WO2016074684A1 - Dérivés d'acide fumarique à usage médical - Google Patents

Dérivés d'acide fumarique à usage médical Download PDF

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WO2016074684A1
WO2016074684A1 PCT/DK2015/050344 DK2015050344W WO2016074684A1 WO 2016074684 A1 WO2016074684 A1 WO 2016074684A1 DK 2015050344 W DK2015050344 W DK 2015050344W WO 2016074684 A1 WO2016074684 A1 WO 2016074684A1
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fumaric acid
agents
group
acid derivatives
derivatives according
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PCT/DK2015/050344
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Zsolt Laszlo ILLÉS
Kate Lykke LAMBERTSEN
Bente FINSEN
Helle Hvilsted NIELSEN
Bettina Hjelm CLAUSEN
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Syddansk Universitet
Region Syddanmark
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Publication of WO2016074684A1 publication Critical patent/WO2016074684A1/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 present invention relates to novel medical uses of fumaric acid derivatives.
  • fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric acid salts, dimethyl fumarate, monomethyl-fumarate, fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof for use in the treatment or prevention of inflammation and cell or tissue necrosis, particularly in connection with stroke.
  • Acute ischemic and haemorrhagic stroke is a major burden of the population even in the developed world, and is the primary cause of long-term disability. Its incidence is increasing with age, and its economic and social impact is huge.
  • Stroke is the third leading cause of death in the United States.
  • Acute ischemic stroke the most common form of stroke, is caused by clotting in the cerebral arteries leading to brain oxygen deprivation and tissue loss (primarily neuronal cell death, but also myelin damage).
  • An acute ischemic stroke is treated in a hospital with intravenous/intraarterial thrombolysis in 4.5-6 hours or by thrombectomy, but the effect of such invasive approaches is limited, major adverse events including death may follow, and there is a controversy regarding the effectivity of intraarterial thrombolysis and thrombectomy.
  • Prevention of stroke in case of risk factors may involve the administration of antiplatelet drugs, such as aspirin and dipyridamole to interfere with platelet aggregation on existing vascular plaques and reduce the risk of local thrombosis and embolisation. This may be combined with controlling other risk factors e.g. reduction of high blood pressure, the use of statins to decrease serum cholesterol, or treatment of diabetes.
  • Hemorrhagic stroke may damage brain tissue due to bleeding into the brain parenchyma or the subarachnoid/subdural space.
  • Subarachnoid haemorrhage is accompanied by vasoconstriction in the acute phase, which may contribute to tissue damage due to ischemia.
  • hypoperfusion to the brain due to low blood pressure or hypoglycemia can cause ischemic stroke.
  • an object of the present invention relates to fumaric acid derivatives which are useful in the protection against neuronal necrosis and inflammation, particular in the brain. It is a particular object of the present invention to protect against such conditions during or in connection with stroke, hypoxia or vasoconstriction. In particular, it is an object of the present invention to provide an improved or alternative treatment that solves the above mentioned problems of the prior art with neuronal cell damage and inflammation in e.g. the brain, particular in connection with stroke, hypoxia or vasoconstriction.
  • one aspect of the present invention is fumaric acid derivatives for use in the prevention or treatment of a condition selected from the group consisting of neuronal necrosis and an inflammatory condition.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a fumaric acid derivative, a medicament selected from the group consisting of thrombolytic agents, fibrinolytic agents, anti-thrombotic agents, antiplatelet aggregation agents, anticoagulants, anti-hypertensive agents, antidiabetic agents, anti-dyslipidemia agents, cholesterol reducing agents, statins, and a pharmaceutically acceptable carrier.
  • the fumaric acid derivatives and pharmaceutical composition may particularly for use in the acute treatment of stroke, hypoxia or vasoconstriction, or primary and secondary prevention for stroke.
  • Yet another aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a fumaric acid derivative, a medicament for use in the prevention or treatment of stroke, hypoxia or vasoconstriction and a
  • Figure 1 shows a proposed mechanism of action of methyl fumarate.
  • FIG. 2 shows heat shock protein (HSP72) levels in the brain tissue were decreased in saline-treated but not in monomethyl fumarate (MMF)-treated mice at 48h. At 6 hours, there was a tendency towards higher HSP72 protein levels in MMF-compared to saline-treated mice.
