EP1879880A2 - Derives de dihydroxyphenylalanine - Google Patents

Derives de dihydroxyphenylalanine

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Publication number
EP1879880A2
EP1879880A2 EP06742338A EP06742338A EP1879880A2 EP 1879880 A2 EP1879880 A2 EP 1879880A2 EP 06742338 A EP06742338 A EP 06742338A EP 06742338 A EP06742338 A EP 06742338A EP 1879880 A2 EP1879880 A2 EP 1879880A2
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Prior art keywords
acid
disease
carbon atoms
chs
radicals
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English (en)
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Gisela Susilo
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Ellneuroxx Ltd
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Ellneuroxx Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • 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
    • A61P25/28—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the invention relates to derivatives of dihydroxyphenylalanine, their preparation and their use and pharmaceutical compositions containing these derivatives of dihydroxyphenylalanine.
  • DOPA is known under the IUPAC name 2-amino-3- (3,4-dihydroxyphenyl) propionic acid and under the common name levodopa and is used in particular in Parkinson's disease.
  • Parkinson's disease also known as Parkinson's disease or Parkinson's disease
  • the course of the disease is characterized by the fact that in the brain in the substantia nigra, the black substance, those nerve cells that contain the messenger dopamine are slowly dying off. This leads to the fact that the formation of the messenger substance dopamine is no longer guaranteed to a sufficient extent. Changes (eg Lewy body) are also detectable in other parts of the brain, such.
  • Dopamine is an essential messenger substance for the control of the musculoskeletal system, whose deficiency leads to movement disorders such as tremor (rest tremor), involuntary muscle tension (rigor) and a slowing down of movement (hypokinesis).
  • movement disorders such as tremor (rest tremor), involuntary muscle tension (rigor) and a slowing down of movement (hypokinesis).
  • tremor rest tremor
  • rigor involuntary muscle tension
  • hyperokinesis hypertension
  • additional movement disorders are added, such as the inability to begin a movement (freezing) and the impossibility of an upright posture with the risk to overthrow.
  • thinking and memory are impaired and feelings are changed with depression and end-stage dementia.
  • Parkinson's disease is divided into a sporadic form (95% of those affected) and a familial form. In the latter case, inheritance of the disease risk is the most important cause.
  • many diseases are described in which movement disorders occur, but their origins are based on other causes. These are called secondary parkinsonism. These forms can be caused by drugs such.
  • Other causes are diseases of the parathyroid gland, a tumor in the brain, a brain injury and multiple closures (infarcts) of cerebral vessels.
  • Other disorders with movement disorders are Alzheimer's disease, diffuse Lewy body disease, frontotemporal dementia, Lytico-Bodig disease (Parkinsonism-dementia-amyotrophic lateral sclerosis), striatonigral degeneration, Shy-Dräger syndrome, sporadic olivo-ponto-cerebellar Degeneration, progressive pallidale atrophy, progressive supranuclear palsy, Hallervorden-Spatz disease, Huntington's disease, x-chromosome linked dystonia (Lubag's disease), mitochondrial cytopathy with striatal necrosis, neuroacanthocytosis and Wilson's disease.
  • L-DOPA was used as a promising drug, however, soon showed side effects of long-term therapy, ranging from dyskinesia (abnormal, involuntary movements) to dystonia (painful muscle spasms) to abruptly alternating motion-solidification phases. It has also been recognized that L-DOPA can accelerate the destruction of dopamine-containing neurons in the brain.
