et al, WO04 / 5295.
• R1 represents H and R2 and R'2 respectively represent Rc and OH
• Rc-HaI compound especially butyllithium, in solution in tetrahydrofuran, optionally followed by deprotection of the cyclic nitrogen.
• the compound of formula (III) in protected form at the cyclic nitrogen level, wherein R1 represents CHReRc or CHReRd, Re being OH, may be prepared from the corresponding 2-keto compound by the action of a compound of ester type of formula RcCOOaIk or RdCOOaIk, Rc and Rd being as defined above, in the presence of lithium diisopropylamide in THF, to obtain a compound of formula (XI): in which Rc, Rd, n and P are as defined above, which is reduced by potassium borohydride in methanol, to obtain a compound of formula (XIl):
• n and P are defined as above, which is treated with a compound of Rc-HaI or Rd-HaI type, HaI being in particular a bromine, in the presence of a base such as butyllithium. The compound is then deprotected.
• the compound of formula (III) in protected form in which R1 represents CHReRc or CHReRd, Re being NH2 or NHRf, can be prepared starting from the compound obtained above, whose OH function is activated by the action of methane chloride. sulfonyl en presence of a base, for example triethylamine, in dichloromethane, then treated with sodium azide in DMF, to obtain the compound of formula XV):
• the compound that is reduced by hydrogen in the presence of palladium on carbon in an alkanol.
• the compound is isolated in protected form on cyclic nitrogen. The compound is then deprotected.
• heterocyclic nitrogen and amines is carried out, as the case may be, 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 silyl derivatives such as tertbutyl dimethyl, trimethyl, triphenyl or diphenyl tertbutyl-silyl derivatives.
• Deprotection is carried out, according to the nature of the protecting group, by sodium or lithium in liquid ammonia, by hydrogenolysis or with the aid of soluble complexes of Palladium 0, by action of an acid, or by the action of fluoride.
• tetrabutyl ammonium or strong bases such as sodium hydride or potassium tert butylate.
• the compound of formula (II) is generally known and can be prepared by the processes described in US Patent 4,801,584.
• the compound of formula (II) in which R 3 and / or R ' 3 represents (s) an alkyl radical optionally substituted with 1 to 3 halogens may be prepared starting from a compound of formula (II) in which R 3 and R ' 3 represents a hydrogen, which is treated with a hot alkaline aqueous base and then neutralized, to obtain the compound of formula (XVI):
• R 3 -C-R ' 3 (XVII) wherein R 3 and R ' 3 are defined as above.
• 1 to 3 halogens can be prepared according to a process of the type described in US Pat.
• the compounds of formula (I) may be in the form of enantiomers or mixtures of enantiomers essentially at the level of the 9-position ring.
• the compounds of formula (I) are obtained. is carried out without racemization and therefore obtaining enantiomers is possible by implementing the corresponding enantiomer of the compound of formula (III) or (IV).
• the compounds according to the invention have remarkable antibacterial properties and these properties are manifested with regard to a broad spectrum of Gram (-) bacteria, but also a broad Gram (+) spectrum.
• the compounds are in particular active on Gram (+) bacteria such that
• Streptococcus uberis or Staphylococcus aureus but also Mycoplasma bovis or bovirhinis, or Clostridium perfringens or Enterococcus faecalis, while being remarkably active on Gram (-) bacteria such as Mannheimia haemolytica, Bordetella bronchiseptica,
• Escherichia coli or Pseudomonas aeruginosa Escherichia coli or Pseudomonas aeruginosa.
• the subject of the present invention is therefore also, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above, as well as their salts with pharmaceutically acceptable acids and bases.
• the subject of the invention is more particularly, as medicaments, the products of formula (I) preferred above, in particular from among them the following compounds: 8-fluoro-3-methyl-6-acid -oxo-9- [3- (pyrazin-2-ylaminomethyl) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid, the acid 8-fluoro-3-methyl-6-oxo-9- (3-pyrazin-2-ylamino) -pyrrolidin-1-yl) -2,3-dihydro-6H-1-oxa-3,3-a-diaza phenalene-5-carboxylic acid, 8-fluoro-3-methyl-6-oxo-9- [3
• compositions containing, as active ingredient, at least one of the medicaments according to the invention as defined above.
• These compositions may be administered orally, rectally, parenterally, in particular intramuscularly, by the respiratory route or locally by topical application to the skin and the mucous membranes.
• the 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 especially be in the form of a powder 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 0.25 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.
• HOBt 1-hydroxybenzotriazole
• DBU 1,8-Diaza-bicyclo [5.4.0] -undec-7-ene
• UBE 4 8,9-difluoro-3-methyl-6-oxo-2,3,3a, 6- tetrahydronaphtho- [1,8-de] [1,3] oxazine-5-carboxylic acid
• NMR NMR: The spectra were determined on spectrometers of 300 or 400 MHz type, the proton and carbon spectra being respectively recorded at 300 and 75 MHz or 400 and 100 MHz, in solution in CDCl 3 , or DMSO-d 6 MeOH-cL ". The values are expressed in ⁇ (ppm) and represent s, d, t, quad, dd and m. The constant J AB is expressed in Hz.
• Reactions are performed, unless otherwise indicated, under inert and dry gas and at room temperature.
• the "general method A” (coupling) consists of reacting in a sealed tube the product "UBE-4" (1.0 equivalent) and the aminated derivative suspended in pyridine (0.2M) overnight at 120 ° C. with stirring. The solvent is evaporated and toluene and / or methanol are added. After concentration to dryness, the crude product is triturated in methanol and filtered and dried.
• the "general method B” (Boc deprotection) consists of adding a large excess of TFA to a solution in dichloromethane at 0 ° C of protected amino derivative (N-Boc). The reaction is conducted at room temperature and followed by chromatography on silica. The solution is concentrated to dryness and toluene and / or methanol are added. The crude product is obtained as a trifluoroacetate.
