EP1173455A2 - Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments - Google Patents

Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments

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Publication number
EP1173455A2
EP1173455A2 EP00920823A EP00920823A EP1173455A2 EP 1173455 A2 EP1173455 A2 EP 1173455A2 EP 00920823 A EP00920823 A EP 00920823A EP 00920823 A EP00920823 A EP 00920823A EP 1173455 A2 EP1173455 A2 EP 1173455A2
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EP
European Patent Office
Prior art keywords
methyl
formula
compounds
radical
product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00920823A
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German (de)
English (en)
French (fr)
Inventor
Jacques Demassey
Michel Klich
Branislav Musicki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novexel SA
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Aventis Pharma SA
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Publication of EP1173455A2 publication Critical patent/EP1173455A2/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/075—Benzo[b]pyran-2-ones
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • New aromatic ribide substituted amides process for their preparation and their use as medicaments
  • the present invention relates to new aromatic amides substituted with a ribose, their preparation process and their use as medicaments.
  • R1 represents an alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-linear or branched or cyclic O-alkynyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms, optionally interrupted by a d atom oxygen, sulfur or nitrogen, an aryl or aralkyl radical containing up to 18 optionally substituted carbon atoms, an heterocyclic radical, aromatic or not, mono or polycyclic optionally substituted, an NH 2 , NHalci or NHalc 2 , NHalc radical 3 or NH0alk 4 , alki, alk 2 , alk 3 and alk representing an alkyl radical containing up to 8 carbon atoms,
  • R 2 represents a hydrogen atom or a halogen atom
  • R 3 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom
  • R 4 represents an NHR 'or NHOR''radical in which R' or R '', identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, an aryl radical containing up to 14 optionally substituted carbon atoms,
  • R 5 represents a hydrogen atom or an O-alkyl radical containing up to 8 carbon atoms
  • R 6 an alkyl or CH 2 -0 -alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms
  • R 7 represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms or else R 6 and R 7 form together with the carbon which carries them a ring as well as their addition salts with bases.
  • bases examples include the salts formed with the amines such as arginine, lysine, Na + , K + , NH 3 + , N (alk) 3 + alk 3 ions representing an alkyl radical containing up to 8 carbon atoms.
  • the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,
  • the halogen is preferably fluorine or chlorine, or bromine
  • the aryl radical is preferably the phenyl radical.
  • R 1 represents an alkyl radical containing up to 4 carbon atoms, for example a radical
  • R 4 represents an NH-O-CH 2 -C ⁇ CH radical.
  • the subject of the invention is very particularly the compounds the preparation of which is given below in the experimental part and very particularly the product of Examples 10 and 11.
  • the products of general formula (I) have a very good antibiotic activity on anaerobic gram bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria.
  • the compounds of the invention can therefore be used as medicaments in the treatment of infections with sensitive germs and, in particular, in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal disease of the face or skin, pyoderma, septic wounds or suppurative, boils, carbuncles, phlegmons, erysipelas and acne, staphylococcal diseases such as acute primary or post-influenza angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever , pneumococcal diseases such as pneumonia, bronchitis and diphtheria.
  • staphylococcal diseases such as staphylococcal septicemia, malignant staphylococcal disease of the face or skin, pyoderma, septic wounds or suppurative, boils, carbuncles, phlegmon
