Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
  • A61P9/08—Vasodilators for multiple indications
• • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/06—Ring systems of three rings
  • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

• the present invention relates to compounds of formula:
• R represents a methylene, N-alk, NH radical or an oxygen or sulfur atom
• R- and R2, which are identical or different, represent a hydrogen or halogen atom or a hydroxy, alkoxy, alkyl, nitro, amino, monoalkylamino, dialkylamino, cyano, polyfluoroalkyl, polyfluoroalkoxy or phenoxy radical,
• R3 and R4 identical or different, represent a hydrogen or halogen atom or an alkyl radical
• alk represents an alkyl radical
• alkyl and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain. 6/02536 PC17FR95 / 00952
• the compounds of formula (I) can also be present in other tautomeric forms. These other tautomeric forms also form part of the invention.
• the polyfluoroalkyl radicals are preferably the trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl radicals.
• the polyfiuoroalkoxy radicals are preferably the trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy radicals.
• R represents a methylene radical
• R-j, R2, R3 and R4 have the same meanings as in formula (I) and R5 represents an alkyl radical.
• This reaction is generally carried out within acetic acid, at the boiling point of the reaction medium.
• the derivatives of formula (II) can be obtained by the action of a 3-morpholino-1 H-indene substituted with R3 and R4, on a derivative of formula:
• R5 represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine atom.
• This reaction is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as a trialkyamine (triethylamine for example), at a temperature in the region of 20 ° C.
• a base such as a trialkyamine (triethylamine for example)
• the 3-morpholino-1 H-indenes substituted with R3 and R4 can be obtained by application or adaptation of the method described by A. T. BLOMQUIST et al., J. Org. Chem., 26, 3761 (1961) from the corresponding 1-indanones.
• the 1-indanones substituted with R3 and R4 can be obtained by application or adaptation of the methods described by M. OLIVIER et al., Bull. Soc. Chim. de France, 3092 (1973), R. SEKA et al., Chem. Ber., 75B, 1730 (1942) and in US patents 4,233,319, US 4,096,173 and EP 314,400.
• the derivatives of formula (III) can be obtained by halogenation of the corresponding acid, by any known method making it possible to pass from an acid to an acid halide.
• the corresponding acids can be obtained by application or adaptation of the method described by WG BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984) from dialkyiphenylmalonates in which the phenyl is substituted by Rj and R2.
• Dialkyiphenylmalonates are commercially available or can be obtained by application or adaptation of the methods described by W. WISLICENUS, Ber., 27, 1091 (1894), WL NELSON et al., J. Am. Chem. Soc, 50, 2760 (1928) and D. IVANOFF et al., Bull. Soc. Chim. de France, 49, 20 (1931) from the corresponding alkylphenylacetates.
• alkylphenylacetates are commercially available or can be obtained by application or adaptation of the methods described by PR AUSTIN et al., J. Am. Chem. Soc, 54, 655 (1932), W. MANN, Ber., 14, 1645 (1881), W. STAEDEL, Ber., 19, 1949 (1886) from the corresponding benzyl bromides which are themselves obtained by application or adaptation of the methods described by Y. HIRSHBERG et al., J. Chem. Soc, 1030 (1951) and F. KROHNKE, Chem. Ber., 83, 35 (1950) by halogenation of the corresponding toluenes.
• R represents an N-alk radical, NH or an oxygen or sulfur atom
• R-, R2, R3 and R4 have the same meanings as in formula (I) and Rg represents an alkyl radical.
• This cyclization takes place in an inert solvent such as tetrahydrofuran, in the presence of lithium bis (trimethylsilyl) amide, at a temperature between 20 ° C and 60 ° C.
• R represents an N-alk radical, NH or an oxygen or sulfur atom
• R3 and R4 have the same meanings as in formula (I) and Rg represents an alkyl radical on a halide of formula:
• and R2 have the same meanings as in formula (I) and Hal represents a halogen atom and, preferably, a chlorine atom.