  • HSP72 heat shock protein
  • Figure 3 shows that MMF treatment induced elevation of anti-inflammatory IL-10 in the sera in contrast to untreated controls.
  • the concentration of proinflammatory IL-12 was reduced in the brain after 48 hours in contrast to untreated controls.
  • Figure 4 shows that the concentration of pro-inflammatory IL-5 and IL-2 was reduced in the sera after 6 and 48 hours, respectively, in contrast to untreated animals.
  • Figure 6A and 6B shows the influence of MMF treatment on the Keapl-Nrf2 pathway within the ischemic brain area of mice. Keap mRNA is reduced on treatment with MMF ( Figure 6A) and Nrf2 protein is increased ( Figure 6B).
  • Figure 7 shows how heat schock protein (Hsp72) levels were decreased in untreated animals and maintined in treated animals reflecting neuronal survival.
  • Figure 8 shows the effects of MMF treatment on cytokine and TNF levels in brain and serum at various time points.
  • Figure 9 shows the effects of MMF treatment on cytokine levels in brain and serum at various time points.
  • the term "stroke” refers to the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood). As a result, the affected area of the brain is unable to function and recovery is limited by the extent of tissue loss and especially by loss of neurons. Ischemic stroke can be caused by obliteration of large vessels (territorial infarcts) or small vessels (lacunar infarcts). Lacunar strokes are frequently silent (asymptomatic), and the patient is typically unaware of a stroke.
  • a silent stroke still causes damage to the brain, and places the patient at increased risk for vascular dementia or a major stroke in the future.
  • Silent strokes typically cause lesions which are detected via the use of neuroimaging, such as MRI.
  • the patient In cases of both territorial and lacunar infarcts, the patient usually has a number of risk factors resulting in a generalized vascular disorder characterized by atherosclerotic plaques not only in the brain but also in other organs. Such atherosclerotic plaques result in damage of the blood vessels partly caused by vascular
  • thrombocytes thrombosis
  • emboli emboli
  • Inflammation or "inflammatory condition” are used interchangeably. Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair. Inflammation may be systemic, or located at a specific organ, e.g. the brain. Various sub-types of inflammation exists, such as e.g.
  • Atherosclerosis also known as arteriosclerotic vascular disease or ASVD
  • ASVD arteriosclerotic vascular disease
  • Another subtype is vascular inflammation also called vasculitis.
  • interleukins are a group of cytokines (secreted proteins and signalling molecules) that were first seen to be expressed by white blood cells (leukocytes). Interleukins regulate immune responses and play a role in
  • IL IL2
  • IL5 IL12
  • IL10 anti-inflammatory
  • Neuronal cell death or “neuronal necrosis” involves premature death of neurons in the brain. Neuronal necrosis may also be termed “brain injury”. This may be a particular problem in connection with lack of blood supply in the brain, e.g. during ischemic stroke or vasoconstriction after subarachnoid hemorrhage.
  • ischemic stroke There are a number of reasons why an ischemic stroke may occur, including Thrombosis (obstruction of a blood vessel by a blood clot forming locally), Embolism (obstruction due to an embolus from elsewhere in the body), Systemic hypoperfusion (general decrease in blood supply, e.g., in shock), and ischemia after subarachnoid haemorrhage. Stroke without an obvious explanation is termed "cryptogenic" (of unknown origin). This form constitutes 30- 40% of all ischemic strokes.
  • cereral infarcts can be cause by vasospasms after an subarachnoid bleeding, a haemorrhagic stroke or an intracerebral bleeding, or due to hypo perfusion of the brain caused by e.g. low blood pressure, hypovolaemic shock or hypoglycaemia.
  • Neuronal necrosis is not to be confused with neurodegeneration, which is a slow degeneration of neurons, whereas neuronal necrosis is acute. Neuronal necrosis may be termed "acute neuronal necrosis".
  • neurodegeneration is a chronic process
  • neurodegenerative diseases are chronic disorders.
  • acute ischemic stroke there is acute neuronal loss due to hypoxia, but this is not
  • the present invention relates to the use of fumaric acid derivatives for treating or preventing systemic and brain tissue inflammation and neuronal necrosis. This is particular interesting in relation to stroke, hypoxia or vasoconstriction, where inflammation and necrosis in the brain, i.e. brain injury, is a particular problem, i.e. as a follow-on effect of the stroke itself.
