EP0876368A1 - Use of mono- or diketone tetracyclic derivatives, resulting novel compounds and therapeutical use thereof - Google Patents

Use of mono- or diketone tetracyclic derivatives, resulting novel compounds and therapeutical use thereof

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Publication number
EP0876368A1
EP0876368A1 EP96941735A EP96941735A EP0876368A1 EP 0876368 A1 EP0876368 A1 EP 0876368A1 EP 96941735 A EP96941735 A EP 96941735A EP 96941735 A EP96941735 A EP 96941735A EP 0876368 A1 EP0876368 A1 EP 0876368A1
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EP
European Patent Office
Prior art keywords
imidazo
dioxo
dihydro
new product
pyridme
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.)
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Application number
EP96941735A
Other languages
German (de)
French (fr)
Inventor
Odile Boutherin-Falson
Stéphanie Desquand-Billiald
Anita Favrou
Michel Finet
Olivier Tembo
Jean-Luc Torregrosa
Sylvie Yannic-Arnoult
Cécile Joubert
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Laboratoires Innothera SAS
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Laboratoires Innothera SAS
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Publication date
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Publication of EP0876368A1 publication Critical patent/EP0876368A1/en
Withdrawn legal-status Critical Current

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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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • 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
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts for obtaining a medicament intended for the treatment of diseases linked to a deterioration of the venous function and / or inflammatory edema and the new compounds obtained It relates more particularly to derivatives of tetracyclic compounds comprising a motif 1, 4-dihydro-1, 4-d ⁇ oxonaphthalene, one of the ketones of which is possibly protected The invention relates to the therapeutic application of all these compounds
  • tetracyclic derivatives and their pharmaceutically acceptable salts according to the present invention correspond to the general formula.
  • X is a carbon atom or a nitrogen atom
  • T is a carbon atom or a nitrogen atom
  • Ri is a hydrogen atom, a halogen atom, an alkyl radical of C] _ to C5,
  • R2 is a hydrogen atom, a halogen atom, a nitro radical, a C ⁇ to C5 alkyl radical, n and m are either equal to 0 or 1, but not independently of one of the other so that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1.
  • the invention also relates to the following new products:
  • the invention also relates to the following intermediate products:
  • the invention also relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts corresponding to the general formula (I) above for obtaining a medicinal product intended:
  • the present invention also relates to the salts of the salifiable compounds of formula (I) These salts include the addition salts of mineral acids such as acid hydrochloric, hydrobromic, sulfuric, phosphoric, or nitric and the addition salts of organic acids such as acetic, propiomic, oxalic, citric, maleic, fumaric, succric, tartaric acid
  • mineral acids such as acid hydrochloric, hydrobromic, sulfuric, phosphoric, or nitric
  • organic acids such as acetic, propiomic, oxalic, citric, maleic, fumaric, succric, tartaric acid
  • Infra-Roucre spectra They were obtained on a NICOLET 205 FT-IR type spectrometer. They are effec ⁇ killed at 1% (m / m) in dispersion in the KBr.
  • the brown solid obtained is pu ⁇ rified on a flash column (support: silica; eluent: dichloromethane / ethyl acetate, 100/0 to 96/4) to provide after discoloration with animal black and recrystallization in the chlorobenzene 0.63 g of ll-chloro-5,6-dihydro-5,6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.
  • the red solid obtained is purified on a flash column (support • silica; eluent: dichloromethane / ethyl acetate, 100/0 to 90/10) to provide, after discoloration with animal black, 0.023 g of 5.6-D ⁇ hydro-5 , 6-dioxo-9-fluoro-napht [l 1 , 2 ': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals. Yid: 2%
  • the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and sodium chloride, then dried over sodium sulfate and evaporated under reduced pressure.
  • the crude product obtained is purified on a medium pressure column (silica support; eluent: dichloromethane / heptane / ethyl acetate, 68/40/2) to provide, after discoloration with animal black, 0.096 g of 6, ll-dihydro-6 , ll-d ⁇ oxo-2-methyl-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals.
  • the precipitate is then diluted in di ⁇ chloromethane then the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and sodium chloride. The organic phase is dried over sodium sulfate, filtered and then evaporated under reduced pressure.
  • the crude product obtained is purified on a flash column (support: silica; eluent: dichloromethane / heptane / methanol, 79.5 / 20 / 0.5) to provide, after discoloration with animal black, 0.07 g of 2-chloro- 6, 11-dihydro-6, 11-dioxo-napht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals.
  • the solid obtained is recrystallized from chlorobenzene to provide, after treatment with animal black, then passage over a micropore filter 0.16 g of 10-chloro-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5 ] imidazo- [1, 2-a] pyridine in the form of orange crystals.
  • reaction immediately turns purple After 30 minutes, 26.4 ⁇ l of hydrazme monohydrate (0.27 mmol, 1 eq) are added After 1 hour of reaction, the reaction mixture is allowed to return to ambient temperature and the brown-purple precipitate is filtered through dried cotton and dissolved in 5 ml of concentrated hydrochloric acid
  • This solution is cooled to -10 ° C. and then a solution formed by 34 mg (0.49 mmol, 1.8 eq) of sodium nitrite and 5 ml of distilled water is added dropwise.
  • the medium is left stirring at this temperature for 0.5 hour.
  • the reaction medium is added dropwise to a solution cooled to -5 ° C, formed with 18 mg (0.18 mmol, 0.7 eq ) copper chloride I and 5 ml of concentrated hydrochloric acid Stirring is continued for 2.5 hours.
  • the reaction medium is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate and then distilled water.
  • reaction mixture After 1 hour of reaction, the reaction mixture is allowed to return to room temperature and the brown-purple precipitate is filtered through dried cotton and dissolved in 15 ml of concentrated hydrobromic acid. This solution is cooled to -15 ° C. and then a solution formed by 64 mg (0.93 mmol, 2.5 eq) of sodium nitrite and 5 ml of distilled water is added dropwise. The medium is left stirring at this temperature for 1.5 hours. The reaction medium is added dropwise to a solution cooled to -5 ° C, formed from 21 mg (0.15 mmol, 0.4 eq) of copper bromide I and 5 ml of concentrated hydrobromic acid. We get a solution violet color whose agitation is continued for 2.5 hours.
  • reaction medium is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate and then distilled water.
  • organic phase is extracted then dried over sodium sulfate and evaporated to dryness.
  • the crude product is purified on preparative plates (support • silica, eluent Di ⁇ chloromethane / Methanol, 95/5) to provide 30 mg of 4-bromo-5, 6-dehydro-5, 6-dioxonapht [1 ', 2' : 4, 5] imidazo [1,2- a] -pyridine in the form of yellow crystals. Yid: 25% F:> 260 ° C
  • 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene Has a solution of 1,4-dihydro-1,4-dioxo-6-fluoro ⁇ naphthalene (CAS No 148541-61- 1) (12.5 g, 71 mmol) in chloroform (250 ml), 36 ml (710 mmol) of bromine. The solution is brought to reflux for 12 hours and then brought to room temperature. After bubbling with compressed air, the solution is concentrated under reduced pressure and the solid obtained is washed five times with hexane.
  • the precipitate is dissolved in 20 ml of concentrated hydrochloric acid. This solution is cooled to -17 ° C. and then a solution formed by 47 mg (0.67 mmol, 2.0 eq) of sodium nitrite and 5 ml of distilled water is added dropwise. The medium is stirred at this temperature for 0.5 hour. The reaction medium is added dropwise to a solution cooled to -10 ° C, formed from 67 mg (0.67 mmol, 2 eq) of copper chloride I and 5 ml of concentrated hydrochloric acid. Agitation is continued for 3 hours. The reaction medium is filtered. The organic phase is neutralized with solid sodium carbonate then extracted in dichloromethane.
  • a first crystallization with dichloromethane delivers 8.25 g of 2,3-dibromo-1,4-dihydro-1,4,4-d ⁇ oxo-5-methylnaphthalene in the form of yellow crystals; a second re-installation with acetonitrile provides 11.90 g of 2,3-d ⁇ bromo- 1, 4-di-hydro-l, 4-d ⁇ oxo-5-methylnaphthalene in the form of yellow crystals.
  • the crude product is purified by chromatography on a preparative plate (support: silica SIL G- 200 UV254 2 mm; eluent: CH 2 Cl 2 / EtOH, 97/3) to provide 6, ll-dihydro-6, ll- dioxo-7-methylnapht- [2 ', 3': 4, 5] - imidazo- [1, 2-a] pyridine or 6, ll-dihydro-6, ll-dioxo-10- methylnapht [2 ', 3' : 4, 5] imidazo [1, 2-a] pyridine or 5,6-di-hydro-5, 6-dioxo-1-methyl-napht [l ', 2': 4, 5] imidazo [l, 2 -a] - pyridine or 5, 6-dihydro-5, 6-dioxo-4-methyl-napht- [1 ', 2': 4, 5] -imidazo [1, 2-
  • the crude product is purified by column chromatography (silica support 6-35 mm, packaging: CH 2 C1 2 / Heptane, 90/10, eluent: gradient CH 2 Cl 2 / AcOEt, 100/0 to 50/50) then on a preparative plate (support: silica SIL G-200 UV254 2 mm; eluent: CH ; C1 2 ) to provide 2-chloro-6, ll-dihydro-6, ll-dioxo-7-methyl-naphth [2 ' , 3 ': 4, 5] imidazo [1, 2-a] pyridine or 2-chloro-6, 11-dihydro-6, 11-dioxo-10- methylnapht [2', 3 ': 4, 5] imidazo [ l, 2-a] -pyridine or 9-chloro- 5, 6-dihydro-5, 6-dioxo-1-methylnapht- [l ', 2': 4,
  • the crude product is purified by two successive chromatographies on a preparative plate (support: silica SIL G-200 UV254 2 mm; eluent 1 st * plate: CH 2 Cl 2 / MeOH, 97/3 and eluent 2 "plate: Heptane / AcOEt, 40/60) to provide 6,11- dihydro-6, 11 -dioxo- 8 -methylnapht [2 ', 3': 4, 5] imidazo [1,2- a] -pyridine or 6, ll-dihydro-6, ll-dioxo-9-methylnapht- [2 ', 3': 4, 5] imidazo [1 , 2-a] pyridine or 5, 6-dihydro-5, 6-di-oxo-2 -methylnaphthfl ', 2': 4, 5] imidazo [l, 2 -ajpyridine or 5,6- dihydro-5, 6 -diox
  • Contractile effects are measured m vi tro under static conditions on vascular rings with capacitance or resistance of saphenous, femoral, jugular, mesenteric veins and on femoral, carotid, basilar, mesenteric, thoracic or abdominal aorta arteries.
  • rat Wistar, 200 to 250 g
  • rabbit New Zealand, 2 to 2.5 kg
  • guinea pig Dunkin Hartley 250 to 300 g).
  • the rings are placed in an isolated organ chamber (25 ml for capacitance vessels and 2.5 ml for resistance vessels according to Mulvany), maintained in isometric conditions by two rigid wires inserted inside the vessel, in avoiding damage to the endothelium
  • the rings are brought to their optimal point of the tension-length relationship.
  • the developed voltages generate an electrical signal via a force sensor (Wheastone bridge).
  • This signal is amplified before being either displayed on a Kipp & Zonen recorder, or digitized to be processed by computer ( IOS, EMKA).
  • IOS, EMKA digitized to be processed by computer
  • Pharmacological studies are carried out after a few preliminary contractile stimulations standardized by a depola ⁇ sante solution (hyperpotassic obtained by replacing NaCl with KC1 in equimolar quantities), rinses and equilibration periods in pure physiological solution. The presence of endothelium is verified by the relaxation induced by increasing concentrations of acetylcholme after stabilization of a vascular pre-contraction.
  • the contraction forces developed by the vascular rings in response to the various compounds are studied on quiescent or electrically stimulated vessels (5-8 Hz), using a hyperpotassic de ⁇ polarizing "physiological" solution (KC1 20, 40 mM ), by no-radrenalme (increasing concentrations), serotomne (increasing concentrations) ...
  • the contractions are expressed in mg force or as a percentage of the maximum contraction on depolansation by a "physiological" hyperpotassic solution. Contractile effects are also measured m vi tro under dynamic flow conditions, by the pressure developed by vascular networks. infused at constant rate. At the mesenteric level, vemoselectivity is studied on the model of simultaneous and separate double perfusion of arterial and venous networks, mo- model developed by T WARNER (B ⁇ tish J Pharmacol 1990, 99, 427-433). The two networks are separated by cutting the vessels and the tissues along the intestinal border. The networks are perfused at 2 ml.mm “ 1 with a Krebs solution (37.5 ° C) aerated at 95% 0 2 and 5% C0 2 .
  • the arterial pressures are measured according to the classic method derived from Riva Rocci, by analysis of the acoustic wave transmitted to the arterial level and transformed by a piezo ceramic transducer placed on the tail of the rat, downstream of '' a sleeve inflated automatically by a pressure generator
  • Riva Rocci a piezo ceramic transducer placed on the tail of the rat
  • a pressure generator At the microcirculatory level, the variations in vein and arteriolar section are studied in vivo in the model of the dorsal cutaneous chamber of a vigilant hamster, after videomicroscopic recording (Leitz Ergolux micro ⁇ scope equipped with '' a halogen source for lighting and a black and white CDD video camera HPR 610) and computer analysis (Visicap software, ICAP pack) of the images.
  • Vascular permeability is studied in vivo by measuring the albumin extravasation, the amount of which is determined using an albumin-binding dye (Evans Blue) Hyperpermeability is induced by in ⁇ tradermal injection of a histamme, bradykmme or zymosan solution.
  • albumin-binding dye Evans Blue
  • the rats (Wistars, 200 to 230 g) are shorn on their abdominal wall one hour before the start of the experiment.
  • the product to be tested is injected i p or orally 1 hour to 4 hours before the sacrifice.
  • the rats are anesthetized with a mixture of halothane Then they receive an intradermal injection on the abdomen of 0.10 or 0.15 ml (either for the histamme, 6.7 or 10 micro ⁇ grams) of inflammatory agent and an intravenous injection of one ml of a 0.5% Evans blue solution into the vein of the penis. These injections are carried out 30 minutes before euthanasia.
  • the skin is cut and placed in glass tubes with a ruffled neck containing 3 ml of fuming hydrochloric acid.
  • the digestion of the skin is carried out by contact of at least one hour in a water bath at 37 ° C. Three ml of 12.8% benzalkonium chloride are then added. After allowing to stand for thirty minutes, 7 ml of di- chloromethane are added.
  • the tubes are agitated periodically for one hour
  • the aqueous phase is removed by suction and the organic phase "dichloromethane" is filtered
  • the optical densities are quantified by absorption spectrophotometry at a length of 620 nm wave, against a blank containing only dichloromethane.
  • the averages of the optical densities of the different batches of treated or control animals are calculated, then a percentage change in the values corresponding to the treated animals compared to those of the control animals
  • the effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamine and bradykmme is also studied after intravenous injection by bolus in the model of the dor ⁇ dirty hamster skin chamber and according to the method developed by GIMENO et al .
  • capillary resistance The increase in capillary resistance is appreciated by the modification of the petechial index (negative pressure inducing the extravasation of erythrocytes), measured by a method derived from angiosterro- Parrot meter
  • the study is carried out on Wistar male rats of a average weight of 200 g (about six weeks old)
  • the lower back region is shaved and then depilated using a paste based on a derivative of thioglycolic acid and calcium hydroxide. After about thirty minutes, the skin is thoroughly rinsed and dried.
  • the rats were kept unconstrained. A vacuum of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) have not appeared within 15 seconds, the depression is increased by compensating by keeping the suction cup in the same place.
  • the minimum depression for which the petechiae appear expresses, in mm of mercury, the value of basic capillary resistance (before any treatment). Two measurements are carried out for each test at different locations on the back. Rats are treated orally. After a determined time (generally 2, 4, 6 hours) following the treatment, the test is repeated on different skin areas, until the appearance of petechiae, providing a new index of depression. All measurements are made. blindly.
  • a percentage change in the capillary resistances of the treated animals with respect to their basic capillary resistance is calculated for each compound studied, at each treatment time and compared with the control group (excipient only) or the reference group.
  • the anti-inflammatory activity of the compounds is also studied by measuring the inhibition of edema and leukocyte migration after induction of rain in the rat by injection of carrageenan into the pleural cavity (ALMEIDA et al ., J. Pharmacol. Exp Therap., 1980, 214: 74).
  • the rats are treated per os with the compounds 2 hours before the injection of carrageenan, as well as 2 and 4 hours after this injection. After a determined time (6 hours) following the induction of pleurisy, the rats are euthanized and the pleural fluid recovered by aspiration and its volume is measured. The leukocyte cells are counted by "cell counter”.
  • the results are expressed in number of leukocytes in the exudate relative to 100 g of animal weight and compared to those of the control batch.
  • the compounds of the invention and their possible salts selectively increase in the majority of cases the contraction of the animal veins produced by norepinephrine, by electrical stimulation or by a depolarizing hyperpotassic solution.
  • a depolarizing hyperpotassic solution By way of illustration, the contractile effect of different compounds on the saphenous vein of rabbits pre-towed by a "physiological" depolarizing solution with potassium concentration equal to 40 mM is shown; the maximum effect produced by each compound is expressed as a percentage of the maximum contraction induced by depolarizing hyperpotash solutions and in ED 50 value):
  • Example c 27 ⁇ 4 157 Example f 56 ⁇ 7 450
  • the oral administration of cer tain ⁇ compounds of the invention and their possible salts increases the capillary resistance of the rat at doses generally taken between 0.01 and 5 mg / kg:
  • the oral administration of certain compounds of the invention and their possible salts reduces the inflammatory hyperpermeability induced by zy-mosan in rats at doses generally comprised between 0, 01 and 5 mg / kg:
  • Example h 0.1 mg / kg -23 - 5
  • Example 2 0.1 mg / kg -10 -15
  • the compounds of the invention and their possible salts are very little toxic. For example, after a single oral administration of 1 g / kg in mice, no observable toxic effect and no mortality is observed for the majority of the compounds, in particular for Example a, Example c and Example 2 .
  • example c is particularly given.
  • the compounds of the invention and their possible salts can be used in human and animal therapy They are in particular indicated in functional, organic venous insufficiency and hemorrhoidal pathologies by their vascular and anti-inflammatory components, as well as in typically inflammatory conditions and in shock states constituted by a significant fall in blood pressure. In the latter case, an improvement in the venous return is likely to maintain the cardiac output and consequently, the blood pressure
  • Functional venous insufficiency is characterized by dilation and hyperdistensitivity of the superficial veins of the lower limbs, edemas, impatience-type paresthesias, restless leg
  • This type of pathology can progress to characterized organic venous insufficiency through the development of varicose veins, valve incontinence, or even towards phlebothrom- bosis and trophic disorders leading to ulcerative lesions.
  • an inflammatory component settles in the early stages and manifests itself more clearly in the advanced stages
  • the present invention therefore comprises the use of the above-mentioned compounds and their possible salts, as active substances for the preparation of medicaments and pharmaceutical compositions for human and veterinary use, comprising at least one of said compounds and salts in combination with a physiologically acceptable carrier or diluent.
  • a physiologically acceptable carrier or diluent for the preparation of medicaments and pharmaceutical compositions for human and veterinary use, comprising at least one of said compounds and salts in combination with a physiologically acceptable carrier or diluent.
  • the form of these drugs and pharmaceutical compositions ceutiques obviously depend on the desired route of administration including oral, parenteral, topical (skin) and rectal, and they can be formulated according to conventional techniques with the use of supports and usual vehicles.
  • oral administration they may be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophili- sat, microcapsule, microgranule.
  • Tablets, tablets and capsules contain the active substance together with a diluent (for example lactose, dextrose, sucrose, mannitol, maltitol, xylitol, sorbitol or cellulose), a lubricant (for example silica, talc or stearate), a binder (for example ami ⁇ don, methylcellulose or gum arabic), a disintegrating agent (alginate for example) and they are produced by known techniques for example of mixing, granulation, pelletizing, coating, compression etc ...
  • a diluent for example lactose, dextrose, sucrose, mannitol, maltitol, xylitol, sorbitol or cellulose
  • a lubricant for example silica, talc or stearate
  • a binder for example ami ⁇ don, methylcellulose or gum arabic
  • a disintegrating agent alginate for example
  • the syrups may contain, as a support, glycerol, mannitol and / or sorbitol.
  • the solutions and suspensions can include water and other physiologically compatible solvents and a support such as a natural gum, agar, sodium alginate or polyvinyl alcohol.
  • the drugs and compositions may take the form of solutions, emulsions or suspensions comprising the active substance and a suitable support or solvent such as sterile water or isotonic saline solutions. sterile.
  • the drugs and compositions can take the form of an ointment, cream or gel, in the form of an emulsion or suspension, solution, 32
  • the drugs and compositions can take the form of capsule, cream, emulsion, gel, foam, ointment, suppository.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The therapeutical use of tetracyclic derivatives and pharmaceutically acceptable salts thereof having general formula (I), for treating diseases related to venous function deficiency and/or inflammatory oedema, is disclosed. In general formula (I), X is a carbon atom or a nitrogen atom; T is a carbon atom or a nitrogen atom; L is an oxygen atom or a ketone function protecting grouping; R1 is a hydrogen atom, a halogen atom or a C1-5 alkyl radical; R2 is a hydrogen atom, a halogen atom, a nitro radical or a C1-5 alkyl radical; and n and m are 0 or 1 but not independently so, whereby when n is 1 then m is 0, and vice versa.

Description

Utilxsation de dérivés de tétracycles mono ou dicétoniques, nouveaux composés obtenus et leur appplication en thérapeutique Use of derivatives of mono or diketonic tetracycles, new compounds obtained and their therapeutic application
La présente invention concerne l'utilisation de dé¬ rivés tétracycliques et de leurs sels acceptables du point de vue pharmaceutique pour l'obtention d'un médica¬ ment destiné au traitement de maladies liées à une alté¬ ration de la fonction veineuse et/ou à l'oedème înflamma- toire et les nouveaux composés obtenus Elle se rapporte plus particulièrement aux dérivés de composés tétracycli¬ ques comprenant un motif 1, 4-dihydro-1, 4-dιoxo- naphtalène, dont l'une des cétones est éventuellement protégée L'invention concerne l'application thérapeuti- que de tous ces composésThe present invention relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts for obtaining a medicament intended for the treatment of diseases linked to a deterioration of the venous function and / or inflammatory edema and the new compounds obtained It relates more particularly to derivatives of tetracyclic compounds comprising a motif 1, 4-dihydro-1, 4-dιoxonaphthalene, one of the ketones of which is possibly protected The invention relates to the therapeutic application of all these compounds
Le document Chem Rev., 63, 279-296 (1963) , par Sar- tori M F , décrit la synthèse de qumones hétérocycli¬ ques à partir des 2, 3-dιchloro-l, 4-dιhydro-l, 4-dιoxo- naphtalènes, en particulier les naphtimidazopyridines diones et leurs dérivés L'article J Amer. Chem. Soc 79, 5708-5710 (1957) par Truitt P., Cooper J. E., Wood F. M., Jr, décrit une synthèse contreversée de la β, ll-dιhydro-6, 11-dιoxo- napht [2 ' , 3 ' •4, 5] îmidazo [1, 2-a] pyridine, alors que le do- cument J. Org. Chem., 24, 374-380 (1959) , par Mosby W L , Boyle R. J. , évoque la possibilité théorique d'obtention de trois types de composés de structures dif¬ férentes 5 , 6-dιhydro-5, 6-dιoxo-napht [1 ' , 2 ' :4, 5] îmidazo- [1, 2-a] pyridine, 5, 6-dιhydro-5, 6-dιoxo-napht [1 ' , 2 ' 4,5]- îmidazo [2 , 3 -a]pyridine, 6, ll-dιhydro-6, 11-dιoxo-napht-The document Chem Rev., 63, 279-296 (1963), by Sartori MF, describes the synthesis of heterocyclic qumones from 2, 3-dιchloro-l, 4-dιhydro-l, 4-dιoxo- naphthalenes, in particular naphtimidazopyridines diones and their derivatives Article J Amer. Chem. Soc 79, 5708-5710 (1957) by Truitt P., Cooper JE, Wood FM, Jr, describes a reverse synthesis of β, ll-dιhydro-6, 11-dιoxonnapht [2 ', 3' • 4, 5] îididazo [1, 2-a] pyridine, while the document J. Org. Chem., 24, 374-380 (1959), by Mosby WL, Boyle RJ, discusses the theoretical possibility of obtaining three types of compounds with different structures 5, 6-deιhydro-5, 6-dιoxo-napht [ 1 ', 2': 4, 5] îmidazo- [1, 2-a] pyridine, 5, 6-dιhydro-5, 6-dιoxo-napht [1 ', 2' 4,5] - îmidazo [2, 3 -a] pyridine, 6, ll-de-hydro-6, 11-de-oxo-naphth-
[2 ' , 3 ' •4, 5] îmidazo [1, 2-a] pyridine Les auteurs démontrent[2 ', 3' • 4, 5] îmidazo [1, 2-a] pyridine The authors demonstrate
1 ' obtention du premier type de structure Sur ce même problème l'article J Org Chem , 26, 1316-1318 (1961), par Mosby W L., décrit la possibilité d'obtenir deux ty- pes de produits avec des réactions similaires la 5,6- dιhydro-5, 6-dιoxo-napht [1 ' , 2 ' :4, 5] îmidazo [1, 2-a]pyridine (forme dite angulaire) et la 6, ll-dιhydro-6, 11-dιoxo- napht [2 ' , 3 ' :4, 5] îmidazo [1, 2-a]pyridine (forme dite li¬ néaire) . Les auteurs notent que la formation de la struc- ture linéaire est obtenue moins facilement que la struc¬ ture angulaire Des conditions plus drastiques sont donc nécessaires pour la formation de cette structure (reflux à haute température) La structure '< angulaire » de la famille est démontrée dans la synthèse de la 5,6-dιhydro- 5 , 6-dιoxo-napht [1' , 2 ' :4, 5] îmidazo [1, 2-a] pyridine en uti¬ lisant un réactif spécifique des orthodicetones dans le document J. Org. Chem. 28, 1019-1022 (1963) par Van Allan J. A., Reynolds G. A..1 obtaining the first type of structure On this same problem the article J Org Chem, 26, 1316-1318 (1961), by Mosby W L., describes the possibility of obtaining two types of products with similar reactions 5,6- dιhydro-5, 6-dιoxo-napht [1 ', 2': 4, 5] îmidazo [1, 2-a] pyridine (so-called angular form) and 6, ll-deιhydro-6, 11 -dιoxo- napht [2 ', 3': 4, 5] îmidazo [1, 2-a] pyridine (form called li¬ born). The authors note that the formation of the linear structure is obtained less easily than the angular structure. More drastic conditions are therefore necessary for the formation of this structure (reflux at high temperature). The " angular" structure of the family is demonstrated in the synthesis of 5,6-dιhydro- 5, 6-dιoxo-napht [1 ', 2': 4, 5] îmidazo [1, 2-a] pyridine by using a specific reagent of orthodicetones in the document J. Org. Chem. 28, 1019-1022 (1963) by Van Allan JA, Reynolds GA.
Le brevet U.S. 2,970,146 , Jan. 31, 1961 (Cl 260- 256.4) , par Boyle R. J., Birsten 0. G., Mosby W L , dé¬ crit la synthèse de nouvelles orthoquinones hétérocycli¬ ques. Le document Indian J Chemistry 18B, 236-239 (1979) par Ayyangar N R., Lugade A. G., Tilak B D décrit la synthèse univoque de la 6, ll-dιhydro-6, ll-dioxo-napht- [2',3' :4,5] îmidazo [1, 2-a]pyridine Le document J. Indian Chem. Soc. 68(9) , 529-531 (1991) par Yanni A. S , décrit la synthèse et l'activité bactéricide et fongicide de la 6, ll-dιhydro-6, 11-dιoxo- pyrido [1 ' , 2 ' : 1, 2] îmidazo [5 , 4-g] quinolme. Enfin le brevet DE 1,108,699 par Schellhammer C. W., Domagk G., décrit l'activité cytostatique et bacteriostatique des dérivés de la 5, 6-dιhydro-5, 6-dιoxo-pyrιdo [1 ' , 2 ' : 1, 2] imidazo [4, 5- f]quinolme.U.S. Patent 2,970,146, Jan. 31, 1961 (Cl 260- 256.4), by Boyle RJ, Birsten 0. G., Mosby WL, describes the synthesis of new heterocyclic orthoquinones. The document Indian J Chemistry 18B, 236-239 (1979) by Ayyangar N R., Lugade AG, Tilak BD describes the unequivocal synthesis of 6, ll-dehydro-6, ll-dioxo-naphth- [2 ', 3' : 4,5] îmidazo [1, 2-a] pyridine The document J. Indian Chem. Soc. 68 (9), 529-531 (1991) by Yanni A. S, describes the synthesis and bactericidal and fungicidal activity of 6, ll-dιhydro-6, 11-dιoxo- pyrido [1 ', 2': 1 , 2] îmidazo [5, 4-g] quinolme. Finally the patent DE 1,108,699 by Schellhammer CW, Domagk G., describes the cytostatic and bacteriostatic activity of the derivatives of 5, 6-dιhydro-5, 6-dιoxo-pyrιdo [1 ', 2': 1, 2] imidazo [ 4, 5- f] quinolme.
