WO1997021710A1 - Use of heteroaromatic and tricyclic 1,4-dihydro-1,4-dioxo-naphthalene derivatives, resulting novel compounds and therapeutical use thereof - Google Patents

Use of heteroaromatic and tricyclic 1,4-dihydro-1,4-dioxo-naphthalene derivatives, resulting novel compounds and therapeutical use thereof Download PDF

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WO1997021710A1
WO1997021710A1 PCT/FR1996/001975 FR9601975W WO9721710A1 WO 1997021710 A1 WO1997021710 A1 WO 1997021710A1 FR 9601975 W FR9601975 W FR 9601975W WO 9721710 A1 WO9721710 A1 WO 9721710A1
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Prior art keywords
dehydro
thiazolo
new product
fluorophenyl
dιoxo
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PCT/FR1996/001975
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French (fr)
Inventor
Odile Boutherin-Falson
Stéphanie Desquand-Billiald
Anita Favrou
Michel Finet
Olivier Tembo
Jean-Luc Torregrosa
Sylvie Yannic-Arnoult
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Laboratoire Innothera
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Priority to EP96941736A priority Critical patent/EP0874844A1/en
Priority to JP09521801A priority patent/JP2000502081A/en
Publication of WO1997021710A1 publication Critical patent/WO1997021710A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the use of tricyclic nitrogen 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 the heteroaromatic and tricyclic derivatives of 1, 4-dihydro-1,4, dioxo-naphthalene. The invention relates to the therapeutic application of all these compounds. It is described in U.S. Patent 3,084,165, by
  • A is either a sulfur atom, oxygen, or ra ⁇ dical R3N or R3 is a hydrogen atom, a radical al ⁇ Kyle C] _ to C5, an aromatic ring substituted or unsubstituted, or a heteroaromatic ring substituted or not,
  • Xi, X_, X 3 , X 4 are independently of each other a carbon atom or a nitrogen atom,
  • R] _ is an alkyl radical C ⁇ to C5, an aroma cycle ⁇ tick substituted or unsubstituted, or a heteroaromatic ring having one or more heteroatoms, substituted or not, R 2 is hydrogen, alkyl Cl to C5.
  • the invention also relates to the following new products:
  • the invention also relates to the use of tricyclic derivatives nitrogens and their pharmaceutically acceptable salts viewpoint of formula g e ⁇ eral (I) above for the production of a medicament:
  • A -NH, S, O
  • 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 hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid and the addition salts of organic acids such as acetic acid, propionic, oxalic, citric, maleic, fumaric, succmic, tartaric.
  • the invention is illustrated by the following non-limiting examples.
  • the examples indicated by a number correspond to new compounds while the examples comprising a letter correspond to known compounds.
  • - Mass spectra They were performed with an AEI MS-50 type spectrometer. The ionization mode is indicated for each analysis.
  • - NMR spectra The 1 H and 13 C NMR spectra were carried out 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.
  • the powder thus obtained is purified on a cake (support: silica; eluent: dichloromethane / isopropanol, 99/1) to provide 0.80 g of 4.9-dehydro-4, 9-de ⁇ oxo-2- (3-fluorophenyl ) -thiazolo [4, 5-g] - quinoline in the form of yellow crystals. Yid: 30% F:> 260 ° C
  • the brown solid thus obtained is taken up in 600 ml of chloroform and washed with 700 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness.
  • the yellow product obtained is purified on cake (support: silica; eluent: dichloromethane / isopropanol, 99/1) to provide 0.27 g of 4,9-d ⁇ hydro-4,9-d ⁇ oxo-2- (4 -fluorophenyl) -thiazolo [4, 5-g] - quinoline in the form of yellow crystals.
  • Rd 23 ° o F:> 260 ° C
  • the precipitate is filtered, washed with water, dried and purified on a flash column (support: silica; dry deposit; eluent: dichloromethane / ethyl acetate, 97.5 / 2.5).
  • the yellow crystals obtained after evaporation of the solvents under reduced pressure are recrystallized after discoloration with animal black in methanol to give 0.308 g of 4, 9-d ⁇ hydro-4, 9-d ⁇ oxo-2- (3-furyl) -thiazolo [ 4, 5-g] quinoline in the form of yellow crystals.
  • [5,4-f] isoquinoline To the 13 g (5/4 mmol) of 7-ammo-6-chloro-5, 8- dehydro-5, 8-d ⁇ oxo- ⁇ soqumolme, we add at room temperature 7 '80 g (32 '5 mmol) of sodium sulfide nona ⁇ hydrate in solution in 6 ml of water. After 4 hours of stirring at 45 ° C., 572 ⁇ l (5 '4 mmol) of 2-fluorobenzaldehyde are added to the reaction medium, which has turned blue. 1250 ml of glacial acetic acid.
  • the compounds are solubi ⁇ lized in pure aqueous solution or containing DMSO (dimethylsulfoxide).
  • Contractile effects are measured m v tro under static conditions on vascular rings with capacitance or resistance of saphenous, femoral, jugular, mesenteric veins, and on femoral arteries, carotids, basilar, mesenteric, thoracic aorta or abdominal ... 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
  • the developed voltages generate an electrical signal only via a force sensor (Wheastone bridge). This signal is amplified before being either displayed on a Kipp & Zonen recorder, or digitized for processing by computer (IOS, EMKA).
  • IOS equimolar pressure
  • Pharmacological studies are carried out after a few preliminary contractile stimulations standardized by a depolarizing 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 "polarizing" physiological solution (Kcl: 20, 40 mM), by the no-radrenalme (increasing concentrations), serotonin (increasing concentrations) ...
  • the contractions are expressed in mg force or as a percentage of the maximum contraction upon depolation by a hyperpotassic "physiological" solution.
  • the animal's back is shorn and epilated so as 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 administration of the products, 48 hours after the operation.
  • the vascular permeability is studied m vi vo by measuring the extravasation of albumin whose quantity e is determined using an albumin binding dye (Evans Blue). Hyperpermeability is induced by in ⁇ tradermal injection of a histamme, bradykmine or zymosan solution. The technique is derived from that described by BEACH
  • 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 per hour 1 to 4 hours before the sacrifice.
  • the rats are anesthetized with a mixture of halothane.
  • they receive an intradermal injection on the abdomen of 0.10 or 0.15 ml (that is to say 6.7 or 10 micrograms) of inflammatory agent and an intravenous injection of one ml d 0.5% Evans blue solution in the vein of the penis. These injections are given 30 minutes before euthanasia.
  • the rats are euthanized by cervical dislocation.
  • the skin is cut and placed in glass tubes with a round neck containing 3 ml of fuming hydrochloric acid.
  • the digestion of the skin is carried out by contact for at least one hour in a water bath at 37 ° C.
  • Three ml of benzalkonium chloride at 12.880 are then added.
  • 7 ml of declorlorhane are added.
  • the tubes are agitated periodically for one minute.
  • the aqueous phase is removed by suction and the organic phase "dichloro- methane "is filtered.
  • the optical densities are quantified by absorption spectrophotometry at a wavelength of 620 nm, 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 is calculated.
  • the effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamma and bra ⁇ ykinme is also studied after injection.
  • the increase in the capillary resistance is ap ⁇ voltageciée by the modification of the petechial index (negative pres ⁇ sion inducing the extravasation of erythrocyte your) measured by a method derived from the angiosterro- meter of Parrot.
  • the study is carried out on male Wistar rats weighing an average of 200 g (around six weeks old). The region of the lower back is shaved and then depilated using a paste based on an ⁇ é ⁇ ve 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 petechies (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 petechies appear expresses, in mm of mercury, the value of basic capillary resistance (before any treatment). Two measurements are made for each test at different locations on the back.
  • the rats are treated orally. After a determined time (generally 2, 4, 6 hours) depending on the treatment, the test is repeated on different areas of skin, until the appearance of petechiae, providing a new index of depression. All measurements are made blind. A percentage change in the capillary resistance of the treated animals with respect to their basic capillary resistance is calculated for each study compound, at each treatment time and compared with the control group (excipient only) or the reference group. Effects on induced pleurisy in rats:
  • 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. Rap., 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 the noradrenal, by electrical stimulation or by a depolarizing hyperpotassic solution.
  • Example d 5 mg / kg -23 -7 Example a 0.1 mg / kg 9 -41
  • Example b 0.1 mg / kg -5 -23
  • Example 4 0.1 mg / kg 3 -37
  • Example 10 0.1 mg / kg -7 -14
  • Example 15 0.1 mg / kg -14 -17
  • the compounds of the invention and their possible salts are very little toxic. For example, after a single oral administration of 500 mg / kg in the penny ⁇ laugh, no ooservable toxicity and no mortality was observed for the majority of compounds espe- link for Example c, Example d, Example 2, Example 3 (orange urine), Example 5.
  • the compounds of the invention and their possible salts can be used in human and animal therapy. They are particularly 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 drop in blood pressure. . In the latter case, an improvement in venous return is likely to maintain the cardiac output and consequently 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 towards organ venous insufficiency characterized by the development of varicose veins, valve incontinence, even towards phlebothromobosis and trophic disorders leading to ulcerative lesions.
  • 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.
  • compositions will obviously depend on the desired route of administration, in particular oral, parenteral, topical (cutaneous) and rectal, and they can be formulated according to conventional techniques with the use of carriers and usual vehicles.
  • oral administration they can be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophili ⁇ sate, microcapsule, microgranule.
  • the 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 (algmate for example) and they are produced by known techniques for example of mixing, granulation, pastillage, 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 for example
  • the syrups can contain, as a support, glycerol, mannitol and / or sorbitol.
  • the solutions and above- pens can include water and other physiologically compatible solvents and a carrier such as 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 an appropriate support or solvent such as sterile water or solutions sté ⁇ - isotonic salines.
  • the drugs and compositions can take the form of an ointment, cream or gel, in the form of an emulsion or suspension, solution, foam, powder.
  • the drugs and compositions can take the form of capsule, cream, emulsion, gel, foam, ointment, suppository.

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Abstract

The therapeutical use of tricyclic nitrogen-containing 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), A is a sulphur or oxygen atom or a radical R3N where R3 is a hydrogen atom, a C1-5 alkyl radical or an optionally substituted aromatic or heteroaromatic ring; each of X1, X2, X3 and X4 is independently a carbon atom or a nitrogen atom; R1 is a C1-5 alkyl radical, an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring having one or more heteroatoms; and R2 is a hydrogen atom or a C1-5 alkyl radical.

Description

Utilxsation de dérivés heteroaromatiques et tricycliques du 1,4-dihydro-l,4-dioxo-naphtalène, nouveaux composés obtenus et leur application en thérapeutique Use of heteroaromatic and tricyclic derivatives of 1,4-dihydro-1,4-dioxo-naphthalene, new compounds obtained and their application in therapy
La présente invention concerne l'utilisation de dé¬ rivés tricycliques azotés 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 inflamma- toire et les nouveaux composés obtenus. Elle se rapporte plus particulièrement aux dérivés heteroaromatiques et tricycliques du 1, 4-dihydro-l, 4-dioxo-naphtalène. L'in¬ vention concerne l'application thérapeutique de tous ces composés. II est décrit dans le brevet U.S. 3,084,165, parThe present invention relates to the use of tricyclic nitrogen 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 the heteroaromatic and tricyclic derivatives of 1, 4-dihydro-1,4, dioxo-naphthalene. The invention relates to the therapeutic application of all these compounds. It is described in U.S. Patent 3,084,165, by
Schellhammer C.W., Petersen S., Domagk G. la synthèse de dérivés substitués en position 2 d' imidazo [4, 5-g] - qumolines à partir de 6, 7-dιammo-5, 8-dihydro-5, 8-dιoxo- quinolines et d'aldéhydes. L'article Collect. Czech. Chem. Commun. 56(9) , 1919- 1925 (1991) par Yanni A.S. décrit la synthèse de nouveaux dérives hétérocycliques des qumones a partir du chlorhy¬ drate de la 6-chloro-5, 8-dιhydro-5, 8-dιoxo-qumolιne, no¬ tamment par reaction avec un amide, une thiouree, un se- micarbazide ou un thiosemicarbazide.Schellhammer CW, Petersen S., Domagk G. synthesis of derivatives substituted in position 2 of imidazo [4, 5-g] - qumolines from 6, 7-dιammo-5, 8-dihydro-5, 8-dιoxo - quinolines and aldehydes. The Collect article. Czech. Chem. Common. 56 (9), 1919- 1925 (1991) by Yanni AS describes the synthesis of new heterocyclic derivatives of qumones from the chlorhy¬ drate of 6-chloro-5, 8-dehydro-5, 8-dιoxo-qumolιne, in particular by reaction with an amide , a thiouree, a semicarbazide or a thiosemicarbazide.
Le document Ann. 624, 108-119 (1959) par Schellham- mer C.W., Petersen S montre la préparation de dérives tricycliques a partir de 6, 7-dιhalo-5, 8-dιhydro-5, 8- dioxo-qumolmes .The document Ann. 624, 108-119 (1959) by Schellhammer C.W., Petersen S shows the preparation of tricyclic drifts from 6, 7-dιhalo-5, 8-de-hydro-5, 8-dioxo-qumolmes.
Enfin le brevet DE 1,137,022 de Schellhammer C.W., Koenig H.B., Petersen S., Domagk G. décrit la préparation αe à, 9-dιnydro-4, 9-dιoxo-tnιazolo [4, 5-gj quinolmes subs¬ tituées en position 2 par un dérive hétérocyclique.Finally the patent DE 1,137,022 of Schellhammer CW, Koenig HB, Petersen S., Domagk G. describes the preparation αe to, 9-dιnydro-4, 9-dιoxo-tnιazolo [4, 5-gj quinolmes substituted in position 2 by a heterocyclic drift.
Les dérives tricycliques azotes et leurs sels accep¬ tables du point de vue pharmaceutique selon la présente invention repondent a la formule générale :The tricyclic nitrogen derivatives and their pharmaceutically acceptable salts according to the present invention correspond to the general formula:
Figure imgf000004_0001
Figure imgf000004_0001
dans laquelle :in which :
A est soit un atome de soufre, d'oxygène, ou un ra¬ dical R3N ou R3 est un atome d'hydrogène, un radical al¬ kyle en C]_ à C5, un cycle aromatique substitue ou non, ou un cycle hétéroaromatique substitue ou non, Xi , X_, X3, X4, sont indépendamment l'un de l'autre un atome de carbone ou un atome d'azote,A is either a sulfur atom, oxygen, or ra¬ dical R3N or R3 is a hydrogen atom, a radical al¬ Kyle C] _ to C5, an aromatic ring substituted or unsubstituted, or a heteroaromatic ring substituted or not, Xi, X_, X 3 , X 4 , are independently of each other a carbon atom or a nitrogen atom,
R]_ est un radical alkyle en C^ a C5, un cycle aroma¬ tique substitue ou non, ou un cycle hétéroaromatique, ayant un ou plusieurs héteroatomes, substitue ou non, R2 est un atome d'hydrogène, un radical alkyle en Cl a C5. L' invention concerne également les produits nouveaux ci-apres : R] _ is an alkyl radical C ^ to C5, an aroma cycle ¬ tick substituted or unsubstituted, or a heteroaromatic ring having one or more heteroatoms, substituted or not, R 2 is hydrogen, alkyl Cl to C5. The invention also relates to the following new products:
- la 4, 9-dιhydro-4, 9-dιoxo-2- (4-fluorophenyl) -1H- îmidazo [4, 5-g] quinoline ; - la 4, 9-dιhydro-4, 9-dιoxo-2- (3-pyπdyD-lH- ιmιdazo [4, 5-g] quinoline ;- 4, 9-dehydro-4, 9-dιoxo-2- (4-fluorophenyl) -1H-imidazo [4, 5-g] quinoline; - 4, 9-dehydro-4, 9-dιoxo-2- (3-pyπdyD-1H- ιmιdazo [4, 5-g] quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoline ;- 4, 9-dehydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (3-fluorophenyl) - thiazolo [4, 5-g] quinoline ;- 4, 9-dehydro-4, 9-dexoxo-2- (3-fluorophenyl) - thiazolo [4, 5-g] quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (4-fluorophenyl) - thiazolo [4, 5-g] quinoline ,- 4, 9-dehydro-4, 9-dιoxo-2- (4-fluorophenyl) - thiazolo [4, 5-g] quinoline,
- la 2- (2, 4-dιfluoro-phenyl) -4, 9-dιhydro-4, 9-dιoxo- thiazolo [4, 5-g] quinoline ; - le sulfate de 4, 9-dιhydro-4, 9-dιoxo-2- (2-pyrιdyl) - thiazolo [4, 5-g] quinoline ;- 2- (2, 4-dιfluoro-phenyl) -4, 9-dehydro-4, 9-dexoxothiazolo [4, 5-g] quinoline; - 4,9-dehydro-4,9-dexoxo-2- (2-pyrιdyl) - thiazolo [4,5-g] quinoline sulfate;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (3-furyl) -thiazolo [4, 5- g] -quinoline ;- 4, 9-dehydro-4, 9-dιoxo-2- (3-furyl) -thiazolo [4, 5 g] -quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2-phenyl-thιazolo [5, 4-g] - quinoline ;- 4, 9-dehydro-4, 9-dιoxo-2-phenyl-thιazolo [5, 4-g] - quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [5, 4-g] quinoline ;- 4, 9-dehydro-4, 9-dexoxo-2- (2-fluorophenyl) - thiazolo [5, 4-g] quinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2-phenyl-thιazolo [5, 4-f] - isoquinoline ; - la 4, 9-dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [5, 4-f] îsoqumoline ;- 4, 9-dehydro-4, 9-dιoxo-2-phenyl-thιazolo [5, 4-f] - isoquinoline; - 4, 9-dehydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [5, 4-f] issoquinoline;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-f] îsoqumolme ;- 4, 9-dehydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-f] issoqumolme;
- la 4, 9-dιhydro-4, 9-dιoxo-2-phenyl-thιazolo [4, 5-g] - quinoxalme ;- 4, 9-dehydro-4, 9-dιoxo-2-phenyl-thιazolo [4, 5-g] - quinoxalme;
- la 4, 9-dιhydro-4, 9-αιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoxalme ;- 4, 9-dehydro-4, 9-αιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoxalme;
- la 4, 9-dιhydro-4, 9-dιoxo-2- (2-furyl) -7-methyl- thiazolo [4, 5-g] îsoquinolme . L' invention concerne également les produits interme- diaires ci-apres :- 4, 9-dehydro-4, 9-dιoxo-2- (2-furyl) -7-methyl-thiazolo [4, 5-g] isquinolme. The invention also relates to intermediate products. diaries below:
- la 7-amιno-6-chloro-5, 8-dιhydro-5, 8-dιoxo- isoquinoline ;- 7-amιno-6-chloro-5, 8-dehydro-5, 8-dexoxoisoquinoline;
- la 6-ammo-7-chloro-5, 8-dιhydro-5, 8-dιoxo- isoquinoline.- 6-ammo-7-chloro-5, 8-dehydro-5, 8-dexoxoisoquinoline.