• This reaction is generally carried out in an inert solvent such as dioxane, in the presence of a base such as a trialkylamine (triethylamine for example), at the boiling temperature of the reaction medium.
• a base such as a trialkylamine (triethylamine for example)
• the derivatives of formula (V) for which R represents an NH radical can be obtained by application or adaptation of the method described by PC UNANGST, J. Heterocyclic Chem., 20, 495 (1983) from 2-cyanoanilines substituted with R3 and R4.
• the 2-cyanoaniines are commercially available or can be obtained by application or adaptation of the methods described by TE NICKSON et al., Synthesis, 669 (1985); JB CAMPBELL et al., Synthetic Comm., 19, 2265 (1989); NV HARRIS et al., J. Med. Chem., 33, 434 (1990); DH KLAUBERT et al., J. Med. Chem., 24, 748 (1981); F.
• an alkyl halide is used, in the presence of an alkali metal hydride such as sodium hydride, in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture of these solvents , at a temperature close to 20 ° C.
• an alkali metal hydride such as sodium hydride
• an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture of these solvents
• the derivatives of formula (V) for which R represents an oxygen atom can be obtained by application or adaptation of the method described by K. GEWALD et al., J. F. Prakt. Chemie, 315, 779 (1973) from 2-cyanophenols substituted with R3 and R4.
• the 2-cyanophenols can be obtained by application or adaptation of the methods described by R.C. LAROCK, "Comprehensive Organic Transformation", ED VCH, page 483 (1989) from the corresponding 2-cyanoanilines.
• the derivatives of formula (V) for which R represents a sulfur atom can be obtained by application or adaptation of the method described by D.E.L. CARRINGTON et al., J. Chem. Soc, 3903 (1971) from 2-cyanothiophenols substituted with R3 and R4.
• the 2-cyanothiophenols can be obtained by application or adaptation of the method described in patent EP 365397 from the corresponding 2-cyanophenols.
• the derivatives of formula (VI) are marketed or can be obtained by halogenation of the corresponding phenylacetic acids by any known method making it possible to pass from an acid to an acid halide.
• Phenylacetic acids are commercially available or can be obtained by hydrolysis of the corresponding alkylphenylacetates, preferably either by means of a base such as an alkali metal hydroxide (soda or potash for example), in a water-alcohol mixture (ethanol for example), at a temperature between 20 and 30 ° C, either by means of a strong acid (hydrochloric or hydrobromic acid) in water, at reflux of the mixture.
• a base such as an alkali metal hydroxide (soda or potash for example)
• ethanol water-alcohol mixture
• ethanol ethanol
• groups protecting the amino and hydroxy functions are those that allow them to be eliminated without affecting the rest of the molecule.
• groups protecting the amino function mention may be made of tert-butyl or methyl carbamates which can be regenerated by means of iodotrimethylsilane.
• protecting groups for the hydroxy function mention may be made of trimethylsilyl, benzyl.
• Other protective groups which can be used are described by W. GREENE et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons.
• the compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
• the compounds of formula (I) comprising a basic residue can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
• organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
• the compounds of formula (I) comprising an acid residue can optionally be transformed into metal salts according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth, for example) on a compound of formula (I), in a solvent. The salt formed is separated by the usual methods.
• a metal base alkaline or alkaline earth, for example
• salts there may be mentioned addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene- bis- ⁇ - oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate), the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium).
• mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene- bis- ⁇ - oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate
• the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the NMDA receptor.
• NMDA N-methyl-D-aspartate receptor
• These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and the disease by PARKINSON.
• These compounds can also be used vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to the degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3 , 299-302 (1992) or retina (JL MONSINGER et al., Exp. Neurol., 113, 10-17 (1991), anxiety (KEHNE et al., Eur. J. Pharmacol., 193 , 283 (1991)), depression (TRULLAS et al. Eur. J.
• mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric-aminoaciduria, saturnine encephalopathy (intoxication chronic lead) and sulfite oxidase deficiency.
