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WO2006000294A1 - Nouveaux composes diazeniumdiolate, procede de preparation correspondant et utilisation therapeutique de ces derniers - Google Patents

Nouveaux composes diazeniumdiolate, procede de preparation correspondant et utilisation therapeutique de ces derniers Download PDF

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Publication number
WO2006000294A1
WO2006000294A1 PCT/EP2005/006080 EP2005006080W WO2006000294A1 WO 2006000294 A1 WO2006000294 A1 WO 2006000294A1 EP 2005006080 W EP2005006080 W EP 2005006080W WO 2006000294 A1 WO2006000294 A1 WO 2006000294A1
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Prior art keywords
alkyl
aryl
optionally substituted
oalkyl
group
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PCT/EP2005/006080
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English (en)
Inventor
Philippe Guedat
Claude Lardy
Jean-Yves Nioche
Valérie Guyard-Dangremont
Stéphane YVON
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Merck Patent Gmbh
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Publication of WO2006000294A1 publication Critical patent/WO2006000294A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/12—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/16—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/48—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the invention relates to novel diazeniumdiolate derivatives, to pharmaceutical compositions comprising them, and to the use thereof for the preparation of medicaments that can be used in the treatment of proliferative diseases.
  • the migration and proliferation of smooth muscle cells in the vascular intima are involved in the development of atherosclerosis (Ross, Nature, 1990 362:801- 809; Schwartz et al., Diabetes Care, 1992, 9:1156-1167) and also play a role in restenosis or stenosis after angioplasty with or without a stent, bypass surgery, heart transplants, etc. (Hanke et al., Circ. Res.
  • Molecules that inhibit the proliferation of smooth muscle cells may therefore be very useful for inhibiting the excessive proliferation of smooth muscle cells that is associated with vascular pathologies, such as atherosclerosis and restenosis, or for the treatment of and preventing any other pathological condition or complica ⁇ tion associated with excessive proliferation of smooth muscle cells.
  • Nitrogen oxide or nitric oxide NO * ) is an important mediator in the physiology of cardiovascular, immune and central and peripheral nervous systems. It acts, among other mechanisms, by activation of guanylate cyclase.
  • Oxidative stress is generated by many factors, for instance hyperglycaemia, dyslipidaemia (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 transplanta- tion, the majority of inflammatory processes, and smoking.
  • Oxidative stress is characterized at the vascular level by an increase in free radicals, in particular in superoxide anions (O 2 * ).
  • the administration of active principles capable of reducing the biological activity of oxidative free-radical species (such as superoxide and peroxynitrite anions) and of increasing the level of nitrogen oxide via a twofold mechanism: non-conversion into peroxynitrites and exogenous supply, is thus particularly desirable in the treatment of these pathologies.
  • the present invention provides compounds of the formula (I) defined below that have these two effects, i.e. antioxidant and nitrogen oxide-donating, in the same molecule. These compounds are capable of generating nitrogen oxide and of trapping oxidative free radicals.
  • aryl is optionally substituted by one or more groups chosen from -OH, -Oalkyl, -CN, -NO 2 , -perfluoroalkyl and -NR"2 R"3, in which R"2 represents H, -alkyl or -NO and R"3 represents -alkyl or -aryl;
  • ° -Oalkyl optionally substituted by one or more groups chosen from -OH, -Oalkyl, -CN, -NO 2 , -perfluoroalkyl and -NR2R3, in which R2 represents H or -alkyl and R3 represents -alkyl or -aryl;
  • ° -Oalkylaryl optionally substituted by one or more groups chosen from -OH, -alkyl, -Oalkyl, -CN, -NO 2 , -perfluoroalkyl and -NR2R3, in which R2 represents H or -alkyl and R3 represents -alkyl or -aryl;
  • ° -N(NO)-aryl optionally substituted by one or more groups chosen from -OH, -Oalkyl, -CN, -perfluoroalkyl and -NR2R3, in which R2 represents H or -alkyl and R3 represents -alkyl or -aryl;
  • A represents a 2,4-di OH or 2,5-di OH group
  • M + represents a cation.
  • M + represents NH 4 + or an alkali metal cation, such as Na + or K + .
