WO2010103273A2 - Composés d'acide gras essentiel - Google Patents

Composés d'acide gras essentiel Download PDF

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Publication number
WO2010103273A2
WO2010103273A2 PCT/GB2010/000430 GB2010000430W WO2010103273A2 WO 2010103273 A2 WO2010103273 A2 WO 2010103273A2 GB 2010000430 W GB2010000430 W GB 2010000430W WO 2010103273 A2 WO2010103273 A2 WO 2010103273A2
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WO
WIPO (PCT)
Prior art keywords
drug
dopa
reserpine
acid
effects
Prior art date
Application number
PCT/GB2010/000430
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English (en)
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WO2010103273A3 (fr
Inventor
Mehar Manku
Original Assignee
Amarin Neuroscience Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Amarin Neuroscience Limited filed Critical Amarin Neuroscience Limited
Priority to JP2011553508A priority Critical patent/JP2012520274A/ja
Priority to CA2754902A priority patent/CA2754902A1/fr
Priority to AU2010222692A priority patent/AU2010222692A1/en
Publication of WO2010103273A2 publication Critical patent/WO2010103273A2/fr
Publication of WO2010103273A3 publication Critical patent/WO2010103273A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P25/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to essential fatty acid compounds and their therapeutic applications.
  • Levodopa or L-DOPA (3,4-dihydroxy-L-phenylalanine), is shown as Formula 1 below:
  • Dopamine is formed by the decarboxylation of L-DOPA.
  • Dopamine is shown in Formula 2 below:
  • L-DOPA is used in the management of Parkinson's disease (PD), as a prodrug to increase dopamine levels.
  • PD Parkinson's disease
  • L-DOPA is the only easily accessible and low-invasive therapy for PD patients. It is able to cross the blood-brain barrier whereas dopamine itself cannot.
  • CNS central nervous system
  • L-DOPA markedly increases the quality of life of patients suffering from Parkinson's disease.
  • L-DOPA therapy includes fluctuations of motor responses to L-DOPA.
  • Motor fluctuations can range from relatively simple "wearing off' of medications prior to the next dose, also called end-of-dose failure, to random, severe fluctuations in motor functioning.
  • a patient may rapidly and unpredictably alternate from having severe Parkinsonian symptoms ("off') to a near normal motor state ("on") and then to a state of marked involuntary movements (dyskinesia), the so- called "on-off' phenomenon.
  • Motor fluctuations are related to pre-synaptic problems, including variable absorption of L-DOPA and reduced pre-synaptic storage capacity. This results in excessive pulsatile stimulation of the dopamine receptors rather than continuous delivery of the drug.
  • L-DOPA L-DOPA
  • the amount of L-DOPA that eventually reaches the brain after a single oral dose depends on the speed of gastric emptying, presence of competition for intestinal transport of the alternative amino acids, and, most of all, the degree of peripheral metabolism. After taking it, only about 5% of L-DOPA can cross the blood-brain barrier. Patients have to take a very high dose and several times a day, leading to marked plasma drug fluctuations. Increased bioavailability would have some major advantages to the PD patient, such as the decreased fluctuations, but also decreased dose-related peripheral side effects, including nausea, vomiting, and hypotension.
  • L-DOPA is taken up by the surviving striatal neurons, converted by intraneuronal AADC to dopamine (DA), which is, in turn, released presynaptically.
  • DA dopamine
  • the present invention provides compounds of L-DOPA or dopamine with an essential fatty acid. These are show in general terms in formula 3:
  • R 1 is acyl or fatty acid group derived from C 12 -C 30 fatty acids, preferably C 16 -C 30 fatty acids desirably with two or more cis or trans double bonds;
  • R 3 is H or CH 3 ; n is O or 1 ; m is O or 1 ;
  • Y is a bond; or for example, when Y is a linker group.
  • the compounds are derivatives of a fatty acid with the available carboxyl or amino group of L-DOPA, or the amino group of dopamine, such that a single, well defined chemical entity is formed.
  • the coupling may be direct yielding bipartate compounds or spaced with an appropriate linker group, yielding tripartate compounds, in terms of the number of moieties into which the compounds split.
  • the linker groups Y, Z may be a phosphate, succinate or moeity derived from a difunctional acid.
  • a phosphate, succinate or difunctional acid derived linker Z or Y may be interposed between the R 1 and/or R 2 group and the 1 ,3-propane diol residue, as shown in Formula 3 above.
  • a linker Y may be between the diol and the L-DOPA or dopamine moeity.
  • any fatty acid suitably C 12 -C 30 or C 16 -C 30 and desirably with two or more cis or trans carbon-carbon double bonds may be of use.
