WO2004056306A2 - Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases - Google Patents
Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases Download PDFInfo
- Publication number
- WO2004056306A2 WO2004056306A2 PCT/DE2003/004204 DE0304204W WO2004056306A2 WO 2004056306 A2 WO2004056306 A2 WO 2004056306A2 DE 0304204 W DE0304204 W DE 0304204W WO 2004056306 A2 WO2004056306 A2 WO 2004056306A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dopa
- derivatives
- physiologically tolerable
- tolerable salts
- prophylaxis
- Prior art date
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- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 35
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- 229960004940 sulpiride Drugs 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
- A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- L-DOPA L-DOPA
- its derivatives and medicaments containing these compounds for the prophylaxis of psychotic diseases
- the invention relates to the use of 3, 4-dihydroxy-L-phenylalanine (L-DOPA) and its derivatives for the manufacture of medicaments and their use for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyrosine transport or tyrosine decarboxylase become.
- L-DOPA 3, 4-dihydroxy-L-phenylalanine
- L-DOPA is usually administered in drugs with active additives.
- combinations of L-DOPA with peripheral decarboxylase inhibitors with inhibitors of catechol-O-methyltransferase (COMT), with inhibitors of monoamine oxidase (MAO) and inhibitors for dopamine- ⁇ -hydroxylase are used.
- CCT catechol-O-methyltransferase
- MAO monoamine oxidase
- Calcium 5-butylpicolinate and calcium 5-pentylpicolinate are described as inhibitors for dopamine- ⁇ -hydroxylase (DE-A 2 049 115).
- L-DOPA can be used for the prophylaxis of psychotic diseases. This is all the more astonishing since psychotic disorders are known as side effects with high doses of L-DOPA.
- L-DOPA L-DOPA
- its derivatives and their physiologically tolerable salts in combination with an enzyme inhibitor or several enzyme inhibitors for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyro- sintransport or disturbed tyrosine decarboxylase.
- composition in which the enzyme inhibitor or the enzyme inhibitors are decarboxylase inhibitors and / or catechol-O-
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- Life Sciences & Earth Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the use of L-DOPA, the derivatives or pharmacologically-acceptable salts thereof for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase. The invention further relates to pharmaceutical compositions which contain L-DOPA, the derivatives or pharmacologically-acceptable salts thereof for the prophylaxis of psychotic diseases along with pharmacologically-acceptable auxiliaries and adjuncts and, furthermore, the combination of L-DOPA, the derivatives or pharmacologically-acceptable salts thereof with enzyme inhibitors for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase and the corresponding pharmaceutical compositions for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase.
Description
Verwendung von L-DOPA, seiner Derivate und diese Verbindungen enthaltender Arzneimittel zur Prophylaxe psychotischer ErkrankungenUse of L-DOPA, its derivatives and medicaments containing these compounds for the prophylaxis of psychotic diseases
Die Erfindung betrifft die Verwendung von 3, 4-Dihydroxy- L-phenylalanin (L-DOPA) und seiner Derivate zur Herstellung von Arzneimitteln sowie deren Verwendung zur Prophylaxe von psychotischen Erkrankungen sowie zur Behandlung von Erkrankungen, die durch gestörten Tyrosintransport oder gestörte Tyrosindecarboxylase hervorgeru en werden.The invention relates to the use of 3, 4-dihydroxy-L-phenylalanine (L-DOPA) and its derivatives for the manufacture of medicaments and their use for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyrosine transport or tyrosine decarboxylase become.
Die Behandlung der Symptome schizophrener Erkrankungen erfolgt zur Zeit üblicherweise mittels Neuroleptika wie Chlorpromazin, Haloperidol, Sulpirid und deren chemischen Verwandten. Da die Behandlung mit Neuroleptika die Grunderkrankung nicht heilt, führt das Aussetzen der Behandlung in der Regel zu einem Rückfall der Patienten.The treatment of symptoms of schizophrenic diseases is currently usually carried out using neuroleptics such as chlorpromazine, haloperidol, sulpiride and their chemical relatives. As the treatment with neuroleptics does not cure the underlying disease, the suspension of the treatment usually leads to a relapse of the patient.
Verschiedene psychische Erkrankungen werden mit einerDifferent mental illnesses are treated with one
Störung im Stoffwechsel von Noradrenalin, Dopamin und Se- rotonin in Verbindung gebracht.Metabolism of norepinephrine, dopamine and serotonin has been implicated.