  • X represents a single bond, -O- or -NR1-, in which R1 represents an optionally substituted -aryl group and A, Ar, Y, m, n and p are as defined above.
  • R1 represents an -aryl group substituted by -NO 2 .
  • R2 represents a hydrogen atom and R3 represents an -alkyl group.
  • R"2 represents a hydrogen atom and R"3 represents an -aryl group.
  • R4 represents an -alkyl group and R5 represents an -aryl group substituted by an -Oalkyl group.
  • R6 represents an -aryl group substituted by an -Oalkyl group.
  • the preferred embodiments mentioned hereinabove or hereinbelow are under- stood to be taken either individually or in combination with each other or with the general embodiment of the invention.
  • the compounds of the formula (I) or (I 1 ) are chosen from: ammonium 1 -[4-(4-methoxyphenoxy)benzyl]-2-oxohydrazinolate; ammonium 1 - ⁇ 4-[(4-methoxyphenyl)thio]benzyl ⁇ -2-oxohydrazinolate; ammonium 1 -(2,4-dimethoxybenzyl)-2-oxohydrazinolate; ammonium 1 -[4-(benzyloxy)benzyl]-2-oxohydrazinolate; ammonium 1 -(4-butoxybenzyl)-2-oxohydrazinolate; ammonium 1-(1 ,3-benzodioxol-5-ylmethyl)-2-oxohydrazinolate; ammonium 2-oxo-1-(2,3,4-trimethoxybenzyl)hydrazinolate; ammonium 1 -(4-methoxy
  • the preferred compounds are those chosen from: ammonium 1- ⁇ 2-[(4-anilinophenoxy)methyl]benzyl ⁇ -2-oxohydrazinolate; ammonium 1- ⁇ 5-[(4-methoxyphenyl)(4-nitrophenyl)amino]pentyl ⁇ -2-oxohydrazino- late; ammonium 1-(4- ⁇ 2-[(2E)-2-(2-hydroxy-4-methoxybenzylidene)hydrazino]-2-oxo- ethoxy ⁇ benzyl)-2-oxohydrazinolate; in free form or in the form of a salt thereof, and also the enantiomers, diastereo- isomers, racemic mixtures and pharmaceutically acceptable salts.
  • the alkyl groups represent saturated hydrocarbon-based groups, in a straight or branched chain of 1 to 20 carbon atoms and preferably of 1 to 5 carbon atoms. If they are linear, mention may be made especially of methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl groups.
  • Alkoxy groups are groups of the for ⁇ mula -O-alkyl, the alkyl being as defined above.
  • Halogen atoms that are more particularly mentioned are fluorine, chlorine, bromine and iodine atoms, preferably fluorine.
  • the alkenyl groups represent hydrocarbon-based groups in a straight or lin ⁇ ear chain, and comprise one or more ethylenic unsaturations.
  • alkenyl groups that may especially be mentioned are allyl or vinyl groups.
  • the alkynyl groups represent hydrocarbon-based groups, in a straight or linear chain, and comprise one or more acetylenic unsaturations.
  • alkynyl groups mention may be made especially of acetylene.
  • the cycloalkyl group is a saturated or partially unsaturated, non-aromatic mono-, bi- or tricyclic hydrocarbon-based group of 3 to 10 carbon atoms, espe ⁇ cially, such as cyclopropyl, cyclopentyl, cyclohexyl or adamantyl, and also the cor ⁇ responding rings containing one or more unsaturations.
  • Aryl denotes a monocyclic or bicyclic hydrocarbon-based aromatic system of 6 to 10 carbon atoms.
  • aryl groups that may especially be mentioned are phenyl and naphthyl groups, more particularly substituted by at least one halogen atom.
  • the-alkylaryl groups mention may be made especially of benzyl and phenethyl groups.
  • Het denotes a heteroaryl or heterocyclyl group.
  • the heteroaryl groups denote monocyclic or bicyclic aromatic systems of 5 to 10 carbon atoms, comprising one or more hetero atoms chosen from nitrogen, oxygen and sulfur.
