WO2002098851A1 - Derives de n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees, procede de production de leurs sels et de leurs bases, n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees physiologiquement actives, composition pharmaceutique et methode de traitement - Google Patents

Derives de n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees, procede de production de leurs sels et de leurs bases, n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees physiologiquement actives, composition pharmaceutique et methode de traitement Download PDF

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WO2002098851A1
WO2002098851A1 PCT/RU2002/000283 RU0200283W WO02098851A1 WO 2002098851 A1 WO2002098851 A1 WO 2002098851A1 RU 0200283 W RU0200283 W RU 0200283W WO 02098851 A1 WO02098851 A1 WO 02098851A1
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Prior art keywords
methyl
ethyl
allyl
benzyl
phenyl
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PCT/RU2002/000283
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English (en)
Russian (ru)
Inventor
Sergey Evgenievich Tkachenko
Aleksey Nikolaevich Proshin
Sergey Olegovich Bachurin
Ljudmila Nikolaevna Petrova
Nikolay Serafimovich Zefirov
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Institut Fiziologicheski Aktivnykh Veschestv Rossiyskov Akademii Nauk
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Publication of WO2002098851A1 publication Critical patent/WO2002098851A1/fr

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    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A61P25/28—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5304—Acyclic saturated phosphine oxides or thioxides

Definitions

  • This invention is subject to a new derivative 8, 8-substituted ⁇ ', ⁇ '-disubstituted urea, having a pharmacological activity.
  • a more concise, present invention is missing from ⁇ , ⁇ -substituted by ⁇ '-1 - [(hetero) aryl] alkyl- ⁇ '-
  • the glutamate system is the primary excitatory system in the brain and is involved in the implementation of a whole series of physiological and process processes. It is known that there is a widespread case of neurodevelopmental diseases, (such as B. 2 aminocslost ( ⁇ ) - glutamate and machinery ⁇ Good ⁇ . ⁇ Brass ⁇ réelle ⁇ ⁇ DD ⁇ vie ⁇ êt ⁇ ⁇ réelle ⁇ £ £ whatsoever £ £ £ £:::::::::::::::::::::::::::::::::: machinery ⁇ Good ⁇ . ⁇ réelle ⁇ réelle ⁇ ⁇ , ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ . 1999, ⁇ .81, ⁇ ° 3, ⁇ . 163-221).
  • ⁇ ⁇ ezul ⁇ a ⁇ e ⁇ vedenny ⁇ issled ⁇ vany, na ⁇ avlenny ⁇ on ⁇ is ⁇ ney ⁇ e ⁇ ny ⁇ s ⁇ edineny in ⁇ m including ⁇ bladayuschi ⁇ s ⁇ s ⁇ bn ⁇ s ⁇ yu zaschischa ⁇ ne ⁇ vnye ⁇ le ⁇ i ⁇ ney ⁇ siches ⁇ i ⁇ ⁇ ntsen ⁇ atsy i ⁇ n ⁇ v ⁇ altsiya in chas ⁇ n ⁇ s ⁇ i, s ⁇ edi s ⁇ edineshsh, ⁇ bladayu ⁇ gi ⁇ an ⁇ i- ⁇ a ⁇ ivn ⁇ s ⁇ yu, iz ⁇ b ⁇ e ⁇ a ⁇ eli ⁇ bna ⁇ uzhili shi ⁇ uyu g ⁇ ugshu ⁇ izv ⁇ dny ⁇ 4 ⁇ , ⁇ -substituted x ⁇ '- ⁇ - [(he
  • [(hetero) aryl] metal urea which is a specific property of the indicated type of activity.
  • a further aspect of the invention includes a method for generating these compounds.
  • the following aspect of the invention is a method of treating a number of diseases, which is included in the appointment of patients for the treatment of an effective treatment of a patient having an I or pharmacotherapy.