  • R 3 is a radical -CH 2 CH 2 OR 5 , -H, -C ⁇ CH, -C ⁇ C-CH 3 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 J 2 , -C 4 H 9 , -CH 2 -CH (CH 3 ) 2 , -CH (CH 3 ) -C 2 H 5, -C (CH 3 ) 3 , -C 5 H 11 , -CH (CHs ) -C 3 H 7 , -CH 2 -CH (CH 3 ) -C 2 H 5 , -CH (CH 3 ) -CH (CH 3 ) 2 , -C (CH 2 ) 2 -C 2 H 5 , -CH 2 -C (CHs) 3 , -CH (C 2 H 5 , -C 2 -C (CHs) 3 , -CH (C 2 H 5 , -C 2 -C (CHs
  • R 4 and R 5 independently represent a group -CO-R 6 or -CO-R 7 or -H, wherein R 3 and R 4 are not simultaneously -H;
  • R 6 and R 7 independently of one another represent the following radicals: -R 10 , -R 11 , a linear saturated alkyl chain having 2 to 25 carbon atoms, a branched saturated alkyl chain having 2 to 25 carbon atoms, a branched or unbranched alkenyl chain having 2 to 25 carbon atoms, a branched or unbranched alkynyl chain having 2 to 25 carbon atoms, a polyunsaturated branched or unbranched alkenyl chain having 2 to 25 carbon atoms, a polyunsaturated branched or unbranched alkynyl chain having 2 to 25 carbon atoms, a polyunsaturated branched or unbranched alkenynyl chain having 2 to 25 carbon atoms, a branched or unbranched alkyl chain having 2 to 25 carbon atoms comprising a carbocycle or heterocycle, a branched or unbranched alkyl chain having 2 to 25 carbon atoms comprising one or
  • R 8 , R 9 , R 10 and R 11 independently of one another represent the following radicals:
  • R 12 - R 47 independently of one another represent the following radicals:
  • -CH C (CH 3 ) 2
  • -C CH
  • -C C-CH 3 , -CH 2 -C ⁇ CH
  • pharmacologically acceptable salts, solvates, hydrates, complex compounds, enantiomers, diastereomers and racemates of the abovementioned compounds as well as pharmacologically acceptable salts, solvates, hydrates, complex compounds, enantiomers, diastereomers and racemates of the abovementioned compounds.
  • the compounds of the formula (I) according to the present invention may be administered by themselves or in the form of a pharmacologically active salt. Since the compounds of the general formula (I) are basic
  • salts of these compounds can be prepared by conventional methods.
  • Suitable examples of these salts of the compounds of formula (I) include acid addition salts, alkali metal salts and salts with amines.
  • alkali metal salts such as the sodium salt, the potassium salt, the lithium salt or the magnesium salt, the calcium salt, alkyl amino salts or amino acid salts, for example with basic amino acids such as lysine may be mentioned.
  • acids which one Acid addition salt of the compound of the formula (I), the following may be mentioned: sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, gluconic acid (glyconic, dextronic acid) , Lactic acid, malic acid, tartaric acid, tartronic acid (hydroxymalonic acid, hydroxypropanedioic acid), fumaric acid, citric acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, (o-, m-, p-) toluic acid, benzoic acid, p-aminobenzoic acid, p- Hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, methanesulfonic acid,
  • Naphthylamine sulfonic acid Naphthylamine sulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic acid (quinic acid), o-methyl-mandelic acid, hydrogenbenzenesulfonic acid, picric acid (2,4,6-trinitrophenol), adipic acid, do-tolyltartaric acid, amino acids such as methionine, tryptophan, arginine and especially acidic amino acids such as glutamic acid or aspartic acid.
  • betaine forms are also possible.
  • R 3 and R 4 have the meaning given above. Again, the S configuration at carbon atom 2 of the propionic acid chain is again preferred.
  • R 1 , R 2 and R 6 have the meanings given above. Again, it is preferred if the amino group-bearing carbon atom is S-configured.
  • R 1 , R 2 and R 7 have the meanings given above.
  • the S configuration at carbon atom 2 of the propionic acid chain is again preferred.
  • the groups R 1 and R 2 in formula (IV) are both hydrogen or an acetyl group or an alkyl group.
  • the groups -CO-R 6 and -CO-R 7 are preferably fatty acid groups derived from the corresponding fatty acids HOOC-R 6 and HOOC-R 7 .
  • the radicals -R 6 and -R 7 represent the carbon chain of the fatty acids. This carbon chain consists of 2 to 25 and in the case of the substituted carbon chains preferably of 5 to 9 carbon atoms. As is known, these carbon chains of the fatty acids may be saturated or unsaturated, have branches and in particular have one or more isolated, conjugated or polyconjugated double and / or triple bonds.
  • fatty acid represents an acyl group of a fatty acid, especially the fatty acids described herein.
  • the carbon chains of these fatty acids are also referred to herein as R 6 and R 7 .
  • a carbon number of from 7 to 25 atoms is preferred.
  • a number of carbon atoms of 5-24 are preferred, more preferably 7-23, further preferably 9-22, further preferably 11-21 and especially preferably from 13 to 20 carbon atoms.
  • the cyclic or the substituted carbon radicals in particular the lipoic acid radical and the dihydrolipoic acid radical are preferred.
  • fatty acid is an example of the compounds HOOC-R 6 and HOOC-R 7 :
  • This fatty acid is referred to as 6,9-octadecenoic acid or octadec-6-en-9-amino acid.