  • heteroaryl groups that may be mentioned are pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1 ,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridine, imidazo[2,1-b]thia- zolyl, cinnolinyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzazaindole, 1 ,2,4- triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, triazolyl, tetrazol
  • the preferred het ⁇ roaryl groups comprise thienyl, pyrrolyl, quinoxalinyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, quina- zolinyl, quinolinyl, thiazolyl, carbazolyl and thiadiazolyl, and groups derived from fusion with a phenyl nucleus, and more particularly quinolyl, carbazolyl and thiadia- zolyl.
  • heterocyclic groups denote saturated or partially unsaturated, non-aro ⁇ matic monocyclic or bicyclic systems of 5 to 10 carbon atoms, comprising one or more hetero atoms chosen from N, O and S.
  • heterocycles mention may be made especially of epoxyethyl, oxiranyl, aziridinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazoli- dinyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrothio- pyranyl, dithianyl, thiomorpholinyl, dihydrofuranyl, 2-imidazolinyl, 2,3-pyrrolinyl, pyrazolinyl, dihydrothioph
  • pharmaceutically acceptable salts refers to the relatively non-toxic mineral and organic acid-addition salts, and the base-addition salts, of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds.
  • the acid- addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed.
  • acid-addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaph- thoates, gentisic acid, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulf
  • the acid-addition salts may also be prepared by separately reacting the purified compound in its acid form with an organic or mineral base and isolating the salt thus formed.
  • the acid-addition salts include amine salts and metal salts.
  • the suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium and aluminium salts. The ammonium, sodium and potassium salts are preferred.
  • the suitable mineral base-addition salts are pre- pared from metallic bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide and zinc hydroxide.
  • the suitable amine base-addition salts are prepared from amines whose basicity is sufficient to form a stable salt, and preferably include amines that are often used in medicinal chemistry on account of their low toxicity and their acceptability for medical use: ammonia, ethylenediamine, N- methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzyl-phenethylamine, di- ethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, e
  • the invention also relates to the tautomeric forms, enantiomers, diastereo- isomers, epimers and organic or mineral salts of the compounds of the general formula (I).
  • the compounds of the invention of the formula (I) as defined above contain ⁇ ing a sufficiently acidic function or a sufficiently basic function, or both, may in ⁇ clude the corresponding pharmaceutically acceptable salts of an organic or min ⁇ eral acid or of an organic or mineral base.
  • the present patent application furthermore also relates to the process for the preparation of the compounds according to the above invention. According to the invention, the process includes the step consisting in performing a nitrosation on the -NH-OH group of a corresponding compound.
  • the nitrosation is performed using a compound of nitrite type, such as an alkyl nitrite, especially tert-butyl nitrite or ethyl nitrite, or an alkali metal nitrite, such as sodium or potassium nitrite.
  • nitrosating agents known in the art, such as AgONO, BF 4 NO, HOSO 3 NO, nBuONO and tBuONO, or alternatively Et-ONO.
  • the amount of nitrosating agent required depends on the nature of the nitrosating agents used and on the reactivity of the substrate of the formula II. It is at least stoichiometric.
  • the molar ratio of nitrosating agent to the substrate of the formula Il generally ranges between 1 and 30 equivalents and preferably between 1 and 20 equivalents.
  • the nitrosating agent is an alkali metal nitrite
  • a person skilled in the art can readily adapt the reaction conditions so as to use only from 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.
  • the nitrosating agent is an alkyl nitrite, it is preferable to work in the pres- ence of 10 to 25 molar equivalents and preferably from 15 to 20 molar equivalents of nitrite, 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.
  • 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 halogenated hydrocarbon (such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichloro- benzene).
  • the solvent is preferably tetrahydrofuran, diethyl ether or chloroform.
  • the reaction temperature will generally be maintained between -33° and 70 0 C and better still between -33° and 60 0 C, in the case of AgONO, nBuONO, tBuONO and EtONO. More particularly in the case of EtONO 1 the process is performed at between 15 and 30 0 C. More particularly in the case of AgONO and nBuONO, the process will be performed in tetrahydrofuran or diethyl ether at a temperature of between 0° and 30 0 C, for example between 0° and 5 0 C.
  • the process will preferably be performed in ether or tetrahydrofuran in the presence of liquid ammonia at a temperature of between -33° and 2O 0 C.
  • the nitrosating agent is AgONO, it is desirable to add thionyl chloride to the reaction medium.