Les dérivés tétracycliques et leurs sels acccepta- bles du point de vue pharmaceutique selon la présente in¬ vention répondent à la formule générale .The tetracyclic derivatives and their pharmaceutically acceptable salts according to the present invention correspond to the general formula.
(I) dans laquelle indépendamment les uns des autres :(I) in which independently of each other:
X est un atome de carbone ou un atome d'azote, T est un atome de carbone ou un atome d'azote,X is a carbon atom or a nitrogen atom, T is a carbon atom or a nitrogen atom,
Ri est un atome d'hydrogène, un atome d'halogène, un radical alkyle en C]_ à C5,Ri is a hydrogen atom, a halogen atom, an alkyl radical of C] _ to C5,
R2 est un atome d'hydrogène, un atome d'halogène, un radical nitro, un radical alkyle en C^ à C5, n et m sont soit égal à 0 soit à 1, mais non indé¬ pendamment l'un de l'autre de telle sorte que si n est égal à 1 alors m est égal à 0, et si n est égal à 0 alors m est égal à 1.R2 is a hydrogen atom, a halogen atom, a nitro radical, a C ^ to C5 alkyl radical, n and m are either equal to 0 or 1, but not independently of one of the other so that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1.
L'invention concerne également les produits nouveaux ci-après :The invention also relates to the following new products:
- la 5, 6-dιhydro-5, 6-dιoxo-9-méthyl-napht- [1' , 2 ' :4, 5] îmidazo[1,2-a]pyridine ;- 5, 6-dιhydro-5, 6-dιoxo-9-methyl-napht- [1 ', 2': 4, 5] îididazo [1,2-a] pyridine;
- la 5, 6-dιhydro-5, 6-dιoxo-10-méthyl-napht- [l' , 2 ' :4, 5] îmidazo [1, 2-a]pyridine ,- 5, 6-dιhydro-5, 6-dιoxo-10-methyl-napht- [l ', 2': 4, 5] îmidazo [1, 2-a] pyridine,
- la 5, 6-dιhydro-5, 6-dιoxo-ll-méthyl-napht- [1 ' , 2 ' -4,5] îmidazo [1, 2-a] pyridine ;- 5, 6-dιhydro-5, 6-dιoxo-ll-methyl-napht- [1 ', 2' -4,5] îmidazo [1, 2-a] pyridine;
- la ll-chloro-5 , 6-dιhydro-5, 6-dιoxo-napht- [1 ' , 2 ' :4, 5] îmidazo[1, 2-a]pyridine ;- ll-chloro-5,6-dιhydro-5,6-dιoxo-napht- [1 ', 2': 4, 5] îmidazo [1, 2-a] pyridine;
- la 5, 6-dιhydro-5, 6-dιoxo-9-fluoro-napht- [1 ' , 2 ' :4, 5] imidazo [1, 2-a]pyridine ;- 5, 6-dιhydro-5, 6-dιoxo-9-fluoro-napht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine;
- la 9-chloro-5, 6-dιhydro-5, 6-dioxo-4-nιtro-napht- [1 ' , 2 ' : 4, 5] imidazo [1, 2-a] pyridine ;- 9-chloro-5, 6-dehydro-5, 6-dioxo-4-nιtro-napht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine;
- la 6, ll-dιhydro-6, ll-dioxo-2-méthyl-napht- [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine ,- 6, ll-dιhydro-6, ll-dioxo-2-methyl-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine,
- la 2-chloro-6, ll-dιhydro-6, 11-dιoxo-napht- [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine ;- 2-chloro-6,11-dehydro-6,11-dιoxo-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine;
- la 4-chloro-6, ll-dιhydro-6, 11-dιoxo-napht- [2 ', 3 ' :4, 5] imidazo [1, 2-a] pyridine ,- 4-chloro-6, ll-dehydro-6, 11-dιoxo-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine,
- la 6, ll-dihydro-6, ll-dιoxo-2-fluoro-napht- [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine.- 6, ll-dihydro-6, ll-dιoxo-2-fluoro-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine.
- la 2-chloro-6, ll-dιhydro-6, ll-dιoxo-7-nιtro-napht- [2 ' , 3 ' -4, 5] imidazo [1, 2-a]pyridine - la 2-chloro-6, ll-dιhydro-6, ll-dιoxo-10-nιtro- napht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine- 2-chloro-6, ll-dehydro-6, ll-dιoxo-7-nιtro-napht- [2 ', 3' -4, 5] imidazo [1, 2-a] pyridine - 2-chloro- 6, ll-dιhydro-6, ll-dιoxo-10-nιtro- napht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine
- la 10-chloro-5, 6-dιhydro-5, 6-dιoxonapht- [1 ' , 2 ' :4, 5] imidazo [1, 2-a] pyridine- 10-chloro-5,6-dehydro-5,6-dιoxonapht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine
- la 4-chloro-5 , 6-dihydro-5, 6-dιoxonapht- [1 ' , 2 ' :4, 5] imidazo [1, 2-a]pyridine- 4-chloro-5, 6-dihydro-5, 6-dιoxonapht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine
- la 4-bromo-5, 6-dihydro-5, 6-dιoxonapht- [1 ' , 2 ' 4,5]- îmidazo [1, 2-a] pyridine- 4-bromo-5, 6-dihydro-5, 6-dιoxonapht- [1 ', 2' 4,5] - îmidazo [1, 2-a] pyridine
- la 5 , 6-dιhydro-5, 6-dιoxo-2-nιtronapht [1 ' , 2 ' 4,5]- imidazo [1, 2-a] pyridine - la 6, ll-dιhydro-6, 11-dιoxo-7-nιtronapht-- 5, 6-dehydro-5, 6-dιoxo-2-nιtronapht [1 ', 2' 4,5] - imidazo [1, 2-a] pyridine - 6, ll-deιhydro-6, 11-dιoxo -7-nιtronapht-
[2 ' , 3 ' :4, 5] imidazo [1,2-a]pyridine[2 ', 3': 4, 5] imidazo [1,2-a] pyridine
- la 6, ll-dιhydro-6, ll-dιoxo-10-nιtronapht- [2 ' , 3 ' .4,5] imidazo [1,2-a] pyridine- 6, ll-dehydro-6, ll-dιoxo-10-nιtronapht- [2 ', 3' .4,5] imidazo [1,2-a] pyridine
- la 6, ll-dιhydro-6, ll-dιoxo-8-fluoronapht- [2' , 3' -4,5] imidazo [1, 2-a] pyridine - la 6, ll-dihydro-6, ll-dioxo-9-fluoronapht- [ 2 ' , 3 ' : 4 , 5] imidazo [1, 2-a] pyridine- 6, ll-dιhydro-6, ll-dιoxo-8-fluoronapht- [2 ', 3' -4,5] imidazo [1, 2-a] pyridine - la 6, ll-dihydro-6, ll-dioxo-9-fluoronapht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine
- la 5, β-dihydro-5, 6-dioxo-2-fluoronap.it [1 ' , 2 ' :4, 5] - imidazo [1 , 2-a] pyridine - la 5, 6-dihydro-5, 6-dioxo-3 -fluoronapht [1 ' , 2 ' : 4, 5] - imidazo [1, 2-a] pyridine- 5, β-dihydro-5, 6-dioxo-2-fluoronap.it [1 ', 2': 4, 5] - imidazo [1, 2-a] pyridine - 5, 6-dihydro-5, 6-dioxo-3 -fluoronapht [1 ', 2': 4, 5] - imidazo [1, 2-a] pyridine
- la 6, 11-dihydro-6, 11-dioxo-7-fluoronapht- [2 ' , 3 ' :4, 5] -imidazo [1, 2-a] pyridine- 6, 11-dihydro-6, 11-dioxo-7-fluoronapht- [2 ', 3': 4, 5] -imidazo [1, 2-a] pyridine
- la 6, ll-dihydro-6 , 11-dioxo-10-fluoronapht- [2' ,3' :4,5] imidazo [1, 2-a] pyridine- la 6, ll-dihydro-6, 11-dioxo-10-fluoronapht- [2 ', 3': 4,5] imidazo [1, 2-a] pyridine
- la 5, 6-dihydro-5, 6-dioxo-l-fluoronapht [1 ' , 2 ' :4, 5] - imidazo [1, 2-a] pyridine- 5, 6-dihydro-5, 6-dioxo-1-fluoronapht [1 ', 2': 4, 5] - imidazo [1, 2-a] pyridine
- la 5, 6-dihydro-5, 6-dioxo-4-fluoronapht [1 ' , 2 ' :4, 5] - imidazo [1, 2-a] pyridine - la 4 , 9-dichloro-5 , 6-dihydro-5 , 6-dioxonapht- [1 ' , 2 ' :4 , 5] imidazo [1, 2-a] pyridine- 5, 6-dihydro-5, 6-dioxo-4-fluoronapht [1 ', 2': 4, 5] - imidazo [1, 2-a] pyridine - 4, 9-dichloro-5, 6- dihydro-5, 6-dioxonapht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine
- la 6, ll-dihydro-6 , ll-dioxo-7-méthylnapht- [2 ' , 3 ' : 4 , 5] imidazo [1 , 2-a] pyridine- 6,11-dihydro-6,11-dioxo-7-methylnaphth- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine
- la 6, ll-dihydro-6, ll-dioxo-10-méthylnapht- [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridine- la 6, ll-dihydro-6, ll-dioxo-10-methylnapht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine
- la 5 , 6-dihydro-5 , 6-dioxo-1-méthyl-naphtfl ' , 2 ' : 4 , 5]- imidazo [1,2 -a] pyridine- 5, 6-dihydro-5, 6-dioxo-1-methyl-naphthfl ', 2': 4, 5] - imidazo [1,2 -a] pyridine
- la 5 , 6-dihydro-5 , 6-dioxo-4-méthyl-napht[l ' , 2 ' : 4 , 5]- imidazo [1 , 2-a] pyridine - la 2-chloro-6, ll-dihydro-6, ll-dioxo-7-méthylnapht- [2 ' , 3 ' : 4 , ] imidazo[l, 2- ] pyridine- 5, 6-dihydro-5, 6-dioxo-4-methyl-napht [l ', 2': 4, 5] - imidazo [1, 2-a] pyridine - 2-chloro-6, ll- dihydro-6, ll-dioxo-7-methylnapht- [2 ', 3': 4,] imidazo [l, 2-] pyridine
- la 2-chloro-6 , ll-dihydro-6 , ll-dioxo-10-méthyl- napht [2 ' , 3 ' :4, ] imidazo[l, 2-a] pyridine- 2-chloro-6,11-dihydro-6,11-dioxo-10-methyl-naphth [2 ', 3': 4,] imidazo [1,2-a] pyridine
- la 9-chloro-5 , 6-dihydro-5, 6-dioxo-l-méthylnapht- [1 ' , 2 ' : 4 , ] imidazo [1, 2-a] pyridine- 9-chloro-5,6-dihydro-5,6-dioxo-1-methylnaphth- [1 ', 2': 4,] imidazo [1, 2-a] pyridine
- la 9-chloro-5, 6-dihydro-5 , 6-dioxo-4-méthylnapht- [1 ' , 2 ' :4, 5] imidazo [1, 2-a] pyridine- 9-chloro-5,6-dihydro-5,6-dioxo-4-methylnapht- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine
- la 6 , ll-dihydro-6 , ll-dioxo-8-méthylnapht- [2 ' , 3 ' -.4 , 5] -imidazo [1 , 2-a] pyridine - la 6, ll-dihydro-6, ll-dioxo-9-méthylnapht- [2 ' , 3 ' :4, 5] -imidazo [1, 2-a] pyridine- 6, ll-dihydro-6, ll-dioxo-8-methylnapht- [2 ', 3' -.4, 5] -imidazo [1, 2-a] pyridine - 6, ll-dihydro-6, ll-dioxo-9-methylnaphth- [2 ', 3': 4, 5] -imidazo [1, 2-a] pyridine
- la 5, 6-dihydro-5, 6-dioxo-2-méthylnapht-[l' , 2 ' :4, 5]- imidazo[l, 2-a] pyridine- la 5, 6-dihydro-5, 6-dioxo-2-methylnapht- [l ', 2': 4, 5] - imidazo [l, 2-a] pyridine
- la 5, 6-dihydro-5, 6-dioxo-3-méthylnapht- [1 ' , 2 ' :4, 5] -imidazo[1, 2-a] pyridine- 5, 6-dihydro-5, 6-dioxo-3-methylnapht- [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine
L'invention concerne également les produits intermé¬ diaires ci-après :The invention also relates to the following intermediate products:
- le 2, 3-dibromo-l, 4-dihydro-l, 4-dioxo-6-fluoro- naphtalène - le 2, 3-dibromo-l, 4-dihydro-l, 4-dioxo-5-fluoro- naphtalène- 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene - 2,3-dibromo-1,4-dihydro-4-dioxo-5-fluoronaphthalene
- le 2, 3-dibromo-l, 4-dihydro-l, 4-dioxo-5-méthyl- naphtalène- 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene
L'invention se rapporte aussi à l'utilisation des dérivés tétracycliques et de leurs sels acceptables du point de vue pharmaceutique répondant à la formule géné¬ rale (I) ci-dessus pour l'obtention d'un médicament des¬ tiné :The invention also relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts corresponding to the general formula (I) above for obtaining a medicinal product intended:
- au traitement de l'insuffisance veineuse fonction- nelle et organique ;- to the treatment of functional and organic venous insufficiency;
- au traitement des pathologies hémorroidaires ;- the treatment of hemorrhoidal pathologies;
- au traitement de la migraine ;- to the treatment of migraine;
- au traitement des inflammations ostéoarticulaires dermatologiques et cardiovasculaires ; - au traitement des états de chocs constitués par une chute importante' de la pression artérielle, plus par¬ ticulièrement dans les états de chocs septiques .- to the treatment of osteoarticular dermatological and cardiovascular inflammations; - the treatment of states of shock constituted by a substantial drop 'blood pressure, more par¬ ticularly in states of septic shock.
De façon spécifique, les composés de la présente in vention répondent à la formule générale (I) illustrée c après : Specifically, the compounds of the present invention correspond to the general formula (I) illustrated below:
(I) ou n = 0 ou 1 m = 0 ou 1 T ≈ C, N X = C, N (I) or n = 0 or 1 m = 0 or 1 T ≈ C, NX = C, N
R. = H, N02, Cl, Br, F, CH3 La présente invention concerne également les sels des composés salifiables de formule (I) Ces sels compren¬ nent les sels d'addition d'acides minéraux tels que l'acide chlorhydrique, bromhydrique, sulfurique, phospho¬ rique, ou nitrique et les sels d'addition d'acides orga- niques tels que l'acide acétique, propiomque, oxalique, citrique, maléique, fumarique, succmique, tartriqueR. = H, N0 2 , Cl, Br, F, CH 3 The present invention also relates to the salts of the salifiable compounds of formula (I) These salts include the addition salts of mineral acids such as acid hydrochloric, hydrobromic, sulfuric, phosphoric, or nitric and the addition salts of organic acids such as acetic, propiomic, oxalic, citric, maleic, fumaric, succric, tartaric acid
L'invention est illustrée par les exemples non limi¬ tatifs ci-aprèsThe invention is illustrated by the following nonlimiting examples
Les exemples indiqués par un chiffre correspondent à de nouveaux composés tandis que les exemples comprenant une lettre correspondent à des composés connusThe examples indicated by a number correspond to new compounds while the examples comprising a letter correspond to known compounds
Dans tous les exemples, les analyses sont réalisées comme indiqué ci-aprèsIn all the examples, the analyzes are carried out as indicated below
- Points de fusion Ils ont été réalisés sur un ap- pareil de type «Banc de Kofler» LEICA - REICHERT modèle- Melting points They were made on a LEICA “Kofler bench” type device - REICHERT model
WMEWME
- Chromatocrraphies sur couche mince Elles ont été obtenues sur des plaques de gel de silice avec indicateur de fluorescence UV2S4 de 0,25 mm d'épaisseur de type MACHEREY-NAGEL (Référence 805 023) . Les solvants d'élution sont indiqués pour chaque composé.- Thin layer chromatographs They were obtained on silica gel plates with indicator 0.25 mm thick UV fluorescence 2S4 type MACHEREY-NAGEL (Reference 805 023). Elution solvents are indicated for each compound.
- Spectres de masse : Ils ont été effectués soit sur un spectrometre de type AEI MS-50 soit sur un spectrome¬ tre de type FISONS VG PLATFORM. Le mode d'ionisation est indiqué pour chaque analyse.- Mass spectra: They were carried out either on a spectrometer of the AEI MS-50 type or on a spectrometer of the FISONS VG PLATFORM type. The ionization mode is indicated for each analysis.
- Spectres RMN : Les spectres de RMN du XH et du 13C ont été réalisés soit sur un spectrometre de type JEOL respectivement à 270 MHz et à 68 MHz, soit sur un spec¬ trometre de type BRUCKER respectivement à 400 MHz et à 100 MHz Les solvants deutérés utilisés sont indiqués pour chaque analyse.- NMR spectra: The X H and 13 C NMR spectra were performed either on a JEOL type spectrometer at 270 MHz and 68 MHz respectively, or on a BRUCKER type spectrometer at 400 MHz and 100 respectively. MHz The deuterated solvents used are indicated for each analysis.
- Spectres Infra-Roucre Ils ont été obtenus sur un spectrometre de type NICOLET 205 FT-IR. Ils sont effec¬ tués à 1 % (m/m) en dispersion dans le KBr.- Infra-Roucre spectra They were obtained on a NICOLET 205 FT-IR type spectrometer. They are effec¬ killed at 1% (m / m) in dispersion in the KBr.
Exemple 1Example 1
5, 6-Dihvdro-5, 6-dioxo-9-méthyl-napht[1' ,2 ' :4, 5] - imidazo [1 , 2-a]pyridine A une suspension de 10 g (44 mmoles) de 2,3- dιchloro-1, 4-dihydro-l, 4-dιoxo-naphtalène dans 150 ml d'éthanol que l'on porte à reflux, on ajoute 4,76 g (44 mmoles) de 2-amιno-5-méthylpyrιdme en solution dans 50 ml d'éthanol. Après 48 heures de reflux le mélange réactionnel est évaporé à sec et purifié sur colonne flash (support silice ; conditionnement heptane éluant . dichlorométhane) pour fournir sur du sulfate 5 g de 5, 6-dihydro-5, 6-dioxo-9-méthyl-napht [l' ,2' :4,5]- îmidazo [1, 2-a]pyridine sous forme de cristaux orange. Rdt : 48 % F : > 260°C5, 6-Dihvdro-5, 6-dioxo-9-methyl-napht [1 ', 2': 4, 5] - imidazo [1, 2-a] pyridine To a suspension of 10 g (44 mmol) of 2 , 3- dιchloro-1, 4-dihydro-l, 4-dιoxo-naphthalene in 150 ml of ethanol which is brought to reflux, 4.76 g (44 mmol) of 2-amιno-5-methylpyrιdme are added dissolved in 50 ml of ethanol. After 48 hours of reflux the reaction mixture is evaporated to dryness and purified on a flash column (silica support; heptane conditioning eluent. Dichloromethane) to provide on sulphate 5 g of 5,6-dihydro-5,6-dioxo-9-methyl -naphth [l ', 2': 4,5] - îmidazo [1, 2-a] pyridine in the form of orange crystals. Yid: 48% F:> 260 ° C
Rf : 0,54 (CH2Cl2/Méthanol, 98/2) SM (I.E.) . m/z 262 (M+.) RMN du % (CDC13) : δ (ppm) 9,11 (s, IH, H-8) 8,13 (m, 2H, H-l, H-4)Rf: 0.54 (CH 2 Cl 2 / Methanol, 98/2) MS (IE). m / z 262 (M +.) NMR of% (CDC1 3 ): δ (ppm) 9.11 (s, IH, H-8) 8.13 (m, 2H, Hl, H-4)
7,68 (2m, 2H, H-2, H-3)7.68 (2m, 2H, H-2, H-3)
7,50 (m, 2H, H-10, H-ll)7.50 (m, 2H, H-10, H-ll)
2,47 (s, 3H, CH3) RMN du 13C (CDC13) : δ (ppm)2.47 (s, 3H, CH 3 ) 13 C NMR (CDC1 3 ): δ (ppm)
182,16, 167,14 (2C, Cquat)182.16, 167.14 (2C, Cquat)
153,85, 149,24 (2C, Cquat)153.85, 149.24 (2C, Cquat)
135,24, 134,95 (2C, C-2, C-3)135.24, 134.95 (2C, C-2, C-3)
131,58 (1C, Cquat) 130,57 (2C, C-10, Cquat)131.58 (1C, Cquat) 130.57 (2C, C-10, Cquat)
130,00, 124,48 (2C, C-l, C-4)130.00, 124.48 (2C, C-l, C-4)
127,25 (1C, C-8)127.25 (1C, C-8)
120,40 (1C, Cquat)120.40 (1C, Cquat)
117,39 (1C, C-ll) 18,25 (1C, CH3)117.39 (1C, C-ll) 18.25 (1C, CH 3 )
IR (KBr) : μ (cm-1)IR (KBr): μ (cm -1 )
1689, 1652 (C=0)1689, 1652 (C = 0)
Exemple 2Example 2
5, 6-Dihydro-5, 6-dioxo-10-méthyl-napht [1' , 2 ' :4, 51 - imidazo [1.2-alpyridine5, 6-Dihydro-5, 6-dioxo-10-methyl-napht [1 ', 2': 4, 51 - imidazo [1.2-alpyridine
A une suspension de 4,54 g ( 20 mmoles) de 2,3- dichloro-l, 4-dihydro-l, 4-dioxo-naphtalène dans 200 ml d'éthanol que l'on porte à reflux, on ajoute 2,16 g (20 mmoles) de 2-amino-4-méthylpyridine en solution dans 50 ml d'éthanol. Après 18 heures de reflux, le mélange réac¬ tionnel est évaporé " à sec et purifié sur colonne flashTo a suspension of 4.54 g (20 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxo-naphthalene in 200 ml of ethanol which is brought to reflux, 2 is added, 16 g (20 mmol) of 2-amino-4-methylpyridine in solution in 50 ml of ethanol. After 18 hours of reflux, the mixture is evaporated tional réac¬ "to dryness and purified on a flash column
(support : silice ; conditionnement : heptane ,- éluant : dichlorométhane) pour fournir 3,19 g de 5, 6-dihydro-5, 6- dioxo-10-méthyl-napht [1 ' , 2 ' :4, 5] imidazo [1, 2-a]pyridine. Rdt : 61 %(support: silica; packaging: heptane, - eluent: dichloromethane) to provide 3.19 g of 5, 6-dihydro-5, 6 dioxo-10-methyl-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine. YId: 61%
F : > 260°CF:> 260 ° C
Rf : 0,64 (CH2Cl2/Méthanol, 97/3)Rf: 0.64 (CH 2 Cl 2 / Methanol, 97/3)
SM ( I . E . ) : m/ z 262 ( M+ . )SM (I. E.): M / z 262 (M +.)
RMN du *H (CDCI3 ) : δ (ppm) 9 , 11 ( d , IH , H- 8 , JH9.H9 = 6 , 71 Hz ) 8,08 (m, 2H, H-l, H-4)* H NMR (CDCI3): δ (ppm) 9, 11 (d, IH, H- 8, J H9 . H9 = 6.71 Hz) 8.08 (m, 2H, Hl, H-4)
7,65, 7,53 (2m, 2H, H-2, H-3)7.65, 7.53 (2m, 2H, H-2, H-3)
7,48 (m, IH, H-ll)7.48 (m, 1H, H-ll)
7,02 (d, IH, H-9, JH9.H9 ≈ 6,71 Hz) 2,52 (s, 3H, CH3)7.02 (d, IH, H-9, J H9 . H9 ≈ 6.71 Hz) 2.52 (s, 3H, CH 3 )
RMN du 13C (CDCI3) : δ (ppm) 13 C NMR (CDCI3): δ (ppm)
182,39, 167,26 (2C, Cquat)182.39, 167.26 (2C, Cquat)
153,20, 150,79 (2C, Cquat)153.20, 150.79 (2C, Cquat)
144,48 (1C, Cquat) 135,22, 130,68 (2C, C-2, C-3)144.48 (1C, Cquat) 135.22, 130.68 (2C, C-2, C-3)
131,51 (1C, Cquat)131.51 (1C, Cquat)
130,02, 124,63 (3C, C-l, C-4, Cquat)130.02, 124.63 (3C, C-1, C-4, Cquat)
128, 18 (1C, C-8)128, 18 (1C, C-8)
120, 01 (1C, Cquat) 118, 99 (1C, C-ll)120, 01 (1C, Cquat) 118, 99 (1C, C-ll)
117,15 (1C, C-9)117.15 (1C, C-9)
22,00 (1C, CH3)22.00 (1C, CH3)
IR (KBr) : μ (cm1)IR (KBr): μ (cm 1 )
1701, 1656 (C=0) Exemple 31701, 1656 (C = 0) Example 3
5, 6-Dihydro-5, 6-dioxo-11-méthyl-napht [!' .2 ' .-4,51 - imidazo [1, 2-a]pyridine5, 6-Dihydro-5, 6-dioxo-11-methyl-napht [! ' .2 '.-4,51 - imidazo [1, 2-a] pyridine
A une suspension de 10 g (44 mmoles) de 2,3- dichloro-1, 4-dihydro-1, 4-dioxo-naphtalène dans 150 ml d'éthanol que l'on porte à reflux, on ajoute 4,76 g (44 mmoles) de 2-amino-3-méthylpyridine en solution dans 50 ml d'éthanol. Après 48 heures de reflux le mélange réac¬ tionnel est évaporé à sec et purifié sur colonne flashTo a suspension of 10 g (44 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxo-naphthalene in 150 ml of ethanol which is brought to reflux, 4.76 g is added (44 mmol) of 2-amino-3-methylpyridine in solution in 50 ml of ethanol. After 48 hours of reflux, the reaction mixture is evaporated to dryness and purified on a flash column.
(support : silice ; conditionnement : heptane ,- éluant : dichlorométhane) pour fournir 6 g de 5, 6-dihydro-5, 6- dioxo-11-méthyl-napht [1 ' , 2 • :4, 5] imidazo [1,2-a] pyridine sous forme de cristaux orange.(support: silica; packaging: heptane, - eluent: dichloromethane) to provide 6 g of 5, 6-dihydro-5, 6 dioxo-11-methyl-napht [1 ', 2 • : 4, 5] imidazo [1 , 2-a] pyridine in the form of orange crystals.
