WO2003033467A1 - Nitroso diphenylamine derivatives as nitrogen monoxide generating agents - Google Patents

Nitroso diphenylamine derivatives as nitrogen monoxide generating agents Download PDF

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WO2003033467A1
WO2003033467A1 PCT/EP2002/010607 EP0210607W WO03033467A1 WO 2003033467 A1 WO2003033467 A1 WO 2003033467A1 EP 0210607 W EP0210607 W EP 0210607W WO 03033467 A1 WO03033467 A1 WO 03033467A1
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optionally substituted
formula
optionally
compound
halogenated
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PCT/EP2002/010607
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French (fr)
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Claude Lardy
Didier Festal
Lidia Caputo
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Merck Patent Gmbh
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/92—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of 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
    • C07C243/04—N-nitroso compounds
    • C07C243/06—N-nitroso-amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • 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
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • 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 invention relates to nitroso diphenylamine derivatives, to pharmaceutical compositions comprising them and to their use for preparing medicinal products that can be used for treating pathologies characterized by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide
  • Nitrogen monoxide (or nitric oxide NO*) is an important mediator in the physiology of cardiovascular, immune and central and peripheral nervous sys- terns. It acts, among other mechanisms, by activation of guanylate cyclase.
  • Oxidative stress is generated by many factors, for instance hyperglycaemia, dyslipidaemias (production of oxidized, highly atherogenic "low-density" lipoproteins (LDL)), hypoxia, insulin resistance, atherosclerosis, revascularization techniques (including angioplasties with or without a stent), chronic rejection after transplantation, the majority of inflammatory processes, and addiction to smoking.
  • Oxidative stress is characterized at the vascular level by an increase in free radicals, in particular of superoxide anions (O2* "). These ⁇ 2* ⁇ radicals are capable of trapping the NO endogenously produced by the endothelial cells to form free-radical species that are even more deleterious, for instance peroxynitrites.
  • the administration of active principles capable of reducing the biological activity of oxidative free-radical species (such as superoxide anions and peroxynitrites) and of increasing the content of nitrogen monoxide by a two-fold mechanism: non-conversion into peroxynitrites and exogenous supply, is thus particularly desirable in the treatment of these pathologies.
  • the present invention provides compounds that have these two effects, antioxidant and nitrogen monoxide-donating, in the same molecule.
  • These compounds are capable of spontaneously generating nitrogen monoxide under physiological conditions and of trapping oxidative free radicals.
  • the spontaneous NO-donating effect does not induce a tachyphylactic effect, unlike compounds that are substrates of NO synthase, and unlike nitro derivatives or derivatives of oxadiazole or oxatriazole type which mobilize endogenous thiols groups to release NO.
  • pharmacological NO activity may be achieved in pathologies in which the activity of NO synthase is insufficient.
  • the invention relates to the compounds of the formula I:
  • - W represents O or S;
  • the radicals R f which may be identical or different, represent a halogen atom; a saturated or unsaturated aliphatic hydrocarbon group, optionally interrupted by O and/ or S and optionally halogenated; nitro; carboxyl or cyano;
  • - i represents an integer from 0 to 5, preferably 0, 1 or 2;
  • R 1 represents an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical; -E-Q, in which E represents optionally substituted alkylene or alkenylene and Q represents an amino group which is optionally substituted by one or two saturated or unsaturated aliphatic hydrocarbon groups; or -E-Ar, in which E is as defined above and Ar represents an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical or alternatively an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; or an optionally halogenated, saturated aliphatic hydrocarbon group; with the exclusion of the compounds of the formula I in which i is 1; R 4 represents 2-methyl and R 1 represents -CHs, and their pharmaceutically tolerable derivatives, solvates and stereoisomers.
  • Hydrates and solvates are understood as meaning, for example, the hemi-, mono- or dihydrates, solvates are understood as meaning, for example, alcohol addition compounds such as, for example, with methanol or ethanol.
  • pharmaceutically tolerable derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.
  • prodrug derivatives is taken to mean, for example, compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to give the effective compounds according to the invention.
  • biodegradable polymer derivatives of the compounds according to the invention as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or fluorine atom.
  • aliphatic hydrocarbon group means a hydrocarbon group containing a linear or branched chain, preferably containing from 1 to 14 carbon atoms, preferably from 1 to 10 and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • saturated aliphatic hydrocarbon groups are alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1- methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl- butyl, 1-methyl-l-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4- dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloc
  • the aliphatic hydrocarbon group may contain one or two unsaturations.
  • the unsaturations are either of the ethylenic or acetylenic type. They are preferably ethylenic.
  • the unsaturated chains contain at least two carbon atoms.
  • Alkenyl and alkynyl groups are examples of unsaturated aliphatic hydrocarbon groups.
  • Examples of unsaturated aliphatic hydrocarbon groups are allyl and vinyl.
  • any carbon atom of the hydrocarbon chain may be replaced with an oxygen or sulfur atom, where it is not possible for this carbon atom to be located at the free end of the hydrocarbon chain.
  • the hydrocarbon chain which may be alkyl, may contain a plurality of oxygen and/ or sulfur atoms, the hetero atoms preferably being separated from each other by at least one carbon atom and better still by at least two carbon atoms.
  • An example of an aliphatic hydrocarbon chain which is interrupted by O or S is alkoxy or thioalkoxy.
  • saturated, unsaturated and/ or aromatic cyclic (carbocyclic or heterocyclic) radical means that the same radical may contain a saturated moiety and/ or an unsaturated moiety and/ or an aromatic moiety.
  • the carbocyclic and heterocyclic radicals include mono- and polycyclic radicals; these radicals preferably denote mono-, bi- or tricyclic radicals.
  • polycyclic radicals it should be understood that these consist of monocycles fused in pairs (for example ortho-fused or peri-fused), i.e. having at least two carbon atoms in common.
  • each monocycle is 3- to 8- membered and better still 5- to 7-membered.
  • heterocyclic groups comprise hetero atoms generally chosen from O, N and S, optionally in oxidized form (in the case of S and N).
  • each of the monocycles constituting the heterocycle contains from 1 to 4 hetero atoms and better still from 1 to 3 hetero atoms.
  • aromatic heterocyclic groups are 5- to 7-membered mono- cyclic heteroaryls, such as pyridine, furan, thiophene, pyrrole, pyrazole, imid- azole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.
  • Examples of unsaturated 7-membered heterocycles include trithiatri- azepines and trithiadiazepines.
  • Examples of 5- to 7-membered saturated mono- cyclic heterocycles especially include tetrahydrofuran, dioxolane, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, trithiane, oxepine and azepine.
  • aromatic bicyclic heterocyclic groups in which each mono- cycle is 5- to 7-membered are indolizine, indole, isoindole, benzofuran, benzo- pyran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridines, pyrazolotriazine (such as pyrazolo- 1,3,4-triazine), pyrazolopyrimidine and pteridine groups.
  • the saturated and unsaturated derivatives of these groups are examples of saturated, or unsaturated, bicyclic heterocyclic groups.
  • aromatic tricyclic heterocyclic groups are those consisting of 5- to 7-membered monocycles such as acridine or carbazole.
  • the aromatic carbocyclic radicals are preferably Ce-Cis. Among these, mention may be made especially of phenyl, naphthyl, anthryl and phenanthryl radicals.
  • Saturated carbocyclic radicals are especially cycloalkyl radicals, preferably C 3 -Ci8 and better still C3-Q0 cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norbornyl.
  • the unsaturated carbocyclic groups comprise one or more, preferably 1 to 3, ethylenic double bonds and generally consist of 6 to 18 and better still from 6 to 10 carbon atoms.
  • examples of these are cycloalkenyl radicals, and especially cyclohexenyl radicals.
  • alkylene represents a linear or branched divalent hydrocarbon chain containing from 1 to 14, preferably from 1 to 10 and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • Preferred examples of alkylene chains are methylene, ethylene and propylene chains.
  • R 1 represents an optionally substituted aromatic carbocyclic radical; an optionally substituted aromatic heterocyclic radical; an optionally substituted heterocyclic radical with an aromatic moiety; -E-Q, in which E represents alkylene and Q represents amino, alkylamino or dialkylamino; -E-Ar, in which E represents alkenylene and Ar represents an optionally substituted aromatic carbocyclic radical, an optionally substituted aromatic heterocyclic radical or an optionally substituted radical with an aromatic moiety.
  • heterocycle with an aromatic moiety means a heterocycle consisting of one or more monocycles each preferably being 5- to 7-membered, in which at least one of the monocycles is aromatic and at least one of the monocycles is heterocyclic, and in which the monocycles are ortho- or peri-fused in pairs.
  • the non-aromatic monocycles may be saturated or unsaturated and that the aromatic monocycle is heterocyclic or non-heterocyclic.
  • at least one of the monocycles of the heterocycle with an aromatic moiety is non-aromatic.
  • the heterocyclic monocycle(s) contain(s) one or more endocyclic hetero atoms (preferably 1 to 4 and better still 1 to 3) chosen from O, N and S, optionally in oxidized form (in the case of S or N).
  • the carbocyclic aromatic monocycles of the heterocycle with an aromatic moiety are preferably phenyl nuclei.
  • heterocyclic aromatic monocycles of the heterocycle with an aryl moiety are preferably pyridine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazine, oxazole, oxadiazole, triazole or thiadiazole nuclei.
  • heterocyclic saturated monocycles of the heterocycle with an aryl moiety are, for example, tetrahydrofuran, dioxolane, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, trithiane, oxepine or azepine nuclei.
  • the heterocycle with an aryl moiety may contain one or more unsaturated monocycles derived from the aromatic or heterocyclic monocycles described above.
  • the heterocycle with an aryl moiety is mono- or polycyclic, preferably bi- or tricyclic.
  • each of the saturated and/ or unsaturated monocycles of the heterocycle with an aryl moiety may be substituted by oxo.
  • heterocycles with an aryl moiety are especially the nuclei of the formulae:
  • each of the nuclei Bl to B12 comprises at least one hetero atom optionally in oxidized form, and R is chosen from O, S and N.
  • T represents O, S or SO2 and M represents N or C.
  • T represents O
  • in B2 T represents O or S
  • in B3, T represents S0 2 or O and M represents C or N
  • M, T or R represents N, it is preferably substituted by a hydrogen atom, alkyl or alkylcarbonyl.