  • linoleic acid is referred to as cis-9, cis-12-
  • Octadecadienoic acid (chemical nomenclature) or ⁇ 9,12-octadecadienoic acid or octadecadienoic acid (18: 2) or octadecadienoic acid 18: 2 (n-6) (biochemical or physiological nomenclature).
  • octadecadienoic acid 18: 2 (n-6) n is the number of carbon atoms and the number "6" indicates the position of the last double bond.
  • 18: 2 (n-6) is thus a fatty acid having 18 carbon atoms, two double bonds and a distance of 6 carbon atoms from the last double bond to the outer methyl group.
  • the compounds of the present invention have a carboxylic acid residue via either an ester bond to the carboxylate group of DOPA (2-amino-3- (3,4-dihydroxyphenyl) -propionic acid) with an intermediate Ethylene glycol group (see formula III) or a carboxylic acid radical via an amide bond to the amino group of DOPA (see formula IV) are referred to below carboxylic acids and in particular fatty acids which can be used according to the invention for the preparation of the compounds of general formula (I) ,
  • the corresponding carbonyl groups are represented by the radicals -CO-R 6 and -CO-R 7 and the corresponding carbon chains of the carboxylic acids by the radicals -R 6 and -R 7 .
  • Table 1 shows a list of linear and saturated carboxylic acids.
  • Table 2 shows a list of monoolefinic fatty acids.
  • Table 3 shows a list of polyunsaturated fatty acids.
  • Table 4 shows a list of acetylenic fatty acids.
  • carboxylic acids are preferably used for the preparation of the compounds according to the invention: linoleic acid, ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid, arachidonic acid, 7,10,13,16-docosatetraenoic acid, 4,7,10,13,16-docosapentaenoic acid, ⁇ - Linolenic acid, stearidonic acid, 8,11,14,17-eicosatetraenoic acid, EPA, DPA, DHA, meadic acid, eleostearic acid, calendic acid, catalpinic acid, stellaheptanoic acid, taxoleinic acid, Pinolenic acid, sciadic acid, retinoic acid, isopalmitic acid, pristanic acid, phytanic acid, 11,12-methyleneoctadecanoic acid, 9,10-methylenehexadecanoic acid, coronaric acid, (R, S)
  • Dithianoctanoic acid (R) -6,8-dithianoctanoic acid, (S) -6,8-dithianoctanoic acid, tariric acid, santalbic acid, stearolic acid, 6,9-octadecenoic acid, pyrulic acid, crepenoic acid, heisteric acid, t8, t10-octadecadiene-12-acetic acid, ETYA, cerebronic acid, hydroxynvonic acid, ricinoleic acid, lesquerolic acid, brassylic acid and thapsic acid.
  • carboxylic acids particular preference is given to ⁇ -linolenic acid, ⁇ -linolenic acid, EPA, DHA, (R, S) -lipoic acid, (S) -liponic acid and (R) -lipoic acid, 6,8-bis (methylsulfanyl) -octanoic acid, 4 , 6-bis (methylsulfanyl) hexanoic acid, 2,4-bis (methylsulfanyl) butanoic acid, 1, 2-dithiolane carboxylic acid.
  • radicals -CO-R 6 and -CO-R 7 are preferably dodecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, tetracosanoyl, cis-9-tetradecenoyl, cis-9-hexadecenoyl, cis-6-octadecenoyl, cis-9-octadecenoyl , cis-11-octadecenoyl, cis-9-eicosenoyl, cis-1 1-eicosenoyl, cis-13-docosenoyl, cis-15-tetracosenoyl, 9,12-octadecadienoyl, 6,9,12-octadecatrienoyl, 8,1 1 , 14-eicosatrienoyl, 5,
  • Octadecatetraenoyl 8,11,14,17-eicosatetraenoyl, 5,8,11,14,17-eicosapentaenoyl, 7,10,13,16,19-docosapentaenoyl, 4,7,10,13,16,19-
  • fatty acid residues may also be substituted by one, two or more substituents selected from the group denoted by R 12 -R 47 .
  • Particularly preferred radicals as -CO-R 6 and -CO-R 7 are the following groups: 9,12-octadecadienoyl, 6,9,12-octadecatrienoyl, 8,11,14-eicosatrienoyl, 5,8,11,14- Eicosatetraenoyl, 9,12,15-octadecatrienoyl, 6,9,12,15-octadecatetraenoyl, 8,11,14,17-eicosatetraenoyl, 5,8,1,1,14,7-eicosapentaenoyl, 7,10,13,16 , 19-docosapentaenoyl, 4,7,10,13,16,19-
  • the compounds according to the invention are obtained by protecting or derivatizing the two hydroxyl groups of L-DOPA and then, for example by means of anhydrides, amide formation with the fatty acid or
  • Carboxylic acid forms or the amino group of L-DOPA masked and the
  • the amino group can be unmasked and reacted with the same or a further fatty acid or carboxylic acid to form an amide bond. Finally, the hydroxy protecting groups can still be removed.