• General method C (peptide coupling) consists of adding 1.2 to 2.0 equivalents of EDCI and 1.2 to 2.0 equivalents of HOBt or DMAP and 1.2 to 2.0 equivalents of heteroaryl carboxylic acid, at 0 ° C, to a 0.2 to 0.6M solution in DMF of amino derivative (piperidine) protected N-Boc or N-CBz. The mixture is stirred at room temperature for 16 to 18 hours, then diluted with ethyl acetate and washed with water. The solution is then dried and concentrated to dryness under reduced pressure and then the residue is purified by chromatography on silica eluting with cyclohexane-ethyl acetate.
• a 900 mg mixture obtained from 3a and 3b is dissolved in 25 ml of dichloromethane and 3 ml of trifluoroacetic acid is added. The mixture is stirred at ambient temperature for 6 hours. The reaction medium is concentrated under reduced pressure and coevaporated with toluene and methanol. The residue is purified by chromatography on silica, eluting with dichloromethane-NH 3 7N methanol (gradient from 5% to 100% NH 3 7N methanol),
• 4a and 4b are separated during chromatographic separation to obtain 4a and 4b in quantitative amounts as a colorless oil.
• Step C 8-Fluoro-3-methyl-6-oxo-9- [3- (pyrazin-2-ylaminomethyl) -pyrrolidin-1-yl-2,3-dihydro-6H-1-oxa-3,3a
• 200 mg of 8,9-difluoro-3-methyl-6-oxoacetate are suspended in a sealed tube.
• Compound 5b is obtained from 180 mg (1.0 eq) of "UBE-4" and 330 mg of compound 4b obtained in Example 1 (1.29 mmol, 2.02 eq) following procedure indicated for the preparation of 5a.
• the mixture is evaporated and then coevaporated with toluene, the product is taken up in ethanol, the mixture is brought to reflux and then filtered to obtain the expected product in the form of a yellow solid (145 mg, 43%).
• Step C 9- (3 - ((D-pyridin-2-yl-amino) -methyl-pyrrolidin-1-yl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic
• tert-butyl ester 6 (1.5 g, 7.19 mmol, 2.2 eq.) In 25 ml of anhydrous THF are added. 2.4 g (8.88 mmol, 1.5 eq.) of triphenylphosphine were added. After dissolution, 4 ml of a solution of diethylazodicarboxylate in toluene (8.98 mmol, 1.5 eq.) And 1.2 g of thiazol-2-yl-carbamic acid, tert- butyl ester 7a (5.99 mmol, 1.0 equiv).
• Step C 8-Fluoro-3-methyl-6-oxo-9-F3- (miazol-2-ylaminomethyl) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3,3a diaza-phenalene-5-carboxylic
• Compound 8b is obtained by following the method described in Preparation 8a by substituting product 7b for product 7a.
• the crude product obtained is purified by chromatography on silica, eluting with a cyclohexane-ethyl acetate mixture (9: 1 to 1: 1) and the product 8b is obtained in the form of a thick oil (1.7 g).
• Stage C Preparation of 9b
• Step D 8-Fluoro-3-methyl-9- ⁇ 3 - [(5-methyl-1, 3,4-oxadiazol-2-ylamino) -methyl-pyrrolidin-1-yl) -6-oxo-2 -acid , 3-dihydro-6H-l-oxa-3,3a-diaza-phenalene-5-carboxylic
• Step C 8-Fluoro-9- (3 - [(furan-2-carbonyl) -aminolmethyl-pyrrolidin-1-yl) -3-methyl-6-oxo-2,3-dihydro-6H-1- oxa-3,3a-diaza-phenalene-5-carboxylic
• Stage C 8-Fluoro-3-methyl-6-oxo-9- ⁇ 3- (pyrazin-2-ylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3,3a diaza-phenalene-5-carboxylic
• Step C 8-Fluoro-3-methyl-9- [3- (5-methyl-3, 41-oxodiazol-2-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H- l-oxa-3,3a-diaza-phenalene-5-carboxylic
• Step C 8-Fluoro-3-methyl-6-oxo-9- [3 - ([1,3,4] thiadiazol-2-ylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-l oxa-3,3a-diaza-phenalene-5-carboxylic
• Example 1 8-Fluoro-3-methyl-6-oxo-9- [3 - ([1, 3,4] thiadiazol-5-ylamino) -pyrrolidin-1-yl) -2,3-dihydro- 6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (26d)
• Stage C 8-Fluoro-3-methyl-6-oxo-9- [3 - ([K 3, 4-thiadiazol-5-ylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic
• Step D 9- ⁇ 3- (4,5-dimethyl-thiazol-2-ylamino) -pyrrolidin-1-yl ⁇ -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (27d)
• Step C 8-Fluoro-3-methyl-9- [3- (4-methyl-thiazol-2-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic acid (28d)
• the method described in the preparation of 5c is used substituting product 28c for product 4c (1.0 g, 5.46 mmol, 4.0 eq.) .
• the product is evaporated under reduced pressure and the residue is triturated in ether and then filtered and dried.
• An analytical sample is obtained by chromatography on silica, eluting with the dichloromethane-methanol mixture (gradient of 2.5% to 5% of methanol) and the expected product is obtained in the form of a yellow solid (100 mg, 33%) .
• Step D 8-Fluoro-3-methyl-9- [3- (5-methyl-thiazol-2-ylamino) -pyrrolidin-1-yl ] -6-oxo-2,3-dihydro-6H-1-acid -oxa-3,3a-diaza-phenalene-5-carboxylic acid (29d)
• Stage C 8-Fluoro-3-methyl-9- [3- (3-methyl-isothiazol-5-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1-oxa-3 3a-diaza-phenalene-5-carbox yl (3 Od)
• Example 16 8-Fluoro-3-methyl-9- [3- (3-methyl-isoxazol-5-ylamino) -pynolinidine-1-yl] -
• Step C 8-Fluoro-3-methyl-9- [3- (3-methyl-isoxazol-5-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1- oxa-3,3a-diaza-phenalene-5-carboxylic acid
• the method described in the preparation of the product 5c is used, substituting the product
• Stage C 8-Fluoro-3-methyl-9- [3- (5-methyl-isoxazol-3-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1- oxa-3.3a-diaza-phenalene-5-carboxylic
• Step C Acid 8-fluoro-3-methyl-6-oxo-9-i ⁇ SV3- (thiazol-2-yl-ylaminoVpwolidine "
• the process of making 10b is used by substituting product 35a for product 9a (780 mg, 4.61 mmol, 3.0 eq.).