  • the fatty acid is an n-6 or n-3 series essential fatty acid or oleic acid, columbinic acid, parinaric acid or conjugated linoleic acid.
  • the twelve essential (n-6) and (n-3) essential fatty acids are shown in Figure 1.
  • the essential fatty acids which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g.
  • the application of lipophilic essential fatty acids in the treatment of CNS disorders has been documented, for example reference is made to WO 98/16216 and WO 00/44361.
  • the blood-brain barrier is essentially composed of lipids and the essential fatty acids are able to cross this barrier.
  • GLA Gamma-linolenic acid
  • DGLA dihomo-gamma-linolenic acid
  • Other fatty acids such as any of the essential fatty acids (EFAs) and in particular the twelve natural acids of the n-6 and n-3 series EFAs of Figure 1 , can be used.
  • EFAs essential fatty acids
  • arachidonic acid, adrenic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid n-3 and docosahexaenoic acid are of particular interest.
  • Conjugated linoleic acid (cLA), oleic acid and columbinic acid (CA) are examples of further fatty acids, though not included in Figure 1 , likely to be of particular use.
  • the present invention further provides a pharmaceutical composition comprising a compound according to the invention for the treatment of Parkinson's disease or other movement disorders including Huntington's disease and other illnesses known to be linked to excessive numbers of trinucleotide repeats in certain genes, including fragile X syndrome, Friedreich's ataxia, spinal and bulbar muscular atrophy, spinocerebellar ataxia type I, dentato-rubral-pallidoluysian atrophy, Haw River syndrome, Machado-Joseph disease, and myotonic dystrophy.
  • Parkinson's disease or other movement disorders including Huntington's disease and other illnesses known to be linked to excessive numbers of trinucleotide repeats in certain genes, including fragile X syndrome, Friedreich's ataxia, spinal and bulbar muscular atrophy
  • Methods of manufacture of such medicaments are provided, as are methods of treating, preventing or delaying the onset of the symptoms of these disorders.
  • the compounds of the invention are shown to increase significantly brain levels of dopamine.
  • the levels are steady and there is less peripheral breakdown of L-DOPA. This leads to fewer doses per day, reducing the peaks and troughs believed to contribute to a cycle of on/off and/or dyskinesia.
  • the compounds of present invention provide to an improved way to incorporate L-DOPA or dopamine in the CNS.
  • the compounds of the present invention are stable, which gives an advantage for drug regulatory concerns. They are readily incorporated into the body as an oral, parenteral or topical formulation, which is well tolerated. The moieties are delivered simultaneously in a single molecule. This avoids the regulatory problems which can ensue when more than one molecule are administered as separate compounds, and avoids the possibility of chiral centres. Once through the blood brain barrier, the compound readily separates to release the L-DOPA or dopamine. The essential fatty acid is also released.
  • fatty acids are likely to be able to add to the efficacy of L-DOPA or dopamine.
  • the fatty acids are remarkably nontoxic and can be administered safely in large doses without the risk of important side effects.
  • the individual fatty acids may be purified from natural animal, vegetable or microbial sources or may be chemically synthesised by methods known to those skilled in the art or developed hereafter.
  • Fatty acid pairs may for example be linked directly as fatty acid- fatty alcohol esters or as anhydrides, and if diol linkers are used ether links to fatty alcohols are an alternative to the more generally convenient ester links to fatty acids as such; in all cases linking may again be by chemistry known in itself.
  • the present invention provides a pharmaceutical preparation comprising the dopamine or L-DOPA compounds of the first aspect of the invention.
  • the active ingredient of these pharmaceutical compositions may comprises essentially only the the dopamine or L-DOPA compound(s) of the invention.
  • the compounds may be formulated in any way appropriate and which is known to those skilled in the art of preparing pharmaceuticals, skin care products or foods. They may be administered orally, enterally, topically, parenterally (subcutaneously, intramuscularly, intravenously), rectally, vaginally or by any other appropriate route.
  • the 1 ,3-propane diol diesters may be readily emulsified using phospholipid or particularly galactolipid emulsifiers. Such emulsions are particularly useful for administration via oral, enteral and intravenous routes.
  • Anti-microbial preservatives for example potassium sorbate, and flavour, can also be added to an oral emulsion.
