WO1997021432A1 - Utilisation de derives de bicycles mono- ou dicetoniques, composes obtenus et leur application comme medicament destine au traitement des inflammations, de la migraine et des etats de chocs - Google Patents
Utilisation de derives de bicycles mono- ou dicetoniques, composes obtenus et leur application comme medicament destine au traitement des inflammations, de la migraine et des etats de chocs Download PDFInfo
- Publication number
- WO1997021432A1 WO1997021432A1 PCT/FR1996/001972 FR9601972W WO9721432A1 WO 1997021432 A1 WO1997021432 A1 WO 1997021432A1 FR 9601972 W FR9601972 W FR 9601972W WO 9721432 A1 WO9721432 A1 WO 9721432A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dihydro
- dioxo
- new product
- phenylamino
- naphthalene
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
- C07C225/26—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings
- C07C225/30—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings of condensed quinone ring systems formed by two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/28—Cinnolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Definitions
- the present invention relates to the use of derivatives of mono or diketonicon bicycles and their pharmaceutically acceptable salts for obtaining a medicament intended for the treatment of diseases linked to impaired venous function and / or inflammatory edema and the new compounds obtained. It relates more particularly to derivatives of naphthalene 1,4-diones and their mono or poly-heterocyclic analogs and also includes diketonicrue derivatives of the indole type and compounds of the oxo-ben ⁇ opyran type. The invention relates to the therapeutic application of all these compounds.
- Morley reports the synthesis of 5- and 8-amino-cmnolme in two stages starting from the cmnoline mono-hydrochloride.
- the mono or oiketonic bicyclic derivatives and their pharmaceutically acceptable salts according to the present invention correspond to the general formula.
- X 1 ( X ,, X 3 , X 4 are independently of each other a carbon atom or a nitrogen atom, and where n takes as value either 0 or 1,
- A is chosen from an oxygen atom, or a carbonyl group
- R 1 and R 2 are, independently of each other, either a hydrogen atom, an aromatic ring, substituted or not, or heteroaro ⁇ matic having one or more heteroatoms substituted or not, a saturated ring having or not one or several hetero atoms, whether or not substituted by an alkyl chain, a chain having from one to four atoms, composed of nitrogen substituted or not, of carbonyl group, terminated or not by a substituted or unsubstituted aromatic ring, or substituted heteroaromatic or not having one or more heteroatoms or not,
- R3 is a hydrogen atom, a halogen atom, an alkyl radical of C] _ to C5, a nitrogen radical substituted by two groups which are independently of each other a hydrogen atom or an alkyl group in C ⁇ _ to C5 incorporating or not incorporating a carbonyl group, or an aromatic ring,
- R4 is a hydrogen atom, a halogen atom, a C ⁇ _ to C5 alkyl radical, an oxygen derivative substituted or not, excluding 6-phenylarm.no-5, 8-qumolmed ⁇ one and 2 -N-acetylammo-l, 4-naphthoquinone, for obtaining a medicament intended for the treatment of diseases linked to impaired venous function and / or to inflammatory edema.
- the present invention also relates to the following new products - 1, 4-dehydro-l, 4-d ⁇ oxo-2- [(4-fluorophenyl) amino-carbonylamino] -naphthalene; 1, 4-dihydro-l, 4-d ⁇ oxo-2- [(4-fluorophenyl) - carbonylhydrazino] -naphthalene; 1,4-dihydro-1,4-dioxo-2- [(4-pyridyl) carbonylhydrazino] -naphthalene hydrochloride; 2-amino-1,4-dihydro-1,4-dioxo-3-methyl-naphthalene sulfate; 1,4-dihydro-1,4-dioxo-2- (4-fluorophenylamino) -3-methyl-naphthalene; 3-chloro-1,4-dihydro-1,4-dioxo-2- [1- (4-
- shock states consisting of a significant drop in blood pressure, more particularly in the states of septic shock.