  • the nitrosating agent is HOSO 3 NO, the reaction is preferably performed in an alkali metal salt of a lower (C-i-C 5 )carboxylic acid, such as sodium acetate, at a reaction temperature of between -1O 0 C and 30 0 C and better still between -5 and 25°C.
  • a suitable solvent is a nitrite, such as acetonitrile or isobutyronitrile. It is desirable to add pyridine or N-dimethylamino- pyridine to the reaction medium, the reaction temperature being maintained at between -30 and 10°C and preferably between -25 and 5 0 C.
  • the nitrosating agent is an alkali metal nitrite, the nitrosation reaction is preferably performed in a highly polar protic medium.
  • the reaction medium advantageously comprises water and a Bronsted or Lewis acid. Suitable acids are a hydrohalic acid (such as HCI), sulfuric acid, Al 2 (SO 4 ) 3 and acetic acid, and mixtures thereof.
  • an aliphatic alcohol of (Ci-C 4 )alkanol type (such as methanol or butanol) may be added.
  • one of the following systems may be selected as suitable reaction medium: - 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 AI 2 (SO 4 ) 3 ; or alternatively - a mixture of water and hydrochloric acid.
  • the reaction of the alkali metal nitrite with the substrate of the formula Il is performed 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 Il in acetic acid.
  • the reaction of the alkali metal nitrite with the substrate of the formula Il is performed at a temperature that depends on the reactivity of the species present; this temperature generally ranges between -10 and 50 0 C and preferably between -5 and 25 0 C.
  • a temperature of between 15 and 25°C is particularly suitable.
  • the reaction of the alkyl nitrite with the substrate of the formula Il is prefera ⁇ bly performed in the presence of a Ci-C 4 alkanol in a polar aprotic solvent.
  • Suitable alkanols include methanol, ethanol, isopro- panol and tert-butanol, ethanol being particularly preferred.
  • Preferred polar solvents include halogenated hydrocarbons, such as methyl ⁇ ene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitrites, such as acetonitrile or isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorylamide; and mixtures of these solvents in any proportions.
  • halogenated hydrocarbons such as methyl ⁇ ene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene
  • ethers such as diethyl ether,
  • the process according to the invention allows the preparation of the corresponding ammonium salt (I 1 ) in situ, by bubbling through ammonia gas.
  • the process according to the invention also comprises the step of pre ⁇ paring the free form (I) from the corresponding ammonium salt (I'). This step may be performed by application or adaptation of any method known per se.
  • the process is performed via any method for regenerating the free species, especially by addition of base, for example aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • the compounds of the formula (II) may be pre ⁇ pared via any means within the capacity of a person skilled in the art.
  • the -NHOH group is obtained from the -NO 2 group.
  • the process is performed via reduction using the corresponding compounds of the formula (III): (A) m -Ar-(X) n -(Y) p -NO 2 (
  • A, Ar, Y, m, n and p are as defined above.
  • This reaction may be performed using any method for forming a hydroxylamine group usually used, starting from the nitro group, and which does not interfere with the other functional groups present.
  • use is made of sulfuric or hydro ⁇ chloric acid in EtOH medium and electrolysis; AI-HG, in aqueous medium in the presence of alcohol or THF, ether ethyl acetate; sodium liquid NH3; Zn in the presence of aqueous NH 4 CI and/or THF, EtOH; hydrogenation in the presence of Pd-C (oxalic acid) EtOH HCI, Zn in the presence of alcohol + acetic acid; SMI 2 in the presence of THF MeOH; BH 3 .
  • the process may be performed using Zn, in the presence of NH 4 CI, in a suitable solvent medium, at a temperature of between room tempera ⁇ ture and the reflux temperature of the solvent.
  • the process is preferably performed using from 1 to 5 equivalents and preferably about 2 equivalents of Zn, in a polar protic solvent medium, such as water or alcohols, and more preferably an etha- nol/water mixture.
  • This reaction may be performed via any oxime reduction method usually used that does not interfere with the other functional groups present.
  • sodium borohydride or NaCNBH 3 is used as reagent. More specifically, the process may be performed using sodium borohydride NaBH 4 , in the presence of acid, in a suitable solvent medium, at a temperature of between O 0 C and room temperature.