• the affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described. by T. CANTON et al., J. Pharm. Pharmacol., 44, 812 (1992).
• the [ 3 H] -DCKA (20 nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5.
• the non-specific fixation is determined in the presence of 1 mM glycine.
• the bound radioactivity is separated by filtration on Whatman GF / B filters.
• the inhibitory activity of these products is less than or equal to 100 ⁇ M.
• the evaporation residue is treated with 100 ml of ethyl acetate and 50 ml of 5N sodium hydroxide, and the aqueous phase is washed with ethyl acetate, added with 50 ml of methanol and brought to pH 1 with 1N hydrochloric acid.
• the precipitate formed is filtered, washed with water until neutral and recrystallized from 20 ml of dimethylformamide and 20 ml of water. After drying at 80 ° C., 0.68 g of 4-hydroxy-3-phenyl-benzothieno [3,2-b] pyridine-2 (1H) -one is obtained in the form of a cream-colored solid melting at 330 ° C.
• Ethyl 3-phenylacetylaminobenzo [b] thiophene-2-carboxylate can be prepared as follows: to a solution of 3 g of ethyl 3-aminobenzo [bjthiophene-2-carboxylate in 70 ml of dioxane is added 3 , 78 ml of triethylamine and heated to reflux.
• Ethyl 3-aminobenzo [b] thiophene-2-carboxylate can be prepared as described by D. E. L CARRINGTON, K. CLARKE and R. M. SCROWSTON, J. Chem. Soc. (C), 3903 (1971).
• the ethyl 3- (3-morpholino-1 H-indene-2-yl) -3-oxo-2-phenylpropionate can be prepared as follows: to 1.86 g of monoethyl phenylmalonate is added in portions 18 ml of thionyl chloride containing a drop of dimethylformamide. The mixture is kept for 18 hours at a temperature in the region of 20 ° C., then evaporated on a rotary evaporator. To the evaporation residue is added 40 ml of tetrahydrofuran and 1.25 ml of triethylamine.
• Monoethyl phenylmalonate can be prepared as described by W.G. BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984).
• 3-Morpholino-1H-indene can be prepared as described by J. SCHOEN et al., Rocz. Chem., 45, 73 (1971) or by analogy with the method described by A.T. BLOMQUIST and E.J. MORICONI, J. Org. Chem., 26, 3761 (1961).
• Ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate can be prepared as follows: a mixture of 5 is refluxed for 27 hours g of 6-chloroindan-1-one, 60 ml of toluene, 5.2 ml of morpholine and 75 mg of p.toluenesulfonic acid as collecting the water formed by means of a Dean-Stark apparatus.
• reaction mixture is evaporated on a rotary evaporator and the evaporation residue containing 5-chloro-3-morpholino-1H-indene is added with 65 ml of tetrahydrofuran, 5.6 ml of triethylamine and a solution of phenylmalonate chloride of monoethyl in 25 ml of tetrahydrofuran.
• the reaction mixture is stirred for 48 hours at a temperature in the region of 20 ° C., filtered and the filtrate is evaporated on a rotary evaporator.
• the evaporation residue is purified by chromatography on a silica column (400 g), first eluting with dichloromethane, then with a cyclohexane-ethyl acetate mixture (70/30 by volume).
• 1.6 g of ethyl 3- (5-chloro-3-mo ⁇ holino-1 H-inden-2-yl) -3-oxo-2-phenylpropionate are obtained in the form of a greenish yellow solid melting at 175 ° C.
• Monoethyl phenylmalonate chloride can be prepared as described by W.G. BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984) from 4.2 g of monoethyl phenylmalonate.
• the monoethyl phenylmalonate chloride obtained is in the form of a yellow oil used as it is.
• 6-chloroindan-1-one can be prepared according to the method described by R. SEKA and W. KELLERMANN, Chem. Ber., 75, 1730 (1942).