  • a subject of the invention is therefore the compounds of formula (I) as well as their pharmaceutically acceptable salts as medicaments.
  • a more particular subject of the invention is, as medicaments, the compounds indicated above as preferred compounds.
  • a subject of the invention is also the pharmaceutical compositions containing as active principle at least one of the medicaments defined above.
  • compositions can be administered by the buccal, rectal, parenteral route or by the local route by topical application to the skin and the mucous membranes, but the preferred route of administration is the buccal or injectable route.
  • They can be solid or liquid and come in the pharmaceutical forms commonly used in medicine.
  • human cine such as for example simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels; they are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • compositions can also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile non-hydrogenated water.
  • the dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It may, for example, be between 50 mg and 3000 mg per day by oral or injectable route, in adults for the preferred products.
  • the subject of the invention is a process for preparing the compounds of formula (I) characterized in that a compound of formula (II) is subjected:
  • a subject of the invention is also, as new chemicals, the compounds of formula (II) and (III).
  • Hal is a chlorine atom.
  • the compounds of formula (II) used as starting materials for the process of the invention can be prepared as indicated below in the experimental part.
  • the preparation of the compounds of formula (II) described in the experimental part can be schematized as follows:
  • the invention also relates to a process characterized in that a compound of formula (V) is subjected:
  • the products of formula (V) used as starting materials are new products and are in themselves an object of the invention.
  • the compounds of formula (V) can be prepared according to the process indicated in the experimental part.
  • the experimental part can be schematized as follows. Preparation 1: 4,7-dihydroxy-8-methyl-3- (phenylazo) -2H-1- benzopyran-2-one Stage A: C 6 H 5 N + ⁇ N, C1 ⁇
  • Stage B cyclic 2,3-carbonate and 1- (2,2,2-trichloro-etanimidate) of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxo-hexopyranose Introduced 276 mg of cesium carbonate, 18.17 g of the product prepared in stage A and 16 ml of trichloromethane cyanide in 250 ml of methylene chloride. The reaction mixture is kept under stirring for 3 hours. 7 ml of trichloromethane cyanide are added. Stirring is continued for 1 hour and the product obtained is brought to dryness, eluting with a cyclohexane ethyl acetate mixture (5-5). 27.01 g of sought product are thus obtained.
  • Stage A 7- [(2,3-0-carbonyl-6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4-hydroxy-8 -methyl-3- (phenylazo) -2H-1-benzopyran-2-one
  • Stage B 3-amino-7- [(2, 3 -0-carbonyl-6-deoxy-5-C-methyl-4-0- methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4 -hydroxy-8-methyl- 2H-1-benzopyran-2-one
  • Stage C N- [7- [(2,3-0-carbonyl-6-deoxy-5-C-methyl-4-0- methyl- .alpha. -L-lyxo-hexopyranosyl) oxy]] -4- hydroxy-8-methyl- 2-oxo-2H-1-benzopyran-3 -yl] -cyclopropanecarboxamide
  • Stage D Cyclopropyl-carbamic acid 3 ′ -N- ester [7 - [(6-deoxy-5-C-methyl-4-0-methyl-. Alpha. -L-lyxo-hexopyranosyl) oxy] -4- hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -cyclopro- panamide
  • Stage A 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] -3-0 [(triethylsily) oxy ] - .alpha. -L-lyxohexopyrano-syl] oxy] -4-hydroxy-8-methyl-2H-1-benzopyran-2-one It is subjected to hydrogenation under reduced pressure in the presence of palladium on carbon 28.0 g of product P prepared below. The palladium is filtered and rinsed with THF. Concentration is carried out under reduced pressure and 32.48 g of product are obtained which is purified on silica eluting with hexane / ethyl acetate 6-4.