- X 3 atom of C, atom of N
- X 4 atom of C, atom of N
- R H
- R 4 -H, -OH, -CH 3 .
- the present invention also relates to the salts of the salifiable compounds of formula I
- These salts include the addition salts of mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid and the addition salts organic acids such as acetic, propionic, oxalic, citric, maleic, fumaric, succinic, tartaric acid
- mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid
- organic acids such as acetic, propionic, oxalic, citric, maleic, fumaric, succinic, tartaric acid
- 1,4-dihydro-1, 4-dioxo-2-f (4-fluorophenyl) amino-carbonylamino] -naphthalene A 1.73 g (10 mmol) of 2-amino-1, 4-d ⁇ hydro-1, 4- dioxo-naphthalene in solution in 70 ml of anhydrous toluene, 20 ml of triethylamine are added at room temperature. After 10 minutes with stirring at 70 ° C., 12 ml (10 mmol) of 4-fluorophenylisocyanate are added.
- 2-Amino-1,4-dihydro-1,4-dioxo-3-methylnaphthalene sulphate 500 mg (2, .67 mmol) of 2-amino-1,4-dihydro-1,4-dioxo- 3-methyl-naphthalene in solution in 5 ml of metha ⁇ nol 142 ⁇ l (2.67 mmol) of sulfuric acid are added in the cold.
- the red precipitate formed is filtered through glass, washed three times with ether to provide 760 mg of 2-amino-1, 4-dehydro-l, 4-d ⁇ oxo-3-methylnaphthalene sulfate, in the form of red crystals.
- the orange precipitate formed during the reaction is filtered hot on sintered glass and purified on a flash co ⁇ (support: silica; packaging - heptane, eluent dichloromethane / heptane, 90/10 then dichloromé ⁇ thane / methanol, 95 / 5)
- the product thus obtained is recrystallized after discoloration in methanol to provide 3.40 g of 1, 4-d ⁇ hydro-l, 4-d ⁇ oxo-3-hydroxy-2- (4- 35 pyridylammo) -napntalene in the form red crystals YId: 64%
- the organic phases are dried over magnesium sulfate and evaporated under reduced pressure.
- the red powder obtained is purified on a flash column (support: silica; packaging: heptane; eluent: dichloromethane / heptane, 80/20).
- the red product thus obtained is recrystallized after discoloration from dichloromethane to give 1.50 g of 1, 4-dihydro-1, 4-dioxo-2- (4-fluorophenylamino) - 5-hydroxy-naphthalene in the form of dark red crystals ⁇ these.
- the mixture of the two isomers is then passed over a preparative HP L C. column (support: silica; eluent: dichloromethane / heptane / isopropyl alcohol, 95/4, 5/0, .5) of mother to achieve good separation.
- a preparative HP L C. column support: silica; eluent: dichloromethane / heptane / isopropyl alcohol, 95/4, 5/0, .5) of mother to achieve good separation.
- the di ⁇ chloromethane is evaporated under reduced pressure to provide 424 mg of 5,8-dihydro-5,8-dioxo-7-phenylamino-isoquinoline sulfate, in the form of dark red crystals.
- the crude product is purified on a flash column (support: alumina; eluent: dichloromethane / heptane, 90 / 1C at 100/0 then with dichloromethane / methanol, 99.25 / 0.75).
- the red powder thus obtained is then discolored and re-installed in dichloromethane to provide 3.2 g of 7- (4-fluorophenylamino) -5, 8-dihydro-5, 8-dioxo-isoquinoline in the form of dark red crystals.
- the reaction mixture which turns from yellow to orange, is heated at 70 ° C. for 72 hours and the brown precipitate obtained is filtered through sintered glass and rinsed with ether.
- the orange powder collected is discolored and re ⁇ crystallized from ethanol. , to provide 1.5 g of 3- (4-fluorophenylamino) -4H-4-oxo-benzopyran as yellow crystals.
