Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P35/00—Antineoplastic 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• New naphthvridine derivatives are useful in particular as antiproliferative drugs
• the present invention relates, as new products, to the naphthvridine derivatives of general formula (I) below and their addition salts, in particular the pharmaceutically acceptable addition salts.
• the compounds of the invention which have antiproliferative properties can be used in the treatment of cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathology due to cell proliferation in mammals and in particular in mammals. 'man.
• the present invention also relates to the process for the preparation of said products and their applications in therapy.
• X represents:
• Y represents: - the oxygen atom
• R and Ri represent not simultaneously - a hydrogen atom - a CN radical
• R' being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms
• n is an integer from 0 to 5 and R "represents the hydrogen atom, a halogen atom or a lower alkyl radical of 1 to 6 carbon atoms - an NO2 radical
• R2 represents:
• lower alkyl means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched.
• a lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl radical.
• C 3 -C 7 cycloalkyl radical is understood to mean a saturated cyclic hydrocarbon radical, it is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl radical.
• Halogen means a chlorine, bromine, iodine or fluorine atom. In the description, the following abbreviations have been used:
• - R represents a pyridine
• the particularly preferred compounds of the invention are those which are chosen from the products of formula:
• R 2 carries a substantial substitution with certain reducing agents, such as for example nitro or cyano
• the reduction of the ester will be chosen by a reducing agent respecting this substitution, for example lithium borohydride prepared "in situ" from potassium borohydride and lithium chloride in tetrahydrofuran or sodium borohydride in dioxane.
• a mild oxidant such as for example MnC> 2
• an organic solvent such as dichloromethane or chloroform, toluene or xylene, at a temperature between 20 and 80 ° C. alcohol of formula (V)
• R' ⁇ represents a lower alkyl radical of 1 to 6 carbon atoms, optimally the methyl radical or also with a dialkoxy propionitrile of formula (VII ")
• Y' represents an oxygen atom in the case where the reaction was carried out with the compound of formula (VII) or an NH group in the case where the reaction was carried out with the compound of formula (VII ').
• dialkyl acetal derivatives of formula (VIII) will be hydrolyzed for example by the action of hydrochloric acid in a solvent such as tetrahydrofuran to give the aldehydes of formula (IX)
• R and Rj have the same definition as in formula (I) according to the conventional Knoevenagel reaction methods, for example by heating in an alcohol such as methanol or ethanol in the presence of piperidine or of a sodium or potassium alcoholate or sodium or potassium carbonate will lead to the compounds of formula (XI)
• derivatives of formula (XI) are derivatives of formula (I) and the derivatives of formula (XI) in which Y 'represents the oxygen atom may, by treatment with P S ⁇ o in xylene at reflux, lead to the derivatives of formula (I) where Y represents the sulfur atom.
• the derivatives of formula (I) where R 2 has a nitro function can be reduced to derivatives where R2 has an amino function.
• Addition salts of certain compounds of formula (I) can be obtained by reaction of these compounds with a mineral or organic acid according to a method known per se.
• acids which can be used for this purpose are hydrochloric, hydrobromic, sulfuric, phosphoric, 4-toluene sulfonic, methane sulfonic, cyclohexyl sulfamic, oxalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic, glutamic acids. , N-acetylaspartic, N-acetylglutamic, ascorbic, malic, benzoic, nicotinic and acetic.
• the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.
• compositions can be administered by the oral, rectal, parenteral, transdermal or ocular route.
• These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, transdermal systems and eye drops. They are prepared according to the usual methods.
• the active principle consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above or one of its pharmaceutically acceptable addition salts, can be incorporated therein into excipients usually used in these pharmaceutical compositions , such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, bodies animal or vegetable fats, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors.
• excipients usually used in these pharmaceutical compositions , such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, bodies animal or vegetable fats, glycols, various
• the invention also covers an antiproliferative pharmaceutical composition making it possible in particular to favorably treat any pathology due to cell proliferation characterized in that it comprises a pharmaceutically effective amount at least one compound of the above formula (I) or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.
• the invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is incorporated. pharmaceutically acceptable addition to a pharmaceutically acceptable excipient, vehicle or carrier.
• a pharmaceutical composition with antiproliferative activity is prepared which makes it possible in particular to favorably treat cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathology due to cell proliferation.
• a composition is prepared formulated in the form of capsules or tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg.
• the invention also covers a method for the therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is administered to this mammal. pharmaceutically acceptable addition.
• the compound of formula (I) either alone or in combination with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 mg to 1000 mg for administration by orally, or in the form of injectable preparations dosed from 0.1 to 500 mg or also in the form of suppositories, ointments, creams, gels, aerosol preparations or eye drops.
• the compounds of formula (I) and their salts can be administered alone or in combination with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of injectable solution.
• a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of injectable solution.
• Other forms of administration such as suppositories, ointments, creams, gels, aerosol preparations or eye drops can be considered.
• the compounds according to the invention can be administered in human therapy in the abovementioned indications orally in the form of tablets or capsules dosed from 1 mg to 1000 mg or parenterally in the form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg.
• the daily dose that can be used is between 0.1 and 100 mg per kg.