  • the heterocycle with an aryl moiety has the formula:
  • a preferred sub-group of the compounds of the invention consists of compounds for which R 1 represents optionally substituted phenyl; optionally substituted naphthyl; optionally substituted pyridyl; optionally substituted quinolyl; optionally substituted benzofuryl; optionally substituted oxazolyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; optionally substituted coumarinyl; phenylalkenylene in which the phenyl nucleus is optionally substituted; 4-oxo-4H-benzopy rany 1.
  • the substituents on the carbocyclic and heterocyclic groups are preferably chosen from oxo; optionally halogenated alkyl; optionally halogenated alkoxy; cyano; halogen; carboxyl; alkylcarbonyl; alkoxycarbonyl; and aryl itself optionally substituted by alkyl, alkoxy, halogen, cyano or nitro.
  • the oxo radical is a substituent of the saturated or unsaturated nuclei.
  • the substituent is chosen from halogen atoms and the following groups: cyano; carboxyl; nitro; optionally halogenated (C ⁇ -C ⁇ )alkoxy (and preferably trifluoromethoxy); optionally halogenated (C 1 -C 1 )thioalkoxy, preferably (C 1 -C o)thioalkoxy; optionally halogenated and preferably perhalo (C ⁇ -C 4 )alkyl (and especially methyl or trifluoromethyl); (Q-C 14 )alkylcarbonyl in which the alkyl moiety is optionally halogenated; (C ⁇ -Cu)alkoxycarbonyl in which the alkoxy moiety is optionally halogenated; (C6-C 18 )arylcarbonyl in which the aryl moiety is optionally substituted one or more times by halogen, optionally halogenated (C ⁇ -C )alkyl and optionally halogenated (C ⁇ -C ⁇ 4
  • R* represents:
  • O-Q alkoxy optionally halogenated C ⁇ -C 4 alkyl; halogen; cyano; C ⁇ -C alkylthio; or carboxyl.
  • the invention is directed not only towards the compounds of the formula I, but also towards the salts thereof.
  • the compound of the formula I contains an acid function, and for example a carboxylic function, this compound may form a salt with a mineral or organic base.
  • salts with organic or mineral bases include the salts formed with metals and especially alkali metals, alkaline-earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminium) or with bases, for instance ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).
  • alkali metals alkaline-earth metals and transition metals
  • transition metals such as sodium, potassium, calcium, magnesium or aluminium
  • bases for instance ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-
  • this compound may form a salt with an organic or mineral acid.
  • the salts with organic or mineral acids are, for example, the hydro- chloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, nitrate, trifluoroacetate, citrate, maleate, fumarate, 2-naphthalenesulfonate and para-toluenesulf onate .
  • the invention also covers salts that allow a suitable separation or crystallization of the compounds of the formula I, such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid.
  • a preferred sub-group of salts consists of salts of the compounds of the formula I with pharmaceutically acceptable acids or bases.
  • Formula I includes all the types of geometrical isomers and stereoisomers of the compounds of the formula I.
  • (R3 , R4) (a , b) means that one from among R3 and R represents a and the other represents b.
  • the compounds of the invention may be simply prepared by nitrosation of the corresponding compounds of the formula II, of the formula: in which R f , i, W and R 1 are as defined above for formula I, by the action of a suitable nitrosating agent.
  • nitrosating agents are an alkali metal nitrite (and especially sodium or potassium nitrite) or a Ci-Q alkyl nitrite.
  • a preferred alkali metal nitrite that may be mentioned is sodium nitrite.
  • a preferred alkyl nitrite that may be mentioned is ethyl nitrite.
  • nitrosating agent known in the art, such as AgONO, BF 4 NO, HOSO3NO, nBuONO and tBuONO.
  • the amount of nitrosating agent required depends on the nature of the nitrosating agent used and on the reactivity of the substrate of the formula II. It is at least stoichiometric. In general, the molar ratio of the nitrosating agent to the substrate of the formula II ranges between 1 and 30 equivalents and preferably between 1 and 20 equivalents.
  • nitrosating agent is an alkali metal nitrite
  • a person skilled in the art may readily adapt the reaction conditions so as to use only 1 to 10, preferably from 1 to 5 and better still from 1 to 3 equivalents of nitrite relative to the substrate of the formula II.
  • nitrosating agent is an alkyl nitrite
  • the solvent is advantageously chosen from a cyclic or non-cyclic ether (such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether), an aliphatic or aromatic halohydrocarbon (such as chloro- form, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene).
  • the solvent is tetrahydrofuran, diethyl ether or chloroform.
  • the reaction temperature will generally be maintained between 15 and 70°C and better still between 17 and 60°C, in the case of AgONO, nBuONO and tBuONO.
  • the process will be performed in tetrahydrofuran or diethyl ether at a temperature of between 15 and 30°C, for example between 18 and 25°C.
  • the process will preferably be performed in chloro- form at a temperature of between 40 and 65°C, for example between 50 and 60°C.
  • nitrosating agent is AgONO, it is desirable to add thionyl chloride to the reaction medium.
  • the reaction is preferably carried out in an alkali metal salt of a lower (C1-C5) carboxylic acid, such as sodium acetate, at a reaction temperature of between -10°C and 30°C and better still between -5°C and 25°C.
  • a lower (C1-C5) carboxylic acid such as sodium acetate
  • a suitable solvent is a nitrile such as acetonitrile or isobutyronitrile. It is desirable to add pyridine or N-dimethyl- aminopyridine to the reaction medium, the reaction temperature being maintained between -30°C and 10°C and preferably between -25°C and 5°C.
  • the nitrosating agent is an alkali metal nitrite
  • the nitrosation reaction is preferably carried out in a strongly polar protic medium.
  • the reaction medium advantageously comprises water and a Bronsted or Lewis acid.
  • Suitable acids are a hydrohalic acid (such as HC1), sulfuric acid, Al 2 (S0 4 )s and acetic acid, and mixtures thereof.
  • an aliphatic alcohol of (C 1 -C )alkanol type (such as methanol or butanol) may be added.
  • a suitable reaction medium that may be selected is one of the following systems: - a mixture of methanol, water, hydrochloric acid and sulfuric acid;
  • the reaction of the alkali metal nitrite with the substrate of the formula II is advantageously carried out in a mixture of acetic acid and water, the ratio of the acetic acid to water ranging between 80:20 and 20:80 and preferably between 60:40 and 40:60, for example a 50:50 mixture.
  • the alkali metal nitrite, predissolved in water is added dropwise to a solution of the substrate of the formula II in acetic acid.
  • the reaction of the alkali metal nitrite with the substrate of the formula II is carried out at a temperature which depends on the reactivity of the species present; this temperature generally ranges between -10°C and 50°C and preferably between -5°C and 25°C.
  • a temperature of between 15°C and 25°C is particularly suitable.
  • the reaction of the alkyl nitrite with the substrate of the formula II is preferably carried out in the presence of a Ci-Q alkanol in a polar aprotic solvent.
  • Suitable alkanols include methanol, ethanol, iso- propanol and tert-butanol, ethanol being particularly preferred.
  • Preferred polar solvents are halohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitriles such as acetonitrile or isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphoramide; and mixtures of these solvents in any proportions.
  • halohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene
  • ethers such as diethyl ether, diisopropyl ether,
  • the nitrosation reaction (if an alkyl nitrite is used as nitrosating agent) is advantageously carried out in a mixture based on an aliphatic halohydrocarbon and a nitrile, and for example in a 90:10 to 50:50 and preferably a 90:10 to 70:30 mixture of chloroform and acetonitrile, in the presence of ethanol.
  • the amount of alkanol that needs to be incorporated into the reaction medium is not critical according to the invention. It generally represents 5% to 50% by weight of the reaction medium, and preferably from 5% to 25% by weight.
  • the reaction temperature is generally maintained at between -20°C and 20°C and preferably at between -10°C and 10°C, for example at between 0°C and 5°C.
  • a solution of the alkyl nitrite in the alkanol is added dropwise to the substrate of the formula II predissolved in the selected polar solvent.
  • the reaction is carried out in a strongly polar medium consisting of a mixture of a Ci- aliphatic carboxylic acid ((C 1 -C 4 )alkyl-COOH), the corresponding acid anhydride and the corresponding alkali metal carboxylate salt, in the presence of P2O5.
  • a reaction medium consisting of acetic acid, acetic anhydride, potassium acetate and P2O5 may be selected.
  • the reaction temperature is advantageously maintained between 10°C and
  • the compounds of the formula II may be prepared by carrying out one of the following processes.
  • T-CH 2 -R ! IN in which T represents a leaving group and R 1 is as defined above for formula II.
  • Suitable leaving groups are halogen atoms (and especially a chlorine or bromine atom) and groups of the formula -0-S ⁇ 2-alk and -0-S0 2 -Ar in which alk represents an optionally halogenated alkyl group such as trifluoro- methyl or methyl and Ar represents phenyl which is optionally substituted by alkyl, which is itself optionally halogenated.
  • This reaction is preferably carried out in the presence of an organic or mineral base.
  • bases are hydroxides (such as alkali metal hydroxides or ammonium hydroxides), carbonates (such as alkali metal carbonates or ammonium carbonates), alkali metal alkoxides, organic hydrides, alkali metal amides, ammonia and amines of the type such as triethylamine, tributylamine, pyridine or ⁇ -methylmorpholine.
  • reaction of the alcohol III with the compound of the formula IN is advantageously carried out in the presence of caesium carbonate as base.
  • T does not represent an iodine atom
  • This reaction is preferably performed in a polar aprotic solvent such as a halohydrocarbon (for example methylene chloride, chloroform, carbon tetra- chloride, dichloroethane, chlorobenzene or dichlorobenzene); an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a nitrile such as an acetonitrile or isobutyro- nitrile; an amide such as formamide, dimethylformamide, dimethylacetamide, ⁇ - methyl-2-pyrrolidinone or hexylmethylphosphorylamide; or a ketone such as acetone or 2-butanone.
  • a polar aprotic solvent such as a halohydrocarbon (for example methylene chloride, chloroform, carbon tetra- chloride, dichloro
  • the solvent is preferably acetone or 2-butanone.