- the crude 5,8-dihydro-5,8- dioxo-cinnoline obtained is dissolved in 45 ml of ethanol and then 0.9 ml of aniline is added at room temperature.
- the reaction medium which changes from a brown to dark red color, remains under stirring for 3 hours.
- the product is purified on a flash column (support: silica; liquid deposit; eluent: dichloromethane / isopropanol, 99.8 / 0.2 to 99.5 / 0.5 to 99/1) to provide 0, 11 g of 5,8-dihydro-5,8-dioxo-6- (phenylamino) -cinnoline (Example 23) and 0.06 g of 5,8-dihydro-5,8-dioxo-7- (phenylamino) - cinnoline (Example 24) in the form of dark purple crystals.
- 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 veinotonic, affecting the arterial system only at concentrations much higher than those active on the veins, except certain arteries, in particular cerebral.
- the compounds show no affinity or a very weak affinity for known membrane pharmacological receptors.
- they increase capillary resistance, decrease the vascular hyperpermeability induced by certain inflammatory agents. These properties are highlighted in mam- mifers such as hamsters, rats, guinea pigs and rabbits, under in vitro conditions (isolated vessels or vascular networks) and in vivo.
- the compounds are dissolved in pure aqueous solution or containing DMSO (dimethyl sulfoxide).
- the rings are placed in an isolated organ chamber (25 ml for capacitance vessels and 2.5 ml for resistance vessels according to Mulvany), maintained in isometric conditions by two rigid wires inserted inside the vessel, in avoiding damage to the endothelium.
- the rings are brought to their optimum point of the tension-length relationship.
- 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 (KC1: 20, 40 mM), by no ⁇ radrenaline (increasing concentrations), serotonin (increasing concentrations) ...
- the contractions are expressed in mg force or as a percentage of the maximum contraction on depolarization by a "physiological" hyperpotassic solution.
- the arterial and venous pressures are measured in the anesthetized animal, in basal conditions and after circulatory arrest caused by the swelling of a balloon catheter introduced at the level of the right atrium.
- 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).
- the arterial pressures are measured according to the classic method derived from Riva Rocci, by analysis of the acoustic wave transmitted to the arterial level and transformed by a piezo ceramic transducer placed on the tail of the rat, downstream of '' a sleeve inflated automatically by a pressure generator. Effects on induced capillary hyperpermeability
- Vascular permeability is studied in vi vo by measuring the extravasation of albumin, the quantity of which is determined using an albumin-binding dye (Evans Blue). Hyperpermeability is induced by in ⁇ tradermal injection of a solution of histamine, bradykinin or zymosan.
- 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 hour 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 (either for histamine 6.7 or 10 micro ⁇ grams) 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 carried out 30 minutes before euthanasia.
- the rats are euthanized by cervical dislocation.
- the skin is cut and placed in glass tubes with a ruffled neck containing 3 ml of fuming hydrochloric acid.
- the digestion of the skin is carried out by contact for at least one hour in a water bath at 37 ° C. Three ml of 12.8% benzalkonium chloride is then added. After having allowed to stand for thirty minutes, 7 ml of dichloromethane are added.
- the tubes are agitated periodically for one hour.
- the aqueous phase is removed by suction and the "dichloromethane" organic phase 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.
- Effects on capillary resistance The increase in capillary resistance is appreciated by the modification of the petechial index (negative pressure inducing the extravasation of erythrocytes), measured by a method derived from 1 "Parrot angiosterrometer. The study is carried out on male Wistar rats weighing an average of 200 g (about six weeks old), the lower back region is shaved and then depilated using a paste based on a derived from thioglycolic acid and calcium hydroxide After about thirty minutes, the skin is thoroughly rinsed and dried.
- the rats were kept unconstrained. A vacuum of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) have not appeared within 15 seconds, the depression is increased step by step by keeping the suction cup in the same place.