  • ⁇ hereinafter, the pharmaceutically acceptable acid is provided; ⁇ and ⁇ may be the same or different and independently represent aryl or heteroal; the symbol (#) hereinafter means the possibility of the availability of a chrome house;
  • ⁇ 1 represents ⁇ , lower alkyl, aryl
  • ⁇ 2 represents lower alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or a group of the general formula: 6
  • - (sleep 2 ) ⁇ - ⁇ in ⁇ : ⁇ 1 ⁇ 4, and> is selected from a group consisting of: aryl; getter; tetrapagid ⁇ Titan ⁇ Titana; cycloalkyl; ethenyl, optionally mono-, or di-substituted lower alkyl; C ⁇ groups (in the case of ⁇ , ⁇ is alkyl, phenyl); groups C ⁇ 2 ⁇ (in the sense it has the meanings given above); g ⁇ u ⁇ y ⁇ ⁇ (in ⁇ y ⁇ and ⁇ m ⁇ gu ⁇ by ⁇ ⁇ dina ⁇ vymi or ⁇ azlichnymi and ⁇ azhdy nezavisim ⁇ ⁇ eds ⁇ avlyae ⁇ : ⁇ ; al ⁇ il; tsi ⁇ l ⁇ al ⁇ il; a ⁇ al ⁇ il; ⁇ din of zames ⁇ i ⁇ eley ⁇ or ⁇ m ⁇ zhe ⁇ ⁇ ;
  • ⁇ U is selected from the group consisting of: arila; getter; cycloalkyl; ethenyl, not necessarily mono-, or di-substituted by lower alkyl;
  • 7 7 groups ⁇ (in the case of ⁇ there are ⁇ , alkyl, phenyl); GROUPS ⁇ 2 ⁇ 7 (in ⁇ ⁇ 7 it has the meanings given above); 7 piles ⁇ 8 ⁇ 9 (in short, ⁇ 8 and ⁇ 9 may be the same or different, and each independently delivers: ⁇ ; alkyl; cyclic; do not eat; in ⁇ y ⁇ imee ⁇ values ⁇ edelennye above; ⁇ ⁇ or ⁇ y ⁇ and ⁇ m ⁇ gu ⁇ s ⁇ vmes ⁇ n ⁇ ⁇ b ⁇ az ⁇ vyva ⁇ not ⁇ byaza ⁇ eln ⁇ substituted 1,4 or 1,5-bu ⁇ ilen ⁇ vuyu ⁇ en ⁇ ame ⁇ ilen ⁇ vuyu tse ⁇ ch ⁇ i and ⁇ a ⁇ zhe tse ⁇ ch ⁇ u -S ⁇ S ⁇ 2-0 2-2 S ⁇ S ⁇ 2 -); g ⁇ u ⁇ y ⁇ ( ⁇ 10) h + ⁇ "
  • cycloalkyl means a cyclic saturated carbohydrate jam with 5-7 ring carbon atoms, its examples include cyclic and cyclic.
  • “Aril” means unsubstituted or substituted phenyl or essential group.
  • Alternatives to phenyl bog can be halogens (for example, fp, p, cool, and similar), lower alkali groups (for example, methyl, ethyl, isothermal, or non-anal similar), cyanide, nitrous, and third-party groups (for example, third-party and analogue- 8), optionally substituted amine groups (for example, amine, dimethylamine, acetylamine, Clearly-pyperidine, ⁇ -phthalimide group and similar), acyl group, for example, ⁇ , ⁇ -diethyl carbamide group and similar), large group, large group and similar.
  • the substituents of the large group may be phth, p, brom, methyl, and blasting.
  • aralkyl means the aforementioned aryl, the alkyl group connected to the above is connected to the aforesaid.
  • heterofuril means a 5- or 6-membered ⁇ -, ⁇ -, or 8-hetero-cycle or its benzene derivative.
  • suitable substituents include optionally substituted furoan, thiophene, pyrupul, indole, pyridine, chinoline, etc.
  • galogen as used here refers to chl ⁇ , brom, ⁇ or iod.
  • alkoxy means the group, ⁇ ⁇ , in the case of the alkaline group, this is the same as the group above the alkyl group.
  • alkali groush examples include methoxy, ethoxy, butyx and similar groups.
  • acyl means the C ⁇ group (in the case of ⁇ , it means ⁇ , alkyl, aryl and aralkyl, as defined above).
  • examples of acyl group include phenyl, acetyl, benzyl, phenylacetyl and similar groups.
  • pharmaceutical acceptable acid excludes all pharmaceutical acceptable acids, such as non-organic (salted, non-ferrous); such and organic (for example, oxalic, citric, wine, maleic, succinic, methylaceous, ⁇ -glucose sulfate And ⁇ . D.).