  • the reaction temperature is set as a function of the reactivity of the species present and the nature of the solvent used. The temperature generally ranges between -10°C and 100°C. Usually, when the base used is an alkali metal or alkaline-earth metal carbonate, the process is performed at the reflux temperature of the solvent. In a particularly advantageous manner, the reaction of the alcohol III with the compound IN is carried out in the presence of CS2CO3, in a ketone solvent (such as acetone or 2-butanone) at a temperature of between 40 and 70°C.
  • a ketone solvent such as acetone or 2-butanone
  • the molar ratio of compound IN to compound III ranges between 0.8 and 2, preferably between 1 and 1.5, for example between 1.1 and 1.3, a slight excess of compound IN being desirable.
  • the amount of base to be introduced into the reaction medium is generally an excess relative to the molar amount of the compound of the formula III.
  • the molar ratio of the base used to the compound III ranges between 1 and 2 equivalents, for example between 1.1 and 1.3 equivalents.
  • the compounds of the formula II may be prepared by reacting an amine of the formula N:
  • W and R 1 are as defined above for formula II and Hal represents a halogen atom such as bromine or chlorine, preferably bromine.
  • This reaction is advantageously carried out in the presence of a base.
  • bases that may be selected are any one of those mentioned above.
  • an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or tert-butoxide will be selected, and will be introduced into the reaction medium in a proportion of 1 to 2 equivalents per one equivalent of compound NI, for example between 1.2 and 1.7 equivalents.
  • This reaction is generally carried out at a temperature of between 50 and 180°C and preferably at a temperature of between 80 and 150°C.
  • the temperature depends on the nature of the species present and especially the strength of the base and the reactivity of the compounds V and NI present.
  • the solvent is generally chosen from the polar aprotic solvents defined above.
  • Preferred solvents that may be mentioned include ethers and especially glymes such as 1,2-dimethoxy ethane, diethylene glycol dimethyl ether (diglyme) or triethylene glycol dimethyl ether (triglyme), diglyme being more particularly preferred.
  • the molar ratio of the amine V to the compound NI ranges between 1 and 2 and better still between 1 and 1.5, for example between 1.1 and 1.3.
  • Such a catalyst may be obtained by introducing into the reaction medium the system (dba) 3 Pd2 (tris(dibenzylideneacetone)dipalladium(O)) + BI ⁇ AP in which BI ⁇ AP is the diphosphine of the formula:
  • each of the catalytic substances (dba) 3 Pd 2 and BI ⁇ AP is introduced into the reaction medium in a proportion of less than 10% by weight.
  • the molar ratio of the BI ⁇ AP to the (dba) 3 Pd 2 ranges between 1.5 and 4 and preferably between 2 and 3.
  • R 4 and i are as defined for formula I, which are novel, form an integral part of the invention.
  • a first sub-group of these compounds consists of compounds in which W represents S.
  • preferred compounds are those for which R 1 represents optionally substituted pyridyl, for example optionally substituted 3-pyridyl.
  • a second sub-group of these compounds is composed of the compounds of the formula Ila:
  • R 1 represents optionally substituted naphthyl; unsubstituted pyridyl; optionally substituted coumarinyl; optionally substituted oxazolyl; optionally substituted benzoxazolyl; optionally substituted benzofuryl; optionally substituted 4-oxo-4H-benzo- pyranyl; cinnamyl which is optionally substituted on the phenyl nucleus; aminoalkyl; alkylaminoalkyl; or dialkylaminoalkyl; phenyl which is substituted by one or more substituents chosen from the following groups: cyano; carboxyl; nitro; halogenated (C ⁇ -Q)alkoxy (and preferably trifluoromethoxy); optionally halogenated (C ⁇ -C 1 )thioalkoxy, preferably (C ⁇ -C 1 o)thioalkoxy; halogenated and preferably perhalo (C ⁇ -
  • R 1 represents dialkylaminoalkyl
  • R 1 it is preferred for R 1 to be dialkylamino(C3-C ⁇ o)alkyl or di(C3-C 1 o)alkylamino- (C ⁇ -C 2 )alkyl.
  • R 1 represents substituted phenyl
  • the preferred substituents are cyano, halogenated (C 1 -C ⁇ 4 )alkyl, carboxyl and (C 1 -C 1 )alkoxycarbonyl groups in which the alkoxy moiety is optionally halogenated, better still trifluoromethyl, cyano, carboxyl or methoxy carbonyl.
  • preferred compounds are those for which R 1 represents optionally substituted pyridyl, for example optionally substituted 3- pyridyl.
  • R 1 and R l are those mentioned above.
  • the compounds of the formula II above be used as intermediates in the synthesis of the compounds of the formula I, but also they show antioxidant activity that makes them capable of limiting the destructive activity of oxidative free-radical species.
  • the invention relates to a pharma- ceutical composition
  • a pharma- ceutical composition comprising at least one compound of the formula I as defined above, in combination with at least one pharmaceutically acceptable exci- pient.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the formula II, in combination with at least one pharmaceutically acceptable excipient.
  • a solid composition for oral administration is prepared by adding to the active principle a filler and, where appropriate, a binder, a crumbling agent, a lubricant, a colorant or a flavour corrector, and by shaping the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
  • fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide
  • binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethyl- cellulose, calcium citrate, dextrin and pectin.
  • lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils.
  • the colorant may be any colorant permitted for use in medicinal products.
  • flavour correctors include cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Needless to say, the tablet or granulate may be suitably coated with sugar, gelatin or the like.
  • An injectable form containing the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer agent, a suspending agent, solubilizing agent, a stabilizer, a tonicity agent and/ or a preserving agent, and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a conventional process.
  • the injectable form obtained may be freeze-dried by a conventional process.
  • suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxy- methylcellulose and polyethoxylated sorbitan monolaurate.
  • solubilizing agents include castor oil solidified with polyoxy- ethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
  • the stabilizer encompasses sodium sulfite, sodium metasulfite and ether
  • the preserving agent encompasses methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • the substances according to the invention are as a rule preferably administered in doses between approximately 0.1 and 100 mg, in particular between 1 and 10 mg, per dose unit.
  • the daily dose is preferably between approximately 0.001 and 10 mg/kg of body weight.
  • the specific dose for each patient depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
  • the invention relates to the use of a compound of the formula I as defined above, for the preparation of a medicinal product for treating pathologies characterized by a lack of nitrogen monoxide production and/ or an oxidative stress condition.
  • the invention relates to the use of a compound of the formula II for the preparation of an antioxidant medicinal product that may be used as a free-radical scavenger.
  • the nitrogen monoxide-donating effect of the compounds of the invention of the formula I may be demonstrated simply by carrying out the following procedure.
  • a solution of a compound of the invention spontaneously releases nitric oxide.
  • the nitrite ions resulting therefrom are titrated by colorimetry by means of a specific reagent (Griess).
  • a specific reagent Gibcos's reagent
  • bacterial nitrate reductase is added to the reaction medium to reduce the nitrate ions formed.
  • the reactions and measurements are performed in transparent 96-well plates.
  • the test products are dissolved at the time of use, at a concentration of 3 mM in dimethyl sulfoxide.
  • 95 ⁇ l of a reagent containing nitrate reductase (0.18 U/ml in 100 mM pH 7.5 PBS buffer, 210 ⁇ M ⁇ -NADPH, 5 ⁇ M FAD) and 5 ⁇ l of the solution of the test product (final concentration of 150 ⁇ M) are then added to each well. After stirring, the mixtures are incubated for 4 hours at 37°C. The reaction is then stopped by adding 100 ⁇ l of Griess' reagent (Sigma G4410).
  • the compounds of the formula I and the compounds of the formula II of the invention show antioxidant activity, which makes them suitable for reducing the biological activity of oxidative free-radical species.
  • the antioxidant activity of the compounds of the formulae I and II is especially revealed in vitro, for example by evaluating their ability to prevent the chemical oxidation of low molecular weight human lipoproteins, as described previously (Table 2).
  • the mixture is then incubated for a further 22 hours, to take a second reading under the same conditions.
  • the difference between the two values obtained is the measurement of the oxidation of the LDLs in solution. This difference is proportionately smaller the greater the antioxidant power of the test product.
  • Probucol is used as reference product at a concentration of 10 ⁇ M.
  • IC50 50% inhibitory concentrations (IC50) for the oxidation, obtained for some of the compounds of the invention, are given in Table 2 below. They are produced from three concentrations of product.
  • the frequency of the NMR machine used to record the proton spectra of the examples given below is 300 MHz.
  • s denotes a singlet;
  • d denotes a doublet;
  • t denotes a triplet;
  • q denotes a quartet and
  • m denotes a multiplet.
  • m.p. denotes the melting point.
  • racemic BINAP 2,2-bis(diphenylphosphino)-l,l-binaphthyl
  • the reaction medium is heated at 130°C for 18 hours, and then poured into
  • Example 2a Obtained as in Example 2a starting with 3-[(4-bromophenoxy)methyl]- pyridine and ethyl 4-aminobenzoate.
  • Example 27 The compounds of Examples 27 to 33 were obtained as in Example 2.
  • the compounds of Example 26 were obtained as in Example 2, starting with 3- ⁇ [(4-bromophenyl)thio]methyl ⁇ pyridine, prepared according to Haviv F. et al., J. Med. Chem. (1983) 26, 218-222.

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Abstract

The present invention relates to compounds of the formula (I): in which: W, Rt, i and R1 are as defined in Claim 1, that can be used for treating pathologies characterized by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide (NO°).

Description

NITROSO DIPHENYLAMINE DERIVATIVES AS NITROGEN MONOXIDE GENERATING AGENTS
The invention relates to nitroso diphenylamine derivatives, to pharmaceutical compositions comprising them and to their use for preparing medicinal products that can be used for treating pathologies characterized by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide
(NO#).
Nitrogen monoxide (or nitric oxide NO*) is an important mediator in the physiology of cardiovascular, immune and central and peripheral nervous sys- terns. It acts, among other mechanisms, by activation of guanylate cyclase.
Its action is ubiquitous: it is vasodilatory and gives a basal tonus to the entire vascular system. It has anti-clotting activity: its production by normal endothelial cells inhibits the formation of a thrombus. It is anti-proliferative, especially on the smooth muscle cells underlying the endothelial cells. It also inhibits the adhesion of monocytes to the vascular wall and, consequently, its conversion to a macrophage. It regulates endothelial permeability.