Rdt : 52 %Yid: 52%
F : > 260°C Rf : 0,46 (CH2Cl2/Méthanol, 99/1) SM (I.E.) : m/z 262 (M+ . ) RMN du % (CDC13) : δ (ppm)F:> 260 ° C Rf: 0.46 (CH 2 Cl 2 / Methanol, 99/1) MS (IE): m / z 262 (M +.) NMR of% (CDC1 3 ): δ (ppm)
9, 16 (d, IH, H-8, JH8.Hg = 6,72 Hz)9, 16 (d, IH, H-8, J H8 . Hg = 6.72 Hz)
8,23 (d, IH, H-l, JH1.HJ = 7,63 Hz) 8,11 (d, IH, H-4, JH3.H4 = 7,63 Hz)8.23 (d, IH, Hl, J H1 . HJ = 7.63 Hz) 8.11 (d, IH, H-4, J H3 . H4 = 7.63 Hz)
7,69 (dd, IH, H-3, JH3-H4 = JH2.H3 = 7, 63 Hz)7.69 (dd, IH, H-3, J H3-H4 = J H2 . H3 = 7.63 Hz)
7,50 (dd, IH, H-2, JH2.H3 = JH1.H3 = 7,63 Hz)7.50 (dd, IH, H-2, J H2 . H3 = J H1 . H3 = 7.63 Hz)
7,43 (d, IH, H-10, JH9-H10 = 7,32 Hz)7.43 (d, IH, H-10, J H9-H10 = 7.32 Hz)
7,09 (dd, IH, H-9, JHβ-H9 = JH9-H10 = 6,72 Hz) 2,72 (S, 3H, CH3)7.09 (dd, IH, H-9, J Hβ-H9 = J H9-H10 = 6.72 Hz) 2.72 (S, 3H, CH 3 )
RMN du 13C (CDCI3) : δ (ppm) 13 C NMR (CDCI3): δ (ppm)
182,29 (1C, C-5)182.29 (1C, C-5)
167,32 (1C, C-6a)167.32 (1C, C-6a)
153,61 (1C, C-12a) 150,56 (1C, C-lla)153.61 (1C, C-12a) 150.56 (1C, C-lla)
135,18 (1C, C-2)135.18 (1C, C-2)
131,73 (1C, C-4a)131.73 (1C, C-4a)
131,32 (1C, C-10)131.32 (1C, C-10)
130,82 (1C, C-12b) 130,55 (1C, C-3)130.82 (1C, C-12b) 130.55 (1C, C-3)
130,00 (1C, C-4)130.00 (1C, C-4)
128,73 (1C, Cquat)128.73 (1C, Cquat)
126,72 (1C, C-8)126.72 (1C, C-8)
124,75 (1C, C-l) 116,65 (1C, C-9)124.75 (1C, C-1) 116.65 (1C, C-9)
16,87 (1C, CH3)16.87 (1C, CH3)
IR (KBr) : μ (cm1)IR (KBr): μ (cm 1 )
1691, 1646 (C=0)1691, 1646 (C = 0)
Exemple 4 ll-Chloro-5.6-dihvdrσ-5, 6-dioxo-napht ri' .2 ' :4.51 - imidazo [1, 2-a]pyridineExample 4 ll-Chloro-5.6-dihvdrσ-5, 6-dioxo-napht ri '.2': 4.51 - imidazo [1, 2-a] pyridine
A une suspension de 2,86 g (10,3 mmoles) du 1,2- dihydro-1, 2-dioxo-4-sulfonate de potassiumnaphtalene dansTo a suspension of 2.86 g (10.3 mmol) of 1,2-dihydro-1,2,2-dioxo-4-sulfonate of potassiumnaphthalene in
50 ml d'eau distillée, on ajoute 2,00 g (15,56 mmoles) de 2-amino-3-chloropyridine . Ce mélange est porté à reflux pendant 4 heures 30 minutes. Après complet refroidisse¬ ment, le précipité est filtré sur verre fritte, lavé à l'eau distillée et séché. Le solide marron obtenu est pu¬ rifié sur colonne flash (support : silice ; éluant : di- chlorométhane/acétate d'ethyle, 100/0 à 96/4) pour four¬ nir après décoloration au noir animal et recristallisa- tion dans le chlorobenzene 0,63 g de ll-chloro-5, 6- dihydro-5, 6-dioxo-napht [1 ' , 2 ' :4, 5] imidazo [1, 2-a] pyridine . Rdt : 21 % Rf : 0,37 (CH2C12/Acétate d'ethyle, 96/4) SM (I.E.) : m/z 282, 284 (M+ . ) RMN du ^-H (CDCI3) : δ (ppm) 9,25 (d, IH, H-8, JHβ-H9 = 6,71 Hz) 8,33 (d, IH, H-l, JH1.H2 = 7,33 Hz) 8,15 (dd, IH, H-4, JH3.H4 = 7,94 Hz) 7,70 (m, 2H, H-10, H-3)50 ml of distilled water, 2.00 g (15.56 mmol) of 2-amino-3-chloropyridine are added. This mixture is brought to reflux for 4 hours 30 minutes. After complete cooling, the precipitate is filtered through sintered glass, washed with distilled water and dried. The brown solid obtained is pu¬ rified on a flash column (support: silica; eluent: dichloromethane / ethyl acetate, 100/0 to 96/4) to provide after discoloration with animal black and recrystallization in the chlorobenzene 0.63 g of ll-chloro-5,6-dihydro-5,6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine. Yield: 21% Rf: 0.37 (CH 2 C1 2 / Ethyl acetate, 96/4) MS (IE): m / z 282, 284 (M +.) ^ -H NMR (CDCI3): δ ( ppm) 9.25 (d, IH, H-8, J Hβ-H9 = 6.71 Hz) 8.33 (d, IH, Hl, J H1 . H2 = 7.33 Hz) 8.15 (dd, IH, H-4, J H3.H4 = 7.94 Hz) 7.70 (m, 2H, H-10, H-3)
7 , 54 ( t , IH , H- 2 , JH2.H3 = JH1.H2 = 7 , 56 Hz ) 7 , 14 ( t , IH , H- 9 , JH8 -H9 = JH9.H10 = 6 , 9. Hz ) RMN du 13C ( CDCI3 ) : δ (ppm) 135,50 (1C, C-2) 131,08 (1C, C-10) 130,95 (1C, C-3) 130,33 (1C, C-4) 127,40 (1C, C-8) 125,32 (1C, C-l) 124,61 (1C, C-ll) 116,35 (1C, C-9) IR (KBr) : μ (cm1) 1653 (C=0) Exemple 57.54 (t, IH, H- 2, J H2 . H3 = J H1 . H2 = 7.56 Hz) 7, 14 (t, IH, H- 9, J H8 -H9 = J H9 . H10 = 6 , 9. Hz) 13 C NMR (CDCI3): δ (ppm) 135.50 (1C, C-2) 131.08 (1C, C-10) 130.95 (1C, C-3) 130.33 (1C, C-4) 127.40 (1C, C-8) 125.32 (1C, Cl) 124.61 (1C, C-ll) 116.35 (1C, C-9) IR (KBr): μ (cm 1 ) 1653 (C = 0) Example 5
5, 6-Dihydro-5, 6-dioxo-9-fluoro-napht [1' ,2' :4, 51 - imidazo C1.2-alpyridine5, 6-Dihydro-5, 6-dioxo-9-fluoro-napht [1 ', 2': 4, 51 - imidazo C1.2-alpyridine
A une suspension de 1,200 g (4,3 mmoles) de 1,2- dihydro-1, 2-dioxo-4-suifonate de potassium-naphtalène dans 40 ml d'eau, on ajoute 0,635 g (5,7 mmoles) de 2- ammo-5-fluoropyridme. Le mélange réactionnel est chauf¬ fé à reflux pendant 3 heures. Après complet refroidisse¬ ment, le précipité formé est filtré sur verre fritte, la¬ vé à l'eau et séché. Le solide rouge obtenu est purifié sur colonne flash (support • silice ; éluant : dichloro- méthane/acétate d'ethyle, 100/0 à 90/10) pour fournir après décoloration au noir animal 0,023 g de 5,6-Dιhydro- 5, 6-dioxo-9-fluoro-napht [l1 , 2 ' :4, 5] imidazo [1, 2-a] pyridine sous forme de cristaux jaunes. Rdt : 2 %To a suspension of 1.200 g (4.3 mmol) of 1,2-dihydro-1,2-dioxo-4-potassium sulfonate-naphthalene in 40 ml of water, 0.635 g (5.7 mmol) of 2- ammo-5-fluoropyridme. The reaction mixture is heated under reflux for 3 hours. After complete cooling, the precipitate formed is filtered through sintered glass, washed with water and dried. The red solid obtained is purified on a flash column (support • silica; eluent: dichloromethane / ethyl acetate, 100/0 to 90/10) to provide, after discoloration with animal black, 0.023 g of 5.6-Dιhydro-5 , 6-dioxo-9-fluoro-napht [l 1 , 2 ': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals. Yid: 2%
Rf : 0,42 (CH,C12/Acétate d'ethyle, 90/10) SM (I.E.) : m/z 266 (M+.) RMN du XΗ. (270 MHz, CDC13) : d (ppm) 9,27 (m, IH, H-8, JHβ.F = 4,88 Hz) 8,17, 8,15 (2d, 2H, H-l, H-4, JH1.H2 = JH3-H4 = 7,32 Hz)Rf: 0.42 (CH, C1 2 / Ethyl acetate, 90/10) MS (IE): m / z 266 (M +.) X Η NMR. (270 MHz, CDC1 3 ): d (ppm) 9.27 (m, IH, H-8, J Hβ . F = 4.88 Hz) 8.17, 8.15 (2d, 2H, Hl, H- 4, J H1 . H2 = J H3-H4 = 7.32 Hz)
7,80 (dd, IH, H-10, JH10 H11 = 9,77 Hz, JH10.F = 4, 88 Hz) 7,71 (t, IH, H-2, JH1_H. = JH2.H3 = 7,63 Hz 7,53 (m, 2H, H-3, H-ll) IR (KBr) : μ (cm-1) 1686, 1654, 1633 (C=0) Exemples 6 et 77.80 (dd, IH, H-10, J H10 H11 = 9.77 Hz, J H10 . F = 4.88 Hz) 7.71 (t, IH, H-2, J H1 _ H. = J H2 . H3 = 7.63 Hz 7.53 (m, 2H, H-3, H-ll) IR (KBr): μ (cm -1 ) 1686, 1654, 1633 (C = 0) Examples 6 and 7
2-Chloro-6,11-dihydro-6.11-dioxo-7-nitronapht- [2' , 3' :4, 51 imidazo[1, 2-alpyridine ou2-Chloro-6,11-dihydro-6.11-dioxo-7-nitronapht- [2 ', 3': 4, 51 imidazo [1, 2-alpyridine or
2-Chloro-6,ll-dihvdro-6, ll-dιoxo-10-nιtronapht- [2" , 3' :4, 51 imidazo[1, 2-alpyridine et2-Chloro-6, ll-dihvdro-6, ll-dιoxo-10-nιtronapht- [2 ", 3 ': 4, 51 imidazo [1, 2-alpyridine and
9-Chloro-5, 6-dihvdro-5, 6-dioxo-4-nitronapht- [1' .2' :4, 51 imidazo [1,2-alpyridine9-Chloro-5, 6-dihvdro-5, 6-dioxo-4-nitronapht- [1 '.2': 4, 51 imidazo [1,2-alpyridine
A une solution de 2,50 g (11,0 mmoles) de 2,3- dιchloro-1, 4-dihydro-1, 4-dioxo-5-nitronaphtalêne dans 500 ml d'éthanol, on ajoute 2,50 g (19,0 mmoles) de 2- aramo-5-chloropyridme. Ce mélange est chauffé à reflux pendant 62h50mιnutes . La solution passe du jaune au bor¬ deaux puis à l'orange. Après refroidissement, on filtre le milieu réactionnel. Le précipité est lavé à l'ethanol puis séché à l'étuve pendant 20 h. Le précipité obtenu est recristallisé dans 650 ml d'éthanol. Ce précipité est purifié sur colonne flash (support : silice ; éluant : dichlorométhane) . On recueille 0,260 g de 2-chloro-6, 11- dιhydro-6, ll-dιoxo-7-nιtronapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] - pyridine ou 2-chloro-6, ll-dihydro-6, ll-dioxo-10-nιtro- napht [2 ', 3 ' :4, 5] imidazo [1, 2-a] pyridine sous forme de cristaux oranges et 0,495 g de 10-chloro-5, 6-dιhydro-5, 6- dιoxo-4-nιtronapht [1 ' , 2 ' .-4,5] imidazo [1, 2-a]pyridine sous forme de cristaux oranges . 2-Chloro-6,11-dihydro-6, ll-dioxo-7-nitronapht-To a solution of 2.50 g (11.0 mmol) of 2,3-dιchloro-1, 4-dihydro-1, 4-dioxo-5-nitronaphthalene in 500 ml of ethanol, 2.50 g is added ( 19.0 mmol) of 2- aramo-5-chloropyridme. This mixture is heated at reflux for 62 h 50 min. The solution changes from yellow to boreaux and then to orange. After cooling, the reaction medium is filtered. The precipitate is washed with ethanol and then dried in an oven for 20 h. The precipitate obtained is recrystallized from 650 ml of ethanol. This precipitate is purified on a flash column (support: silica; eluent: dichloromethane). 0.260 g of 2-chloro-6, 11- dehydro-6, ll-dιoxo-7-nιtronapht [2 ', 3': 4, 5] imidazo [1, 2-a] - pyridine or 2-chloro- are collected 6, ll-dihydro-6, ll-dioxo-10-nιtro- napht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of orange crystals and 0.495 g of 10-chloro- 5, 6-dehydro-5, 6-dιoxo-4-nιtronapht [1 ', 2'.-4,5] imidazo [1, 2-a] pyridine in the form of orange crystals. 2-Chloro-6,11-dihydro-6, ll-dioxo-7-nitronapht-
[2 ' , 3 ' :4, 51 imidazo [1,2-alpyridine ou[2 ', 3': 4, 51 imidazo [1,2-alpyridine or
2-Chloro-6,11-dihydro-6, 11-dioxo-10-nitronapht-2-Chloro-6,11-dihydro-6, 11-dioxo-10-nitronapht-
[2' , 3 ' :4, 5] imidazo[1,2-al[2 ', 3': 4, 5] imidazo [1,2-al
Rdt : 9 % F : > 260°CYid: 9% F:> 260 ° C
Rf : 0,75 (CH2Cl2/MeOH, 98/2)Rf: 0.75 (CH 2 Cl 2 / MeOH, 98/2)
SM (I.E.) : 327, 329 (M' )SM (I.E.): 327, 329 (M ')
RMN du '"H (CDjCl2) : δ (ppm)1 H NMR (CDjCl 2 ): δ (ppm)
9,38 (dd, IH, H-l, JHi.H3 = 1,66 Hz, JH1.H4 = 0,83 Hz) 8,30 (dd, IH, H-10 ou H-7, JH,.H10 ou JH7.H8 = 7,05 ou 7,479.38 (dd, IH, Hl, J Hi . H3 = 1.66 Hz, J H1 . H4 = 0.83 Hz) 8.30 (dd, IH, H-10 or H-7, J H ,. H10 or J H7 . H8 = 7.05 or 7.47
Hz, JHB-HIO OU JH7.H9 = 2,08 ou 1,66 Hz)Hz, J HB - HIO OR J H7 . H9 = 2.08 or 1.66 Hz)
7, 82 (dd, IH, H-4, JH3.H4 = 9,55 Hz ou JH1.H4 = 0,83 Hz)7.82 (dd, IH, H-4, J H3 . H4 = 9.55 Hz or J H1 . H4 = 0.83 Hz)
7,60(m, 3H, H-3, H-8 et H-9)7.60 (m, 3H, H-3, H-8 and H-9)
IR (KBr) : v (cm'1) 1650 (C=0) , 1540, 1400 (N02)IR (KBr): v (cm '1 ) 1650 (C = 0), 1540, 1400 (N0 2 )
9-Chloro-5, 6-dihydro-5, 6-dioxo-4-nitronapht-9-Chloro-5, 6-dihydro-5, 6-dioxo-4-nitronapht-
El' .2 ' :4, 5] imidazo[1,2-alpyridineEl '.2': 4, 5] imidazo [1,2-alpyridine
Rdt : 13 %Yid: 13%
F : > 260°C Rf : 0,35 (CH2Cl2/MeOH, 98/2)F:> 260 ° C Rf: 0.35 (CH 2 Cl 2 / MeOH, 98/2)
SM (I.E.) : 327, 329 (M*.)SM (IE): 327, 329 (M * .)
RMN du 'H (CD2C12) : δ (ppm)'H NMR (CD 2 C1 2 ): δ (ppm)
9,30 (dd, IH, H-8, JHβ.H10 = 2,16 Hz, J„,.H11 = 0,83 Hz)9.30 (dd, IH, H-8, J Hβ . H10 = 2.16 Hz, J „,. H11 = 0.83 Hz)
8,40 (dd, IH, H-l, JHi.H2 = 7, 89 Hz, JH1.H3 = 1,25 Hz) 7, 86 (C, XH, H- 2 , *J H2-H3 = ^m-H2 = 7, 89 HZ) 7,82 (dd, IH, H-ll, JHlβ.H11 = 9,55 Hz, JHβ.HX1 = 0, 83 Hz) 7, 68 (dd, IH, H-10, J„lβ H11 = 9,55 Hz ou JH9.H10 = 2,16 Hz) 7,52 (dd, IH, H-3, JH2.H3 = 7,89 Hz ou JH1_H- = 1,25 Hz) RMN du "C (CD2C12) : δ (ppm) 166,94 (1C, Cquat)8.40 (dd, IH, Hl, J Hi . H2 = 7.89 Hz, J H1 . H3 = 1.25 Hz) 7.86 (C, XH, H- 2, * J H2 - H3 = ^ m - H2 = 7.89 HZ) 7.82 (dd, IH, H-ll, J Hlβ . H11 = 9.55 Hz, J Hβ . HX1 = 0.83 Hz) 7.68 (dd, IH, H-10, J „ lβ H11 = 9 , 55 Hz or J H9 . H10 = 2.16 Hz) 7.52 (dd, IH, H-3, J H2.H3 = 7.89 Hz or J H1 _ H - = 1.25 Hz) NMR of " C (CD 2 C1 2 ): δ (ppm) 166.94 (1C, Cquat)
136,87 (1C, C-2) 134,26 (1C, C-l) 127,58 (1C, C-3) 119,26 (1C, C-ll) IR (KBr) : v (cm"1)136.87 (1C, C-2) 134.26 (1C, Cl) 127.58 (1C, C-3) 119.26 (1C, C-ll) IR (KBr): v (cm "1 )
1650 (C=0) , 1540 (N02) Exemple 81650 (C = 0), 1540 (N0 2 ) Example 8
6,11-Dihydro-6, 11-dioxo-2-méthyl-napht[2' , 3' :4, 5] - imidazo [1,2-a]pyridine A une suspension de 0,45 g (2,16 mmoles) de 3- chloro-1, 4-dihydro-1, 4-dioxo-2-hydroxy-naphtalène dans 15 ml de 1, 2-dιméthoxyéthane, on ajoute 0,55 g (5,08 mmoles) de 2-ammo-5-méthylpyπdine . Le milieu réactionnel est porté à reflux pendant 21 heures. Après complet refroi- dissement, il est dilué avec 120 ml de dichlorométhane. La phase organique est lavée successivement avec une so¬ lution saturée d'hydrogénocarbonate de sodium et de chlo¬ rure de sodium puis séchée sur du sulfate de sodium et évaporée sous pression réduite. Le produit brut obtenu est purifié sur colonne moyenne pression (support si¬ lice ; éluant : dichlorométhane/heptane/acétate d'ethyle, 68/40/2) pour fournir après décoloration au noir animal 0,096 g de 6, ll-dihydro-6, ll-dιoxo-2-méthyl-napht- [2 ', 3 ' :4, 5] imidazo [1, 2-a]pyridine sous forme de cristaux jaunes.6,11-Dihydro-6, 11-dioxo-2-methyl-napht [2 ', 3': 4, 5] - imidazo [1,2-a] pyridine A suspension of 0.45 g (2.16 mmol) of 3-chloro-1, 4-dihydro-1, 4-dioxo-2-hydroxy-naphthalene in 15 ml of 1, 2-dιméthoxyéthane, 0.55 g (5.08 mmol) of 2-ammo is added -5-methylpyπdine. The reaction medium is brought to reflux for 21 hours. After complete cooling, it is diluted with 120 ml of dichloromethane. The organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and sodium chloride, then dried over sodium sulfate and evaporated under reduced pressure. The crude product obtained is purified on a medium pressure column (silica support; eluent: dichloromethane / heptane / ethyl acetate, 68/40/2) to provide, after discoloration with animal black, 0.096 g of 6, ll-dihydro-6 , ll-dιoxo-2-methyl-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals.
Rdt : 17 %YId: 17%
Rf : 0,34 (CH2C12/Acétate d'ethyle, 94/6)Rf: 0.34 (CH 2 C1 2 / Ethyl acetate, 94/6)
SM (I.E.) : m/z 262 (M+.)SM (I.E.): m / z 262 (M +.)
RMN du !H (CD2C12) : δ (ppm) 9,21 (s, IH, H-l) 8,22 (m, 2H, H-7, H-10) 7,78 (m, 3H, H-4, H-8, H-9)! H NMR (CD 2 C1 2 ): δ (ppm) 9.21 (s, IH, Hl) 8.22 (m, 2H, H-7, H-10) 7.78 (m, 3H, H-4, H-8, H-9)
7,49 (dd, IH, H-3, JH3-H4 = 9,16 Hz, JH1.HJ = 1,52 Hz) 2,48 (s, 3H, CH3) IR (KBr) : v (cm1) 1685 (C=0) Exemple 97.49 (dd, IH, H-3, J H3-H4 = 9.16 Hz, J H1 . HJ = 1.52 Hz) 2.48 (s, 3H, CH 3 ) IR (KBr): v ( cm 1 ) 1685 (C = 0) Example 9
2-Chloro-6,11-dihydro-6,11-dioxo-napht[2' ,3' :4, 51 - imidazo [1,2-alpyridine A une suspension de 1,29 g (6,21 mmoles) de 3- chloro-l, 4-dihydro-l, 4-dioxo-2-hydroxy-naphtalène en so¬ lution dans 10 ml de 1, 2-diméthoxyéthane, on ajoute 1,58 g (12,30 mmoles) de 2-amino-5-chloropyridine . Le milieu réactionnel est porté à reflux pendant 23 heures. Après complet refroidissement, le milieu est dilué dans 10 ml d'eau. Le précipité est filtré, lavé à l'eau, à l'heptane puis séché. Le précipité est ensuite dilué dans le di¬ chlorométhane puis la phase organique est lavée successi¬ vement par une solution saturée d'hydrogénocarbonate de sodium et de chlorure de sodium. La phase organique est séchée sur du sulfate de sodium, filtrée puis évaporée sous pression réduite. Le produit brut obtenu est purifié sur colonne flash (support : silice ; éluant : dichloro- méthane/heptane/méthanol, 79,5/20/0,5) pour fournir après décoloration au noir animal 0,07 g de 2-chloro-6, 11- dihydro-6, ll-dioxo-nàpht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine sous forme de cristaux jaunes. Rdt : 4 % F : > 300°C Rf : 0,27 (CH2C12/Acétate d'ethyle, 96/4) SM (I.E.) : m/z 282 (M+.) RMN du iH (CD2C12) : δ (ppm) 9,49 (d, IH, H-l, JH1.H3 = 2,13 Hz) 8,25 (m, 2H, H-7, H-10) 7,87 (d, IH, H-4, JH3.H4 = 9,77 Hz) 7,79 (m, 2H, H-8, H-9)2-Chloro-6,11-dihydro-6,11-dioxo-napht [2 ', 3': 4, 51 - imidazo [1,2-alpyridine To a suspension of 1.29 g (6.21 mmol) of 3- chloro-1,4-dihydro-1,4-dioxo-2-hydroxy-naphthalene in solution in 10 ml of 1,2-dimethoxyethane, 1.58 g (12.30 mmol) of 2- amino-5-chloropyridine. The reaction medium is brought to reflux for 23 hours. After complete cooling, the medium is diluted in 10 ml of water. The precipitate is filtered, washed with water, with heptane and then dried. The precipitate is then diluted in di¬ chloromethane then the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate and sodium chloride. The organic phase is dried over sodium sulfate, filtered and then evaporated under reduced pressure. The crude product obtained is purified on a flash column (support: silica; eluent: dichloromethane / heptane / methanol, 79.5 / 20 / 0.5) to provide, after discoloration with animal black, 0.07 g of 2-chloro- 6, 11-dihydro-6, 11-dioxo-napht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals. Yield: 4% F:> 300 ° C Rf: 0.27 (CH 2 C1 2 / Ethyl acetate, 96/4) SM (IE): m / z 282 (M +.) IH NMR (CD 2 C1 2 ): δ (ppm) 9.49 (d, IH, Hl, J H1 . H3 = 2.13 Hz) 8.25 (m, 2H, H-7, H-10) 7.87 (d, IH , H-4, J H3 . H4 = 9.77 Hz) 7.79 (m, 2H, H-8, H-9)
7,61 (dd, IH, H-3, JH3.H4 = 9,76 Hz, JH1.H3 = 2,13 Hz)7.61 (dd, IH, H-3, J H3 . H4 = 9.76 Hz, J H1 . H3 = 2.13 Hz)
RMN du 13C (CD2C12) : δ (ppm) 13 C NMR (CD 2 C1 2 ): δ (ppm)
183,08 (1C, C=0) 178,13 (1C, C=0)183.08 (1C, C = 0) 178.13 (1C, C = 0)
162,73, 160,86 (2C, Cquat)162.73, 160.86 (2C, Cquat)
149,26, 148,08, 146,75 (3C, Cquat)149.26, 148.08, 146.75 (3C, Cquat)
134,59, 134,30 (2C, C-8, C-9)134.59, 134.30 (2C, C-8, C-9)
132,53 (1C, C-3) 130,40 (1C, C-2)132.53 (1C, C-3) 130.40 (1C, C-2)
127,70, 126,85 (2C, C-7, C-10)127.70, 126.85 (2C, C-7, C-10)
126,73 (1C, C-l)126.73 (1C, C-1)
120,24 (1C, C-4)120.24 (1C, C-4)
IR (KBr) : v (cm1) 1686, 1651 (C=0)IR (KBr): v (cm 1 ) 1686, 1651 (C = 0)
Exemple 10Example 10
4-chloro-6, 11-dihydro-6, 11-dioxo-napht [2'.3' ;4,5]- imidazo [1,2-alpyridine4-chloro-6, 11-dihydro-6, 11-dioxo-napht [2'.3 '; 4,5] - imidazo [1,2-alpyridine
850 mg (2,66 mmoles) de 2- (3-chloro-2-pyridylamino) - 3-chloro-l, 4-dihydro-l, 4-dioxo-naphtalène en solution dans 80 ml de glycérol sont portés à 190°C pendant 20 mi¬ nutes. Après complet refroidissement, le précipité jaune obtenu est filtré sur un verre fritte, lavé à l'eau dis¬ tillé et recristallisé dans du méthanol après décolora- tion au noir animal pour fournir 300 mg de 4-chloro-6, 11- dihydro-6, 11-dioxo-nâpht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine sous forme de cristaux jaunes.850 mg (2.66 mmol) of 2- (3-chloro-2-pyridylamino) - 3-chloro-1,4, dihydro-1,4, dioxo-naphthalene in solution in 80 ml of glycerol are brought to 190 ° C for 20 minutes. After complete cooling, the yellow precipitate obtained is filtered through a sintered glass, washed with distilled water and recrystallized from methanol after decolorization in animal black to provide 300 mg of 4-chloro-6,11-dihydro- 6, 11-dioxo-nâpht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals.
Rdt : 40 %Yid: 40%
F : > 300°C Rf : 0,10 (CH2C12)F:> 300 ° C Rf: 0.10 (CH 2 C1 2 )
SM (I.E.) : m/z 282 (MH+ . )SM (I.E.): m / z 282 (MH +.)
