WO2009153009A1 - Dérivés de la taxifoline pour la prophylaxie et le traitement de troubles neurologiques et psychiatriques du système nerveux central - Google Patents

Dérivés de la taxifoline pour la prophylaxie et le traitement de troubles neurologiques et psychiatriques du système nerveux central Download PDF

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Publication number
WO2009153009A1
WO2009153009A1 PCT/EP2009/004276 EP2009004276W WO2009153009A1 WO 2009153009 A1 WO2009153009 A1 WO 2009153009A1 EP 2009004276 W EP2009004276 W EP 2009004276W WO 2009153009 A1 WO2009153009 A1 WO 2009153009A1
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WIPO (PCT)
Prior art keywords
derivatives
taxifoline
disease
formula
use according
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PCT/EP2009/004276
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German (de)
English (en)
Inventor
Wilfried Dimpfel
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Otkrytoe Aktsionernoe Obschestvo Zavod Ekologicheskoy Tekhniki I Ekopitaniya "Diod"
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Priority to EP09765589A priority Critical patent/EP2307005A1/fr
Publication of WO2009153009A1 publication Critical patent/WO2009153009A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • Taxifoline derivatives for the prophylaxis and treatment of neurological and psychiatric disorders of the central nervous system
  • the present invention relates to the use of Taxifolinderivaten for the prophylaxis and / or treatment of neurological and psychiatric disorders of the central nervous system, in particular dementias, Parkinson's disease, Alzheimer's disease and depression and pain.
  • Taxifolin also known as 2,3-dihydroquercitin or 3,3 ', 4', 5,7-pentahydroxyflavanone, of the structure
  • taxifolin can be isolated from a natural product, especially from the Siberian larch.
  • the flavonoids in turn belong to the group of polyphenols and are present in all cells that are capable of photosynthesis. They are therefore widely used in the plant world, especially in fruits such as apples, berries, vegetables and lettuce plants, as well as tea and coffee.
  • the content which depends inter alia on the plant variety, the climate and the harvest month, may be in onions, broccoli and black tea at over 50 mg / kg. By eating fruit, vegetables and salad, as well as the enjoyment of tea and coffee so flavonoids are absorbed with the daily food.
  • a biological or pharmacological effect of taxifoline derivatives on the central nervous system has hitherto been described only in terms of an antioxidant, neuroprotective effect (eg Dok-Go H, Lee KH, Kim HJ, Lee EH, Lee J, Song YS, Lee YH, Jin C , Lee YS, Cho J .: Neuroprotective effects of antioxidant flavonoids, quercetin, (+) - dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. Sabote; Brain Res. 2003 Mar 7; 965 (1- 2): 130-6), but not with respect to degenerative and psychiatric disorders of the brain.
  • the drugs currently used in the treatment of diseases of the central nervous system have a wide spectrum of side effects.
  • prophylaxis or treatment with a drug with good therapeutic efficacy with the lowest possible rate of side effects e.g. for the administration of modified foods or dietary supplements.
  • Taxifolinderivate possess valuable pharmacological properties for the prophylaxis and / or treatment of diseases of the central nervous system.
  • a low rate of side effects is to be expected, as it is a natural flavonoid which, as shown above, is usually taken with food.
  • hydroxy groups are at least partially alkylated, methylated, glycated, sulfated, phosphated, esterified or etherified.
  • One or more phenolic hydroxyl groups are preferably blocked by esterification or etherification.
  • R 2 - R 5 independently of one another represent OR 7 , where R 4 and R 5 can also be thio (C 1 -C 4 -) alkyl or NR 8 R 9 ,
  • R 6 is C 1 -C 8 -alkyl or C 6 -C 12 -aryl
  • GIy is a mono- or oligoglycoside radical
  • alkyl refers to straight-chain or branched saturated hydrocarbons having preferably 1 to 20 carbon atoms, in particular 1 to 10, particularly preferably 1 to 4, carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
  • cycloalkyl is, unless otherwise indicated, includes an organic radical derived from a monocyclic preferably (C 3 -C 1 0) - cycloalkyl compound, in particular (C 3 -C 6) -CycloalkylENS is derived by removal of a hydrogen radical from a Ring carbon of the cycloalkyl compound.
  • cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.
  • aryl means a cyclic or polycyclic ring consisting of preferably 6 to 12 carbon atoms. Examples of aryl groups are phenyl or naphthyl.
  • acyl means a functional group derived from an oxo acid, preferably carboxylic acid and sulfonic acid, in which one or more OH groups have been removed.
  • Mono- or oligoglycoside radicals are preferably selected from the group of hexosyl or Pentosyireste, such as Rhamnosyi, glucosyl, allosyl, galactosyl, Mannosylreste.
  • pharmaceutically acceptable salts includes acid addition salts with conventional pharmaceutically acceptable acids, e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid,