L'invention se rapporte aussi a l'utilisation des dérives tricycliques azotes et de leurs sels acceptables du point de vue pharmaceutique repondant à la formule gé¬ nérale (I) ci-dessus pour l'obtention d'un médicament destine :The invention also relates to the use of tricyclic derivatives nitrogens and their pharmaceutically acceptable salts viewpoint of formula g e ¬ eral (I) above for the production of a medicament:
- au traitement de l'insuffisance veineuse fonction¬ nelle et organique ;- to the treatment of functional and organic venous insufficiency;
- au traitement des pathologies hemorroidaires ;- the treatment of hemorrhoidal pathologies;
- au traitement de la migraine ; - au traitement αes inflammations osteoarticulaires dermatologiques et cardiovasculaires ;- to the treatment of migraine; - to the treatment of osteoarticular dermatological and cardiovascular inflammations;
- au traitement des états de chocs constitues par une chute importante de la pression artérielle plus par¬ ticulièrement dans les états de chocs septiques. De façon spécifique, les composes de la présente in¬ vention repondent a la formule générale (I) illustrée ci- apres :- In the treatment of shock states constituted by a significant drop in blood pressure, more particularly in the states of septic shock. Specifically, the compounds of the present invention correspond to the general formula (I) illustrated below:
Figure imgf000006_0001
I! ou :
Figure imgf000006_0001
I! or :
A = -NH, S, OA = -NH, S, O
Λli X2 , X3 , X4 C ou N
Figure imgf000007_0001
Λli X2, X3, X4 C or N
Figure imgf000007_0001
La présente invention concerne également les sels des composes salifiables de formule (I) . Ces sels com¬ prennent les sels d'addition d'acides minéraux tels que l'acide chlorhyαrique, bromhydrique, sulfurique, phospho- rique, ou nitrique et les sels d'addition d'acides orga¬ niques tels que l'acide acétique, propionique, oxalique, citrique, maléique, fumarique, succmique, tartrique.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 hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid and the addition salts of organic acids such as acetic acid, propionic, oxalic, citric, maleic, fumaric, succmic, tartaric.
L'invention est illustrée par les exemples non limi¬ tatifs ci-apres. Les exemples indiqués par un chiffre correspondent à de nouveaux composes tandis que les exemples comprenant une lettre correspondent a des composes connus.The invention is illustrated by the following non-limiting examples. The 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 indique ci-apres : - Points de fusion : Ils ont ete réalises sur un ap¬ pareil de type «Banc de Kofler» LEICA - REICHERT modèle WME.In all the examples, the analyzes are carried out as indicated below: - Melting points: They were carried out on a LEICA - REICHERT WME model "Kofler bench" type device.
- Chromatographies sur couche mince : Elles ont été obtenues sur des plaques de gel de silice avec indicateur de fluorescence UV25J de 0,25 mm d'épaisseur de type MACHEREY-NAGEL (Référence 805 023) . Les solvants d' élution sont indiques pour chaque compose.- Thin layer chromatographies: They were obtained on silica gel plates with 0.25 mm thick 25 J UV fluorescence indicator of the MACHEREY-NAGEL type (Reference 805 023). Elution solvents are indicated for each compound.
- Spectres de masse : Ils ont ete effectues avec un spectrometre αe type AEI MS-50. Le mode d'ionisation est indique pour chaque analyse. - Spectres RMN : Les spectres de RMN du 1H et du l3C ont ete réalisés soit sur un spectrometre de type JEOL respectivement a 270 MHz et à 68 MHz, soit sur un spec¬ trometre de type BRUCKER respectivement a 400 MHz et à 100 MHz. Les solvants deuterés utilisés sont indiques pour chaque analyse.- Mass spectra: They were performed with an AEI MS-50 type spectrometer. The ionization mode is indicated for each analysis. - NMR spectra: The 1 H and 13 C NMR spectra were carried out 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-Rouge : Ils ont été obtenus sur un spectrometre de type NICOLET 205 FT-IR. Ils sont effec¬ tués a lo (m/m) en dispersion dans le KBr. Exemple 1- Infra-Red Spectra: They were obtained on a NICOLET 205 FT-IR type spectrometer. They are carried out at lo (m / m) in dispersion in the KBr. Example 1
4 ,9-Dιhydro-4 , 9-dιoxo-2- (4-fluorophenyl) -lH-3.nu.dazo- [4 ,5-g]quinoline4, 9-Dιhydro-4, 9-dιoxo-2- (4-fluorophenyl) -lH-3.nu.dazo- [4, 5-g] quinoline
A 1,0 g (5,29 mmoles) de 6, 7-dιammo-5, 8-dιhydro- 5, 8-dιoxo-qumolιne en suspension dans 15 ml d'eau, on ajoute a température ambiante 0,567 ml (5,29 mmoles) de 4-fluorobenzaldéhyde et 1,800 ml d'acide acétique gla¬ cial. La réaction est agitée 30 minutes a reflux et le précipité marron qui se forme est filtre sur verre fritte et purifié sur cake (support : silice ; éluant : dichlo- rométhane) . Le solide obtenu est décoloré puis recristal- lise dans 500 mi de méthanol pour fournir 0,8 g de 4,9- αιhydro-4, 9-dιoxo-2- (4-fluorophenyl) -lH-imidazo- [4,5- g] quinoline sous forme de cristaux bruns. Rdt : 52 â F : > 260°CTo 1.0 g (5.29 mmol) of 6, 7-dammo-5, 8-dehydro-5, 8-dexoxo-qumolene suspended in 15 ml of water, 0.567 ml (5, 29 mmol) of 4-fluorobenzaldehyde and 1,800 ml of glacial acetic acid. The reaction is stirred for 30 minutes at reflux and the brown precipitate which forms is filtered on sintered glass and purified on cake (support: silica; eluent: dichloromethane). The solid obtained is discolored and then recrystallized from 500 ml of methanol to give 0.8 g of 4.9-αιhydro-4, 9-dιoxo-2- (4-fluorophenyl) -lH-imidazo- [4,5- g] quinoline in the form of brown crystals. Rdt: 52 to F:> 260 ° C
Rf : 0.50 (CH2Cl2/Méthanol, 90/10) SM (I.E.) : m/z 293 (M+ . ) RMN du 1H (DMSO d6) : δ (ppm) 14.48 (ls, IH, NH) 8.97 (m, IH, H-7)Rf: 0.50 (CH 2 Cl 2 / Methanol, 90/10) SM (IE): m / z 293 (M +.) 1 H NMR (DMSO d 6 ): δ (ppm) 14.48 (ls, IH, NH) 8.97 (m, IH, H-7)
8.43 (d, IH, H-5, JHS-HO=7.94Hz) 8.27 (m, 2H, H-2 ' , H-6') 7.81 (m, IH, H-6) 7.39 (m, 2H, H-3', H-5') RMN du 13C (DMSO d6) : δ (ppm) 176.47 (1C, C=0) 160.45 (1C, Cquat) 153.25 (1C, C-"7) 152.58 (1C, Cquat) 148.93 (1C, Cquat) 140.33 (1C, Cquat) 134.24 (1C, C-5) 130.07 (1C, Cquat) 129.23 (2C, C-3', C-5') 127.43 (1C, C-6)8.43 (d, IH, H-5, J HS - HO = 7.94Hz) 8.27 (m, 2H, H-2 ', H-6') 7.81 (m, IH, H-6) 7.39 (m, 2H, H-3 ', H-5') 13 C NMR (DMSO d 6 ): δ (ppm) 176.47 (1C, C = 0) 160.45 (1C, Cquat) 153.25 (1C, C- "7 ) 152.58 (1C, Cquat) 148.93 (1C, Cquat) 140.33 (1C, Cquat) 134.24 (1C, C-5) 130.07 (1C, Cquat) 129.23 (2C, C-3 ', C-5') 127.43 (1C, C-6)
116.23 (1C, Cquat)116.23 (1C, Cquat)
116.23 et 115.90 (2C, C-2 ' , C-6')116.23 and 115.90 (2C, C-2 ', C-6')
IR (KBr) : μ (cm"1)IR (KBr): μ (cm "1 )
3225 (NH) ; 1663, 1644 (CO) Exemple 23225 (NH); 1663, 1644 (CO) Example 2
4 ,9-Dιhydro-4 ,9-dιoxo-2-(3-pyrιdyl) -lH-imidazo[4 ,5- glqumoline4, 9-Dιhydro-4, 9-dιoxo-2- (3-pyrιdyl) -lH-imidazo [4, 5-glqumoline
A 900 mg (4,77 mmoles) de 6, 7-dιammo-5, 8-dιhydro- 5, 8-dιoxo-qumolme en suspension dans 15 ml d'eau, on ajoute à température ambiante 0,450 ml (4,77 mmoles) de 3-pyrιdιnecarboxaldéhyde et 1,80 ml d'acide acétique gla¬ cial. La reaction est agitée 45 minutes a reflux et le précipite marron qui se forme est filtre sur verre frit¬ te, lave a l'eau glacée et purifié sur cake isupport : silice ; éluant : dichlorométhane/méthanol, 98/2 a 95/5) . Le solide obtenu est décoloré puis recristallisé dans un mélange dichloromethane/methanol, 98/2 pour fournir 700 mg de 4, 9-dιhydro-4, 9-dιoxo-2- (3-pyrιdyl) -lH-imidazo [4, 5- g] quinoline sous forme de cristaux roux. Rdt : 53 l F : > 260°C0.450 ml (4.77 mmol) is added to ambient 900 mg (4.77 mmol) of 6,7-dιammo-5,8-dιhydro- 5,8-dιoxo-qumolme suspended in 15 ml of water ) of 3-pyrιdιnecarboxaldehyde and 1.80 ml of glacial acetic acid. The reaction is stirred for 45 minutes at reflux and the brown precipitate which forms is filtered on frit¬ glass, washed with ice water and purified on isupport cake: silica; eluent: dichloromethane / methanol, 98/2 to 95/5). The solid obtained is discolored and then recrystallized from a dichloromethane / methanol mixture, 98/2 to provide 700 mg of 4, 9-dιhydro-4, 9-dιoxo-2- (3-pyrιdyl) -lH-imidazo [4, 5- g] quinoline in the form of red crystals. Yd: 53 l F:> 260 ° C
Rf : 0.50 (CH2Cl2/Méthanol, 90/10) SM (I.E.) : m/z 276 (M+ . ) RMN du XH (DMSO dg) : 5 (ppm) 14.50 (Is, IH, NH) 9.36 (s, IH, H-2')Rf: 0.50 (CH 2 Cl 2 / Methanol, 90/10) MS (IE): m / z 276 (M +.) X H NMR (DMSO dg): 5 (ppm) 14.50 (Is, IH, NH) 9.36 (s, IH, H-2 ')
8.97 (d, IH, H-7, JHb.ri-=4.57Hz)8.97 (d, IH, H-7, J Hb ri -. = 4.57Hz)
8.68 (d, IH, H-5, JH5-H6=4.88Hz)
Figure imgf000010_0001
8.68 (d, IH, H-5, J H5 - H6 = 4.88Hz)
Figure imgf000010_0001
3.45 (d, IH, H-4', JH4..„5.=7.93Hz)3.45 (d, IH, H-4 ', J H4 .. „ 5. = 7.93Hz)
7.82 (m, IH, H-6) 7 .82 (m, IH, H-6)
7.57 (m, IH, H-5')7.57 (m, IH, H-5 ')
RMN du 13C (DMSO d6) : δ (ppm) 13 C NMR (DMSO d 6 ): δ (ppm)
176,55 (1C, C=0)176.55 (1C, C = 0)
174,45 (1C, C=0)174.45 (1C, C = 0)
153.31 (1C, C-7)153.31 (1C, C-7)
151.32 (12, Cquat) 150.83 (1C, C-2') 148.80 (1C, Cquat) 147.71 (1C, C-6') 134.32 (1C, C-5) 134.54 (1C, C-4') 130.14 (1C, Cquat) 127.49 (1C, C-6) 125.54 (1C, C quat) 124.01 (1C, C-5*) IR (KBr) : μ (cm"1)151.32 (12, Cquat) 150.83 (1C, C-2 ') 148.80 (1C, Cquat) 147.71 (1C, C-6') 134.32 (1C, C-5) 134.54 (1C, C-4 ') 130.14 (1C , Cquat) 127.49 (1C, C-6) 125.54 (1C, C quat) 124.01 (1C, C-5 *) IR (KBr): μ (cm "1 )
3104 (NH) ; 1660, 1646 (C=0) Exemple 33104 (NH); 1660, 1646 (C = 0) Example 3
4 ,9-Dιhydro-4 ,9-dιoxo-2-(2-fluorophenyl) - thiazolo[4 ,5-g]quinoline4, 9-Dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoline
A 0,80 g (3,84 mmoles) de 6-amιno-7-chloro-5, 8- dιhydro-5, 8-dιoxo-quιnolme, on ajoute a température am¬ biante 5,53 g (23,02 mmoles) de sulfure de sodium nonahy- drate en solution dans 9,6 ml d'eau. Après 5 minutes, on ajoute au milieu réactionnel devenu bleu 405 ul (3,84 mmoles) de 2-fluorobenzaldehyde et 880 μl d'acide acéti¬ que glacial. La reaction est agitée pendant 10 minutes a 80°C et le précipite noir qui se forme est filtre sur verre fritte ouïs lave a l'éthanol. Le solide brun ainsi obtenu est repris dans 400 ml de chloroforme et lavé avecTo 0.80 g (3.84 mmol) of 6-amino-7-chloro-5, 8-dehydro-5, 8-dexoxo-quιnolme, 5.53 g (23.02 mmol) are added at room temperature ) sodium sulfide nonahydrate in solution in 9.6 ml of water. After 5 minutes, 405 μl (3.84 mmol) of 2-fluorobenzaldehyde and 880 μl of glacial acetic acid are added to the reaction medium which has turned blue. The reaction is stirred for 10 minutes at 80 ° C. and the black precipitate which forms is filtered on sintered glass which is washed with ethanol. The solid brown as well obtained is taken up in 400 ml of chloroform and washed with
400 ml d'eau. La phase organique est ensuite séchée sur du chlorure de calcium et évaporée à sec. Le produit jaune obtenu est purifié sur cake (support : silice ; éluant : dichloromethane/ isopropanol, 99/1) pour fournir400 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product obtained is purified on a cake (support: silica; eluent: dichloromethane / isopropanol, 99/1) to provide
0,30 g de 4, 9-dihydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoline sous forme de cristaux jaunes.0.30 g of 4,9-dihydro-4,9-dιoxo-2- (2-fluorophenyl) - thiazolo [4,5-g] quinoline in the form of yellow crystals.
Rdt : 25 %Yid: 25%
F : > 260°C Rf : 0.60 (CH2Cl2/Méthanol, 97/3)F:> 260 ° C Rf: 0.60 (CH 2 Cl 2 / Methanol, 97/3)
SM (I.E.) : m/z 310 (M+.)SM (I.E.): m / z 310 (M +.)