There is thus, in the physiological state, a situation of equilibrium between the production of free-radical species and the availability of NO.
Disequilibrium of this balance, the result of which is an excess of superoxide anions in the face of a lack of NO, leads to the development of many pathologies.
Oxidative stress is generated by many factors, for instance hyperglycaemia, dyslipidaemias (production of oxidized, highly atherogenic "low-density" lipoproteins (LDL)), hypoxia, insulin resistance, atherosclerosis, revascularization techniques (including angioplasties with or without a stent), chronic rejection after transplantation, the majority of inflammatory processes, and addiction to smoking. Oxidative stress is characterized at the vascular level by an increase in free radicals, in particular of superoxide anions (O2* "). These θ2*~ radicals are capable of trapping the NO endogenously produced by the endothelial cells to form free-radical species that are even more deleterious, for instance peroxynitrites.
Among the pathologies concerned by a lack of production of endothelial nitrogen monoxide and/ or an increase in tissue oxidative stress, mention may be made of (Recent Progress in Hormone Research (1988), 53, 43-60, table V): ■ atherosclerosis-associated ischaemias (lipid peroxidation, development, progress and rupture of atheroma plaques, platelet activation); restenosis after angioplasty; ■ stenosis after vascular surgery; diabetes; insulin resistance; retinal and renal microvascular complications of diabetes; the cardiovascular risk of diabetes in so far as it is not explained by the conventional factors; male erectile dysfunction; cerebral hypoxia; chronic rejection after organ transplantation; articular pathologies. The administration of active principles capable of reducing the biological activity of oxidative free-radical species (such as superoxide anions and peroxynitrites) and of increasing the content of nitrogen monoxide by a two-fold mechanism: non-conversion into peroxynitrites and exogenous supply, is thus particularly desirable in the treatment of these pathologies. The present invention provides compounds that have these two effects, antioxidant and nitrogen monoxide-donating, in the same molecule.
These compounds are capable of spontaneously generating nitrogen monoxide under physiological conditions and of trapping oxidative free radicals. The spontaneous NO-donating effect does not induce a tachyphylactic effect, unlike compounds that are substrates of NO synthase, and unlike nitro derivatives or derivatives of oxadiazole or oxatriazole type which mobilize endogenous thiols groups to release NO.
Via the spontaneous NO-donating effect, pharmacological NO activity may be achieved in pathologies in which the activity of NO synthase is insufficient.
More specifically, the invention relates to the compounds of the formula I:
Figure imgf000004_0001
in which:
- W represents O or S; - the radicals Rf, which may be identical or different, represent a halogen atom; a saturated or unsaturated aliphatic hydrocarbon group, optionally interrupted by O and/ or S and optionally halogenated; nitro; carboxyl or cyano;
- i represents an integer from 0 to 5, preferably 0, 1 or 2;
- R1 represents an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical; -E-Q, in which E represents optionally substituted alkylene or alkenylene and Q represents an amino group which is optionally substituted by one or two saturated or unsaturated aliphatic hydrocarbon groups; or -E-Ar, in which E is as defined above and Ar represents an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical or alternatively an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; or an optionally halogenated, saturated aliphatic hydrocarbon group; with the exclusion of the compounds of the formula I in which i is 1; R4 represents 2-methyl and R1 represents -CHs, and their pharmaceutically tolerable derivatives, solvates and stereoisomers.
Hydrates and solvates are understood as meaning, for example, the hemi-, mono- or dihydrates, solvates are understood as meaning, for example, alcohol addition compounds such as, for example, with methanol or ethanol.
The term pharmaceutically tolerable derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.
The term prodrug derivatives is taken to mean, for example, compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to give the effective compounds according to the invention.
These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
The invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of stereoisomeric compounds.
The expression "halogen atom" means a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or fluorine atom.
The expression "aliphatic hydrocarbon group" means a hydrocarbon group containing a linear or branched chain, preferably containing from 1 to 14 carbon atoms, preferably from 1 to 10 and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. Examples of saturated aliphatic hydrocarbon groups are alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1- methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl- butyl, 1-methyl-l-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4- dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl. If the aliphatic hydrocarbon group is unsaturated, it may contain one or two unsaturations. The unsaturations are either of the ethylenic or acetylenic type. They are preferably ethylenic. The unsaturated chains contain at least two carbon atoms. Alkenyl and alkynyl groups are examples of unsaturated aliphatic hydrocarbon groups.
Examples of unsaturated aliphatic hydrocarbon groups are allyl and vinyl.
The expression "optionally interrupted by O and/ or S" means that any carbon atom of the hydrocarbon chain may be replaced with an oxygen or sulfur atom, where it is not possible for this carbon atom to be located at the free end of the hydrocarbon chain. The hydrocarbon chain, which may be alkyl, may contain a plurality of oxygen and/ or sulfur atoms, the hetero atoms preferably being separated from each other by at least one carbon atom and better still by at least two carbon atoms. An example of an aliphatic hydrocarbon chain which is interrupted by O or S is alkoxy or thioalkoxy.
In the context of the invention, the expression "saturated, unsaturated and/ or aromatic cyclic (carbocyclic or heterocyclic) radical" means that the same radical may contain a saturated moiety and/ or an unsaturated moiety and/ or an aromatic moiety.
The carbocyclic and heterocyclic radicals include mono- and polycyclic radicals; these radicals preferably denote mono-, bi- or tricyclic radicals. In the case of polycyclic radicals, it should be understood that these consist of monocycles fused in pairs (for example ortho-fused or peri-fused), i.e. having at least two carbon atoms in common. Preferably, each monocycle is 3- to 8- membered and better still 5- to 7-membered.
The heterocyclic groups comprise hetero atoms generally chosen from O, N and S, optionally in oxidized form (in the case of S and N).
Preferably, each of the monocycles constituting the heterocycle contains from 1 to 4 hetero atoms and better still from 1 to 3 hetero atoms. Examples of aromatic heterocyclic groups are 5- to 7-membered mono- cyclic heteroaryls, such as pyridine, furan, thiophene, pyrrole, pyrazole, imid- azole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole. Examples of unsaturated 7-membered heterocycles include trithiatri- azepines and trithiadiazepines. Examples of 5- to 7-membered saturated mono- cyclic heterocycles especially include tetrahydrofuran, dioxolane, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, trithiane, oxepine and azepine. Examples of aromatic bicyclic heterocyclic groups in which each mono- cycle is 5- to 7-membered are indolizine, indole, isoindole, benzofuran, benzo- pyran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridines, pyrazolotriazine (such as pyrazolo- 1,3,4-triazine), pyrazolopyrimidine and pteridine groups.
The saturated and unsaturated derivatives of these groups are examples of saturated, or unsaturated, bicyclic heterocyclic groups.
Examples of aromatic tricyclic heterocyclic groups are those consisting of 5- to 7-membered monocycles such as acridine or carbazole. The aromatic carbocyclic radicals are preferably Ce-Cis. Among these, mention may be made especially of phenyl, naphthyl, anthryl and phenanthryl radicals.
Saturated carbocyclic radicals are especially cycloalkyl radicals, preferably C3-Ci8 and better still C3-Q0 cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norbornyl.
The unsaturated carbocyclic groups comprise one or more, preferably 1 to 3, ethylenic double bonds and generally consist of 6 to 18 and better still from 6 to 10 carbon atoms. Examples of these are cycloalkenyl radicals, and especially cyclohexenyl radicals. According to the invention, "alkylene" represents a linear or branched divalent hydrocarbon chain containing from 1 to 14, preferably from 1 to 10 and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. Preferred examples of alkylene chains are methylene, ethylene and propylene chains. The term "alkenylene" means a linear or branched, divalent aliphatic hydrocarbon chain comprising one or more ethylenic unsaturations. Examples of these are C2-C14 and preferably C2-C10 chains, for example C2-Cό chains, such as -CH=C- and -CH=CH-CH2-.
In a particularly advantageous manner, R1 represents an optionally substituted aromatic carbocyclic radical; an optionally substituted aromatic heterocyclic radical; an optionally substituted heterocyclic radical with an aromatic moiety; -E-Q, in which E represents alkylene and Q represents amino, alkylamino or dialkylamino; -E-Ar, in which E represents alkenylene and Ar represents an optionally substituted aromatic carbocyclic radical, an optionally substituted aromatic heterocyclic radical or an optionally substituted radical with an aromatic moiety. According to the invention, the expression "heterocycle with an aromatic moiety" means a heterocycle consisting of one or more monocycles each preferably being 5- to 7-membered, in which at least one of the monocycles is aromatic and at least one of the monocycles is heterocyclic, and in which the monocycles are ortho- or peri-fused in pairs. It should be understood that the non-aromatic monocycles may be saturated or unsaturated and that the aromatic monocycle is heterocyclic or non-heterocyclic. Furthermore, at least one of the monocycles of the heterocycle with an aromatic moiety is non-aromatic. The heterocyclic monocycle(s) contain(s) one or more endocyclic hetero atoms (preferably 1 to 4 and better still 1 to 3) chosen from O, N and S, optionally in oxidized form (in the case of S or N).
The carbocyclic aromatic monocycles of the heterocycle with an aromatic moiety are preferably phenyl nuclei.
The heterocyclic aromatic monocycles of the heterocycle with an aryl moiety are preferably pyridine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazine, oxazole, oxadiazole, triazole or thiadiazole nuclei. The heterocyclic saturated monocycles of the heterocycle with an aryl moiety are, for example, tetrahydrofuran, dioxolane, imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, trithiane, oxepine or azepine nuclei. The heterocycle with an aryl moiety may contain one or more unsaturated monocycles derived from the aromatic or heterocyclic monocycles described above.
The heterocycle with an aryl moiety is mono- or polycyclic, preferably bi- or tricyclic.
It should be understood that each of the saturated and/ or unsaturated monocycles of the heterocycle with an aryl moiety may be substituted by oxo.
