EP2307005A1

EP2307005A1 - Taxifolin derivatives for the prophylaxis and treatment of neurological and psychiatric disorders of the central nervous system

Info

Publication number: EP2307005A1
Application number: EP09765589A
Authority: EP
Inventors: Wilfried Dimpfel
Original assignee: Otkrytoe Aktsionernoe Obschestvo Zavod Ekologicheskoy Tekhniki I Ekopitaniya 'Diod'
Current assignee: Otkrytoe Aktsionernoe Obschestvo Zavod Ekologicheskoy Tekhniki I Ekopitaniya 'Diod'
Priority date: 2008-06-20
Filing date: 2009-06-13
Publication date: 2011-04-13
Also published as: WO2009153009A1; DE102008029460A1

Abstract

The present invention relates to the use of taxifolin derivatives for the prophylaxis and/or treatment of neurological and psychiatric disorders of the central nervous system, in particular of dementias, Parkinson’s disease, Alzheimer’s disease and depressions and pain.

Description

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

and its derivatives are described, for example, in DE 100 31 457 A1.

As one of the naturally occurring flavonoids, 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, in particular dementias, Parkinson's disease and depression have a wide spectrum of side effects.

Therefore, there is a need for further possibilities of prophylaxis or treatment with a drug with good therapeutic efficacy with the lowest possible rate of side effects. In particular, this also applies to the prophylaxis, e.g. for the administration of modified foods or dietary supplements.

It has now surprisingly been found that Taxifolinderivate possess valuable pharmacological properties for the prophylaxis and / or treatment of diseases of the central nervous system. When administering taxifolin, 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.

As taxifoline derivatives in the context of the present invention, in addition to taxifolin, essentially derivatives are to be understood in which the 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.

The taxifoline derivatives used according to the invention correspond to the following general formula (I)

wherein

R ¹ is H, _{Ci-C2o-alkyl,} dC preferably ₄ alkyl, acyl, especially (-C (= O) R ^6), or is Gly,

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,

R ^{7 is} H, Ci-0 ₂₀ alkyl, Ci-C ₂₀ alkenyl, C _r C ₂ o-hydroxyalkyl, wherein the hydroxy group (s) may be bonded to primary or secondary carbon atoms of the chain and the alkyl chain to be interrupted by oxygen can, C ₃ -C ₀ cycloalkyl, _{_C3-Ci2} cycloalkenyl, acyl, in particular (- C (= O) R ^6), or Gly, R ⁸ and R ^{9 are} identical or different and are H or C ₁ -C ₄ -alkyl,

and their pharmaceutically acceptable salts, hydrates, solvates and complexes.

"Unless stated otherwise," 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. Examples of such alkyl groups (provided that the designated length includes the specific example) 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.

The term "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₎ -Cycloalkylverbindung is derived by removal of a hydrogen radical from a Ring carbon of the cycloalkyl compound. Examples of cycloalkyl groups (provided the designated length includes the specific example) are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.

The term "aryl" means a cyclic or polycyclic ring consisting of preferably 6 to 12 carbon atoms. Examples of aryl groups are phenyl or naphthyl.

The term "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.

The term "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.

The 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.

For the purposes of the present invention, 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.

According to the invention, 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.

Particularly preferred is the use of taxifolin.

The taxifoline derivatives of the formula (I) may optionally be used in combination (simultaneously or with a time delay) with other active ingredients.

For administration, 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.

If 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.

The pharmaceutical 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.

For example, 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.

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. Compositions for topical application, eg creams, lotions or pastes, can be prepared by mixing the active ingredient with a conventional oleaginous or emulsifying carrier.

Exemplary typical dosages of a dosage unit of the drug are described below.

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.

Dosage forms for application to the skin and mucous membranes (eg solutions, lotions, emulsions, ointments, etc.) 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.

An adaptation of the specific dose depending on the age, sex, weight, condition, etc. of the patient and the active ingredient used (as pure compound, salt, hydrate, etc.) is within the skill of the artisan and is carried out in a manner known to those skilled in the art.

The following examples and figures serve to illustrate the invention.