  • Phosphoric acid lactic acid, pyruvic acid, acetic acid, succinic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and glucuronic acid.
  • Suitable salt formers besides customary pharmaceutically acceptable acids are also the corresponding anions.
  • taxifoline derivatives of formula (I) may be in any stereoisomeric form or mixtures thereof.
  • the present invention therefore relates to the use of taxifoline derivatives of the formula (I), including their pharmaceutically acceptable salts, hydrates, solvates and complexes, for the manufacture of a medicament for the prophylaxis and / or treatment of neurological and psychiatric disorders of the central nervous system, in particular dementias, of morbidity Parkinson's, Alzheimer's disease and depression and pain.
  • the term "pharmaceutical” also means food supplements or foods modified or added with taxifoline derivatives.
  • Another object of the invention is a medicament for the prophylaxis and / or treatment of neurological and psychiatric disorders of the central nervous system, in particular dementias, Parkinson's disease, Morbus Alzheimer's and depression and pain conditions containing at least one taxifoline derivative of formula (I) 1 including its pharmaceutically acceptable salts, hydrates, solvates and complexes.
  • the present invention also relates to the use of taxifoline derivatives of the formula (I), including their pharmaceutically acceptable salts, hydrates, derivatives and complexes, for the prophylaxis and / or treatment of neurological and psychiatric disorders of the central nervous system, in particular dementias, Parkinson's disease, Morbus Alzheimer's and depression and pain.
  • Another object of the invention is a method for the prophylaxis and / or treatment of neurological and psychiatric disorders of the central nervous system, in particular dementias, Parkinson's disease, Alzheimer's disease and depression and pain, wherein at least one taxifoline derivative of the formula (I), including the pharmaceutically acceptable Salts, hydrates, solvates and complexes, administered to a patient in a therapeutically effective amount.
  • Taxifoline derivatives of the formula (I) are preferably used in a dosage of from 40 to 400 mg, in particular from 100 to 300, particularly preferably 150 mg per day.
  • Taxifoline derivatives of the formula (I) can be used according to the invention together with conventional pharmaceutically acceptable carriers, auxiliaries and / or additives, such as diluents.
  • the taxifoline derivatives of the formula (I) can be administered in various ways: orally, topically, parenterally, intravenously, intramuscularly, subcutaneously, nasally, by inhalation, rectally or transdermally.
  • the taxifoline derivatives of the formula (I) are preferably administered orally.
  • taxifoline derivatives of the formula (I) may optionally be used in combination (simultaneously or with a time delay) with other active ingredients.
  • the medicament of the invention containing as active ingredient taxifolin or structurally related molecules, e.g. in the form of tablets, capsules, pills, dragees, granules, suppositories, pellets, solutions, dispersions, wherein the active ingredient may optionally be combined with pharmaceutically acceptable excipients and carriers.
  • the medicament according to the invention is in the form of a solution, it preferably contains from 0.1 to 10% by weight, more preferably from 1 to 5% by weight, of the active ingredient.
  • composition according to the invention can be prepared in a customary manner familiar to the person skilled in the art and administered in a pharmaceutically suitable form.
  • solid oral forms in addition to the active ingredient in addition to conventional excipients and carriers such as extenders, such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch;
  • Lubricants for example silicate, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols;
  • Binders for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone;
  • Disintegrants eg starch, alginic acid, alginates or sodium starch glycolates, intumescent mixtures; dyes; sweeteners; Wetting agents such as lecithin, polysorbates, laurylsulfates; as well as other customary formulation auxiliaries.
  • the pharmaceutical preparations may be prepared in known manner, e.g. by mixing, granulating, tabletting, sugar coating or coating coating processes.
  • Liquid dosage forms for oral administration may be e.g. Dispersions, syrups, emulsions and suspensions.
  • a syrup may be used as a carrier e.g. Sucrose or sucrose with glycerol and / or mannitol and / or sorbitol.
  • Suspensions and emulsions may be used as carriers, e.g. a natural resin, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol.
  • Suspensions or solutions for intramuscular injections may contain, together with the active ingredient, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. Propylene glycol, and optionally containing an appropriate amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. Propylene glycol, and optionally containing an appropriate amount of lidocaine hydrochloride.
  • Solutions for intravenous injection or infusion may be used as carriers e.g. contain sterile water or they may preferably be in the form of sterile, aqueous, isotonic saline solutions.