• the reaction medium is concentrated to dryness under reduced pressure.
• the residue is triturated with methanol and then filtered. 462 mg of crude product is obtained.
• An analytical sample is obtained by chromatography on silica, eluting with the mixture dichloromethane-methanol (gradient from 2.5% to 5% methanol).
• the expected product is obtained in the form of a yellow solid (30 mg, 17%).
• Step C 8-Fluoro-3-methyl-6-oxo-9-fluoro-3-ylazol-2-ylamino) -pyrrolidin-1-yl) 2,3-dihydro-6H-1-oxa-3, 3-diaza-diaza phenalene-5-carboxylic
• Example 20 9- [3- (4,5-Dihydro-thiazol-2-ylamino) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-acid -oxa-3,3a-diaza-phenylene-5-carboxylic acid (40)
• Stage D 9- [3- (4,5-Dihydro-thiazol-2-ylamino) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-23-dihydro-6H-1-oxa acid -3,3a-diaza-phenalene-5-carboxylic
• Example 21 8-Fluoro-3-methyl-6-oxo-9- [3- (R, 2,4-triazolo-1-yl) -pyrrolidin-2,3-dihydro-6H-1-oxa-3 3 ⁇ -diaza-phenylene-5-carboxylic acid and 8-fluoro-3-methyl-6-oxo-9- [3- [1,3,4] triazolo-1-yl) pyrrolidine-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic acid (44a-44b)
• Step C 8-Fluoro-3-methyl-6-oxo-9- [3- (1H-2,4-triazol-1-yl) -pyrrolidinyl-2,3-dihydro-6H-1-oxa-3,3a-diaza) phenalene-5-carboxylic acid and 8-fluoro-3-methyl-6-oxo-9- [3- [1, 3,4] triazol-1-yl) pyrrolidine-2,3-dihydro-6H-1 oxa-3,3a-diaza-phenalene-5-carboxylic
• the expected products are prepared using the process of the preparation of 5a by substituting the product mixture 43a-43b for product 4a (555 mg, 4.02 mmol, 2.8 eq.). The precipitate is filtered and washed with water. The residue is triturated in hot methanol and after filtration the expected product is obtained in the form of a yellow solid (371 mg, 65%).
• EXAMPLE 22 8-Fluoro-3-methyl-6-oxo-9- [3- (1H-triazolo-1-yl) -pyrrolidine] -2,3-dihydro-6H-1-oxa-3,3a diaza-phenalene-5-carboxylic acid and 8-fluoro-3-methyl-6-oxo-9- [3- (1,2,5) triazolo-1-yl) pyrrolidine-2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (49a-49b)
• Step C 8-Fluoro-3-methyl-6-oxo-9-r3-f ⁇ .2.31-triazolo-1-yl) -pyrrolidine] -2,3-dihydro-6H-1-oxa-3.3 ⁇ diaza-phenalene-5-carboxylic acid and 8-fluoro-3-methyl-6-oxo-9- [3-
• Stage C 8-Fluoro-3-methyl-6-oxo-9-r3-f ⁇ , 2.31-triazol-1-yn-pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3, 3a-diaza-phenalene-5-carboxylic acid
• Example 24 8-Fluoro-3-methyl-6-oxo-9- [3- (1H-tetrazol-5-yl) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa 3,3a-diaza-phenalene-5-carboxylic acid (54)
• Stage D 8-Fluoro-3-methyl-6-oxo-9-r-1H-tetrazol-5-yl) pyrrolidin-1-yl-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene 5-carboxylic acid
• product 53 for product 4c (780 mg, 5.61 mmol, 4.0 eq).
• the reaction medium is poured into ethanol and the precipitate is filtered.
• the residue is triturated in water and then filtered, then in methanol and finally in dichloromethane and the expected product is obtained in the form of a yellow solid (60 mg, 11%).
• Step C 8-Fluoro-3-methyl-6-oxo-9- [3- (3H-trifluoropropionylamino) -pyrrolidin-1-yl] -DH-dihydro-4H-1-oxa-5H-diaza-phenalene S-Carboxylic
• the method for the preparation of 5a is used, substituting the product 56c for the product
• Stage C 8-Fluoro-3-methyl-6-oxo-9- [3- (2,2,2-trifluoroacetylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic
• Example 28 8-Fluoro-3-methyl-6-oxo-9-r (S) -3- (2,2,2-trifluoroacetylamino) pyrrolidin-1-yl-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic acid (57e)
• Example 30 8-Fluoro-3-methyl-6-oxo-9- (S) -3- (trifluoromethanesulfonylamino) pyrrolidine-1-yn-2,3-dihydro-6H-1-oxa-3,3a -diaza-phenalene-5-carboxylic acid (60a)
• the crude product obtained is purified by chromatography on silica, eluting with a cyclohexane-ethyl acetate mixture (9: 1 to 6: 4) and the expected product 58a is obtained in the form of a yellow oil (1.1 g, 42%).
• the expected product 59a is obtained as a trifluoroacetic acid salt as a yellow oil (1.0 g, 87%).
• Stage C 8-Fluoro-3-methyl-6-oxo-9 - [(S) -3- (trifluoromethanesulfonylamino) pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3 3a-diaza-phenalene-5-carboxylic
• Example 32 8-Fluoro-9 - [(R, S) -4-hydroxy-3,3-dimethyl-pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (75a)
• Step C 9-f (RS) -4-hydroxy-3,3-dimethyl-pyrrolidin-1-yl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a diaza-phenalene-5-carboxylic
• Example 33 9 - ((R, S) -4-amino-3,3-dimethyl-pyrrolidin-1-yl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (75b)
• Step B 9 - ((R) -Si-4-amino-33-dimethyl-pmolidin-1-yl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3, 3-en diaza-phenalene-5-carboxylic acid
• the product 75b is obtained from "UBE-4" (304 mg, 1.07 mmol, 1.0 eq.), 74b (370 mg).