  • ⁇ and ⁇ have the meanings given above for the formula I; ⁇ and provides alkyl, alkenyl, cycloalkyl, aryl, aralkyl, 2-methoxyethyl, 3-methoxypropyl, 2-dialkylaminethyl, 3-dialkylaminyl,
  • the most suitable parti cles among substances, which correspond to formula I, are: 1.2. ⁇ , 8-substituted ⁇ '-1- ( ⁇ , 8) -phenylethyl- ⁇ '- (hetero) arylmethyl urea in the form of a racemic mixture (or an additive mixture of a thermal mixture) of a total of 1.2
  • ⁇ 11 has the meanings given above for formula 1.1
  • ⁇ 12 has the meanings given above for formula 1.1;
  • More preferred compounds according to the invention in the range of urea formulas 1.1 are: 1.1.1, 8-substituted
  • ⁇ 13 represents methyl, ethyl, butyl, aryl, allyl, 2-methoxyethyl, 3-methoxypropyl, 2-dialkylaminethyl, 3-dialkylaminopropyl,
  • connection groups that may be provided by forum
  • ⁇ 1 provides: phenyl, (not necessarily a lot or di-substituted with such substituents, like galogen, lower alkyl, methoxy, ethoxy, methyl); 15 methylenedioxyphenyl; 2-phur.
  • ⁇ 14 represents methyl, ethyl, butyl, aryl, allyl, 2-methoxyethyl-, 3-methoxypropyl, 2-dialkylaminoethyl, 3-dialkylaminopropyl, benzyl, 1- (phenyl, phenyl, phenyl, phenyl, phenyl) 0 ⁇ 15 is selected from the group consisting of: lower alkyl; allyl; benzyl, not necessarily substituted in the benzene ring; thirteen
  • Preferred compounds are also:
  • ⁇ 1 , ⁇ 1 and ⁇ have the corresponding meanings given above for formula 1.2.1.
  • P ⁇ i e ⁇ m is ⁇ lzue ⁇ sya 5-50- ⁇ a ⁇ ny izby ⁇ schel ⁇ chn ⁇ g ⁇ agen ⁇ a ⁇ ⁇ n ⁇ sheniyu ⁇ s ⁇ li I.
  • the reactive mixture is cooled, the catalyst is removed, the vaporizer is evaporated.
  • the resulting oil is distilled by removing a fraction of 164-166 ° C / 1 mm ⁇ . ct. ⁇ 2.26 g (0.01 mol) of the obtained benzyl [(4 methoxyphenyl) methyl] amine in 50 ml of ethanol add 0.99 g (0.01 mol) of the allylate, boil 1.5 hours, add 1.7 hours (0,012 moles), the yielding to the metal, they’ll take another 1.5 hours. Then the distributor and the non-reacting metalide are discouraged, the recovered crystals of the process are removed from 20 ml of isopropane. ⁇ d 2.9 g (62.1%), ⁇ . ⁇ . 85-87 ° C.
  • Example 4 8-Methyl- ⁇ -allyl- ⁇ '-benzyl- ⁇ '- [(2- ⁇ phenyl) methyl] urea (compound 13).
  • a solution of 12.4 g (0.1 mole) of 2-phenyl benzaldehyde, 10.7 g (0.1 mole) of benzylamine in 100 ml of carbohydrate is boiled with a nozzle of the Dean-Starter to protect the water from the product. The reactive mixture is vaporized.
  • the reactive mixture is cooled, the catalyst is removed, the vaporizer is evaporated.
  • the resulting oil is distilled by removing a fraction of 150-152 ° C / 1mm ⁇ . ct. ⁇ 2.15 g (0.01 mol) of the resulting benzyl [(2-phenyl) methyl] amine in 50 ml of ethanol added 0.99 g (0.01 25 mol) of the allilitian, boil 1.5 hours, add 1.7 g (0.012 mol) of methyldehyde, boil another 1.5 hours. Then the solvent and the non-reactive metalide are discarded, the obtained crystals are converted from 20 ml of isopropane. ⁇ d 3.1 g (68.0%), ⁇ . ⁇ . 149-151 ° C.
  • Example 5 8-allyl- ⁇ -allyl- ⁇ '-benzyl- ⁇ '- [(4- ⁇ phenyl) methyl] urea (compound 14).