L-DOPA und seine Derivate, insbesondere Ester, werden bislang unter anderem zur Therapie von Morbus Parkinson und des Restless-Legs Syndroms eingesetzt. L-DOPA wirkt auf den Dopaminspiegel in den Nervenzellen des Gehirns. Anders als Dopamin selbst kann es die Blut-Hirn Schranke passieren und wird im Gehirn zu Dopamin umgewandelt.L-DOPA and its derivatives, especially esters, have so far been used, among other things, for the therapy of Parkinson's disease and restless legs syndrome. L-DOPA acts on the level of dopamine in the nerve cells of the brain. Unlike dopamine itself, it can cross the blood-brain barrier and is converted to dopamine in the brain.
L-DOPA wird in Arzneimitteln in der Regel mit aktiven Zusatzstoffen verabreicht. Insbesondere Kombinationen von L-DOPA mit peripheren Decarboxylasehemmern, mit Hemmern der Catechol-O-Methyltransferase (COMT) , mit Inhibitoren der Monoaminoxidase (MAO) und Hemmstoffen für die Dopa- min-ß-Hydroxylase finden Verwendung.
In diesem Zusammenhang verwendete Decarboxylasehemmer sind beispielsweise D, L-Serin-2- (2, 3, 4- trihydroxybenzyl) hydrazid (Benserazid) , (-)-L-a- Hydrazino-3, 4-dihydroxy-a-methylhydrozimtsäure (Carbid- opa) , L-Serin-2- (2, 3, 4-trihydroxybenzyl) hydrazid, Glycin- 2- (2, 3, 4-trihydroxybenzyl) hydrazid und L-Tyrosin-2- (2, 3, 4-trihydroxybenzyl) hydrazid. Beispiele für Kombinationspräparate aus L-DOPA und Decarboxylasehemmern sind unter anderem Madopar® (L-DOPA und Benserazid-L-DOPA is usually administered in drugs with active additives. In particular, combinations of L-DOPA with peripheral decarboxylase inhibitors, with inhibitors of catechol-O-methyltransferase (COMT), with inhibitors of monoamine oxidase (MAO) and inhibitors for dopamine-β-hydroxylase are used. Decarboxylase inhibitors used in this connection are, for example, D, L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide (benserazide), (-) - La-hydrazino-3, 4-dihydroxy-a-methylhydrocinnamic acid (carbide-opa ), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide , Examples of combination preparations made from L-DOPA and decarboxylase inhibitors include Madopar® (L-DOPA and benserazide
Hydrochlorid) sowie Nacoiri® (L-DOPA und Carbidopa) .Hydrochloride) and Nacoiri® (L-DOPA and Carbidopa).
Beispiele für COMT-Hemmer sind Entacapon (Comtan®) und Cabergolin und häufig verwendete MAO-Hemmer sind Selegi- lin-Hydrochlorid, Moclobemid und Tranylcypromin.Examples of COMT inhibitors are entacapone (Comtan®) and cabergoline and frequently used MAO inhibitors are selegiline hydrochloride, moclobemide and tranylcypromine.
Als Hemmstoffe für die Dopamin-ß-Hydroxylase werden Cal- cium-5-butylpicolinat und Calcium-5-pentylpicolinat beschrieben (DE-A 2 049 115) .Calcium 5-butylpicolinate and calcium 5-pentylpicolinate are described as inhibitors for dopamine-β-hydroxylase (DE-A 2 049 115).
Erfindungsgemäß bevorzugt ist die Verwendung zur Rückfall-Prophylaxe bei psychotischen Erkrankungen, insbesondere bei schizophrenen Erkrankungen.According to the invention, use for relapse prophylaxis in psychotic diseases, in particular in schizophrenic diseases, is preferred.
Überraschenderweise wurde gefunden, dass L-DOPA für die Prophylaxe psychotischer Erkrankungen verwendet werden kann. Dieses ist umso erstaunlicher, als psychotische Störungen als Nebenwirkungen bei hoher Dosierung von L- DOPA bekannt sind.Surprisingly, it was found that L-DOPA can be used for the prophylaxis of psychotic diseases. This is all the more astonishing since psychotic disorders are known as side effects with high doses of L-DOPA.
Bevorzugt ist hierbei die Verwendung L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze in Kombination mit einem Enzymhemmer oder mehreren Enzymhemmern zur Prophylaxe psychotischer Erkrankungen sowie zur Be- handlung von Erkrankungen, die durch gestörten Tyro-
sintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden.The use of L-DOPA, its derivatives and their physiologically tolerable salts in combination with an enzyme inhibitor or several enzyme inhibitors for the prophylaxis of psychotic diseases and for the treatment of diseases caused by disturbed tyro- sintransport or disturbed tyrosine decarboxylase.