• Example 35 9 - ((R) -4-amino-3,3-dimethyl-pyrrolidin-1-yl ' ) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1 acid -oxa-3,3a-diaza-phenalene-5-carboxylic acid (75d)
• the method described for the preparation of 5a is used to obtain the product 75d from 140 mg of "UBE-4" (0.50 mmol, 1.0 eq.), 200 mg of (R) -4-amino -3,3-dimethylpyrrolidine (1.33 mmol, 2.7 eq.) In 5 ml of pyridine and 0.20 ml of N-methylmorpholine (0.91 mmol, 3.6 equiv). The medium is evaporated and the residue is triturated in boiling methanol and filtered and dried and 60 mg of the product obtained is obtained in the form of a yellow solid (31%).
• Example 36 8-Fluoro-9- (3-hydroxy-3-thiazol-2-yl-pyrrolidin-1-yl) -3-methyl-6-oxo-2,3-dihydro-6H-1-oxa 3,3a-diaza-phenalene-5-carboxylic acid (82)
• product 82 is obtained from 475 mg of "UBE-4" (1.68 mmol, 1.0 eq.), 1.4 g of trifluoroacetate acid salt 81 (5.05 mmol,
• Product 84 is prepared according to the process described in WO 2005/026514 by substituting 1-benzyl-2-pyrrolidinone for 1- (1R-phenyl-ethyl) -pyrrolidin-2-one (7.0 g, 39.95 mmol). , 1.0 eq.). The product 84 is obtained in the form of a brown oil (8.15 g, 84%). Stage B: Preparation of 85
• Step E 8-Fluoro-9- [3- (1-hydroxy-2,2,2-trifluoroethyl) pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic acid (88)
• product 88 is obtained from 300 mg of "UBE-4" (1.06 mmol, 1.0 eq.) And 707 mg of product 87 as hydrochloride ( 3.44 mmol, 3.2 eq.) In 10 ml of pyridine and 0.80 ml of triethylamine (5.73 mmol, 5.4 eq.). The reaction medium is concentrated to dryness under reduced pressure and the residue is purified by chromatography on silica eluting with the mixture of dichloromethane-methanol 5% and the expected product is obtained in the form of a yellow solid (19 mg, 7%).
• the product 89 was prepared according to the process described in WO 2005/026154 by substituting 3-hydromethyl-pyrrolidine-1-carboxylic acid, tert-butyl ester for benzyloxycarbonylpyrrolidin-3-yl-methanol (3.4 g, 17.06 mmol, 1 eq). The product 89 is obtained in the form of a yellow oil (2.15 g, 82%). Stage B: Preparation of 90
• Product 90 was prepared according to the method described in WO 2005/026154 by substituting 89 for benzyloxycarbonyl-pyrrolidine-3-thiazol-2-yl-methanol (2.15 g, 10.79 mmol, 1.0 eq. The product 89 was obtained as a yellow oil (2.39 g, 78%). Stage C: Preparation of 91
• Step D acid 8-fluoro-9- [3- (hydroxy-thiazol-2-yl-methyl *) -pyrrolidin-l-yl] -3-methyl-6-oxo-23-dihydro-6H-l-oxa -3,3a-diaza-phenalene-5-carboxylic acid (92)
• Product 94 was prepared according to the method described in EP 1 182202 by substituting 93 for 4- (R) - [1-azido-1- (thiazol-2-yl) methyl] -1- [1 - (R) ) -phenylethyl] -2-pyrrolidinone (1.5 g, 4.84 mmol, 1.0 eq.).
• the expected product 94 is obtained as a colorless oil (1.3 g, 70%).
• HPLC gradient 5% to 95% ACN in H 2 O:> 99%
• Product 95 was prepared according to the process described in EP 1 182 202 by substituting product 94 for 3- (R) - [1-tert-butoxycarbonylamino-1- (thiazol-2-yl) methyl] -1-benzyloxycarbonyl. pyrrolidine (1.3 g, 3.39 mmol, 1.0 eq.). The product 95 is obtained in the form of di-trifluoroacetate in the form of an oil (1.35 g, 100%). HPLC (gradient 5% to 95% ACN in H 2 O):> 99% MS (ESI +) (+ 0.1%, HCOOH): 184.1 [C 8 H, 3 N 3 S + H] + (m / z).
• Stage D 9- [3- (Amino-thiazol-2-yl-methyl-pyrrolidin-1-yl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3,3a-diaza-phenalene-5-carboxylic acid (96)
• product 96 is obtained from 80 mg of "UBE-4" (0.28 mmol, 1.0 eq.) And 200 mg of product 90 (0.49. mmol, 1.7 eq.) in 5 ml of pyridine and 1.3 ml of triethylamine.
• the reaction medium is evaporated under reduced pressure and the residue is purified by chromatography on silica eluting with 5% dichloromethane-methanol and the expected product is obtained in the form of a yellow product (34 mg, 27%).
• Example 40 9- (3 - [(Z / E) -methoxyimino "] -pyrrolidine-1-yl-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6-Hl-oxa 3,3a-diaza-phenalene-5-carboxylic acid (105)
• Step C 8-Fluoro-9- ⁇ 3 - [(Z / E) -methoxyimino] -pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6-H-oxa 3,3a-diaza-phenalene-5-carboxylic acid (105)
• the "general method B” is used substituting 4N hydrochloric acid in dioxane for trifluoroacetic acid to deprotect 1.14 g of product a (5.03 mmol, 1.0 eq).
• the product is purified by chromatography on silica eluting with a mixture of dichloromethane NH 3 7N in methanol (gradient of 5 to 20% of NH 3 7N in methanol) and the expected product 107a (900 mg, X%) is obtained.
• Step C Acid 8-fluoro-3-methyl-6-oxo-9- [4- (pyrazin-2-yl-ylaminoVpi réelledine '
• UBE-4" (355 mg, 1.26 mmol, 1.0 eq.) is coupled with 900 mg of product 107a (5.05 mmol, 4 mmol). 0 eq.) And 0.28 ml of N-methylmorpholine (2.0 eq.)