  • a solution of 12.4 g (0.1 mol) of 4-phenyl benzaldehyde, 10.7 g (0.1 mol) of benzylamine in 100 ml of benzyl amine is stored with the Dynamo nozzle to protect the water from the product. The reactive mixture is vaporized.
  • Example 7 8-Methyl- ⁇ -allyl- ⁇ '-benzyl- ⁇ '- [(2-chloro-phenyl) methyl] urea (compound 23). ⁇ 2.31 g (0.01 mol) benzyl [(2-chlorophenyl) methyl] amine in 50 ml of ethanol add 0.99 g (0.01 mol) of allyl isocyanate, boil 1.5 hours, add 1.70 g ( 0.012 mol) methyloidide, boil for another 1.5 hours. Then 29 The distributor and the non-reacting metalide are discarded, the obtained crystals are converted and lysed from 20 ml of isopropanol. ⁇ d 3.0 g (63.5%), ⁇ . ⁇ . 164-166 ° C.
  • Hydrohydride 8-allyl- ⁇ -allyl- ⁇ '-benzyl- ⁇ '- [(2-chlorophenyl) methyl] - urea (compound 49). ⁇ y ⁇ d 57%, ⁇ . Pl. 107-112 ° ⁇ . Hydrohydride 8-ethyl- gleich-allyl- ⁇ '-benzyl- ⁇ '- [(2-chlorophenyl) methyl] - urea (compound 50). ⁇ y ⁇ d 47%, ⁇ . Pl. 116-120 ° C.
  • Example 8-Methyl-tician-allyl- ⁇ '-benzyl- ⁇ '- (2-phenylmethyl) - urea (compound 24).
  • a solution of 9.6 g (0.1 mole) of flour and 10.7 g (0.1 mole) of benzylamine in 100 ml of body is boiled with a nozzle of the Dean-Straw for the disposal of water.
  • the reactive mixture is vaporized.
  • the resulting benzyl (2-furumetan) imine is restored by catalytic hydration: the basis of Shiffa (20 g) in 50 ml of water and 2 g of 1% oxygen is used for pressure control. Disposal of water at the disposal of the property.
  • the reactive mixture is cooled, the catalyst is removed, the vaporizer is evaporated.
  • the resulting oil is distilled by breaking down at a temperature of 117-120 ° C / 1.5 mm ⁇ . ct. ⁇ 1.87 g of the resulting benzyl (2-ferylmethyl) amine in 50 ml of ethanol add 0.99 g (0.01 mol) of all the charge, take 1.5 hours, add 1.7 g (0.012 mol) 30 yodistogo methyl, boilers another 1.5 hours. Then the solvent and the non-reactive metalide are discarded, the obtained crystals are converted from 20 ml of isopropane. ⁇ d 2.5 g (58.4%), ⁇ . ⁇ . 98-100 ° C.
  • the reactive mixture can withstand at a temperature of 40 ° C for 72 hours. Above the crystals, they are filtered and they are removed from 30 ml of isopropanol.
  • Example 10 8-Methyl- ⁇ -allyl- ⁇ ', ⁇ '-di [(4-methoxyphenyl) - methyl] urea (hydride) urea (compound 35). 33 a). ⁇ -allyl- ⁇ ', ⁇ ' - [(4-methoxyphenyl) methyl] urea.
  • the reactive mixture is cooled, the catalyst is removed, the vaporizer is evaporated.
  • the crystalline crystals of di [(4-methoxyphenyl) methyl] amine are crystallized from 50 ml of isopropanol. ⁇ 25.7 g (0.1 mol) of the resulting [(4-methoxyphenyl) methyl] amine in 150 ml of ether was added while stirring 9.9 g (0.1 mol) of the allylate. Above the crystals, they are filtered and recovered from 100 ml of isopropanol. ⁇ regulate 32.2 g (90.5%), ⁇ . ⁇ . 98-100 ° C.
  • the crusted crystals are filtered and removed from 20 ml of isopropanol.
  • the reactive mixture can withstand at a temperature of 40 ° C for 24 hours.
  • the crusted crystals are filtered and removed from 20 ml of isopropanol.
  • the reactive mixture is vaporized.
  • the resulting understanding of the Shiffa restores the catalytic hydrogenation: 20 g of [(4-phenylmethyl) methyl] -4-methoxyphenylmeanimine, 50 ml of hydrogen, 2% Disposal of water at the disposal of the property.