Vorteilhaft ist es, wenn es sich bei dem Enzymhemmer bzw. den Enzymhemmern um Decarboxylasehemmer und/oder Cate- chol-O-Methyltransferase-Hemmer und/oder Monoa inoxidase- Hemmer und/oder ß-Hydroxylase-Hemmer handelt.It is advantageous if the enzyme inhibitor or the enzyme inhibitors are decarboxylase inhibitors and / or catechol-O-methyltransferase inhibitors and / or monoa inoxidase inhibitors and / or β-hydroxylase inhibitors.
Besonders vorteilhaft ist es, wenn der Decarboxylasehem- mer ausgewählt wird aus der Gruppe, bestehend aus D,L- Serin-2- (2, 3, 4-trihydroxybenzyl) -hydrazid (Benserazid) , (-) -L-a-Hydrazino-3, 4-dihydroxy-a-methylhydrozimtsäure (Carbidopa) , L-Serin-2- (2,3, 4-trihydroxybenzyl) ydrazid, Glycin-2- (2, 3, 4-trihydroxybenzyl) hydrazid und L-Tyrosin- 2- (2, 3, 4-trihydroxybenzyl) hydrazid sowie deren physiologisch verträglicher Salze.It is particularly advantageous if the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3,4-trihydroxybenzyl) hydrazide (benserazide), (-) -La-hydrazino-3 , 4-dihydroxy-a-methylhydrocinnamic acid (carbidopa), L-serine-2- (2,3, 4-trihydroxybenzyl) ydrazide, glycine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) hydrazide and their physiologically tolerable salts.
Insbesondere vorteilhaft ist es außerdem, wenn der Cate- chol-O-Methyltransferase-Hemmer ausgewählt wird aus Enta- capon und Cabergolin sowie deren physiologisch verträglicher Salze.It is also particularly advantageous if the catechol-O-methyltransferase inhibitor is selected from entacon and cabergoline and their physiologically tolerable salts.
Bevorzugt ist es auch, wenn der Monoaminoxidase-Hemmer ausgewählt wird aus der Gruppe, bestehend aus Selegilin, Moclobemid und Tranylcypromin sowie deren physiologisch verträglicher Salze.It is also preferred if the monoamine oxidase inhibitor is selected from the group consisting of selegiline, moclobemide and tranylcypromine and their physiologically tolerable salts.
Besonders bevorzugt ist es weiterhin, wenn der ß- Hydroxylase-Hemmer ausgewählt wird aus Calcium-5- butylpicolinat und Calcium-5-pentylpicolinat sowie deren physiologisch verträglicher Salze.It is furthermore particularly preferred if the β-hydroxylase inhibitor is selected from calcium 5-butylpicolinate and calcium 5-pentylpicolinate and their physiologically tolerable salts.
Ein weiterer Gegenstand der Erfindung ist die Verwendung von L-DOPA, seiner Derivate und deren physiologisch ver- fraglicher Salze zur Herstellung von Arzneimitteln zur Prophylaxe psychotischer Erkrankungen sowie zur Behand-
lung von Erkrankungen, die durch gestörten Tyrosintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden.Another object of the invention is the use of L-DOPA, its derivatives and their physiologically questionable salts for the production of medicaments for the prophylaxis of psychotic diseases and for the treatment of treatment of diseases caused by impaired tyrosine transport or tyrosine decarboxylase.
Eine anderer Gegenstand der vorliegenden Erfindung ist eine pharmazeutische Zusammensetzung, welche L-DOPA, seine Derivate sowie deren physiologisch verträgliche Salze zur Prophylaxe psychotischer Erkrankungen sowie zur Behandlung von Erkrankungen, die durch gestörten Tyro- sintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden, neben pharmazeutisch verträglichen Hilfsund Zusatzstoffen, enthält.Another object of the present invention is a pharmaceutical composition which L-DOPA, its derivatives and their physiologically tolerable salts for the prophylaxis of psychotic diseases and for the treatment of diseases which are caused by disturbed tyrosine transport or disturbed tyrosine decarboxylase, in addition to pharmaceutically acceptable auxiliaries and additives , contains.
Besonders vorteilhaft ist hierbei eine pharmazeutische Zusammensetzung, welche L-DOPA, seine Derivate sowie deren physiologisch verträgliche Salze zur Prophylaxe psychotischer Erkrankungen sowie zur Behandlung von Erkrankungen, die durch gestörten Tyrosintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden und einen oder mehrere Enzymhemmer, neben pharmazeutisch verträglichen Hilfs- und Zusatzstoffen, enthält.A pharmaceutical composition which contains L-DOPA, its derivatives and their physiologically compatible salts for the prophylaxis of psychotic diseases and for the treatment of diseases which are caused by disturbed tyrosine transport or tyrosine decarboxylase and one or more enzyme inhibitors, in addition to pharmaceutically acceptable auxiliary substances, is particularly advantageous. and additives.