RMN du 1H (CDCI3) : δ (ppm) 1 H NMR (CDCI3): δ (ppm)
9.04 (d, IH, H-7, JH6_H7=9.55Hz)
Figure imgf000011_0001
3.52 (m, IH, H-6')9.04 (d, IH, H-7, J H6 _ H7 = 9.55Hz)
Figure imgf000011_0001
3.52 (m, IH, H-6 ')
7.76 (m, IH, H-6)7.76 (m, IH, H-6)
7.52 (m, IH, H-4 ' )7.52 (m, IH, H-4 ')
7.25 (m, 2H, H-3\ H-5')7.25 (m, 2H, H-3 \ H-5 ')
RMN du 13C (CDCI3) : δ (ppm) 176.60, 176.18 (2C, C=0) 13 C NMR (CDCI3): δ (ppm) 176.60, 176.18 (2C, C = 0)
162.94 (1C, C-2')162.94 (1C, C-2 ')
158.44 (1C, C-2)158.44 (1C, C-2)
154.06 (1C, C-7)154.06 (1C, C-7)
148.34 (1C, Cquat) 135.34 (1C, C-5)148.34 (1C, Cquat) 135.34 (1C, C-5)
133.58 (2C, C-6, Cquat)133.58 (2C, C-6, Cquat)
129.52 (2C, Cquat, C-6')129.52 (2C, Cquat, C-6 ')
127.44 (1C, C-4')127.44 (1C, C-4 ')
124.58 (2C, C-5', Cquat) 115.77, 115.68 (2C, C-l' C-3')124.58 (2C, C-5 ', Cquat) 115.77, 115.68 (2C, C-l' C-3 ')
IR (KBr) : μ (cm"1)IR (KBr): μ (cm "1 )
3045 (CH) ; 1682, 1671 (C≈O)3045 (CH); 1682, 1671 (C≈O)
Exemple 4Example 4
4 , 9-Dιhydro-4 , 9-dιoxo-2- (3-fluorophenyl) - thiazolo[4 , 5-q]quinoline A 1,80 g (8,60 mmoles) de ό-ammo-7~chloro-5, 8- dιhydro-5, 8-dιoxo-qumolme, on ajoute à température am¬ biante 12,44 g (51,70 mmoles) de sulfure de sodium nona¬ hydrate en solution dans 22 ml d'eau. Apres 2 heures à 40°C, on ajoute 4,14 g (17,23 mmoles) de sulfure de so¬ dium nonahydrate au milieu réactionnel. Celui-ci devient alors bleu et on ajoute 0,911 ml (8,60 mmoles) de 3- fluorobenzaldéhyde et 1,960 ml d'acide acétique. La réac¬ tion est maintenue 1 heure 30 minutes à 80°C et le préci- pité brun qui se forme est filtré sur verre fritte puis lave avec 150 ml d'éthanol. Le solide brun ainsi obtenu est repris dans 500 ml de chloroforme et lave avec 500 ml d'eau. La phase organique est sechee sur du chlorure de calcium et évaporée à sec . La poudre ainsi obtenue est purifiée sur cake (support : silice ; éluant : dichloro¬ methane/ isopropanol, 99/1) pour fournir 0,80 g de 4,9- dιhydro-4, 9-dιoxo-2- (3-fluorophenyl) -thiazolo [4, 5-g] - quinoline sous forme de cristaux jaunes. Rdt : 30 % F : > 260°C4, 9-Dιhydro-4, 9-dιoxo-2- (3-fluorophenyl) - thiazolo [4, 5-q] quinoline To 1.80 g (8.60 mmol) of ό-ammo-7 ~ chloro-5, 8- dehydro-5, 8-dιoxo-qumolme, 12.44 g (51.70 mmol) are added at room temperature ) of sodium sulfide nona¬ hydrate in solution in 22 ml of water. After 2 hours at 40 ° C., 4.14 g (17.23 mmol) of sodium sulphide nonahydrate are added to the reaction medium. This then becomes blue and 0.911 ml (8.60 mmol) of 3-fluorobenzaldehyde and 1.960 ml of acetic acid are added. The reaction is maintained for 1 hour 30 minutes at 80 ° C. and the brown precipitate which forms is filtered through sintered glass and then washed with 150 ml of ethanol. The brown solid thus obtained is taken up in 500 ml of chloroform and washed with 500 ml of water. The organic phase is dried over calcium chloride and evaporated to dryness. The powder thus obtained is purified on a cake (support: silica; eluent: dichloromethane / isopropanol, 99/1) to provide 0.80 g of 4.9-dehydro-4, 9-deιoxo-2- (3-fluorophenyl ) -thiazolo [4, 5-g] - quinoline in the form of yellow crystals. Yid: 30% F:> 260 ° C
Rf : 0.43 (CH2C12/Acetate d'éthyle, 80/20) SM (I.E.) : m/z 310 (M+.; RMN du XH (CDCI3) : δ (ppm)Rf: 0.43 (CH 2 C1 2 / Ethyl acetate, 80/20) MS (IE): m / z 310 (M + .; X H NMR (CDCI3): δ (ppm)
Figure imgf000012_0001
7.91 (m, 2H, H-2 ' , H-6') 7.78 (m, IH, H-5') 7.53 (m, IH, H-6) 7.31 (m, IH, H-4') RMN du 13C (CDCI3) : δ (ppm) 176,55 (2C, C=0) 164.50 (1C, C-3') 161.20 (1C, Cquat) 154.28 (1C, C-7) 148.80 (1C, Cquat) 141.75 (1C, C quat) 135.71 (1C, C-5) 131.50 (1C, C-6) 129.40 (1C, Cquat) 127.05 (1C, C-5'} 123.50 (1C, C-6') 129.40 (2C, Cquat) 114.55 (2C, C-2', C-4') IR (KBr) : μ (cm"1) 1671 (C=0) Exemple 5
Figure imgf000012_0001
7.91 (m, 2H, H-2 ', H-6') 7.78 (m, IH, H-5 ') 7.53 (m, IH, H-6) 7.31 (m, IH, H-4') NMR of 13 C (CDCI3): δ (ppm) 176.55 (2C, C = 0) 164.50 (1C, C-3 ') 161.20 (1C, Cquat) 154.28 (1C, C-7) 148.80 (1C, Cquat) 141.75 (1C, C quat) 135.71 (1C, C-5) 131.50 (1C, C-6) 129.40 (1C, Cquat) 127.05 (1C, C-5 '} 123.50 (1C, C-6') 129.40 (2C , Cquat) 114.55 (2C, C-2 ', C-4') IR (KBr): μ (cm "1 ) 1671 (C = 0) Example 5
4 , 9-Dιhydro-4 , 9-dιoxo-2- (4-fluorophenyl) - thiazolo[4 ,5-g]quinoline4, 9-Dιhydro-4, 9-dιoxo-2- (4-fluorophenyl) - thiazolo [4, 5-g] quinoline
A 0,80 g (3,84 mmoles) de 6-amιno-7-chloro-5, 8- dιhydro-5, 8-dιoxo-qumolme, on ajoute à température am¬ biante 5,53 g (23,02 mmoles) de sulfure de sodium nonahy¬ drate en solution dans 9,6 ml d'eau. Apres 5 minutes, on ajoute au milieu réactionnel devenu bleu 411 μl (3,84 mmoles) de 4-fluorobenzaldéhyde et 880 μl d'acide acéti- que glacial. La réaction est maintenue 10 minutes à 80°C et le précipité brun qui se forme est filtré sur verre fritte puis lave a l'éthanol. Le solide brun ainsi obtenu est repris dans 600 ml de chloroforme et lave avec 700 ml d'eau. La phase organique est ensuite séchée sur du chlo- rure de calcium et évaporée a sec. Le produit jaune obte¬ nu est purifié sur cake (support : silice ; éluant : di- chlorométhane/isopropanol, 99/1) pour fournir 0,27 g de 4, 9-dιhydro-4, 9-dιoxo-2- (4-fluorophenyl) -thiazolo [4, 5-g] - quinoline sous forme de cristaux jaunes. Rdt : 23 °o F : > 260°CTo 0.80 g (3.84 mmol) of 6-amιno-7-chloro-5, 8- dehydro-5, 8-dιoxo-qumolme, 5.53 g (23.02 mmol) are added at room temperature ) of sodium sulfide nonahy¬ drate in solution in 9.6 ml of water. After 5 minutes, 411 μl (3.84 mmol) of 4-fluorobenzaldehyde and 880 μl of glacial acetic acid are added to the reaction medium which has turned blue. The reaction is maintained for 10 minutes at 80 ° C. and the brown precipitate which forms is filtered through sintered glass and then washed with ethanol. The brown solid thus obtained is taken up in 600 ml of chloroform and washed with 700 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product obtained is purified on cake (support: silica; eluent: dichloromethane / isopropanol, 99/1) to provide 0.27 g of 4,9-dιhydro-4,9-dιoxo-2- (4 -fluorophenyl) -thiazolo [4, 5-g] - quinoline in the form of yellow crystals. Rd: 23 ° o F:> 260 ° C
Rf : 0.60 (CH2Cl2/Metnanol, 97/3) SM (I.E.) : m/z 310 \R+ . ) RMN du 1H (DMSO d6) : δ (ppm) 9.09 (m, IH, K-i ) 8 . 54 ( d, IH, H- 5 , JHS-H6= 8 . 43Hz ) 8 . 31 (m, 2H, H-2 ' , H- 6 ' ) 7 . 95 (m, IH , H- 6 ) 7 . 4 6 (m, 2H, H- 3 ' , H- 5 ' ) IR (KBr) : μ (cm"1)Rf: 0.60 (CH 2 Cl 2 / Metnanol, 97/3) SM (IE): m / z 310 \ R +. ) 1 H NMR (DMSO d 6 ): δ (ppm) 9.09 (m, IH, Ki) 8. 54 (d, IH, H- 5, J HS - H6 = 8.43Hz) 8. 31 (m, 2H, H-2 ', H- 6') 7. 95 (m, 1H, H- 6) 7. 4 6 (m, 2H, H- 3 ', H- 5') IR (KBr): μ (cm "1 )
3052 (CH) ; 1678, 1667 (C=0) Exemple 63052 (CH); 1678, 1667 (C = 0) Example 6
2- (2,4-Difluorophenyl) -4 ,9-dιhydro-4 ,9-dιoxo- thiazolo[4 ,5-g]quιnolme A 1,220 g (5,80 mmoles) de 6-ammo-7-chloro-5, 8- dιhydro-5, 8-dιoxo-qumolme, on ajoute a température am¬ biante 4,220 g (17,50 mmoles) de sulfure de sodium nona¬ hydrate en solution dans 21,6 ml d'eau. Apres 10 minutes, on ajoute au milieu réactionnel devenu bleu 0,64 ml (5,85 mmoles) de 2, 4-dιfluorobenzaldéhyde et 1,33 ml d'acide acétique glacial . La reaction est maintenue 4 heures a 80°C et le précipite noir qui se forme est filtré sur verre fritte puis lave a l'éthanol. Le solide brun ainsi obtenu est repris par 250 ml de chloroforme et lavé avec 150 ml d'eau. La phase organique est ensuite sechee sur du chlorure de calcium e' évaporée a sec. Le produit jaune ootenu est purifie sur cake (support : silice ; éluant : dichloromethane/isopropanol, 99,5/0,5) pour fournir 0,821 g de 2- (2, 4-dιfluorophenyl) -4, 9-dιhydro- 4, 9-dιoxo-thιazolo [4, 5-g]quinoline sous forme αe cristaux jaunes . Rdt : 43 l F : > 260°C Rf : 0.46 (CH2C12/ Méthanol, 99/1) SM (I.E.) : m/z 328 (M+.)2- (2,4-Difluorophenyl) -4,9-dehydro-4,9-dexoxothiazolo [4,5-g] qunolme A 1,220 g (5.80 mmol) of 6-ammo-7-chloro-5 , 8- dehydro-5, 8-dexoxo-qumolme, 4.220 g (17.50 mmol) of sodium sulfide nona¬ hydrate dissolved in 21.6 ml of water are added at ambient temperature. After 10 minutes, 0.64 ml (5.85 mmol) of 2,4-dιfluorobenzaldehyde and 1.33 ml of glacial acetic acid are added to the reaction medium, which has turned blue. The reaction is maintained for 4 hours at 80 ° C. and the black precipitate which forms is filtered through sintered glass and then washed with ethanol. The brown solid thus obtained is taken up in 250 ml of chloroform and washed with 150 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product ootenu is purified on cake (support: silica; eluent: dichloromethane / isopropanol, 99.5 / 0.5) to provide 0.821 g of 2- (2, 4-dιfluorophenyl) -4, 9-deιhydro- 4, 9-dιoxo-thιazolo [4, 5-g] quinoline in the form of yellow crystals. Yd: 43 l F:> 260 ° C Rf: 0.46 (CH 2 C1 2 / Methanol, 99/1) SM (IE): m / z 328 (M +.)
RMN du !H (CDC13) : δ (ppm) 9.11 (d, IH, H-7, JH6-H-=4.58HZ) 8.67 (m, 2H, H-5, H-6') 7.79 (m, IH, H-6) 7.09 (m, 2H, H-3', H-5') RMN du 13C (CDCI3) : δ (ppm)! H NMR (CDC1 3 ): δ (ppm) 9.11 (d, IH, H-7, J H6 - H - = 4.58HZ) 8.67 (m, 2H, H-5, H-6 ') 7.79 (m , IH, H-6) 7.09 (m, 2H, H-3 ', H-5') 13 C NMR (CDCI3): δ (ppm)
177.02, 176.57 (2C, C=0)177.02, 176.57 (2C, C = 0)
167.10 flC, C-2')167.10 flC, C-2 ')
154.74 (1C, C-7) 148.89 (1C, Cquat)154.74 (1C, C-7) 148.89 (1C, Cquat)
135.71 (1C, C-5)135.71 (1C, C-5)
131.54 (2C, Cquat)131.54 (2C, Cquat)
129.85 (1C, C-6')129.85 (1C, C-6 ')
127.94 (1C, C-6) 113.21 (1C, Cquat)127.94 (1C, C-6) 113.21 (1C, Cquat)
113.17 (1C, C-5')113.17 (1C, C-5 ')
105.25 '1C, Cquat/105.25 '1C, Cquat /
104.88 (1C, C-3')104.88 (1C, C-3 ')
104.51 (1C, Cquat) IR (KBr) : μ (cm"1)104.51 (1C, Cquat) IR (KBr): μ (cm "1 )
3071 (CH) ; 1683, 1670 (C≈O)3071 (CH); 1683, 1670 (C≈O)
Exemple π Example π
Sulfate de 4 ,9-Dιhydro-4 ,9-dιoxo-2- (2-pyπdyl) - thiazolo[4 ,5-g]quinoline A 200 mg (0,68 mmoles) de 4, 9-dιhydro-4, 9-dιoxo-2-4,9-Dehydro-4,9-dexoxo-2- (2-pyπdyl) - thiazolo [4,5-g] quinoline sulphate 200 mg (0.68 mmol) 4,9-dehydro-4,9 -dιoxo-2-
(2-pyrιdyl) -thiazolo [4, 5-g] quinoline en solution dans 200 ml de cnloroforme, on ajoute a 0°C 56 μl (0,68 mmoles) d'acide sulfurique. Apres 30 minutes sous agitation a température ambiante le précipite orange qui se forme est filtre sur verre fritte, lave a l'éther puis au pentane pour fournir 266 mg de sulfate de 4, 9-dιhydro-4, 9-dιoxo-(2-pyrιdyl) -thiazolo [4, 5-g] quinoline dissolved in 200 ml of chloroform, 56 μl (0.68 mmol) of sulfuric acid are added at 0 ° C. After 30 minutes with stirring at room temperature, the orange precipitate which forms is filtered on sintered glass, washed with ether and then with pentane to provide 266 mg of 4, 9-dehydro-4, 9-deoxo- sulphate.
2- (2-pyπdyl) -thiazolo[4, 5-g] quinoline, sous forme de cristaux orange.2- (2-pyπdyl) -thiazolo [4, 5-g] quinoline, in the form of orange crystals.