  • the reactive mixture cools, removes the catalyst, and evaporates the solvent.
  • the resulting oil is distilled by removing a fraction of 143-147 ° C / 1 mm ⁇ . ct.
  • P ⁇ ischezn ⁇ venii ⁇ ya ⁇ na is ⁇ dn ⁇ g ⁇ ⁇ sn ⁇ vaniya Shi ⁇ a ⁇ ea ⁇ tsi ⁇ nnuyu mixture vylivayu ⁇ 150 ml v ⁇ dy, e ⁇ s ⁇ agi ⁇ uyu ⁇ e ⁇ i ⁇ m (3 ⁇ 30 mL) e ⁇ i ⁇ nye e ⁇ s ⁇ a ⁇ y ⁇ bedinyayu ⁇ , susha ⁇ ⁇ a 2 80 4 and u ⁇ a ⁇ ivayu ⁇ .
  • the resulting oil is distilled by removing a fraction of 97-99 ° C / 1 mm ⁇ .st.
  • Example 14 8-Methyl- ⁇ -ethyl- ⁇ '-benzyl- ⁇ '- [(3,4-methylenedioxyphenyl) methyl] urea (compound 44).
  • the preparation is 15.0 g (0.1 mol) of pyrene, 10.7 g (0.1 mol) of benzylamine, 100 ml of the body is stored with the nozzle of the Dean Stacker to protect the water from the waste. The reactive mixture is vaporized.
  • the obtained base of the valve is restored by catalytic hydrogenation: 20 g of benzyl- (3,4-methylenedioxyphenyl) methanimine, 50 ml of water, 2 g of 1% water pressure Disposal of water at the disposal of the property.
  • Example 15 8-methyl- ⁇ -methyl- ⁇ '- (2-thienylmethyl) - ⁇ ' - (2-methylmethyl) urea (hydride urea) compound (compound 45).
  • 11 A solution of 11.2 g (0.1 mol) of 2-compound of saldehyde, 8.5 g (0.1 mol) of 2-phenyl methyl amine, 50 ml of housing contains 5 g of freshly molten sieve 4 ⁇ . The reactive mixture can withstand a large temperature switch, the discharge of the mixture will not become discharged. The sys- tem is filtered, the pressure relief valve is relieved of pressure relief.
  • P ⁇ ischezn ⁇ venii ⁇ ya ⁇ na is ⁇ dn ⁇ g ⁇ ⁇ sn ⁇ vaniya Shi ⁇ a ⁇ ea ⁇ tsi ⁇ nnuyu mixture vylivayu ⁇ 150 ml v ⁇ dy, e ⁇ s ⁇ agi ⁇ uyu ⁇ e ⁇ i ⁇ m (3 ⁇ 30 mL) e ⁇ i ⁇ nye e ⁇ s ⁇ a ⁇ y ⁇ bedinyayu ⁇ , susha ⁇ ⁇ a 2 80 4 and u ⁇ a ⁇ ivayu ⁇ .
  • the resulting oil is distilled by removing a fraction of 137-139 ° C / 1.5 mm ⁇ .st.
  • this extract which is excreted in the salt, removes urea, grows in 20 ml of acetone and adds 1.7 g (0.012 mol) of acid.
  • the reactive mixture is excreted and tempered
  • ⁇ v ⁇ y is ⁇ lz ⁇ vali ⁇ iginalny ⁇ d ⁇ d ⁇ na ⁇ avlenn ⁇ mu ⁇ is ⁇ u s ⁇ edineny, s ⁇ s ⁇ bny ⁇ bl ⁇ i ⁇ va ⁇ ⁇ azvi ⁇ ie i ⁇ say ⁇ siches ⁇ i ⁇ ⁇ tsess ⁇ v and ⁇ a ⁇ im ⁇ b ⁇ az ⁇ m ⁇ yavlya ⁇ ney ⁇ e ⁇ n ⁇ e deys ⁇ vie and imenn ⁇ : ⁇ is ⁇ and ⁇ b ⁇ s ⁇ edineny s ⁇ s ⁇ bny ⁇ ingibi ⁇ va ⁇ glu ⁇ ama ⁇ dependent v ⁇ d ⁇ altsiya.