RMN du XH (CD2C12) : δ (ppm) X H NMR (CD 2 C1 2 ): δ (ppm)
9,37 (dd, IH, H-l, JH1.H2 = 7,01 Hz, JH1.B3 = 0,91 Hz)9.37 (dd, IH, Hl, J H1 . H2 = 7.01 Hz, J H1 . B3 = 0.91 Hz)
8,26 (m, 2H, H-7, H-10) 7,81 (m, 2H, H-8, H-9) 7,71 (dd, IH, H-3, JH3.H2 ≈ 7,63 Hz, JH3 H1 = 0,91 Hz) 7,21 (t, IH, H-2, JH2 H3 = 7,32 Hz) IR (KBr) : v (cm-1) 1682, 1649 (C=0) Exemple 118.26 (m, 2H, H-7, H-10) 7.81 (m, 2H, H-8, H-9) 7.71 (dd, IH, H-3, J H3 . H2 ≈ 7.63 Hz, J H3 H1 = 0.91 Hz) 7.21 (t, IH, H-2, J H2 H3 = 7.32 Hz) IR (KBr): v (cm -1 ) 1682, 1649 (C = 0) Example 11
6,ll-Dihvdro-6,ll-dioxo-2-fluoro-napht [2' ,3' :4,51 - imidazo [1,2-alpyridine6, ll-Dihvdro-6, ll-dioxo-2-fluoro-napht [2 ', 3': 4,51 - imidazo [1,2-alpyridine
A une suspension de 0,98 g (4,72 mmoles) de 3- chloro-1, 4-dιhydro-l, 4-dιoxo-2-hydroxy-naphtalène en so- lution dans 10 ml de 1, 2-dιméthoxyéthane, on ajoute 0,98 g (8,75 mmoles) de 2-ammo-5-fluoropyridme Le milieu réactionnel est porté à reflux pendant 23 heures. Après complet refroidissement, le milieu est dilué dans 10 ml d'eau. Le précipité est filtré, lavé à l'eau, à 1 'heptane puis séché. Le précipité est ensuite dilué dans le di¬ chlorométhane puis la phase organique est lavée successi¬ vement par une solution saturée d'hydrogénocarbonate de sodium puis de chlorure de sodium. La phase organique est séchée sur du sulfate de sodium, filtrée puis évaporée sous pression réduite. Le produit brut obtenu est purifié sur colonne flash (support . silice , éluant • dichloro- méthane/méthanol, 99/1) pour fournir après décoloration au noir animal 0,03 g de 6, ll-dιhydro-6 , ll-dιoxo-2- fluoro-napht [2 ', 3 ' :4, 5] -imidazo [1, 2-a] pyridine sous forme de cristaux jaunes. Rdt : 2, 3 %To a suspension of 0.98 g (4.72 mmol) of 3-chloro-1,4-dehydro-1,4-dιoxo-2-hydroxy-naphthalene in solution in 10 ml of 1,2-methoxyethane, 0.98 g (8.75 mmol) of 2-ammo-5-fluoropyridme is added. The reaction medium is brought to reflux for 23 hours. After complete cooling, the medium is diluted in 10 ml of water. The precipitate is filtered, washed with water, with heptane and then dried. The precipitate is then diluted in di¬ chloromethane then the organic phase is washed successively with a saturated solution of sodium hydrogencarbonate then of sodium chloride. The organic phase is dried over sodium sulfate, filtered and then evaporated under reduced pressure. The crude product obtained is purified on a flash column (support. Silica, eluent • dichloromethane / methanol, 99/1) to provide, after discoloration with animal black, 0.03 g of 6, ll-dιhydro-6, ll-dιoxo- 2- fluoro-naphth [2 ', 3': 4, 5] -imidazo [1, 2-a] pyridine in the form of yellow crystals. Yid: 2, 3%
Rf : 0,55 (CH2C12/Acétate d'ethyle, 96/4) SM (I.E.) : m/z 266 (M+ . ) RMN du % (CD.C12) : δ (ppm) 9,37 (m, IH, H-l, JH1 F = JH1-H3 = 3,36 Hz) 8,25 (m, 2H, H-7, H-10)Rf: 0.55 (CH 2 C1 2 / Ethyl acetate, 96/4) SM (IE): m / z 266 (M +.) NMR of% (CD.C1 2 ): δ (ppm) 9.37 (m, IH, Hl, J H1 F = J H1-H3 = 3.36 Hz) 8.25 (m, 2H, H-7, H-10)
7,91 (dd, IH, H-4, JH3 H4 = 9,76 Hz, JH4.F = 4,88 Hz) 7,80 (m, 2H, H-8, H-9) 7,56 (m, IH, H-3, JH3-H< = 10,07 Hz, JH3.F = 7, 94 Hz, JH1 H3 = 2,75 Hz) IR (KBr) : v (cm1)7.91 (dd, IH, H-4, J H3 H4 = 9.76 Hz, J H4 . F = 4.88 Hz) 7.80 (m, 2H, H-8, H-9) 7.56 (m, IH, H-3, J H3-H < = 10.07 Hz, J H3 . F = 7.94 Hz, J H1 H3 = 2.75 Hz) IR (KBr): v (cm 1 )
1686, 1681 (C=0) Exemple 121686, 1681 (C = 0) Example 12
10-Chloro-5, 6-dihvdro-5, 6-dioxonapht [!' ,2 ' :4.51 - imidazo [1,2-alpyridine10-Chloro-5, 6-dihvdro-5, 6-dioxonapht [! ' , 2 ': 4.51 - imidazo [1,2-alpyridine
A une suspension de 6,64 g (28,9 mmoles) de 2,3- dichloro-l, 4-dihydro-l, 4-dioxonaphtalène dans 95 ml de glycérol, on ajoute 3,27 g (25,9 mmoles) de 2-amino-4- chloropyridine . Ce mélange est chauffé à 205°C pendant 10 minutes. La solution passe du jaune au marron foncé.To a suspension of 6.64 g (28.9 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 95 ml of glycerol, 3.27 g (25.9 mmol) is added of 2-amino-4-chloropyridine. This mixture is heated at 205 ° C for 10 minutes. The solution changes from yellow to dark brown.
Après refroidissement complet, on ajoute au milieu réactionnel 5 ml de méthanol puis on l'extrait au dichlo¬ rométhane. La phase organique est séchée, filtrée puis évaporée à sec . Ce précipité est purifié sur cake (support : si¬ lice ; éluant : heptane/dichlorométhane/acétate d'ethyle, 100/0/0 à 0/95/5) . Le solide obtenu est recristallisé dans le chlorobenzène pour fournir après traitement au noir animal puis passage sur filtre micropore 0,16 g de 10-chloro-5, 6-dihydro-5, 6-dioxonapht [1 ' , 2 ' :4, 5] imidazo- [1, 2-a]pyridine sous forme de cristaux oranges.After complete cooling, 5 ml of methanol are added to the reaction medium and then it is extracted with dichlo¬ romethane. The organic phase is dried, filtered and then evaporated to dryness. This precipitate is purified on a cake (support: si¬ lice; eluent: heptane / dichloromethane / ethyl acetate, 100/0/0 to 0/95/5). The solid obtained is recrystallized from chlorobenzene to provide, after treatment with animal black, then passage over a micropore filter 0.16 g of 10-chloro-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5 ] imidazo- [1, 2-a] pyridine in the form of orange crystals.
Rdt : 2 %Yid: 2%
F : > 300°CF:> 300 ° C
Rf : 0,30 (CH2Cl2/Ac0Et, 96/4) SM (I.E.) : m/z 282/284 (M* ) , 254/256 (M-CO)Rf: 0.30 (CH 2 Cl 2 / Ac0Et, 96/4) SM (IE): m / z 282/284 (M * ), 254/256 (M-CO)
RMN du XE (CD2C12) : δ (ppm) X E NMR (CD 2 C1 2 ): δ (ppm)
9,28 (d, IH, H-8, JHβ-H9 = 6, 67 Hz)9.28 (d, IH, H-8, J Hβ-H9 = 6.67 Hz)
8,28 (d, IH, H-l, JH1.H2 = 6,13 Hz)8.28 (d, IH, Hl, J H1 . H2 = 6.13 Hz)
8,20 (d, IH, H-4, JH3.H4 = 8,00 Hz) 7,93 (S, IH, H-ll)8.20 (d, IH, H-4, J H3 . H4 = 8.00 Hz) 7.93 (S, IH, H-ll)
7,82 (dd, IH, H-2, JK1-K2 ou J„2.K3 = 6,67 Hz)7.82 (dd, IH, H-2, J K1-K2 or J „ 2 .. K3 = 6.67 Hz)
7,65 (dd, IH, H-3, JH2.H3 ou JH3.K4 = 8,00 Hz)7.65 (dd, IH, H-3, J H2 . H3 or J H3 . K4 = 8.00 Hz)
7,30 (dd, IH, H-9, JHβ.H9 = 6,93 Hz, JH9.H11 = 2,13 Hz)7.30 (dd, IH, H-9, J Hβ . H9 = 6.93 Hz, J H9 . H11 = 2.13 Hz)
IR (KBr) : v (cm1) 1699, 1650 (C=0) , 1626 (C = N) Exemple 13IR (KBr): v (cm 1 ) 1699, 1650 (C = 0), 1626 (C = N) Example 13
4-Chloro-5, 6-dihydro-5, 6-dioxonapht[1' ,2 ' ;4,51 - imidazo [1, 2-a]pyridine4-Chloro-5, 6-dihydro-5, 6-dioxonapht [1 ', 2'; 4,51 - imidazo [1, 2-a] pyridine
A une suspension orange de 80 mg (0,27 mmole, 1 éq) de 5, 6-dιhydro-5, 6-dιoxo-4-nιtronapht [1 ' , 2 ' 4,5]ιmιdazo- [1, 2-a] pyridine dans l'ethanol sous argon, on ajoute une quantité catalytique de palladium sur charbon à 10 % et on porte le mélange à reflux On additionne alors 26,4 μl d'hydrazme monohydratée (0,27 mmole, 1 éq) Le mélange réactionnel se colore immédiatement en violet Apres 30 minutes, on ajoute 26,4 μl d'hydrazme monohydratée (0,27 mmole, 1 éq) Après 1 heure de réaction, le mélange réactionnel est laissé revenir à température ambiante et le précipité marron-violet est filtré sur coton séché et solubilisé dans 5 ml d'acide chlorhydrique concentréTo an orange suspension of 80 mg (0.27 mmol, 1 eq) of 5, 6-dehydro-5, 6-dιoxo-4-nιtronapht [1 ', 2' 4,5] ιmιdazo- [1, 2-a ] pyridine in ethanol under argon, a catalytic amount of palladium on carbon at 10% is added and the mixture is brought to reflux. 26.4 μl of hydrazme monohydrate (0.27 mmol, 1 eq) are then added. reaction immediately turns purple After 30 minutes, 26.4 μl of hydrazme monohydrate (0.27 mmol, 1 eq) are added After 1 hour of reaction, the reaction mixture is allowed to return to ambient temperature and the brown-purple precipitate is filtered through dried cotton and dissolved in 5 ml of concentrated hydrochloric acid
Cette solution est refroidie à -10°C puis on additionne goutte à goutte une solution formée par 34 mg (0,49 mmo¬ le , 1,8 éq) de nitrite de sodium et 5 ml d'eau dis¬ tillée. Le milieu est laissé sous agitation à cette tem- pérature pendant 0,5 heure On ajoute goutte à goutte le milieu réactionnel à une solution refroidie a -5°C, for¬ mée de 18 mg (0,18 mmole , 0,7 éq) de chlorure de cuivre I et de 5 ml d'acide chlorhydrique concentré L'agitation est poursuivie pendant 2,5 heures. Le milieu réactionnel est ensuite dilué dans du dichlorométhane, lavé successi¬ vement par une solution saturée de carbonate de sodium puis d'eau distillée. La phase organique est extraite puis séchée sur du sulfate de sodium et évaporée a sec Le produit brut est purifié sur plaques préparatives (support . silice, éluant dichlorométhane/méthanol, 90/10) pour fournir 10 mg de 4-chloro-5 , 6-dιhydro-5, 6- dioxonapht [1 ' , 2 ' 4, 5] imidazo [1, 2-a] pyridine sous forme de cristaux jaunes Rdt : 14 % F : > 260°C Rf : 0,60 (Dichlorométhane/Méthanol, 98/2) SM (APcI-) : m/z 282/284 (M-) RMN du λH (CD2C12) : δ (ppm) 9,14 (d, IH, H-8, JHa.H9 = 6,43 Hz) 8,16 (d, IH, H-l, JH1.H2 = 7,54 Hz, JH1.H3 = 1,51 Hz) 7,75 (d, IH, H-ll, JHlβ.H11 = 8,41 Hz) 7,60 (t, IH, H-10, JH9-H1Û = JJUO-HH = 8,40 Hz) 7,53 (t, IH, H-2, JHι-H2 - JH2-H3 = 7,91 Hz) 7,46 (d, IH, H-3, JH2.H3 = 7,51 Hz, JH1.H3 = 1,51 Hz) 7,15 (t, IH, H-9, JHa.H9 = JH9.H10 = 6,43 Hz) IR (KBr) : v (cm-1) 1662 (C=0) Exemple 14This solution is cooled to -10 ° C. and then a solution formed by 34 mg (0.49 mmol, 1.8 eq) of sodium nitrite and 5 ml of distilled water is added dropwise. The medium is left stirring at this temperature for 0.5 hour. The reaction medium is added dropwise to a solution cooled to -5 ° C, formed with 18 mg (0.18 mmol, 0.7 eq ) copper chloride I and 5 ml of concentrated hydrochloric acid Stirring is continued for 2.5 hours. The reaction medium is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate and then distilled water. The organic phase is extracted then dried over sodium sulfate and evaporated to dryness The crude product is purified on preparative plates (support. Silica, eluent dichloromethane / methanol, 90/10) to provide 10 mg of 4-chloro-5,6 -dιhydro-5, 6- dioxonapht [1 ', 2' 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals Yield: 14% F:> 260 ° C Rf: 0.60 (Dichloromethane / Methanol, 98/2) SM (APcI-): m / z 282/284 (M-) NMR of λ H (CD 2 C1 2 ): δ (ppm) 9.14 (d , IH, H-8, J Ha . H9 = 6.43 Hz) 8.16 (d, IH, Hl, J H1 . H2 = 7.54 Hz, J H1 . H3 = 1.51 Hz) 7.75 (d, IH, H-ll, J Hlβ . H11 = 8.41 Hz) 7.60 (t, IH, H-10, J H9-H1Û = J JUO - HH = 8.40 Hz) 7.53 ( t, IH, H-2, J Hι -H2 - J H2 - H3 = 7.91 Hz) 7.46 (d, IH, H-3, J H2 . H3 = 7.51 Hz, J H1 . H3 = 1.51 Hz) 7.15 (t, IH, H-9, J Ha . H9 = J H9 . H10 = 6.43 Hz) IR (KBr): v (cm -1 ) 1662 (C = 0) Example 14
4-Bromo-5, 6-dihydro-5, 6-dioxonapht [!' ,2 ' :4. SI - imidazo [1,2-alpyridine4-Bromo-5, 6-dihydro-5, 6-dioxonapht [! ' , 2 ': 4. SI - imidazo [1,2-alpyridine
A une suspension orange de 110 mg (0,37 mmole, 1 éq) de 5, 6-dihydro-5, 6-dioxo-4-nιtronapht [1 ' , 2 ' :4, 5] imidazo- [1, 2-a]pyπdme dans l'ethanol sous argon, on ajoute une quantité catalytique de palladium sur charbon à 10 % et on porte le mélange à reflux. On additionne alors 36,3 μl d'hydrazme monohydratée (0,37 mmole, 1 éq) . Le mélange réactionnel se colore immédiatement en violet. Après 30 minutes, on ajoute 36,3 μl d'hydrazme monohydratée (0,37 mmole, 1 éq) . Après 1 heure de réaction, le mélange réactionnel est laissé revenir à température ambiante et le précipité marron-violet est filtré sur coton séché et solubilisé dans 15 ml d'acide bromhydrique concentré. Cette solution est refroidie à -15°C puis on additionne goutte à goutte une solution formée par 64 mg (0,93 mmo- le, 2,5 éq) de nitrite de sodium et 5 ml d'eau distillée. Le milieu est laissé sous agitation à cette température pendant 1,5 heure. On ajoute goutte à goutte le milieu réactionnel à une solution refroidie à -5°C, formée de 21 mg (0,15 mmole, 0,4 éq) de bromure de cuivre I et de 5 ml d'acide bromhydrique concentré. On obtient une solu- tion violette dont l'agitation est poursuivie pendant 2,5 heures. Le milieu réactionnel est ensuite dilué dans du dichlorométhane, lavé successivement par une solution sa¬ turée de carbonate de sodium puis d'eau distillée La phase organique est extraite puis séchée sur du sulfate de sodium et évaporée à sec. Le produit brut est purifié sur plaques préparatives (support • silice, éluant Di¬ chlorométhane/Méthanol, 95/5) pour fournir 30 mg de 4- bromo-5, 6-dιhydro-5, 6-dioxonapht [1' , 2 ' :4, 5] imidazo [1,2- a] -pyridine sous forme de cristaux jaunes. Rdt : 25 % F : > 260°CTo an orange suspension of 110 mg (0.37 mmol, 1 eq) of 5, 6-dihydro-5, 6-dioxo-4-nιtronapht [1 ', 2': 4, 5] imidazo- [1, 2- a] pyπdme in ethanol under argon, a catalytic amount of palladium on carbon at 10% is added and the mixture is brought to reflux. 36.3 μl of hydrazme monohydrate (0.37 mmol, 1 eq) are then added. The reaction mixture immediately turns purple. After 30 minutes, 36.3 μl of hydrazme monohydrate (0.37 mmol, 1 eq) are added. After 1 hour of reaction, the reaction mixture is allowed to return to room temperature and the brown-purple precipitate is filtered through dried cotton and dissolved in 15 ml of concentrated hydrobromic acid. This solution is cooled to -15 ° C. and then a solution formed by 64 mg (0.93 mmol, 2.5 eq) of sodium nitrite and 5 ml of distilled water is added dropwise. The medium is left stirring at this temperature for 1.5 hours. The reaction medium is added dropwise to a solution cooled to -5 ° C, formed from 21 mg (0.15 mmol, 0.4 eq) of copper bromide I and 5 ml of concentrated hydrobromic acid. We get a solution violet color whose agitation is continued for 2.5 hours. The reaction medium is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate and then distilled water. The organic phase is extracted then dried over sodium sulfate and evaporated to dryness. The crude product is purified on preparative plates (support • silica, eluent Di¬ chloromethane / Methanol, 95/5) to provide 30 mg of 4-bromo-5, 6-dehydro-5, 6-dioxonapht [1 ', 2' : 4, 5] imidazo [1,2- a] -pyridine in the form of yellow crystals. Yid: 25% F:> 260 ° C
Rf : 0,60 (Dichlorométhane/Méthanol, 98/2) SM (APcI+) : m/z 326/328 (M+H*) RMN du "H (CD2C12) : δ (ppm)Rf: 0.60 (Dichloromethane / Methanol, 98/2) SM (APcI +): m / z 326/328 (M + H * ) "H NMR (CD 2 C1 2 ): δ (ppm)
9,13 (d, IH, H-8, JHβ.H9 = 6,93 Hz) 8,21 (d, IH, H-l, JH1 H2 = 7,42 Hz) 7,75 (d, IH, H-ll, JH10-H11 = 8,90 Hz) 7,71 (d, IH, H-3, JH2.H3 = 7, 91 Hz) 7,60 (dd, IH, H-10, JH9.H10 = JH10-H11 = 8,90 Hz)9.13 (d, IH, H-8, J Hβ . H9 = 6.93 Hz) 8.21 (d, IH, Hl, J H1 H2 = 7.42 Hz) 7.75 (d, IH, H -ll, J H10-H11 = 8.90 Hz) 7.71 (d, 1H, H-3, J H2 . H3 = 7.91 Hz) 7.60 (dd, IH, H-10, J H9 . H10 = J H10-H11 = 8.90 Hz)
7,42 (t, IH, H-2, JH1.H2 = JH2.H3 = 7,42 Hz) 7,15 (t, IH, H-9, JHβ H9 = JH9 H10 = 7,91 Hz) IR (KBr) : v (cm1) 1610 (C=0) Exemple 15 ou Exemple i7.42 (t, IH, H-2, J H1 . H2 = J H2 . H3 = 7.42 Hz) 7.15 (t, IH, H-9, J Hβ H9 = J H9 H10 = 7.91 Hz) IR (KBr): v (cm 1 ) 1610 (C = 0) Example 15 or Example i
5, 6-dihydro-5, 6-dioxo-2-nitronapht [l',2' ;4,51- imidazo [1,2-alpyridine ou5, 6-dihydro-5, 6-dioxo-2-nitronapht [l ', 2'; 4,51- imidazo [1,2-alpyridine or
5, 6-dihydro-5, 6-dioxo-3-nitronapht[1' ,2' :4,51 - imidazo [1.2-alpyridine A une solution de 1,00 g (3,67 mmoles, 1,0 éq) de5, 6-dihydro-5, 6-dioxo-3-nitronapht [1 ', 2': 4.51 - imidazo [1.2-alpyridine To a solution of 1.00 g (3.67 mmol, 1.0 eq) of
2, 3-dichloro-1, 4-dihydro-1, 4-dιoxo-6-nιtronaphtalène dans 200 ml d'éthanol on ajoute 0,42 g (4,41 mmoles, 1,2 éq) de 2-amιnopyrιdme. Le mélange réactionnel est porté à reflux 24 heures. La réaction est laissée refroidir à température ambiante, le précipité orange formé durant la réaction est filtré puis purifié sur colonne flash (support : silice 6-35 μm, h = 30 cm, d = 9 cm ; condi¬ tionnement : heptane-acétate d'ethyle, 70/30 ; éluant heptane/acétate d'ethyle, 70/30 puis dichlorométhane/ acétate d'ethyle, 50/50) pour fournir après evaporation la fraction la plus polaire 0,20 g de 5, 6-dιhydro-5, 6- dιoxo-2-nιtronapht [1 ' , 2 ' :4, 5] imidazo [1,2-a] pyridine ou 5, 6-dihydro-5, 6-dioxo-3-nιtronapht [1 ' , 2 ' :4, 5] imidazo- [1, 2-a]pyridine sous forme de cristaux ocre. Rdt : 18,5 % F : > 300°C2, 3-dichloro-1, 4-dihydro-1, 4-dιoxo-6-nιtronaphthalene in 200 ml of ethanol 0.42 g (4.41 mmol, 1.2 eq) of 2-amnopyride is added. The reaction mixture is brought to reflux for 24 hours. The reaction is allowed to cool to room temperature, the orange precipitate formed during the reaction is filtered and then purified on a flash column (support: silica 6-35 μm, h = 30 cm, d = 9 cm; conditioning: heptane-ethyl acetate, 70/30; eluent heptane / ethyl acetate, 70/30 then dichloromethane / ethyl acetate, 50/50) to provide, after evaporation, the most polar fraction 0.20 g of 5, 6-dehydro-5, 6-dιoxo-2-nιtronapht [1 ', 2' : 4, 5] imidazo [1,2-a] pyridine or 5, 6-dihydro-5, 6-dioxo-3-nιtronapht [1 ', 2': 4, 5] imidazo- [1, 2-a] pyridine in the form of ocher crystals. Yid: 18.5% F:> 300 ° C
Rf : 0,20 (heptane/acétate d'ethyle, 70/30) SM (APcI-) : m/z 293 (M-) , 263 (M - NO) RMN du XE (DMSO-ds) : δ (ppm) 9,36 (d, IH, H-8, JHβ.H9 = 7,62 Hz)Rf: 0.20 (heptane / ethyl acetate, 70/30) SM (APcI-): m / z 293 (M-), 263 (M - NO) X E NMR (DMSO-d s ): δ (ppm) 9.36 (d, 1H, H-8, J Hβ . H9 = 7.62 Hz)
8,96 (s, IH, H-l ou H-4, en α du nitro)8.96 (s, IH, H-l or H-4, in α of nitro)
8,57 (d, IH, H-l ou H-4, JH1.H2 = JH3.H4 = 8,54 Hz, en β du nitro)8.57 (d, IH, Hl or H-4, J H1 . H2 = J H3 . H4 = 8.54 Hz, in β of nitro)
8,43 (d, IH, H-2 ou H-3, JH1-H2 = JH3.H4 = 8,54 Hz) 7,92 (d, IH ; H-ll, JH10-H11 = 7,63 Hz)8.43 (d, IH, H-2 or H-3, J H1-H2 = J H3 . H4 = 8.54 Hz) 7.92 (d, IH; H-ll, J H10-H11 = 7, 63 Hz)
7,75 (t, IH, H-10, JH9.Hi0 = JH10-H11 = 7,63 Hz) 7,32 (t, IH, H-9, JH8.H9 = JH9.H10 = 7, 63 Hz) IR (KBr) : v (cm"1) 1649 (C=0) , 1522 (N02) Exemple 167.75 (t, IH, H-10, J H9 . Hi0 = J H10-H11 = 7.63 Hz) 7.32 (t, IH, H-9, J H8.H9 = J H9 . H10 = 7 , 63 Hz) IR (KBr): v (cm "1 ) 1649 (C = 0), 1522 (N0 2 ) Example 16
6,ll-dihvdro-6, ll-dioxo-7-nitronapht [2 ' ,3 ' :4, 51 - imidazo [1, 2-alpyridine ou6, ll-dihvdro-6, ll-dioxo-7-nitronapht [2 ', 3': 4, 51 - imidazo [1, 2-alpyridine or
6,11-dihydro-6, 11-dioxo-10-nitronapht [2' ,3 ' ;4, 51 - imidazo[1,2-alpyridine A une solution de 5,00 g (18 mmoles ; 1 éq) de 2,3- dichloro-l, 4-dihydro-1, 4-dioxo-5-nitronaphtalêne dans 400 ml d'éthanol, on ajoute 1,73 g (18 mmoles ,- 1 éq) de 2-aminopyridine. Le mélange est porté à reflux 5 heures. Après apparition d'un précipité orange, la réaction est laissée refroidir à température ambiante et le précipité est filtré puis purifié sur colonne flash (support : si¬ lice 6-35 μm, h = 45 cm, d = 16 cm ; conditionnement : heptane/acétate d'ethyle, 50/50 ,- éluant : heptane/acé¬ tate d'ethyle, 50/50 à 70/30) pour obtenir 0,54 g de 6 , ll-dihydro-6 , ll-dioxo-7-nitro-napht [2 ' , 3 ' : 4 , 5] imidazo- [1, 2-a] pyridine ou 6 , ll-dihydro-6, ll-dioxo-10-nitro- napht- [2 ' , 3 ' : 4, 5] imidazo [1, 2-a] pyridine qui après recris¬ tallisation dans le 1, 2-dichlorobenzène fournit 0,24 g de produit attendu sous forme de cristaux oranges. Rdt : 4, 5 %6,11-dihydro-6, 11-dioxo-10-nitronapht [2 ', 3'; 4, 51 - imidazo [1,2-alpyridine To a solution of 5.00 g (18 mmol; 1 eq) of 2 , 3-dichloro-1,4-dihydro-1,4,4-dioxo-5-nitronaphthalene in 400 ml of ethanol, 1.73 g (18 mmol, -1 eq) of 2-aminopyridine are added. The mixture is brought to reflux for 5 hours. After the appearance of an orange precipitate, the reaction is allowed to cool to room temperature and the precipitate is filtered and then purified on a flash column (support: 6-35 μm silice, h = 45 cm, d = 16 cm; packaging: heptane / ethyl acetate, 50/50, - eluent: heptane / acetate d 'ethyle, 50/50 to 70/30) to obtain 0.54 g of 6, ll-dihydro-6, ll-dioxo-7-nitro-napht [2', 3 ': 4, 5] imidazo- [1 , 2-a] pyridine or 6, ll-dihydro-6, ll-dioxo-10-nitro- naphth- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine which after recris¬ tallization in 1,2-dichlorobenzene provides 0.24 g of the expected product in the form of orange crystals. Yid: 4.5%