  • the process is preferably performed using from 1 to 5 equivalents and preferably about 3 equivalents of NaBH 4 , in a polar protic solvent medium, such as alcohols, especially ethanol.
  • a polar protic solvent medium such as alcohols, especially ethanol.
  • the tem ⁇ perature is between 5°C and room temperature. Any organic or mineral acid can be used as acid. Hydrochloric acid HCI is preferably used.
  • the process may also be performed using NaCNBH 3 in the presence of acid, in a suitable solvent medium, at a temperature of between O 0 C and room temperature.
  • the process is preferably performed using from 1 to 5 equivalents and preferably about 3 equivalents of NaCNBH 3 , in a polar protic sol ⁇ vent medium, such as alcohols, for instance ethanol, or water.
  • the tem ⁇ perature is between 5°C and room temperature. Any organic or mineral acid can be used as acid. Hydrochloric acid is preferably used.
  • the compounds of the formula (III) or (IV) are commercially available or may be prepared by application or adaptation of methods known per se.
  • the products of the formulae (III) and (IV) may especially be prepared by application or adaptation of the representative procedures described in the examples below.
  • the starting products are commercially available or may be prepared by appli ⁇ cation or adaptation of methods known per se.
  • the said process may also include the step consisting in isolating the product obtained.
  • reac ⁇ tive functional groups for example the hydroxyl, amino, imino, thio or carboxyl groups, if they are desired in the final product, to avoid their unwanted participation in the reactions.
  • the conventional protecting groups can be used in accordance with the standard practice; for examples, see T.W. Green and P. G. M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991 ; J.F.W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.
  • the compound thus prepared may be recovered from the reaction mixture via the conventional means.
  • the compounds may be recovered by distilling the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the mixture of the solution, pouring the remainder into water, followed by extraction with a water-immiscible organic solvent, and distilling the solvent from the extract.
  • the product may also be purified, if so desired, by various techniques, such as recrystallization, reprecipitation or various chromato- graphic techniques, especially column chromatography or preparative thin-layer chromatography.
  • the compounds that are useful according to the present invention may contain asymmetric centres. These asymmetric centres may be, independently, of R or S configuration. It will be apparent to a person skilled in the art that certain compounds that are useful according to the invention may also exhibit geometrical isomerism.
  • the present invention includes individual geometrical isomers and stereoisomers, and mixtures thereof, including racemic mixtures, of compounds of the formula (I) above.
  • Iso ⁇ mers of this type may be separated from their mixtures by application or adapta- tion of known processes, for example chromatography techniques or recrystalliza ⁇ tion techniques, or they are prepared separately from suitable isomers of their intermediates.
  • the tautomeric forms are included in the citation of a given group, for example thio/mercapto or oxo/hydroxyl.
  • the acid-addition salts are formed with the compounds that are useful according to the invention in which a basic function, such as an amino, alkylamino or dialkylamino group is present.
  • a basic function such as an amino, alkylamino or dialkylamino group is present.
  • the pharmaceutically acceptable, i.e. non-toxic, acid-addition salts are preferred.
  • the selected salts are optimally chosen so as to be compatible with the usual pharmaceutical vehicles and suitable for oral or par ⁇ enteral administration.
  • the acid-addition salts of the compounds that are useful according to the present invention may be prepared by reacting the free base with the appropriate acid, by application or adaptation of known processes.
  • the acid-addition salts of the compounds that are useful according to the pre ⁇ sent invention may be prepared either by dissolving the free base in water or in a basified aqueous solution or suitable solvents comprising the appropriate acid, and isolating the solvent by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates out directly or may be obtained by concentrating the solution.
  • the acid-addition salts of the compounds that are useful according to the present invention may be regenerated from the salts by application or adaptation of known processes.
  • the parent compounds that are useful accord- ing to the invention may be regenerated from their acid-addition salts by treatment with an alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • the compounds that are useful according to the present invention may be regenerated from their base-addition salts by application or adaptation of known processes.
  • the parent compounds that are useful according to the invention may be regenerated from their base-addition salts by treatment with an acid, for example hydrochloric acid.
  • the base-addition salts may be formed if the compound that is useful according to the invention contains a carboxyl group, or a sufficiently acidic bio- isostere.