  • the doses of the actives to be administered largely range from I mg to 200 g per day, preferably 10 mg to 10 g and very preferably 10 mg to 3 g.
  • the compound need only be taken once or twice a day.
  • Fig 1 essential fatty acids and their metabolism
  • Fig 3 DA levels in the striatum in Experiment 1 of Example 5;
  • Fig 4 neurotransmitters in the cortex in Experiment 1 of Example 5;
  • Fig 6 DA levels in the striatum in Experiment 2 of Example 5;
  • Fig 7 neurotransmitters in the cortex in Experiment 2 of Example 5;
  • Fig 10 DA levels in the striatum in Experiment 3 of Example 5;
  • Fig 11 DPOA/DA levels in the striatum in Experiment 3 of Example 5;
  • Fig 12 L-DOPA levels in the striatum in Experiment 3 of Example 5.
  • Boc-Levadopa 14 (20.1g) and tert-butyldimethylchlorosilane (29.5g) in acetonitrile (250ml) was cooled down to O 0 C with an ice bath. After stirring 10 min, DBU (29.87g) was added over 10 min and the resulting mixture was stirred at 0 0 C then at room temperature 16 hours.
  • the protected intermediate 16 (19.7g) was dissolved in THF (200ml). The solution was cooled to 0 0 C for 10 min. To this solution was added TBAF (1M solution in THF, 46.7ml). The resulting mixture was stirred at 0 0 C for 30 min. Saturated ammonium chloride water solution (400ml) was added to the reaction mixture and was extracted with ethyl acetate (500ml). The organic phase was washed with water, brine, dried over sodium sulfate and concentrated to dryness to give intermediate 17 (13.5g).
  • L-DOPA L-DOPA
  • rodent models of PD such as the reserpine or MPTP-induced model.
  • the reserpine model is the first animal model, which was widely used to test the effects of anti-parkinsonian drugs.
  • the mechanisms of this anti-hypertensive drug to induce parkinsonism are still not fully understood, but it involves depletion of synaptic vesicles of neurotransmitter content (in particular DA, but also other neurotransmitters) and reduced terminal reuptake of neurotransmitters.
  • reserpine is that it's relatively quick acting, has robust effects on behavior and is non-toxic, whereas MPTP is far more toxic to handle and has much less severe effects on animals' behavior, even though it selectively destroys nigrostriatal neurons.
  • Animals 56 C57BL/6 male (10-12 weeks old, 25g) from Charles River, Canada. Animals were kept in the animal holding room (21 ⁇ 1 'C) in normal 12h light-dark cycle (lights on at 6:00 am and off at 6:00 pm) for 1 week of habituation to the new environment, prior to experimental procedures. They had ad-lib access to food and water.
  • Drugs L-DOPA (Sigma, Canada) and DRUG 1 (conjugate of Example 3) and 2 (conjugate of Example 4) were dissolved at 1 mg/ml in vegetable oil. Prepared solutions were kept on ice and stored in 4 "C overnight.
  • Biochemical analyses Immediately after an Open Field testing, the animal was brought to a surgery room and sacrificed using cervical dislocation. Striatum and other brain regions were dissected and stored in eppendorf tubes containing a buffer (250ml H2O with 2.2 mg L-ascorbic acid, 2.33 ml 70% HCIO 4 and 25 mg EDTA) for HPLC analyses. Samples were centrifuged at 11000 RPM and 4°C, for 25 minutes. DA, DOPAC and other neurotransmitters were analyzed later with HPLC equipment. This report limits to DA and DOPAC.
  • Animals 42 male (10-12 weeks old, 25g) C57BL/6 from Charles River, Canada. Animals were kept in the animal holding room (21 ⁇ 1 0 C) in 12h light-dark cycle (lights on at 6:00 am and off at 6:00 pm) for 1 week of habituation to the new environment, prior to experimental procedures. They had ad-lib access to food and water.
  • Drugs L-DOPA and DRUG 2 (see Example 5.1). Reserpine (Sigma, Canada) was dissolved in 1% acetic acid in sterile dd H2O (Visanji et al., 2006). All drugs were prepared as in Example 5.1.
  • L-DOPA did not change grooming in animals treated with reserpine compared to reserpine only treated mice, but DRUG 2 significantly increased grooming in mice treated with reserpine compared to reserpine only treated mice (##p ⁇ 0.01).
  • Increased absorption would imply increased content of L-DOPA in the brain.
  • the L-DOPA then becomes converted to DA.
  • no difference on total L-DOPA levels may be observed after DRUG 2 treatment, as all the administered L-DOPA may be converted to DA at the time of measurement.
  • the increase of L-DOPA levels after reserpine treatment was hard to explain. The variation of this result was high and perhaps unreliable.
  • Reserpine inhibits the vesicular monoamine transporter (VMAT) and thus less DA can be stored in vesicles and becomes metabolized by monoamine oxidase. Thus, a decrease of DA would be expected, but not an increase of L-DOPA. Reserpine does not inhibit tyrosine hydroxylase, so the increase of L-DOPA levels cannot be explained by a reduction of conversion of L-DOPA to DA. Both L-DOPA and DRUG2 attenuated this effect of reserpine.
  • VMAT vesicular monoamine transporter