• the residue is triturated in hot methanol and the expected product is obtained as a beige solid (67 mg, 12%) .
• Example 42 8-Fluoro-3-methyl-6-oxo-9- [4- (pyrazin-2-ylamino) -piperidin-1-yl] -2,3-dihydro-6H-1-oxa-3,3a -diaza-phenalene-5-carboxylic acid (108b)
• Step C 8-Fluoro-3-methyl-6-oxo-9- [4- (pwazin-2-ylamino) -piperidin-1-yl] -2,3-dihydro-6H-1-oxa-3,3a -diaza-phenalene-5-carboxylic acid (108b)
• reaction medium is concentrated to dryness under reduced pressure, and the neutral residue is purified by chromatography on silica, eluting with the cyclohexane-ethyl acetate mixture (95: 5 to 85:15) and the product 109 is obtained in the form of dichloromethane. a colorless gum (1.95 g, 85%).
• Stage B Preparation of 113 The procedure is carried out according to the "general method B", to deprotect 5.1 g of the product 112 (17.32 mmol, 1.0 eq.). The residue is purified by chromatography on silica eluting with 10% dichloromethane-methanol and then dichloromethane-NH 3 7N in methanol.
• the product 113 is obtained as a white foam (3.0 g, 89%).
• Stage C 8-Fluoro-9- (4-yl) -2-carbonylaminol-piperidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a diaza-phenalene-5-carboxylic acid (114)
• Example 48 3-Methyl-6-oxo-9 - [(R) -3- (thiazol-2-ylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa-3, 3a-diaza-phenalene-5-carboxylic acid (1 18)
• the product 118 is obtained from the product 8-des-fluoro-9-fluoro corresponding (prepared according to the process described in US-4 801 584) (100 mg, 0.038 mmol, 1, 0 eq.); and 35b (480 mg, 1.21 mmol, 3.2 eq) in 2.5 ml anhydrous pyridine and 0.2 ml N-methylmorpholine (1.82 mmol, 4.8 eq).
• the reaction mixture is evaporated under reduced pressure and the residue is taken up in boiling methanol and purified by chromatography on silica.
• the expected product is obtained in the form of a yellow solid (20 mg, 13%).
• product X is obtained from the corresponding 8-fluoro-9-fluoro product (prepared according to the process described in US Pat. No. 4,801,584) (80 mg, 0.30 mmol, 1.0 eq.) And 56e product (200 mg, 1.33 mmol, 4.4 eq.) In 3 ml of anhydrous pyridine and 0.3 ml of N-methylmorpholine (2.73 mmol, 9.0 equiv. .). The reaction mixture is evaporated under reduced pressure and the residue is triturated in methanol and purified by preparative TLC. The expected product is obtained in the form of a yellow solid (11 mg, 12%).
• Example 50 acid 8-fluoro-2-methyl-3-methyl-6-oxo-9-r (S) -3- (2 ⁇ 2,2-trifluoro-acetylamino) - Pyrrolidine-l-yll-2,3 -dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (121)
• Step C 8-Fluoro-2-methyl-3-methyl-6-oxo-9-rrS) -3- (2,2,2-trifluoroacetylamino) pyrrolidin-1-yl] -2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenalene-5-carboxylic
• the desired product is obtained from 100 mg of product 120 (0.34 mmol, 1.0 eq.) And the product 56e (300 mg, 1.01 mmol, 3.0 eq) in 2 ml anhydrous pyridine and 0.2 ml N-methylmorpholine (1.82 mmol, 5.0 eq).
• the reaction mixture is evaporated under reduced pressure and the residue is taken up in methanol.
• the mixture is filtered and dried and the expected product is obtained in the form of a yellow solid (54 mg, 35%).
• Example 51 8-Fluoro-2,2-dimethyl-3-methyl-6-oxo-9-r (SV3- (2,2,2-trifluoroacetylamino) pyrrolidin-1-yl] -2,3- dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (123)
• product 122 is obtained from 500 mg of product 119 (1.85 mmol, 1.0 eq) and 6.2 ml of anhydrous acetone (89 mmol) in 20 ml of anhydrous dioxane.
• the reaction medium is evaporated under reduced pressure.
• the residue is triturated in boiling methanol, filtered and dried.
• the expected product is obtained in the form of a white solid (610 mg, 100%).
• Step B 8-Fluoro-2,2-dimethyl-3-methyl-6-oxo-9-r (SV3-f2.2.2-trifluoroacetylamino) pyrrolidin-1-yl] -2,3-dihydro-6H -l-oxa-3,3a-diaza-phenalene-5-carboxylic
• the desired product is obtained from 100 mg of product 122 (0.32 mmol, 1.0 eq.) And the product 56e (280 mg, 0.96 mmol, 3.0 eq) in 2 ml anhydrous pyridine and 0.2 ml N-methylmorpholine (1.82 mmol, 5.0 eq).
• the reaction mixture is evaporated under reduced pressure and the residue is purified by chromatography on silica and then triturated in ethyl ether.
• the expected product is obtained in the form of a yellow solid (35 mg, 23%).
• Example 52 2-Methyl-3-methyl-6-oxo-9-yl) -3- (2,2,2-trifluoroacetylamino) pyrrolidine-1-yl-2,3-dihydro-6H-1-yl oxa-3,3a-diaza-phenalene-5-carboxylic acid (126)
• the desired product is obtained from 400 mg of product 124 (1.43 mmol, 1.0 eq) and 12.0 ml of acetaldehyde (214 mmol) in 30 ml. ml of anhydrous dioxane.
• the reaction medium is evaporated under reduced pressure.
• the residue is triturated in boiling methanol, filtered and dried.
• the expected product is obtained in the form of a brown solid (305 mg, 77%).
• product 126 is obtained from 100 mg of product 125 (0.36 mmol, 1.0 eq.) And product 56e (210 mg, 1.95 mmol, 2.9). eq) in 2 ml anhydrous pyridine and 0.2 ml N-methylmorpholine (1.82 mmol, 5.0 eq). The mixture The reaction mixture is evaporated under reduced pressure and the residue is triturated in ethyl ether and then purified by chromatography on silica. The expected product is obtained in the form of a yellow solid (21 mg, 13%).