F : > 300°C (décomposition)F:> 300 ° C (decomposition)
Rf : 0,40 (heptane/acétate d'ethyle, 70/30)Rf: 0.40 (heptane / ethyl acetate, 70/30)
SM (APcI+) : m/z 294 (M+H*)SM (APcI +): m / z 294 (M + H * )
RMN du 'H (CDC13) : δ (ppm) 9,35 (d, IH, H-l, JH1.H2 = 6,38 Hz)1 H NMR (CDC1 3 ): δ (ppm) 9.35 (d, IH, Hl, J H1 . H2 = 6.38 Hz)
8,33 (d, IH, H-4, JH3.H4 = 6,39 Hz)8.33 (d, IH, H-4, J H3 . H4 = 6.39 Hz)
7,89 (d, IH, H-7 ou H-10, JH7.HB ou JH9.H10 = 8,44 Hz) 7,73 - 7, 65 (m, 3H, H-2, H-3, H-8 ou H-9) 7,27 (m, IH, H-8 ou H-9, en β du nitro) IR (KBr) : v (cm"1)7.89 (d, IH, H-7 or H-10, J H7 . HB or J H9 . H10 = 8.44 Hz) 7.73 - 7.65 (m, 3H, H-2, H-3 , H-8 or H-9) 7.27 (m, IH, H-8 or H-9, in β of nitro) IR (KBr): v (cm "1 )
1660 (C=0) , 1540 (N02) Exemple 171660 (C = 0), 1540 (N0 2 ) Example 17
6, 11-dihydro-6, ll-dioxo-8-fluoronapht [2 ' , 3 ' :4, 51 - imidazo [1, 2-alpyridine ou 6, 11-dihvdro-6.11-dioxo-9-fluoronapht [2' ,3' :4,51 - imidazo [1,2-alpyridine ou6, 11-dihydro-6, ll-dioxo-8-fluoronapht [2 ', 3': 4, 51 - imidazo [1, 2-alpyridine or 6, 11-dihvdro-6.11-dioxo-9-fluoronapht [2 ' , 3 ': 4.51 - imidazo [1,2-alpyridine or
5, 6-dihydro-5, 6-dioxo-2-fluoronapht [1' , 2 ' :4, 51 - imidazo [1, 2-a]pyridine ou5, 6-dihydro-5, 6-dioxo-2-fluoronapht [1 ', 2': 4, 51 - imidazo [1, 2-a] pyridine or
5, 6-dihydro-5, 6-dioxo-3-fluoronapht [1' ,2' :4,51 - imidazo [1, 2-alpyridine5, 6-dihydro-5, 6-dioxo-3-fluoronapht [1 ', 2': 4,51 - imidazo [1, 2-alpyridine
Intermédiaire de synthèse :Synthesis intermediary:
2, 3-dibromo-l, 4-dihydro-1, 4-dioxo-6-fluoronaphtalène A une solution de 1, 4-dihydro-l , 4-dioxo-6-fluoro¬ naphtalène (N° CAS 148541-61-1) (12,5 g, 71 mmoles) dans le chloroforme (250 ml) , on ajoute 36 ml (710 mmoles) de brome. La solution est portée au reflux pendant 12 heures puis ramenée à température ambiante . Après un barbotage d'air comprimé, la solution est concentrée sous pression réduite et le solide obtenu est lavé cinq fois à l'hep- tane. On obtient 15, 0 g d'une poudre beige de 2,3- dibromo-1, 4-dihydro-1, 4-dioxo-6-fluoronaphtalêne Rdt : 65 % F : 158°C Rf : 0,80 (dichlorométhane) SM (APcI-) : m/z 332, 334, 336 (M ) RMN du "H (CDC13) : δ (ppm)2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene Has a solution of 1,4-dihydro-1,4-dioxo-6-fluoro¬ naphthalene (CAS No 148541-61- 1) (12.5 g, 71 mmol) in chloroform (250 ml), 36 ml (710 mmol) of bromine. The solution is brought to reflux for 12 hours and then brought to room temperature. After bubbling with compressed air, the solution is concentrated under reduced pressure and the solid obtained is washed five times with hexane. 15.0 g of a beige powder of 2,3-dibromo-1,4-dihydro-1,4, dioxo-6-fluoronaphthalene are obtained. Yield: 65% F: 158 ° C Rf: 0.80 (dichloromethane) MS (APcI-): m / z 332, 334, 336 (M) "H NMR (CDC1 3 ): δ (ppm)
8,22 (dd, IH, H-8, JH7 H9 = 8,55 Hz, JH F = 5,19 Hz) 7,81 (dd, IH, H-5, JH F = 8,55 Hz, JHS.H7 = 2,75 Hz) 7,45 (td, IH, H-7, JH.F = JH7.H8 = 8,55 Hz, JHS.H7 = 2,75 Hz) IR (KBr) : v (cm"1)8.22 (dd, IH, H-8, J H7 H9 = 8.55 Hz, J HF = 5.19 Hz) 7.81 (dd, IH, H-5, J HF = 8.55 Hz, J HS . H7 = 2.75 Hz) 7.45 (td, IH, H-7, J H. F = J H7 . H8 = 8.55 Hz, J HS . H7 = 2.75 Hz) IR (KBr) : v (cm "1 )
1680 (C=0)1680 (C = 0)
6, 11-dihydro-6, 11-dioxo-8-fluoronapht[2 ' , 3 ' :4, 51 - imidazo [1, 2-alpyridine ou6, 11-dihydro-6, 11-dioxo-8-fluoronapht [2 ', 3': 4, 51 - imidazo [1, 2-alpyridine or
6,ll-dιhvdro-6,11-dioxo-9-fluoronapht[2 ' ,3 ' :4, 51 - imidazo [1, 2-alpyridine ou6, ll-dιhvdro-6,11-dioxo-9-fluoronapht [2 ', 3': 4, 51 - imidazo [1, 2-alpyridine or
5, 6-dihydro-5, 6-dioxo-2-fluoronapht[1' .2 ' :4, 51 - imidazo [1, 2-alpyridine ou5, 6-dihydro-5, 6-dioxo-2-fluoronapht [1 '.2': 4, 51 - imidazo [1, 2-alpyridine or
5, 6-dihydro-5, 6-dioxo-3-fluoronapht[!' , 2 ' :4, 51 - imidazo [1, 2-alpyridine A une suspension de 2,5 g (7,5 mmoles , 1,0 éq) de5, 6-dihydro-5, 6-dioxo-3-fluoronapht [! ' , 2 ': 4, 51 - imidazo [1, 2-alpyridine A suspension of 2.5 g (7.5 mmol, 1.0 eq) of
2, 3-dιbromo-1, 4-dihydro-1,4-dιoxo-6-fluoronaphtalène dans 50 ml d'éthanol, on ajoute 1,4 g (15 mmoles, 2 éq) de 2- aminopyπdme . Le mélange réactionnel est porté au reflux du solvant pendant 20 heures puis ramené à température ambiante . Le précipité marron formé est filtré et lavé abondamment à l'ethanol Le solide obtenu est purifié par chromatographie flash sur colonne de gel de silice (support : silice 6-35 mm ; (0 10 cm ; h 25 cm , éluant dichlorométhane/acétate d'ethyle, 70/30) On obtient 494 mg de 6, ll-dιhydro-6, ll-dιoxo-8-fluoronapht- [2 ', 3 ' 4,5]- imidazo [1, 2-a] pyridine ou 6, ll-dihydro-6, ll-dιoxo-9- fluoronapht [2 ' , 3 ' :4, 5] imidazo [1,2-a]pyridine ou 5, 6-di¬ hydro-5, 6-dioxo-2-fluoronapht [1' , 2 ' : 4, 5] imidazo- [1, 2-a] - pyridine ou 5, 6-dihydro-5 , 6-dioxo-3-fluoronapht- [1 ', 2 ' :4, 5] -imidazo [1, 2-a] pyridine sous forme de cristaux jaunes . Rdt : 42 % F : > 260°C Rf : 0,58 (dichlorométhane/acétate d'ethyle, 70/30) SM (APCI+) : m/z 267 (M+H+) RMN du XH (CD2C12) : δ (ppm) 9,20 (d, IH, H-pyπdyle, J = 6,72 Hz)2, 3-dιbromo-1, 4-dihydro-1,4-dιoxo-6-fluoronaphthalene in 50 ml of ethanol, 1.4 g (15 mmol, 2 eq) of 2-aminopyπdme are added. The reaction mixture is brought to reflux of the solvent for 20 hours and then brought to room temperature. The brown precipitate formed is filtered and washed thoroughly with ethanol. The solid obtained is purified by flash chromatography on a column of silica gel (support: silica 6-35 mm; (0 10 cm; h 25 cm, eluent dichloromethane / acetate d 'ethyle, 70/30) We obtain 494 mg of 6, ll-dehydro-6, ll-dιoxo-8-fluoronapht- [2', 3 '4,5] - imidazo [1, 2-a] pyridine or 6, ll-dihydro-6, ll-dιoxo-9-fluoronapht [2 ', 3': 4, 5] imidazo [1,2-a] pyridine or 5, 6- di¬ hydro-5, 6-dioxo-2-fluoronapht [1 ', 2': 4, 5] imidazo- [1, 2-a] - pyridine or 5, 6-dihydro-5, 6-dioxo-3- fluoronapht- [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine in the form of yellow crystals. Yield: 42% F:> 260 ° C Rf: 0.58 (dichloromethane / ethyl acetate, 70/30) MS (APCI +): m / z 267 (M + H +) X H NMR (CD 2 C1 2 ): δ (ppm) 9.20 (d, 1H, H-pyπdyle, J = 6.72 Hz)
8,07 (dd, IH, H-aromatique, J = 8,54 Hz, JH_F = 5,49 Hz) 7,81 (dd, IH, H-aromatique, JH.F = 8,54 Hz, J = 2,45 Hz) 7,78 (d, IH, H-pyπdyle, J = 9,77 Hz)8.07 (dd, IH, H-aromatic, J = 8.54 Hz, J H _ F = 5.49 Hz) 7.81 (dd, IH, H-aromatic, J H. F = 8.54 Hz , J = 2.45 Hz) 7.78 (d, 1H, H-pyπdyle, J = 9.77 Hz)
7,63 (td, IH, H-aromatique, JH.F = 8,54 Hz, J = 2,45 Hz) 7,16 (m, 2H, H-pyridyle) IR (KBr) : v (cm"1) 1660 (C=0) Exemple 187.63 (td, IH, H-aromatic, J H. F = 8.54 Hz, J = 2.45 Hz) 7.16 (m, 2H, H-pyridyle) IR (KBr): v (cm " 1 ) 1660 (C = 0) Example 18
6, 11-Dihydro-6,ll-dioxo-7-fluoronapht [2 ' , 3 ' :4, 51 - imidazo [1,2-a]pyridine ou6, 11-Dihydro-6, ll-dioxo-7-fluoronapht [2 ', 3': 4, 51 - imidazo [1,2-a] pyridine or
6,ll-Dihydro-6, ll-dioxo-10-fluoronapht [2 ' , 3 ' :4, 51 - imidazo[1,2-alpyridine ou 5, 6-Dihydro-5, 6-dioxo-1-fluoronapht[1' , 2 ' :4,51 - imidazo [1,2-alpyridine ou6, ll-Dihydro-6, ll-dioxo-10-fluoronapht [2 ', 3': 4, 51 - imidazo [1,2-alpyridine or 5, 6-Dihydro-5, 6-dioxo-1-fluoronapht [ 1 ', 2': 4.51 - imidazo [1,2-alpyridine or
5, 6-Dihydro-5, 6-dioxo-4-fluoronapht[1' , 2 ' :4, 51 - imidazo[1,2-alpyridine5, 6-Dihydro-5, 6-dioxo-4-fluoronapht [1 ', 2': 4, 51 - imidazo [1,2-alpyridine
Intermédiaire de synthèse 2, 3-Dibromo-1,4-dihydro-l,4-dioxo-5-fluoronaphtalèneSynthesis intermediate 2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene
A une solution de 1,4-dιhydro-l, 4-dioxo-5-fluoro¬ naphtalène (N° CAS 62784-46-7) 2,45 g (71 mmoles) dans le chloroforme (60 ml) , on ajoute 7,34 ml (143 mmoles) de brome. La solution est portée au reflux pendant 12 heures puis ramenée à température ambiante . Après un barbotage d'air comprimé, la solution est concentrée sous pression réduite et le produit solide beige obtenu est purifié sur colonne flash (support : silice ; conditionnement : hep¬ tane ; éluant : CH2C12/heptane) pour fournir 3,44 g de 2, 3-dibromo-l, 4-dihydro-1, 4-dioxo-5-fluoronaphtalene sous forme de cristaux beiges . Rdt : 74 % F : 100°CTo a solution of 1,4-dehydro-1,4-dioxo-5-fluoro¬ naphthalene (CAS No. 62784-46-7) 2.45 g (71 mmol) in chloroform (60 ml), 7 is added. , 34 ml (143 mmol) bromine. The solution is brought to reflux for 12 hours and then brought to room temperature. After splashing of compressed air, the solution is concentrated under reduced pressure and the beige solid product obtained is purified on a flash column (support: silica; packaging: hep¬ tane; eluent: CH 2 C1 2 / heptane) to provide 3.44 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene in the form of beige crystals. Yid: 74% F: 100 ° C
Rf : 0,63 (dichlorométhane/heptane : 80/20) SM (I.E.) : m/z 333, 335, 337 (MH* ) RMN du 'H (CDC1,) : δ (ppm) 8,01 (d, IH, H-8, JH7.H3 = 7,94 Hz) 7,77 (m, IH, H-7) 7,52 (m, IH, H-6) IR (KBr) : v (cm"1) 1704 (C=0)Rf: 0.63 (dichloromethane / heptane: 80/20) MS (IE): m / z 333, 335, 337 (MH * ) 1 H NMR (CDC1,): δ (ppm) 8.01 (d, IH, H-8, J H7 . H3 = 7.94 Hz) 7.77 (m, IH, H-7) 7.52 (m, IH, H-6) IR (KBr): v (cm "1 ) 1704 (C = 0)
6,ll-Dihvdro-6,ll-dioxo-7-fluoronapht[2 ' ,3' :4.51 - imidazo [1,2-a]pyridine ou6, ll-Dihvdro-6, ll-dioxo-7-fluoronapht [2 ', 3': 4.51 - imidazo [1,2-a] pyridine or
6, ll-Dihvdro-6,ll-dioxo-10-fluoronapht[2 ' , 3 ' :4, 51 - imidazo [1,2-alpyridine ou6, ll-Dihvdro-6, ll-dioxo-10-fluoronapht [2 ', 3': 4, 51 - imidazo [1,2-alpyridine or
5, 6-Dihydro-5, 6-dioxo-1-fluoronapht[1' , 2 ' :4, 51 - imidazo [1, 2-alpyridine ou5, 6-Dihydro-5, 6-dioxo-1-fluoronapht [1 ', 2': 4, 51 - imidazo [1, 2-alpyridine or
5, 6-Dihydro-5, 6-dioxo-4-fluoronapht [1' , 2 ' :4, 51 - imidazo [1,2-a]pyridine A une suspension de 3,77 g (11,28 mmoles, 1,2 éq) de 2, 3-dibromo-l, 4-dihydro-1, 4-dioxo-5-fluoronaphtalene dans 180 ml d'éthanol, on ajoute 0,885 g (9,4 mmoles, 1 éq) de 2-aminopyridine.5, 6-Dihydro-5, 6-dioxo-4-fluoronapht [1 ', 2': 4, 51 - imidazo [1,2-a] pyridine A suspension of 3.77 g (11.28 mmol, 1 , 2 eq) of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene in 180 ml of ethanol, 0.885 g (9.4 mmol, 1 eq) of 2-aminopyridine is added .
Le mélange réactionnel est porté à reflux, au bout de 2 heures tout passe en solution. Il apparait un préci¬ pité marron à partir de la cinquième heure. Après 15 heu¬ res de reflux, l'ethanol est évaporé à sec. On obtient un produit solide marron que l'on purifie sur cake (support silice 6-35 μm ; conditionnement : heptane ; éluant : heptane/acétated'éthyie : 90/10) pour fournir 375 mg de 6, 11-dihydro-6, ll-dιoxo-7-fluoronapht [2 ' , 3 ' 4,5] imidazo- [1, 2-a] pyridine ou 6, ll-dιhydro-6, ll-dιoxo-10-fluoro¬ napht [2 ', 3 ' :4, 5] imidazo [1, 2-a]pyridine ou 5,6-dιhydro- 5, 6-dioxo-1-fluoronapht [1' , 2 ' :4, 5] imidazo [1, 2-a]pyridine ou 5, 6-dιhydro-5, 6-dioxo-4-fluoronapht [1' , 2 ' :4, 5] îmidazo- [1, 2-a]pyridine sous forme de cristaux jaune-orangé Rdt : 15 % F : > 260°C Rf : 0,55 (AcOEt/Heptane, 70/30) SM (I.E.) : m/z 266 (M* )The reaction mixture is brought to reflux, after 2 hours everything passes into solution. A brown precipitate appears from the fifth hour. After 15 hours of reflux, the ethanol is evaporated to dryness. A brown solid product is obtained which is purified on a cake (silica support 6-35 μm; packaging: heptane; eluent: heptane / acetate of ethyl: 90/10) to provide 375 mg of 6, 11-dihydro-6, ll-dιoxo-7-fluoronapht [2 ', 3' 4,5] imidazo- [1, 2-a] pyridine or 6, ll-dιhydro-6, ll-dιoxo-10- fluoro¬ naphth [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine or 5,6-dehydro- 5, 6-dioxo-1-fluoronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine or 5, 6-dehydro-5, 6-dioxo-4-fluoronapht [1 ', 2': 4, 5] îidido- [1, 2-a] pyridine in the form of crystals yellow-orange Yield: 15% F:> 260 ° C Rf: 0.55 (AcOEt / Heptane, 70/30) SM (IE): m / z 266 (M * )
RMN du lE (CD2C12) : δ (ppm) L E NMR (CD 2 C1 2 ): δ (ppm)
9,27 (d, IH, H-pyridyle, J = 6,74 Hz)9.27 (d, 1H, H-pyridyle, J = 6.74 Hz)
7,89 (dd, IH, H-aromatique, J = 7,02 Hz, J = 1,22 Hz)7.89 (dd, IH, H-aromatic, J = 7.02 Hz, J = 1.22 Hz)
7,83 (d, IH, H-pyridyle, J = 9,13 Hz) 7 , 62 (m, IH , H-pyridyle)7.83 (d, 1H, H-pyridyle, J = 9.13 Hz) 7.62 (m, 1H, H-pyridyl)
7,42 (m, 2H, H-aromatique)7.42 (m, 2H, H-aromatic)
7,19 (t, IH, H-pyridyle, J = 6,71 Hz)7.19 (t, 1H, H-pyridyl, J = 6.71 Hz)
IR (KBr) : v (cm1)IR (KBr): v (cm 1 )
1700, 1645 (C=0) Exemple 191700, 1645 (C = 0) Example 19
4, 9-Dichloro-5, 6-dihvdro-5,6-dioxonapht[1' ,2 ' :4, 51 - imidazo [1, 2-a]pyridine4, 9-Dichloro-5, 6-dihvdro-5,6-dioxonapht [1 ', 2': 4, 51 - imidazo [1, 2-a] pyridine
125 mg (0,370 mmole, 1,0 éq) de 9-chloro-5, 6-dι- hydro-5, 6-dioxo-4-nitronapht [1 ' , 2 ' -4,5] imidazo [1, 2-a] - pyridine sont chauffés à reflux dans 150 ml d'éthanol ab¬ solu sous argon, on ajoute alors le palladium sur char¬ bon, après 30 mm un équivalent d'hydrazme est ajouté puis un deuxième équivalent et après 15 min un troisième équivalent soit en tout 56 μl (1,11 mmole, 3,0 éq) Le milieu est filtré à froid125 mg (0.370 mmol, 1.0 eq) of 9-chloro-5, 6-dι- hydro-5, 6-dioxo-4-nitronapht [1 ', 2' -4,5] imidazo [1, 2- a] - pyridine are heated at reflux in 150 ml of ethanol ab¬ solute under argon, then palladium on char¬ is added, after 30 mm an equivalent of hydrazme is added, then a second equivalent and after 15 min a third equivalent, in all 56 μl (1.11 mmol, 3.0 eq) The medium is filtered cold
Le précipité est solubilisé dans 20 ml d'acide chlor-hydrique concentré. Cette solution est refroidie à -17°C puis on additionne goutte à goutte une solution formée par 47 mg (0,67 mmole, 2,0 éq) de nitrite de so- dium et 5 ml d'eau distillée Le milieu est agité à cette température pendant 0,5 heure. On ajoute goutte à goutte le milieu réactionnel à une solution refroidie à -10°C, formée de 67 mg (0,67 mmole, 2 éq) de chlorure de cuivre I et de 5 ml d'acide chlorhydrique concentré. L'agitation est poursuivie pendant 3 heures . Le milieu réactionnel est filtré. La phase organique est neutralisée par du carbonate de sodium solide ensuite extraite dans du di¬ chlorométhane. La phase organique est séchée sur du sul¬ fate de sodium, filtrée et évaporée à sec Le produit brut est purifié sur plaques préparatives (support . si¬ lice, éluant . dichlorométhane/méthanol, 98/2) pour four¬ nir 8 mg de 4 , 9-dιchloro-5, 6-dihydro-5 , 6-dioxonapht- - [1' , 2 ' :4, 5] -imidazo[1, 2-a] pyridme sous forme de cristaux oranges . Rdt : 4 %The precipitate is dissolved in 20 ml of concentrated hydrochloric acid. This solution is cooled to -17 ° C. and then a solution formed by 47 mg (0.67 mmol, 2.0 eq) of sodium nitrite and 5 ml of distilled water is added dropwise. The medium is stirred at this temperature for 0.5 hour. The reaction medium is added dropwise to a solution cooled to -10 ° C, formed from 67 mg (0.67 mmol, 2 eq) of copper chloride I and 5 ml of concentrated hydrochloric acid. Agitation is continued for 3 hours. The reaction medium is filtered. The organic phase is neutralized with solid sodium carbonate then extracted in dichloromethane. The organic phase is dried over sodium sul¬ fate, filtered and evaporated to dryness. The crude product is purified on preparative plates (support. Silica, eluent. Dichloromethane / methanol, 98/2) to provide 8 mg of 4, 9-dιchloro-5, 6-dihydro-5, 6-dioxonapht- - [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridme in the form of orange crystals. Yid: 4%
F : > 260°CF:> 260 ° C
Rf : 0,27 (Dichlorométhane/Méthanol, 98/2)Rf: 0.27 (Dichloromethane / Methanol, 98/2)
SM (I.E.) t m/z 316, 318, 320 (MMSM (I.E.) t m / z 316, 318, 320 (MM
RMN du XH (CD2C12) : δ (ppm) 9,34 (d, IH, H-8, JH8 „10 = 1,74 Hz) 8,20 (d, IH, H-l, JH1 H2 = 7,0 Hz) 7,76 (m, IH, H-ll) X H NMR (CD 2 C1 2 ): δ (ppm) 9.34 (d, IH, H-8, J H8 „ 10 = 1.74 Hz) 8.20 (d, IH, Hl, J H1 H2 = 7.0 Hz) 7.76 (m, IH, H-ll)
7,79 à 7,56 (m, 4H, H-10, H-2, H-3) IR (KBr) : v (cm1) 1662 (C=0) Exemple 207.79 to 7.56 (m, 4H, H-10, H-2, H-3) IR (KBr): v (cm 1 ) 1662 (C = 0) Example 20
6,ll-Dihvdro-6,ll-dioxo-7-méthylnapht[2 ' ,3 ' ;4,51 - imidazo [1, 2-alpyridine ou6, ll-Dihvdro-6, ll-dioxo-7-methylnapht [2 ', 3'; 4,51 - imidazo [1, 2-alpyridine or
6,ll-Dihvdro-6,ll-dioxo-10-méthylnapht [2' , 3 ' :4,51 - imidazo [1, 2-alpyridine ou6, ll-Dihvdro-6, ll-dioxo-10-methylnapht [2 ', 3': 4,51 - imidazo [1, 2-alpyridine or
5 , 6 -Dihydro- 5 , 6 -dioxo-l-méthylnaphtH ' , 2 ' : 4 , 51 - imidazoll , 2 -al pyridme ou5, 6 -Dihydro- 5, 6 -dioxo-1-methylnaphthH ', 2': 4, 51 - imidazoll, 2 -al pyridme or
5 , 6 -Dihydro- 5 , 6 -dioxo-4 -méthylnapht[l ' , 2 ' : 4 , 51 - imidazori , 2 -al pyridme Intermédiaire de synthèse • 2, 3-Dibromo-l, 4-dihydro-l, 4-dioxo-5-méthylnaphtalène5, 6 -Dihydro- 5, 6 -dioxo-4 -methylnapht [l ', 2': 4, 51 - imidazori, 2 -al pyridme Synthetic intermediate • 2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene
A 14,5 g (84 mmoles, 1 éq) de 1, 4-dιhydro-l, 4-dιoxo- 5-méthylnaphtalène, on ajoute 200 ml de tétrachlorure de carbone puis 17,2 ml (337 mmoles, 4 éq) de brome. La so- lution devient rouge, on ajoute alors 22,94 g i168 mmo¬ les, 2 éq) d'acétate de sodium. Après 96 h à reflux, le milieu réactionnel est filtré, lavé avec du tétrachlorure de carbone et évaporé à sec , Le produit est purifié sur cake (σ = 6,5 cm, hauteur = 5 cm, dépôt = solide, sup- port = silice, éluant CH2C1:) ; On obtient après evapora¬ tion à sec une pâte marron orangé. Une première cristal¬ lisation avec du dichlorométhane délivre 8,25 g de 2,3- dibromo-l, 4-dihydro-l, 4-dιoxo-5-méthylnaphtalène sous forme de cristaux jaunes ; une seconde recπstallisation avec de l'acétonitrile fournit 11,90 g de 2,3-dιbromo- 1, 4-di-hydro-l,4-dιoxo-5-méthylnaphtalène sous forme de cristaux jaunes. Rdt : 72 % Rf : 0,70 (acétate d' éthyle/heptane, 50/50) SM (APcI-) : m/z 328, 330, 332 (M- ) RMN du "H (CDC13) : δ (ppm)To 14.5 g (84 mmol, 1 eq) of 1, 4-dιhydro-l, 4-dιoxo- 5-methylnaphthalene, 200 ml of carbon tetrachloride are added and then 17.2 ml (337 mmol, 4 eq) of bromine. The solution turns red, then 22.94 g i168 mmo¬ les, 2 eq) of sodium acetate are added. After 96 h at reflux, the reaction medium is filtered, washed with carbon tetrachloride and evaporated to dryness, The product is purified on cake (σ = 6.5 cm, height = 5 cm, deposit = solid, support = silica, eluent CH 2 C1:); After evaporation to dryness, an orange-brown paste is obtained. A first crystallization with dichloromethane delivers 8.25 g of 2,3-dibromo-1,4-dihydro-1,4,4-dιoxo-5-methylnaphthalene in the form of yellow crystals; a second re-installation with acetonitrile provides 11.90 g of 2,3-dιbromo- 1, 4-di-hydro-l, 4-dιoxo-5-methylnaphthalene in the form of yellow crystals. Yield: 72% Rf: 0.70 (ethyl acetate / heptane, 50/50) MS (APcI-): m / z 328, 330, 332 (M-) "H NMR (CDC1 3 ): δ ( ppm)