Insbesondere bevorzugt ist eine pharmazeutische Zusammensetzung, bei der es sich bei dem Enzymhemmer bzw. den En- zymhemmern um Decarboxylasehemmer und/oder Catechol-O-Particularly preferred is a pharmaceutical composition in which the enzyme inhibitor or the enzyme inhibitors are decarboxylase inhibitors and / or catechol-O-
Methyltransferase-Hemmer und/oder Monoaminoxidase-Hemmer und/oder b-Hydroxylase-Hemmer handelt.Methyltransferase inhibitors and / or monoamine oxidase inhibitors and / or b-hydroxylase inhibitors.
Weiterhin bevorzugt ist eine pharmazeutische Zusammenset- zung bei welcher der Decarboxylasehemmer ausgewählt wird aus der Gruppe, bestehend aus D, L-Serin-2- (2, 3, 4- trihydroxybenzyl) hydrazid (Benserazid) , (-)-L-a- Hydrazino-3, -dihydroxy-a-methylhydrozimtsäure (Carbid- opa) , L-Serin-2- (2, 3, 4-trihydroxybenzyl) hydrazid, Glycin- 2- (2, 3, -trihydroxybenzyl) hydrazid und L-Tyrosin-2-
(2, 3, 4-trihydroxybenzyl) hydrazid sowie deren physiologisch verträglicher Salze.Also preferred is a pharmaceutical composition in which the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2,3,4-trihydroxybenzyl) hydrazide (benserazide), (-) - La-hydrazino- 3, -dihydroxy-a-methylhydrocinnamic acid (carbide-opa), L-serine-2- (2, 3, 4-trihydroxybenzyl) hydrazide, glycine-2- (2, 3, -trihydroxybenzyl) hydrazide and L-tyrosine-2 - (2, 3, 4-trihydroxybenzyl) hydrazide and their physiologically tolerable salts.
Besonders vorteilhaft ist eine pharmazeutische Zusammen- Setzung, bei welcher der Catechol-O-Methyltransferase-A pharmaceutical composition in which the catechol-O-methyltransferase is particularly advantageous is
Hemmer ausgewählt wird aus Entacapon und Cabergolin sowie deren physiologisch verträglicher Salze.Inhibitors are selected from entacapone and cabergoline and their physiologically tolerable salts.
Weiterhin vorteilhaft ist eine pharmazeutische Zusammen- Setzung, bei welcher der Monoaminoxidase-Hemmer ausgewählt wird aus der Gruppe, bestehend aus Selegilin, Moc- lobe id und Tranylcypromin sowie deren physiologisch verträglicher Salze.Also advantageous is a pharmaceutical composition in which the monoamine oxidase inhibitor is selected from the group consisting of selegiline, moclobe id and tranylcypromine and their physiologically tolerable salts.
Außerdem bevorzugt ist eine pharmazeutische Zusammensetzung, bei welcher der ß-Hydroxylase-Hemmer ausgewählt wird aus Calcium-5-butylpicolinat und Calcium-5- pentylpicolinat sowie deren physiologisch verträglicher Salze .Also preferred is a pharmaceutical composition in which the β-hydroxylase inhibitor is selected from calcium 5-butyl picolinate and calcium 5-pentyl picolinate and their physiologically tolerable salts.
Die Herstellung von L-DOPA und seiner Derivate wie zum Beispiel der Alkylester ist an sich bekanntThe production of L-DOPA and its derivatives such as the alkyl ester is known per se
Zur Herstellung physiologisch verträglicher Salze von L- DOPA und seinen Derivaten können übliche, physiologisch verträgliche anorganische und organische Säuren wie Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Schwefelsäure, Oxalsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Salicylsäure, Adipin- säure und Benzoesäure, verwendet werden. Weitere verwendbare Säuren sind beispielweise in Fortschritte der Arzneimittelforschung, Bd. 10, Seiten 224-225, Birkhäuser Verlag, Basel und Stuttgart (1966) und Journal of Pharmaceutical Sciences, Bd. 66, Seiten 1-5 (1977) beschrieben.