Examples of heterocycles with an aryl moiety are especially the nuclei of the formulae:
Figure imgf000009_0001
in which M and T are chosen, independently, from O, S, S02, N and C, it being understood that each of the nuclei Bl to B12 comprises at least one hetero atom optionally in oxidized form, and R is chosen from O, S and N. According to the preferred embodiments of the invention:
T represents O, S or SO2 and M represents N or C. Preferably, in Bl, T represents O ; in B2, T represents O or S ; in B3, T represents S02 or O and M represents C or N ; in B4, R represents S ; in B5, T represents O ; in B6, T represents O ; in B7, T represents O ; in B8, T represents O ; in B9, R represents S ; in BIO, T represents O ; in Bll, T represents O ; in B12, R represents N.
If M, T or R represents N, it is preferably substituted by a hydrogen atom, alkyl or alkylcarbonyl.
Preferably, the heterocycle with an aryl moiety has the formula:
Figure imgf000010_0001
A preferred sub-group of the compounds of the invention consists of compounds for which R1 represents optionally substituted phenyl; optionally substituted naphthyl; optionally substituted pyridyl; optionally substituted quinolyl; optionally substituted benzofuryl; optionally substituted oxazolyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; optionally substituted coumarinyl; phenylalkenylene in which the phenyl nucleus is optionally substituted; 4-oxo-4H-benzopy rany 1.
The substituents on the carbocyclic and heterocyclic groups are preferably chosen from oxo; optionally halogenated alkyl; optionally halogenated alkoxy; cyano; halogen; carboxyl; alkylcarbonyl; alkoxycarbonyl; and aryl itself optionally substituted by alkyl, alkoxy, halogen, cyano or nitro. The oxo radical is a substituent of the saturated or unsaturated nuclei.
More generally, the substituent is chosen from halogen atoms and the following groups: cyano; carboxyl; nitro; optionally halogenated (Cι-Cι )alkoxy (and preferably trifluoromethoxy); optionally halogenated (C1-C1 )thioalkoxy, preferably (C1-C o)thioalkoxy; optionally halogenated and preferably perhalo (Cι-C 4)alkyl (and especially methyl or trifluoromethyl); (Q-C14)alkylcarbonyl in which the alkyl moiety is optionally halogenated; (Cι-Cu)alkoxycarbonyl in which the alkoxy moiety is optionally halogenated; (C6-C18)arylcarbonyl in which the aryl moiety is optionally substituted one or more times by halogen, optionally halogenated (Cι-C )alkyl and optionally halogenated (Cι-Cι4)alkoxy; (Cι-Cι4)- alkylcarbonylamino in which the alkyl moiety is optionally halogenated; (Cβ-Ciβ)- arylcarbonylamino, in which the aryl is optionally substituted one or more times by halogen, optionally halogenated (Q-C1 )alkyl and optionally halogenated (Gι-C1 )alkoxy; and (C6-C18)aryl which is optionally substituted one or more times by halogen, optionally halogenated (Cι-C14)alkyl, such as trifluoromethyl, and optionally halogenated (Cι-C4)alkoxy, such as trifluoromethoxy. The heterocyclic and carbocyclic groups may be substituted one or more times by one or more of the substituents listed above, preferably one to three times, for example once or twice.
Preferably, R* represents:
O-Q alkoxy; optionally halogenated Cι-C4 alkyl; halogen; cyano; Cι-C alkylthio; or carboxyl.
The invention is directed not only towards the compounds of the formula I, but also towards the salts thereof.
If the compound of the formula I contains an acid function, and for example a carboxylic function, this compound may form a salt with a mineral or organic base.
Examples of salts with organic or mineral bases that may be mentioned include the salts formed with metals and especially alkali metals, alkaline-earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminium) or with bases, for instance ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).
If the compound of the formula I contains a basic function, and for example a nitrogen atom, this compound may form a salt with an organic or mineral acid. The salts with organic or mineral acids are, for example, the hydro- chloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, nitrate, trifluoroacetate, citrate, maleate, fumarate, 2-naphthalenesulfonate and para-toluenesulf onate . The invention also covers salts that allow a suitable separation or crystallization of the compounds of the formula I, such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid. However, a preferred sub-group of salts consists of salts of the compounds of the formula I with pharmaceutically acceptable acids or bases.
Formula I includes all the types of geometrical isomers and stereoisomers of the compounds of the formula I.
The compounds illustrated in the examples are preferred. Among these compounds, mention will be made more specifically of the following compounds of the formula:
Figure imgf000012_0001
in which:
W = O ; (Rs , R_) = (-H, 4-cyano) : Example 29b W = O ; (Rs , R4) = (-H, 3-cyano) : Example 31b ■ W = S ; (R3 , R4) = (-H, 4-methoxy) : Example 26b
W = O ; (Rs , R4) = (-H , 4-chloro) : Example 28b
it being understood that (R3 , R4) = (a , b) means that one from among R3 and R represents a and the other represents b. The compounds of the invention may be simply prepared by nitrosation of the corresponding compounds of the formula II, of the formula:
Figure imgf000013_0001
in which Rf, i, W and R1 are as defined above for formula I, by the action of a suitable nitrosating agent.
Particularly advantageous examples of nitrosating agents are an alkali metal nitrite (and especially sodium or potassium nitrite) or a Ci-Q alkyl nitrite.
A preferred alkali metal nitrite that may be mentioned is sodium nitrite.
A preferred alkyl nitrite that may be mentioned is ethyl nitrite.
Nevertheless, a person skilled in the art can use any nitrosating agent known in the art, such as AgONO, BF4NO, HOSO3NO, nBuONO and tBuONO. The amount of nitrosating agent required depends on the nature of the nitrosating agent used and on the reactivity of the substrate of the formula II. It is at least stoichiometric. In general, the molar ratio of the nitrosating agent to the substrate of the formula II ranges between 1 and 30 equivalents and preferably between 1 and 20 equivalents. If the nitrosating agent is an alkali metal nitrite, a person skilled in the art may readily adapt the reaction conditions so as to use only 1 to 10, preferably from 1 to 5 and better still from 1 to 3 equivalents of nitrite relative to the substrate of the formula II.
If the nitrosating agent is an alkyl nitrite, it is preferable to perform the process in the presence of 10 to 25 molar equivalents of nitrite, and preferably from 15 to 20 molar equivalents, relative to the amount of substrate of the formula II.
The choice of solvent and the temperature conditions depend especially on the type of nitrosating agent selected for the reaction. If the nitrosating agent is AgONO, nBuONO or tBuONO, the solvent is advantageously chosen from a cyclic or non-cyclic ether (such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether), an aliphatic or aromatic halohydrocarbon (such as chloro- form, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene). Preferably, the solvent is tetrahydrofuran, diethyl ether or chloroform.
The reaction temperature will generally be maintained between 15 and 70°C and better still between 17 and 60°C, in the case of AgONO, nBuONO and tBuONO.
More particularly, in the case of AgONO and nBuONO, the process will be performed in tetrahydrofuran or diethyl ether at a temperature of between 15 and 30°C, for example between 18 and 25°C.
In the case of tBuONO, the process will preferably be performed in chloro- form at a temperature of between 40 and 65°C, for example between 50 and 60°C.
If the nitrosating agent is AgONO, it is desirable to add thionyl chloride to the reaction medium.
If the nitrosating agent is HOS03NO, the reaction is preferably carried out in an alkali metal salt of a lower (C1-C5) carboxylic acid, such as sodium acetate, at a reaction temperature of between -10°C and 30°C and better still between -5°C and 25°C.
If the nitrosating agent is BF NO, a suitable solvent is a nitrile such as acetonitrile or isobutyronitrile. It is desirable to add pyridine or N-dimethyl- aminopyridine to the reaction medium, the reaction temperature being maintained between -30°C and 10°C and preferably between -25°C and 5°C.
If the nitrosating agent is an alkali metal nitrite, the nitrosation reaction is preferably carried out in a strongly polar protic medium. The reaction medium advantageously comprises water and a Bronsted or Lewis acid.
Suitable acids are a hydrohalic acid (such as HC1), sulfuric acid, Al2(S04)s and acetic acid, and mixtures thereof.
According to one particular embodiment of the invention, an aliphatic alcohol of (C1-C )alkanol type (such as methanol or butanol) may be added.
Thus, a suitable reaction medium that may be selected is one of the following systems: - a mixture of methanol, water, hydrochloric acid and sulfuric acid;
- a mixture of water and sulfuric acid; - a mixture of water and acetic acid;
- a mixture of water, butanol and hydrochloric acid;
- a mixture of water and A12(S0 )3, or
- a mixture of water and hydrochloric acid. The reaction of the alkali metal nitrite with the substrate of the formula II is advantageously carried out in a mixture of acetic acid and water, the ratio of the acetic acid to water ranging between 80:20 and 20:80 and preferably between 60:40 and 40:60, for example a 50:50 mixture. According to one preferred embodiment, the alkali metal nitrite, predissolved in water, is added dropwise to a solution of the substrate of the formula II in acetic acid.
The reaction of the alkali metal nitrite with the substrate of the formula II is carried out at a temperature which depends on the reactivity of the species present; this temperature generally ranges between -10°C and 50°C and preferably between -5°C and 25°C. When the nitrosation reaction is carried out in a mixture of acetic acid and water, a temperature of between 15°C and 25°C is particularly suitable.
The reaction of the alkyl nitrite with the substrate of the formula II is preferably carried out in the presence of a Ci-Q alkanol in a polar aprotic solvent. Suitable alkanols that may be mentioned include methanol, ethanol, iso- propanol and tert-butanol, ethanol being particularly preferred.
Preferred polar solvents are halohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitriles such as acetonitrile or isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphoramide; and mixtures of these solvents in any proportions.
The nitrosation reaction (if an alkyl nitrite is used as nitrosating agent) is advantageously carried out in a mixture based on an aliphatic halohydrocarbon and a nitrile, and for example in a 90:10 to 50:50 and preferably a 90:10 to 70:30 mixture of chloroform and acetonitrile, in the presence of ethanol.
The amount of alkanol that needs to be incorporated into the reaction medium is not critical according to the invention. It generally represents 5% to 50% by weight of the reaction medium, and preferably from 5% to 25% by weight.
If the nitrosating agent is an alkyl nitrite, the reaction temperature is generally maintained at between -20°C and 20°C and preferably at between -10°C and 10°C, for example at between 0°C and 5°C. According to one preferred embodiment of the invention, a solution of the alkyl nitrite in the alkanol is added dropwise to the substrate of the formula II predissolved in the selected polar solvent.