The figures show:

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 (δ), theta (θ), alpha (α1), alpha2 (α2), betai (β1) and beta2 (β2). FIG. 1 thus serves as proof of stable experimental conditions,

2a: the effect of 10 mg / kg taxifolin on the EEG frequencies up to 5 hours after administration (time-dependent changes in the EEG frequencies, mean values of n = 6 animals). 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. 2b: analogously the effect of 20 mg / kg taxifolin on the EEG frequencies up to 5 hours after application (mean values of n = 6 animals),

2c: analogously the effect of 40 mg / kg taxifolin on the EEG frequencies up to 5 hours after application (mean values of n = 6 animals),

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. 4: analogously, the effect of 40 mg / kg taxifolin on the EEG frequencies during the last hour after application (mean of n = 6 animals). It shows a strong similarity to known drugs used to treat dementia, Parkinson's disease, Alzheimer's disease, depression: selegiline (Parkinson's disease); Tacrine, donepezil and galantamine (Alzheimer's disease),

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 investigations were carried out analogously to the method described by W. Dimpfel (see Dimpfel W Preclinical data base of pharmaco-specific rat EEG fingerprints (tele-stereo-EEG).) Eur J Med Res (2003) 8: 199-207, to which full content referred to) is carried out as follows:

Six male adult Fischer-344 rats (day-night converted) were implanted at the age of 6 months 4 bipolar concentric electrodes together with a micro connector on a common base plate. The plug was used to record a 4-channel transmitter for telemetric transmission of the field potentials derived from the frontal cortex, hippocampus, striatum and formatio reticularis. The signals were subjected to Fast Fourier Transformation in real time on a computer system ("EEG Analysis" software, OS Science operating system, "LabTeam" lab computer from MediSyst, Linden, DE), and the power density spectra were each averaged over 60 minutes. The subdivision of the spectra into 6 different frequency ranges allowed the detection of pharmaco-specific changes with respect to the pre-values measured before each application within these frequency bands.

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.

The administration of saline hardly resulted in changes in electrical activity (μV ² Ω) compared to the pre-phase values (Figure 1).

The administration of taxifolin resulted in increasingly stable changes in power density in all brain areas, especially during the third to fifth hour after application (Figures 2a-c), the changes being significantly different from those after saline administration despite the small number of animals.

Oral administration of 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.).

The observed frequency changes were compared by means of a discriminant analysis with the results of drugs for the treatment of dementias and brain psychiatric disorders, as well as with drugs for other indications. Drugs already tested in the same model were available for comparison purposes (see table). The information there refers to a dosage in mg / kg body weight. Table (Reference substances for discriminant analysis)