- the minimum depression for which the petechiae appear expresses, in mm of mercury, the basic capillary resistance value (before any treatment). Two measurements are made for each test at locations different from the back. Rats are treated orally. After a determined time (generally 2, 4, 6 hours) following the treatment, the test is repeated on different skin areas, until the appearance of petechiae, providing a new index of depression. All measurements are made blind.
- a percentage change in the capillary resistances of the treated animals with respect to their basic capillary resistance is calculated for each compound studied, at each treatment time and compared with the control group (excipient only) or the reference group. 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 pleurisy in rats by injection of carrageenan into the pleural cavity (ALMEIDA et al ., J. Pharmacol. Exp. Therap., 1980, 214: 74).
- the rats are treated per os with the compounds 2 hours before the injection of carrageenan, as well as two and four hours after this injection. After a defined time (6 hours) following the induction of pleurisy, the rats are euthanized and the pleural fluid recovered by suction and its volume is measured. The leukocyte cells are counted by the technique called "cell counter”. The results are expressed in number of leuco ⁇ cytes in 1 exudate reported to 100 g of animal weight and compared to those of the control batch.
- the anti-lipoperoxidative activity is studied in vitro by a lipid peroxidation model based on the peroxidation of a linoleic acid emulsion by iron in the presence of oxygen and light, method modified by compared to that described by SUTHERLAND et al., Arch. Bio-chem. Biophys. , 1982, 214: 1-11. Examples of pharmacological effects
- the compounds of the invention and their possible salts selectively increase in the majority of cases the contraction of the animal veins produced by noradrenaline, by electrical stimulation or by a depolarizing hyperpotassic solution.
- Example 11 36 ⁇ 10,937
- Example 12 29 ⁇ 7,560
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9521798A JP2000502334A (ja) | 1995-12-12 | 1996-12-10 | モノまたはジケトン二環式化合物の誘導体の使用、それにより得られた化合物、並びに炎症、片頭痛およびショックの治療用薬剤としてのそれらの用途 |
EP96941733A EP0866692A1 (fr) | 1995-12-12 | 1996-12-10 | Utilisation de derives de bicycles mono- ou dicetoniques, composes obtenus et leur application comme medicament destine au traitement des inflammations, de la migraine et des etats de chocs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9514682A FR2742151B1 (fr) | 1995-12-12 | 1995-12-12 | Utilisation de derives de bicycles mono ou dicetoniques, nouveaux composes obtenus et leur application en therapeutique |
FR95/14682 | 1995-12-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997021432A1 true WO1997021432A1 (fr) | 1997-06-19 |
Family
ID=9485392
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1996/001972 WO1997021432A1 (fr) | 1995-12-12 | 1996-12-10 | Utilisation de derives de bicycles mono- ou dicetoniques, composes obtenus et leur application comme medicament destine au traitement des inflammations, de la migraine et des etats de chocs |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0866692A1 (fr) |
JP (1) | JP2000502334A (fr) |
FR (1) | FR2742151B1 (fr) |