  • Stage B 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] -3-0 [(triethylsily) oxy ] - .alpha. -L-lyxo- hexopyrano-syl] oxy] -4-hydroxy-8-methyl-3- (phenylazo) 2H-1- benzopyran-2-one
  • Stage D 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propanyyloxy) -amino] carbonyl] -2-0- [(tetrahydro- 2H-pyran-2-yl) oxy] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl -3- (phenylazo) -2H-1-benzopyran-2-one a) Dissolved at 0 ° C in 250 ml of methylene chloride 17 55 g of the product from the previous stage. 9.62 g of DMAP and 9 g of paranitrophenol chloroformate are added.
  • Stage E 3-amino-7- [[6-deoxy-5-C-methyl-4-0-methyl-3-0- [[(2-propynyl-oxy) -amino] carbonyl] -2-0- [(tetrahydro-2H-pyran-2- yl) oxy] - .alpha. -L-lyxo-hexopyranosyl] oxy] -4-hydroxy-8 methyl- 2H-1-benzopyran-2 -one Dip into a bath of oil at 85 ° C, a suspension containing 16 g of the product of the previous stage, 22.7 g of sodium dithionite, 10.7 g of sodium acetate, 400 ml of water and 90 ml of ethyl alcohol. Stirring is continued for 60 minutes. We filter. The filtrate is kept for 2 hours in an ice bath. The crystals obtained are filtered off and washed with water. It is dried and 10.26 g of sought product is obtained.
  • Stage A 4- (diphenylmethoxy) -8 -methyl -7- (tetrahydro-2H- pyran-2 -yl) -2H-1-benzopyran-2 -one 55 g of 4-hydroxy-8-methyl-7- (tetrahydro-2H-pyran-2-yl) -2H-1-benzopyran-2-one are introduced into 250 ml of anhydrous dimethylformamide heated to 40 ° C., and added dropwise a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF. The addition is made in 3 hours while maintaining the temperature at 40 ° C.
  • a mixture of 91.13 g of stage B product, 58.6 g of 6-deoxy-5-C-methyl-4-0-methyl-L-lyxohexopyranose and 80 g of triphenylphosphine are cooled to 0 ° C. in 900 ml of dichloromethane. 60 ml of diisopropylazodicarboxylate are added dropwise. The mixture is stirred for 1 hour at room temperature. 34 g of triphenylphosphine are added and 25 ml of diisopropylazodicarboxylate. The mixture is stirred for 1 hour at room temperature.
  • Stage D 7- [[6-deoxy-5-C-methyl-4-0-methyl-3-O- (triethylsilyl) -alpha-L-lyxo-hexopyranosyl] oxy] -4- (diphenylmethoxy) - 8-methyl-2H-1-benzopyran-2 -one
  • Stage E 7- [[6-deoxy-5-C-methyl-4-0-methyl-2-O- (tetrahydro- 2H-pyran-2-yl) -3-0- (triethylsilyl) -alpha-L -lyxo- hexopyranosyl] oxy] -4- (diphenylmethoxy) -8-methyl -2H-1- benzopyran-2 -one 19 ml of dihydropyran and 400 mg of APTS are added to a solution containing 67 g of product from the previous stage and 1 l of dichloromethane. The mixture is stirred for 40 minutes at room temperature, 300 mg of APTS are added.
  • EXAMPLE 4 3-(2-Propynyloxy) -carbamic acid N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran- 3-yl] -benzamide 60 ⁇ l of triethylamine and 50 ⁇ l of benzyl chloride are added to a solution containing 200 mg of product of the preparation 3 and 4 ml of methylene chloride. The mixture is stirred for 1 hour 30 minutes at 0 ° C. The temperature is allowed to rise to 20 ° C.
  • Stage B (2-Propynyloxy) -carbamic acid 3 '-N- [7- [(6-deoxy-5-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy ester ] -4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl] -2- [(1, 2, 5-thiadiazol-3-yl) oxy] -acetamide
  • 0.105 g of the product from the preceding stage is poured at 0 ° C. into 10 ml of methylene chloride.
  • 0.164 ml of pyridine and 0.200 g of the product of preparation 3 are added to 10 ml of methylene chloride. Stirring is continued for 20 minutes. Poured onto an ice-cold solution of sodium chloride. It is extracted with methylene chloride and dried. A product is obtained which is chromatographed on silica, eluting with a 90-10 methylene chloride-methanol mixture.
  • Stage A [4S- [4-. alpha. , 5- .alpha. (S *)]] - ⁇ , ⁇ -diethyl-2, 2-dimethyl-5- (hydroxymethyl) - ⁇ -methoxy-1, 3-dioxolan-4-ethanol Introduced into 250 ml of tetrahydrofuran (THF) 400 ml of 1 M ethyl magnesium bromide dissolved in THF, stirred for 15 minutes, then 25.2 g of .Delta are introduced. -actone of 2-0-methyl-3, 4-0- (1-methyl-ethylidene) -L-arabinonic acid and 126 ml of THF. The mixture is stirred for 1 hour 30 minutes while returning to ambient temperature.