  • MMF prodrugs having high gastrointestinal permeability and/or absorption, improved solubility, ordered hydrolysis (i.e., preferential cleavage of promoieties), and minimal cleavage in the gut lumen or enterocyte cytoplasm are desirable.
  • Such MMF prodrugs that provide higher oral
  • bioavailability and plasma levels of MMF, DMF, and/or other metabolites may enhance the efficacy /responder rate compared to present fumaric acid esters; facilitate the use of lower doses, reduced dosing frequency, and standardized dosing regimens; reduce food effects; reduce gastrointestinal side effects/toxicity; and reduce interpatient treatment variability.
  • pro-inflammatory changes in the atherosclerotic plaque are major pathways in atherosclerotic plaque formation and maintenance. Similar pro- inflammatorymechanisms characterize the infarct, which contribute to neuronal cell loss. Activation of anti-oxidant pathways may therefore be important mechanisms preceding and following acute stroke, partly by interfering with atherosclerotic plaque formation and maintenance or preventing neuronal cell death in the ischemic penumbra after stroke.
  • endothelial VCAM-1, ICAM-1, TNF-alpha and iNOS are tightly regulated by the activation of NF- ⁇ in endothelial cells.
  • Keapl/Nrf2 One of the major up-istream pathways is Keapl/Nrf2 through the regulation of expression of phase II genes encoding enzymes, major players in anti-oxidation. Keapl knockdown in endothelial cells prevents vascular inflammation, LPS-induced expression of adhesion molecules, NO and TNF-alpha production.
  • FIG 1 shows a proposed mechanism of action of methyl fumarate.
  • Reactive oxygen species ROS
  • NF- ⁇ which is a master regulator of ROS
  • NF-kB plays a major role in inflammation and cell death in the infarct tissue following stroke and also in vascular inflammation contributing to atherosclerotic plaque genesis and maintenance.
  • Methyl fumarate is proposed to act on Keapl/Nrf2, and facilitates the nuclear translocation of Nrf2, which increases the transcription of phase II enzyme genes.
  • Keapl/Nrf2 pathway may be powerful drugs to prevent stroke (atherosclerosis) or treat stroke.
  • fumaric acid derivatives of the present invention may be particularly useful in the treatment or alleviation of the effects of stroke, i.e. protection against neuronal necrosis and reduction of inflammation, both systemic and in the brain tissues.
  • one aspect of the present invention is fumaric acid derivatives for use in the prevention or treatment of a condition selected from the group consisting of neuronal necrosis and an inflammatory condition.
  • An alternative aspect of the present invention is fumaric acid derivatives for use in the prevention or treatment of a condition selected from the group consisting of brain injury and an inflammatory condition.
  • An alternative aspect of the present invention is fumaric acid derivatives for use in the prevention or treatment of brain injury in connection with stroke.
  • Another aspect of the present invention is fumaric acid derivatives for use in the primary and secondary prevention of stroke.
  • Fumaric acid derivatives appear to influence both neuronal necrosis and inflammation, and thus in a preferred embodiment the fumaric acid derivatives are for use in the prevention or treatment of neuronal necrosis and an
  • Stroke, hypoxia or vasoconstriction may lead to neuronal necrosis, i.e. brain injury, and inflammatory conditions, thus in a preferred embodiment the neuronal necrosis or an inflammatory condition as described above occurs in connection with a further condition selected from the group consisting of stroke, hypoxia or vasoconstriction, preferably stroke. In a preferred embodiment these conditions are in the brain, i.e. in brain tissue. Stroke may be due to an ischemic process, an intracerebral or subarachnoid bleeding, a central venous trombosis or due to hypoperfusion due to low blood pressure or hypovolemic shock or hypoglycaemia.
  • the stroke may in preferred embodiments be ischemic stroke or hemorrhagic stroke, preferably an ischemic stroke, such as acute ischemic stroke.
  • Vasoconstriction may particularly be vasoconstriction in connection with or after subarachnoid haemorrhage. Hypoxia may be in connection with syncope or hypoglycaemia or vascular inflammation (vasculitis).