WO (1) | WO1997021432A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004098601A1 (fr) * | 2003-05-06 | 2004-11-18 | Chemon Inc. | Inhibiteur de la pkc, inhibiteur de l'angiogenese contenant de la 6-anilinoquinoline-5,8-quinone comme ingredient actif |
WO2014028909A1 (fr) * | 2012-08-16 | 2014-02-20 | Ohio State Innovation Foundation | Inhibiteurs de stat3 et leur utilisation anticancéreuse |
US8697680B2 (en) | 2008-09-05 | 2014-04-15 | Ramot At Tel Aviv University Ltd. | Naphthoquinone derivatives useful for prevention of amyloid deposits and treatment of diseases involving amyloidogenesis |
WO2017155991A1 (fr) * | 2016-03-08 | 2017-09-14 | The Regents Of The University Of Michigan | Inducteurs de petites molécules de dérives réactifs de l'oxygène et inhibiteurs de l'activité mitochondriale |
WO2020181207A1 (fr) * | 2019-03-06 | 2020-09-10 | The Regents Of The University Of Michigan | Quinones bicycliques et tétracycliques substituées et procédés d'utilisation associés |
CN112770735A (zh) * | 2018-07-29 | 2021-05-07 | Musc研究发展基金会 | 用于治疗神经或线粒体疾病的化合物 |
CN113956248A (zh) * | 2021-11-12 | 2022-01-21 | 贵州中医药大学 | 一种具有抗炎作用的化合物衍生物及其制备方法和应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2127813A (en) * | 1982-09-30 | 1984-04-18 | Lilly Co Eli | 7-anilinoisoquinoline-5, 8-quinones |
EP0147778A2 (fr) * | 1983-12-31 | 1985-07-10 | Troponwerke GmbH & Co. KG | Dérivés de 1,4-naphthoquinone anti-inflammatoires |
EP0149818A2 (fr) * | 1983-12-31 | 1985-07-31 | Troponwerke GmbH & Co. KG | Dérivés de 1,4-naphtoquinone, procédé pour leur préparation et leur utilisation comme médicaments |
EP0566446A1 (fr) * | 1992-04-03 | 1993-10-20 | Innothera | Dérivés d'indane-1, 3-dione et d'indane-1,2,3-trione, leurs procédés de préparation et leur application en thérapeutique |
WO1993023052A1 (fr) * | 1992-05-08 | 1993-11-25 | Brigham And Women's Hospital | Utilisation d'inhibiteurs de guanylate cyclase dans le traitement des etats de choc |
EP0646579A1 (fr) * | 1993-10-01 | 1995-04-05 | LABORATOIRE INNOTHERA Société Anonyme | Dérivés d'indane cétoniques et de leurs analogues hétérocycliques et leur utilisation thérapeutique |
JPH08113555A (ja) * | 1994-10-14 | 1996-05-07 | Japan Tobacco Inc | 2−アミノ−3−ハロゲノ−1,4−ナフトキノン誘導体及びその医薬用途 |
-
1995
- 1995-12-12 FR FR9514682A patent/FR2742151B1/fr not_active Expired - Fee Related
-
1996
- 1996-12-10 JP JP9521798A patent/JP2000502334A/ja active Pending
- 1996-12-10 WO PCT/FR1996/001972 patent/WO1997021432A1/fr not_active Application Discontinuation
- 1996-12-10 EP EP96941733A patent/EP0866692A1/fr not_active Withdrawn
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2127813A (en) * | 1982-09-30 | 1984-04-18 | Lilly Co Eli | 7-anilinoisoquinoline-5, 8-quinones |
EP0147778A2 (fr) * | 1983-12-31 | 1985-07-10 | Troponwerke GmbH & Co. KG | Dérivés de 1,4-naphthoquinone anti-inflammatoires |
EP0149818A2 (fr) * | 1983-12-31 | 1985-07-31 | Troponwerke GmbH & Co. KG | Dérivés de 1,4-naphtoquinone, procédé pour leur préparation et leur utilisation comme médicaments |
EP0566446A1 (fr) * | 1992-04-03 | 1993-10-20 | Innothera | Dérivés d'indane-1, 3-dione et d'indane-1,2,3-trione, leurs procédés de préparation et leur application en thérapeutique |
WO1993023052A1 (fr) * | 1992-05-08 | 1993-11-25 | Brigham And Women's Hospital | Utilisation d'inhibiteurs de guanylate cyclase dans le traitement des etats de choc |