Rdt : 100 % F : > 260°CYield: 100% F:> 260 ° C
Rf : 0.48 (CH2Cl2/Methanol, 98/2)Rf: 0.48 (CH 2 Cl 2 / Methanol, 98/2)
RMN du XH (DMSO d6) : δ (ppm) X H NMR (DMSO d 6 ): δ (ppm)
9.05 (d, IH, H-7, JHo.^=4.58Hz)9.05 (d, IH, H-7, J Ho . ^ = 4.58Hz)
3 . 76 ( d, IH , H- 6 ' , JH5 _Ho =4 . 96Hz ) 3 . 56 ( d, IH , H- 5 , JHD-,, = 7 . 94Hz )
Figure imgf000016_0001
8.10 (m, IH, H-4') 7.93 (m, IH, H-6) 7.68 (m, IH, H-5') 4.02 (ls, IH, NH+) IR (KBr) : μ (cm"1) 3392 (NH+) ; 1687, 1674 (C=0) Exemple 83. 76 (d, IH, H- 6 ', J H5 _ Ho = 4. 96Hz) 3. 56 (d, IH, H- 5, J HD - ,, = 7. 94Hz)
Figure imgf000016_0001
8.10 (m, IH, H-4 ') 7.93 (m, IH, H-6) 7.68 (m, IH, H-5') 4.02 (ls, IH, NH +) IR (KBr): μ (cm "1 ) 3392 (NH +); 1687, 1674 (C = 0) Example 8
4,9-Dιhydro-4 ,9-dιoxo-2- (3-furyl) -thiazolo[4,5- g]quιnolme4,9-Dιhydro-4, 9-dιoxo-2- (3-furyl) -thiazolo [4,5- g] quιnolme
A 2,00 g (9,6 mmoles) de 6-amιno-7-chloro-5, 8- dιhydro-5, 8-αιoxo-quιnolme, on ajoute a température am¬ biante 13,85 g (57,4 mmoles) de sulfure de sodium nonahy¬ drate en solution dans 36 ml d'eau. Apres chauffage a 40°C, lorsque la couleur de la solution passe du rouge au bleue, on ajoute 0,923 g (9,6 mmoles) de 3-furaldéhyde puis 2,74 ml d'acide acétique glacial. Apres une heure d'agitation, il se forme un léger précipite marron. On ajoute alors 100 ml de carbonate de sodium (5o) pour tout faire précipiter. Le précipite est filtre, lave avec de l'eau, sèche et purifie sur colonne flash (support : si¬ lice ; dépôt sec ; éluant : dichloromethane/acetate d'éthyle, 97,5/2,5) . Les cristaux jaunes obtenus après evaporation des solvants sous pression réduite sont re- cristallises après décoloration au noir animal dans du méthanol pour fournir 0,308 g de 4, 9-dιhydro-4, 9-dιoxo-2- (3-furyl) -thiazolo [4, 5-g]quinoline sous forme de cristaux jaunes . Rdt : 11 °o Rf : 0.43 (CH2C1:/Acetate d' éthyle, 75/25) SM (I.E.) : m/z 282 (M+ . ) RMN du 1H (CD2C12) : δ (ppm)
Figure imgf000016_0002
8.61 (dd, IH, H-5,
Figure imgf000016_0003
.83Hz) 8.30 (s, IH, H-2') 7.75 (αd, IH, H-6, JH5-H6=7.93Hz, JHo-H-=4.58Hzi 7.61 (m, IH, H-5') 7.00 (m, IH, H-4')To 2.00 g (9.6 mmol) of 6-amino-7-chloro-5, 8-dehydro-5, 8-αιoxo-quιnolme, 13.85 g (57.4 mmol) are added at room temperature ) of sodium sulfide nonahy¬ drate in solution in 36 ml of water. After heating to 40 ° C, when the color of the solution changes from red to blue, 0.923 g (9.6 mmol) of 3-furaldehyde is added, then 2.74 ml of glacial acetic acid. After one hour of agitation, a slight brown precipitate is formed. Then add 100 ml of sodium carbonate (5o) to precipitate everything. The precipitate is filtered, washed with water, dried and purified on a flash column (support: silica; dry deposit; eluent: dichloromethane / ethyl acetate, 97.5 / 2.5). The yellow crystals obtained after evaporation of the solvents under reduced pressure are recrystallized after discoloration with animal black in methanol to give 0.308 g of 4, 9-dιhydro-4, 9-dιoxo-2- (3-furyl) -thiazolo [ 4, 5-g] quinoline in the form of yellow crystals. Yield: 11 ° o Rf: 0.43 (CH 2 C1 : / Ethyl acetate, 75/25) SM (IE): m / z 282 (M +.) 1 H NMR (CD 2 C1 2 ): δ (ppm )
Figure imgf000016_0002
8.61 (dd, IH, H-5,
Figure imgf000016_0003
.83Hz) 8.30 (s, IH, H-2 ') 7.75 (αd, IH, H-6, J H5 - H6 = 7.93Hz, J Ho - H - = 4.58Hzi 7.61 (m, IH, H-5 ') 7.00 (m, IH, H-4')
RMN du : L3C (CD,C12) : δ (ppm)NMR of : L 3 C (CD, C1 2 ): δ (ppm)
187.42 (IC C=0)187.42 (IC C = 0)
186.27 (IC C=0)186.27 (IC C = 0)
170.73 (IC Cquat)170.73 (IC Cquat)
163.56 (IC Cquat)163.56 (IC Cquat)
154.81 (IC C-7)154.81 (IC C-7)
145.48 (IC C-2' )145.48 (IC C-2 ')
144.53 (IC C-5' )144.53 (IC C-5 ')
139.54 (IC Cquat)139.54 (IC Cquat)
135.88 (IC C-5)135.88 (IC C-5)
128.29 (IC C-6)128.29 (IC C-6)
121.25 (IC Cquat)121.25 (IC Cquat)
117.77 (IC Cquat)117.77 (IC Cquat)
109.41 (IC C-4' )109.41 (IC C-4 ')
102.29 (IC , Cquat)102.29 (IC, Cquat)
IR (KBr 1 : μ (cm"1)IR (KBr 1: μ (cm "1 )
1683, 1655 (C=0)1683, 1655 (C = 0)
Exemple 9Example 9
4, 3-D.ιhydro-4 9-dιoxo-2-phenyl-thiazolo [5,4 -g3- quinoline4, 3-D.ιhydro-4 9-dιoxo-2-phenyl-thiazolo [5,4 -g3- quinoline
A 0,50 g (2,4 mmoles) de 7-ammo-6-chloro-5, 8- dιhydro-5, 8-dιoxo-qumolme, on ajoute a température am¬ biante 3,45 g (14,4 mmoles) de sulfure de sodium nonahy¬ drate en solution dans 6 ml d'eau. Apres 5 minutes d'agitation a 40°C, on ajoute au milieu réactionnel deve¬ nu bleu 243 μl (2,4 mmoles) de benzaldéhyde et 550 μl d'acide acétique glacial. Apres 5 minutes à 40°C, le mi¬ lieu réactionnel est dilué avec 1000 ml de chloroforme. La phase organique est extraite, lavée 3 fois avec 400 ml α'eau, séchée sur du chlorure de calcium et évaporée sous pression réduite. La poudre ainsi obtenue est purifiée sur cake (support : silice ; éluant : dichloromé- thane/methanol, 99/1) pour fournir 0,25 g de 4,9-dιhydro- 4, 9-dιoxo-2-phenyl-thιazolo [5, 4-g]quinoline sous forme de cristaux jaunes. Rdt : 36 % F : > 260°CA 0.50 g (2.4 mmol) of 7-amino-6-chloro-5, 8- dιhydro-5, 8-dιoxo-qumolme, was added am ¬ ature temperature 3.45 g (14.4 mmol ) of sodium sulfide nonahy¬ drate in solution in 6 ml of water. After 5 minutes of stirring at 40 ° C., 243 μl (2.4 mmol) of benzaldehyde and 550 μl of glacial acetic acid are added to the blue reaction medium. After 5 minutes at 40 ° C, the reaction medium is diluted with 1000 ml of chloroform. The organic phase is extracted, washed 3 times with 400 ml of water, dried over calcium chloride and evaporated under reduced pressure. The powder thus obtained is purified on a cake (support: silica; eluent: dichlorome- thane / methanol, 99/1) to provide 0.25 g of 4,9-dehydro-4,9-dexoxo-2-phenyl-thιazolo [5,4-g] quinoline in the form of yellow crystals. Yid: 36% F:> 260 ° C
Rf : 0.53 (CH2Cl2/Méthanol, 98/2) SM (I.E.) : m/z 292 (M+ . ) RMN du 1H (CDC13) : δ (ppm)Rf: 0.53 (CH 2 Cl 2 / Methanol, 98/2) SM (IE): m / z 292 (M +.) 1 H NMR (CDC1 3 ): δ (ppm)
Figure imgf000018_0001
Figure imgf000018_0001
7.94 (d, 2H, H-2', H-6', JH2-H3'=JHV-H0'=7.01Hz)7.94 (d, 2H, H-2 ', H-6', J H2 - H3 ' = J HV - H0' = 7.01Hz)
7.52 (m, IH, H-7)7.52 (m, IH, H-7)
7.31 (m, 3H, H-3', H-4', H-5')7.31 (m, 3H, H-3 ', H-4', H-5 ')
RMN du 13C (CDCI3) : δ (ppm) 154.45 (IC, C-6) 134.41 (IC, C-8) 132.27 (IC, C-7) 128.87 (2C, C-3', C-5') 127.45 (2C, C-2', C-6') 127.09 (IC, C-4') 123.55 (IC, Cquat) IR (KBr) : μ (cm-1) 1687, 1654 (C=0) Exemple IC 4 , 9-Dιhydro-4 , 9-dιoxo-2- (2-fluorophenyl) -thiazolo- 13 C NMR (CDCI3): δ (ppm) 154.45 (IC, C-6) 134.41 (IC, C-8) 132.27 (IC, C-7) 128.87 (2C, C-3 ', C-5') 127.45 (2C, C-2 ', C-6') 127.09 (IC, C-4 ') 123.55 (IC, Cquat) IR (KBr): μ (cm -1 ) 1687, 1654 (C = 0) Example IC 4, 9-Dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) -thiazolo-
[5,4-g]quinoline[5.4-g] quinoline
A 0,300 g (1,43 mmoles) de 7-ammo-6-chloro-5, 8- dιhydro-5, 8-dιoxo-quιnolιne, on ajoute a température am¬ biante 2,073 g (8,63 mmoles) de sulfure de sodium nonahy- drate en solution dans 6 ml d'eau. Apres 5 minutes d'agitation a 40°C, on ajoute au milieu réactionnel deve¬ nu bleu 151 μl (1,41 mmoles) de 2-fluorobenzaldéhyαe et 330 μl d'acide acétique glacial. Apres 10 minutes a 55°C, le milieu réactionnel est dilue avec 1000 ml de chloro- forme. La pnase organique est lavée 3 fois avec 200 ml d'eau, sechee sur du chlorure de calcium et évaporée sous pression réduite. La poudre ainsi obtenue est purifiée sur cake (support : silice ; éluant : dichlorome- thane/ethanol, 95/5) pour fournir 0,400 g de 4,9-dιhydro-To 0.300 g (1.43 mmol) of 7-ammo-6-chloro-5, 8- dehydro-5, 8-dexoxo-quinolene, 2.073 g (8.63 mmol) of sulphide is added at ambient temperature sodium nonahydrate in solution in 6 ml of water. After 5 minutes of stirring at 40 ° C., 151 μl (1.41 mmol) of 2-fluorobenzaldéhyαe and 330 μl of glacial acetic acid are added to the blue deve¬ blue reaction medium. After 10 minutes at 55 ° C., the reaction medium is diluted with 1000 ml of chloroform. The organic pnase is washed 3 times with 200 ml of water, dried over calcium chloride and evaporated under reduced pressure. The powder thus obtained is purified on a cake (support: silica; eluent: dichloromethane / ethanol, 95/5) to provide 0.400 g of 4,9-dehydro-
4, 9-dιoxo-2- (2-fluorophenyl) -thiazolo [5, 4-g] quinoline sous forme de cristaux jaunes.4, 9-dιoxo-2- (2-fluorophenyl) -thiazolo [5, 4-g] quinoline in the form of yellow crystals.
Rdt : 90 %YId: 90%
F : y 260°CF: y 260 ° C
Rf : 0.56 (CH2Cl2/Methanol, 98/2)Rf: 0.56 (CH 2 Cl 2 / Methanol, 98/2)
SM (I.E.) : m/z 310 (M+ . )SM (I.E.): m / z 310 (M +.)
RMN du 1E (CDC13) : δ (ppm) 1 E NMR (CDC1 3 ): δ (ppm)
9.14 (d, IH, H-6, JHB-H—4.88Hz)9.14 (d, IH, H-6, J HB - H —4.88Hz)
8.61 (m, 2H, H-8, H-6')8.61 (m, 2H, H-8, H-6 ')
7.75 (m, IH, H-7)7.75 (m, IH, H-7)
7.57 (m, IH, H-4') 7.34 (m, 2H, H-3', H-5' RMN du 13C (CDCI3) δ (ppm)7.57 (m, IH, H-4 ') 7.34 (m, 2H, H-3', H-5 '13 C NMR (CDCI3) δ (ppm)
17"7.88 (IC, C=0) 158.94 (IC, C-2) 154.97 (IC, C-6) 134.94 (IC, C-8) 133.93 (IC, C-7) 130.18 (IC, C-6'17 "7 .88 (IC, C = 0) 158.94 (IC, C-2) 154.97 (IC, C-6) 134.94 (IC, C-8) 133.93 ( IC, C-7) 130.18 (IC, C- 6 '
127 Di :ιc, c-4127 Di: ιc, c-4
125.15 (IC, C-5' 116.50 (IC, C-3' 116.19 (IC, C-l' IR (KBr) : μ (cm"1) 1693, 1659 (C=0) Exemple 11125.15 (IC, C-5 '116.50 (IC, C-3' 116.19 (IC, Cl 'IR (KBr): μ (cm "1 ) 1693, 1659 (C = 0) Example 11
4 , 9-Dιhydro-4 , 9-dιoxo-2-phenyl-thiazolo[5 ,4-f] - isoσuinoline4, 9-Dιhydro-4, 9-dιoxo-2-phenyl-thiazolo [5, 4-f] - isoσuinoline
Synthèse de l'intermédiaire :Summary of the intermediary:
7-amιno-6-chloro-5 ,8-dιhydro-5,8-dιoxo-ιsoquιnolιne7-amιno-6-chloro-5, 8-dehydro-5,8-dιoxo-ιsoquιnolιne
A 8 20 g (0 036 mmole) de 6, 7-dιchloro-5, 8-dιhydro- 5, 8-dιoxo-ιsoqumolme en suspension dans 350 ml d'acide acétique, on ajoute 3,74 g (0,057 mmole) de nitrure de sodium en solution dans 16 ml d'eau. Le milieu réaction¬ nel est agite a 100°C pendant 2 heures. Apres refroidis- sèment, on introduit 300 ml d'éther. Il y a apparition d'un précipite qui est filtre. Ce précipite est purifie sur une colonne flash (support : silice ; dépôt solide ; éluant : acétate d'éthyle, 100%) pour fournir 5,34 g de 7-ammo-6-chloro-5, 8-dιhydro-5, 8-dιoxo-ιsoqumolme. Rdt : 72 °,A 8 20 g (0366 mmol) of 6,7-dιchloro-5,8-dehydro- 5, 8-dιoxo-ιsoqumolme suspended in 350 ml of acetic acid, 3.74 g (0.057 mmol) of sodium nitride in solution in 16 ml of water are added. The reaction medium is stirred at 100 ° C for 2 hours. After cooling, 300 ml of ether are introduced. A precipitate appears which is filtered. This precipitate is purified on a flash column (support: silica; solid deposit; eluent: ethyl acetate, 100%) to provide 5.34 g of 7-ammo-6-chloro-5, 8-dehydro-5, 8 -dιoxo-ιsoqumolme. Rdt: 72 °,
RMN du 1H (CD2C12) : δ (ppm) 1 H NMR (CD 2 C1 2 ): δ (ppm)
9.32 (s, IH, H-l)9.32 (s, IH, H-l)
9 . 25 ( s , 2H , NH ) 9 . 00 ( d, I H , H- 3 , JH3-H4 = 4 . 89Hz ) 7 . 82 ( d , IH , H- 4 , JH 3-H4=4 . 88Hz )9. 25 (s, 2H, NH) 9. 00 (d, IH, H- 3, J H3 - H4 = 4.89Hz) 7. 82 (d, IH, H- 4, J H 3 - H4 = 4. 88Hz)
IR (KBr) : μ ( cm"1 )IR (KBr): μ (cm "1 )
3354 (NH,) ; 1610, 1588 (C=0)3354 (NH,); 1610, 1588 (C = 0)
4 , 9-Dιhydro-4 , 9-dιoxo-2-phenyl-thiazolo[5,4-f] - isoquinoline (Exemple 11) A l'20 g (5' 7 mmoles) de 7-ammo-6-chloro-5, 8- dιhydro-5, 8-dιoxo-ιsoqumolιne, on ajoute en une seule fois 8' 31 g (34' b mmoles) de sulfure de sodium nonahydra¬ te en solution αans 42' 4 ml d'eau distillée. Apres une heure d'agitation a température ambiante, on ajoute au milieu réactionnel devenu rouge 0'59 ml (5' 8 mmoles) de benzaldéhyde puis goutte a goutte l' 31 ml d'acide acéti¬ que glacial. Apres deux heures sous agitation, on extrait au chloroforme. La pnase organique est lavée a l'eau, se¬ chee sur du chlorure de calcium, filtrée et évaporée a sec. Le produit est ensuite purifie sur colonne flash4, 9-Dιhydro-4, 9-dιoxo-2-phenyl-thiazolo [5,4-f] - isoquinoline (Example 11) At 20 g (5 '7 mmoles) of 7-ammo-6-chloro- 5, 8- dehydro-5, 8-dιoxo-ιsoqumolιne, 8 '31 g (34' b mmoles) of sodium sulfide nonahydra¬ te in solution is added in 42 '4 ml of distilled water. After one hour of stirring at room temperature was added to the reaction mixture became red 0'59 ml (5 '8 mmol) of benzaldehyde and then dropwise the 31 ml of glacial aceti acid ¬. After two hours with stirring, extraction is carried out with chloroform. The organic pnase is washed with water, dried over calcium chloride, filtered and evaporated to dryness. The product is then purified on a flash column
(support : silice , dépôt liquide ; dichlorome- thane/acetate d'éthyle, 80/20) . On obtient ainsi après décoloration au noir animal et recπstallisation dans le méthanol 0'50 g de 4, 9-dιhydro-4, 9-dιoxo-2-phenyl- thiazolo [5, 4-f] îsoqumolme, sous rorme de cristaux jau- nés .(support: silica, liquid deposit; dichloromethane / ethyl acetate, 80/20). Is thus obtained after discoloration in animal black and re-installation in methanol 0'50 g of 4, 9-dιhydro-4, 9-dιoxo-2-phenyl- thiazolo [5, 4-f] issoqumolme, in the form of yellow crystals born.
Rdt : 30 %Yid: 30%
Pf : 238°CMp: 238 ° C
Rf : 0.56 (CH2C12/Acétate d'éthyle, 80/20) SM (I.E.) : m/z 292 (M+. )Rf: 0.56 (CH 2 C1 2 / Ethyl acetate, 80/20) SM (IE): m / z 292 (M +.)