  • THF tetrahydrofuran
  • the reaction medium is poured onto 480 g of an ice-water mixture (1: 1) and stirred for 15 minutes.
  • the aqueous phase is decanted and 80 g of sodium chloride is added thereto.
  • the aqueous phase is re-extracted with methylene chloride.
  • the organic phases (THF + methylene chloride) are combined, dried over sodium sulfate, filtered and then evaporated to dryness under vacuum in a bath at 50 ° C. Dried and obtained 32.9 g of the desired product.
  • Stage B .Delta. -5-C-ethyl-6-C-methyl-4-O-methyl-2, 3-0- (1-methylethylidene) -L-lyxonic lactone It is introduced into 450 ml of methylene chloride,
  • DMSO dimethylsulfoxide
  • TAA triethylamine
  • 45.6 g of the product obtained according to stage A 90 g of trioxide sulfide complex are added in portions while maintaining the temperature below 30 ° C. pyridine. Stirring is continued for 2 hours 30 minutes. Then 500 ml of ether are introduced and the reaction medium is poured onto 500 g of ice + water (1: 1). Decanted, the aqueous phase is reextracted with 500 ml of ether. The organic phases are combined, dried over sodium sulfate, filtered and then evaporated to dryness under vacuum. 66 g of product are obtained.
  • DMSO dimethylsulfoxide
  • TAA triethylamine
  • Stage C 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-2, 3-0- (1- methyl ethylidene) -L-lyxohexopyranose
  • Stage D 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-L- lyxohexopyranose
  • Stage A 2, 3-cyclic carbonate of 6-deoxy-5-C-ethyl-6-C-methyl-4-O-methyl-L-lyxohexopyranose
  • a mixture of 3.083 g of 6- is cooled to 0 ° C. deoxy-5- C-ethyl-6-C-methyl-4-0-methyl-L-lyxohexopyranose and 50 ml of methylene chloride.
  • 3.4 g of 1.1 carbonyldiimidazole and 0.168 ml of 1.8-diazo-bicyclo [5-4-0] -undec-7-ene are added. Poured onto 30 ml of a 1M sodium hydrogenphosphate solution and extracted with methylene chloride.
  • Stage B 2, 3 -cyclic carbonate and 1- (2, 2, 2-trichloro ethanimidate) of 6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl-L- lyxo-hexopyranoside
  • Stage D 3-amino-7- [(2,3-0-carbonyl-6-deoxy-5-C-ethyl-6-C- methyl-4-O-methyl- .alpha. -L-lyxo-hexopyranosyl ) oxy] -4- hydroxy-8-methyl-2H-1-benzopyran-2-one
  • a mixture of 2.32 g of product from stage C 200 is placed under hydrogen pressure (approximately 1400 m bar) for 2 hours ml of ethanol and 232 mg of palladium on carbon at 10%. Filtered, washed with an ethanol mixture of methylene chloride and concentrated in a rotary evaporator under reduced pressure. 1.54 g of product are obtained.
  • Stage E N- [7- [(2,3-0-carbonyl-6-deoxy-5-C-ethyl-6-C-methyl- 4-O-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8- methyl-2-oxo-2H-1-benzopyran-3 -yl] -2-methyl-propanamide
  • 0.55 ml of pyridine and 0.4 ml of chloride are introduced dropwise isobutyryl in a mixture of 1.5 g of product from the previous stage and 30 ml of methylene chloride. Stirring is continued for one hour. Poured onto 20 ml of a 1 M sodium hydrogen phosphate solution, extract with methylene chloride. The organic phases are washed, dried, filtered and concentrated. 1.8 g of sought product is obtained.
  • Stage F N- [7- [(6-deoxy-5-C-ethyl-6-C-methyl-4-0-methyl- .alpha. -L-lyxo-hexopyranosyl) oxy] -4-hydroxy-8 -methyl-2-oxo- 2H-1-benzopyran-3 -yl] -2 -methyl-propanamide
  • Stage C [8R- (8.alpha., 9.alpha, 10.beta)] -10-methoxy-6- oxaspiro [4.5] -decane-7, 8, 9-triol
  • the mixture is stirred at -3 ° C for 1 hour.
  • 1 liter of a 1 M solution of double sodium and potassium tartrate is added.
  • the mixture is stirred for 15 minutes at room temperature.
  • the reaction medium is extracted with an ethyl acetate-heptane 1-1 mixture.
  • Stage E [7R- (7. alpha., 8.beta., 9.beta., 10. alpha.)] -4- (diphenyl-methoxy) -7- [[8-hydroxy-10-methoxy-9 - [(triethylsily) oxy] -6-oxaspiro [4.5] -decan-7-yl) oxy] -8-methyl- 2H-1-benzopyran-2-one