  • the inflammatory condition may be a vascular inflammation and in another preferred embodiment the inflammatory condition is systemic. In another preferred embodiment the inflammatory condition may be in the brain tissue. In a preferred embodiment the inflammatory condition is atherosclerosis. Neuronal cell death and/or inflammatory conditions are associated with stroke and thus also with a number of treatments used in connection with stroke or other conditions that e.g. increases risk of stroke or are connected with necrosis and/or
  • the compounds of the present invention are particularly effective if administered realtively soon after a condition selected from the group consisting of stroke, hypoxia or vasoconstriction has occured.
  • a condition selected from the group consisting of stroke, hypoxia or vasoconstriction has occured.
  • the fumaric acid derivative is administered within 10 days from the occurrence of a condition selected from the group consisting of stroke, hypoxia or
  • vasoconstriction such as within 7 days, 5 days, 4 days, 3 days, 2 days, 24 h, 12 h, 6h, 5h, 4h, 3h, 2h, lh, such as within 30 minutes from the occurrence of a condition selected from the group consisting of stroke, hypoxia or vasoconstriction.
  • the fumaric acid derivative is administered in combination with a further medicament selected from the group consisting of thrombolytic agents, fibrinolytic agents, anti-thrombotic agents, anti-platelet aggregation agents, anticoagulants, anti-hypertensive agents, anti-diabetic agents, anti-dyslipidemia agents, cholesterol reducing agents, statins.
  • a further medicament selected from the group consisting of thrombolytic agents, fibrinolytic agents, anti-thrombotic agents, anti-platelet aggregation agents, anticoagulants, anti-hypertensive agents, anti-diabetic agents, anti-dyslipidemia agents, cholesterol reducing agents, statins.
  • the administration may be in combination with a pharmaceutically acceptable carrier.
  • the thrombolytic agents may preferably be selected from the group consisting of tissue plasminogen activators including alteplase, reteplase, and tenecteplase, anistreplase, streptokinase, and urokinase.
  • the anti-platelet aggregation agents may preferably be selected from the group consisting of Irreversible cyclooxygenase inhibitors including Aspirin and Triflusal, Adenosine diphosphate (ADP) receptor inhibitors including Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine, Phosphodiesterase inhibitors including Cilostazol, Protease- activated receptor- 1 (PAR-1) antagonists including Vorapaxar, Glycoprotein IIB/IIIA inhibitors including Abciximab, Eptifibatide, Tirofiban, Adenosine reuptake inhibitors including Dipyridamole, Thromboxane inhibitors, Thromboxane synthase inhibitors, Thromboxane receptor antagonists, including Terutroban, and acetylsalisilic acid, epoprostenol, ilopros, abciximab, eptifibatid and defibrotid.
  • the statins may preferably be selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bezafibrat, and gemfibrozil.
  • the anti-hypertensive agents may preferably be selected from the group consisting of Diuretics, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor antagonists, Adrenergic receptor antagonists, Vasodilators,
  • the anti-diabetic agents may preferably be selected from the group consisting of insulin derivatives, glyburide, glimepiride, glipizide, metformin, acarbose, miglitol, voglibose, Pioglitazone, and Rosiglitazone. Any combinations of the above drugs may also be used.
  • a stroke may also be treated via surgery, i.e. a thrombectomy, thus, in a preferred embodiment the fumaric acid derivatives according to the invention, is administered in connection with a thrombectomy.
  • Another aspect of the invention is a method of treating a condition selected from the group consisting of neuronal necrosis and an inflammatory condition by administering fumaric acid derivatives to a patient in need thereof.
  • Another aspect of the present invention is the use of fumaric acid derivatives for the manufacture of a medicament for use in the treatment of a condition selected from the group consisting of neuronal necrosis and an inflammatory condition.
  • Another aspect of the present invention is a method of regulating heat shock protein concentration levels in the brain by administering fumaric acid derivatives to a patient in need thereof.
  • the heat shock protein may HSP72.
  • Another aspect of the present invention is a method of regulating interleukin concentration levels in the serum and/or brain by administering fumaric acid derivatives to a patient in need thereof.
  • pro-inflammatory interleukins usch as IL-2, IL-5, IL-12, IL-6.