RMN du 1H (CD2Cl2) : δ (ppm) 1 H NMR (CD 2 Cl 2 ): δ (ppm)
9.51 (s, IH, H-5)
Figure imgf000021_0001
9.51 (s, IH, H-5)
Figure imgf000021_0001
8.16 (dd, 2H, H-2' , H-6' , JH2'-H3'
Figure imgf000021_0002
=
Figure imgf000021_0003
8.16 (dd, 2H, H-2 ', H-6', J H2 ' -H3 '
Figure imgf000021_0002
=
Figure imgf000021_0003
3.00 (d, IH, H-8, JH7-H8=4.58Hz)3.00 (d, IH, H-8, J H7 - H8 = 4.58Hz)
^.60 (m, 2H, H-3' , H-5' )^ .60 (m, 2H, H-3 ', H-5')
7.55 (m, IH, H-4' )7.55 (m, IH, H-4 ')
RMN du 13C (CD2Cl2) : δ (ppm) 177.68 (2C, C≈O) 13 C NMR (CD 2 Cl2): δ (ppm) 177.68 (2C, C≈O)
165.33 (IC, Cquat)165.33 (IC, Cquat)
156.19 (IC, C-7)156.19 (IC, C-7)
149.73 (IC, C-5)149.73 (IC, C-5)
138.66 (IC, Cquat) 133.06 (IC, C-4')138.66 (IC, Cquat) 133.06 (IC, C-4 ')
132.27 (IC, Cquat)132.27 (IC, Cquat)
129.41 (2C, C-3', C-5')129.41 (2C, C-3 ', C-5')
128.07 (2C, C-2', C-6')128.07 (2C, C-2 ', C-6')
118.97 (IC, C-8) IR (KBr) : μ (cm"1)118.97 (IC, C-8) IR (KBr): μ (cm "1 )
1684, 1659 (C≈O)1684, 1659 (C≈O)
Exemple 12Example 12
4 , 9-Dihydro-4 , 9-dιoxo-2- (2-fluorophenyl) -thiazolo-4, 9-Dihydro-4, 9-dιoxo-2- (2-fluorophenyl) -thiazolo-
[5,4-f]isoquinoline A l'13 g (5/ 4 mmoles) de 7-ammo-6-chloro-5, 8- dιhydro-5, 8-dιoxo-ιsoqumolme, on ajoute à température ambiante 7' 80 g (32' 5 mmoles) de sulfure de sodium nona¬ hydrate en solution dans 6 ml d'eau. Apres 4 heures d'agitation à 45°C, on ajoute au milieu réactionnel deve- nu bleu 572 μl (5' 4 mmoles) de 2-fluorobenzaldéhyde et 1250 ml d'acide acétique glacial. Après 5 minutes à 45°C, on laisse revenir a température ambiante puis le contenu du tricol est versé dans 1000 ml de chloroforme. La phase organique est lavée 3 fois avec 400 ml d'eau, séchée sur du chlorure de calcium et évaporée sous pression réduite. La poudre ainsi obtenue est purifiée sur cake (support : silice ; éluant : dichloromethane/acetate d'éthyle, 95/5) pour fournir 0'40 g de 4, 9-dιhydro-4, 9-dιoxo-2- (2- fluorophenyl) -thiazolo [5, 4-f] îsoqumoline sous forme de cristaux jaunes. Rdt : 24 K. F : > 260°C[5,4-f] isoquinoline To the 13 g (5/4 mmol) of 7-ammo-6-chloro-5, 8- dehydro-5, 8-dιoxo-ιsoqumolme, we add at room temperature 7 '80 g (32 '5 mmol) of sodium sulfide nona¬ hydrate in solution in 6 ml of water. After 4 hours of stirring at 45 ° C., 572 μl (5 '4 mmol) of 2-fluorobenzaldehyde are added to the reaction medium, which has turned blue. 1250 ml of glacial acetic acid. After 5 minutes at 45 ° C., the mixture is allowed to return to ambient temperature then the contents of the three-necked flask are poured into 1000 ml of chloroform. The organic phase is washed 3 times with 400 ml of water, dried over calcium chloride and evaporated under reduced pressure. The powder thus obtained is purified on a cake (support: silica; eluent: dichloromethane / ethyl acetate, 95/5) to provide 0'40 g of 4, 9-dιhydro-4, 9-dιoxo-2- (2- fluorophenyl) -thiazolo [5, 4-f] isqumoline in the form of yellow crystals. Yd: 24 K. F:> 260 ° C
Rf : 0.50 (CH2C12/Acetate d'éthyle, 80/20) SM (I.E.) : m/z 310 (M+ . ) RMN du 1H (CD2C12) : δ (ppm)Rf: 0.50 (CH 2 C1 2 / Ethyl acetate, 80/20) SM (IE): m / z 310 (M +.) 1 H NMR (CD 2 C1 2 ): δ (ppm)
9.52 (s, IH, H-5)
Figure imgf000022_0001
)9.52 (s, IH, H-5)
Figure imgf000022_0001
)
8.53 (m, IH, H-6' )8.53 (m, IH, H-6 ')
8.01 (d, IH, H-8, JH7-HΘ = 5.19HZ) 7.60 (m, IH, H-4 ' )8.01 (d, IH, H-8, J H7 - HΘ = 5.19HZ) 7.60 (m, IH, H-4 ')
7.37 (m, 2H, H-3', H-5')7.37 (m, 2H, H-3 ', H-5')
RMN du 13C (CD2C12) : δ (ppm) 13 C NMR (CD 2 C1 2 ): δ (ppm)
156.31 (IC, C-7)156.31 (IC, C-7)
153.83 (IC, Cquat) 149.85 (IC, C-5)153.83 (IC, Cquat) 149.85 (IC, C-5)
138.84 (IC, Cquat) 134.60 (IC, C-6') 130.14 (IC, C-4') 125.67 (2C, C-5', Cquat) 119.06 (IC, C-8)138.84 (IC, Cquat) 134.60 (IC, C-6 ') 130.14 (IC, C-4') 125.67 (2C, C-5 ', Cquat) 119.06 (IC, C-8)
116.98 (IC, C-3' )116.98 (IC, C-3 ')
116.67 (IC, C-l' )116.67 (IC, C-l ')
IR (KBr) : μ (cm"1)IR (KBr): μ (cm "1 )
1673 (C≈O) Exemp l e 1 31673 (C≈O) Example 1 3
4 , 9-Dιhydro-4 , 9-dιoxo-2- (2-fluorophenyl) - thiazolo[4 ,5-f] isoquinoline4, 9-Dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-f] isoquinoline
Syntnese de l'intermédiaire : 6-amιno-7-chloro-5,8-dιhydro-5,8-dιoxo-ιsoquιnolιneSyntnese of the intermediary: 6-amιno-7-chloro-5,8-dιhydro-5,8-dιoxo-ιsoquιnolιne
Dans une suspension de 17' 00 g (0'075 mole) de 6,7- dιchloro-5, 3-dιhydro-5, 8-dιoxo-ιsoquιnolιne dans 500 ml de chloroforme, on fait passer un courant d'ammoniac pen¬ dant 25 minutes. Le milieu réactionnel, qui s'échauffe de 26°C a 50°C se colore en rouge fonce et il y a apparition d'un précipite. L'excès de solvant est évapore sous pres¬ sion reαuite et le résidu solide obtenu qui contient un mélange de 6-ammo-7-chloro-5, 8-dιhydro-5, 8-dioxo-ιso- quinoline et de 7-amιno-6-chloro-5, 8-dιhydro-5, 8-dιoxo- îsoqumoline est lave à l'eau, filtré, séché puis purifié sur colonne moyenne pression (support : silice ; éluant : dichloromethane/acétate d'éthyle, 30/20) pour fournir 0'203 g de 5-ammo-7-chloro-5, 8-dιhydro-5, 8-dιoxo-ιso- quinolme. Rdt : 1.3 %In a suspension of 17 '00 g (0'075 mole) of 6,7- dechloro-5, 3-dehydro-5, 8-dexoxo-ιsoquιnolιne in 500 ml of chloroform, a stream of ammonia is passed through. for 25 minutes. The reaction medium, which heats from 26 ° C to 50 ° C becomes dark red in color and a precipitate appears. The excess solvent is evaporated under reduced pressure and the solid residue obtained which contains a mixture of 6-ammo-7-chloro-5, 8-deιhydro-5, 8-dioxo-ιso-quinoline and 7-amιno -6-chloro-5, 8-dιhydro-5, 8-dιoxo- îsoqumoline is washed with water, filtered, dried and purified on a medium pressure column (support: silica; eluent: dichloromethane / ethyl acetate, 30 / 20) to provide 0.203 g of 5-ammo-7-chloro-5, 8-dehydro-5, 8-dexoxo-ιso-quinolme. YId: 1.3%
RMN du XH (CD2C12) : δ (ppm) 9.37 (s, 2H, NH j 9.35 [ s , IH, K-1) 9.02 (d, IH, H-3) 7.87 (d, IH, H-4) IR (KBr) : μ (cm"1) 3409 (NH2) ; 1632, 1614 (C≈O) X H NMR (CD 2 C1 2 ): δ (ppm) 9.37 (s, 2H, NH j 9.35 [s, IH, K-1) 9.02 (d, IH, H-3) 7.87 (d, IH, H -4) IR (KBr): μ (cm "1 ) 3409 (NH 2 ); 1632, 1614 (C≈O)
4 , 9-Dιhydro-4 ,9-dιoxo-2- (2-fluorophenyl) -thiazolo- [4 ,5-f]isoguinolme (Exemple 13) A 0,150 g (0,72 mmole) de 6-ammo-7-chloro-5, 8- dιhydro-5, 8-dιoxo-ιsoqumoline, on ajoute a température ambiante 1,040 g (4,3 mmoles) de sulfure de sodium nona¬ hydrate en solution dans 2,7 ml d'eau. Apres 2 heures d'agitation a 50°C, on ajoute au milieu réactionnel deve- nu bleu 6 μl (0,72 mmoles) de 2-fluorobenzaldehyde et 164 μl d'acide acétique glacial. Après 20 minutes, le préci¬ pité est filtré, lave 3 fois avec 10 ml d'eau, séché puis purifié sur colonne flash (support : silice ; éluant : dichloromethane/acétate d'éthyle, 80/20) pour fournir 0,075 g de 4, 9-dihydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-f] isoqumolme sous forme de cristaux jau¬ nes.4, 9-Dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) -thiazolo- [4, 5-f] isoguinolme (Example 13) At 0.150 g (0.72 mmol) of 6-ammo-7- chloro-5, 8- dehydro-5, 8-dexoxo-ιsoqumoline, 1.040 g (4.3 mmol) of sodium sulfide nona¬ hydrate dissolved in 2.7 ml of water is added at room temperature. After 2 hours of stirring at 50 ° C., 6 μl (0.72 mmol) of 2-fluorobenzaldehyde and 164 are added to the reaction medium, which has turned blue. μl of glacial acetic acid. After 20 minutes, the precipitate is filtered, washed 3 times with 10 ml of water, dried and then purified on a flash column (support: silica; eluent: dichloromethane / ethyl acetate, 80/20) to provide 0.075 g of 4, 9-dihydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-f] isoqumolme in the form of yellow crystals.
Rdt : 34 %Yid: 34%
F : > 260°C Rf : 0.61 (CH2C12/Acétate d'éthyle, 80/20)F:> 260 ° C Rf: 0.61 (CH 2 C1 2 / Ethyl acetate, 80/20)
SM (I.E.) : m/z 310 (M+ . )SM (I.E.): m / z 310 (M +.)
RMN du 1H (CD2C12) : δ (ppm) 1 H NMR (CD 2 C1 2 ): δ (ppm)
9.44 (s, IH, H-8)
Figure imgf000024_0001
8.51 (m, IH, H-6')9.44 (s, IH, H-8)
Figure imgf000024_0001
8.51 (m, IH, H-6 ')
8.08 (d, IH, H-5, JH5-H6=5.19Hz)8.08 (d, IH, H-5, J H5 - H6 = 5.19Hz)
7.60 (m, IH, H-4')7.60 (m, IH, H-4 ')
7.37 (m, 2H, H-3', H-5')7.37 (m, 2H, H-3 ', H-5')
RMN du 13C (CD2C12) : δ (ppm) 178.47, 177.39 (2C, C≈O) 13 C NMR (CD 2 C1 2 ): δ (ppm) 178.47, 177.39 (2C, C≈O)
163.12 (IC, Cquat)163.12 (IC, Cquat)
159.30 (IC, Cquat)159.30 (IC, Cquat)
156.67 (IC, C-6)156.67 (IC, C-6)
153.74 (IC, Cquat) 149.00 (IC, C-8)153.74 (IC, Cquat) 149.00 (IC, C-8)
138.50 (IC, Cquat)138.50 (IC, Cquat)
134.53 (2C, C-6', Cquat)134.53 (2C, C-6 ', Cquat)
130.06 (IC, C-4')130.06 (IC, C-4 ')
126.22 (2C, C-5', Cquat) 119.87 (IC, C-5)126.22 (2C, C-5 ', Cquat) 119.87 (IC, C-5)
117.00 (IC, C-3')117.00 (IC, C-3 ')
116.69 (IC, C-l')116.69 (IC, C-l)
IR (KBr) : μ (cm"1)IR (KBr): μ (cm "1 )
1687, 1658 (C≈O) Exempl e 141687, 1658 (C≈O) Example 14
4 , 9-Dιhydro-4 , 9-dιoxo-2-phényl-thιazolo[4 ,5-g] - quinoxalme4, 9-Dιhydro-4, 9-dιoxo-2-phenyl-thιazolo [4, 5-g] - quinoxalme
Synthèse de l' intermédiaire : 6-amιno-7-bromo-5 ,8-dιhydro-5 ,8-dioxo-quinoxalmeSynthesis of the intermediate: 6-amιno-7-bromo-5, 8-de-hydro-5, 8-dioxo-quinoxalme
A une solution de 4,0 g (12,5 moles) de 6, 7-dιbromo- 5, 8-dmydro-5, 8-dιoxo-quιnoxalιne dans 160 ml d'acide acétique, on ajoute 1,3 g (20,0 moles) de nitrure de so¬ dium en solution dans 8,2 ml d'eau. Le milieu réactionnel est chauffe a reflux pendant 2 heures et passe du rouge fonce au noir. Apres complet refroidissement, on intro¬ duit 300 ml d'etner. Le précipite ainsi forme est filtre et sèche pour fournir 3,2 g de 6-ammo-7-bromo-5, 8- dιhvdro-5, 8-dιoxo-qumoxalιne sous forme de cristaux mar- ron-rouges . Rdt : 100%To a solution of 4.0 g (12.5 moles) of 6, 7-debromo- 5, 8-dmydro-5, 8-dιoxo-quιnoxalene in 160 ml of acetic acid, 1.3 g (20 0.0 moles) of sodium nitride dissolved in 8.2 ml of water. The reaction medium is heated at reflux for 2 hours and changes from dark red to black. After complete cooling, 300 ml of etner are introduced. The precipitate thus formed is filtered and dried to provide 3.2 g of 6-ammo-7-bromo-5, 8-dιhvdro-5, 8-dexoxo-qumoxalene in the form of brown-red crystals. Yid: 100%
SM (I.E.) : m/z 254 (M+ . ) RMN du 1H (DMSO d6) : δ (ppm) 8.97, 8.95 (m, 2H, H-2, H-3) 4 ,9-Dιhydro-4 , 9-dιoxo-2-phényl-thιazolo[4 ,5-g] - quinoxalme (Exemple 14)MS (IE): m / z 254 (M +.) 1 H NMR (DMSO d 6 ): δ (ppm) 8.97, 8.95 (m, 2H, H-2, H-3) 4, 9-Dιhydro-4 , 9-dιoxo-2-phenyl-thιazolo [4, 5-g] - quinoxalme (Example 14)
A 1,14 g \4,48 mmoles) de 6-amιno-7-bromo-5, 8- αιh/dro-5, 8-αιoxo-quιnoxalιne on ajoute a température am¬ biante 7,54 g (31,41 mmoles) de sulfure de sodium nonahy- drate en solution dans 12 ml d'eau. Apres une heure de reflux on ajoute successivement 0,454 ml (4,48 mmoles) de benzaldéhyde et 1,250 ml d'acide acétique. Le mélange réactionnel devenu noir est maintenu a reflux pendant une heure. Apres complet refroidissement, on extrait avec 300 ml de chloroforme. La phase organique est lavée avec 100 ml d'eau, sechee sur du chlorure de calcium et évaporée a sec . La poudre orange obtenue est purifiée sur cakeAt 1.14 g \ 4.48 mmol) of 6-amιno-7-bromo-5, 8- αιh / dro-5, 8-αιoxo-quιnoxalene is added at room temperature 7.54 g (31.41 mmoles) of sodium sulfide nonahydrate in solution in 12 ml of water. After one hour of reflux, 0.454 ml (4.48 mmol) of benzaldehyde and 1.250 ml of acetic acid are successively added. The reaction mixture which has turned black is kept at reflux for one hour. After complete cooling, extraction is carried out with 300 ml of chloroform. The organic phase is washed with 100 ml of water, dried over calcium chloride and evaporated to dryness. The orange powder obtained is purified on a cake
(support : silice ; éluant : dichloromethane/methanol,(support: silica; eluent: dichloromethane / methanol,
100/0 a 99/1) pour fournir après décoloration et recπs-
Figure imgf000025_0001
dans du dichloromethane 0,50 g de 4,9- dihydro-4, 9-dιoxo-2-phenyl-thiazolo [4, 5-g] quinoxalme sous forme de cristaux jaunes. Rdt : 38 c- F : > 260°C Rf : 0.55 (CH2Cl2/Méthanol, 97/3) SM (I.E.) : m/z 293 (M+ . ) RMN du XH (CDC13) : δ (ppm)100/0 to 99/1) to provide after discoloration and recπs-
Figure imgf000025_0001
in dichloromethane 0.50 g of 4.9- dihydro-4, 9-dιoxo-2-phenyl-thiazolo [4, 5-g] quinoxalme in the form of yellow crystals. Yield: 38 c - F:> 260 ° C Rf: 0.55 (CH 2 Cl 2 / Methanol, 97/3) SM (IE): m / z 293 (M +.) X H NMR (CDC1 3 ): δ ( ppm)
9.09, 9.12 (2d, 2H, H-6, H-7, JH6-H7=2.14Hz) 8.19 (d, 2H, H-2', H-6') 7.58 (m, 3H, H-3', H-4 ' , H-5')9.09, 9.12 (2d, 2H, H-6, H-7, J H6 - H 7 = 2.14Hz) 8.19 (d, 2H, H-2 ', H-6') 7.58 (m, 3H, H-3 ', H-4', H-5 ')
RMN du 13C (CDCI3) : δ (ppm) 178.55, 179.30 (2C, C≈O) 148.82, 148.40 (2C, C-6, C-7) 145.07 (IC, Cquat) 133.06 (IC, C~4') 13 C NMR (CDCI3): δ (ppm) 178.55, 179.30 (2C, C≈O) 148.82, 148.40 (2C, C-6, C-7) 145.07 (IC, Cquat) 133.06 (IC, C ~ 4 ' )
131.59 (IC, Cquat) 129.46 (2C, C-2', C-6') 128.02 (2C, C-3', C-5') IR (KBr) : μ (cm"1) 1698, 1678 (C≈O)131.59 (IC, Cquat) 129.46 (2C, C-2 ', C-6') 128.02 (2C, C-3 ', C-5') IR (KBr): μ (cm "1 ) 1698, 1678 (C ≈O)