  • Stage B 4- (diphenylmethoxy) -7 -hydroxy- 8-methyl-2H-1-benzopyran-2 -one 35 ml of a 0.9 M hydrochloric acid solution in methanol is added to a solution containing a mixture of 20 g of stage A product, 100 ml of dichloromethane and 100 ml of methanol. The mixture is stirred for 2 hours at room temperature and the solvents are evaporated. The residue is dispersed in absolute ethanol cooled to 0 ° C. The insoluble material is drained and rinsed with iced alcohol and then with sulfuric ether. Dried and collected 15.53 g of product which is dispersed in ether, drained and dried.
  • Stage C [3'aR- (3'a. ⁇ ., 4' ⁇ ., 7' ⁇ ., 7'a. ⁇ )] -4 '- [[4-dihydro-8- methyl-3- ( phenylazo) -2H-1-benzopyran-7-yl] oxy] -7 '-methoxy- tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo [4, 5- c] pyran] -2 '-one
  • stage B product (2.42 g) and carbonyldiimidazole (1.6 g) in anhydrous tetrahydrofuran (30 ml) is heated to reflux. After forty five minutes, the cooled reaction mixture is poured onto an aqueous solution of sodium hydrogen sulphate (10% sol.: 20 ml) then extracted with dichloromethane. The organic phase is dried over magnesium sulfate. We filter and evaporate until dryness. The residue is purified by chromatography on silica, eluting with a dichloromethane-acetone mixture (95-5). 2.35 g of the desired product are collected.
  • Stage D [3 'aR- (3' a. ⁇ ., 4 ' ⁇ ., 7' ⁇ ., 7 'a. ⁇ .)] -4' - [[3-amino-4-hydroxy-8- methyl-2-oxo-2H-1-benzopyran-7-yl] oxy] -7 '-methoxy- tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo [4, 5-c] pyran ] -2 '-one
  • Stage E [3'aR- (3 'a. ⁇ ., 4' ⁇ ., 7' ⁇ ., 7'a. ⁇ .)] -N- [4-hydroxy-7- [(7' -methoxy -2 '-oxo-tetrahydro-spiro [cyclopentane-1, 6' [6H- 1,3] dioxolo [4, 5-c] pyran] -4 '-yl) oxy] -8-methyl-2-oxo- 2H-1- benzopyran-3-yl] -benzamide
  • Triethylamine (177 ⁇ l) is added dropwise to the suspension cooled to 0 ° C. of product from the preceding stage in dichloromethane (5 ml). 134 ⁇ l of benzoyl chloride are added to the syringe. The reaction solution is stirred for 1 hour at 0 ° C. Again triethylamine (18 ⁇ l) and benzoyl chloride (13 ⁇ l) are added and the reaction mixture is stirred for an additional hour at 0 ° C. The reaction solution is poured onto an aqueous solution of sodium dihydrogen phosphate (1 M: 100 ml). Extraction is carried out with an AcOEt-heptane mixture (80:20).
  • Stage F [7R- (7. ⁇ ., 8 ⁇ ., 9 ⁇ ., 10. ⁇ )] - (2-propynyloxy) - 8-hydroxy-7- [4-hydroxy-8-methyl-2-carbamate -oxo-3- (benzoylamino) -2H-1-benzopyran-7-yl] -10-methoxy-6- oxaspiro [4.5] decan-9-yle
  • Hydrogenation is carried out for 2 hours under an atmosphere of H 2 in the presence of palladium on carbon a solution of 810 mg of product of stage C of the preceding example, namely [3'aR- (3'a. ⁇ ., 4' ⁇ ., 7' ⁇ ., 7'a. ⁇ .)] -4 '- [[4-hydroxy -8- methyl-3-phenylazo) -2-oxo-2H-1-benzopyran- 7-yl] oxy] - 1 '- methoxy-tetrahydro-spiro [cyclopentane-1, 6' [6H-1, 3] dioxolo- [4, 5-c] pyran] -2 '-one to obtain the product 3 - corresponding amino.
  • Stage B [7R- (7. ⁇ ., 8 ⁇ ., 9 ⁇ ., 10. ⁇ )] - (2 -propynyloxy) - carbamate of 7- [4-hydroxy-8-methyl-3- [(2 -methyl-l-oxo- propyl) amino] -2-oxo-2H-1-benzopyran-7-yl] -10-methoxy-6-oxaspiro [4.5] decan-9-yl
  • a solution containing 680 mg of the preceding stage product, 1.4 g of o-propargyl hydroxylamine and 139 mg of lithium perchlorate and 6 ml of pyridine is stirred at ambient temperature for 2 and a half days.
  • the reaction solution is poured onto a 10% aqueous sodium hydrogensulfate solution and extracted with a hexane-ethyl acetate 1-1 mixture.
  • the organic phase is dried and the solvents are evaporated.
  • the product obtained is chromatographed on silica eluting with a methylene chloride / ethyl acetate / acetic acid 80-20-1 mixture and 310 mg of sought product is obtained.
  • Injectables have also been prepared from salified products.
  • a series of tubes has been prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities 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 ° C, the growth inhibition is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (MIC) expressed in micrograms / cm 3 .
  • MIC minimum inhibitory concentrations
  • EX. 10 EX. 11 Staph.aureus 011HT18 ⁇ 0.04 ⁇ 0.04