  • TNF-a, IL-17, IF-g are down-regulated while antiinflammatory interleukins, such IL-10, IL-4 are up-regulated.
  • the fumaric acid derivatives to be used according to the invention may be one or several selected from the group consisting of dialkyl fumarates (fumaric acid dialkyl esters), monoalkyl hydrogen fumarates (fumaric acid monoalkyl esters), monoalkyl ester fumaric acid salts (fumaric acid monoalkyl ester salts) of physiologically acceptable cations, in particular alkaline or alkaline earth metal cations or transition metal cations such as Li + , Na + , K + , NH4 + , Mg 2 + , Ca 2 + , Fe 2 + , Mn 2 + , and Zn 2 + , fumaric acid monoamides and fumaric acid diamides and their salts, carbocyclic and oxacarbocyclic oligomers of these compounds and mixtures thereof.
  • One aspect of the present invention relates to fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof for use in the treatment or prevention of stroke.
  • Another aspect relates to a pharmaceutical composition for treating or preventing stroke comprising fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • Yet another aspect relates to fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof for use in the treatment or prevention of vascular inflammation in atherosclerotic plaques.
  • One aspect relates to a pharmaceutical composition for treating or preventing vascular inflammation in atherosclerotic plaques comprising fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid
  • Another aspect relates to fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof for use in the treatment or prevention of atherosclerosis.
  • Still another aspect relates to a pharmaceutical composition for treating or preventing atherosclerosis comprising fumaric acid derivatives selected from the group consisting of dialkyi fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • fumaric acid derivatives selected from the group consisting of dialkyi fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • the fumaric acid derivatives according to the invention are preferably selected from the group consisting of dialkyi fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • the fumaric acid derivative is selected from the group consisting of optionally substituted fumaric acid dialkyi esters and fumaric acid monoalkyi esters in the form of the free acid or its salts and mixtures thereof. Particularly preferred in this case is the use of fumaric acid dialkyi esters of the Formula I
  • Ri, and R 2 which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated Ci-24 alkyl radical or a C5-20 aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci-4 alkoxy, O-4-alkyl, nitro or cyano.
  • Ri and/or R2 represent an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2-hydroxy propyl, 3-hydroxy propyl, 2,3- dihydroxypropyl, 2-methoxy ethyl, methoxy methyl, 2-methoxy propyl, 3- methoxy propyl and 2,3-dimethoxy propyl.
  • Ri and/or R2 represent an alkyl radical selected from the group consisting of methyl and ethyl.
  • aryl radical is to be understood as an optionally substituted aryl, alkyl substituted aryl or aralkyl group having 5 to 20 carbon atoms.
  • an aryl, alkyl substituted aryl or aralkyl group have 6 to 10 carbon atoms.
  • Ri and/or R2 represent an aryl radical selected from the group consisting of phenyl, benzyl, phenethyl, methyl phenyl, ethyl phenyl, propyl phenyl, butyl phenyl, t- butyl phenyl.
  • Ri and/or R2 represent an alkyl radical selected from the group consisting of phenyl and benzyl.
  • the substituents of said radicals are preferably selected from the group consisting of halogen (F, CI, Br, I), hydroxy, Ci-4 alkoxy, Ci-4 alkyl, nitro and cyano.
  • the fumaric acid derivative is selected from one or more fumaric acid monoalkyl esters of the formula II
  • Ri represents a linear, branched or cyclic, saturated or unsaturated Ci-24 alkyl radical or a C5-20 aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci-4 alkoxy, Ci-4-alkyl, nitro or cyano;
  • A represents hydrogen, an alkaline or alkaline earth metal cat ion or a physiologically acceptable transition metal cat ion, and wherein n equals 1 or 2.
  • n represents hydrogen, an alkaline or alkaline earth metal cat ion or a physiologically acceptable transition metal cat ion, and wherein n equals 1 or 2.
  • the fumaric acid derivative is selected from the group consisting of fumaric acid dimethyl ester, fumaric acid diethyl ester, fumaric acid methyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate, calcium methyl fumarate, calcium ethyl fumarate, magnesium methyl fumarate, magnesium ethyl fumarate, zinc methyl fumarate, zinc ethyl fumarate, iron methyl fumarate, and iron ethyl fumarate. They can be used individually or as mixtures. Because of their volatility and sublimability, fumaric acid esters may have the disadvantage of being difficult to handle when preparing pharmaceutical products, especially those in solid form for oral administration.