  • the bases that can be used to prepare the base-addition salts preferably include those that produce, if they are combined with a free acid, pharmaceutically acceptable salts, i.e. salts whose cations are not toxic to the patient in the phar ⁇ maceutical doses of the salts, such that the beneficial inhibitory effects intrinsic to the free base are not negated by the side effects attributable to the cations.
  • the pharmaceutically acceptable salts include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, cal ⁇ cium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)- aminomethane, tetramethylammonium hydroxide and the like.
  • the compounds that are useful according to the present invention may be readily prepared, or formed during the process of the invention, in the form of sol ⁇ vates (for example hydrates).
  • the hydrates of the compounds that are useful according to the present invention may be readily prepared by recrystallization of an aqueous/organic solvent mixture, using organic solvents, such as dioxane, tetrahydrofuran or methanol.
  • organic solvents such as dioxane, tetrahydrofuran or methanol.
  • the basic products or the reagents used are commercially available and/or may be prepared by application or adaptation of known processes, for example processes as described in the Reference Examples or obvious chemical equiva- lents thereof.
  • the present invention furthermore also relates to the compounds of the for ⁇ mula (I) as medicament.
  • the present invention thus relates to pharmaceutical com ⁇ positions comprising a compound of the formula (I) and a pharmaceutically accept ⁇ able vehicle or excipient.
  • the compounds of the for ⁇ mula (I) show inhibitory activity on the proliferation of smooth muscle cells.
  • the present invention thus relates to the use of a compound of the general formula (I) for the preparation of pharmaceutical composi ⁇ tions for inhibiting the proliferation of smooth muscle cells.
  • the present invention relates to the use of a compound of the general formula (I) for the prevention and/or treatment of vascular pathologies associated with the proliferation of smooth muscle cells.
  • the present invention relates to the use of a com ⁇ pound of the general formula (I) for the prevention and/or treatment of a pathology chosen from atherosclerosis, restenosis and stenosis.
  • the present invention relates to the use of a com ⁇ pound of the general formula (I) for the prevention and/or treatment of any compli ⁇ cation associated with angioplasty with or without a stent, bypass surgery or trans ⁇ plants.
  • the compounds of the formula (I) have antioxidant and NO-generating activity.
  • the present invention thus relates to the use of a compound of the general formula (I) for the preparation of pharmaceutical composi ⁇ tions for inhibiting oxidative free-radical species and for generating NO.
  • the present invention relates to the use of a compound of the general formula (I) for the prevention and/or treatment of patholo ⁇ gies associated with a defect of NO production and/or an increase in tissue oxida ⁇ tive stress.
  • the present invention relates to the use of a com ⁇ pound of the general formula (I) for the prevention and/or treatment of a pathology chosen from atherosclerosis, restenosis, stenosis, hyperglycaemia, insulin resis ⁇ tance, diabetes, dyslipidaemia, retinal and/or renal vascular complications of diabe ⁇ tes, hypoxia, inflammatory processes, cardiovascular diseases, articular patholo ⁇ gies, male erectile dysfunction, and smoking.
  • the pharmaceutical compositions according to the invention may be pre- sented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration.
  • water, aqueous solutions, physiological saline and iso- tonic solutions are the vehicles most appropriately used.
  • the dosage may vary within wide ranges (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, and also on the age and weight of the patient.
  • the examples that follow are given as non-limiting illustrations of the present invention.
  • the process according to the invention may be performed by appli ⁇ cation or adaptation of the various routes presented above, under the following operating conditions, in which are mentioned as a guide Ra-Re, which represent any suitable substituent, Z, which represents a carbon, nitrogen or oxygen atom, Gr, which represents an optionally substituted aryl group, and p represents 0 or 1.
  • ROUTE 3 Coupling reaction Reagent aryl halide Base: CS 2 CO 3 or tBuONa or tBuOK Catalyst: Pd 2 (dba) 3 2.5 % M eq
  • Ligand racemic BINAP 7,5 % M eq.
  • Hydroxylammonium chloride 3 eq. (90 mmol; 6.25 g) is dissolved in 50 ml of ethanol, and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (30 mmol; 7.3 g) and pyridine 3 eq (90 mmol; 7.3 ml) dissolved in 400 ml of ethanol are then added.