  • glucose aspartic and their agonists
  • Another aspect of the invention is the use of compounds of the general formula I, as an active substance for the device 52 le ⁇ a ⁇ s ⁇ venny ⁇ ⁇ e ⁇ a ⁇ a ⁇ v for the treatment and ⁇ edu ⁇ ezhdeniya zab ⁇ levany, svyazash ⁇ y ⁇ with dis ⁇ un ⁇ tsiey glu ⁇ ama ⁇ e ⁇ giches ⁇ y ney ⁇ e ⁇ edachi
  • ⁇ e ⁇ iz ⁇ b ⁇ e ⁇ eniya s ⁇ s ⁇ avlyae ⁇ is ⁇ lz ⁇ vanie le ⁇ a ⁇ s ⁇ venny ⁇ ⁇ e ⁇ a ⁇ a ⁇ v and ⁇ a ⁇ matsev ⁇ iches ⁇ i ⁇ ⁇ m ⁇ zitsy on ⁇ sn ⁇ ve s ⁇ edineny ⁇ bschey ⁇ muly I for the treatment and ⁇ edu ⁇ ezhdeniya zab ⁇ levany, svyazanny ⁇ with dis ⁇ un ⁇ tsiey glu ⁇ ama ⁇ e ⁇ giches
  • ⁇ aznachae maya for ⁇ iema d ⁇ za a ⁇ ivn ⁇ g ⁇ ⁇ m ⁇ nen ⁇ a (s ⁇ edineniya ⁇ muly I or eg ⁇ ⁇ a ⁇ matsev ⁇ iches ⁇ i ⁇ iemlemy ⁇ s ⁇ ley) va ⁇ i ⁇ ue ⁇ in zavisim ⁇ s ⁇ i ⁇ mn ⁇ gi ⁇ ⁇ a ⁇ v, ⁇ a ⁇ i ⁇ ⁇ a ⁇ v ⁇ z ⁇ as ⁇ , ⁇ l, ⁇ atsien ⁇ a weight sim ⁇ my and ⁇ yazhes ⁇ zab ⁇ levaniya, ⁇ n ⁇ e ⁇ n ⁇ nicnachaem ⁇ e s ⁇ edinenie, s ⁇ s ⁇ b ⁇ iema, ⁇ ma ⁇ e ⁇ a ⁇ a ⁇ a, as ⁇ y an active connection is assigned.
  • the usual, commonly prescribed dose is 1 to 200 mg per day.
  • the total dose may be divided into a few doses, for example, for an average of 1 to 4 times per day. For general use, it was generally given up to 10 mg to 200 mg per day, preferably 15 mg to 150 mg. At a parenteral dose, the prescribed dose is 5 to 100 mg per day; preferably, 5 to 50 mg and a daily dose of 25 mg per day is 1 day. A lateral dose may be selected by the attending physician.
  • liquid formulations for injections and parenteral administration include excipients, emulsions, suspensions and others.
  • excipients include excipients, emulsions, suspensions and others.
  • emulsions include emulsions, suspensions and others.
  • use is made with standard products that allow for the mixing of active compounds with liquid or finely chopped liquids.
  • binders magnesium aluminum silicate, excellent stock, gelatine, agent, methyl cellulose, carboxymethyl cellulose and polyl vinyl pyrrolide;
  • the card may be packaged by using an accessory or form of active ingredient with one or more additional ingredients.
  • tetrazine indigo
  • sodium metabolite sodium fuel.
  • the offered yellow capsules contain from 1 to 20% of the active ingredient. 55 ⁇ 2.
  • Injection companies are predominantly responsible for industrial or suspension products.
  • the aforementioned formulations can be sterilized and contain additives, such as consumables: sodium metabolic, benzoyl acid, sodium metabolic, and metabolism; stabilization: abrasive and aromatic gum, dextrin, extreme sticks, methyl cellulose, tween; salt regulating the pressure (hydrochloride pressure), or 56 buffers. Otherwise, they may contain other useful therapeutic substances.