• product 127 is obtained from 400 mg of product 124 (1.43 mmol, 1.0 eq) and from 4 ml of anhydrous acetone (57.3 mmol) in 30 ml of anhydrous dioxane.
• the reaction medium is evaporated under reduced pressure.
• the residue is triturated in boiling methanol, filtered and dried.
• the expected product is obtained in the form of a brown solid (338 mg, 70%).
• HPLC gradient 5% to 95% ACN in H 2 O:> 99%
• Step B 2,2-dimethyl-3-methyl-6-oxo-9-r (S) -3- (2,2,2-trifluoroacetylamino) pyrrolidin-1-yl] -2,3-dihydro-6H- l-oxa-3,3a-diaza-phenalene-5-carboxylic
• product 128 is obtained from 1.1 mg of product 127 (0.38 mmol, 1.0 eq.) And product 56e (340 mg, 1.15 mmol, 0 eq) in 2 ml of anhydrous pyridine and 0.2 ml of N-methylmorpholine (1.82 mmol, 5.0 eq.).
• the reaction mixture is evaporated under reduced pressure and the residue is triturated in methanol and then purified by chromatography on silica.
• the expected product is obtained in the form of a yellow solid (20 mg, 12%).
• product 129 is obtained from product 120 (300 mg, 1.01 mmol, 1.0 eq.); and 35b (620 mg, 3.03 mmol, 3.0 eq) in 6 ml of anhydrous pyridine and 0.6 ml of N-methylmorpholine (5.05mmol, 5.0 eq).
• the reaction mixture is evaporated off under reduced pressure and the residue is purified by chromatography on silica eluting with a dichloromethane / methanol mixture (gradient of 0 to 5% of methanol).
• the expected product is obtained in the form of a yellow solid (50 mg, 15%).
• product 130 is obtained from 200 mg of product 112 (0.64 mmol, 1.0 eq.) And product 35b (770 mg, 1.93 mmol, 3.0 eq.) in 4 ml anhydrous pyridine and 0.35 ml N-methylmorpholine (3.20 mmol, 5.0 eq).
• the reaction mixture is evaporated off under reduced pressure and the residue is purified by chromatography on silica and then by preparative TLC.
• the expected product is obtained in the form of a yellow solid (8 mg, 3%).
• product 131 is obtained from 190 mg of product 125 (0.36 mmol, 1.0 eq) and product 35b (860 mg, 2.16 mmol, 3.2). eq.) in 5 ml of anhydrous pyridine and 0.5 ml of N-methylmorpholine (4.55 mmol, 6.7 eq.). The reaction mixture is evaporated under reduced pressure and the residue is triturated in ethyl ether and then purified by chromatography on silica eluting with dichloromethane-methanol (100: 0 to 96: 4) and the expected product is obtained in the form of a yellow solid (20 mg, 7%).
• Example 57 acid 2,2,3-trimethyl-6-oxo-9 - [(R) -3- (thiazol-2-ylamino ') -pyrrolidin-l-yl-2,3-dihydro-6H-l - oxa-3,3a-diaza-phenalene-5-carboxylic acid (132)
• product 132 is obtained from 200 mg of product 127 (0.68 mmol, 1.0 eq.) And product 35b (870 mg, 2.19 mmol, 3.2 eq.) in 5 ml of anhydrous pyridine and 0.5 ml of N-methylmorpholine (4.55 mmol, 6.7 eq.).
• the reaction mixture is evaporated under reduced pressure and the residue is triturated in methanol and then purified by preparative TLC.
• the expected product is obtained in the form of a yellow solid (21 mg, 7%).
• product 133 is obtained from 2.0 g of product 19 (7.40 mmol, 1.0 eq.), 6.6 mL of ethyl diethoxyacetate ( 89 mmol) and 0.5 ml of trifluoroacetic acid (6.70 mmol, 0.9 eq) in 80 ml of anhydrous dioxane.
• the expected product is obtained as a white solid (2.0 g, 76%).
• HPLC gradient 5% to 95% ACN in H 2 O:> 85%
• Step B 2,2,3-trimethyl-6-oxo-9 - [(R) -3- (thia-2-ylamino) -pyrrolidin-1-yl] -2,3-dihydro-6H-1-oxa acid -3,3a-diaza-phenalene-5-carboxylic acid
• product 134 is obtained from 300 mg of product 133 (0.84 mmol, 1.0 eq.) And product 35b (720 mg, 2.42 mmol, 3.0 eq.) in 6 ml of anhydrous pyridine and 0.45 ml of N-methylmorpholine (4.20 mmol, 5.0 eq).
• the reaction mixture is evaporated under reduced pressure and the residue is triturated in methanol and then purified by preparative TLC.
• the expected product is obtained in the form of a yellow solid (13 mg, 3%).
• HPLC gradient 5% to 95% ACN in H 2 O:> 95%
• product 135 is obtained from product 120 (230 mg, 0.78 mmol, 1.0 eq.) And product 74b (200 mg, 1.33 mmol, 1.7 g. eq.) in 1 ml of anhydrous pyridine and 2 ml of anhydrous acetonitrile in the presence of DABCO (250 mg, 2.23 mmol, 2.9 eq.) -
• the reaction medium is filtered and the precipitate washed with acetonitrile .
• the solid obtained is triturated in methanol and washed with methanol and then with ethyl ether.
• the expected product is obtained in the form of a yellow solid (105 mg, 34%).
• Example 60 9 - ((R) -4-amino-3,3-dimethyl-pyrrolidin-1-yl) -8-fluoro-2,2,3-trimethyl-6-oxo-2,3-dihydrogen 6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (136)
• product 136 is obtained from 220 mg of product 112 (0.71 mmol, 1.0 eq.) And product 74b (200 mg, 1.33 mmol, 1.9 g. eq.) in 4 ml of anhydrous pyridine and 2 ml of anhydrous acetonitrile in the presence of DABCO (250 mg, 2.23 mmol, 3.1 eq.).
• DABCO 250 mg, 2.23 mmol, 3.1 eq.
• the reaction medium is filtered and the precipitate washed with acetonitrile.