  • Suppositories may contain, together with the active ingredient, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitol fatty acid ester or lecithin.
  • a pharmaceutically acceptable carrier for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitol fatty acid ester or lecithin.
  • Compositions for topical application eg creams, lotions or pastes, can be prepared by mixing the active ingredient with a conventional oleaginous or emulsifying carrier.
  • Peroral dosage forms preferably contain 40 to 400 mg, more preferably 100 to 300 mg, of active ingredient per daily dose.
  • the daily dose can be administered, for example, in 1 to 3 single doses, preferably in two single doses, daily.
  • Parenteral dosage forms such as dosage forms for intravenous, subcutaneous, intramuscular administration, preferably contain 40 to 80 mg, more preferably 30 mg, of active ingredient per daily dose.
  • the daily dose may be administered, for example, in 1 to 3 single doses, preferably in a single dose daily.
  • Dosage forms for rectal administration preferably contain 100 to 200 mg, more preferably 150 mg, of active ingredient per daily dose.
  • the daily dose may be administered, for example, in 1 to 3 single doses, preferably in a single dose daily.
  • Dosage forms for application to the skin and mucous membranes preferably contain 80 to 180 mg of active ingredient, more preferably 100 mg, of active ingredient per single dose.
  • the daily dose may be administered, for example, in 1 to 6 single doses, preferably in 1 to 3 single doses, daily.
  • Pure dietary supplements especially as an addition to beverages, preferably contain 200 to 600 mg of active ingredient, more preferably 300 mg.
  • Fig. 1 the time course of EEG frequencies after application of a saline solution as a control (baseline). The time in hours after application is plotted on the y-axis. The x-axis gives the frequency ranges after the Fast Fourier transformation of the data: delta ( ⁇ ), theta ( ⁇ ), alpha ( ⁇ 1), alpha2 ( ⁇ 2), betai ( ⁇ 1) and beta2 ( ⁇ 2).
  • FIG. 1 thus serves as proof of stable experimental conditions
  • the x and y axes of the diagram correspond to those in FIG. Additionally indicated are statistical significances: * corresponds to an error probability of p ⁇ 0.1; ** correspond to p ⁇ 0.05; *** correspond to p ⁇ 0.025,
  • Fig. 3 the effect of 20 mg / kg taxifolin on the EEG frequencies during the last hour after administration in comparison with known drugs for the treatment of Parkinson's disease (amantadine), Alzheimer's disease (memantine) or in depression (imipramine, amitriptyline) .
  • Fig. 5 the documentation of the result of a discriminant analysis on the basis of four brain regions and 6 frequency bands (24 variables).
  • the first and second discriminant functions are shown on the x and y axes.
  • the third discriminant axis is on the z-axis.
  • the fourth to sixth in the colors red-green-blue.
  • the color dots are created from an additive color mixture that represents these axes.
  • the effect of the high dose of taxifolin is in the vicinity of galantamine, tacrine and selegiline.
  • the numbers behind the preparation indicate the dosage in mg / kg.
  • the changes in the EEG frequencies were determined by tele-stereo EEG after administration of saline (control) or orally by taxifolin (10, 20 or 40 mg / kg body weight).
  • the substances were administered orally 45 minutes after the start of the measurements (pre-value). Five minutes later, measurements were restarted, continuously analyzed for at least the next 5 hours, and pooled into 60-minute periods.
  • the test substance was applied at a dose of 10, 20 and 40 mg / kg (taxifolin).
  • the experimental series was started with the injection of saline (control), which did not cause a noticeable change ( Figure 1).
  • the statistical comparison of the experiments to the results, which were measured after administration of saline, took place with the aid of a multivariate analysis according to Ahrens and Läuter (see H. Ahrens, J. Läuter “Multidimensional Analysis of Variance” (1974), Akademie Verlag, Berlin) the basis of changes within each frequency band in all brain regions as variables.
  • Taxifolin as a single dose results in changes in brain electrical activity in the test animals following those following administration of selegiline, galantamine, tacrine, amantadine, amitriptyline, imipramine or memantine.
  • This pattern correlates conspicuously with the patterns used for drugs commonly used for the treatment of dementia, Parkinson's disease and depression ( Figures 3 and 4), but not with patterns seen with drugs for other indications (Dimpfel, loc. Cit.).
  • Taxifolin in the tele-stereo EEG model in rats shows dose-dependent changes in the EEG frequencies ( Figure 4) as known after administration
  • Drugs used to treat dementia / Alzheimer's disease galantamine, tacrine, a cholinesterase inhibitor), Parkinson's disease (selegiline), as well as depression (paroxetine, imipramine).
  • taxifolin causes the same characteristic changes in EEG frequencies as common drugs used to treat dementia, Parkinson's disease, Alzheimer's disease and depression, it can be concluded that taxifolin is effective in treating the same indications .