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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP00920823A 1999-04-19 2000-04-18 Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments Withdrawn EP1173455A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9904866A FR2792320B1 (fr) 1999-04-19 1999-04-19 Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments
FR9904866 1999-04-19
PCT/FR2000/000999 WO2000063222A2 (fr) 1999-04-19 2000-04-18 Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments

Publications (1)

Publication Number Publication Date
EP1173455A2 true EP1173455A2 (fr) 2002-01-23

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EP00920823A Withdrawn EP1173455A2 (fr) 1999-04-19 2000-04-18 Nouveaux amides aromatiques substitues par un ribose, leur procede de preparation et leur application comme medicaments

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US (1) US6579902B1 (enExample)
EP (1) EP1173455A2 (enExample)
JP (1) JP2002542253A (enExample)
KR (1) KR100693258B1 (enExample)
CN (1) CN1213055C (enExample)
AP (1) AP2001002312A0 (enExample)
AU (1) AU769514B2 (enExample)
CA (1) CA2363945A1 (enExample)
CZ (1) CZ20013708A3 (enExample)
EA (1) EA004304B1 (enExample)
FR (1) FR2792320B1 (enExample)
HK (1) HK1046690B (enExample)
HU (1) HUP0200778A3 (enExample)
ID (1) ID30562A (enExample)
IL (1) IL146018A0 (enExample)
NO (1) NO320703B1 (enExample)
NZ (1) NZ515108A (enExample)
PL (1) PL354192A1 (enExample)
SK (1) SK14842001A3 (enExample)
TR (1) TR200103009T2 (enExample)
UA (1) UA72919C2 (enExample)
WO (1) WO2000063222A2 (enExample)
YU (1) YU80301A (enExample)
ZA (1) ZA200108627B (enExample)