Exemple 15Example 15
4 , 9-Dιhydro-4 , 9-dιoxo-2- (2-f luorophenyl) -thiazolo- [4 , 5-g] quinoxalme4, 9-Dιhydro-4, 9-dιoxo-2- (2-f luorophenyl) -thiazolo- [4, 5-g] quinoxalme
A 1,50 g (5,9 mmoles) de 6-amιno-7-bromo-5, 8- dιhydro-5, 8-dιoxo-qumoxalme, on ajoute à température ambiante 7,54 g (35,0 mmoles) de sulfure de sodium nona¬ hydrate en solution dans 16,5 ml d'eau. Après une heure de reflux, on ajoute successivement 0,632 ml (5,9 mmoles) de 2-fluorobenzaldéhyde et 1,650 ml d'acide acétique. Le mélange réactionnel devenu noir est maintenu à reflux pendant une heure puis après complet refroidissement, on extrait avec 300 ml de dichloromethane. La phase organi¬ que est lavée avec 100 ml d'eau, séchée sur du sulfate de magnésium et évaporée a sec. La poudre orange obtenue est purifiée sur cake (support : silice ; éluant : dichloro- methane/methanol, 100/0 a 99/1) pour fournir après déco¬ loration et recristallisation dans du dichloromethane 0,70 g de 4, 9-dιhydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [4, 5-g] quinoxalme sous forme de cristaux jaunes. Rdt : 38 °o F : ^ 255°CTo 1.50 g (5.9 mmol) of 6-amιno-7-bromo-5, 8- dehydro-5, 8-dιoxo-qumoxalme, 7.54 g (35.0 mmol) of sodium sulfide nona¬ hydrate in solution in 16.5 ml of water. After one hour of reflux, 0.632 ml (5.9 mmol) of 2-fluorobenzaldehyde and 1.650 ml of acetic acid are successively added. The reaction mixture, which has become black, is kept at reflux for one hour and then, after complete cooling, is extracted with 300 ml of dichloromethane. The organic phase is washed with 100 ml of water, dried over magnesium sulfate and evaporated to dryness. The orange powder obtained is purified on a cake (support: silica; eluent: dichloro- methane / methanol, 100/0 to 99/1) to provide, after deco¬ loration and recrystallization from dichloromethane, 0.70 g of 4, 9-dehydro-4, 9-dιoxo-2- (2-fluorophenyl) - thiazolo [ 4, 5-g] quinoxalme in the form of yellow crystals. Rd: 38 ° o F: ^ 255 ° C
Rf : 0.60 (CH2Cl2/Methanol, 97/3) SM (I.E. ) : m/z 311 (M+. ) RMN du ^-H (CD2C12) : δ (ppm) 9.06 et 9.0-a (2d, 2H, H-6, H-7, JH6-ri7≈2.14Hz) 8.52 (m, IH, H-6') ~\99 (m, IH, H-5') '" . S S (m, IH, H-4'i 7.30 (m, IH, H-3') RMN du 13C (CD2C12) : δ (ppm) 149.17, 148.82 (2C, C-6, C-7) 134.71 (IC, Cquat)Rf: 0.60 (CH 2 Cl 2 / Methanol, 97/3) SM (IE): m / z 311 (M +.) NMR of ^ -H (CD 2 C1 2 ): δ (ppm) 9.06 and 9.0-a ( 2 d, 2H, H-6, H-7, J H6 - ri 7≈2.14Hz) 8.52 (m, IH, H-6 ') ~ \ 99 (m, IH, H-5') ' ". SS (m, IH, H-4'i 7.30 (m, IH, H-3 ') 13 C NMR (CD 2 C1 2 ): δ (ppm) 149.17, 148.82 (2C, C-6, C-7) 134.71 (IC, Cquat)
134.58 (IC, Cquat) 130.10 (IC, C-6') 125 . 65 ( I C , C- 4 ' )134.58 (IC, Cquat) 130.10 (IC, C-6 ') 125. 65 (I C, C- 4 ')
125 . 59 ( IC , C- 5 ' )125. 59 (IC, C- 5 ')
116.94, 116.53 (2C, C-l', C-3') IR (KBr) : μ (cm"1) 1698, 1679 (C≈O) Exemple 16116.94, 116.53 (2C, C-l ', C-3') IR (KBr): μ (cm "1 ) 1698, 1679 (C≈O) Example 16
4 , 9-dιhydro-4 , 9-dιoxo-2- (2-furyl) -7-méthyl-thιazolo- [4 ,5-g]qumolιne4, 9-dehydro-4, 9-dιoxo-2- (2-furyl) -7-methyl-thιazolo- [4, 5-g] qumolιne
A 1,50 g (6,75 mmoles) de 6-ammo-7-chloro-5, 8- dιhydro-5, 8-dιoxo-2-methyl-quιnolme sous forme solide, on ajoute 9,73 g (40,50 mmoles) de sulfure de sodium no¬ nahydrate en solution dans 25,2 ml d'eau. On laisse sous agitation pendant 6 heures a température ambiante jusqu'à apparition d'une coloration bleue. On additionne 584 ml (6,75 mmoles) de 2-furaldehyde puis 1,93 ml (33,7 mmoles) d'acide acétique glacial. Le produit organique est ex- trait par 5 fois 500 ml d'acétate d'éthyle. Les phases organiques sont réunies, lavées à l'eau, sechées sur du sulfate de magnésium, filtrées et évaporées sous pression réduite. On obtient 0,70 g de produit solide marron clair qui est purifié sur colonne flash (support : silice ; éluant : dichloromethane/ isopropanol, 100/0 a 99,75/To 9.50 g (6.75 mmol) of 6-ammo-7-chloro-5, 8- dehydro-5, 8-deιoxo-2-methyl-quιnolme in solid form, 9.73 g is added (40, 50 mmol) of sodium sulfide no¬ nahydrate in solution in 25.2 ml of water. The mixture is left stirring for 6 hours at room temperature until a blue color appears. 584 ml (6.75 mmol) of 2-furaldehyde are added, followed by 1.93 ml (33.7 mmol) of glacial acetic acid. The organic product is ex- milked with 5 times 500 ml of ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. 0.70 g of light brown solid product is obtained which is purified on a flash column (support: silica; eluent: dichloromethane / isopropanol, 100/0 to 99.75 /
0,25) pour fournir, après décoloration, 0,31 g de 4,9- dιhydro-4, 9-dioxo-2- (2-furyl) -7-méthyl-thiazolo [4, 5-g] - quinoline sous forme de cristaux jaune-orangé. Rdt : 16.3 °5 0.25) to provide, after discoloration, 0.31 g of 4,9-dιhydro-4,9-dioxo-2- (2-furyl) -7-methyl-thiazolo [4,5-g] - quinoline under form of orange-yellow crystals. Rd: 16.3 ° 5
F : > 260°CF:> 260 ° C
Rf : 0.50 (CH^Cl2/Méthanol, 99/1)Rf: 0.50 (CH ^ Cl 2 / Methanol, 99/1)
SM (I.E.) : m/z 296 (M+.)SM (I.E.): m / z 296 (M +.)
RMN du 1H (CD2C12) : δ (ppm) 8.46 (d, IH, H-5, Jhb.H6=l .94Hz) 1 H NMR (CD 2 C1 2 ): δ (ppm) 8.46 (d, IH, H-5, J hb . H6 = 1.94Hz)
7.71 (d, IH, H-5' )7.71 (d, IH, H-5 ')
7.60 (d, IH, H-6, J45_H6=8.24Hz)7.60 (d, IH, H-6, J 45 _ H6 = 8.24Hz)
7.43 (d, IH, H-3')7.43 (d, IH, H-3 ')
6.69 (m, IH, H-4') 2.77 (s, 3H, CH3)6.69 (m, 1H, H-4 ') 2.77 (s, 3H, CH 3 )
RMN du 13C (CD2C12) : δ (ppm) 13 C NMR (CD 2 C1 2 ): δ (ppm)
181.0 (IC, C≈O)181.0 (IC, C≈O)
146." (IC, C-5')146. " (IC, C-5 ')
135.9 (IC, C-5) 128.1 (IC, C-6)135.9 (IC, C-5) 128.1 (IC, C-6)
114.2 (IC, C-3')114.2 (IC, C-3 ')
113.7 (IC, C-4')113.7 (IC, C-4 ')
25.3 (CH3)25.3 (CH 3 )
IR (KBr) : μ (cm"1) 1723, 1685 (C≈O)IR (KBr): μ (cm "1 ) 1723, 1685 (C≈O)
Exemple aExample a
4 ,9-Dihydro-4 , 9-dιoxo-2-phényl-lH-ιmιdazo[4 ,5-g] - quinoline4, 9-Dihydro-4, 9-dιoxo-2-phenyl-1H-ιmιdazo [4, 5-g] - quinoline
Référence : CA. 59 P13957a Rdt : 71 z F : > 260°CReference: CA. 59 P13957a Yd: 71 z F:> 260 ° C
Rf : 0.50 (CH2Ci2/Méthanol, 90/10)Rf: 0.50 (CH 2 Ci 2 / Methanol, 90/10)
SM (I.E.) : m/z 275 (M+ . )SM (I.E.): m / z 275 (M +.)
RMN du 1H (DMSO dg) : δ (ppm) 14.48 (ls, IH, NH) 1 H NMR (DMSO dg): δ (ppm) 14.48 (ls, IH, NH)
9.99 (m, IH, H-7)9.99 (m, IH, H-7)
8.45 (d, IH, H-5, JH5-H6=7.33Hz)8.45 (d, IH, H-5, J H5 - H6 = 7.33Hz)
8.24 (m, 2H, H-2', H-6')8.24 (m, 2H, H-2 ', H-6')
7.83 (m, IH, H-6) 7.61 (m, 3H, H-3', H-4 ' , H-5')7.83 (m, IH, H-6) 7.61 (m, 3H, H-3 ', H-4', H-5 ')
RMN du 13C (DMSO d6) : δ (ppm) 13 C NMR (DMSO d 6 ): δ (ppm)
153.26 (IC, C-7)153.26 (IC, C-7)
148.50 (IC, Cquat)148.50 (IC, Cquat)
134.25 (IC, C-5) 130.08 (IC, Cquat)134.25 (IC, C-5) 130.08 (IC, Cquat)
129.25 (2C, C-3', C-5')129.25 (2C, C-3 ', C-5')
127.45 (IC, C-6)127.45 (IC, C-6)
125.43 (IC, C-4')125.43 (IC, C-4 ')
116.24, 115.92 (2C, C-2', C-6') IR (KBr) : μ (cm"1)116.24, 115.92 (2C, C-2 ', C-6') IR (KBr): μ (cm "1 )
3232 (NH) ; 1669, 1650 (C≈O)3232 (NH); 1669, 1650 (C≈O)
Exemple bExample b
4 ,9-Dιhydro-4 , 9-dιoxo-2-phenyl-oxazolo [4 ,5-g] quinoline Référence : CA. 115 256051q4, 9-Dιhydro-4, 9-dιoxo-2-phenyl-oxazolo [4, 5-g] quinoline Reference: CA. 115 256051q
Rdt : 61 °όRd: 61 ° ό
F : > 260°CF:> 260 ° C
Rf : 0.45 <CH2Cl2/Méthanol, 95/5)Rf: 0.45 <CH 2 Cl 2 / Methanol, 95/5)
SM (I.E.) : m/z 276 (MH+ . ) RMN du 1H (CDC13) : δ (ppm)
Figure imgf000029_0001
MS (IE): m / z 276 (MH +.) 1 H NMR (CDC1 3 ): δ (ppm)
Figure imgf000029_0001
8.44 (d, IH, H-5, Jh5-.rie=8.18Hz)
Figure imgf000029_0002
8.44 (d, IH, H-5, J h5 -. E ri = 8.18Hz)
Figure imgf000029_0002
7.56 (m, IH, H-6) 7.35 (m, 3H, H-3*, H-4', H-5') RMN du 13C (CDC13) : δ (ppm)7.56 (m, IH, H-6) 7.35 (m, 3H, H-3 *, H-4 ', H-5') 13 C NMR (CDC1 3 ): δ (ppm)
176.40, 170.68 (2C, C-4, C-9)176.40, 170.68 (2C, C-4, C-9)
154.15 (IC, C-7)154.15 (IC, C-7)
147.65 (IC, Cquat) 134.93 (IC, C-5)147.65 (IC, Cquat) 134.93 (IC, C-5)
132.90 (IC, C-6)132.90 (IC, C-6)
129.07 (IC, Cquat)129.07 (IC, Cquat)
128.81 (2C, C-3', C-5')128.81 (2C, C-3 ', C-5')
127.95 (2C, C-2', C-6') 127.28 (IC, C-4')127.95 (2C, C-2 ', C-6') 127.28 (IC, C-4 ')
124.38 (IC, Cquat)124.38 (IC, Cquat)
IR (KBr) : μ (cm-1)IR (KBr): μ (cm -1 )
1665, 1623 (C≈O)1665, 1623 (C≈O)
Exemple c 4 ,9-Dihydro-4 ,9-dioxo-2-phenyl-thiazolo[4 ,5-g] - quinolineExample c 4, 9-Dihydro-4, 9-dioxo-2-phenyl-thiazolo [4, 5-g] - quinoline
Référence : CA. 5_4 500gReference: CA. 5_4 500g
Rdt : 36 %Yid: 36%
F : > 260°C Rf : 0.55 (CH2Cl2/Méthanol, 98/2)F:> 260 ° C Rf: 0.55 (CH 2 Cl 2 / Methanol, 98/2)
SM (I.E.) : m/z 292 (M+.)SM (I.E.): m / z 292 (M +.)
RMN du 1H (CDCI3) : δ (ppm) 1 H NMR (CDCI3): δ (ppm)
9.09 (d, IH, H-7, JH6-H7=4.88Hz)9.09 (d, IH, H-7, J H6 - H 7 = 4.88Hz)
8.65 (d, IH, H-5, JH5-H6=8.43Hz) 8.17 (d, 2H, H-2', H-6')8.65 (d, IH, H-5, J H5 - H 6 = 8.43Hz) 8.17 (d, 2H, H-2 ', H-6')
7.75 (m, IH, H-6)7.75 (m, IH, H-6)
7.61 (m, 3H, H-3', H-4 ' , H-5')7.61 (m, 3H, H-3 ', H-4', H-5 ')
RMN du 13C (CDCI3) : δ (ppm) 13 C NMR (CDCI3): δ (ppm)
176.55 (2C, C≈O) 154.48 (IC, C-7)176.55 (2C, C≈O) 154.48 (IC, C-7)
148.80 (IC, Cquat)148.80 (IC, Cquat)
135.81 (IC, C-5) 132.71 (IC, C-6)135.81 (IC, C-5) 132.71 (IC, C-6)
131.79, 129.81 (2C, C quat) 129.36 (2C, C-3', C-5') 127 . 87 ( 3C , C- 2 ' , C- 4 ' , C- 6 ' )131.79, 129.81 (2C, C quat) 129.36 (2C, C-3 ', C-5') 127. 87 (3C, C- 2 ', C- 4', C- 6 ')
IR (KBr) : μ ( cm"1 )IR (KBr): μ (cm "1 )
3051 (NH) ; 1665 (C≈O) Exemple d 4 ,9-Dιhydro-4 , 9-dιoxo-2- (2-pyπdyl) -thiazolo[4 ,5-g] quinoline3051 (NH); 1665 (C≈O) Example d 4, 9-Dιhydro-4, 9-dιoxo-2- (2-pyπdyl) -thiazolo [4, 5-g] quinoline
Référence : CA. 5_5 19008bReference: CA. 5_5 19008b
Rdt : 27 liYd: 27 l i
F : > 260°C Rf : 0.52 (CH2Cl2/Méthanol, 97/3)F:> 260 ° C Rf: 0.52 (CH 2 Cl 2 / Methanol, 97/3)
SM (I.E.) : m/z 293 (M+.)SM (I.E.): m / z 293 (M +.)
RMN du TH (CDC13) : δ (ppm)
Figure imgf000031_0001
 T H NMR (CDC1 3 ): δ (ppm)
Figure imgf000031_0001
8.63 (m, 2H, H-5, H-6') 8.40 (d, IH, H-3\ J43.-H4—7.93Hz)8.63 (m, 2H, H-5, H-6 ') 8.40 (d, IH, H-3 \ J 43 .- H4 —7.93Hz)
7.81 (m, IH, H-4')7.81 (m, IH, H-4 ')
7.70 (m, IH, H-6)7.70 (m, IH, H-6)
7.42 (m, IH, H-5')7.42 (m, IH, H-5 ')
RMN du 13C (CDCI3) : δ (ppm) 154.06 (IC, C-7) 13 C NMR (CDCI3): δ (ppm) 154.06 (IC, C-7)
149.47 (IC, C-6')149.47 (IC, C-6 ')
148.39 (IC, C-2') 143.80, 142.33 (2C, Cquat) 136.32 (IC, C-4') 135.30 (IC, C-5)148.39 (IC, C-2 ') 143.80, 142.33 (2C, Cquat) 136.32 (IC, C-4') 135.30 (IC, C-5)
134.10, 132.30 (2C, Cquat)134.10, 132.30 (2C, Cquat)
126.29 (IC, C-6)126.29 (IC, C-6)
127.40 (IC, C-3') 120.25 (IC, C-5') IR (KBr) : μ (cm"1)127.40 (IC, C-3 ') 120.25 (IC, C-5') IR (KBr): μ (cm "1 )
3059 (CH) ; 1665 (C≈O)3059 (CH); 1665 (C≈O)
Exemple eExample e
4 , 9-Dιhydro-4 , 9-dιoxo-2- (3-pyndyl) -thiazolo[4 ,5-g]• quinoline Référence : CA. 58 P5695e Rdt : 39 %4, 9-Dιhydro-4, 9-dιoxo-2- (3-pyndyl) -thiazolo [4, 5-g] • quinoline Reference: CA. 58 P5695e Yid: 39%
F : > 2 60 °CF:> 2 60 ° C
Rf : 0.43 (CH2Cl2/Methanol, 95/5)Rf: 0.43 (CH 2 Cl 2 / Methanol, 95/5)
SM (I.E.) : m/z 293 (M+. ) RMN du 3-H (CDC13) : δ (ppm)MS (IE): m / z 293 (M +.) 3-H NMR (CDC1 3 ): δ (ppm)
9.36 (s, IH, H-2';9.36 (s, 1H, H-2 ';
9.12 (d, IH, H-7, 0^-^=3.06Hz)9.12 (d, IH, H-7, 0 ^ - ^ = 3.06Hz)
8.82 (d, IH, H-6', JH5--H0'=3.96Hz)8.82 (d, IH, H-6 ', J H5 - H0' = 3.96Hz)
8.72 (m, IH, H-5) 8.48 (d, IH, H-4', JH4--HS-=7.93Hz)8.72 (m, IH, H-5) 8.48 (d, IH, H-4 ', J H4 - HS - = 7.93Hz)
7.79 (m, IH, H-6)7.79 (m, IH, H-6)
7.51 (m, IH, H-5')7.51 (m, IH, H-5 ')
RMN du 13C (CDC13) : δ (ppm) 13 C NMR (CDC1 3 ): δ (ppm)
177.55, 178.43 (2C, C≈O) 172.50 (IC, Cquat)177.55, 178.43 (2C, C≈O) 172.50 (IC, Cquat)
154.68 (IC, C-7)154.68 (IC, C-7)
153.15, 148.70 (2C, C-2', C-6')153.15, 148.70 (2C, C-2 ', C-6')
135.91 (IC, C-5)135.91 (IC, C-5)
134.93 (IC, C-4') 129.81 (IC, Cquat)134.93 (IC, C-4 ') 129.81 (IC, Cquat)
128.07 (IC, C- 6 )128.07 (IC, C- 6)
124.08 (IC, C-5') IR (KBr) : μ (cm"1) 1671 (C≈O) Propriétés pharmacologiques124.08 (IC, C-5 ') IR (KBr): μ (cm "1 ) 1671 (C≈O) Pharmacological properties
L'étude des composes de la présente invention et de leurs sels éventuels a démontre qu'ils possèdent diverses propriétés pharmacologiques. Ainsi, ils sont sélective¬ ment vemotoniques, n'affectant le système artériel qu'a des concentrations largement supérieures a celles actives sur les veines, excepte certaines artères, en particulier cérébrales. Les composes ne montrent aucune affinité soit une très faible affinité pour les récepteurs pharmacolo¬ giques membranaires connus. Par ailleurs, ils augmentent la résistance capillaire, diminuent l' hyperpermeabilite vasculaire induite par certains agents inflammatoires.The study of the compounds of the present invention and their possible salts has demonstrated that they have various pharmacological properties. Thus, they are selectively vemotonic, 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, ie a very weak affinity for the known membrane pharmacological receptors. Furthermore, they increase capillary resistance, decrease hyperpermeability vascular 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 vitro (vaisseaux ou reseaux vascu- laires isoles) et m vivo.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.