EP0646579A1 (fr) * | 1993-10-01 | 1995-04-05 | LABORATOIRE INNOTHERA Société Anonyme | Dérivés d'indane cétoniques et de leurs analogues hétérocycliques et leur utilisation thérapeutique |
JPH08113555A (ja) * | 1994-10-14 | 1996-05-07 | Japan Tobacco Inc | 2−アミノ−3−ハロゲノ−1,4−ナフトキノン誘導体及びその医薬用途 |
Non-Patent Citations (8)
Title |
---|
ACTA CRYSTALLOGR., SECT. B (1969), 25(PT. 3), 546-8 * |
AGENTS ACTIONS, vol. 17, no. 2, 1985, pages 197 - 204 * |
CHEMICAL ABSTRACTS, vol. 104, no. 13, 31 March 1986, Columbus, Ohio, US; abstract no. 102126, R. P. CARLSON ET AL.: "Modulation of mouse ear edema by cyclooxygenase and lipoxygenase inhibitors and other pharmacologic agents" page 38; XP002010772 * |
CHEMICAL ABSTRACTS, vol. 70, no. 18, 5 May 1969, Columbus, Ohio, US; abstract no. 81049, GAULTIER, JACQUES ET AL: "Bifurcated hydrogen bonds" XP002010774 * |
CHEMICAL ABSTRACTS, vol. 70, no. 21, 26 May 1969, Columbus, Ohio, US; abstract no. 96457, AKATSUKA, MASAMI: "Quinones. III. Reaction of naphthoquinone derivatives with acid hydrazides" XP002010773 * |
DATABASE WPI Section Ch Week 9628, Derwent World Patents Index; Class B05, AN 96-272741, XP002010775 * |
PRESCOTT, BENJAMIN: "Potential antimalarial agents. Derivatives of 2-chloro-1,4- naphthoquinone", J. MED. CHEM. (1969), 12(1), 181-2, XP002010771 * |
YAKUGAKU ZASSHI (1969), 89(1), 7-20 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004098601A1 (fr) * | 2003-05-06 | 2004-11-18 | Chemon Inc. | Inhibiteur de la pkc, inhibiteur de l'angiogenese contenant de la 6-anilinoquinoline-5,8-quinone comme ingredient actif |
US8697680B2 (en) | 2008-09-05 | 2014-04-15 | Ramot At Tel Aviv University Ltd. | Naphthoquinone derivatives useful for prevention of amyloid deposits and treatment of diseases involving amyloidogenesis |
US9272993B2 (en) | 2008-09-05 | 2016-03-01 | Ramot At Tel Aviv University Ltd. | Naphthoquinone derivatives useful for prevention of amyloid deposits and treatment of diseases involving amyloidogenesis |
WO2014028909A1 (fr) * | 2012-08-16 | 2014-02-20 | Ohio State Innovation Foundation | Inhibiteurs de stat3 et leur utilisation anticancéreuse |
US9783513B2 (en) | 2012-08-16 | 2017-10-10 | Ohio State Innovation Foundation | STAT3 inhibitors and their anticancer use |
WO2017155991A1 (fr) * | 2016-03-08 | 2017-09-14 | The Regents Of The University Of Michigan | Inducteurs de petites molécules de dérives réactifs de l'oxygène et inhibiteurs de l'activité mitochondriale |
US10781183B2 (en) | 2016-03-08 | 2020-09-22 | The Regents Of The University Of Michigan | Small molecule inducers of reactive oxygen species and inhibitors of mitochondrial activity |
EP3829560A4 (fr) * | 2018-07-29 | 2022-08-03 | Musc Foundation for Research Development | Composés pour le traitement de maladies neurologiques ou mitochondriales |
CN112770735A (zh) * | 2018-07-29 | 2021-05-07 | Musc研究发展基金会 | 用于治疗神经或线粒体疾病的化合物 |
US11771685B2 (en) | 2018-07-29 | 2023-10-03 | Musc Foundation For Research Development | Compounds for the treatment of neurological or mitochondrial diseases |
WO2020181207A1 (fr) * | 2019-03-06 | 2020-09-10 | The Regents Of The University Of Michigan | Quinones bicycliques et tétracycliques substituées et procédés d'utilisation associés |
CN113710241A (zh) * | 2019-03-06 | 2021-11-26 | 密执安大学评议会 | 取代的双环和四环醌及相关使用方法 |
CN113956248A (zh) * | 2021-11-12 | 2022-01-21 | 贵州中医药大学 | 一种具有抗炎作用的化合物衍生物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