Abstract

La présente invention concerne l'utilisation de dérivés de la taxifoline pour la prophylaxie et/ou le traitement de troubles neurologiques et psychiatriques du système nerveux central, en particulier des démences, de la maladie de Parkinson, de la maladie d'Alzheimer, de dépressions et de syndromes douloureux.
PCT/EP2009/004276 2008-06-20 2009-06-13 Dérivés de la taxifoline pour la prophylaxie et le traitement de troubles neurologiques et psychiatriques du système nerveux central WO2009153009A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09765589A EP2307005A1 (fr) 2008-06-20 2009-06-13 Dérivés de la taxifoline pour la prophylaxie et le traitement de troubles neurologiques et psychiatriques du système nerveux central

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DE102008029460A DE102008029460A1 (de) 2008-06-20 2008-06-20 Taxifolinderivate zur Prophylaxe und Behandlung von neurologischen und psychiatrischen Störungen des zentralen Nervensystems
DE102008029460.8 2008-06-20

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JP2013053133A (ja) * 2011-08-10 2013-03-21 Taisho Pharmaceutical Co Ltd 認知機能障害の予防及び／または治療用組成物
WO2016067265A1 (fr) * 2014-10-31 2016-05-06 Centre National De La Recherche Scientifique Utilisation d'un inhibiteur de transcriptase inverse dans la prevention et le traitement des maladies degeneratives
US9808440B2 (en) 2013-05-24 2017-11-07 Research Institute For Nutrition And Aging Co., Ltd. Pharmaceutical combination comprising metformin and dihydroquercetin and its use for the treatment of cancer
WO2017199755A1 (fr) * 2016-05-19 2017-11-23 国立研究開発法人国立循環器病研究センター Médicament pour prévenir et/ou traiter la démence
US11793814B2 (en) 2019-01-25 2023-10-24 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013053133A (ja) * 2011-08-10 2013-03-21 Taisho Pharmaceutical Co Ltd 認知機能障害の予防及び／または治療用組成物
US9808440B2 (en) 2013-05-24 2017-11-07 Research Institute For Nutrition And Aging Co., Ltd. Pharmaceutical combination comprising metformin and dihydroquercetin and its use for the treatment of cancer
US10292962B2 (en) 2013-05-24 2019-05-21 Research Institute For Nutrition And Aging Co., Ltd. Pharmaceutical combination comprising metformin and dihydroquercetin and its use for the treatment of cancer
WO2016067265A1 (fr) * 2014-10-31 2016-05-06 Centre National De La Recherche Scientifique Utilisation d'un inhibiteur de transcriptase inverse dans la prevention et le traitement des maladies degeneratives
FR3027804A1 (fr) * 2014-10-31 2016-05-06 Centre Nat Rech Scient Utilisation d'un inhibiteur de transcriptase inverse dans la prevention et le traitement des maladies degeneratives
US10100307B2 (en) 2014-10-31 2018-10-16 Centre National De La Recherche Scientifique Use of a reverse-transcriptase inhibitor in the prevention and treatment of degenerative diseases
EP3212200B1 (fr) 2014-10-31 2021-01-20 Centre National De La Recherche Scientifique Utilisation d'un inhibiteur de transcriptase inverse dans la prevention et le traitement des maladies degeneratives
WO2017199755A1 (fr) * 2016-05-19 2017-11-23 国立研究開発法人国立循環器病研究センター Médicament pour prévenir et/ou traiter la démence
JPWO2017199755A1 (ja) * 2016-05-19 2019-05-30 国立研究開発法人国立循環器病研究センター 認知症の予防及び／又は治療のための薬剤
US11925633B2 (en) 2016-05-19 2024-03-12 National Cerebral And Cardiovascular Center Drug for preventing and/or treating dementia
US11793814B2 (en) 2019-01-25 2023-10-24 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders

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EP2307005A1 (fr) 2011-04-13

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