Pour les études m vitro, les composés sont solubi¬ lises en solution aqueuse pure ou contenant du DMSO (dimethylsulfoxyde) .For in vitro studies, the compounds are solubi¬ lized in pure aqueous solution or containing DMSO (dimethylsulfoxide).
Pour les études m vivo, ils sont administres par voie intraveineuse ou mtrapeπtoneale sous forme de so¬ lution aqueuse contenant ou non du DMSO, ou par voie orale en suspension dans la carboxymethylcellulose a 1°, administres a l'aide d'une sonde de gavage sous un volume de 10 ml/kg. Modèles d' études pharmacologiques Effets contractilesFor m vivo studies, they are administered intravenously or mtrapeπtoneale in the form of an aqueous solution containing or not DMSO, or orally suspended in carboxymethylcellulose at 1 °, administered using a probe of force-feeding in a volume of 10 ml / kg. Pharmacological study models Contractile effects
Les effets contractiles sont mesures m vi tro dans des conditions statiques sur des anneaux vasculaires a capacitance ou a résistance de veines saphènes, fémora- les, jugulaires, mesenteriques, caves... et sur artères fémorales, carotides, basilaires, mesenteriques, aorte thoracique ou abdominale... de rat (Wistar, 200 a 250 g), lapin (New Zealand, 2 a 2,5 kg) , cobaye (Dunkin Hartley 250 a 300 g) . Les anneaux sont places en chambre d'organe isoleContractile effects are measured m v tro under static conditions on vascular rings with capacitance or resistance of saphenous, femoral, jugular, mesenteric veins, and on femoral arteries, carotids, basilar, mesenteric, thoracic aorta or abdominal ... 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 pour les vaisseaux a capacitance et 2,5 ml pour les vaisseaux a résistance selon Mulvany) , maintenus dans des conditions isométriques par deux fils rigides insères a l' intérieur du vaisseau, en évitant d'endommager l' endothelium. Les vaisseaux sont baignes 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 = II), aeree en permanence par un mélange gazeux a 95 ", 02 et 5 -> C02, a pH = 7,4 et thermostates a 37°C. Les anneaux sont amenés a leur point optimal de la rela- tion tension-longueur.(25 ml for capacitance vessels and 2.5 ml for resistance vessels according to Mulvany), maintained under isometric conditions by two rigid wires inserted inside the vessel, avoiding damage to the endothelium. The vessels are bathed with 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; NaHC03 = 25; glucose = II), permanently aerated by a gas mixture at 95 ", 0 2 and 5 -> C0 2 , at pH = 7.4 and thermostats at 37 ° C. The rings are brought to their optimal point of the rela- tension-length.
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- sualise sur enregistreur Kipp & Zonen, soit digitalisé pour être traité par ordinateur (IOS, EMKA) . Les études pharmacologiques sont réalisées après quelques stimula¬ tions contractiles préliminaires standardisées par une solution dépolarisante (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' endothelium est vérifiée par la relaxation induite par des concentrations croissantes d' acetylcholme après stabilisation d'une précontraction vasculaire.The developed voltages generate an electrical signal only via a force sensor (Wheastone bridge). This signal is amplified before being either displayed on a Kipp & Zonen recorder, or digitized for processing by computer (IOS, EMKA). Pharmacological studies are carried out after a few preliminary contractile stimulations standardized by a depolarizing 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.
Les forces de contraction développées par les an¬ neaux vasculaires en réponse aux différents composés sont étudiées sur des vaisseaux quiescents ou stimules élec¬ triquement (5-8 Hz), par une solution "physiologique" dé- polarisante hyperpotassique (Kcl : 20, 40 mM) , par la no- radrenalme (concentrations croissantes) , la sérotonine (concentrations croissantes) ...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 "polarizing" physiological solution (Kcl: 20, 40 mM), by the no-radrenalme (increasing concentrations), serotonin (increasing concentrations) ...
Les contractions sont exprimées en mg force ou en pourcentage de la contraction maximale a la dépolaπsa- tion par une solution "physiologique" hyperpotassique.The contractions are expressed in mg force or as a percentage of the maximum contraction upon depolation by a hyperpotassic "physiological" solution.
Les effets contractiles sont également mesurés in 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 développe par T. WARNER ( British J. Pharmacol. 1990, 99, 427-433) . La séparation des deux réseaux est réalisée en coupant les vaisseaux et les tissus le long de la bordure intestinale. Les réseaux sont perfusés à 2 JJContractile effects are also measured in vi tro under dynamic flow conditions, by the pressure developed by vascular networks perfused at constant flow. At the mesenteric level, vemoselectivity is studied on the model of double perfusion simultaneous and separate from arterial and venous networks, model developed by T. WARNER (British J. Pharmacol. 1990, 99, 427-433). The two networks are separated by cutting the vessels and tissues along the intestinal border. Networks are infused at 2 not a word
ml.mm~lpar une solution αe Krebs (37,5°C) aeree a 95 o 02 et 5 t, C02.ml.mm ~ lpar a Krebs solution (37.5 ° C) aerated at 95 o 0 2 and 5 t, C0 2 .
In vi vo, les pressions artérielles et veineuses sont mesurées chez l'animal anesthesie, dans des conditions basales et après arrêt circulatoire provoque par le gon¬ flement d'un cathéter a ballonnet introduit au niveau de l'oreillette droite. Lors de l'arrêt cardiaque, le tonus veineux (pression moyenne circulatoire de remplissage a volume sanguin constant) est calcule a partir des pres- sions veineuses et artérielles mesurées a l'équilibre et corrigées en fonction des différences relatives de com- pliance entre ces deux reseaux (SAMAR & COLEMAN, Am. J. Physiol. 1978, 234 :H94-100; YAMAMOTO et al., Am. J. Phy- siol. 1980, 238:H823-828) . Chez l'animal éveille, 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 place sur la queue du rat, en aval d'un manchon gonfle automatiquement par un générateur de pressionIn vi vo, arterial and venous pressures are measured in anesthesia animals, in basal conditions and after circulatory arrest caused by the swelling of a balloon catheter introduced at the level of 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. Physol. 1980, 238: H823-828). In awake animals, 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 inflates automatically by a pressure generator
Au niveau microcirculatoire, les variations de sec¬ tion vemulaire et arteriolaire sont étudiées m vivo dans le modèle de la chambre cutanée dorsale de hamster vigile, après enregistrement videomicroscopique (microscope Leitz Ergolux équipe d'une source halogène pour l'éclairage et une caméra video CDD noir et blanc HPR 610) et analyse informatique (logiciel Visicap, Pack ICAP) des images.At the microcirculatory level, the variations of vemular and arteriolar sec ¬ tion are studied in vivo in the model of the dorsal cutaneous chamber of a vigilant hamster, after videomicroscopic recording (Leitz Ergolux microscope equipped with a halogen source for lighting and a video camera Black and white CDR HPR 610) and computer analysis (Visicap software, ICAP pack) of the images.
Apres anesthesie au pentobarbital sodique (60 mg/kg en i.p.), le dos de l'animal est tondu et epile de ma¬ nière a 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'observation. Un cathéter jugulaire est place pour l'administration i.v. des produits, 48 heures après 1' opération.After anesthesia with sodium pentobarbital (60 mg / kg ip), the animal's back is shorn and epilated so as 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 administration of the products, 48 hours after the operation.
Effets sur l'hyperperméabilité capillaire induiteEffects on induced capillary hyperpermeability
La perméabilité vasculaire est étudiée m vi vo par la mesure de l' extravasation d' albumine dont la quantité est déterminée grâce a un colorant liant l'albumine (Bleu Evans) . L' hyperpermeabilite est induite par injection in¬ tradermique d'une solution d'histamme, de bradykmine ou de zymosan. La technique est dérivée de celle décrite par BEACHThe vascular permeability is studied m vi vo by measuring the extravasation of albumin whose quantity e is determined using an albumin binding dye (Evans Blue). Hyperpermeability is induced by in¬ tradermal injection of a histamme, bradykmine or zymosan solution. The technique is derived from that described by BEACH
& STEINETZ, J. Pharmacol. Exp. Therap., 1961, 131: 400- 406.& STEINETZ, J. Pharmacol. Exp. Therap., 1961, 131: 400-406.
Les rats (Wistars, 200 a 230 g) sont tondus sur leur paroi abdominale une heure avant le début de l'expeπmen- tation. Le produit a tester est injecte par voie î.p. ou per os 1 heure a 4 heures avant le sacrifice. Les rats sont anesthésies par un mélange d'halothane. Ensuite, ils reçoivent une injection intradermique sur l'abdomen de 0,10 ou 0,15 ml (soit pour l'histalme 6,7 ou 10 micro- grammes ) d'agent inflammatoire et une injection intra¬ veineuse d'un ml d'une solution de bleu Evans a 0,5 % dans la veine du pénis. Ces injections sont réalisées 30 minutes 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 per hour 1 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 (that is to say 6.7 or 10 micrograms) of inflammatory agent and an intravenous injection of one ml d 0.5% Evans blue solution in the vein of the penis. These injections are given 30 minutes before euthanasia.
30 minutes après ces deux injections, les rats sont euthanasies par dislocation cervicale.30 minutes after these two injections, the rats are euthanized by cervical dislocation.
A l'endroit αe l'injection de l'agent inflammatoire, la peau est découpée et placée dans des tubes en verre a col rôde contenant 3 ml α' acide chlorhydrique fumant. La digestion de la peau est réalisée par un contact d'au moins une heure au bain marie a 37°C. Trois ml αe chlo¬ rure de benzalkonium a 12, 8O sont ensuite ajoutes. Apres avoir laisse reposer durant trente minutes, 7 ml de di- cnloromethane sont aαditionnes. Les tubes sont agites pé¬ riodiquement penαaπt une neure. La phase aqueuse est eli- mmee par aspiration et la phase organique "dichloro- méthane" est filtrée. Les densités optiques sont quanti¬ fiées par spectrophotométrie d'absorption à une longueur d'onde de 620 nm, contre un blanc contenant uniquement le 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 traites par rapport à celles des animaux témoins est calculé. L'effet des composes sur l' hyperperméabilité induite par des agents inflammatoires, comme l'histamme et la braαykinme est également étudié après injection intra¬ veineuse par bolus αans le modèle de cnambre cutanée dor¬ sale de hamster et selon la méthode développée par GIMENO et al., décrite précédemment (A new technique using m- travital videomicroscopy for macromolecular permeability measurement, 18° Congres 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 a 1 ml/kg) . Le microscope est équipé d'une source fluorescente et d'une comomaison de filtres (excitation dans le bleu 450-490 nm et filtre d'arrêt 515 nm) .At the site of the injection of the inflammatory agent, the skin is cut and placed in glass tubes with a round neck containing 3 ml of fuming hydrochloric acid. The digestion of the skin is carried out by contact for at least one hour in a water bath at 37 ° C. Three ml of benzalkonium chloride at 12.880 are then added. After leaving to stand for thirty minutes, 7 ml of declorlorhane are added. The tubes are agitated periodically for one minute. The aqueous phase is removed by suction and the organic phase "dichloro- methane "is filtered. The optical densities are quantified by absorption spectrophotometry at a wavelength of 620 nm, 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 is calculated.The effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamma and braαykinme is also studied after injection. intravenous by bolus in the golden hamster skin model and according to the method developed by GIMENO et al., described previously (A new technique using m- travital videomicroscopy for macromolecular permeability measurement, 18 ° European Congress of microcirculation, Rome 1994) by videomicroscopy and image analysis by quantification of the distribution of the f mtra and extravascular fluorescence marker (FITC-Dextran) injected as a bolus by the jugular catheter (63 mg / kg for a volume defined at 1 ml / kg). The microscope is equipped with a fluorescent source and a combination of filters (excitation in blue 450-490 nm and stop filter 515 nm).
Effets sur la résistance capillaire :Effects on capillary resistance:
L'augmentation de la résistance capillaire est ap¬ préciée par la modification de l'index pétéchial (pres¬ sion négative induisant l' extravasation des érythrocy- tes), mesuré par une méthode dérivée de l' angiosterro- mètre de Parrot .The increase in the capillary resistance is ap¬ préciée by the modification of the petechial index (negative pres ¬ sion inducing the extravasation of erythrocyte your) measured by a method derived from the angiosterro- meter of 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 αéπve de l'acide thioglycolique et d'hydroxyde de calcium. Apres environ trente minutes, la peau est abondamment rinçee et sechee.The study is carried out on male Wistar rats weighing an average of 200 g (around six weeks old). The region of the lower back is shaved and then depilated using a paste based on an αéπve 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- quee. Si les petechies (extravasation d' erythrocytes) 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 petechies (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 petechies exprime, en mm de mercure, la valeur de ré¬ sistance capillaire de base (avant tout traitement) . Deux mesures sont réalisées pour chaque essai a des emplace¬ ments différents du dos.The minimum depression for which the petechies appear expresses, in mm of mercury, the value of basic capillary resistance (before any treatment). Two measurements are made for each test at different locations on the back.
Les rats sont traites par voie orale. Apres un temps détermine (généralement 2, 4, 6 heures) suivant le trai¬ tement, le test est renouvelle sur des plages de peau différentes, jusqu'à l'apparition des petechies, procu¬ rant un nouvel index de dépression. Toutes les mesures se font en aveugle. Un pourcentage de variation des résistances capil¬ laires des animaux traites par rapport a leur résistance capillaire de base est calcule pour chague compose étu¬ die, a chaque temps de traitement et compare avec le groupe témoin (excipient seul) ou le groupe de référence. Effets sur la pleurésie induite chez le rat :The rats are treated orally. After a determined time (generally 2, 4, 6 hours) depending on the treatment, the test is repeated on different areas of skin, until the appearance of petechiae, providing a new index of depression. All measurements are made blind. A percentage change in the capillary resistance of the treated animals with respect to their basic capillary resistance is calculated for each study compound, at each treatment time and compared with the control group (excipient only) or the reference group. Effects on induced pleurisy in rats:
L'activité antimflammatoire des composes 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 carraghenme 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. Rap., 1980, 214: 74).
Les rats sont traites per os par les composes 2 heu¬ res avant l' injection de carraghenme, ainsi que 2 et 4 heures après cette injection. Apres un temps détermine (6 heures) suivant l'mαuction de la pleurésie, les rats sont euthanasies et le liquide pleural récupéré par aspi¬ ration et son volume est mesure. 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 l'exudat rapporte a 100 g de poids αe l'animal et compares a 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 pharmacologiques :Examples of pharmacological effects:
Les composes de l'invention et leurs sels éventuels augmentent sélectivement dans la majorité des cas la con- traction des veines animales produite par la noradréna- lme, par la stimulation électrique ou par une solution hyperpotassique depolarisante.The compounds of the invention and their possible salts selectively increase in the majority of cases the contraction of the animal veins produced by the noradrenal, by electrical stimulation or by a depolarizing hyperpotassic solution.