• the solid obtained is triturated in methanol and washed with methanol and then with ethyl ether.
• the expected product is obtained in the form of a yellow solid (110 mg, 38%).
• Example 61 9 - [(S) -3,3-Dimethyl-4- (thia-2-yl-2-ylamino) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-acid Dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (141)
• the compound 138 is obtained by following the method described in the preparation of the product 8a by substituting the product 137 for the product 6.
• the crude product obtained is purified by chromatography on silica eluting with the dichloromethane-methanol mixture (10: 0 to 9: 1 ) and obtained the product 138 as a brown foam (385mg, 25%).
• Stage C Preparation of 139
• the crude expected product is obtained which is purified by chromatography on silica eluting with dichloromethane-methanol (10: 0 to 9: 1) followed by an SCX column and the expected product 140 is obtained in the form of a brown oil ( 85 mg, 61%).
• Step E 9-r (SV3.3-dimethyl-4- (thiazol-2-ylamino) -pyrrolidin-1-yl-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-acid 3.3a-oxa-diaza-phenalene-5-carboxylic
• product 141 is obtained from 65 mg of "UBE-4" (0.23 mmol, 1.0 eq.) And 140 (80 mg, 0.41 mmol). 2.0 eq.) In 0.5 ml anhydrous pyridine and 1 mM acetonitrile in the presence of DABCO (50 mg, 0.45 mmol, 2.0 eq.). The reaction medium is filtered and the precipitate washed with acetonitrile. The solid obtained is triturated in methanol and washed with methanol and then with ethyl ether. The expected product is obtained in the form of a yellow solid (23 mg, 22%).
• Example 62 acid 9 - [(R) -3,3-dimethyl-4- (thiazol-2-ylamino ') -pyrrolidin-l-yl] -8-fluoro-3-methyl-6-oxo-23-dihydro 6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid (146)
• the compound 143 is obtained by following the method described in the preparation of 8a by substituting the product 142 for the product 6.
• the crude product obtained is purified by chromatography. on silica, eluting with dichloromethane-methanol (10: 0 to 93: 7) and obtaining 143 as a yellow oil (865 mg, 22%).
• Stage C Preparation of 144
• product 144 is obtained from 143 (860 mg, 1.13 mmol, 1.0 eq.).
• the crude expected product is obtained which is purified by chromatography on silica eluting with cyclohexane-ethyl acetate (10: 0 to 9: 1) and the expected product 144 is obtained in the form of a colorless oil (445 mg, 91%).
• Stage D Preparation of 145
• product 145 is obtained from 144
• the crude expected product is obtained which is purified by chromatography on silica eluting with dichloromethane-methanol (10: 0 to 9: 1) followed by an SCX column and the expected product 140 is obtained in the form of a colorless oil.
• Step E 9 - [(R) -3,3-dimethyl-4 - ((thiazol-2-ylamino) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3- Dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid Using the process for preparing 5a, product 146 is obtained from
• Step C ⁇ -Fluoro-S-methyl- ⁇ -oxo-g- (R) -sulfon-1-triazol-1-yl-pyrrolidin-1-yl) dihydro-6H-1-oxa-3,3a-diaza -phénalène-5-carboxylic acid
• Step C 8-Fluoro-3-methyl-9 - [(R ' ) -3- (3-methyl-isoxazol-5-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydrogen 6H-l-oxa-3,3a-diaza-phenalene-5-carboxylic
• 155 is obtained from 50 mg of "UBE-4" (0.18 mmol, 1.0 eq.) And 154 (50 mg, 0.30 mmol). 1.7 eq.) In 0.5 ml of anhydrous pyridine and 1 ml of anhydrous acetonitrile in the presence of DABCO (50 mg, 0.45 mmol, 2.5 eq.). The reaction medium is evaporated and the solid obtained is triturated in methanol and washed with methanol and then with ethyl ether. The expected product is obtained in the form of a yellow solid (53 mg, 68%). HPLC (gradient 5% to 95% ACN in H 2 O):> 95%
• Example 66 8-Fluoro-3-methyl-9 - [(3S- (3-methylisoxazol-5-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1-oxa 3,3a-diaza-phenalene-5-carboxylic acid (158)
• Step C 8-Fluoro-3-methyl-9 - [(S) -3- (3-methyl-isoxazol-5-yl) amino] pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1 -oxa-3,3a-diaza-phenalene-5-carboxylic acid
• product 158 is obtained from 150 mg of "UBE-4" (0.53 mmol, 1.0 eq.
• product 160 is obtained from 159 (11.2 g, 37.84 mmol, 1.0 eq.).
• the crude expected product is obtained which is purified by chromatography on silica eluting with cyclohexane-ethyl acetate (10: 0 to 4: 6) and the expected product 160 is obtained in the form of a yellow solid (3.7). g, 35%).
• Stage C Preparation of 161
• Step E 8-Fluoro-9 - [(3S- (1H-imidazol-2-ylamino) -pyrrolidin-1-yl) -3-methyl-6-oxo-2,3-dihydro-6H-1-oxa 3,3a-diaza-phenalene-5-carboxylic
• product 163 is obtained from 100 mg of "UBE-4" (0.35 mmol, 1.0 eq.) And product 162 (305 mg, 0.62 mmol). 1.8 eq.) In 1 ml anhydrous pyridine and 2 ml anhydrous acetonitrile in the presence of DABCO (80 mg, 0.71 mmol, 2.0 eq.). The reaction medium is co-evaporated with methanol. The residue obtained is purified on an SCX column and the solid obtained is then triturated in hot methanol and filtered. The expected product is obtained in the form of a yellow solid (24 mg, 16%).
• Example 68 8-Fluoro-9- (R) -3- (1H-imidazol-2-ylamino) -pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H- 1-oxa-3,3a-diaza-phenal-ene-5-carboxylic
• Step C 8-Fluoro-9 - [(R ' ) - 3 - (1H-imidazol-2-ylamino) -pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H -l-oxa-3,3a-diaza-phenalene-5-carboxylic
• product 166 is obtained from 140 mg of "UBE-4" (0.50 mmol, 1.0 eq.) And 165 (460 mg, 0.93 mmol). 1.9 equiv) in 1.5 ml anhydrous pyridine and 3 ml anhydrous acetonitrile in the presence of DABCO (110 mg, 0.98 mmol, 2.0 eq.). The reaction medium is co-evaporated with methanol. The residue obtained is purified on an SCX column and then on a Sephadex® LH-20 column. The solid obtained is triturated in water, methanol and then ethyl ether. The expected product is obtained in the form of a yellow solid (44 mg, 21%).