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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur des composés qui comprennent de la L-DOPA ou de la dopamine liée à un acide gras essentiel. La formule générale est la suivante : R1-Z-O-(CH2)n-CH(R3)-(CH2)mO-Y-R2 R1 est issu d'un acide gras et R2 est issu de la L-DOPA ou de la dopamine. Une liaison privilégiée a la structure de 1,3 propane diol.
PCT/GB2010/000430 2009-03-12 2010-03-10 Composés d'acide gras essentiel WO2010103273A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2011553508A JP2012520274A (ja) 2009-03-12 2010-03-10 必須脂肪酸化合物
CA2754902A CA2754902A1 (fr) 2009-03-12 2010-03-10 Composes d'acide gras essentiel
AU2010222692A AU2010222692A1 (en) 2009-03-12 2010-03-10 Essential fatty acid compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0904300.1A GB0904300D0 (en) 2009-03-12 2009-03-12 Essential fatty acid compounds
GB0904300.1 2009-03-12

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WO2010103273A2 true WO2010103273A2 (fr) 2010-09-16
WO2010103273A3 WO2010103273A3 (fr) 2010-11-04

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JP (1) JP2012520274A (fr)
AU (1) AU2010222692A1 (fr)
CA (1) CA2754902A1 (fr)
GB (1) GB0904300D0 (fr)
WO (1) WO2010103273A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015522531A (ja) * 2012-05-07 2015-08-06 セリックスビオ プライヴェート リミテッド 神経筋疾患及び神経変性疾患の治療のための組成物及び方法
CN104968643A (zh) * 2013-02-05 2015-10-07 伊莫菲尔股份公司 位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物
WO2019097120A1 (fr) 2017-11-16 2019-05-23 Orion Corporation Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques
WO2020169012A1 (fr) 2019-02-18 2020-08-27 海南大学 Procédé de synthèse d'un intermédiaire d'oligopeptide dopa et utilisation, composition et préparation associées

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016216A1 (fr) 1996-10-11 1998-04-23 Scotia Holdings Plc Preparation pharmaceutique contenant de l'acide eicosapentanoïque et/ou de l'acide stearidonique
WO2000044361A2 (fr) 1999-01-27 2000-08-03 Laxdale Limited Acide eicosapentanoique ethylique hautement purifie et autres derives de l'acide eicosapentanoique pour le traitement des troubles psychiatriques et neurologiques

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
LU85757A1 (fr) * 1985-02-04 1986-09-02 Univ Catholique Louvain Derives nouveaux de la l-dopa,procedes pour leur preparation et compositions pharmaceutiques concernant de tels composes
ZA200610042B (en) * 2004-06-04 2008-06-25 Xenoport Inc Levodopa prodrugs, and compositions and uses thereof
US7829592B2 (en) * 2006-12-21 2010-11-09 Xenoport, Inc. Catechol protected levodopa diester prodrugs, compositions, and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016216A1 (fr) 1996-10-11 1998-04-23 Scotia Holdings Plc Preparation pharmaceutique contenant de l'acide eicosapentanoïque et/ou de l'acide stearidonique
WO2000044361A2 (fr) 1999-01-27 2000-08-03 Laxdale Limited Acide eicosapentanoique ethylique hautement purifie et autres derives de l'acide eicosapentanoique pour le traitement des troubles psychiatriques et neurologiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015522531A (ja) * 2012-05-07 2015-08-06 セリックスビオ プライヴェート リミテッド 神経筋疾患及び神経変性疾患の治療のための組成物及び方法
CN104968643A (zh) * 2013-02-05 2015-10-07 伊莫菲尔股份公司 位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物
CN104968643B (zh) * 2013-02-05 2020-03-03 梯瓦制药国际有限责任公司 位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物
WO2019097120A1 (fr) 2017-11-16 2019-05-23 Orion Corporation Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques
WO2020169012A1 (fr) 2019-02-18 2020-08-27 海南大学 Procédé de synthèse d'un intermédiaire d'oligopeptide dopa et utilisation, composition et préparation associées

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AU2010222692A1 (en) 2011-10-13
WO2010103273A3 (fr) 2010-11-04
GB0904300D0 (en) 2009-04-22
CA2754902A1 (fr) 2010-09-16
JP2012520274A (ja) 2012-09-06

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