As a variant, the reaction is carried out in a strongly polar medium consisting of a mixture of a Ci- aliphatic carboxylic acid ((C1-C4)alkyl-COOH), the corresponding acid anhydride and the corresponding alkali metal carboxylate salt, in the presence of P2O5. By way of example, a reaction medium consisting of acetic acid, acetic anhydride, potassium acetate and P2O5 may be selected. In this case, the reaction temperature is advantageously maintained between 10°C and
100°C and preferably between 15°C and 85°C. The compounds of the formula II may be prepared by carrying out one of the following processes.
A - Preparation of the compounds of the formula II in which W represents O One method for preparing the compounds of the formula II in which W represents O consists in reacting a compound of the formula III:
Figure imgf000016_0001
in which: Rl and i are as defined above for formula II, with a compound of the formula IN :
T-CH2-R! IN in which T represents a leaving group and R1 is as defined above for formula II.
Examples of suitable leaving groups are halogen atoms (and especially a chlorine or bromine atom) and groups of the formula -0-Sθ2-alk and -0-S02-Ar in which alk represents an optionally halogenated alkyl group such as trifluoro- methyl or methyl and Ar represents phenyl which is optionally substituted by alkyl, which is itself optionally halogenated.
This reaction is preferably carried out in the presence of an organic or mineral base. Examples of bases are hydroxides (such as alkali metal hydroxides or ammonium hydroxides), carbonates (such as alkali metal carbonates or ammonium carbonates), alkali metal alkoxides, organic hydrides, alkali metal amides, ammonia and amines of the type such as triethylamine, tributylamine, pyridine or Ν-methylmorpholine.
The reaction of the alcohol III with the compound of the formula IN is advantageously carried out in the presence of caesium carbonate as base.
According to one preferred embodiment of the invention, if T does not represent an iodine atom, it is desirable to add to the reaction medium a few crystals of alkali metal iodide, in catalytic amount.
This reaction is preferably performed in a polar aprotic solvent such as a halohydrocarbon (for example methylene chloride, chloroform, carbon tetra- chloride, dichloroethane, chlorobenzene or dichlorobenzene); an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a nitrile such as an acetonitrile or isobutyro- nitrile; an amide such as formamide, dimethylformamide, dimethylacetamide, Ν- methyl-2-pyrrolidinone or hexylmethylphosphorylamide; or a ketone such as acetone or 2-butanone. The solvent is preferably acetone or 2-butanone. The reaction temperature is set as a function of the reactivity of the species present and the nature of the solvent used. The temperature generally ranges between -10°C and 100°C. Usually, when the base used is an alkali metal or alkaline-earth metal carbonate, the process is performed at the reflux temperature of the solvent. In a particularly advantageous manner, the reaction of the alcohol III with the compound IN is carried out in the presence of CS2CO3, in a ketone solvent (such as acetone or 2-butanone) at a temperature of between 40 and 70°C.
Usually, the molar ratio of compound IN to compound III ranges between 0.8 and 2, preferably between 1 and 1.5, for example between 1.1 and 1.3, a slight excess of compound IN being desirable.
The amount of base to be introduced into the reaction medium is generally an excess relative to the molar amount of the compound of the formula III. Preferably, the molar ratio of the base used to the compound III ranges between 1 and 2 equivalents, for example between 1.1 and 1.3 equivalents.
To carry out this reaction, a person skilled in the art may be inspired by Synthetic Comm. (1995), 25, 1367 - 1370. B - General method for preparing the compounds of the formula II
As a variant, the compounds of the formula II may be prepared by reacting an amine of the formula N:
Figure imgf000018_0001
in which Rf and i are as defined above for formula II, with a compound of the formula VI:
Figure imgf000018_0002
in which W and R1 are as defined above for formula II and Hal represents a halogen atom such as bromine or chlorine, preferably bromine. This reaction is advantageously carried out in the presence of a base. Examples of bases that may be selected are any one of those mentioned above. Preferably, an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or tert-butoxide will be selected, and will be introduced into the reaction medium in a proportion of 1 to 2 equivalents per one equivalent of compound NI, for example between 1.2 and 1.7 equivalents.
This reaction is generally carried out at a temperature of between 50 and 180°C and preferably at a temperature of between 80 and 150°C. The temperature depends on the nature of the species present and especially the strength of the base and the reactivity of the compounds V and NI present.
The solvent is generally chosen from the polar aprotic solvents defined above. Preferred solvents that may be mentioned include ethers and especially glymes such as 1,2-dimethoxy ethane, diethylene glycol dimethyl ether (diglyme) or triethylene glycol dimethyl ether (triglyme), diglyme being more particularly preferred.
According to one preferred embodiment of the invention, the molar ratio of the amine V to the compound NI ranges between 1 and 2 and better still between 1 and 1.5, for example between 1.1 and 1.3.
Advantageously, it is desirable to introduce a palladium(O) catalyst into the reaction medium.
Such a catalyst may be obtained by introducing into the reaction medium the system (dba)3Pd2 (tris(dibenzylideneacetone)dipalladium(O)) + BIΝAP in which BIΝAP is the diphosphine of the formula:
Figure imgf000019_0001
By way of illustration, each of the catalytic substances (dba)3Pd2 and BIΝAP is introduced into the reaction medium in a proportion of less than 10% by weight. In a particularly advantageous manner, the molar ratio of the BIΝAP to the (dba)3Pd2 ranges between 1.5 and 4 and preferably between 2 and 3. To carry out this reaction, a person skilled in the art may be inspired by J. Org. Chem. (2000), 65, 1144 - 1157.
The compounds of the formula II:
Figure imgf000020_0001
in which R4 and i are as defined for formula I, which are novel, form an integral part of the invention.
A first sub-group of these compounds consists of compounds in which W represents S.
More particularly, preferred compounds are those for which R1 represents optionally substituted pyridyl, for example optionally substituted 3-pyridyl.
A second sub-group of these compounds is composed of the compounds of the formula Ila:
Figure imgf000020_0002
in which i and R* are as defined above for formula I and R1 represents optionally substituted naphthyl; unsubstituted pyridyl; optionally substituted coumarinyl; optionally substituted oxazolyl; optionally substituted benzoxazolyl; optionally substituted benzofuryl; optionally substituted 4-oxo-4H-benzo- pyranyl; cinnamyl which is optionally substituted on the phenyl nucleus; aminoalkyl; alkylaminoalkyl; or dialkylaminoalkyl; phenyl which is substituted by one or more substituents chosen from the following groups: cyano; carboxyl; nitro; halogenated (Cι-Q)alkoxy (and preferably trifluoromethoxy); optionally halogenated (Cι-C1 )thioalkoxy, preferably (Cι-C1o)thioalkoxy; halogenated and preferably perhalo (Cι-C1 )alkyl (and especially trifluoromethyl); (C1-C14)alkylcarbonyl in which the alkyl moiety is optionally halogenated; (Cι-C14)alkoxycarbonyl in which the alkoxy moiety is optionally halogenated; (C6-C 8)arylcarbonyl in which the aryl moiety is optionally substituted one or more times by halogen, optionally halogenated (C1-Cι )alkyl and optionally halogenated (Cι-Cι )alkoxy; (Cι-C14)alkylcarbonylamino in which the alkyl moiety is optionally halogenated; (C6-C18)arylcarbonylamino in which the aryl is optionally substituted one or more times by halogen, optionally halogenated (Cι-C )alkyl and optionally halogenated (Cι-C1 )alkoxy; and (C6-C18)aryl optionally substituted one or more times by halogen, optionally halogenated (Cι-C14)alkyl, such as trifluoromethyl, and optionally halogenated (C1-C4)alkoxy, such as trifluoro- methoxy; with the exclusion of the compounds of the formula Ila in which R1 represents dimethylaminomethyl; dimethylaminoethyl; and diethylaminomethyl.
It should moreover be noted that when R1 represents dialkylaminoalkyl, it is preferred for R1 to be dialkylamino(C3-Cιo)alkyl or di(C3-C1o)alkylamino- (Cι-C2)alkyl.
In addition, when R1 represents substituted phenyl, the preferred substituents are cyano, halogenated (C1-Cι4)alkyl, carboxyl and (C1-C1 )alkoxycarbonyl groups in which the alkoxy moiety is optionally halogenated, better still trifluoromethyl, cyano, carboxyl or methoxy carbonyl. Among these compounds, preferred compounds are those for which R1 represents optionally substituted pyridyl, for example optionally substituted 3- pyridyl.
In addition, for each of the sub-groups of compounds of the formula II defined above, preferred meanings of R1 and Rl are those mentioned above. Not only can the compounds of the formula II above be used as intermediates in the synthesis of the compounds of the formula I, but also they show antioxidant activity that makes them capable of limiting the destructive activity of oxidative free-radical species.
According to another of its aspects, the invention relates to a pharma- ceutical composition comprising at least one compound of the formula I as defined above, in combination with at least one pharmaceutically acceptable exci- pient.
According to yet another of its aspects, the invention relates to a pharmaceutical composition comprising at least one compound of the formula II, in combination with at least one pharmaceutically acceptable excipient.
These compounds may be administered orally in the form of tablets, gel capsules or granules with immediate release or controlled release, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel. A solid composition for oral administration is prepared by adding to the active principle a filler and, where appropriate, a binder, a crumbling agent, a lubricant, a colorant or a flavour corrector, and by shaping the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethyl- cellulose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils. The colorant may be any colorant permitted for use in medicinal products. Examples of flavour correctors include cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Needless to say, the tablet or granulate may be suitably coated with sugar, gelatin or the like.
An injectable form containing the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer agent, a suspending agent, solubilizing agent, a stabilizer, a tonicity agent and/ or a preserving agent, and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a conventional process. Where appropriate, the injectable form obtained may be freeze-dried by a conventional process. Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxy- methylcellulose and polyethoxylated sorbitan monolaurate.
Examples of solubilizing agents include castor oil solidified with polyoxy- ethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
In addition, the stabilizer encompasses sodium sulfite, sodium metasulfite and ether, while the preserving agent encompasses methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
The substances according to the invention are as a rule preferably administered in doses between approximately 0.1 and 100 mg, in particular between 1 and 10 mg, per dose unit. The daily dose is preferably between approximately 0.001 and 10 mg/kg of body weight. The specific dose for each patient, however, depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
According to another of its aspects, the invention relates to the use of a compound of the formula I as defined above, for the preparation of a medicinal product for treating pathologies characterized by a lack of nitrogen monoxide production and/ or an oxidative stress condition. According to one of its final aspects, the invention relates to the use of a compound of the formula II for the preparation of an antioxidant medicinal product that may be used as a free-radical scavenger.