  • the present invention relates to pharmaceutical compositions prepared using at least one compound of the invention or a salt thereof.
  • the pharmaceutical compositions contain a pharmacologically acceptable carrier, excipient and / or solvent.
  • compositions may be in the form of drops, mouth spray, nasal spray, pills, tablets, film-coated tablets, coated tablets,
  • Emulsions, dispersions, microcapsules, capsules, powders or injection solutions are prepared and administered.
  • the pharmaceutical compositions of the invention include formulations such as layered tablets for the controlled and / or continuous release of the active ingredient as well as
  • Microencapsulation as a special dosage form is a special dosage form.
  • Such formulations include but are not limited to inhalation or intravenous, intraperitoneal, intramuscular, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, buccal, intradermal, intragastric, intracutaneous, intranasal, intrabuccal, percutaneous or sublingual administration.
  • lactose starch, sorbitol, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol and the like can be used as pharmacologically acceptable carriers.
  • Powders as well as tablets may consist of 5 to 95% of such a carrier.
  • Starch gelatin, natural sugars, both natural and synthetic gums such as acacia or guar gum, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes may also be used as binders.
  • lubricant boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like can be used.
  • disintegrating agents, dyes, flavorings and / or binders may be added to the pharmaceutical compositions.
  • Liquid formulations include solutions, suspensions, sprays and emulsions.
  • solutions for example, water-based or water-propylene glycol-based injection solutions for parenteral injections.
  • fatty acid esters and glycerides are preferably used.
  • Capsules are made, for example, from methylcellulose, polyvinyl alcohols or denatured gelatin or starch.
  • Starch sodium carboxymethyl starch, natural and synthetic gums such as locust bean gum, karaya, guar, tragacanth and agar, and cellulose derivatives such as methyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose and alginates, clays and bentonites can be used as disintegrants. These ingredients can be used in amounts of 2 to 30 wt .-%.
  • a binder sugar, starch from grain, rice or potatoes, natural gums such as acacia, gelatin, tragacanth, alginic acid, sodium alginate, ammonium calcium alginate, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and inorganic Compounds such as magnesium-aluminum-silicates are added.
  • the binders can be added in amounts of 1 to 30 wt .-%.
  • stearates such as magnesium stearate, calcium stearate, potassium stearate, stearic acid, refractory waxes, as well as water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and amino acids such as leucine can be used.
  • water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and amino acids such as leucine can be used.
  • Such lubricants can be used in amounts of 0.05 to 15 wt .-%.
  • the compounds according to the invention and the pharmaceutical compositions described above are, for example, for the treatment and / or prophylaxis of or for the preparation of a pharmaceutical formulation for the treatment and / or prophylaxis of movement disorders, especially movement disorders such as early dyskinesias, akathisia, Parkinsonoid and especially Rigor and tremor, more extrapyramidal disorders such as segmented and generalized dystonia, drug-induced extrapyramidal symptoms, movement disorders due to causes other than Parkinson's disease and various forms of Parkinson's syndrome (endogenous, atherosclerotic, postzephalitic, drug), neurodegenerative diseases, Alzheimer's,
  • Parkinson's disease hemi-hemiparcinoma, Parkinson's syndrome due to hydrocephalus (hydrocephalus), hypoxia, brain infections (encephalitis), manganese poisoning, carbon monoxide (CO), 1-methyl-4-phenyl-1, 2, 3,6-tetrahydropyridine (MPTP) and cyanide, parathyroid disease, brain tumor, brain injury, infarction, as well as Lewy body disease, frontotemporal dementia, Lytico-Bodig Disease (Parkinsonism-dementia-amyotrophic lateral sclerosis), striatonigrale
  • movement disorders includes, in particular, spastic disorders, hyperkinesias, dystonias, athetoses, dyskinesias, myoclonus syndromes, M. Wilson, choreatic syndromes, tics, Tourette's disorder, ballism, tremor syndrome and Parkinson's disease.