Die Säureadditionssalze von L-DOPA und seinen Derivaten werden in der Regel in an sich bekannter Weise durch Mischen der freien Base oder deren Lösungen mit der entsprechenden Säure oder deren Lösungen in einem organi- sehen Lösungsmittel, beispielsweise einem niederen Alkohol wie Methanol, Ethanol, n-Propanol oder Isopropanol oder einem niederen Keton wie Aceton, Methylethylketon oder Methyl-isobutylketon oder einem Ether wie Diethy- lether, Tetrahydrofuran oder Dioxan, erhalten. Zur besse- ren Kristallabscheidung können auch Mischungen der genannten Lösungsmittel verwendet werden. Darüber hinaus können physiologisch verträgliche wässrige Lösungen von Säureadditionssalzen der erfindungsgemäß verwendeten Verbindungen in einer wässrigen Säurelösung hergestellt wer- den.For the production of physiologically compatible salts of L-DOPA and its derivatives, customary, physiologically compatible inorganic and organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and Benzoic acid. Other acids that can be used are described, for example, in Progress in Pharmaceutical Research, vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart (1966) and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977). The acid addition salts of L-DOPA and its derivatives are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or their solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, etc. -Propanol or isopropanol or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.
Die Säureadditionssalze von L-DOPA und seinen Derivaten können in an sich bekannter Weise, z. B. mit Alkalien o- der Ionenaustauschern, in die freie Base überführt wer- den. Von der freien Base lassen sich durch Umsetzung mit anorganischen oder organischen Säuren, insbesondere solchen, die zur Bildung von therapeutisch verwendbaren Salzen geeignet sind, weitere Salze gewinnen. Diese oder auch andere Salze der neuen Verbindung, wie z. B. das Pikrat, können auch zur Reinigung der freien Base dienen, indem man die freie Base in ein Salz überführt, dieses abtrennt und aus dem Salz wiederum die Base freisetzt.The acid addition salts of L-DOPA and its derivatives can be used in a manner known per se, e.g. B. with alkalis or ion exchangers, are converted into the free base. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for forming therapeutically usable salts. These or other salts of the new compound, such as. B. the picrate, can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.
Gegenstand der vorliegenden Erfindung sind auch Arznei- mittel zur oralen, buccalen, sublingualen, nasalen, rektalen, subeutanen, intravenösen oder intramuskulären Applikation sowie zur Inhalation, die neben üblichen Träger- und Verdünnungsmitteln L-DOPA, ein Derivat oder deren Säureadditionssalz als Wirkstoff enthalten.
Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutischtechnischen Hilfsstoffen entsprechend der gewünschten Ap- plikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Lutschtabletten, Filmtabletten, Dragees, Kap- sein, Pillen, Pulver, Lösungen, Aerosole oder Suspensionen oder Depotformen.The present invention also relates to medicaments for oral, buccal, sublingual, nasal, rectal, subeutan, intravenous or intramuscular application and for inhalation, which, in addition to conventional carriers and diluents, contain L-DOPA, a derivative or the acid addition salt thereof as an active ingredient. The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical technical adjuvants in accordance with the desired type of application with a suitable dosage. The preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, lozenges, film-coated tablets, coated tablets, capsules, pills, powders, solutions, aerosols or suspensions or depot forms.
Selbstverständlich kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien genannt.Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations.
Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zu- cker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmitteln wie Maisstärke oder Alginsäure, Bindemitteln wie Stärke oder Gelantine, Gleitmitteln wie Magnesiumstearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes wie Carboxylpolymethylen, Carboxylmethylcellulose, Cellu- loseacetatphthalat oder Polyvinylacetat, erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents Achieving a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.
Entsprechend können Dragees, auch für kontrolliert oder verzögert freisetzende Zubereitungsformen, durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Polyvinylpyrrolidon oder Schellack, Gummiara- bicum, Talk, Titandioxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten
bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets, also for controlled or delayed release preparation forms, can accordingly be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet can also consist of several layers exist, wherein the excipients mentioned above for the tablets can be used.
Lösungen oder Suspensionen mit dem erfindungsgemäß ver- wendeten Wirkstoff können zusätzlich geschmacksverbessernde Mittel wie Saccharin, Cyclamat oder Zucker sowie z. B. Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspendierhilfsstoffe wie Natriumcarboxymethylcellulose oder Konservierungsstoffe wie p-Hydroxybenzoate enthalten. Wirkstoffe enthaltende Kapseln können beispielsweise hergestellt werden, indem man den Wirkstoff mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkapselt.Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyäthylenglykol bzw. deren Derivaten herstellen.Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
Die Herstellung der erfindungsgemäßen pharmazeutischen Zubereitungen ist an sich bekannt und in den dem Fachmann bekannten Handbüchern beschrieben, beispielsweise Hager' s Handbuch (5.) 2, 622-1045; List et al., Arzneiformenleh- re, Stuttgart: Wiss. Verlagsges. 1985; Sucker et al.,The preparation of the pharmaceutical preparations according to the invention is known per se and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, 622-1045; List et al., Pharmaceutical Forms, Stuttgart: Wiss. Verlagsges. , 1985; Sucker et al.,
Pharmazeutische Technologie, Stuttgart: Thieme 1991; Ull- ann's Enzyklopädie (5.) A 19, 241-271; Voigt, Pharmazeutische Technologie, Berlin: Ullstein Mosby 1995.Pharmaceutical Technology, Stuttgart: Thieme 1991; Ullann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.