FR2742151A1 (fr) | 1997-06-13 |
JP2000502334A (ja) | 2000-02-29 |
FR2742151B1 (fr) | 1998-03-06 |
EP0866692A1 (fr) | 1998-09-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
FR2530626A1 (fr) | Composes de carbostyryle | |
EP0447324B1 (fr) | Dérivés de pyrimidinedione-2,4 et médicaments les contenant | |
BE1000573A4 (fr) | Derives de 1-(hydroxystyryl)-5h-2,3-benzodiazepine, procede pour les preparer et compositions pharmaceutiques les contenant. | |
EP0566445B1 (fr) | Dérivés d'indane-1,3-dione et d'indane-1,2,3-trione, leurs procédés de préparation et leur application en thérapeutique | |
WO1997021432A1 (fr) | Utilisation de derives de bicycles mono- ou dicetoniques, composes obtenus et leur application comme medicament destine au traitement des inflammations, de la migraine et des etats de chocs | |
EP0366511A1 (fr) | Nouveaux dérivés benzoxazolinoniques, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent | |
EP0556872A1 (fr) | Utilisation de dérivés du diméthyl-2,2 chromène dans le traitement de l'asthme | |
EP0876356B1 (fr) | Utilisation de derives tricycliques du 1,4-dihydro-1,4-dioxo-1h-naphtalene, nouveaux composes obtenus et leur application en therapeutique | |
EP0385848A1 (fr) | Nouveaux dérivés benzoxazolinoniques, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent | |
WO1997021710A1 (fr) | Utilisation de derives heteroaromatiques et tricycliques du 1,4-dihydro-1,4-dioxo-naphtalene, nouveaux composes obtenus et leur application en therapeutique | |
CA1034576A (fr) | Procedes de preparation de nouveaux derives de la piperazine | |
CA2045849A1 (fr) | Derives d'oxazolo pyridines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent | |
EP0487423A1 (fr) | Nouveaux dérivés de la benzosélénazolinone, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent | |
EP0646579A1 (fr) | Dérivés d'indane cétoniques et de leurs analogues hétérocycliques et leur utilisation thérapeutique | |
CH637650A5 (fr) | Procede de preparation d'un acide chromone carboxylique. | |
EP0000306A1 (fr) | Hexahydro benzopyrano (3,2-c) pyridines substituées, leur procédé de préparation et médicament les contenant | |
WO1997021709A1 (fr) | Utilisation de derives de tetracycles mono ou dicetoniques, nouveaux composes obtenus et leur application en therapeutique | |
EP0170549B1 (fr) | Dérivés de tétrahydro-4,5,6,7 furo ou 1H-pyrrolo[2,3-c]pyridine, leur préparation et leur application en therapeutique | |
CA1263862A (fr) | Derives d'amino-5 pentanenitrile et leur procede de preparation | |
EP1131293A1 (fr) | Derives de 1-aminoethylquinoleine pour le traitement de l'incontinence urinaire | |
KR0169357B1 (ko) | 신규한 2-이미다졸론유도체 및 그의 제조방법 | |
EP0390673A1 (fr) | Nouveaux dérivés d'acyl-5 benzoxazolinone, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent | |
JPH10120680A (ja) | 新規インドリジン化合物 | |
FR2764292A1 (fr) | Utilisation de derives de tetracycles dicetoniques, nouveaux composes obtenus et leur application en therapeutique | |
EP0646574A1 (fr) | Dérivés d'indane cétoniques, leur procédé d'obtention, leur application thérapeutique |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1996941733 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1997 521798 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 1996941733 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1996941733 Country of ref document: EP |