  • a further aspect of the present invention is directed to a pharmaceutical composition which, in addition to the at least one compound according to the invention, further comprises one, two or more further pharmacologically active substances suitable for the treatment and / or prophylaxis of movement disorders, neurodegenerative diseases, Alzheimer's, Parkinson's disease, hemiatrophy Hemiparkinsonian, Parkinson's syndrome, Rigor, tremor, dystonia, Lewy body disease, frontotemporal dementia, Lytico-Bodig disease (Parkinsonism-dementia-amyotrophic lateral sclerosis), striatonigral degeneration, Shy-Dräger syndrome, sporadic olivo-pontocerebellar degeneration, progressive pallidale Atrophy, progressive supranuclear palsy, Hallervorden-Spatz disease, Huntington's disease, x-chromosome linked dystonia (Lubag's disease), mitochondrial cytopathy with striatal necrosis, neuroacanthocytosis, rest
  • These other agents include, for example, dopamine receptor agonists such as bromocriptine, cabergoline, lisuride, dihydroergocriptine, bromocriptine,
  • Dopamine agonists entacapone, ropinirole, pramipexole, pergolide mesilate, pergolide,
  • Budipine monoamine oxidase B inhibitors such as selegiline, catechol-o
  • Methyltranferase inhibitors such as entacapone, anticholinergics such as benzatropine, biperiden, boronaprine, procyclidine, trihexyphenidyl, antioxidants such as vitamin C and vitamin E.
  • Lipoic acid was converted into the lipoic acid monoethylene glycol ester with an excess of ethylene glycol and DCC.
  • L-DOPA was reacted with Fmoc-succinimide for N-Fmoc-L-DOPA and under Schotten-Baumann conditions with acetic anhydride to give N-Fmoc-O, O 'diacetyl-L-DOPA acetylated.
  • the reaction with the above lipoic acid monoethylene glycol ester by means of DCC afforded the coupling product N-Fmoc-O, O'-diacetyl-L-DOPA-ethylene glycol rac-lipoic acid ester.
  • Lipoic acid chloride was derived from lipoic acid and oxalyl chloride, lipoic acid succinimidyl ester from lipoic acid, hydroxysuccinimide and DCC. Purity (HPLC) 97%, yellow high viscosity oil 13 C-NMR (100.6 MHz, d 4 -methanol), ⁇ (ppm):
  • compound 4 could be obtained by acylation with lipoic acid hydroxysuccinimidyl ester. A much better access to the target compound was provided by the two-step synthesis. Here, 1, 8 g of the target compound 4 (yield: 39%) were obtained.
  • Citric acid solution and 10 ml Verd. Hydrochloric acid added and stirred vigorously for 1 h. After addition of 120 ml of ethyl acetate and 50 ml of water, the phases were separated. The org. Phase was successively with sat. Citric acid solution and sat. NaCl solution washed.
  • Example 7 Preparation of 0,0'-dibutanonyl-L-DOPA-DHA-amide (Compound 7) and butanonyl-L-DOPA-di-DHA derivative (Compound 7A and 7B)
  • L-Dopa was converted to the n-butyl ester with n-butanol and thionyl chloride.
  • the fatty acid DHA at -1O 0 C was transferred with isobutyl chloroformate in the mixed "Aktivester" and reacted with the L-Dopa-n-butyl ester.
  • the further reaction with butyryl chloride yielded two products which were separated by chromatography.
  • the more polar Compound was obtained in a yield of 23% and, according to NMR analysis, is the desired target compound.
  • the less polar compound was obtained in 34% yield and contains two DHA fatty acid residues by NMR. It is not clear whether the second DHA fatty acid is bound to the para or metastatic phenolic group.
  • reaction solution was mixed with 50 ml of 2N HCl solution and with 50 ml
  • Example 8 Preparation of L-DOPA diacetylic acid derivative (compound 8A and 8B) and L-DOPA triacetylic acid derivative (compound 8)
  • L-DOPA derivatives referred to hereinafter as compound 1, compound 2, compound 3
  • salts of these compounds are used according to the invention for the prophylaxis and / or therapy of, for example, Parkinson's disease and other movement disorders (secondary Parkinsons syndrome) can be.
  • the rats were pretreated with benserazide, an aromatic amino acid decarboxylase inhibitor, to reduce degradation of the test substances in the blood and thereby achieve sufficient concentrations of dopamine and ⁇ -lipoic acid in the brain.
  • L-DOPA standard therapy for Parkinson's disease
  • Compound 1 Compound 2
  • Compound 3 was injected into the peritoneal cavity (intraperitoneally, i.p.) at L-DOPA equivalent doses.