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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.
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
KR100649357B1 (ko) * 2004-05-04 2006-11-24 제일약품주식회사 항염증 활성을 갖는 크로멘-2-온 모핵 히드록사민 산유도체, 이의 제조방법 및 이를 포함하는 염증 질환의치료를 위한 조성물
US8212011B2 (en) * 2004-11-03 2012-07-03 University Of Kansas Novobiocin analogues
US9120774B2 (en) 2004-11-03 2015-09-01 University Of Kansas Novobiocin analogues having modified sugar moieties
US7608594B2 (en) * 2004-11-03 2009-10-27 University Of Kansas Novobiocin analogues as anticancer agents
US7622451B2 (en) * 2004-11-03 2009-11-24 University Of Kansas Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders
US8212012B2 (en) * 2004-11-03 2012-07-03 University Of Kansas Novobiocin analogues having modified sugar moieties
US7960353B2 (en) * 2007-05-10 2011-06-14 University Of Kansas Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders
WO2010014617A1 (en) * 2008-07-28 2010-02-04 University Of Kansas Heat shock protein 90 inhibitor dosing methods
US20110082098A1 (en) * 2009-09-30 2011-04-07 University Of Kansas Novobiocin analogues and treatment of polycystic kidney disease
US11827664B2 (en) 2018-05-14 2023-11-28 Reata Pharmaceuticals, Inc Biaryl amides with modified sugar groups for treatment of diseases associated with heat shock protein pathway

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Publication number Priority date Publication date Assignee Title
US3652536A (en) * 1969-06-02 1972-03-28 Upjohn Co Novenamine compounds and derivatives
US3890297A (en) * 1973-03-29 1975-06-17 Upjohn Co Process for n-acylating novenamine

Non-Patent Citations (1)

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Title
See references of WO0063222A2 *

Also Published As

Publication number Publication date
EA004304B1 (ru) 2004-02-26
EA200101100A1 (ru) 2002-04-25
AP2001002312A0 (en) 2001-12-31
FR2792320B1 (fr) 2003-05-09
WO2000063222A3 (fr) 2001-05-31
NO20015058L (no) 2001-12-17
YU80301A (sh) 2005-07-19
FR2792320A1 (fr) 2000-10-20
HUP0200778A3 (en) 2003-03-28
IL146018A0 (en) 2002-07-25
AU769514B2 (en) 2004-01-29
PL354192A1 (en) 2003-12-29
ZA200108627B (en) 2002-10-21
KR20020008155A (ko) 2002-01-29
CA2363945A1 (fr) 2000-10-26
TR200103009T2 (tr) 2002-05-21
HK1046690A1 (en) 2003-01-24
UA72919C2 (uk) 2005-05-16
NZ515108A (en) 2004-01-30
ID30562A (id) 2001-12-20
WO2000063222A2 (fr) 2000-10-26
CZ20013708A3 (cs) 2002-04-17
CN1357001A (zh) 2002-07-03
KR100693258B1 (ko) 2007-03-13
US6579902B1 (en) 2003-06-17
JP2002542253A (ja) 2002-12-10
HUP0200778A2 (hu) 2002-07-29
SK14842001A3 (sk) 2003-05-02
NO320703B1 (no) 2006-01-16
AU4125600A (en) 2000-11-02
CN1213055C (zh) 2005-08-03
HK1046690B (zh) 2006-03-10
NO20015058D0 (no) 2001-10-18

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