8,11 (dd, IH, H-8, JH7 Ha = 7,02 Hz, JH6 H8 = 1,53 Hz) 7,63 (m, 2H, H-6, H-7) 2,76 (s, 3H, CH3) IR (KBr) : v (cm1)8.11 (dd, IH, H-8, J H7 Ha = 7.02 Hz, J H6 H8 = 1.53 Hz) 7.63 (m, 2H, H-6, H-7) 2.76 ( s, 3H, CH 3 ) IR (KBr): v (cm 1 )
1670 ( C=0) ; 1570 (C = C)1670 (C = 0); 1570 (C = C)
6,ll-dihvdro-6,ll-dioxo-7-méthylnaphtr2' , 3' ;4,51 - imidazo [1,2-alpyridine ou6, ll-dihvdro-6, ll-dioxo-7-methylnaphtr2 ', 3'; 4,51 - imidazo [1,2-alpyridine or
6,ll-dihvdro-6,ll-dioxo-10-méthylnaρhtr2' ,3' :4,51 - imidazo [1,2-alpyridine ou6, ll-dihvdro-6, ll-dioxo-10-methylnaρhtr2 ', 3': 4.51 - imidazo [1,2-alpyridine or
5 , 6 -dihydro- 5 , 6 -dioxo- l -méthylnaphtfl ' , 2 ' : 4 , 5] - imidazof 1 , 2 -al pyridine ou5, 6 -dihydro- 5, 6 -dioxo- l -methylnaphthfl ', 2': 4, 5] - imidazof 1, 2 -al pyridine or
5 , 6 -dihvdro- 5 , 6 -dioxo-4 -méthylnapht[l ' , 2 ' : 4 , 5] - imidazofl , 2 -a] pyridine A une suspension de 4,00 g (12,12 mmoles, 1 éq) de 2, 3-dibromo-l, 4-dihydro-1,4-dioxo-5-méthylnaphtalène dans 500 ml d'éthanol, sont ajoutés 2,72 g en deux fois (28,88 mmoles, 2,4 éq) de 2-amino-pyridine. Ce mélange est porté au reflux pendant 48 heures. Après refroidisse- ment jusqu'à température ambiante, l'ethanol est éliminé par evaporation sous pression réduite. Le 2,3-dibromo- 1, 4-dihydro-1, 4-dioxo-5-méthylnaphtalène n'ayant pas réa¬ gi est éliminé par précipitation dans un mélange CH2C12/ Heptane, 80/20. Le produit brut est purifié par chromato- graphie sur plaque préparative (support : silice SIL G- 200 UV254 2 mm ; éluant : CH2Cl2/EtOH, 97/3) pour fournir la 6, ll-dihydro-6 , ll-dioxo-7-méthylnapht- [2 ' , 3 ' : 4 , 5] - imidazo- [1, 2-a]pyridine ou 6, ll-dihydro-6, ll-dioxo-10- méthylnapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine ou 5,6-di- hydro-5, 6-dioxo-1-méthyl-napht[l' , 2 ' :4, 5]imidazo[l, 2-a]- pyridine ou 5, 6-dihydro-5, 6-dioxo-4-méthyl-napht- [1' , 2 ' : 4, 5] -imidazo [1, 2-a]pyridine sous forme de cristaux jaune-orangé. Rdt : 7 % F : 218°C (décomp)5, 6 -dihvdro- 5, 6 -dioxo-4 -methylnapht [l ', 2': 4, 5] - imidazofl, 2 -a] pyridine To a suspension of 4.00 g (12.12 mmol, 1 eq ) of 2, 3-dibromo-1,4, dihydro-1,4-dioxo-5-methylnaphthalene in 500 ml of ethanol, are added 2.72 g in two batches (28.88 mmol, 2.4 eq) of 2 -amino-pyridine. This mixture is brought to reflux for 48 hours. After cooling to room temperature, the ethanol is removed by evaporation under reduced pressure. The 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene which has not reacted is eliminated by precipitation in a mixture of CH 2 C1 2 / Heptane, 80/20. The crude product is purified by chromatography on a preparative plate (support: silica SIL G- 200 UV254 2 mm; eluent: CH 2 Cl 2 / EtOH, 97/3) to provide 6, ll-dihydro-6, ll- dioxo-7-methylnapht- [2 ', 3': 4, 5] - imidazo- [1, 2-a] pyridine or 6, ll-dihydro-6, ll-dioxo-10- methylnapht [2 ', 3' : 4, 5] imidazo [1, 2-a] pyridine or 5,6-di-hydro-5, 6-dioxo-1-methyl-napht [l ', 2': 4, 5] imidazo [l, 2 -a] - pyridine or 5, 6-dihydro-5, 6-dioxo-4-methyl-napht- [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine in the form of yellow crystals -orange. Yd: 7% F: 218 ° C (decomp)
Rf : 0,61 (CH2Cl2/EtOH, 97/3) S. M. (I.E.) : m/z 262 (M* ) RMN du 'H (CD2C12) : δ (ppm)Rf: 0.61 (CH 2 Cl 2 / EtOH, 97/3) SM (IE): m / z 262 (M * ) 1 H NMR (CD 2 C1 2 ): δ (ppm)
9.38 (d, IH, H-pyridyle, J = 6,64 Hz) 8,00 (d, IH, H-pyridyle, J = 6,64 Hz)9.38 (d, IH, H-pyridyle, J = 6.64 Hz) 8.00 (d, IH, H-pyridyle, J = 6.64 Hz)
7,84 (d, IH, H-aromatique, J = 8,72 Hz)7.84 (d, 1H, H-aromatic, J = 8.72 Hz)
7,67 (m, IH, H-pyridyle)7.67 (m, 1H, H-pyridyl)
7,52 (d, IH, H-aromatique, J = 7,47 Hz)7.52 (d, 1H, H-aromatic, J = 7.47 Hz)
7.39 (t, IH, H-aromatique, J = 7,47 Hz) 7,23 (t, IH, H-pyridyle, J = 6,64 Hz)7.39 (t, IH, H-aromatic, J = 7.47 Hz) 7.23 (t, IH, H-pyridyle, J = 6.64 Hz)
2,98 (s, 3H, CH3) RMN du "C (CDC13) : δ (ppm) 139,34 (1C, C-aromatique) 132,30 (1C, C-pyridyle) 130,30 (1C, C-aromatique) 129,35 (1C, C-pyridyle) 129,25 (1C, C-aromatique) 118,91 (1C, C-pyridyle) 117,22 (1C, C-pyridyle) 23,18 (1C, CH3)2.98 (s, 3H, CH 3) NMR "C (CDC1 3): δ (ppm) 139.34 (1C, C-aromatic) 132.30 (1C, C-pyridyl) 130.30 (1C, C-aromatic) 129.35 (1C, C-pyridyl) 129.25 (1C, C-aromatic) 118.91 (1C, C-pyridyl) 117.22 (1C, C-pyridyl) 23.18 (1C, CH 3 )
IR (KBr) : v (cm"1)IR (KBr): v (cm "1 )
2940 ,-1745 (C=0) ; 1700 (C = C) ; 1650 (C = N)2940, -1745 (C = 0); 1700 (C = C); 1650 (C = N)
Exemple 21Example 21
2-chloro-6,11-dihydro-6,ll-dioxo-7-méthγlnapht- 12 ' , 3 ' ;4, 51 imidazoll, 2-alpyridine ou2-chloro-6,11-dihydro-6, ll-dioxo-7-méthγlnapht- 12 ', 3'; 4, 51 imidazoll, 2-alpyridine or
2-chloro-6,11-dihydro-6,11-dioxo-10-méthylnapht- 12 ' , 3 ' :4, 51 imidazofl,2-alpyridine ou2-chloro-6,11-dihydro-6,11-dioxo-10-methylnaphth- 12 ', 3': 4, 51 imidazofl, 2-alpyridine or
9-chloro-5, 6-dihydro-5, 6-dioxo-l-méthylnapht- fl' , 2 ' :4, 51 imidazofl, 2-a]pyridine ou 9-chloro-5, 6-dihydro-5, 6-dioxo-4-méthylnapht-9-chloro-5, 6-dihydro-5, 6-dioxo-1-methylnaphth- fl ', 2': 4, 51 imidazofl, 2-a] pyridine or 9-chloro-5, 6-dihydro-5, 6 -dioxo-4-methylnapht-
11' ,2 ' ;4, 51 imidazori,2-alpyridine11 ', 2'; 4, 51 imidazori, 2-alpyridine
A une suspension de 4,00 g (12,12 mmoles, 1 éq) de 2 , 3-dibromo-l, 4-dihydro-1, 4-dioxo-5-methylnaphtalene dans 500 ml d'éthanol, sont ajoutés 3,74 g en deux fois (28,88 mmoles, 2,4 éq) de 2-amino-5-chloropyridine . Ce mélange est porté au reflux pendant 48 heures. Après re¬ froidissement jusqu'à température ambiante, l'ethanol est éliminé par evaporation sous pression réduite. Le 2,3- dibromo-l,4-dihydro-1, 4-dioxo-5-methylnaphtalene n' ayant pas réagi est éliminé par précipitation dans un mélange CH,C12/Heptane, 80/20 ! Le produit brut est purifié par chromatographie sur colonne (support silice 6-35 mm, con¬ ditionnement : CH2C12/Heptane, 90/10, éluant : gradient CH2Cl2/AcOEt, 100/0 à 50/50) puis sur plaque préparative (support : silice SIL G-200 UV254 2 mm ; éluant : CH;C12) pour fournir la 2-chloro-6, ll-dihydro-6, ll-dioxo-7- méthyl-napht [2 ', 3 ' :4, 5] imidazo [1, 2-a] pyridine ou 2- chloro-6, 11-dihydro-6, 11-dioxo-10- méthylnapht[2 ' , 3 ' :4, 5]imidazo[l, 2-a]-pyridine ou 9-chloro- 5, 6-dihydro-5, 6-dioxo-l-méthylnapht-[l ' , 2 ' :4, 5]imidazo[l, 2- a]pyridine ou 9-chloro-5 , 6-dihydro-5 , 6-dioxo-4- méthylnapht [lτ , 2 ' :4, 5] imidazo [1, 2-a] pyridine sous forme de cristaux oranges . Rdt : 6 % Rf : 0,76 (CH2Cl2/EtOH, 97/3)To a suspension of 4.00 g (12.12 mmol, 1 eq) of 2,3-dibromo-1,4-dihydro-1,4,4-dioxo-5-methylnaphthalene in 500 ml of ethanol are added 3, 74 g in two batches (28.88 mmol, 2.4 eq) of 2-amino-5-chloropyridine. This mixture is brought to reflux for 48 hours. After cooling to room temperature, the ethanol is removed by evaporation under reduced pressure. The unreacted 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene is eliminated by precipitation in a CH, C1 2 / Heptane, 80/20 mixture! The crude product is purified by column chromatography (silica support 6-35 mm, packaging: CH 2 C1 2 / Heptane, 90/10, eluent: gradient CH 2 Cl 2 / AcOEt, 100/0 to 50/50) then on a preparative plate (support: silica SIL G-200 UV254 2 mm; eluent: CH ; C1 2 ) to provide 2-chloro-6, ll-dihydro-6, ll-dioxo-7-methyl-naphth [2 ' , 3 ': 4, 5] imidazo [1, 2-a] pyridine or 2-chloro-6, 11-dihydro-6, 11-dioxo-10- methylnapht [2', 3 ': 4, 5] imidazo [ l, 2-a] -pyridine or 9-chloro- 5, 6-dihydro-5, 6-dioxo-1-methylnapht- [l ', 2': 4, 5] imidazo [l, 2- a] pyridine or 9-chloro-5, 6-dihydro-5, 6-dioxo-4-methylnapht [l τ , 2 ': 4, 5] imidazo [1, 2-a] pyridine in the form of orange crystals. Yid: 6% Rf: 0.76 (CH 2 Cl 2 / EtOH, 97/3)
S. M. (I.E.) : m/z 296 et 298 (M* ) RMN du XE (CD2C12) : δ (ppm) 9,33 (d, IH, H-pyridyle, J = 1,83 Hz) 7,91 (m, IH, H-aromatique) 7,69 (dd, IH, H-pyridyle, J = 0,91 Hz, J = 9,46 Hz)SM (IE): m / z 296 and 298 (M * ) X E NMR (CD 2 C1 2 ): δ (ppm) 9.33 (d, IH, H-pyridyle, J = 1.83 Hz) 7 , 91 (m, 1H, H-aromatic) 7.69 (dd, 1H, H-pyridyle, J = 0.91 Hz, J = 9.46 Hz)
7,53 (dd, IH, H-pyridyle, J = 2,14 Hz, J = 9,46 Hz) 7,42 (m, IH, H-aromatique) 7,31 (t, IH, H-aromatique, J = 7,63 Hz) 2,86 (s, 3H, CH3) Exemple 227.53 (dd, 1H, H-pyridyle, J = 2.14 Hz, J = 9.46 Hz) 7.42 (m, 1H, H-aromatic) 7.31 (t, 1H, H-aromatic, J = 7.63 Hz) 2.86 (s, 3H, CH 3 ) Example 22
6, 11-dihydro-6, 11-dioxo-8-méthylnapht[2 ' , 3 ' :4, 51 - imidazo[1,2-alpyridine ou6, 11-dihydro-6, 11-dioxo-8-methylnapht [2 ', 3': 4, 51 - imidazo [1,2-alpyridine or
6,11-dihvdro-6, 11-dioxo-9-méthylnapht [2 ' ,3 ' :4, 51 - imidazo[1,2-alpyridine ou 5,6-dihvdro-5,6-dioxo-2-méthylnaphtfl' ,2' :4,51 - imidazori,2-a]pyridine ou6,11-dihvdro-6, 11-dioxo-9-methylnapht [2 ', 3': 4, 51 - imidazo [1,2-alpyridine or 5,6-dihvdro-5,6-dioxo-2-methylnaphtfl ' , 2 ': 4.51 - imidazori, 2-a] pyridine or
5, 6-dihvdro-5, 6-dioxo-3-méthylnaphtfl' ,2 ' :4,51 - imidazofl, 2-alpyridine5, 6-dihvdro-5, 6-dioxo-3-methylnaphthfl ', 2': 4.51 - imidazofl, 2-alpyridine
A une suspension de 4,00 g (12,12 mmoles, 1 éq) de 2 , 3-dibromo-l, 4-dihydro-l, 4-dioxo-6-méthylnaphtalène (N° CAS 72364-92-2) dans "500 ml d'éthanol, sont ajoutés 2,72 g en deux fois (28,88 mmoles, 2,4 éq) de 2-amino- pyridine. Ce mélange est porté au reflux pendant 48 heu¬ res. Après refroidissement jusqu'à température ambiante, l'ethanol est éliminé par evaporation sous pression ré¬ duite. Le 2, 3-dibromo-l,4-dihydro-l, 4-dioxo-6-méthyl- naphtalène n'ayant pas réagi est éliminé par précipita¬ tion dans un mélange CH2C12/Heptane, 70/30. Le produit brut est purifié par deux chromatographies successives sur plaque préparative (support : silice SIL G-200 UV254 2 mm ; éluant 1er* plaque : CH2Cl2/MeOH, 97/3 et éluant 2" plaque : Heptane/AcOEt , 40/60) pour fournir la 6,11- dihydro-6, 11 -dioxo- 8 -méthylnapht [2 ' , 3 ' :4, 5] imidazo [1,2- a] -pyridine ou 6 , ll-dihydro-6 , ll-dioxo-9-méthylnapht- [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridine ou 5 , 6-dihydro-5 , 6-di- oxo-2 -méthylnaphtfl ' , 2 ' :4 , 5]imidazo[l, 2 -ajpyridine ou 5,6- dihydro-5 , 6 -dioxo- 3 -méthylnaphtfl ' , 2 ' : 4 , 5]imidazo[l, 2-a]- pyridine sous forme de cristaux orange.To a suspension of 4.00 g (12.12 mmol, 1 eq) of 2,3-dibromo-1,4-dihydro-1,4, dioxo-6-methylnaphthalene (CAS No 72364-92-2) in " 500 ml of ethanol are added 2.72 g in two batches (28.88 mmol, 2.4 eq) of 2-amino-pyridine. This mixture is brought to reflux for 48 hours. After cooling until at room temperature, the ethanol is eliminated by evaporation under reduced pressure. The unreacted 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-methyl-naphthalene is eliminated by precipitate ¬ in a CH 2 C1 2 / Heptane mixture, 70/30. The crude product is purified by two successive chromatographies on a preparative plate (support: silica SIL G-200 UV254 2 mm; eluent 1 st * plate: CH 2 Cl 2 / MeOH, 97/3 and eluent 2 "plate: Heptane / AcOEt, 40/60) to provide 6,11- dihydro-6, 11 -dioxo- 8 -methylnapht [2 ', 3': 4, 5] imidazo [1,2- a] -pyridine or 6, ll-dihydro-6, ll-dioxo-9-methylnapht- [2 ', 3': 4, 5] imidazo [1 , 2-a] pyridine or 5, 6-dihydro-5, 6-di-oxo-2 -methylnaphthfl ', 2': 4, 5] imidazo [l, 2 -ajpyridine or 5,6- dihydro-5, 6 -dioxo- 3 -methylnaphthfl ', 2': 4, 5] imidazo [1,2-a] - pyridine in the form of orange crystals.
Rdt : 18 % F : 244°C (décomp.)Yd: 18% F: 244 ° C (decomp.)
Rf : 0,67 (CH,Cl2/MeOH, 95/5)Rf: 0.67 (CH, Cl 2 / MeOH, 95/5)
S. M. (I.E.) : m/z 262 (M* )SM (IE): m / z 262 (M * )
RMN du XH (CD2C12) : δ (ppm) X H NMR (CD 2 C1 2 ): δ (ppm)
9,36 (d, IH, H-pyridyle, J = 6,64 Hz) 8,12 (si, IH, H-α du CH3)9.36 (d, IH, H-pyridyle, J = 6.64 Hz) 8.12 (si, IH, H-α of CH 3 )
8,08 (d, IH, H-β du CH3, J = 7,88 Hz)8.08 (d, 1H, H-β of CH 3 , J = 7.88 Hz)
7,91 (d, IH, H-pyridyle, J = 9,14 Hz)7.91 (d, 1H, H-pyridyle, J = 9.14 Hz)
7,75 (ddd, IH, H-pyridyle, J = 9,14 Hz, J = 7,05 Hz, J =7.75 (ddd, IH, H-pyridyle, J = 9.14 Hz, J = 7.05 Hz, J =
1,24 Hz) 7,44 (dd, IH, H-α du CH3 , J = 7,89 Hz, J = 1,24 Hz)1.24 Hz) 7.44 (dd, IH, H-α of CH 3 , J = 7.89 Hz, J = 1.24 Hz)
7,32 (td, IH, H-pyridyle, J = 7,05 Hz, J = 7,89 Hz)7.32 (td, 1H, H-pyridyle, J = 7.05 Hz, J = 7.89 Hz)
2,60 (s, 3H, CH3)2.60 (s, 3H, CH 3 )
RMN du "C (CDC13) : δ (ppm)"C (CDC1 3 ) NMR: δ (ppm)
132,34 (1C, C-aromatique) 131,66 (1C, C-aromatique)132.34 (1C, C-aromatic) 131.66 (1C, C-aromatic)
130,27 (1C, C-pyridyle)130.27 (1C, C-pyridyle)
129,21 (1C, C-pyridyle)129.21 (1C, C-pyridyl)
125,53 (1C, C-aromatique)125.53 (1C, C-aromatic)
118,45 (1C, C-pyridyle) 116,93 (1C, C-pyridyle)118.45 (1C, C-pyridyle) 116.93 (1C, C-pyridyle)
22,06 (1C, CH3)22.06 (1C, CH 3 )
IR (KBr) : v (cm1)IR (KBr): v (cm 1 )
1700 (C = C) ; 1650 (C = N) ; 16001700 (C = C); 1650 (C = N); 1600
Exemple a 5 , 6-Dihvdro-5, 6-dioxo-napht [1' ,2 ' :4, 51 imidazo [1,2- _>5Example a 5, 6-Dihvdro-5, 6-dioxo-napht [1 ', 2': 4, 51 imidazo [1,2- _> 5
a]pyridinea] pyridine
Référence : CA. 5_8 12542e Rdt : 44 %Reference: CA. 5_8 12,542nd Yd: 44%
F : > 260°C Rf : 0,50 (CH2C12/Méthanol, 95/5)F:> 260 ° C Rf: 0.50 (CH 2 C1 2 / Methanol, 95/5)
SM (I.E.) : m/z 248 (M+. )SM (I.E.): m / z 248 (M +.)
RMN du XH (CDC13) : δ (ppm) X H NMR (CDC1 3 ): δ (ppm)
9,07 (d, IH, H-8, JHβ.H9 = 6,73 Hz)9.07 (d, 1H, H-8, J Hβ . H9 = 6.73 Hz)
8,06 (d, IH, H-l, JH1.H2 = 7,53 Hz) 7,94 (d, IH, H-4, JH3.H4 = 7,99 Hz)8.06 (d, IH, Hl, J H1 . H2 = 7.53 Hz) 7.94 (d, IH, H-4, J H3 . H4 = 7.99 Hz)
7,63 (d, IH, H-ll, JH10.H11 = 8,73 Hz)7.63 (d, IH, H-ll, J H10 . H11 = 8.73 Hz)
7,51 (dt, IH, H-2, J41.H2 = JH2_H3 = 7,43 Hz, JH2.H4 = 1,02 Hz)7.51 (dt, IH, H-2, J 41. H2 = J H2 _ H3 = 7.43 Hz, J H2 . H4 = 1.02 Hz)
7,41 (dt, IH, H-10, JH9.H10 = JH10.Hιι = 7,30 Hz, JHβ.Hi0 = 1,227.41 (dt, IH, H-10, J H9 . H10 = J H10 . Hιι = 7.30 Hz, J Hβ . Hi0 = 1.22
Hz) 7,33 (dt, IH, H-3, JH2.H3 = JH3.H4 = 7,95 Hz, JH1.H3 = 1,03 Hz)Hz) 7.33 (dt, IH, H-3, J H2 . H3 = J H3 . H4 = 7.95 Hz, J H1 . H3 = 1.03 Hz)
6,96 (dd, IH, H-9, JH8.H9 = 6,81 Hz6.96 (dd, IH, H-9, J H8 . H9 = 6.81 Hz
RMN du 13C (CDCI3) : δ (ppm) 13 C NMR (CDCI3): δ (ppm)
181,5 (1C, C-5)181.5 (1C, C-5)
153,7 (1C, C-12a) 150,1 (1C, C-lla)153.7 (1C, C-12a) 150.1 (1C, C-lla)
135,65 (1C, C-2)135.65 (1C, C-2)
132,50 (1C, C-10)132.50 (1C, C-10)
131,09 (1C, C-3)131.09 (1C, C-3)
130,44 (1C, C-4) 129,34 (1C, C-8)130.44 (1C, C-4) 129.34 (1C, C-8)
124,94 (1C, C-l)124.94 (1C, C-1)
118.49 (1C, C-ll)118.49 (1C, C-ll)
116.50 (1C, C-9) IR (KBr) : v (cm1) 1685, 1650 (C=0)116.50 (1C, C-9) IR (KBr): v (cm 1 ) 1685, 1650 (C = 0)
Exemple bExample b
5, 6-Dihydro-5, 6-dioxo-8-méthyl-napht [1' ,2 ' :4, 5] - imidazo [1.2-a]pyridine5, 6-Dihydro-5, 6-dioxo-8-methyl-napht [1 ', 2': 4, 5] - imidazo [1.2-a] pyridine
Référence : CA. 55. P25998e Rdt : 52 % F : > 260°CReference: CA. 55. P25998e Rdt: 52% F:> 260 ° C
Rf : 0,55 (CH2Cl2/Méthanol, 97/3)Rf: 0.55 (CH 2 Cl 2 / Methanol, 97/3)
SM (I.E.) : m/z 262 (M+ . )SM (I.E.): m / z 262 (M +.)
RMN du λE (CDCI3) : δ (ppm) 8,21 (m, 2H, H-l, H-4) Λ E NMR (CDCI3): δ (ppm) 8.21 (m, 2H, Hl, H-4)
7,72 (m, 3H, H-2, H-3, H-ll)7.72 (m, 3H, H-2, H-3, H-ll)
7,51 (m, IH, H-10)7.51 (m, IH, H-10)
6,97 (d, IH, H-9, JH9-H1o = 7,02 Hz)6.97 (d, IH, H-9, J H9-H1o = 7.02 Hz)
3,12 (s, 3H, CH3) RMN du 13C (CDCI3) : δ (ppm)3.12 (s, 3H, CH 3 ) 13 C NMR (CDCI3): δ (ppm)
183,01 (1C, Cquat)183.01 (1C, Cquat)
173,45 (1C, Cquat)173.45 (1C, Cquat)
151,45, 149,64 (2C, Cquat)151.45, 149.64 (2C, Cquat)
141,32 (1C, Cquat) 134,33, 133,06 (2C, C-2, C-3)141.32 (1C, Cquat) 134.33, 133.06 (2C, C-2, C-3)
131,40, 126,71 (3C, C-1, C-4, Cquat)131.40, 126.71 (3C, C-1, C-4, Cquat)
127,36 (1C, C-10)127.36 (1C, C-10)
124,15 (1C, Cquat)124.15 (1C, Cquat)
119,92 (1C, Cquat) 118,09 (1C, C-ll)119.92 (1C, Cquat) 118.09 (1C, C-ll)
117,24 (1C, C-9)117.24 (1C, C-9)
23,55 (1C, CH3)23.55 (1C, CH 3 )
IR (KBr) : v (cm1)IR (KBr): v (cm 1 )
1701, 1656 (C=0) Exemple c1701, 1656 (C = 0) Example c
9-Chloro-5, 6-dihvdro-5, 6-dioxo-napht [1' , 2 ' :4, 51 - imidazo [1, 2-alpyridine9-Chloro-5, 6-dihvdro-5, 6-dioxo-napht [1 ', 2': 4, 51 - imidazo [1, 2-alpyridine
Référence : CA. 5_5. P25998eReference: CA. 5_5 . P25998e
Rdt : 61 % F : > 260°CYid: 61% F:> 260 ° C
Rf : 0,40 (CH2Cl2/Méthanol, 98/2)Rf: 0.40 (CH 2 Cl 2 / Methanol, 98/2)
SM (I.E.) : m/z 282 (M+ . )SM (I.E.): m / z 282 (M +.)
RMN du λE (CDCI3) : δ (ppm) Λ E NMR (CDCI3): δ (ppm)
9,31 (dd, IH, H-8, JH8.HIO = 2-06 Hz, JH8.H11 = 0,72 Hz) 8,14 (dd, IH, H-l, JH1.H2 = 7,70 Hz, JH1.H3 = 0,83 Hz) 8,11 (dd, IH, H-4, JH3.H4 = 7,79 Hz, JH2.H4 = 1,04 Hz) 7,73 (dd, IH, H-ll, JHlβ.R11 = 9,46 Hz, JHβ.Hli = 0, 69 Hz) 7, 68 (dt, IH, H-2, JH1.H2 = JH2-H3 = 7,57 Hz, JH2.H4 = 1,31 Hz) 7,58 (dd, IH, H-10, Jκlβ.H11 = 9,45 Hz, JH8_H10 = 2,05 Hz) 7,51 (dt, IH, H-3, JH2.H3 = JH3-H4 = 7,66 Hz, JH1.H3 = 1,20 Hz)9.31 (dd, IH, H-8, J H8 . HIO = 2 -06 Hz, J H8 . H11 = 0.72 Hz) 8.14 (dd, IH, Hl, J H1 . H2 = 7.70 Hz, J H1 . H3 = 0.83 Hz) 8.11 (dd, IH, H-4, J H3 . H4 = 7.79 Hz, J H2 . H4 = 1.04 Hz) 7.73 (dd, IH, H-ll, J Hlβ . R11 = 9 , 46 Hz, J Hβ . Hli = 0.69 Hz) 7.68 (dt, IH, H-2, J H1 . H2 = J H2-H3 = 7.57 Hz, J H2 . H4 = 1.31 Hz ) 7.58 (dd, IH, H-10, J κlβ . H11 = 9.45 Hz, J H8 _ H10 = 2.05 Hz) 7.51 (dt, IH, H-3, J H2 . H3 = J H3-H4 = 7.66 Hz, J H1 . H3 = 1.20 Hz)
RMN du 13C (CDC13) : δ (ppm) 13 C NMR (CDC1 3 ): δ (ppm)
181.45 (1C, C-5) 167,70 (1C, C-6a) 154,27 (1C, C-12a) 148,61 (1C, C-lla)181.45 (1C, C-5) 167.70 (1C, C-6a) 154.27 (1C, C-12a) 148.61 (1C, C-lla)
135.46 (1C, C-2) 133,13 (1C, C-10) 131,17 (1C, C-12b) 130,97 (1C, C-3) 130,79 (1C, C-4a)135.46 (1C, C-2) 133.13 (1C, C-10) 131.17 (1C, C-12b) 130.97 (1C, C-3) 130.79 (1C, C-4a)
130,31 (1C, C-4)130.31 (1C, C-4)
126,89 (1C, C-8)126.89 (1C, C-8)
124,95 (1C, C-9)124.95 (1C, C-9)
124,75 (1C, C-1) 118,34 (1C, C-ll)124.75 (1C, C-1) 118.34 (1C, C-ll)
IR (KBr) : v (cm"1)IR (KBr): v (cm "1 )
1680, 1650 (C=0)1680, 1650 (C = 0)
Exemple dExample d
9-Bromo-5 , 6-dihvdro-5, 6-dioxo-napht [1' .2' .-4,5] - imidazo [1, 2-alpyridine9-Bromo-5, 6-dihvdro-5, 6-dioxo-napht [1 '.2'.-4,5] - imidazo [1, 2-alpyridine
Référence : CA. 55 P25998eReference: CA. 55 P25998e
Rdt : 21 %Yid: 21%
F : 280°CF: 280 ° C
Rf : 0,48 (CH2C12/Acétate d'ethyle, 90/10) SM (I.E.) : m/z 326, 328 (M+ . )Rf: 0.48 (CH 2 C1 2 / Ethyl acetate, 90/10) SM (IE): m / z 326, 328 (M +.)
RMN du XH (270 MHz, CDC13) : δ (ppm) X H NMR (270 MHz, CDC1 3 ): δ (ppm)
9,45 (s, IH, H-8)9.45 (s, 1H, H-8)
8,17 (t, 2H, H-l, H-4, JH1.H2 = JH3.H4 = 7,63 Hz)8.17 (t, 2H, Hl, H-4, J H1 . H2 = J H3 . H4 = 7.63 Hz)
7,71 (m, 3H, H-2, H-10, H-ll) 7,54 (t, IH, H-3, JH2.H3 = JH3.H4 = 6,94 Hz) RMN du "C (270 MHz, CDC1.) : δ (ppm)7.71 (m, 3H, H-2, H-10, H-ll) 7.54 (t, IH, H-3, J H2 . H3 = J H3 . H4 = 6.94 Hz) "C NMR (270 MHz, CDC1.): Δ (ppm)
135,5, 135,4 (2C, C-2, C-10)135.5, 135.4 (2C, C-2, C-10)
131,0 (1C, C-3)131.0 (1C, C-3)
130,4 (1C, C-4) 129,0 (1C, C-8)130.4 (1C, C-4) 129.0 (1C, C-8)
124,8 (1C, C-1)124.8 (1C, C-1)
118,6 (1C, C-ll)118.6 (1C, C-ll)
111,4 (1C, C-9)111.4 (1C, C-9)
IR (KBr) : v (cm1) 1650, 1622 (C≈O)IR (KBr): v (cm 1 ) 1650, 1622 (C≈O)
Exemple eExample e
5 , 6-Dihvdro-5, 6-dioxo-4-nitro-napht [1' , 2 ' :4, 51 imidazo [1, 2-alpyridine5, 6-Dihvdro-5, 6-dioxo-4-nitro-napht [1 ', 2': 4, 51 imidazo [1, 2-alpyridine
Référence : CA. 5_5 P25998h Rdt : 25 %Reference: CA. 5_5 P25998h Yield: 25%
F : > 260°CF:> 260 ° C
Rf : 0,34 (CH2C12/Méthanol, 98/2)Rf: 0.34 (CH 2 C1 2 / Methanol, 98/2)
SM (I.E.) : m/z 293 (M+. )SM (I.E.): m / z 293 (M +.)