• Example 44 1- (3,5-dichlorophenyl) -1, 2-dihydro-3-dimethoxymethyl-2-oxo-1, 8-naphthyridine
• Example 60 [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin 3-yl] carboxaldehyde
• Example 75 [1, 2-dihydro-1- (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde
• Example 77 3- [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8,8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) propionitrile
• R 1 CN
• Example 78 3- [1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile
• Example 79 3- [1- (3,5-dichlorophenyl) -1, 2-dlhydro-2-oxo-1, 8- naphthyrldln-3-yl] -2- (2-pyridyl) -2-propene nitrile
• Example 80 3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (4-pyridyl) -2-propene nitrile
• Example 81 3- [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyrldin-3-yl] -2- (4-pyridyl) -2-propene nitrile
• Example 80 According to the procedure of Example 80 but starting from 3.2 g of [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde , after recrystallization from methoxy ethanol 1.68 g of 3- [1- (3,5-dichlorophenyl) -1,2- dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (4-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point 256-257 ° C. Yield 40%.
• Example 82 3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile
• Example 79 According to the procedure of Example 79 but starting from 2.8 g of [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde and 1, 3 ml of 3-pyridyl acetonitrile (1.2 eq), 2.5 g of yellow solid are obtained which are purified by chromatography on a silica column (eluent dichloromethane - ethyl ether 9/1).
• Example 83 3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (2-pyridyl) -2-propene nitrile
• Example 104 [[1, 2-dihydro-1- (3-methylphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -methylene-3-yl] oxindole
• Example 83 According to the procedure of Example 83, 3 g of [1,2-dihydro-1- (3-methylphenyl) - 2-0x0-1, 8-naphthyridin-3-yl] carboxaldehyde prepared in Example 64 give 2.9 g of [[1,2-dihydro-1- (3-methylphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -methylene-3-yl] oxindole in the form of an orange solid of melting point>310'C. Yield 75%.
• Example 105 3-fl - (3.5-dlchlorophenyl.-1.2-dlhydro-2-thloxo-1.8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile
• the medium is filtered hot and the filtrate brought to room temperature.
• the precipitate formed is drained, washed with ether.
• Example 107 3- [1, 2-dihydro-1 - (3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) -propionitrile
• Example 108 3- [6-chloro-1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -3-hydroxy-2- (3- pyridyl) propionitrile
• Example 109 3- [1, 2-dihydro-1- (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin- 3-yl] -2- (3-pyridyl) -2-propene nitrile
• reaction medium is hydrolyzed by adding 100 ml of water, then the aqueous phase is separated, extracted several times with dichloromethane. A precipitate appears which is wrung, washed with acetone and dried. 0.21 g of 3- [1, 2-dihydro-1 - (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2- is thus obtained.
• Example 110 3- [6-chloro-1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2 -propene nitrile
• Example 78 According to the procedure of Example 78 but using 2.1 g of 3- [6-chloro-1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin -3-yl] -3-hydroxy-2- (3-pyridyl) propionitrile, prepared in Example 108, 1.9 g of 3- [6-chloro-1 - (3,5-dichlorophenyl) - are obtained 1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point 279 ° C. Yield 94%.
• Example 111 3-ri .2-dihvdro-l - (3-nitrophén ⁇ l.-2-oxo-1.B- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile
• Example 78 According to the procedure of Example 78 but starting from 4.2 g of 3- [1, 2-dihydro-1- (3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -3 -hydroxy-2- (3-pyridyl) -propionitrile, prepared in Example 107, after purification on a column of silica (eluent: dichloromethane), 0.7 g of 3- [1, 2-dihydro-1 - ( 3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point of 272-274 ° C. Yield 18%.
• Example 112 3- [1 - (3-aminophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile
• Example 115 According to the procedure of Example 115, 2.8 g of [1, 2-dihydro-l- (4-methoxyphenyl) - 2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde and 1.9 g of N- (3-methylphenyl) methyl) cyanacetamide (1eq) prepared in Example 114 react to give after purification on a silica column (eluent: cylohexane / ethyl acetate 5/5) and recrystallization from isopropanol 0, 43g of N- (3-methylphenyl) methyl 2-cyano-3- [1, 2-dihydro-1- (4-methoxyphenyl) - 2-oxo-1,8, naphthyridin-3-yl] -2-propenamide form of a yellow solid with a melting point of 188 ° C. 9.5% yield PHARMACOLOGY
• the inhibition of cell proliferation induced by a growth factor is evaluated by measuring the incorporation of 3 H-thymidine into the fibroblasts balb c 3T3.
• the blab fibroblasts c 3T3 cells are grown at 37 ° C in 5% C0 2 to the sub-confluence and then placed for 24 hours in a quiescent low serum medium. They are then pretreated for one hour with the molecule to be tested and then stimulated for 24 hours by a growth factor (example: PDGF).
• a growth factor example: PDGF
• the incorporation of 3 H-thymidine is carried out during the last 2 hours. All these steps are carried out at 37 "C, in 5% C0 2 .
• the reaction is terminated by aspiration of the reaction medium, detachment of the cells, then filtration of the lysed cells through glass fiber filters.
• the results are expressed as a percentage inhibition of the stimulation of incorporation of 3 H-thymidine due to the action of the growth factor.

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• 1993
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• 1994
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