  • blood and brain tissue striatum
  • a low (25 mg / kg body weight) and a higher (50 mg / kg) dose of L-DOPA were chosen.
  • Table 5 Summary statistics of the effects of L-DOPA, Compound 1, Compound 2, Compound 3 on the levels of dopamine, its metabolites Dopac, HVA and 3-MT as well as serotonin (5-HT) and its metabolite 5-HIAA in the Brain (striatum) of the rat. Values are given in pg per mg striatum.
  • Table 5 shows that the low doses of L-DOPA and Compounds 1, 2 and 3 do not increase the levels of dopamine in a brain part (striatum).
  • the metabolites DOPAC and HVA are increased to L-DOPA, Compound 3 (HVA only), Compound 2 and Compound 1. This means that the turnover of the messenger substance dopamine in the nerve cells increases through the treatments.
  • the results show that from L-DOPA, compound 3 (little), compound 2 and compound 1 in the examined brain part of the messenger dopamine is increasingly formed.
  • the higher doses of L-DOPA, Compounds 3 and 2 increased the levels of dopamine in the brain part examined.
  • Concentrations of dopamine metabolites DOPAC and HVA were also increased after L-DOPA, Compounds 1, 2 and 3, and almost always more than after the low dose. This means that all substances used increased the turnover of dopamine in the dopamine-containing nerve cells.
  • the results suggest that compounds 1, 2, and 3, as known from L-DOPA, can balance deficits of dopamine in dopamine-containing neurons. Such deficits are known to be the cause of movement disorders in Parkinson's disease.
  • Compound 2 also increased the 5-HT concentration. This is interesting because it is assumed that 5-HT-containing neurons in the brain assume proxy function for the underlying dopamine-containing neurons in Parkinson's disease.
  • Table 6 Summary of the effect of application of L-DOPA and equimolar doses of Compound 1 and Compound 2 on the levels of dopamine and its metabolites Dopac, HVA and 3-MT, and 5-HT and its metabolite 5-HIAA in the blood plasma the rat. The values are given in pg per ml of plasma.

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  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des dérivés de dihydroxyphénylalanine dont la production et les compositions pharmaceutiques contiennent ces dérivés de dihydroxyphénylalanine. L'invention concerne également l'utilisation de ces dérivés de dihydroxyphenylalanine et les compositions pharmaceutiques destinées au traitement et à la prévention de troubles locomoteurs, de maladies neurodégénératives, de la maladie d'Alzheimer, de Parkinson, d'hémiatrophie-hémiparkinson, du syndrome de Parkinson, de la maladie des corps de Lewy, la démence fronto-temporale, la maladie Lytico-Bodig (Parkinsonisme-démence-sclérose latérale amyotrophique), la dégénération striatonigrale, le syndrome Shy-Drager, la dégénération sporadique olivo-ponto-cerébelleuse, l'atrophie pallidale progressive, la paralysie supranucléaire progressive (progressive supranuclear palsy), maladie de Hallervorden-Spatz, maladie de Huntington, dystonie liée au chromosome x (Morbus Lubag), cytopathie mitochondriale avec nécrose striatale, neuroakanthocytose, syndrome des jambes sans repos, maladie de Wilson.
EP06742338A 2005-05-13 2006-05-14 Derives de dihydroxyphenylalanine Withdrawn EP1879880A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005022276A DE102005022276A1 (de) 2005-05-13 2005-05-13 Derivate von Dihydroxyphenylalanin
PCT/DE2006/000830 WO2006119758A2 (fr) 2005-05-13 2006-05-14 Derives de dihydroxyphenylalanine

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EP1879880A2 true EP1879880A2 (fr) 2008-01-23

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EP06742338A Withdrawn EP1879880A2 (fr) 2005-05-13 2006-05-14 Derives de dihydroxyphenylalanine

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US (1) US20090285888A1 (fr)
EP (1) EP1879880A2 (fr)
JP (1) JP2008540465A (fr)
CN (1) CN101208326A (fr)
CA (1) CA2607198A1 (fr)
DE (1) DE102005022276A1 (fr)
WO (1) WO2006119758A2 (fr)

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JP2008540465A (ja) 2008-11-20
CA2607198A1 (fr) 2006-11-16
WO2006119758A3 (fr) 2007-03-22
DE102005022276A1 (de) 2006-11-16
US20090285888A1 (en) 2009-11-19
WO2006119758B1 (fr) 2007-05-24
CN101208326A (zh) 2008-06-25
WO2006119758A2 (fr) 2006-11-16

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