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Abstract

Cette invention concernes de nouveaux dérivés de N'-1(hétéro)aryl alkyl-N'-(hétéro)aryl méthyle isothiourées N,S-substituées, de même que leurs bases et leurs sels, conteant des acides pharmaceutiquement acceptables, ainsi que des isomères optiques isolés des compositions ci-décrites ou des mélanges de ces compositions, représentées par la formule générale (I), selon laquelle R?1, R2, R3¿, X, Y et Z sont tels que définis dans la description. Ces compositions présentent des propriétés de neuroprotecteurs-bloqueurs efficaces du transport d'ions de calcium induit par le glutamate. Cette invention concerne également des méthodes de production de ces compositions, ainsi que des bases stables et des isomères optiques. Elle porte également sur des compositions physiologiquement actives représentées par la formule (I) qui sont des bloqueurs efficaces et sélectifs du transport des ions de calcium induit par le glutamate, ainsi que sur une méthode de production d'un système glutamatergique à l'aide de ces derniers. En outre, elle porte sur une méthode de traitement de diverses maladies (telles que la maladie d'Alzheimer et la chorée de Huntingtdon) qui consiste à administrer aux patients une quantité efficace de la composition représentée par la formule (I). Enfin, elle concerne des compositions pharmaceutiques contenant une quantité thérapeutiquement efficace de la composition (I) ainsi que des agents auxiliaires inertes acceptables.
PCT/RU2002/000283 2001-06-04 2002-06-04 Derives de n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees, procede de production de leurs sels et de leurs bases, n'-1-[(hetero)aryl] alkyl-n'-[(hetero)aryl] methyle isothiourees n,s-substituees physiologiquement actives, composition pharmaceutique et methode de traitement WO2002098851A1 (fr)

Applications Claiming Priority (2)

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RU2001114922 2001-06-04
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EP1577294A1 (fr) * 2002-12-05 2005-09-21 Institut Fiziologicheski Aktivnykh Veschestv Rossiyskov Akademii Nauk N-1- (hetero)aryl alkyl-n - (hetero)aryl ;alkylisothiocarbamides s-substitues, procede de production associe, n-1- (hetero)aryl alkyl-n - (hetero)aryl alkylisothiocarbamides s-substitues physiologiquement actifs, composition pharmaceutique et methode
WO2019246454A1 (fr) * 2018-06-20 2019-12-26 Neuropore Therapies, Inc. Méthode de traitement d'une affection associée à une neurodégénérescence faisant appel à des inhibiteurs d'oat3
US11008294B2 (en) 2017-10-30 2021-05-18 Neuropore Therapies, Inc. Substituted phenyl sulfonyl phenyl triazole thiones and uses thereof

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RU2475479C1 (ru) * 2011-12-23 2013-02-20 Федеральное государственное бюджетное учреждение Министерства здравоохранения и социального развития Российской Федерации "Медицинский радиологический научный центр" (ФГБУ МРНЦ Минздравсоцразвития России) Вазоконстрикторное средство

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EP1577294A1 (fr) * 2002-12-05 2005-09-21 Institut Fiziologicheski Aktivnykh Veschestv Rossiyskov Akademii Nauk N-1- (hetero)aryl alkyl-n - (hetero)aryl ;alkylisothiocarbamides s-substitues, procede de production associe, n-1- (hetero)aryl alkyl-n - (hetero)aryl alkylisothiocarbamides s-substitues physiologiquement actifs, composition pharmaceutique et methode
EP1577294A4 (fr) * 2002-12-05 2008-05-28 Medivation Inc N-1- (hetero)aryl alkyl-n - (hetero)aryl ;alkylisothiocarbamides s-substitues, procede de production associe, n-1- (hetero)aryl alkyl-n - (hetero)aryl alkylisothiocarbamides s-substitues physiologiquement actifs, composition pharmaceutique et methode
US11008294B2 (en) 2017-10-30 2021-05-18 Neuropore Therapies, Inc. Substituted phenyl sulfonyl phenyl triazole thiones and uses thereof
US11708338B2 (en) 2017-10-30 2023-07-25 Neuropore Therapies, Inc. Substituted phenyl sulfonyl phenyl triazole thiones and uses thereof
WO2019246454A1 (fr) * 2018-06-20 2019-12-26 Neuropore Therapies, Inc. Méthode de traitement d'une affection associée à une neurodégénérescence faisant appel à des inhibiteurs d'oat3
JP2021527692A (ja) * 2018-06-20 2021-10-14 ニューロポア セラピーズ インコーポレイテッド Ｏａｔ３の阻害剤を用いた神経変性に関連する状態の処置方法

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