Das folgende Beispiel erläutert die Erfindung:The following example explains the invention:
Beispielexample
Zehn Patienten mit akuter Schizophrenie, die danach eine Erhaltungstherapie über ein Jahr mit Fluphenazin bekommen haben und klinisch stabil waren, wurden sukzessive abge-
setzt. Bei ca. 8 von 10 Patienten wäre nach klinischer Erfahrung, s. Gitlin M., Nuechterlein K. , Subotnik K. L. et al., Am. J. Psychiatry (2001) 158(11), S. 1835-42, mit einem Rückfall innerhalb der folgenden 12 Monate gerechnet worden. Unsere Patienten wurden 2 Monate vor Absetzen und während der gesamten Absetzphase mit L-DOPA bzw einem L-DOPA-haltigen Kombinationspräparat behandelt. Bei diesen Patienten trat nur in 2 von 10 Fällen ein Rückfall auf.
Ten patients with acute schizophrenia who subsequently received maintenance therapy with fluphenazine for one year and were clinically stable were gradually withdrawn puts. According to clinical experience, approx. 8 out of 10 patients would see Gitlin M., Nuechterlein K., Subotnik KL et al., Am. J. Psychiatry (2001) 158 (11), pp. 1835-42, with a relapse within the following 12 months. Our patients were treated with L-DOPA or a combination preparation containing L-DOPA 2 months before weaning and throughout the weaning phase. Relapse occurred in only 2 out of 10 of these patients.
Claims
Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze zur Prophylaxe von Psychosen insbesondere auch von schizophrenen Psychosen sowie zur Behandlung von Erkrankungen, die durch gestörten Tyrosintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden.Use of L-DOPA, its derivatives and their physiologically tolerable salts for the prophylaxis of psychoses, in particular also of schizophrenic psychoses, and for the treatment of diseases which are caused by impaired tyrosine transport or tyrosine decarboxylase.
2. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze zur Herstellung von Arzneimitteln zur Prophylaxe vo Psychosen insbesondere auch von schizophrenen Psychosen sowie zur Be- handlung von Erkrankungen, die durch gestörten Tyrosintransport oder gestörte Tyrosindecarboxylase hervorgerufen werden.2. Use of L-DOPA, its derivatives and their physiologically tolerable salts for the production of medicaments for the prophylaxis of psychoses, in particular also of schizophrenic psychoses, and for the treatment of diseases which are caused by impaired tyrosine transport or tyrosine decarboxylase.
3. Verwendung von L-DOPA, seiner Derivate und deren phy- siologisch verträglicher Salze gemäß Anspruch 1 oder3. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 1 or
2 in Kombination mit mindestens einem Enzymhemmer.2 in combination with at least one enzyme inhibitor.
4. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze gemäß Anspruch 3, da- durch gekennzeichnet, dass es sich bei dem/n Enzymhemmer/n um Decarboxylasehemmer und/oder Catechol-0- Methyltransferase-Hemmer und/oder Monoaminoxidase- Hemmer und/oder ß-Hydroxylase-Hemmer handelt.4. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 3, characterized in that the enzyme inhibitor (s) is decarboxylase inhibitor and / or catechol-0-methyltransferase inhibitor and / or monoamine oxidase Inhibitors and / or β-hydroxylase inhibitors.
5. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze gemäß Anspruch 4, dadurch gekennzeichnet, dass der Decarboxylasehemmer ausgewählt wird aus der Gruppe, bestehend aus D,L- Serin-2- (2 , 3 , 4-trihydroxybenzyl) -hydrazid (Bensera- zid) , (-) -L-a-Hydrazino-3 , 4-dihydroxy-a- methylhydrozimtsäure (Carbidopa) , L-Serin-2- (2, 3 ,4- trihydroxybenzyl) hydrazid, Glycin-2- (2,3,4- trihydroxybenzyl) hydrazid und L-Tyrosin-2- (2 , 3 , 4- trihydroxybenzyl) ydrazid sowie deren physiologisch verträglicher Salze.5. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 4, characterized in that the decarboxylase inhibitor is selected from the group consisting of D, L-serine-2- (2, 3, 4-trihydroxybenzyl) -hydrazide (benserazide), (-) -la-hydrazino-3, 4-dihydroxy-a-methylhydrocinnamic acid (carbidopa), L-serine-2- (2, 3, 4- trihydroxybenzyl) hydrazide, glycine-2- (2,3,4-trihydroxybenzyl) hydrazide and L-tyrosine-2- (2, 3, 4-trihydroxybenzyl) ydrazide and their physiologically tolerable salts.
6. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze gemäß Anspruch 4, dadurch gekennzeichnet, dass der Catechol-O- Methyltransferase-Hemmer ausgewählt wird aus Entaca- pon und Cabergolin sowie deren physiologisch verträglicher Salze.6. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 4, characterized in that the catechol-O-methyltransferase inhibitor is selected from entacapone and cabergoline and their physiologically tolerable salts.
7. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze gemäß Anspruch 4, da- durch gekennzeichnet, dass der Monoaminoxidase-Hemmer ausgewählt wird aus der Gruppe, bestehend aus Selegi- lin, Moclobemid und Tranylcypromin sowie deren physiologisch verträglicher Salze.7. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 4, characterized in that the monoamine oxidase inhibitor is selected from the group consisting of selegiline, moclobemide and tranylcypromine and their physiologically tolerable salts.
8. Verwendung von L-DOPA, seiner Derivate und deren physiologisch verträglicher Salze gemäß Anspruch 4, dadurch gekennzeichnet, dass der ß-Hydroxylase-Hemmer ausgewählt wird aus Calcium-5-butylpicolinat und Cal- cium-5-pentylpicolinat sowie deren physiologisch ver- fraglicher Salze. 8. Use of L-DOPA, its derivatives and their physiologically tolerable salts according to claim 4, characterized in that the β-hydroxylase inhibitor is selected from calcium 5-butylpicolinate and calcium 5-pentylpicolinate and their physiologically ver salts in question.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03785594A EP1615631A2 (en) | 2002-12-19 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
| JP2004561055A JP2006511558A (en) | 2002-12-19 | 2003-12-18 | Use of L-DOPA, derivatives thereof and pharmaceuticals containing these compounds for preventing psychotic diseases |
| AU2003294664A AU2003294664A1 (en) | 2002-12-19 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
| CA002513077A CA2513077A1 (en) | 2002-12-19 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
| MXPA05006409A MXPA05006409A (en) | 2002-12-19 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases. |
| EA200500957A EA200500957A1 (en) | 2002-12-19 | 2003-12-18 | APPLICATION OF L-DOPA, ITS DERIVATIVES AND MEDICINES CONTAINING THESE COMPOUNDS FOR THE PREVENTION OF PSYCHOTICAL DISEASES |
| US10/539,793 US20070082953A1 (en) | 2003-12-18 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10261808A DE10261808A1 (en) | 2002-12-19 | 2002-12-19 | Use of L-DOPA, its derivatives and medicaments containing these compounds for the prophylaxis of psychotic diseases |
| DE10261808.9 | 2002-12-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2004056306A2 true WO2004056306A2 (en) | 2004-07-08 |
| WO2004056306A3 WO2004056306A3 (en) | 2004-11-11 |
Family
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|---|---|---|---|
| PCT/DE2003/004204 WO2004056306A2 (en) | 2002-12-19 | 2003-12-18 | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1615631A2 (en) |
| JP (1) | JP2006511558A (en) |
| CN (1) | CN1756542A (en) |
| AU (1) | AU2003294664A1 (en) |
| CA (1) | CA2513077A1 (en) |
| DE (1) | DE10261808A1 (en) |
| EA (1) | EA200500957A1 (en) |
| MX (1) | MXPA05006409A (en) |
| PL (1) | PL377524A1 (en) |
| WO (1) | WO2004056306A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007093450A2 (en) * | 2006-02-17 | 2007-08-23 | Birds Pharma Gmbh Berolina Innovative Research & Development Services | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| JP2008505966A (en) * | 2004-07-12 | 2008-02-28 | ディズリン・メディカル・デザイン・アクチボラゲット | Infusion and injection of levodopa |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105078952A (en) * | 2015-08-10 | 2015-11-25 | 中国康复研究中心 | Levodopa preparation and application thereof |
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| GB2001060A (en) * | 1977-07-01 | 1979-01-24 | Merrell Toraude & Co | alpha -Acetylenic Amino Acids |