  • the reaction medium is stirred at room temperature for 16 hours.
  • the reaction medium is evaporated to dryness and the residue is taken up in water and extracted with dichloromethane.
  • the organic phase is washed (twice), dried over Na 2 SO 4 and evaporated to dryness.
  • the oil obtained is dispersed in hexane, filtered and dried.
  • 2-(4-Phenylaminophenoxymethyl)benzaldehyde oxime (29) 2-(4-Phenylaminophenoxymethyl)benzonitrile (510 mg; 1.7 mmol) is dissolved in 5 ml of anhydrous dichloromethane under an inert atmosphere. 1.0 M DIBAL in THF 1.2 eq. (2 mmol; 2 ml) is added dropwise, the reaction medium is left for 1 hour 30 minutes at room temperature, and hydroxylammonium chloride 3 eq. (51 mmol; 350 mg) is then added. The reaction medium is left at room temperature for 1 hour 30 minutes and then filtered and evaporated to dryness. The residue is taken up in ether and fil ⁇ tered.
  • 1 H NMR (DMSO-d6) 5.03-5.80 (4H, m); 6.88-7.78 (14H 1 m); 12.83 (1 H, broad s).
  • the reaction medium is maintained at 100 0 C for 6 hours and is then left at room temperature for 12 hours.
  • the reaction medium is poured into water and then extracted with ether (3 times).
  • reaction medium is cooled again to -78 0 C and 4 ml of water are added slowly while allow ⁇ ing the medium to return to room temperature.
  • EtOAc and excess NaHCO 3 are then added, and the reaction medium is stirred for 15 minutes and then filtered through Celite.
  • the organic phase is dried over Na 2 SO 4 and then evaporated to dryness.
  • the crude product is chromatographed on silica gel (eluent: CH 2 CI 2 ) to give 740 mg of orange-coloured oil.
  • test products are dissolved extemporaneously at a concentration of 3 mM in dimethyl sulfoxide.
  • 95 ⁇ l of a reagent comprising the nitrate of the solution of the test product (final concentration of 150 ⁇ M) are then introduced into each well. After stirring, the mixture is incubated for four hours at 37°C. The reaction is then quenched by addition of 100 ⁇ l of the Griess reagent (Sigma G4410). This reagent is left to act for five minutes 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 NaNO 2 . The results in Table A are expressed in ⁇ mol/l ( ⁇ M) of nitrites + nitrates released.
  • the proliferation of smooth muscle cells is evaluated by DNA synthesis, which is measured by incorporation of tritiated thymidine into the DNA of the cells.
  • the human smooth muscle cells are obtained from PromoCell (Heidelberg, Germany). They are thawed at 37 0 C for 3 minutes and are immediately placed in a culture medium comprising growth factors (PromoCell: basal medium supplemented with foetal calf serum (5%), epidermal growth factor (10 ng/ml), fibroblast growth factor (2 ng/ml), dexamethasone (0.39 ⁇ g/ml), amphotericin (50 ng/ml), gentamycin (50 ⁇ g/ml)).
  • the smooth muscle cells are placed in 24-well culture plates and are then treated with collagen at a rate of 4x10 4 cells per well in 500 ⁇ l of medium. After incubation for 24 hours, the medium is renewed and the products dis ⁇ solved in dimethyl sulfoxide (DMSO) are added to the cells such that the final con ⁇ centration of DMSO does not exceed 0.2%. After incubation for 22 hours at 37°C, the medium comprising the products is removed. Tritiated thymidine ([methyl- 3 H]-Thymidine, Amersham, specific activity 70- 86 Ci/mmol) is added to the cells so as to have 1 ⁇ Ci per well in a volume of 500 ⁇ l. Incubation is continued for 6 hours.
  • DMSO dimethyl sulfoxide
  • the radioactive medium is then removed and the cells are rinsed twice with phosphate buffer.
  • the reaction is stopped by addition of a solution at 4°C of 5% trichloroacetic acid (TCA). After 15 minutes at 4 0 C, the TCA solution is removed.