The nitrogen monoxide-donating effect of the compounds of the invention of the formula I may be demonstrated simply by carrying out the following procedure. A solution of a compound of the invention spontaneously releases nitric oxide. The nitrite ions resulting therefrom are titrated by colorimetry by means of a specific reagent (Griess). To take account of any release of nitrate ions in addition to the nitrites, bacterial nitrate reductase is added to the reaction medium to reduce the nitrate ions formed.
The reactions and measurements are performed in transparent 96-well plates. The test products are dissolved at the time of use, at a concentration of 3 mM in dimethyl sulfoxide. 95 μl of a reagent containing nitrate reductase (0.18 U/ml in 100 mM pH 7.5 PBS buffer, 210 μM β-NADPH, 5 μM FAD) and 5 μl of the solution of the test product (final concentration of 150 μM) are then added to each well. After stirring, the mixtures are incubated for 4 hours at 37°C. The reaction is then stopped by adding 100 μl of Griess' reagent (Sigma G4410). The resulting mixture is stirred for 5 min at room temperature, and the optical density is then read at 540 nm. This value is proportional to the concentration of nitrites + nitrates in the medium. A calibration range is made for each plate, using NaN02. The results obtained in the case of some of the compounds illustrated in the examples clearly show their ability to increase the level of nitric oxide. These results are collated in Table 1 below and expressed in μmol/1 (μM) of nitrate + nitrite products:
TABLE 1
Figure imgf000025_0001
The compounds of the formula I and the compounds of the formula II of the invention show antioxidant activity, which makes them suitable for reducing the biological activity of oxidative free-radical species.
The antioxidant activity of the compounds of the formulae I and II is especially revealed in vitro, for example by evaluating their ability to prevent the chemical oxidation of low molecular weight human lipoproteins, as described previously (Table 2).
Human LDLs placed in aqueous solution in the presence of cupric ions, become spontaneously oxidized on their protein component, apolipoprotein-B. This oxidation makes the particle fluorescent, which is exploited to measure a pharmacological effect. The reactions and measurements are performed in black 96- well plates. 10 μl of a solution of the test product dissolved in dimethyl sulfoxide are first mixed with 170 μl of a solution of human LDL at a concentration of 120 μg/ml and 20 μl of 100 μM CuC . After stirring, the mixture is incubated for 2 hours at 37°C, and a first fluorescence reading is taken (excitation at 360 nm, reading at 460 nm). The mixture is then incubated for a further 22 hours, to take a second reading under the same conditions. The difference between the two values obtained is the measurement of the oxidation of the LDLs in solution. This difference is proportionately smaller the greater the antioxidant power of the test product. Probucol is used as reference product at a concentration of 10 μM.
The 50% inhibitory concentrations (IC50) for the oxidation, obtained for some of the compounds of the invention, are given in Table 2 below. They are produced from three concentrations of product.
TABLE 2
Figure imgf000026_0001
Figure imgf000027_0001
The present invention is illustrated below in the light of the following examples.
The frequency of the NMR machine used to record the proton spectra of the examples given below is 300 MHz. s denotes a singlet; d denotes a doublet; t denotes a triplet; q denotes a quartet and m denotes a multiplet. m.p. denotes the melting point.
The preparation of some of the compounds of the formulae I and II is more particularly detailed in the case of Examples 1, 2, 34 and 35 of the invention.
EXAMPLE 1
3-({4-[l-(4-methoxyphenyl)-2-oxohydrazino]phenoxy}methyl)pyridine a) N-(4-methoxyphenyl)-N-[4-(pyrid-3-ylmethoxy)phenyl] amine (compound of the formula II : R1 = 3-pyridyl ; W = O ; R* = 4-OCH3 ; i = 1)
0.54 g (3.28 mmol) of 3-chloromethylpyridine hydrochloride is added to a mixture of 0.53 g (2.74 mmol) of 4-[(4-methoxyphenyl)amino]phenol, prepared according to Chem. Abstr. (1958) 7183, and 1.8 g (5.48 mmol) of caesium carbonate in 15 ml of acetone. After stirring for 6.5 hours at reflux, the reaction medium is poured into water and extracted with ethyl ether. The organic phase is washed with water and then dried over Na2S04 and concentrated under vacuum. The residue, purified by chromatography on a column of silica in a heptane/ ethyl acetate mixture (1/2), gives 0.54 g of a pink solid.
Yield : 64.2%. m.p. = 100°C NMR (DMSO-d6) δ (ppm) : 3.7 (3H, s) ; 5.1 (2H, s) ; 6.8 (2H, m) ; 6.9 (6H, m) ; 7.4 (1H, m) ; 7.6 (1H, s) ; 7.8 (1H, m) ; 8.5 (1H, m) ; 8.6 (1H, m).
b) 3-({4-[l-(4-methoxyphenyl)-2-oxohydrazino]phenoxy}methyl)pyridine (Compound of the ormula I : R1 = 3-pyridyl ; W = O ; R* = 4-OCH3 ; i = 1) 62 mg (0.898 mmol) of sodium nitrite in 2.4 ml of water are added to a solution under nitrogen of 250 mg (0.816 mmol) of N-(4-methoxyphenyl)-N-[4- (pyrid-3-ylmethoxy)phenyl]amine in 12.3 ml of acetic acid. The reaction medium is stirred for 3 hours at room temperature and then poured into 100 ml of water and extracted with ether. The organic phase is washed with NaHC03 solution and then with water to pH 7, and dried over Na2S04. After concentration and drying under vacuum, 261.7 mg of a red oil are obtained (Yield: 95.6%), which crystallizes slowly, m.p. = 75-80°C NMR (DMSO-d6) δ (ppm) : 3.8 (3H, 2s) ; 5.2 (2H, s) ; 7.0-7.5 (9H, m) ; 7.9 (1H, m) ; 8.6 (1H, m) ; 8.7 (1H, m).
EXAMPLE 2
3-{[4-(2-oxo-l-phenylhydrazino)phenoxy]methyl}pyridine a) 3-[(4-bromophenoxy)methyl]pyridine A mixture of 4.3 g (25 mmol) of 4-bromophenol, 16.3 g (50 mmol) of caesium carbonate, 0.1 g of KI, 4.95 g (30 mmol) of 3-chloromethylpyridine hydrochloride and 60 ml of acetone is refluxed for 8 hours and then poured into water and extracted with ether. The organic phase is washed with H20 and dried over Na2S0 , and then concentrated to give an oil. Purification by chromato- graphy on a column of silica in a heptane/ ethyl acetate mixture (4/1) gives 5.9 g of a beige-coloured solid (yield: 89.4%). NMR (DMSO-d6) δ (ppm) : 5.15 (2H, s) ; 7.0 (2H, m) ; 7.45 (3H, m) : 7.9 (1H, m) ; 8.5 (1H, m) ; 8.7 (1H, m).
b) N-phenyl-4-(pyrid-3-ylmethoxy)aniline
(compound of the formula II : R1 = 3-pyridyl ; W = O ; i = 0).
26 mg (0.028 mmol) of tris(dibenzylideneacetone)dipalladium (0), 53 mg
(0.085 mmol) of racemic BINAP (2,2-bis(diphenylphosphino)-l,l-binaphthyl) and
164 mg (1.71 mmol) of sodium tert-butoxide are added to a mixture under nitrogen of 0.3 g (1.14 mmol) of 3-[(4-bromophenoxy)methyl]pyridine and 0.127 g
(1.39 mmol) of aniline in 8.7 ml of diglyme (diethylene glycol dimethyl ether).
The reaction medium is heated at 130°C for 18 hours, and then poured into
20 ml of water and extracted with ethyl acetate (20 ml). The organic phase, washed with water, is dried over Na2S0 and then concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica in a heptane/ ethyl acetate mixture (1/1) to give 0.169 g of a solid (yield: 53.9%).
NMR (DMSO-d6) δ (ppm) : 5.1 (2H, s) ; 6.7 (1H, m) ; 6.9-7.2 (8H, m) ; 7.4 (1H, m) ; 7.9 (2H, m) ; 8.5 (1H, m) ; 8.7 (1H, m).
c) 3-{[4-(2-oxo-l-phenylhydrazino)phenoxy]methyl}pyridine
(compound of the formula I : R1 = 3-pyridyl ; W = O ; i = 0) obtained by working as in Example lb). Yield : 98.3 %. NMR (DMSO-d6) δ (ppm) : 5.2 (2H, 2s) ; 7.1-7.25 (4H, m) ; 7.3-7.6 (6H, m) ; 7.9 (1H, m) ; 8.6 (1H, m) ; 8.7 (1H, m).
EXAMPLE 3 :
4-({4-[l-(4-methoxyphenyl)-2-oxohydrazino]phenoxy}methylbenzoic acid a) 4-({4-methoxyphenyl)amino]phenoxy}methyl)benzoic acid (Compound of the formula II : R1 = 4-carboxyphenyl ; W = O ; i = 1 ; Rl = 4-OCHs)
62 mg (1.1 mmol) of KOH dissolved in 10 ml of water are added to a solution of 0.2 g (0.550 mmol) of methyl 4-({4-[(4-methoxyphenyl)amino]- phenoxyjbenzoate prepared in Example 7a in 10 ml of ethanol.
After refluxing for 3 hours, the ethanol is concentrated and the residue is taken up in 100 ml of water and then washed with 2 x 100 ml of ether. The aqueous phase is then acidified with acetic acid. The precipitate formed is filtered off, washed with water and dried under vacuum to give 0.161 g of a grey solid (yield: 83%). m.p. = 198-200°C
NMR (DMSO-d6) δ (ppm) : 3.9 (3H, s) ; 5.1 (2H, s) ; 6.8 (2H, d, J = 8.9 Hz) ; 6.9 (4H, s) ; 6.93 (2H, d, J=8.9 Hz) ; 7.5 (3H, m) ; 7.9 (2H, d, J = 8.2 Hz) ; 12.8 (IH, broad s). b) 4-({4-[l-(4-methoxyphenyl)-2-oxohydrazino] phenoxy}methyl)benzoic acid
(compound of the formula I : R1 = 4 - carboxyphenyl ; W = O ; i = 1 ; Rl = 4-OCH3)
Obtained as in Example lb. NMR (DMSO-d6) (δ ppm) : 3.8 (3H, s) ; 5.25 (2H, s) ; 7.0-7.4 (8H, m) ; 7.6
(2H, m) ; 7.95 (2H, m) ; 13.0 (IH, broad s).