  • the fumaric acid derivative is selected from one
  • R a represents OR3 or a D- or L-amino acid radical -NH-CHR 4 -COOH bonded via an amide bond
  • R3 is hydrogen, linear, branched or cyclic, saturated or unsaturated Ci-2 4 alkyl radical or a Cs zo aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci- 4 alkoxy, Ci- 4-alkyl, nitro or cyano
  • R 4 is a side chain of a natural or synthetic amino acid
  • Rb represents a D- or L-amino acid radical -NH-CHR5-COOH bonded via an amide bond
  • R5 is a side chain of a natural or synthetic amino acid which may be the same as or different from R 4 , or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different.
  • the side chain of a natural or synthetic amino acid is selected from the group consisting of the side chains of Ala, Val, Leu, He, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrulline, Hey, Hse, Hyp, Hyl, Orn, Sar, and Me-Gly.
  • the side chain of a natural or synthetic amino acid is selected from the group consisting of the side chains of Gly, Ala, Val, He, Leu, and Me-Gly.
  • R a is the radical -OR3 and Rb is an L-amino acid radical -NH- CHR5-COOH or a peptide radical, R5 being a side chain of a natural or synthetic amino acid, which may be the same as or different from R 4 , or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different.
  • the fumaric acid derivative is a monoalkyl monoamido fumarate.
  • the fumaric acid derivatives are selected from the group consisting of dimethylfumarate and monomethylfumarate.
  • the fumaric acid amides as defined above can be used individually or in admixture or also in mixture with the fumaric acid monoalkyl or dialkyl esters defined above.
  • the fumaric acid derivative is a carbocyclic oligomer consisting of 2 to 10 fumaric acid moieties as repetitive moieties, wherein the fumaric acid moieties are derived from monomers selected from the group consisting of fumaric acid, dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid monoamides, fumaric acid diamides, monoalkyl monoamido fumarates and salts and mixtures thereof.
  • fumaric acid oligomers are preferably obtained by means of the (olefinic) polymerization of the C-C double bonds (for the carbocyclic oligomers) and/or the C-C double bonds and the carbonyl oxygens of the units (for the oxacarbocyclic oligomers).
  • the units derived from the fumaric acid are derived from monomers selected from the group consisting of fumaric acid and the dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid monoamides, fumaric acid diamides, monoalkyl monoamido fumarates and their salts and mixtures thereof, which are defined above.
  • the oligomer only contains units derived from one or two monomers. Most preferably, the oligomer exclusively contains identical monomer units.
  • the carbocyclic oligomers are composed of the units derived from the fumaric acid in such a way that the units are bonded to the carbon atoms 2 and 3 of the fumaric acid backbone by means of covalent C-C bonds in such a way that a carbocyclic oligomer is formed.
  • the oligomer backbone comprises an even number of carbon atoms and does not contain any other monomers and/or heteroatoms. This backbone is substituted at each carbon atom with one of the carboxylic acid and/or carboxylic acid amide groups of the fumaric acid monomer unit(s), from which it is built up.
  • the oxacarboxylic oligomers are composed of the fumaric acid monomers in such a way that the units are bonded to each other at the carbon atoms 1 and 3 via ether bridges. At the same time, the ethylenic unsaturation of the atoms C2 and C3 is shifted to CI and C2. Thus, the ring contains polyoxypropene units in the case of the oxacarboxyclic oligomers according to the invention.
  • the term "oligomer" refers to a number of at least two fumaric acid monomer units.
  • the carboxyclic fumaric acid oligomer contains 2 to 10, preferably 2 to 6 and most preferably 2 to 3 units derived from fumaric acid.
  • the carboxylic acid and/or carboxylic acid amide groups as substituents of the cycle are all in a transposition to each other.
  • radicals R c and Rd are the same or different and are selected among amine radicals (-NR1R2), amino acid radicals-NH-C(COOH)-R5, peptide radicals having 2 to 100 amino acids, alkoxy radicals (-ORi) and a hydroxyl radical, Ri, R 2 and Rs being as defined above and n being an integer from 2 to 10 inclusive, preferably 2 to 6 inclusive.