• Example 3 The procedure is as in Example 3, but starting with 1.46 g of 3- (5-chloro-3- mo ⁇ holino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate ethyl, 13.8 g of ammonium acetate and 60 ml of acetic acid. After returning to a temperature in the region of 20 ° C., the reaction mixture is added with 40 ml of distilled water, filtered and the brown solid obtained is washed with distilled water, then with ethyl ether and dried at 50 ° C. vacuum (1 mm Hg; 0.13 kPa).
• Ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate can be prepared as follows: as in Example 3 but from 5 g of 6-chloroindan-1-one to prepare the intermediate 5-chloro-3-morpholino-1H-indene on the one hand, and from 6.7 g of ( Monoethyl 3-phenoxyphenyl) malonate to prepare intermediate monoethyl (3-phenoxyphenyl) malonate chloride on the other hand.
• Monoethyl (3-phenoxyphenyl) malonate can be prepared as follows: 22.3 g of diethyl (3-phenoxyphenyl) malonate in 60 ml of absolute ethanol are stirred and cooled to around 5 ° C. a solution of 3.6 g of potassium hydroxide in 120 ml of absolute ethanol is added dropwise. Stirring is continued for 3 to 4 hours at a temperature between 10 and 20 ° C. The reaction mixture is evaporated on a rotary evaporator and the oily residue is poured onto 140 ml of ice water. Three extractions are carried out with ethyl ether (3 ⁇ 100 ml).
• the aqueous phase is acidified to pH 1 with an ice-cold solution of 10% hydrochloric acid and extracted with ethyl ether (3x100 ml).
• the ethereal solution is dried and evaporated on a rotary evaporator to give 6.9 g of monoethyl (3-phenoxyphenyl) malonate in the form of a thick yellow oil used as it is in subsequent syntheses (Rf ⁇ 0.14 (elongated spot), chromatography on a thin layer of silica gel, eluent: cyclohexane-ethyl acetate (80/20 by volume)).
• Diethyl (3-phenoxyphenyl) malonate can be prepared in the following manner: under an inert atmosphere, to a stirred suspension of 3.3 g of 80% sodium hydride in 80 ml of diethyl carbonate is added dropwise a solution of 15.3 g of (3-phenoxyphenyl) ethyl acetate in 60 ml of diethyl carbonate. The agitation is continued for 48 hours at a temperature close to 20 ° C. The reaction mixture is neutralized with acetic acid and diluted with distilled water.
• the aqueous phase is extracted with ethyl ether (3 ⁇ 40 ml), the ethereal extracts are combined and washed with distilled water, dried and evaporated on a rotary evaporator.
• the evaporation residue is purified by chromatography on a silica column (600 g), eluting with a cyclohexane-ethyl acetate mixture (80/20 by volume).
• Ethyl (3-phenoxyphenyl) acetate can be prepared according to the method described by K. OGURA et al., Bull. Chem. Soc Jpn., 52, 2013 (1979).
• the medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other product.
• pharmaceutically compatible which may be inert or physiologically active.
• the medicaments according to the invention can be used orally, parenterally, rectally or topically.
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sac charose, lactose or silica, under a stream of argon.
• inert diluents such as starch, cellulose, sac charose, lactose or silica
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• liquid compositions for oral administration it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil.
• inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil.
• These compositions can include substances other than diluents, for example example of wetting, sweetening, thickening, flavoring or stabilizing products.
• the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
• These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an NMDA receptor antagonist.
• These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo- pontocerebellar atrophy and PARKINSON's disease, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral and spinal traumas, traumas linked to degeneration of the ear internal or retina, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathy, as an analgesic, anti-inflammatory, anti-anorexic, anti-migraine, antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor, as well as neurological disorders associated with viral diseases such as AIDS, rabies, mea
• These compounds are also useful for the prevention of symptoms of drug and alcohol abstinence and the inhibition of addiction and dependence on opiates as well as for the treatment of deficits associated with mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.
• mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.
• the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.
• the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
• capsules containing 50 mg of active product having the following composition are prepared:
• Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

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