RMN du λE (CDC13) : δ (ppm) 9,28 (d, IH, H-8, JH8.H9 = 6,41 Hz) Λ E NMR (CDC1 3 ): δ (ppm) 9.28 (d, IH, H-8, J H8 . H9 = 6.41 Hz)
8,41 (d, IH, H-l, JH1.H2 = 7,93 Hz)8.41 (d, IH, Hl, J H1 . H2 = 7.93 Hz)
7,85 (m, 2H, H-2, H-ll)7.85 (m, 2H, H-2, H-ll)
7,72 (t, IH, H-10, JH9-HIO = Jmo-Hn = 7,63 Hz)7.72 (t, IH, H-10, J H9 - HIO = Jm o - Hn = 7.63 Hz)
7,50 (d, IH, H-3, JH3.H4 = 7,94 Hz) 7,27 (t, IH, H-9, JH9.K9 = JH9.H10 = 6,10 Hz)7.50 (d, IH, H-3, J H3 . H4 = 7.94 Hz) 7.27 (t, IH, H-9, J H9 . K9 = J H9 . H10 = 6.10 Hz)
RMN du 13C (CDCI3) : δ (ppm) 13 C NMR (CDCI3): δ (ppm)
187,68, 182,16 (2C, C-5, C-6)187.68, 182.16 (2C, C-5, C-6)
177,00 (1C, Cquat)177.00 (1C, Cquat)
164,91, 158,70 (2C, Cquat) 144,90 (1C, C-4)164.91, 158.70 (2C, Cquat) 144.90 (1C, C-4)
136,06 (1C, C-2)136.06 (1C, C-2)
132,86 (1C, C-10)132.86 (1C, C-10)
129,17 (1C, C-8)129.17 (1C, C-8)
126,99 (1C, C-1) 124,54 (1C, C-3) J9126.99 (1C, C-1) 124.54 (1C, C-3) D9
118,58 (1C, C-ll)118.58 (1C, C-ll)
117.40 (1C, C-9) IR (KBr) : v (cm"1) 1694, 1651 (C=0) Exemple f117.40 (1C, C-9) IR (KBr): v (cm "1 ) 1694, 1651 (C = 0) Example f
5, 6-Dihydro-5, 6-dioxo-naphto [1' ,2 ' ;4, 51 imidazo [1,2- alpyrimidine5, 6-Dihydro-5, 6-dioxo-naphto [1 ', 2'; 4, 51 imidazo [1,2- alpyrimidine
Référence : CA. 5_5 P25998fReference: CA. 5_5 P25998f
Rdt : 37 % F : > 260°CYid: 37% F:> 260 ° C
Rf : 0,60 (CH2Cl2/Méthanol, 98/2)Rf: 0.60 (CH 2 Cl 2 / Methanol, 98/2)
SM (I.E.) : m/z 249 (M+ . )SM (I.E.): m / z 249 (M +.)
RMN du λE (CDC13) : δ (ppm) Λ E NMR (CDC1 3 ): δ (ppm)
9,52 (d, IH, H-8, JH8.H9 = 5,00 Hz) 8,88 (d, IH, H-10, JH9-H10 = 5,00 Hz)9.52 (d, IH, H-8, J H8 . H9 = 5.00 Hz) 8.88 (d, IH, H-10, J H9-H10 = 5.00 Hz)
8,20, 8,06 (2d, 2H, H-l, H-4, JH1.H2 = JH3.H4 = 7,63 Hz)8.20, 8.06 (2d, 2H, Hl, H-4, J H1 . H2 = J H3 . H4 = 7.63 Hz)
7,78, 7,60 (2m, 2H, H-2, H-3)7.78, 7.60 (2m, 2H, H-2, H-3)
7,45 (m,lH, H-9)7.45 (m, 1H, H-9)
RMN du 13C (CDCI3) : δ (ppm) 169,33 (1C, Cquat) 13 C NMR (CDCI3): δ (ppm) 169.33 (1C, Cquat)
155,58 (1C, C-8)155.58 (1C, C-8)
136,24 (1C, Cquat)136.24 (1C, Cquat)
135,90 (1C, C-10)135.90 (1C, C-10)
135,74, 131,46 (2C, C-2, C-3) 130,41, 125,70 (2C, C-1, C-4)135.74, 131.46 (2C, C-2, C-3) 130.41, 125.70 (2C, C-1, C-4)
125,53 (1C, Cquat)125.53 (1C, Cquat)
112.41 (1C, C-9) IR (KBr) : v (cm"1) 1698, 1653 (C=0) Exemple g112.41 (1C, C-9) IR (KBr): v (cm "1 ) 1698, 1653 (C = 0) Example g
6, 11-Dihvdro-6, 11-dioxo-napht 12' ,3' :4, 51 imidazo [1,2- a]pyridine6, 11-Dihvdro-6, 11-dioxo-napht 12 ', 3': 4, 51 imidazo [1,2- a] pyridine
Référence : CA. 55. 21115bReference: CA. 55 . 21115b
Rdt : 6 % F : 293°C Rf : 0,10 (CH2C12/Acétate d'ethyle, 96/4)Yd: 6% F: 293 ° C Rf: 0.10 (CH 2 C1 2 / Ethyl acetate, 96/4)
SM (I.E.) : m/z 248 (M+.)SM (I.E.): m / z 248 (M +.)
RMN du XH (CD2C12) : δ (ppm) X H NMR (CD 2 C1 2 ): δ (ppm)
9,41 (d, IH, H-l, JH1.H2 = 6,72 Hz) 8,25 (m, 2H, H-7, H-10)9.41 (d, IH, Hl, J H1 . H2 = 6.72 Hz) 8.25 (m, 2H, H-7, H-10)
7,92 (d, IH, H-4, JH3.H4 = 9,15 Hz)7.92 (d, IH, H-4, J H3 . H4 = 9.15 Hz)
7,79 (m, 2H, H-8, H-9)7.79 (m, 2H, H-8, H-9)
7,66 (m, IH, H-2, JH1.H2 = JH2.H3 = 7,02 Hz, JH2.H4 = 1,22 Hz)7.66 (m, IH, H-2, J H1 . H2 = J H2 . H3 = 7.02 Hz, J H2 . H4 = 1.22 Hz)
7,28 (dt, IH, H-3, JH2.H3 = JH3.H4 = 7,02 Hz, JH1_H3 = 0,91 Hz) RMN du 13C (CD3C12) : δ (ppm)7.28 (dt, IH, H-3, J H2 . H3 = J H3 . H4 = 7.02 Hz, J H1 _ H3 = 0.91 Hz) 13 C NMR (CD 3 C1 2 ): δ ( ppm)
182,94 (1C, C≈O)182.94 (1C, C≈O)
176,30 (1C, C≈O)176.30 (1C, C≈O)
149,39, 146,19 (2C, C-5a, C-lla)149.39, 146.19 (2C, C-5a, C-lla)
134,47 (1C, C-8 ou C-9) 134,27, 134,11 (2C, C-6a, C-lOa)134.47 (1C, C-8 or C-9) 134.27, 134.11 (2C, C-6a, C-10a)
134, 00 (1C, C-8 ou C-9)134, 00 (1C, C-8 or C-9)
131,23 (1C, C-3)131.23 (1C, C-3)
120,83 (1C, C-1)120.83 (1C, C-1)
127,55, 126,72 (2C, C-7, C-10) 119,90 (1C, C-2)127.55, 126.72 (2C, C-7, C-10) 119.90 (1C, C-2)
117,46 (1C, C-4)117.46 (1C, C-4)
IR (KBr) : v (cm"1)IR (KBr): v (cm "1 )
1686, 1644 (C≈O)1686, 1644 (C≈O)
Exemple h 6,ll-Dihydro-6,ll-dioxo-pyrido [!' ,2' :1,2] imidazo-Example h 6, ll-Dihydro-6, ll-dioxo-pyrido [! ' , 2 ': 1,2] imidazo-
[5 , 4-g] cruinoline[5, 4-g] cruinoline
Référence : CA. 116 15l679tReference: CA. 116 15l679t
Rdt : 31 %Yid: 31%
F : > 260°C Rf : 0,51 (CH2Cl2/Ethanol, 94/6)F:> 260 ° C Rf: 0.51 (CH 2 Cl 2 / Ethanol, 94/6)
SM (I.E.) : m/z 249 (M+. )SM (I.E.): m / z 249 (M +.)
RMN du λE (CD2C12) : δ (ppm) Λ E NMR (CD 2 C1 2 ): δ (ppm)
9,39 (d, IH, H-l, JH1_H. = 7,02 Hz)9.39 (d, IH, Hl, J H1 _ H. = 7.02 Hz)
9,04 (d, IH, H-8, JHa.H9 = 5,19 Hz) 8,60 (d, IH, H-10, JH9.H10 = 7, 63 Hz) 7,99 (d, IH, H-4, JH3.H4 = 9, 16 Hz) 7,71 (m, 2H, H-2, H-9)9.04 (d, IH, H-8, J Ha . H9 = 5.19 Hz) 8.60 (d, IH, H-10, J H9 . H10 = 7.63 Hz) 7.99 (d, IH, H-4, J H3 . H4 = 9.16 Hz) 7.71 (m, 2H, H-2, H-9)
7.33 (m, IH, H-3)7.33 (m, IH, H-3)
RMN du 13C (CD2C12) : δ (ppm) 154,19 (1C, C-8) 13 C NMR (CD 2 C1 2 ): δ (ppm) 154.19 (1C, C-8)
134.72 (1C, C-10)134.72 (1C, C-10)
131.73 (1C, C-3) 128,82 (1C, C-1) 127,86 (1C, C-9) 120,04 (1C, C-4)131.73 (1C, C-3) 128.82 (1C, C-1) 127.86 (1C, C-9) 120.04 (1C, C-4)
117,82 (1C, C-2)117.82 (1C, C-2)
IR (KBr) : v (cm"1)IR (KBr): v (cm "1 )
1697, 1644 (C=0)1697, 1644 (C = 0)
Exemple i 5, 6-dihvdro-5, 6-dioxo-1-nitronapht[1' , 2 ' :4, 51 - imidazo [1,2-alpyridineExample i 5, 6-dihvdro-5, 6-dioxo-1-nitronapht [1 ', 2': 4, 51 - imidazo [1,2-alpyridine
Référence : CA. 55. P25998hReference: CA. 55 . P25998h
Rdt : 2 %Yid: 2%
Rf : 0,34 (CH,Cl2/Méthanol, 98/2) SM (APcI-) : m/z 293 (M-)Rf: 0.34 (CH, Cl 2 / Methanol, 98/2) SM (APcI-): m / z 293 (M-)
RMN du IH (CDC13) : δ (ppm)1 H NMR (CDC1 3 ): δ (ppm)
9.34 (d, IH, H-8, ma.H9 = 6,41 Hz) 8,32 (d, IH, H-4, JH4.H3 = 7,06 Hz) 7, 86 (m, 2H, H-2 et H-ll) 7,69 (m, IH, H-10)9.34 (d, IH, H-8, ma . H9 = 6.41 Hz) 8.32 (d, IH, H-4, J H4 . H3 = 7.06 Hz) 7.86 (m, 2H, H -2 and H-ll) 7.69 (m, 1H, H-10)
7,51 (m, IH, H-3) 7,30 (m, IH, H-9)7.51 (m, IH, H-3) 7.30 (m, IH, H-9)
Propriétés pharmacoloαiσues :Pharmacological properties:
L'étude des composés de la présente invention et de leurs sels éventuels a démontré qu'ils possèdent diverses propriétés pharmacologiques . Ainsi, ils sont sélective¬ ment veinotoniques, n'affectant le système artériel qu'à des concentrations largement supérieures à celles actives sur les veines, excepté certaines artères, en particulier cérébrales .Les composés ne montrent aucune affinité ou tout au plus une très faible affinité pour la grande ma¬ jorité des récepteurs connus Par ailleurs, ils augmen¬ tent la résistance capillaire, diminuent 1 'hyperpermeabi- lité vasculaire induite par certains agents înflammatoi- resThe study of the compounds of the present invention and their possible salts has demonstrated that they have various pharmacological properties. Thus, they are selectively veinotonic, affecting the arterial system only at concentrations much higher than those active on the veins, except certain arteries, in particular cerebral. The compounds show no affinity or at most a very weak affinity for the large majority of known receptors Furthermore, they increase capillary resistance, decrease the vascular hyperpermeability induced by certain inflammatory agents
Ces propriétés sont mises en évidence chez les mam¬ mifères tels que les hamsters, rats, cobayes et lapins, dans des conditions in vi tro (vaisseaux ou réseaux vascu- laires isolés) et m vivo . Pour les études m vi tro, les composés sont solubi¬ lisés en solution aqueuse pure ou contenant du DMSO (diméthylsuifoxyde)These properties are demonstrated in mammals such as hamsters, rats, guinea pigs and rabbits, under in vitro conditions (isolated vessels or vascular networks) and in vivo. For the m vi tro studies, the compounds are dissolved in a pure aqueous solution or containing DMSO (dimethyl sulfoxide)
Pour les études in vivo, ils sont administrés par voie intraveineuse ou mtrapéritonéale sous forme de so- lution aqueuse contenant ou non du DMSO, ou par voie orale en suspension dans la carboxyméthylcellulose à 1 %, administrés à l'aide d'une sonde de gavage sous un volume de 10 ml/kgFor in vivo studies, they are administered by the intravenous or miterperitoneal route in the form of an aqueous solution containing or not DMSO, or by the oral route in suspension in 1% carboxymethylcellulose, administered using a probe of force-feeding in a volume of 10 ml / kg
Modèles d'études pharmacologiques Effets contractilesPharmacological study models Contractile effects
Les effets contractiles sont mesurés m vi tro dans des conditions statiques sur des anneaux vasculaires à capacitance ou à résistance de veines saphènes, fémora¬ les, jugulaires, mésentériques, caves et sur artères fémorales, carotides, basilaires, mésentériques, aorte thoracique ou abdominale de rat (Wistar, 200 à 250 g) , lapin (New Zealand, 2 à 2,5 kg) , cobaye (Dunkin Hartley 250 à 300 g) .Contractile effects are measured m vi tro under static conditions on vascular rings with capacitance or resistance of saphenous, femoral, jugular, mesenteric veins and on femoral, carotid, basilar, mesenteric, thoracic or abdominal aorta arteries. rat (Wistar, 200 to 250 g), rabbit (New Zealand, 2 to 2.5 kg), guinea pig (Dunkin Hartley 250 to 300 g).
Les anneaux sont placés en chambre d'organe isolé (25 ml pour les vaisseaux à capacitance et 2,5 ml pour les vaisseaux à résistance selon Mulvany) , maintenus dans des conditions isométriques par deux fils rigides insérés à l'intérieur du vaisseau, en évitant d'endommager l'endothélium Les vaisseaux sont baignés par une solu- tion de Krebs modifiée (en mM NaCl = 118 , KC1 = 4,6 , CaCl2 = 2,5, MgS04 = 1,2 , KH2P04 = 1,17; NaHC03 = 25 , glucose = 11) , aérée en permanence par un mélange gazeux à 95 % 02 et 5 % C02, à pH = 7,4 et thermostatés à 37°C Les anneaux sont amenés à leur point optimal de la rela- tion tension-longueur.The rings are placed in an isolated organ chamber (25 ml for capacitance vessels and 2.5 ml for resistance vessels according to Mulvany), maintained in isometric conditions by two rigid wires inserted inside the vessel, in avoiding damage to the endothelium The vessels are bathed in a modified Krebs solution (in mM NaCl = 118, KC1 = 4.6, CaCl 2 = 2.5, MgS0 4 = 1.2, KH 2 P0 4 = 1.17; NaHC0 3 = 25, glucose = 11), permanently aerated by a gas mixture at 95% 0 2 and 5% C0 2 , at pH = 7.4 and thermostatically controlled at 37 ° C The rings are brought to their optimal point of the tension-length relationship.
Les tensions développées génèrent un signal électri¬ que par l'intermédiaire d'un capteur de force (pont de Wheastone) Ce signal est amplifié avant d'être soit vi¬ sualisé sur enregistreur Kipp & Zonen, soit digitalisé pour être traité par ordmateuir (IOS, EMKA) . Les études pharmacologiques sont réalisées après quelques stimula¬ tions contractiles préliminaires standardisées par une solution dépolaπsante (hyperpotassique obtenue en rem¬ plaçant du NaCl par du KC1 en quantités équimolaires) , rinçages et périodes d'équilibration en solution physio¬ logique pure. La présence d' endothélium est vérifiée par la relaxation induite par des concentrations croissantes d'acetylcholme après stabilisation d'une précontraction vasculaire. Les forces de contraction développées par les an¬ neaux vasculaires en réponse aux différents composés sont étudiées sur des vaisseaux quiescents ou stimulés élec¬ triquement (5-8 Hz) , par une solution "physiologique" dé¬ polarisante hyperpotassique (KC1 20, 40 mM) , par la no- radrénalme (concentrations croissantes) , la sérotomne (concentrations croissantes) ...The developed voltages generate an electrical signal via a force sensor (Wheastone bridge). This signal is amplified before being either displayed on a Kipp & Zonen recorder, or digitized to be processed by computer ( IOS, EMKA). Pharmacological studies are carried out after a few preliminary contractile stimulations standardized by a depolaπsante solution (hyperpotassic obtained by replacing NaCl with KC1 in equimolar quantities), rinses and equilibration periods in pure physiological solution. The presence of endothelium is verified by the relaxation induced by increasing concentrations of acetylcholme after stabilization of a vascular pre-contraction. The contraction forces developed by the vascular rings in response to the various compounds are studied on quiescent or electrically stimulated vessels (5-8 Hz), using a hyperpotassic de¬ polarizing "physiological" solution (KC1 20, 40 mM ), by no-radrenalme (increasing concentrations), serotomne (increasing concentrations) ...
Les contractions sont exprimées en mg force ou en pourcentage de la contraction maximale à la dépolansa- tion par une solution "physiologique" hyperpotassique Les effets contractiles sont également mesurés m vi tro dans des conditions dynamiques de flux, par la pression développée par des réseaux vasculaires perfusés à débit constant. Au niveau mésentérique, la vemosélec- tivité est étudiée sur le modèle de double perfusion si- multanée et séparée des réseaux artériels et veineux, mo- dèle développé par T WARNER (Bπtish J Pharmacol 1990, 99, 427-433) . La séparation des deux réseaux est réalisée en coupant les vaisseaux et les tissus le long de la bor¬ dure intestinale. Les réseaux sont perfusés à 2 ml.mm"1 par une solution de Krebs (37,5°C) aérée à 95 % 02 et 5 % C02.The contractions are expressed in mg force or as a percentage of the maximum contraction on depolansation by a "physiological" hyperpotassic solution. Contractile effects are also measured m vi tro under dynamic flow conditions, by the pressure developed by vascular networks. infused at constant rate. At the mesenteric level, vemoselectivity is studied on the model of simultaneous and separate double perfusion of arterial and venous networks, mo- model developed by T WARNER (Bπtish J Pharmacol 1990, 99, 427-433). The two networks are separated by cutting the vessels and the tissues along the intestinal border. The networks are perfused at 2 ml.mm " 1 with a Krebs solution (37.5 ° C) aerated at 95% 0 2 and 5% C0 2 .
In vivo, les pressions artérielles et veineuses sont mesurées chez l'animal anesthésié, dans des conditions basales et après arrêt circulatoire provoqué par le gon- flement d'un cathéter à ballonnet introduit au niveau de l'oreillette droite. Lors de l'arrêt cardiaque, le tonus veineux (pression moyenne circulatoire de remplissage à volume sanguin constant) est calculé à partir des pres¬ sions veineuses et artérielles mesurées à l'équilibre et corrigées en fonction des différences relatives de com- pliance entre ces deux réseaux (SAMAR COLEMAN, Am J Physiol. 1978, 234:H94-100, YAMAMOTO et al., Am. J Phy- siol . 1980, 238:H823-828) .In vivo, arterial and venous pressures are measured in the anesthetized animal, under basal conditions and after circulatory arrest caused by the swelling of a balloon catheter introduced into the right atrium. During cardiac arrest, the venous tone (mean circulatory filling pressure at constant blood volume) is calculated from the venous and arterial pressures measured at equilibrium and corrected according to the relative differences in compliance between these two networks (SAMAR COLEMAN, Am J Physiol. 1978, 234: H94-100, YAMAMOTO et al., Am. J Physiol. 1980, 238: H823-828).
Chez l'animal éveillé, les pressions artérielles sont mesurées selon la méthode classique dérivée de Riva Rocci, par analyse de l'onde acoustique transmise au ni¬ veau artériel et transformée par un transducteur piezo céramique placé sur la queue du rat, en aval d'un manchon gonflé automatiquement par un générateur de pression Au niveau microcirculatoire, les variations de sec¬ tion veinulaire et artériolaire sont étudiées in vivo dans le modèle de la chambre cutanée dorsale de hamster vigile, après enregistrement vidéomicroscopique (micro¬ scope Leitz Ergolux équipé d'une source halogène pour l'éclairage et une caméra vidéo CDD noir et blanc HPR 610) et analyse informatique (logiciel Visicap, Pack ICAP) des images.In awake animals, the arterial pressures are measured according to the classic method derived from Riva Rocci, by analysis of the acoustic wave transmitted to the arterial level and transformed by a piezo ceramic transducer placed on the tail of the rat, downstream of '' a sleeve inflated automatically by a pressure generator At the microcirculatory level, the variations in vein and arteriolar section are studied in vivo in the model of the dorsal cutaneous chamber of a vigilant hamster, after videomicroscopic recording (Leitz Ergolux micro¬ scope equipped with '' a halogen source for lighting and a black and white CDD video camera HPR 610) and computer analysis (Visicap software, ICAP pack) of the images.
Après anesthésié au pentobarbital sodique (60 mg/kg en ι.p.), le dos de l'animal est tondu et épilé de ma- mère à pouvoir placer une chambre d'observation (Prof GEBHARD, Heidelberg) sur la peau du dos. Les deux parties de la chambre sont cousues après avoir enlevé avec pré¬ caution les épaisseurs cutanées pouvant gêner l'obser¬ vation. Un cathéter jugulaire est placé pour l'admims- tration î.v. des produits, 48 heures après l'opération Effets sur l'hyperperméabilité capillaire induite La perméabilité vasculaire est étudiée m vivo par la mesure de 1 ' extravasation d'albumine dont la quantité est déterminée grâce à un colorant liant l'albumine (Bleu Evans) L'hyperperméabilité est induite par injection in¬ tradermique d'une solution d'histamme, de bradykmme ou de zymosan.After anesthetized with sodium pentobarbital (60 mg / kg in ι.p.), the back of the animal is shorn and plucked from mother to be able to place an observation chamber (Prof GEBHARD, Heidelberg) on the skin of the back. The two parts of the chamber are sewn after having carefully removed the skin thicknesses which may hinder observation. A jugular catheter is placed for IV delivery. of the products, 48 hours after the operation Effects on induced capillary hyperpermeability Vascular permeability is studied in vivo by measuring the albumin extravasation, the amount of which is determined using an albumin-binding dye (Evans Blue) Hyperpermeability is induced by in¬ tradermal injection of a histamme, bradykmme or zymosan solution.
La technique est dérivée de celle décrite par BEACH & STEINETZ, J. Pharmacol. Exp. Therap. , 1961, 131:400- 406.The technique is derived from that described by BEACH & STEINETZ, J. Pharmacol. Exp. Therap. , 1961, 131: 400-406.
Les rats (Wistars, 200 à 230 g) sont tondus sur leur paroi abdominale une heure avant le début de l'expérimen¬ tation Le produit à tester est injecté par voie i p ou per os 1 heure à 4 heures avant le sacrifice. Les rats sont anesthésiés par un mélange d'halothane Ensuite, ils reçoivent une injection intradermique sur l'abdomen de 0,10 ou 0,15 ml (soit pour l'histamme, 6,7 ou 10 micro¬ grammes) d'agent inflammatoire et une injection intravei¬ neuse d'un ml d'une solution de bleu Evans à 0,5 % dans la veine du pénis. Ces injections sont réalisées 30 minu¬ tes avant l'euthanasie.The rats (Wistars, 200 to 230 g) are shorn on their abdominal wall one hour before the start of the experiment. The product to be tested is injected i p or orally 1 hour to 4 hours before the sacrifice. The rats are anesthetized with a mixture of halothane Then they receive an intradermal injection on the abdomen of 0.10 or 0.15 ml (either for the histamme, 6.7 or 10 micro¬ grams) of inflammatory agent and an intravenous injection of one ml of a 0.5% Evans blue solution into the vein of the penis. These injections are carried out 30 minutes before euthanasia.
30 minutes après ces deux injections, les rats sont euthanasiés par dislocation cervicale30 minutes after these two injections, the rats are euthanized by cervical dislocation
A l'endroit de l'injection de l'agent inflammatoire, la peau est découpée et placée dans des tubes en verre à col rôdé contenant 3 ml d'acide chlorhydrique fumant La digestion de la peau est réalisée par un contact d'au moins une heure au bain marie à 37°C Trois ml de chlo¬ rure de benzalkonium à 12,8 % sont ensuite ajoutés. Après avoir laissé reposer durant trente minutes, 7 ml de di- chlorométhane sont additionnés Les tubes sont agités pé¬ riodiquement pendant une heure La phase aqueuse est éli¬ minée par aspiration et la phase organique "dichloro¬ méthane" est filtrée Les densités optiques sont quantî- fiées par spectrophotometrie d'absorption à une longueur d'onde de 620 nm, contre un blanc contenant uniquement le dichlorométhane.At the site of the injection of the inflammatory agent, the skin is cut and placed in glass tubes with a ruffled neck containing 3 ml of fuming hydrochloric acid. The digestion of the skin is carried out by contact of at least one hour in a water bath at 37 ° C. Three ml of 12.8% benzalkonium chloride are then added. After allowing to stand for thirty minutes, 7 ml of di- chloromethane are added The tubes are agitated periodically for one hour The aqueous phase is removed by suction and the organic phase "dichloromethane" is filtered The optical densities are quantified by absorption spectrophotometry at a length of 620 nm wave, against a blank containing only dichloromethane.
Les moyennes des densités optiques des différents lots d'animaux traités ou témoins sont calculées, puis un pourcentage de variation des valeurs correspondant aux animaux traités par rapport à celles des animaux témoins est calculéThe averages of the optical densities of the different batches of treated or control animals are calculated, then a percentage change in the values corresponding to the treated animals compared to those of the control animals
L'effet des composés sur l'hyperperméabilité induite par des agents inflammatoires, comme l'histamine et la bradykmme est également étudié après injection intra¬ veineuse par bolus dans le modèle de chambre cutanée dor¬ sale de hamster et selon la méthode développée par GIMENO et al . , décrite précédemment (A new technique using in- travital videomicroscopy for macromolecular permeability measurement, 18° Congrès Européen de microcirculation, Rome 1994) par videomicroscopie et analyse d'images par quantification de la répartition de la fluorescence mtra et extravasculaire du marqueur fluorescent (FITC-Dextran) injecté en bolus par le cathéter jugulaire (63 mg/kg pour un volume défini à 1 ml/kg) Le microscope est équipé d'une source fluorescente et d'une combinaison de filtres (excitation dans le bleu 450-490 nm et filtre d'arrêt 515 nm) .The effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamine and bradykmme is also studied after intravenous injection by bolus in the model of the dor¬ dirty hamster skin chamber and according to the method developed by GIMENO et al . , previously described (A new technique using intra-videomicroscopy for macromolecular permeability measurement, 18th European Congress of microcirculation, Rome 1994) by videomicroscopy and image analysis by quantification of the distribution of mtra and extravascular fluorescence of the fluorescent marker (FITC -Dextran) injected as a bolus through the jugular catheter (63 mg / kg for a defined volume of 1 ml / kg) The microscope is equipped with a fluorescent source and a combination of filters (excitation in blue 450-490 nm and 515 nm stop filter).
Effets sur la résistance capillaire : L'augmentation de la résistance capillaire est ap¬ préciée par la modification de l'index pétéchial (pres¬ sion négative induisant 1 ' extravasation des érythrocy- tes) , mesuré par une méthode dérivée de 1 ' angiosterro- mètre de Parrot L'étude se réalise sur des rats mâles Wistar d'un poids moyen de 200 g (âgés d'environ six semaines) La région du bas du dos est rasée puis épilée à l'aide d'une pâte à base d'un dérivé de l'acide thioglycolique et d'hydroxyde de calcium. Après environ trente minutes, la peau est abondamment rincée et séchée.Effects on capillary resistance: The increase in capillary resistance is appreciated by the modification of the petechial index (negative pressure inducing the extravasation of erythrocytes), measured by a method derived from angiosterro- Parrot meter The study is carried out on Wistar male rats of a average weight of 200 g (about six weeks old) The lower back region is shaved and then depilated using a paste based on a derivative of thioglycolic acid and calcium hydroxide. After about thirty minutes, the skin is thoroughly rinsed and dried.
Le jour de l'étude, les rats sont maintenus sans contrainte. Une dépression de 80 mm de mercure est appli¬ quée. Si les pétéchies (extravasation d' érythrocytes) ne sont pas apparues dans les 15 secondes, la dépression est augmentée par pallier en maintenant la ventouse au même endroit.On the day of the study, the rats were kept unconstrained. A vacuum of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) have not appeared within 15 seconds, the depression is increased by compensating by keeping the suction cup in the same place.
La dépression minimale pour laquelle apparaissent les pétéchies exprime, en mm de mercure, la valeur de ré¬ sistance capillaire de base (avant tout traitement) Deux mesures sont réalisées pour chaque essai à des emplace¬ ments différents du dos. Les rats sont traités par voie orale. Après un temps déterminé (généralement 2, 4, 6 heures) suivant le traitement, le test est renouvelle sur des plages de peau différentes, jusqu'à l'apparition des pétéchies, procurant un nouvel index de dépression Tou¬ tes les mesures se font en aveugle.The minimum depression for which the petechiae appear expresses, in mm of mercury, the value of basic capillary resistance (before any treatment). Two measurements are carried out for each test at different locations on the back. Rats are treated orally. After a determined time (generally 2, 4, 6 hours) following the treatment, the test is repeated on different skin areas, until the appearance of petechiae, providing a new index of depression. All measurements are made. blindly.