Substance Dose Dose [mg / kg] Time No. Substance [mg / kg] Time

LSD 0.05 5 - 35 min CHL chlorpromazine 0.5 5 - 35 min

R-DOM 0.2 5 - 35 min HAL Haloperidol 0.5 5 - 35 min

Dizocilpine 0.25 5 - 35 min THI Thioridazine 5 5 - 35 min

CLO clozapine 3 5 - 35 min

Metanicotine 1 5 - 35 min REM Remoxipride 5 5 - 35 min

Caffeine 1 5 - 35 min OLA Olanzapine 6 5 - 35 min

(+) Amphetamine 0.2 5 - 35 min QUE Quetiapine 2.5 5 - 35 min

Fenfluramine 1 5 - 35 min RIS Risperidone 0,25 5 - 35 min

ZIP Ziprasidone 2.5 5 - 35 min

Tacrine 0.75 5 - 35 min

Paroxetine 2 5 - 35 min MHT Methohexital 20 20 - 50 min

Memantine 3 5 - 35 min MEP Meprobamate 60 20 - 50 min

Galantamine 1 5 - 35 min MID midazolam 0.5 20 - 50 min

Donepezil 1.5 5 - 35 min DIA Diazepam 0.5 20 - 50 min

PHE Phenobarbitone 60 20 - 50 min

Acetylsaliylic acid 200 5 - 35 min

Metadon 1 5 - 35 min VAL Valproic acid 75 65 - 125 min

Metamizol 100 5 - 35 min PTO phenytoin 4 65 - 125 min

Fentanyl 0.075 5 - 35 min CAR Carbamazepine 15 65 ^■ ^■ 125 min

Gababentin 30 125 - 185 min

Fluvoxamine 40 5 - 35 min

Mianserine 5 5 - 35 min

Physiological

Amitriptyline 10 5 - 35 min SLEEP 20-65 min sleeo

Imipramine 10 5 - 35 min

Amantadine 12 5 - 35 min TlO Taxifolin 10 245-305 min

T20 taxifolin, 20 245-305 min

T40 taxifolin 40 245-305 min

Surprisingly, in vivo studies of changes in rat EEG frequencies following administration of taxifolin show, compared with administration of saline solution (Figure 1), that the preparation has an effect in the brain which is useful in the treatment of degenerative and psychiatric disorders of the brain Brain, in particular dementia, Parkinson's disease, Alzheimer's disease and depression is useful.

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).

The changes seen after administration of a dose of taxifolin (10-40 mg / kg) (Figures 2a-c) and after administration of known drugs for the treatment of degenerative and psychiatric diseases (Figures 3 and 4) show one great similarity.

It is apparent from the discriminant analysis shown in Fig. 5 that the characteristic electrical fingerprint (electropharmacogram) typical of known drugs for the treatment of dementias, Parkinson's disease, Alzheimer's disease and depression is also strikingly found in the patterns of taxifolin ,

From the finding that 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 ,

The fact that drugs used in the same indication also cause similar EEG changes was demonstrated by more than 40 reference substances for 8 different indications (see Dimpfel W Preclinical data base of pharmaco-specific rat EEG fingerprints (telephoto stereo). EEG), Eur J Med Res (2003) 8: 199-207, to which full reference is made).

Claims

claims

1. Use of Taxifoline Derivatives of the Formula (I)

wherein

R ¹ is H, C ₁ -C _2O -alkyl, acyl, or Gly,

R ² - R ⁵ independently of one another are OR ⁷ , where R ⁴ and R ^{5 can} also be thio (C 1 -C ⁴ ) -alkyl or NR ⁸ R ⁹ ,

^R6 is d-Ca-alkyl or C ₆ -C ₂ -aryl,

GIy is a mono- or oligoglycoside radical,

R ^{7 is} H, C ₁ -C ₂ o-alkyl, C ₁ -C ₂₀ -alkenyl, C ₁ -C ₂₀ -hydroxyalkyl, where the hydroxy group (s) can be bonded to primary or secondary carbon atoms of the chain and the alkyl chain is interrupted by oxygen C may be ₀ -C ₃ cycloalkyl, C ₃ -C ₂ -cycloalkenyl, acyl or Gly stands,

R ⁸ and R ^{9 are} identical or different and denote H or C 1 -C ₄ -alkyl, and 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, especially dementia, Parkinson's disease, Morbus

Alzheimer's and depression and pain.

2. Use according to claim 1, characterized in that the taxifoline derivatives of the formula (I) are used in a dosage of 40 to 400 mg, in particular from 100 to 300, particularly preferably 150 mg per day.

3. Use according to claim 1 or 2, characterized in that in addition conventional pharmaceutically acceptable carriers, excipients and additives and / or other active ingredients are used.

4. Use according to any one of claims 1-3, characterized in that the taxifoline derivatives of the formula (I) are administered orally.

5. Use according to any one of claims 1-4, characterized in that taxifolin is used.

6. Medicaments 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, comprising at least one taxifoline derivative of the formula (I), including its pharmaceutically acceptable salts, hydrates, Solvates and complexes.

7. Use of taxifoline derivatives of the formula (I), including their pharmaceutically acceptable salts, hydrates, solvates and complexes, 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 conditions.

8. Use according to claim 7, characterized in that the taxifoline derivatives of the formula (I) are used in a dosage of 40 to 400 mg, in particular from 100 to 300, particularly preferably 150 mg per day.

9. Use according to claim 7 or 8, characterized in that in addition conventional pharmaceutically acceptable carriers, excipients and additives and / or other active ingredients are used.

10. Use according to any one of claims 7 - 9, characterized in that the taxifoline derivatives of the formula (I) are administered orally.

11. Use according to any one of claims 7 - 10, characterized in that taxifolin is used.