A titre illustratif, figure l'effet contractile de différents composes sur la veine saphene de lapin precon- tractée par une solution "physiologique" dépolarisante de concentration potassique égale a 40 mM ; l'effet maximal produit par chaque composé est exprimé en pourcentage de la contraction maximale induite par αes solutions hyper- potassiques depolarisantes et en valeur d'ED5Q) :By way of illustration, the contractile effect of different compounds is shown on the saphenous vein of rabbits pre-contracted by a depolarizing "physiological" solution with a potassium concentration equal to 40 mM; the maximum effect produced by each compound is expressed as a percentage of the maximum contraction induced by the hyper-potassium depolarizing solutions and in ED5Q value):
Composés Emax (% Contr.max.) ED50 (nM)Compounds Emax (% Contr.max.) ED 5 0 (nM)
Exemple c 23 4- â 140Example c 23 4- to 140
Exemple e 28 + 6 160Example e 28 + 6 160
Exemple 1 11 + 3 600Example 1 11 + 3,600
Exemple 3 21 + 3 113 Exemple 5 39 + 8 100Example 3 21 + 3,113 Example 5 39 + 8,100
Exemple 8 17 + 5 126Example 8 17 + 5 126
Exemple 10 30 + 8 45Example 10 30 + 8 45
Exemple 12 36 + 8 22Example 12 36 + 8 22
Exemple 14 18 4- 3 150Example 14 18 4- 3 150
A titre illustratif, l'administration orale de cer¬ tains composes de l' invention et de leurs sels éventuels augmente la résistance capillaire du rat a des doses com¬ prises généralement entre 0,01 et 5 mg/kg : Composés Effet à 4 heures Effet à 6 heuresBy way of illustration, the oral administration of certain 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: Compounds Effect at 4 o'clock Effect at 6 o'clock
(en % du témoin) (en % du témoin)(in% of the witness) (in% of the witness)
Exemple c 5 mg/kg 23 19Example c 5 mg / kg 23 19
Exemple d 5 mg/kg 21 23Example d 5 mg / kg 21 23
Exemple 6 5 mg/kg 23 21Example 6 5 mg / kg 23 21
Exemple 7 5 mg/kg 31 24Example 7 5 mg / kg 31 24
Exemple a 0, 1 mg/kg 42 33Example a 0.1 mg / kg 42 33
Exemple b 0, 1 mg/kg 21 13Example b 0.1 mg / kg 21 13
Exemple e 0, 1 mg/kg 34 17Example e 0.1 mg / kg 34 17
Exemple 2 0, 1 mg/kg 23 42Example 2 0.1 mg / kg 23 42
Exemple 3 0, 1 mg/kg 24 26Example 3 0.1 mg / kg 24 26
Exemple 4 0, 1 mg/kg 17Example 4 0.1 mg / kg 17
Exemple 14 0, 1 mg/kg 19 23Example 14 0.1 mg / kg 19 23
A titre illustratif, l'administration orale de cer¬ tains composés de l'invention et de leurs sels éventuels réduit l'hyperpermeabilite inflammatoire induite par le zymosan chez le rat à des doses comprises entre 0,1 et 5 mg/kg :By way of illustration, the oral administration of certain compounds of the invention and their possible salts reduces the inflammatory hyperpermeabilitis induced by zymosan in rats at doses of between 0.1 and 5 mg / kg:
Composés Effet à 2 heures Effet à 4 heuresCompounds Effect at 2 hours Effect at 4 hours
(en % du témoin) (en % du témoin)(in% of the witness) (in% of the witness)
Exemple d 5 mg/kg -23 -7 Exemple a 0,1 mg/kg 9 -41 Exemple b 0,1 mg/kg -5 -23 Exemple 4 0,1 mg/kg 3 -37 Exemple 10 0,1 mg/kg -7 -14 Exemple 15 0,1 mg/kg -14 -17Example d 5 mg / kg -23 -7 Example a 0.1 mg / kg 9 -41 Example b 0.1 mg / kg -5 -23 Example 4 0.1 mg / kg 3 -37 Example 10 0.1 mg / kg -7 -14 Example 15 0.1 mg / kg -14 -17
Par ailleurs, les composes de l'invention et leurs sels éventuels sont très peu toxiques. Par exemple, après une administration orale unique de 500 mg/kg chez la sou¬ ris, aucun effet toxique ooservable et aucune mortalité n'est observée pour la majorité des composes en particu- lier pour l'Exemple c, l'Exemple d, l'Exemple 2, l'Exem¬ ple 3 (urines orangées) , l'Exemple 5.Furthermore, the compounds of the invention and their possible salts are very little toxic. For example, after a single oral administration of 500 mg / kg in the penny ¬ laugh, no ooservable toxicity and no mortality was observed for the majority of compounds espe- link for Example c, Example d, Example 2, Example 3 (orange urine), Example 5.
La plupart des composes se révèlent non cytotoxiques (la viabilité cellulaire étant mesurée par quantification de l'incorporation cellulaire de rouge neutre) jusqu'à des concentrations égales à leur solubilité en milieu aqueux sur des lignées cellulaires fibroblastiques de souris (L929) , en particulier l'Exemple c, l'Exemple 3, 1'Exemple 4 , l'Exemple 6. Parmi les composes préfères de l'invention, on re¬ tient tout particulièrement l'Exemple 3.Most of the compounds prove to be non-cytotoxic (cell viability being measured by quantification of the cellular incorporation of neutral red) up to concentrations equal to their solubility in aqueous medium on fibroblastic cell lines of mice (L929), in particular Example c, Example 3, Example 4, Example 6. Among the preferred compounds of the invention, there is very particularly Example 3.
Ce qui précède montre que les composes de l' inven¬ tion et leurs sels éventuels peuvent être utilises en thérapeutique humaine et animale. Ils sont en particulier indiques dans l'insuffisance veineuse fonctionnelle, or¬ ganique et les pathologies hemorroidaires par leurs com¬ posantes vasculaires et antunflammatoires, ainsi que dans les affections typiquement inflammatoires et dans les états de chocs constitues par une chute importante de la pression artérielle. Dans ce dernier cas, une amélio¬ ration du retour veineux est susceptible de maintenir le αebit cardiaque et des lors par voie de conséquence la pression artérielle.The above shows that the compounds of the invention and their possible salts can be used in human and animal therapy. They are particularly 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 drop in blood pressure. . In the latter case, an improvement in venous return is likely to maintain the cardiac output and consequently blood pressure.
L'insuffisance veineuse fonctionnelle se caractérise par une dilatation et une hyperdistensibilite des veines superficielles des membres inférieurs, oedèmes, paresthe- sies a 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 a des lésions ulcéreuses .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 towards organ venous insufficiency characterized by the development of varicose veins, valve incontinence, even towards phlebothromobosis and trophic disorders leading to ulcerative lesions.
Dans cette pathologie veineuse, une composante in¬ flammatoire s' installe dans les premiers stades et se ma- nifeste plus clairement dans les stades avances. Par leurs effets vemoconstπcteurs, anti-inflamma- 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 indiques dans la migraine.In this venous pathology, an inflammatory component settles in the early stages and manifests itself more clearly in the advanced stages. By their vemoconstπcteurs, anti-inflammatory 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 composes 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 composes et sels en association avec un support ou di¬ luant physiologiquement acceptable.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.
La forme de ces médicaments et compositions pharma¬ ceutiques dépendra bien évidemment de la voie d'adminis- tration souhaitée notamment orale, parenterale, topique (cutanée) et rectale, et ils peuvent être formulés selon les techniques classiques avec mise en oeuvre de supports et véhicules usuels.The form of these pharmaceutical drugs and compositions will obviously depend on the desired route of administration, in particular oral, parenteral, topical (cutaneous) and rectal, and they can be formulated according to conventional techniques with the use of carriers 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, emulsions, suspensions, poudre, granulés, capsule molle, lyophili¬ sât, microcapsule, microgranule.Thus, in the case of oral administration, they can be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophili¬ sate, microcapsule, microgranule.
Les comprimes, 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 (algmate par exemple) et ils sont fabriqués par des techniques connues par exemple de mélange, de granulation, de pastillage, d'enrobage, de compression etc...The 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 (algmate for example) and they are produced by known techniques for example of mixing, granulation, pastillage, coating, compression etc ...
Les sirops peuvent contenir, à titre de support, du 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 i'alginate de sodium ou de l'alcool polyvmylique. Pour l'administration par voie parenterale, les mé¬ dicaments et compositions peuvent prendre la forme de so¬ lutions, d' emulsions ou de suspensions comprenant la sub¬ stance active et un support ou solvant approprié tel que l'eau stérile ou des solutions salines isotoniques stéπ- les.The syrups can contain, as a support, glycerol, mannitol and / or sorbitol. The solutions and above- pens can include water and other physiologically compatible solvents and a carrier such as natural gum, agar, sodium alginate or polyvinyl alcohol. For parenteral administration, the drugs and compositions may take the form of solutions, emulsions or suspensions comprising the active substance and an appropriate support or solvent such as sterile water or solutions stéπ- isotonic salines.
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, mousse, poudre. Pour l'application rectale, les médicaments et com¬ positions peuvent prendre la forme de capsule, crème, émulsion, gel, mousse, pommade, suppositoire. For 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, foam, powder. For rectal application, the drugs and compositions can take the form of capsule, cream, emulsion, gel, foam, ointment, suppository.

Claims

REVENDICATIONS
1. Utilisation de dérives tricycliques azotés et de leurs sels acceptables du point de vue pnarmaceutique re¬ pondant a la formule générale :1. Use of nitrogenous tricyclic drifts and their salts acceptable from the pharmaceutical point of view corresponding to the general formula:
^^
////
oo
(D dans laquelle :(D in which:
A est soit un atome de soufre, d'oxygène, ou un ra- dical R3N ou R3 est un atome d'hydrogène, un radical al¬ kyle en C]_ a C5, un cycle aromatique substitué ou non, ou un cycle hétéroaromatique substitue ou non,A is either a sulfur atom, an oxygen atom, or a radical R3N or R3 is a hydrogen atom, a C 1-6 alkyl radical, a substituted or unsubstituted aromatic ring, or a heteroaromatic ring substitute or not,
Xi, X-, X3, X,,, sont indepenαamment l'un de l'autre un atome αe carbone ou un atome d'azote, R]_ est un radical alkyle en Cj_ a C5, un cycle aroma¬ tique substitué ou non, ou un cycle hétéroaromatique, ayant un ou plusieurs héteroatomes, substitue ou non,Xi, X-, X 3 , X ,,, are independently of one another a carbon atom or a nitrogen atom, R] _ is a Cj_ to C5 alkyl radical, a substituted aromatic ring or not, or a heteroaromatic cycle, having one or more heteroatoms, substituted or not,
R? est un atome d'hydrogène, un radical alkyle en C]_ a C5, pour l'obtention d'un médicament destine au traite- ment de maladies liées a une altération de la fonction veineuse et/ou a I' oedème inflammatoire.R? is a hydrogen atom, a C 1 -C 5 alkyl radical, for obtaining a medicament intended for the treatment of diseases linked to impaired venous function and / or to inflammatory edema.
2. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (4-fluorophenyl) -IH-imidazo [4, 5-g] quinoline.2. As a new product, 4,9-dehydro-4,9-dexo-2- (4-fluorophenyl) -H-imidazo [4,5-g] quinoline.
3. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (3-pyπdyl) -IH-imidazo [4, 5-g] quinoline.3. As a new product, 4,9-dehydro-4,9-dexoxo-2- (3-pyπdyl) -IH-imidazo [4, 5-g] quinoline.
4. A titre αe produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-fluorophenyl) -thiazolo [4, 5-g] quinoline. 5. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (3-fluorophenyl) -thiazolo [4, 4. As a new product, 4, 9-dehydro-4, 9-dexoxo-2- (2-fluorophenyl) -thiazolo [4, 5-g] quinoline. 5. As a new product, 4,9-dehydro-4,9-dexoxo-2- (3-fluorophenyl) -thiazolo [4,
5-g] qumolme.5-g] qumolme.
6. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (4-fluorophenyl) -thiazolo [4, 5-g] qumolme.6. As a new product, 4, 9-dehydro-4, 9-dexo-2- (4-fluorophenyl) -thiazolo [4, 5-g] qumolme.
7. A titre de produit nouveau la 2- (2, 4-dιfluoro¬ phenyl) -4, 9-dιhydro-4, 9-dιoxo-thiazolo [4, 5-g] qumolme.7. As a new product 2- (2, 4-dιfluoro¬ phenyl) -4, 9-dehydro-4, 9-dιoxo-thiazolo [4, 5-g] qumolme.
8. A titre de produit nouveau le sulfate de 4,9- dιhydro-4, 9-dιoxo-2- (2-pyrιdyl) -thiazolo [4, 5-g] qumolme.8. As a new product, 4,9-dehydro-4,9-dexoxo-2- (2-pyrιdyl) -thiazolo [4,5-g] qumolme sulfate.
9. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (3-furyl) -thiazolo [4, 5-g] qumolme.9. As a new product, 4, 9-dehydro-4, 9-dexo-2- (3-furyl) -thiazolo [4, 5-g] qumolme.
10. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dioxo-2-phenyl-thiazolo [5, 4-g] qumolme.10. As a new product 4, 9-dehydro-4, 9-dioxo-2-phenyl-thiazolo [5, 4-g] qumolme.
11. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-fluorophenyl) -thiazolo [5, 4-g] qumolme.11. As a new product, 4,9-dehydro-4,9-dexo-2- (2-fluorophenyl) -thiazolo [5,4-g] qumolme.
12. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dioxo-2-phenyl-thiazolo [5, 4-f] isoqumolme.12. As a new product the 4, 9-dιhydro- 4, 9-dioxo-2-phenyl-thiazolo [5, 4-f] isoqumolme.
13. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-fluorophenyl) -thiazolo [5, 4-f] isoqumolme.13. As a new product 4,9-dehydro-4,9-dexo-2- (2-fluorophenyl) -thiazolo [5,4-f] isoqumolme.
14. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-fluorophenyl) -thiazolo [4, 5-f] isoqumolme.14. As a new product, 4,9-dehydro-4,9-dexo-2- (2-fluorophenyl) -thiazolo [4, 5-f] isoqumolme.
15. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2-phenyl-thιazolo [4, 5-g] quinoxalme.15. As a new product, 4, 9-dehydro-4, 9-dexo-2-phenyl-thιazolo [4, 5-g] quinoxalme.
16. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-fluorophenyl) -thiazolo [4, 5-g] quinoxalme. 16. As a new product, 4,9-dehydro-4,9-dexo-2- (2-fluorophenyl) -thiazolo [4,5-g] quinoxalme.
17. A titre de produit nouveau la 4, 9-dιhydro-4, 9- dιoxo-2- (2-furyl) -7-methyl-thiazolo [4, 5-g] isoqumolme.17. As a new product, 4,9-dehydro-4,9-dexoxo-2- (2-furyl) -7-methyl-thiazolo [4,5-g] isoqumolme.
18. A titre de produit intermédiaire la 7-ammo-6- chloro-5, 8-dιhydro-5, 8-dιoxo-ιsoqumolme.18. As an intermediate product, 7-ammo-6-chloro-5, 8-dehydro-5, 8-dιoxo-ιsoqumolme.
19. A titre de produit intermédiaire la 6-ammo-7- chloro-5, 8-dιhydro-5, 8-dιoxo-ιsoqumolme.19. As an intermediate product, 6-ammo-7-chloro-5, 8-dehydro-5, 8-dιoxo-ιsoqumolme.
20. Utilisation des composes selon l'une quelconque des revendications 1 a 17 pour l'obtention d'un médica¬ ment destine au traitement de I' insuffisance veineuse fonctionnelle et organique.20. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament intended for the treatment of functional and organic venous insufficiency.
21. Utilisation des composes selon l'une quelconque des revendications 1 a 17 pour l'obtention d'un médica¬ ment destine au traitement des pathologies hémorroidai- res .21. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament intended for the treatment of hemorrhoidal pathologies.
22. Utilisation des composes selon l'une quelconque des revendications 1 a 17 pour l'obtention d'un médica¬ ment destine au traitement de la migraine.22. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament intended for the treatment of migraine.
23. Utilisation des composes selon l'une quelconque des revendications 1 a 17 pour l'obtention d'un médica¬ ment destiné au traitement des inflammations osteoarticu- laires dermatologiques et cardiovasculaires .23. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament intended for the treatment of osteoarticular inflammation in dermatology and cardiovascular disease.
24. Utilisation des composes selon l'une quelconque des revendications 1 a 17 pour l'obtention d'un médica¬ ment destine au traitement des états de chocs constitues par une chute importante de la pression artérielle plus particulièrement dans les états de chocs septiques . 24. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament intended for the treatment of shock states constituted by a significant drop in blood pressure, more particularly in septic shock states.
PCT/FR1996/001975 1995-12-12 1996-12-10 Use of heteroaromatic and tricyclic 1,4-dihydro-1,4-dioxo-naphthalene derivatives, resulting novel compounds and therapeutical use thereof WO1997021710A1 (en)

Priority Applications (2)

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EP96941736A EP0874844A1 (en) 1995-12-12 1996-12-10 Use of heteroaromatic and tricyclic 1,4-dihydro-1,4-dioxo-naphthalene derivatives, resulting novel compounds and therapeutical use thereof
JP09521801A JP2000502081A (en) 1995-12-12 1996-12-10 Use of heteroaromatic and tricyclic derivatives of 1,4-dihydro-1,4-dioxonaphthalene, novel compounds obtained and therapeutic uses thereof

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FR9514685A FR2742155B1 (en) 1995-12-12 1995-12-12 USE OF HETEROAROMATIC AND TRICYCLIC DERIVATIVES OF 1,4-DIHYDRO-1,4-DIOXONAPHTALENE, NOVEL COMPOUNDS OBTAINED AND THEIR APPLICATION IN THERAPEUTICS
FR95/14685 1995-12-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032115A1 (en) * 1997-12-19 1999-07-01 Advanced Research And Technology Institute, Inc. Modulators of ryanodine receptors comprising 2-(aryl)-4,7-dioxobenzothiazoles and analogues thereof
US8541192B2 (en) 2006-06-20 2013-09-24 Dana-Farber Cancer Institute, Inc. Methods to identify USP1 deubiquitinating enzyme complex inhibitors
US9518032B2 (en) 2010-04-30 2016-12-13 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US9725425B1 (en) 2014-02-25 2017-08-08 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004112777A1 (en) * 2003-06-20 2004-12-29 Mochida Pharmaceutical Co., Ltd. Composition for prevention/treatment for varicose vein
CN115286594B (en) * 2022-07-24 2023-07-25 浙江工业大学 With S 8 Method for synthesizing quinone thiazole compounds as raw materials

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019211A2 (en) * 1991-05-08 1992-11-12 The Upjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019211A2 (en) * 1991-05-08 1992-11-12 The Upjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032115A1 (en) * 1997-12-19 1999-07-01 Advanced Research And Technology Institute, Inc. Modulators of ryanodine receptors comprising 2-(aryl)-4,7-dioxobenzothiazoles and analogues thereof
US8541192B2 (en) 2006-06-20 2013-09-24 Dana-Farber Cancer Institute, Inc. Methods to identify USP1 deubiquitinating enzyme complex inhibitors
US9518032B2 (en) 2010-04-30 2016-12-13 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US10653676B2 (en) 2010-04-30 2020-05-19 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
US9725425B1 (en) 2014-02-25 2017-08-08 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US10450281B1 (en) 2014-02-25 2019-10-22 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer

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FR2742155A1 (en) 1997-06-13
JP2000502081A (en) 2000-02-22
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EP0874844A1 (en) 1998-11-04

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