  • the radicals R c and Rd each are independently an alkoxyl or hydroxyl radical, R c and Rd not meaning hydroxyl at the same time with the greatest preference.
  • the monomer(s) is(are) preferably one or several monoalkyl hydrogen fumarate(s).
  • both radicals R c and Rd may represent an alkoxy radical - ORI which, still more preferred, is identical.
  • the monomer(s) is(are) dialkyl fumarates.
  • the r- l,t-2,c-3,t-4-tetrakis (methoxy carbonyl) cyclobutane or the r- l,t-2,c-3,t-4,c-5,t-6-hexa(alkoxy carbonyl) cyclohexane preferably the r- l,t-2,c-3,t-4-tetrakis (methoxy carbonyl) cyclobutane and/or the r- l,t-2,c-3,t-4,c-5,t-6-hexa(methoxy carbonyl) cyclohexane is used according to this embodiment.
  • Ri and R 2 are as defined above and n is an integer from 2 to 10 inclusive, more preferably 2 to 6 inclusive.
  • the alkyl radicals having 1 to 24 carbon atoms are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2- or 3- hydroxy propyl, 2,3- di hydroxy propyl, 2-methoxy ethyl, methoxy methyl, 2-methoxy propyl, 3- methoxy propyl or 2,3-dimethoxy propyl.
  • the fumaric acid derivatives to be used according to the invention can be prepared according to known processes as they are e.g. described in EP0980242, US2004038889 or US2005148664. The content of these publications is
  • compositions and dosages of the invention are provided.
  • an interesting aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a fumaric acid derivative, a medicament selected from the group consisting of thrombolytic agents, fibrinolytic agents, anti-thrombotic agents, anti-platelet aggregation agents, anticoagulants, anti-hypertensive agents, anti-diabetic agents, anti-dyslipidemia agents, cholesterol reducing agents, statins, and a pharmaceutically acceptable carrier.
  • composition comprising a fumaric acid derivative, a medicament for use in the prevention or treatment of stroke, hypoxia or vasoconstriction and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions as provided above may particularly for use in the treatment of stroke, such as acute stroke, and/or primary and secondary prevention for stroke.
  • the pharmaceutical compositions as provided above may particularly for use in the treatment of vasoconstriction.
  • the pharmaceutical compositions as provided above may particularly be for use in the treatment of hypoxia.
  • hypoxia may caused by a number of conditions such as syncope, hypoglycaemia and vasculitis.
  • the thrombolytic agents may preferably be selected from the group consisting of tissue plasminogen activators including alteplase, reteplase, and tenecteplase, anistreplase, streptokinase, and urokinase.
  • the anti-platelet aggregation agents may preferably be selected from the group consisting of Irreversible cyclooxygenase inhibitors including Aspirin and Triflusal, Adenosine diphosphate (ADP) receptor inhibitors including Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine, Phosphodiesterase inhibitors including Cilostazol, Protease- activated receptor- 1 (PAR-1) antagonists including Vorapaxar, Glycoprotein IIB/IIIA inhibitors including Abciximab, Eptifibatide, Tirofiban, Adenosine reuptake inhibitors including Dipyridamole, Thromboxane inhibitors, Thromboxane synthase inhibitors, Thromboxane receptor antagonists, including Terutroban, and acetylsalisilic acid, epoprostenol, ilopros, abciximab, eptifibatid and defibrotid.
  • the statins may preferably be selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bezafibrat, and gemfibrozil.
  • the anti-hypertensive agents may preferably be selected from the group consisting of Diuretics, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor antagonists, Adrenergic receptor antagonists, Vasodilators,
  • Anti-hypertensive agents may preferably be selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, epitizide,
  • hydrochlorothiazide chlorothiazide, bendroflumethiazide, indapamide,
  • the anti-diabetic agents may preferably be selected from the group consisting of insulin derivatives, glyburide, glimepiride, glipizide, metformin, acarbose, miglitol, voglibose, Pioglitazone, and Rosiglitazone.
  • the pharmaceutical preparation may be present in a form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary, intracisternal or parenteral application.
  • the pharmaceutical preparation is suited for oral administration.
  • the drug is present in the form of nano-particles, pellets or micro-tablets, which may optionally be filled in sachets or capsules.