| US5330895A (en) * | 1989-10-12 | 1994-07-19 | Ramirez Victor D | Detection reagent and antibody specific for dopamine releasing protein |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52102431A (en) * | 1976-02-25 | 1977-08-27 | Kyowa Hakko Kogyo Co Ltd | Remedies for mental disorder |
-
2002
- 2002-12-19 DE DE10261808A patent/DE10261808A1/en not_active Ceased
-
2003
- 2003-12-18 MX MXPA05006409A patent/MXPA05006409A/en unknown
- 2003-12-18 CA CA002513077A patent/CA2513077A1/en not_active Abandoned
- 2003-12-18 EA EA200500957A patent/EA200500957A1/en unknown
- 2003-12-18 EP EP03785594A patent/EP1615631A2/en not_active Withdrawn
- 2003-12-18 JP JP2004561055A patent/JP2006511558A/en active Pending
- 2003-12-18 WO PCT/DE2003/004204 patent/WO2004056306A2/en not_active Application Discontinuation
- 2003-12-18 CN CNA2003801066148A patent/CN1756542A/en active Pending
- 2003-12-18 PL PL377524A patent/PL377524A1/en not_active Application Discontinuation
- 2003-12-18 AU AU2003294664A patent/AU2003294664A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2001060A (en) * | 1977-07-01 | 1979-01-24 | Merrell Toraude & Co | alpha -Acetylenic Amino Acids |
| US5330895A (en) * | 1989-10-12 | 1994-07-19 | Ramirez Victor D | Detection reagent and antibody specific for dopamine releasing protein |
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| DATABASE WPI Section Ch, Week 198401 Derwent Publications Ltd., London, GB; Class B05, AN 1984-001816 XP002278318 & JP 47 030824 A (KYOWA HAKKO KOGYO KK) 10. November 1972 (1972-11-10) * |
| GERLACH J ET AL: "The effect of L-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: a double-blind cross-over trial with Madopar and placebo." PSYCHOPHARMACOLOGIA. GERMANY, WEST 14 OCT 1975, Bd. 44, Nr. 1, 14. Oktober 1975 (1975-10-14), Seiten 105-110, XP008030065 ISSN: 0033-3158 * |
| HALE M S ET AL: "LOW DOSE PERPHENAZINE AND LEVODOPA/CARBIDOPA THERAPY IN A PATIENT WITH PARKINSONISM AND A PSYCHOTIC ILLNESS" JOURNAL OF NERVOUS AND MENTAL DISEASE, WILLIAMS AND WILKINS, US, Bd. 168, Nr. 5, 1980, Seiten 312-314, XP008020514 ISSN: 0022-3018 * |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008505966A (en) * | 2004-07-12 | 2008-02-28 | ディズリン・メディカル・デザイン・アクチボラゲット | Infusion and injection of levodopa |
| JP2013028609A (en) * | 2004-07-12 | 2013-02-07 | Dizlin Medical Design Ab | Levodopa infusion solution and injection solution |
| US8735382B2 (en) | 2004-07-12 | 2014-05-27 | Dizlin Medical Design Ab | Infusion and injection solution of levodopa |
| JP2015227341A (en) * | 2004-07-12 | 2015-12-17 | ディズリン・メディカル・デザイン・アクチボラゲットＤｉｚｌｉｎ Ｍｅｄｉｃａｌ Ｄｅｓｉｇｎ Ａｂ | Infusion and injection solution of levodopa |
| US9248113B2 (en) | 2004-07-12 | 2016-02-02 | Dizlin Medical Design Ab | Infusion and injection solution of Levodopa |
| WO2007093450A2 (en) * | 2006-02-17 | 2007-08-23 | Birds Pharma Gmbh Berolina Innovative Research & Development Services | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| WO2007093450A3 (en) * | 2006-02-17 | 2007-09-27 | Birds Pharma Gmbh Berolina Inn | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| US8247603B2 (en) | 2006-02-17 | 2012-08-21 | Birds Pharma Gmbh Berolina Innovative | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| EA017983B1 (en) * | 2006-02-17 | 2013-04-30 | Бедс Фарма Гмбх Беролина Инновейтив Ресёч Энд Девелопмент Сёвисиз | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| EP3101001A1 (en) * | 2006-02-17 | 2016-12-07 | ratiopharm GmbH | Deuterated catecholamine derivatives and medicaments comprising said compounds |
| USRE46555E1 (en) | 2006-02-17 | 2017-09-19 | Teva Pharmaceuticals International Gmbh | Deuterated catecholamine derivatives and medicaments comprising said compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004056306A3 (en) | 2004-11-11 |
| AU2003294664A1 (en) | 2004-07-14 |
| CN1756542A (en) | 2006-04-05 |
| CA2513077A1 (en) | 2004-07-08 |
| EA200500957A1 (en) | 2006-02-24 |
| PL377524A1 (en) | 2006-02-06 |
| JP2006511558A (en) | 2006-04-06 |
| MXPA05006409A (en) | 2006-05-31 |
| DE10261808A1 (en) | 2004-07-08 |
| EP1615631A2 (en) | 2006-01-18 |
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