  • TCA trichloroacetic acid
  • the precipitate in each well is dissolved by stirring for 3 minutes at room temperature with 500 ⁇ l of a 1.0% sodium dodecyl sulfate solution in 0.1 N NaOH comprising 2% Na 2 COs.
  • the tritiated thymidine present in the redis- solved sample is quantified by liquid scintillation counting. The results are expressed as a percentage of inhibition relative to the cells that have received no product, but only DMSO (0.2% final).
  • the product SNAP used as reference in the test spontaneously releases NO in aqueous solution and inhibits the synthesis of DNA and the proliferation of vascular smooth muscle cells in culture. SNAP inhibits proliferation by about 80% at a con ⁇ centration of 100 ⁇ M.
  • the results, expressed as a percentage of inhibition of prolif ⁇ eration of smooth muscle cells, are presented in Table B. Table B

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  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne des composés représentés par la formule (I), le procédé de préparation de ces composés ainsi que leur utilisation thérapeutique, notamment leur utilisation en tant qu'antioxydants, que générateurs de NO et en tant qu'inhibiteurs de la prolifération cellulaire des muscles lisses. Formule (I)
PCT/EP2005/006080 2004-06-28 2005-06-07 Nouveaux composes diazeniumdiolate, procede de preparation correspondant et utilisation therapeutique de ces derniers WO2006000294A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099853A3 (fr) * 2008-02-08 2009-12-30 Merck & Co., Inc. Antagonistes des récepteurs de l'angiotensine ii
EP2725029A1 (fr) 2012-10-29 2014-04-30 Laboratoire Biodim Nouveaux composés antibactériens et leurs applications biologiques

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US2954314A (en) * 1956-08-25 1960-09-27 Basf Ag Fungicides
US5212204A (en) * 1989-10-18 1993-05-18 The United States Of America As Represented By The Department Of Health And Human Services Antihypertensive compositions and use thereof
WO1993020806A1 (fr) * 1992-04-13 1993-10-28 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation de complexes d'oxyde nitrique/nucleophile dans le traitement du cancer
US5698738A (en) * 1995-05-15 1997-12-16 Board Of Regents, The University Of Texas System N-nitroso-N-substituted hydroxylamines as nitric oxide donors

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US2954314A (en) * 1956-08-25 1960-09-27 Basf Ag Fungicides
US5212204A (en) * 1989-10-18 1993-05-18 The United States Of America As Represented By The Department Of Health And Human Services Antihypertensive compositions and use thereof
WO1993020806A1 (fr) * 1992-04-13 1993-10-28 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Utilisation de complexes d'oxyde nitrique/nucleophile dans le traitement du cancer
US5698738A (en) * 1995-05-15 1997-12-16 Board Of Regents, The University Of Texas System N-nitroso-N-substituted hydroxylamines as nitric oxide donors

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Title
HOWARD MASKILL: "Solvolysys of substituted benzyl azoxyarenesulfonates ; characterisation of the transition state and the selectivity of benzylic intermediates in 50% aqueous 2,2,2-trifluoroethanol", J.CHEM.SOC.,PERKIN TRANS. 2, vol. 2, 2001, pages 2059 - 2062, XP002324847 *
MITSUHIRO SHIINO: "Synthesis and tyrosinase inhibitory activity of novel N-hydroxybenzyl-N-nitrosohydroxylamines", BIOORGANIC CHEMISTRY, vol. 31, 2003, pages 129 - 135, XP002324846 *
MITSUHIRO SHIINO: "Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 9, 2001, pages 1233 - 1240, XP002324848 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099853A3 (fr) * 2008-02-08 2009-12-30 Merck & Co., Inc. Antagonistes des récepteurs de l'angiotensine ii
JP2011511079A (ja) * 2008-02-08 2011-04-07 メルク・シャープ・エンド・ドーム・コーポレイション アンジオテンシンｉｉ受容体アンタゴニスト
US8106034B2 (en) 2008-02-08 2012-01-31 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
EP2725029A1 (fr) 2012-10-29 2014-04-30 Laboratoire Biodim Nouveaux composés antibactériens et leurs applications biologiques
WO2014067904A1 (fr) 2012-10-29 2014-05-08 Laboratoire Biodim Nouveaux composés antibactériens et leurs applications biologiques

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