Un pourcentage de variation des résistances capil¬ laires des animaux traités par rapport à leur résistance capillaire de base est calculé pour chaque composé étu- dié, à chaque temps de traitement et comparé avec le groupe témoin (excipient seul) ou le groupe de référence.A percentage change in the capillary resistances of the treated animals with respect to their basic capillary resistance is calculated for each compound studied, at each treatment time and compared with the control group (excipient only) or the reference group.
Effets sur la pleurésie induite chez le rat :Effects on induced pleurisy in rats:
L'activité antimflammatoire des composés est égale¬ ment étudiée par la mesure de l'inhibition de l'oedème et de la migration leucocytaire après induction d'une pleu¬ résie chez le rat par injection de carraghénme dans la cavité pleurale (ALMEIDA et al., J. Pharmacol. Exp The- rap. , 1980, 214:74) .The anti-inflammatory activity of the compounds is also studied by measuring the inhibition of edema and leukocyte migration after induction of rain in the rat by injection of carrageenan into the pleural cavity (ALMEIDA et al ., J. Pharmacol. Exp Therap., 1980, 214: 74).
Les rats sont traités per os par les composés 2 heu- res avant l'injection de carraghénme, ainsi que 2 et 4 heures après cette injection. Après un temps déterminé (6 heures) suivant l'induction de la pleurésie, les rats sont euthanasiés et le liquide pleural récupéré par aspi¬ ration et son volume est mesuré. Les cellules leucocytai- res sont comptées par "cell counter" .The rats are treated per os with the compounds 2 hours before the injection of carrageenan, as well as 2 and 4 hours after this injection. After a determined time (6 hours) following the induction of pleurisy, the rats are euthanized and the pleural fluid recovered by aspiration and its volume is measured. The leukocyte cells are counted by "cell counter".
Les résultats sont exprimés en nombre de leucocytes dans 1 ' exudat rapporté à 100 g de poids de l'animal et comparés à ceux du lot témoin.The results are expressed in number of leukocytes in the exudate relative to 100 g of animal weight and compared to those of the control batch.
Exemples d'effets pharmacolocriσues : Les composés de 1 ' invention et leurs sels éventuels augmentent sélectiverment dans la majorité des cas la contraction des veines animales produite par la noradré- naline, par la stimulation électrique ou par une solution hyperpotassique dépolarisante. A titre illustratif, figure l'effet contractile de différents composés sur la veine saphène de lapin précon¬ tractée par une solution "physiologique" dépolarisante de concentration potassique égale à 40 mM ; l'effet maximal produit par chaque composé est exprimé en pourcentage de la contraction maximale induite par des solutions hyper- potassiques dépolarisantes et en valeur d'EDso) :Examples of Pharmacological Effects: The compounds of the invention and their possible salts selectively increase in the majority of cases the contraction of the animal veins produced by norepinephrine, by electrical stimulation or by a depolarizing hyperpotassic solution. By way of illustration, the contractile effect of different compounds on the saphenous vein of rabbits pre-towed by a "physiological" depolarizing solution with potassium concentration equal to 40 mM is shown; the maximum effect produced by each compound is expressed as a percentage of the maximum contraction induced by depolarizing hyperpotash solutions and in ED 50 value):
Composés Rmax '% Coπtr.max. ) ED '50 (nM) Compounds Rmax '% Coπtr.max. ) ED '50 (nM)
Exemple a 32 ± 7 306Example a 32 ± 7,306
Exemple c 27 ± 4 157 Exemple f 56 ± 7 450Example c 27 ± 4 157 Example f 56 ± 7 450
Exemple h 18 ± 3 67Example h 18 ± 3 67
Exemple 1 20 ± 4 170Example 1 20 ± 4,170
Exemple 2 28 ± 4 271Example 2 28 ± 4,271
Exemple 3 18 ± 4 200 Exemple 12 13 + 3 58Example 3 18 ± 4,200 Example 12 13 + 3,58
A titre illustratif, l'administration orale de cer¬ tains composés de l'invention et leurs sels éventuels augmente la résistance capillaire du rat à des doses com¬ prises généralement entre 0,01 et 5 mg/kg :By way of illustration, the oral administration of cer tain ¬ compounds of the invention and their possible salts increases the capillary resistance of the rat at doses generally taken between 0.01 and 5 mg / kg:
Composés Effet à 4 heures Effet à 6 heures (en % dduu ttéémmooiinn)) (en % du témoin)Compounds Effect at 4 o'clock Effect at 6 o'clock (in% dduu ttéémmooiinn)) (in% of control)
Exemple 2 5 mg/kg 1 111 13Example 2 5 mg / kg 1,111 13
Exemple c 5 mg/kg 1 177 10Example c 5 mg / kg 1,177 10
Exemple c 0,1 mg/kg 1199 29Example c 0.1 mg / kg 1,199 29
Exemple e 0,1 mg/kg 00 17Example e 0.1 mg / kg 00 17
Exemple h 0,1 mg/kg 1199 13Example h 0.1 mg / kg 1199 13
A titre illustratif, l'administration orale de cer¬ tains composés de l'invention et leurs sels éventuels ré¬ duit l'hyperperméabilité inflammatoire induite par le zy- mosan chez le rat à des doses comprises généralement en¬ tre 0, 01 et 5 mg/kg :By way of illustration, the oral administration of certain compounds of the invention and their possible salts reduces the inflammatory hyperpermeability induced by zy-mosan in rats at doses generally comprised between 0, 01 and 5 mg / kg:
Composés Effet à 2 heures Effet à 4 heures (en % du témoin) (en % du témoin)Compounds Effect at 2 hours Effect at 4 hours (in% of the control) (in% of the control)
Exemple a 5 mg/kg - 1 -28Example at 5 mg / kg - 1 -28
Exemple c 0,1 mg/kg -14 -11Example c 0.1 mg / kg -14 -11
Exemple h 0,1 mg/kg -23 - 5 Exemple 2 0,1 mg/kg -10 -15Example h 0.1 mg / kg -23 - 5 Example 2 0.1 mg / kg -10 -15
Exemple 3 5 mg/kg -13 -12Example 3 5 mg / kg -13 -12
Par ailleurs, les composés de l'invention et leurs sels éventuels sont très peu toxiques. Par exemple, après une administration orale unique de 1 g/kg chez la souris, aucun effet toxique observable et aucune mortalité n'est observée pour la majorité des composés en particulier pour l'Exemple a, l'Exemple c et l'Exemple 2.Furthermore, the compounds of the invention and their possible salts are very little toxic. For example, after a single oral administration of 1 g / kg in mice, no observable toxic effect and no mortality is observed for the majority of the compounds, in particular for Example a, Example c and Example 2 .
Parmi les composés préférés de l'invention, on re¬ tient tout particulièrement l'Exemple c. Ce qui précède montre que les composés de l'invention et leurs sels éventuels peuvent être utilisés en thérapeutique humaine et animale Ils sont en particu¬ lier indiqués dans l'insuffisance veineuse fonctionnelle, organique et les pathologies hémorroidaires par leurs composantes vasculaires et antimflammatoires, ainsi que dans les affections typiquement inflammatoires et dans les états de chocs constitués par une chute importante de la pression artérielle. Dans ce dernier cas, une amélio¬ ration du retour veineux est susceptible de maintenir le débit cardiaque et dès lors, par voie de conséquence, la pression artérielleAmong the preferred compounds of the invention, example c is particularly given. The above shows that the compounds of the invention and their possible salts can be used in human and animal therapy They are in particular indicated in functional, organic venous insufficiency and hemorrhoidal pathologies by their vascular and anti-inflammatory components, as well as in typically inflammatory conditions and in shock states constituted by a significant fall in blood pressure. In the latter case, an improvement in the venous return is likely to maintain the cardiac output and consequently, the blood pressure
L'insuffisance veineuse fonctionnelle se caractérise par une dilatation et une hyperdistensibilite des veines superficielles des membres inférieurs, oedèmes, paresthé- sies à type d'impatience, de jambe sans repos Ce type de pathologie peut évoluer vers l'insuffisance veineuse or¬ ganique caractérisée par le développement de varices, d'incontinences valvulaires, voire vers la phlébothrom- bose et les troubles trophiques aboutissant à des lésions ulcéreuses . Dans cette pathologie veineuse, une composante in¬ flammatoire s'installe dans les premiers stades et se ma¬ nifeste plus clairement dans les stades avancesFunctional venous insufficiency is characterized by dilation and hyperdistensitivity of the superficial veins of the lower limbs, edemas, impatience-type paresthesias, restless leg This type of pathology can progress to characterized organic venous insufficiency through the development of varicose veins, valve incontinence, or even towards phlebothrom- bosis and trophic disorders leading to ulcerative lesions. In this venous pathology, an inflammatory component settles in the early stages and manifests itself more clearly in the advanced stages
Par leurs effets vemoconstπcteurs, antimflamma¬ toires en particulier sur l'hyperperméabilité vasculaire et leurs effets contractiles sur les artères cérébrales, les composés de l'invention et leurs sels éventuels sont également indiqués dans la migraineBy their vemoconstπcteurs, antimflamma¬ toires effects in particular on vascular hyperpermeability and their contractile effects on the cerebral arteries, the compounds of the invention and their possible salts are also indicated in migraine
La présente invention comprend donc l'utilisation des composés mentionnés ci-dessus et de leurs sels éven- tuels, comme substances actives pour la préparation de médicaments et de compositions pharmaceutiques à usage humain et vétérinaire, comprenant au moins un desdits composés et sels en association avec un support ou di¬ luant physiologiquement acceptable. La forme de ces médicaments et compositions pharma- ceutiques dépendra bien évidemment de la voie d'adminis¬ tration souhaitée notamment orale, parentérale, topique (cutanée) et rectale, et ils peuvent être formulés selon les techniques classiques avec mise en oeuvre de supports et véhicules usuels.The present invention therefore comprises the use of the above-mentioned compounds and their possible salts, as active substances for the preparation of medicaments and pharmaceutical compositions for human and veterinary use, comprising at least one of said compounds and salts in combination with a physiologically acceptable carrier or diluent. The form of these drugs and pharmaceutical compositions ceutiques obviously depend on the desired route of administration including oral, parenteral, topical (skin) and rectal, and they can be formulated according to conventional techniques with the use of supports and usual vehicles.
Ainsi, dans le cas d'une administration par voie orale, ils peuvent se présenter sous la forme de compri¬ més, tablettes, gélules, solutions, sirops, émulsions, suspensions, poudre, granulés, capsule molle, lyophili- sat, microcapsule, microgranule.Thus, in the case of oral administration, they may be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophili- sat, microcapsule, microgranule.
Les comprimés, tablettes et gélules contiennent la substance active conjointement avec un diluant (par exem¬ ple lactose, dextrose, sucrose, mannitol, maltitol, xyli- tol, sorbitol ou cellulose) , un lubrifiant (par exemple silice, talc ou stéarate) , un liant (par exemple ami¬ don,méthylcellulose ou gomme arabique) , un agent de dés¬ intégration (alginate par exemple) et ils sont fabriqués par des techniques connues par exemple de mélange, de granulation, de pastillage, d'enrobage, de compression etc...Tablets, tablets and capsules contain the active substance together with a diluent (for example lactose, dextrose, sucrose, mannitol, maltitol, xylitol, sorbitol or cellulose), a lubricant (for example silica, talc or stearate), a binder (for example ami¬ don, methylcellulose or gum arabic), a disintegrating agent (alginate for example) and they are produced by known techniques for example of mixing, granulation, pelletizing, coating, compression etc ...
Les sirops peuvent contenir, à titre de support, glycérol, mannitol et/ou sorbitol. Les solutions et sus¬ pensions peuvent comprendre de l'eau et d'autres solvants physiologiquement compatibles et un support tel qu'une gomme naturelle, de la gélose, de 1 ' alginate de sodium ou de l'alcool polyvinylique .The syrups may contain, as a support, glycerol, mannitol and / or sorbitol. The solutions and suspensions can include water and other physiologically compatible solvents and a support such as a natural gum, agar, sodium alginate or polyvinyl alcohol.
Pour l'administration par voie parentérale, les mé¬ dicaments et compositions peuvent prendre la forme de so¬ lutions, d' émulsions ou de suspensions comprenant la substance active et un support ou solvant approprié tel que l'eau stérile ou des solutions salines isotoniques stériles.For parenteral administration, the drugs and compositions may take the form of solutions, emulsions or suspensions comprising the active substance and a suitable support or solvent such as sterile water or isotonic saline solutions. sterile.
Pour l'application cutanée, les médicaments et com¬ positions peuvent prendre la forme d'onguent, crème ou gel, sous forme d'émulsion ou de suspension, solution, 32For skin application, the drugs and compositions can take the form of an ointment, cream or gel, in the form of an emulsion or suspension, solution, 32
mousse, poudre.foam, powder.
Pour l'application rectale, les médicaments et com¬ positions peuvent prendre la forme de capsule, crème, émulsion, gel, mousse, pommade, suppositoire. For rectal application, the drugs and compositions can take the form of capsule, cream, emulsion, gel, foam, ointment, suppository.

Claims

REVENDICATIONS
1 Utilisation de dérivés tétracycliques et de leurs sels acceptables du point de vue pharmaceutique ré¬ pondant à la formule générale • 1 Use of tetracyclic derivatives and their pharmaceutically acceptable salts corresponding to the general formula •
dans laquelle indépendamment les uns des autres :in which independently of each other:
X est un atome de carbone ou un atome d'azote, T est un atome de carbone ou un atome d'azote, R1 est un atome d'hydrogène, un atome d'halogène, un radical alkyle en C^ à C5,X is a carbon atom or a nitrogen atom, T is a carbon atom or a nitrogen atom, R 1 is a hydrogen atom, a halogen atom, a C 1 -C 5 alkyl radical,
R2 est un atome d'hydrogène, un atome d'halogène, un radical nitro, un radical alkyle en C]_ à C5, n et m sont soit égal à 0 soit à 1, mais non mdé- pendamment l'un de l'autre de telle sorte que si n est égal à 1 alors m est égal à 0, et si n est égal a 0 alors m est égal à 1, pour l'obtention d'un médicament destiné au traite¬ ment de maladies liées à une altération de la fonction veineuse et/ou à l'oedème inflammatoireR 2 is a hydrogen atom, a halogen atom, a nitro radical, a C 1 -C 5 alkyl radical, n and m are either 0 or 1, but not mdependent of any of the other such that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1, for obtaining a medicament intended for the treatment of related diseases impaired venous function and / or inflammatory edema
2. A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-9-méthyl-napht [1 ' , 2 ' .4,5] imidazo [1, 2-a] pyridme2. As a new product, 5,6-dihydro-5,6-dioxo-9-methyl-naphth [1 ', 2' .4.5] imidazo [1, 2-a] pyridme
3 A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-10-méthyl-napht [!' , 2 ' :4, 5] imidazo [1, 2-a] pyridme. 3 As a new product, 5, 6-dihydro-5, 6 dioxo-10-methyl-napht [! ' , 2 ': 4, 5] imidazo [1, 2-a] pyridme.
4 A titre de produit nouveau la 5, 6-dιhydro-5, 6- dioxo-11-méthyl-napht [1 ' , 2 ' 4,5] imidazo [1, 2-a]pyridme4 As a new product, 5, 6-dehydro-5, 6 dioxo-11-methyl-napht [1 ', 2' 4,5] imidazo [1, 2-a] pyridme
5. A titre de produit nouveau la ll-chloro-5, 6- dιhydro-5, 6-dioxo-napht [1 ' , 2 ' 4, 5] imidazo[1, 2-a]pyridme5. As a new product, ll-chloro-5, 6-dehydro-5, 6-dioxo-napht [1 ', 2' 4, 5] imidazo [1, 2-a] pyridme
6 A titre de produit nouveau la 5, 6-dιhydro-5, 6- dιoxo-9-fluoro-napht [1' , 2 ' :4, 5] imidazo[1, 2-a] pyridme6 As a new product, 5, 6-dehydro-5, 6-dιoxo-9-fluoro-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridme
7 A titre de produit nouveau la 9-chloro-5, 6- dιhydro-5, 6-dioxo-4-nitro-napht [1 ' , 2 ' 4,5] imidazo[1, 2-a] - pyridme7 As a new product 9-chloro-5, 6-dehydro-5, 6-dioxo-4-nitro-napht [1 ', 2' 4,5] imidazo [1, 2-a] - pyridme
8. A titre de produit nouveau la 2-chloro-6, 11- dιhydro-6, ll-dιoxo-7-nιtronapht [2 ' , 3 ' 4, 5] imidazo[1, 2-a] - pyridme.8. As a new product, 2-chloro-6, 11- dehydro-6, ll-dιoxo-7-nιtronapht [2 ', 3' 4, 5] imidazo [1, 2-a] - pyridme.
9 A titre de produit nouveau la 2-chloro-6, 11-dι- hydro-6, ll-dιoxo-10-nιtronapht [2 ' , 3 ' 4,5] imidazo [1, 2-a] - pyridme9 As a new product, 2-chloro-6, 11-dι- hydro-6, ll-dιoxo-10-nιtronapht [2 ', 3' 4,5] imidazo [1, 2-a] - pyridme
10 A titre de produit nouveau la 6 , ll-dιhydro-6 , 11- dιoxo-2 -méthyl -napht [2 ' , 3 ' 4,5] imidazo [1, 2-a] pyridme10 As a new product, 6, ll-dehydro-6, 11- dιoxo-2 -methyl -napht [2 ', 3' 4,5] imidazo [1, 2-a] pyridme
11. A titre de produit nouveau la 2-chloro-6 , 11- dιhydro-6 , ll-dioxo-napht [2 ' , 3 ' 4,5] imidazo [1, 2-a] - pyridme11. As a new product, 2-chloro-6, 11- dehydro-6, ll-dioxo-napht [2 ', 3' 4,5] imidazo [1, 2-a] - pyridme
12. A titre de produit nouveau la 4-chloro-6 , 11- dιhydro-6, ll-dioxo-napht [2 ' , 3 ' 4 , 5] imidazo [1, 2-a] - pyridme12. As a new product, 4-chloro-6, 11- dehydro-6, ll-dioxo-napht [2 ', 3' 4, 5] imidazo [1, 2-a] - pyridme
13. A titre de produit nouveau la 6, ll-dιhydro-6, 11- dιoxo-2-fluoro-napht [2 ' , 3 ' 4,5] imidazo [1, 2-a] pyridme 13. As a new product, 6, ll-dehydro-6, 11- dιoxo-2-fluoro-napht [2 ', 3' 4,5] imidazo [1, 2-a] pyridme
14. A titre de produit nouveau la 10-chloro-5 , 6- dihydro-5, 6-dioxonapht [1' , 2 ' :4, 5] imidazo [1, 2-a]pyridme.14. As a new product, 10-chloro-5,6-dihydro-5,6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridme.
15. A titre de produit nouveau la 4-chloro-5 , 6- dιhydro-5, 6-dιoxonapht [1' , 2 ' :4 , 5] imidazo [1, 2-a] pyridme.15. As a new product, 4-chloro-5, 6-dehydro-5, 6-dιoxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridme.
16. A titre de produit nouveau la 4-bromo-5,6- dιhydro-5, 6-dιoxonapht [1 ' , 2 ' -4,5] imidazo[1, 2-a] pyridme .16. As a new product, 4-bromo-5,6-dehydro-5,6-dιoxonapht [1 ', 2' -4.5] imidazo [1, 2-a] pyridme.
17. A titre de produit nouveau la 5, 6-dihydro-5, 6- dιoxo-2-nιtronapht [1' , 2 ' :4, 5] imidazo [1, 2-a] pyridme.17. As a new product, 5, 6-dihydro-5, 6-dιoxo-2-nιtronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridme.
18. A titre de produit nouveau la 6, ll-dιhydro-6, 11- dioxo-7-nitronapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridme.18. As a new product, 6, ll-dehydro-6, 11-dioxo-7-nitronapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme.
19. A titre de produit nouveau la 6, 11-dihydro-6, 11- dioxo-10-nitronapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridme .19. As a new product, 6, 11-dihydro-6, 11-dioxo-10-nitronapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme.
20 A titre de produit nouveau la 6, ll-dιhydro-6, 11- dioxo-8-fluoronapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridme20 As a new product, 6, ll-dehydro-6, 11-dioxo-8-fluoronapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme
21. A titre de produit nouveau la 6, ll-dιhydro-6, 11- dιoxo-9-fluoronapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridine21. As a new product, 6, ll-dehydro-6, 11-dιoxo-9-fluoronapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine
22. A titre de produit nouveau la 5, 6-dihydro-5, 6- dιoxo-2-fluoronapht [1 ' , 2 ' :4, 5] imidazo [1, 2-a] pyridme22. As a new product, 5, 6-dihydro-5, 6-dιoxo-2-fluoronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridme
23. A titre de produit nouveau la 5 , 6-dihydro-5 , 6- dιoxo-3-fluoronapht [1' , 2 ' 4,5] imidazo [1, 2-a] pyridme23. As a new product, 5, 6-dihydro-5, 6- dιoxo-3-fluoronapht [1 ', 2' 4,5] imidazo [1, 2-a] pyridme
24. A titre de produit nouveau la 6, 11-dihydro-6, 11- dioxo-7-fluoronapht [2 ' , 3 ' :4 , 5] imidazo [1, 2-a]pyridme.24. As a new product, 6, 11-dihydro-6, 11-dioxo-7-fluoronapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme.
25. A titre de produit nouveau la 6, 11-dihydro-6, 11- dιoxo-10-fluoronapht [2 ' , 3 ' -4,5] imidazo[1, 2-a] -pyridme 25. As a new product, 6, 11-dihydro-6, 11- dιoxo-10-fluoronapht [2 ', 3' -4,5] imidazo [1, 2-a] -pyridme
26. A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-1-fluoronapht [1' , 2 ' :4, 5] imidazo [1, 2-a] pyridine.26. As a new product, 5, 6-dihydro-5, 6 dioxo-1-fluoronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.
27. A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-4-fluoronapht (1 ' , 2 ' :4, 5] imidazo [1, 2-a] pyridine.27. As a new product, 5,6-dihydro-5,6-dioxo-4-fluoronapht (1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.
28. A titre de produit nouveau la 4 , 9-dichloro-5, 6- dihydro-5, 6-dioxonapht [1' , 2 ' :4, 5] imidazo [1, 2-a] pyridine.28. As a new product 4,9-dichloro-5,6-dihydro-5,6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.
29. A titre de produit nouveau la 6, 11-dihydro-6, 11- dioxo-7-méthylnapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a]pyridine .29. As a new product, 6, 11-dihydro-6, 11-dioxo-7-methylnaphth [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine.
30. A titre de produit nouveau la 6, ll-dihydro-6, 11- dioxo-10-méthylnapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] -pyridine.30. As a new product, 6,11-dihydro-6,11-dioxo-10-methylnaphth [2 ', 3': 4, 5] imidazo [1, 2-a] -pyridine.
31. A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-1-méthylnapht [1 ' , 2 ' :4, 5] imidazo [1, 2-a]pyridine.31. As a new product, 5, 6-dihydro-5, 6-dioxo-1-methylnaphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.
32. A titre de produit nouveau la 5, 6-dihydro-5, 6- dioxo-4-méthylnaphtfl ' , 2 ' :4, 5]imidazo[l, 2-a]pyridine.32. As a new product, 5, 6-dihydro-5, 6-dioxo-4-methylnaphthfl ', 2': 4, 5] imidazo [1,2-a] pyridine.
33. A titre de produit nouveau la 2-chloro-6, 11- dihydro-6, 11-dioxo-7-méthylnapht [2 ' , 3 ' :4, 5] imidazo[l, 2-a] - pyridine.33. As a new product, 2-chloro-6,11-dihydro-6,11-dioxo-7-methylnaphth [2 ', 3': 4, 5] imidazo [1,2-a] - pyridine.
34. A titre de produit nouveau la 2-chloro-6 , 11- dihydro-6, ll-dioxo-10-méthylnapht[2 ' , 3 ' :4, 5]imidazo[l, 2-a]- pyridine .34. As a new product, 2-chloro-6,11-dihydro-6,11-dioxo-10-methylnaphth [2 ', 3': 4, 5] imidazo [1,2-a] - pyridine.
35. A titre de produit nouveau la 9 -chloro -5 , 6- dihydro-5, 6 -dioxo- 1 -méthylnaphtfl ' , 2 ' :4, 5]imidazo[l, 2-a]- pyridine .35. As a new product, 9-chloro -5,6-dihydro-5,6 -dioxo- 1 -methylnaphthfl ', 2': 4, 5] imidazo [1,2-a] - pyridine.
36. A titre de produit nouveau la 9-chloro-5 , 6- dihydro- 5, 6 -dioxo- 4 -méthylnapht [1 ' , 2 ' : 4, 5]ιmιdazo[l, 2-a]- pyridme .36. As a new product, 9-chloro-5, 6- dihydro- 5, 6 -dioxo- 4 -methylnapht [1 ', 2': 4, 5] ιmιdazo [l, 2-a] - pyridme.
37. A titre de produit nouveau la 6, ll-dιhydro-6 , 11- dioxo -8 -méthylnapht [2 ' , 3 ' :4, 5] imidazo [1, 2-a] pyridme .37. As a new product, 6,11-dehydro-6,11-dioxo -8 -methylnaphth [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme.
38. A titre de produit nouveau la 6, 11 -dihydro- 6 , 11- dioxo- 9 -méthylnapht [2 ' , 3 ' :4 , 5] imidazo [1, 2-a] pyridme38. As a new product, 6, 11 -dihydro- 6, 11- dioxo- 9 -methylnapht [2 ', 3': 4, 5] imidazo [1, 2-a] pyridme
39. A titre de produit nouveau la 5 , 6-dιhydro-5 , 6- dioxo- 2 -méthylnaphtfl ' ,2' : 4 , 5]ιmιdazo[l , 2-a]pyrιdme39. As a new product, 5, 6-dehydro-5, 6 dioxo-2 -methylnaphthfl ', 2': 4, 5] ιmιdazo [l, 2-a] pyrιdme
40. A titre de produit nouveau la 5 , 6-dιhydro-5 , 6- dioxo- 3 -méthylnaphtfl • , 2 ' :4, 5]ιmιdazofl, 2-a]pyπdιne40. As a new product, 5, 6-dehydro-5, 6-dioxo-3 -methylnaphthfl •, 2 ': 4, 5] ιmιdazofl, 2-a] pyπdιne
41. A titre de produit intermédiaire le 2,3-dιbromo- 1, 4-dihydro-1, 4-dioxo-5-fluoronaphtalene41. As an intermediate product 2,3-dιbromo- 1, 4-dihydro-1, 4-dioxo-5-fluoronaphthalene
42. A titre de produit intermédiaire le 2,3-dιbromo- 1, 4-dihydro-1, 4-dioxo-6-fluoronaphtalene42. As an intermediate product 2,3-dιbromo- 1, 4-dihydro-1, 4-dioxo-6-fluoronaphthalene
43. A titre de produit intermédiaire le 2 , 3-dibromo- 1, 4-dιhydro-l, 4-dioxo-5-methylnaphtalene .43. As an intermediate product, 2, 3-dibromo-1, 4-dehydro-l, 4-dioxo-5-methylnaphthalene.
44. Utilisation des composés selon l'une quelconque des revendications 1 à 40 pour l'obtention d'un médica¬ ment destiné au traitement de 1 ' insuffisance veineuse fonctionnelle et organique44. Use of the compounds according to any one of claims 1 to 40 for obtaining a medicament intended for the treatment of functional and organic venous insufficiency
45. Utilisation des composés selon l'une quelconque des revendications 1 à 40 pour l'obtention d'un médica¬ ment destiné au traitement des pathologies hémorroidai- res .45. Use of the compounds according to any one of claims 1 to 40 for obtaining a medicament intended for the treatment of hemorrhoidal pathologies.
46. Utilisation des composés selon l'une quelconque JO46. Use of the compounds according to any one OJ
des revendications 1 à 40 pour l'obtention d'un médica¬ ment destiné au traitement de la migraine.of claims 1 to 40 for obtaining a medicament intended for the treatment of migraine.
47. Utilisation des composés selon l'une quelconque des revendications 1 à 40 pour l'obtention d'un médica¬ ment destiné au traitement des inflammations ostéoarticu- laires dermatologiques et cardiovasculaires.47. Use of the compounds according to any one of claims 1 to 40 for obtaining a medicament intended for the treatment of dermatological and cardiovascular osteoarticular inflammations.
48. Utilisation des composés selon l'une quelconque des revendications 1 à 40 pour l'obtention d'un médica¬ ment destiné au traitement des états de chocs constitués par une chute importante de la pression artérielle plus particulièrement dans les états de chocs septiques. 48. Use of the compounds according to any one of claims 1 to 40 for obtaining a medicament intended for the treatment of shock states consisting of a significant drop in blood pressure, more particularly in septic shock states.
EP96941735A 1995-12-12 1996-12-10 Use of mono- or diketone tetracyclic derivatives, resulting novel compounds and therapeutical use thereof Withdrawn EP0876368A1 (en)

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