EXAMPLE 35
4-{2-oxo-l-[4-(pyrid-3-ylmethoxy)phenyl]hydrazino}benzoic acid a) ethyl 4-{[4-(pyrid-3-ylmethoxy)phenyl]amino}benzoate
Obtained as in Example 2a starting with 3-[(4-bromophenoxy)methyl]- pyridine and ethyl 4-aminobenzoate.
NMR (DMSO-d6) (δ ppm) : 1.2 (3H, t, J = 7, 1Hz) ; 4.2 (2H, q, J = 7.1 Hz) ; 5.1 (2H, s) ; 6.9 (2H, m) ; 7.05 (2H, m) ; 7.15 (2H, m) ; 7.5 (IH, m) ; 7.75 (2H, m) ; 7.9 (IH, m) ; 8.5 (IH, s) ; 8.7 (IH, s) ; 12.1 (IH, broad s). b) 4-{[4-(pyrid-3-ylmethoxy)phenyl]amino}benzoic acid
(Compound of the formula II : R1 = 3-pyridyl ; W = O ; i = 1 ; Rl = 4- carboxy). Obtained as in Example 34a starting with the ester prepared in Example
35a (53.8% yield). m.p. = 222-224°C
NMR (DMSO-d6) (δ ppm) : 5.1 (2H, s) ; 6.9 (2H, d, J = 8.8 Hz) ; 7.0 (2H, m) ; 7.1 (2H, m) ; 7.4 (IH, m) ; 7.7 (2H, d, J = 8.7 Hz) ; 7.9 (IH, m) ; 8.5 (IH, s) ; 8.6 (IH, m) ; 8.7 (IH, m) ; 12.4 (IH, broad s).
c) 4-{2-oxo-l-[4-(pyrid-3-ylmethoxy)phenyl]hydrazino}benzoic acid
(Compound of the formula I : R1 = 3-pyridyl ; W = 0 ; i = l ; Rt = 4- carboxy) Obtained as in Example 2b (26.4% yield)
NMR (DMSO-d6) (δ ppm) : 5.2 (2H, s) ; 7.2 (4H, m) ; 7.35 (IH, m) ; 7.5 (3H, m) ; 7.9 (IH, m) ; 8.05 (2H, m) ; 8.6 (IH, m) ; 8.7 (IH, m)
The compounds of Examples 3 to 25 were obtained as in Example 1.
The compounds of Examples 27 to 33 were obtained as in Example 2. The compounds of Example 26 were obtained as in Example 2, starting with 3-{[(4-bromophenyl)thio]methyl}pyridine, prepared according to Haviv F. et al., J. Med. Chem. (1983) 26, 218-222.
The compounds in Table 3 correspond to the following formula:
Figure imgf000031_0001
TABLE 3
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0002
The compounds in Table 4 correspond to the following formula:
Figure imgf000035_0001
TABLE 4
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
The compounds of Examples 36 to 56 were obtained as in Example 1. The compounds of Examples 57 to 62 were obtained as in Example 2. Examples CHEMISTRY NMR
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Example 63
4-{Nitroso[4-(pyrid-4-ylmethoxy)phenyllamino|benzamide
a) 3- f f 4- (Py r id-4-y lmethoxy ) pheny 11 amino jbenzamide
Obtained after purification by chromatography on a column of silica with an ethyl acetate/ heptane mixture (6/4) from the crude reaction mixture of Example 52a.
Yield : 14% NMR (DMSO-d6) : 5.1 (2H, s) ; 6.8-7.65 (11H, m) ; 7.7-7.9 (IH, m) ; 7.8 (IH, s) ; 8.35 (2H, m); 7.9-8.1 (IH, m); 8.6 (2H, broad s)
b) 4-{Nitrosof4-(pyrid-4-ylmethoxy)phenyl1amino)benzamide Obtained by working as in Example lb. Yield : 75%
NMR (acetone-d6) : 5.25 (2H, 2s); 6.6-8.1 (12H, m); 8.6 (2H, broad s). Biological results
Figure imgf000048_0001

Claims

Compounds of the formula I :
Figure imgf000049_0001
in which:
- W represents O or S;
- the radicals Rl, which may be identical or different, represent a halogen atom; a saturated or unsaturated aliphatic hydrocarbon group, optionally interrupted with O and/ or S and optionally halogenated; nitro; carboxyl or cyano;
- i represents an integer from 0 to 5, preferably 0, 1 or 2;
- R1 represents an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical; -E-Q, in which E represents optionally sub- stituted alkylene or alkenylene and Q represents an amino group which is optionally substituted by one or two saturated or unsaturated aliphatic hydrocarbon groups; or -E-Ar, in which E is as defined above and Ar represents an optionally substituted saturated, unsaturated and/ or aromatic carbocyclic radical or alternatively an optionally substituted saturated, unsaturated and/ or aromatic heterocyclic radical; or an optionally halogenated, saturated aliphatic hydrocarbon group; with the exclusion of the compounds of the formula I in which i is 1; R* represents 2-methyl and R1 represents -CH3, and their pharmaceutically tolerable derivatives, solvates and stereoisomers.
2. Compound according to Claim 1, characterized in that R1 represents an optionally substituted aromatic carbocyclic radical; an optionally substituted aromatic heterocyclic radical; an optionally substituted heterocyclic radical with an aromatic moiety; -E-Q, in which E represents alkylene and Q represents amino, alkylamino or dialkylamino; or -E-Ar, in which E represents alkenylene and Ar represents an optionally substituted aromatic carbocyclic radical, an optionally substituted aromatic heterocyclic radical or a radical with an optionally substituted aromatic moiety.
3. Compound according to Claim 2, characterized in that R1 represents optionally substituted phenyl; optionally substituted naphthyl; optionally substituted pyridyl; optionally substituted quinolyl; optionally substituted benzofuryl; optionally substituted oxazolyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; optionally substituted coumarinyl; phenylalkenylene in which the phenyl nucleus is optionally substituted; 4-oxo-4H-benzopyranyl.
4. Compound of the formula I according to any one of Claims 1 to 3, characterized in that the radical R1 comprises at least one carbocyclic or heterocyclic nucleus which is substituted by one or more substituents chosen from oxo; optionally halogenated alkyl; optionally halogenated alkoxy; cyano; halogen; carboxyl; alkylcarbonyl; alkoxycarbonyl; and optionally substituted aryl.
5. Process for preparing a compound of the formula I according to any one of Claims 1 to 4, characterized in that a nitrosating agent, such as an alkali metal nitrite, is reacted with a compound of the formula II:
Figure imgf000050_0001
in which i, R W and R1 are as defined for formula I.
6. Process according to Claim 5, characterized in that the reaction is carried out in a mixture of acetic acid and water, at a temperature of between 10 and 30°C and preferably between 15 and 25°C.
7. Compound of the formula II :
Figure imgf000051_0001
in which i, R* and R1 are as defined according to any one of Claims 1 to 5.
8. Compound of the formula Ila :
Figure imgf000051_0002
in which i and Rl are as defined in Claim 1 and R1 represents optionally substituted naphthyl; unsubstituted pyridyl; optionally substituted coumarinyl; optionally substituted oxazolyl; optionally substituted benzoxazolyl; optionally substituted benzofuryl; optionally substituted 4-oxo-4H-benzopyranyl; cinnamyl which is optionally substituted on the phenyl nucleus; aminoalkyl; alkylamino- alkyl; or dialkylaminoalkyl; phenyl which is substituted by one or more substituents chosen from the following groups: cyano; carboxyl; nitro; halogenated (Oι-C )alkoxy (and preferably trifluoromethoxy); optionally halogenated (G-C )- thioalkoxy, preferably (Cι-Cιo)thioalkoxy; halogenated and preferably perhalo (Cι-G )alkyl (and especially trifluoromethyl); (Cι-C1 )alkylcarbonyl in which the alkyl moiety is optionally halogenated; (Cι-C14)alkoxycarbonyl in which the alkoxy moiety is optionally halogenated; (C6-C18)arylcarbonyl in which the aryl moiety is optionally substituted one or more times by halogen, optionally halogenated (Cι-G )alkyl and optionally halogenated (Cι-Q4)alkoxy; (Oι-C14)- alkylcarbonylamino in which the alkyl moiety is optionally halogenated; (C6-C18)- arylcarbonylamino in which the aryl is optionally substituted one or more times by halogen, optionally halogenated (Cι-C1 )alkyl and optionally halogenated (G-C1 )alkoxy; and (C6-C18)aryl which is optionally substituted one or more times by halogen, optionally halogenated (C1-C14)alkyl, such as trifluoromethyl, and optionally halogenated (C1-C )alkoxy, such as trifluoromethoxy; with the exclusion of the compounds of the formula Ila in which R1 represents dimethylaminomethyl; dimethylaminoethyl; and diethylaminomethyl.
9. Pharmaceutical composition comprising at least one compound of the formula I according to any one of Claims 1 to 4, in combination with one or more pharmaceutically acceptable excipients.
10. Pharmaceutical composition comprising at least one compound of the formula II according to either of Claims 7 and 8, in combination with one or more pharmaceutically acceptable excipients.
11. Use of a compound of the formula I according to any one of Claims 1 to 4, for the preparation of a medicinal product that may be used in the treatment of pathologies characterized by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide.
12. Use of a compound of the formula II according to either of Claims 7 and 8, for the preparation of an antioxidant medicinal product as a free-radical scavenger.
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FR2862966A1 (en) * 2003-11-27 2005-06-03 Merck Sante Sas NITROSO DERIVATIVES OF DIPHENYLAMINE.
JP2021524487A (en) * 2018-07-09 2021-09-13 アビバックス Aryl-N-aryl derivatives for treating RNA virus infection

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JP2021524487A (en) * 2018-07-09 2021-09-13 アビバックス Aryl-N-aryl derivatives for treating RNA virus infection

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