• Step D 8-Fluoro-3-methyl-9 - [(R) -3- (methyl-thiazol-2-yl-amino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H -l-oxa-3,3a-diaza-phenalene-5-carboxylic
• product 170 is obtained from 100 mg of "UBE-4" (0.35 mmol, 1.0 eq.) And 169 (130 mg, 0.71 mmol). 2.0 eq.) In 0.5 ml anhydrous pyridine and 1 ml anhydrous acetonitrile in the presence of DABCO (120 mg, 1.07 mmol, 3.0 eq.). The reaction medium is co-evaporated with methanol. The solid obtained is triturated in methanol and ethyl ether. The expected product is obtained in the form of a yellow solid (137 mg, 88%).
• Example 70 9 - [(R) -3- (acetyl-thiazol-2-yl-amino) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydrogen 6H-l-oxa-3,3a-diaza-phenalene-5-carboxylic
• Example 71 8-Fluoro-3-methyl-9- [3-amino-4- (thiazol-2-ylamino) -pyrrolidin-1-yl) -6-oxo-2,3-dihydro-6H-1-oxa-3 3 ⁇ -diaza-phenalene-5-carboxylic acid (177)
• Step G 8-fluoro-3-methyl-9- [3-amino-4- (thiazol-2-ylamino) -pyrrolidin-1-yl] -6-oxo-2,3-dihydro-6H-1- oxa-3,3a-diaza-phenalene-5-carboxylic
• product 177 is obtained from 52 mg of "UBE-4" (0.18 mmol, 1.0 eq.)
• product 176 62 mg, 0.36 mmol). 2.0 eq.
• DABCO 101 mg, 0.91 mmol, 2.5 eq.
• the reaction medium is co-evaporated with methanol.
• the solid obtained is triturated in methanol and then purified by preparative TLC.
• the expected product is obtained in the form of a yellow solid (19 mg, 22%).
• Example 72 8-Fluoro-9 - [(R) -3- (1H-imidazol-2-ylamino) -pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H-l -oxa-3,3a-diaza-phenalene-5-carboxylic acid (182)
• Step E acid 8-fluoro-9-r (R) -3- (lH-imidazol-2-ylamino>) -pyrrolidin-l-yll-3-methyl-6-oxo-23-dihydro-6H-l- oxa-3,3a-diaza-phenalene-5-carboxylic
• Step E 8-fluoro-9 - [(S) -3- (1H-imidazol-2-ylamino) -pyrrolidin-1-yl] -3-methyl-6-oxo-2,3-dihydro-6H-1 oxa-3,3a-diaza-phenalene-5-carboxylic
• product 187 is obtained from 100 mg of "UBE-4" (0.35 mmol, 1.0 eq.) And product 186 (150 mg, 0.91 mmol). , 2.6 eq.) In 0.5 ml of anhydrous pyridine and 1.5 ml of anhydrous acetonitrile in the presence of DABCO (100 mg, 0.89 mmol, 2.5 eq.). The precipitate obtained is filtered and then washed with acetonitrile and ethyl ether. The expected product is obtained in the form of a yellow solid (120 mg, 80%). HPLC (gradient 5% to 95% ACN in H 2 O):> 99%
• Lithium hydroxide (227 mg, 5.40 mmol, 5.0 eq) is added to a solution of product 195 (370 mg, 1.08 mmol, 1.0 eq.) In a water / THF mixture. (4ml / 4ml). The reaction medium is stirred at room temperature for 7 hours. The precipitate formed is filtered, washed with ethyl ether and then dried under vacuum The expected product is obtained in the form of a white solid (286 mg, 84%).
• Step I 8-fluoro-3- (2-fluoro-ethyl) -6-oxo-9 - [(R) -3- (thiazol-2-ylamino) -pyrrolidin-1-yl] 2,3-dihydro-6H -l-oxa-3,3a-diaza-phenaIene-5-carboxylic
• product 196 is obtained from 100 mg of product 195 (0.32 mmol, 1.0 eq.) And product 35b (108 mg, 0.64 mmol, 2.0 g. eq.) in 0.8 ml anhydrous pyridine and 1.5 ml anhydrous acetonitrile in the presence of DABCO (72 mg, 0.64 mmol, 2.0 eq).
• the reaction medium is evaporated under reduced pressure.
• the result is triturated in methanol and then purified by preparative TLC.
• the expected product is obtained in the form of a yellow solid (18 mg, 12%).
• MIC minimum inhibitory concentrations
• This comparative study with a reference fluoroquinolone measures the minimum inhibitory concentrations on the main reference and field bacteria, isolated from human and animal pathologies (canines, felines, cattle or pigs). These bacteria represent different populations of resistance to fluoroquinolones for each bacterial species selected and come from the private collection of Vétoquinol S.A. or M. haemolytica ATCC references (2); B. bronchiseptica; P. aeruginosa (2); E. coli (3); S. aureus (3); S. uberis; M. bovis and bovirhinis; C. perfringens. at. CHOICE OF STRAINS
• the strains tested were:
• the MICs are determined by microdilution in a liquid medium.
• the method used for aerobic and anaerobic bacteria refers to the CLSI (NCCLS) guideline M31-A (May 2002) "Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals".
• the method used for mycoplasmas refers to the CLSI (NCCLS) guideline M31-A (May 2002) and the article by F. Poumarat and J. L. Martel.
• the concentrations to be tested with respect to the strains are:
• Man hae Mannheimia haemolytica
• Bor bron Bordetella bronchiseptica
• E. coli Escherichia coli
• Str ube Streptococcus uberis
• Sta aur Staphylococcus aureus
• Myc bov Mycoplasma bovis

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