  • all solid oral dosage forms may be provided with an enteric coating. It may e. g. be applied onto the tablets, micro-tablets, pellets, etc., but may also be applied onto the capsules that contain them.
  • the oral pharmaceutical forms according to the invention may basically be prepared according to the classic compaction method and also by direct compaction and as solid dispersions according to the melting method or by means of the spray drying method.
  • an enteric coating can be poured or sprayed in portions onto the tablet cores in a classic coating pan or applied by means of a fluidized-bed apparatus according to known processes. Subsequently, after drying has been completed, a film coat can be applied in the same apparatus.
  • the fumaric acid derivatives for preparing the pharmaceutical preparations according to the invention are used in such an amount that this pharmaceutical preparation contains an amount of one or more fumaric acid derivative (s) per dosage unit which corresponds and/or is equivalent to an amount of 1 to 500 mg, preferably 10 to 300 mg, and mostly preferred 10 to 200 mg fumaric acid.
  • the preparation is present in a form suitable for this.
  • All customary liquid carriers suitable for the injection can be used.
  • the drug to be produced according to the invention can contain the following individually or in admixture: 10 to 500 mg dialkyl fumarate, in particular dimethyl fumarate and/or diethyl fumarate, 10 to 500 mg calcium alkyl fumarate, in particular calcium methyl fumarate and/or calcium ethyl fumarate, 0 to 250 mg zinc alkyl fumarate, in particular zinc methyl fumarate and/or zinc ethyl fumarate, 0 to 250 mg alkyl hydrogen fumarate, in particular methyl hydrogen fumarate and/or ethyl hydrogen fumarate and 0 to 250 mg magnesium alkyl fumarate, in particular magnesium methyl fumarate and/or magnesium ethyl fumarate, the sum of said amounts corresponding to an equivalent of 1 to 500 mg, preferably 10 to 300 mg and most preferred 10 to 200 mg fumaric acid.
  • Preparations according to the invention that are used with special preference contain exclusively dimethyl fumarate in an amount of 10 to 300 mg.
  • the pharmaceutical preparation is present in the form of micro-tablets or pellets. They have preferably a size and/or a mean diameter of ⁇ 5000 micrometers, preferably 300 to 2500 micrometers, in particular 300 to 1000 micrometers for pellets and 1000 to 2500 micrometers for micro-tablets. Due to the administration of the fumaric acid derivatives in the form of micro-tablets, which is preferred according to the invention, gastrointestinal irritations and/or side effects which cannot be excluded in the administration of conventional single unit dose tablets can be further reduced.
  • micro-tablets preferably enteric coated micro-tablets
  • the micro-tablets already are distributed in the stomach and thus get into the intestine bolus-wise, where the active substances are released in locally smaller doses with the entire dosage being the same. Due to this, the local irritation of the epithelial cells of the intestine can be avoided, the better gastrointestinal tolerance of the micro-tablets as compared with conventional tablets resulting from this.
  • the fumaric acid derivative is provided in a form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary or parenteral application. In another embodiment, the fumaric acid derivative is provided in a
  • compositions in the form of tablets, coated tablets, capsules, granulate, solutions for drinking, liposomes, nano-particles, nano-capsules, microcapsules, micro-tablets, pellets or powders and in the form of granules filled in capsules or sachets, micro-tablets filled in capsules or sachets, pellets filled in capsules or sachets, nano-particles filled in capsules or sachets or powder filled in capsules or sachets.
  • the fumaric acid derivative is present in the form of nano-particles, pellets or micro-tablets which may optionally be filled in sachets or capsules.
  • the solid oral dosage forms are provided with an enteric coating.
  • Item 1 Method of treating or preventing stroke by administering fumaric acid derivatives selected from the group consisting of dialkyi fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid
  • Method of treating or preventing vascular inflammation in atherosclerotic plaques by administering fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • fumaric acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • Item 3 Method of treating or preventing atherosclerosis by administering fumari acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • fumari acid derivatives selected from the group consisting of dialkyl fumarates, monoalkyi hydrogen fumarates, fumaric acid monoalkyi ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.
  • Ri, and R 2 which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated Ci-24 alkyl radical or a C5-20 aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci- 4 alkoxy, Ci- 4 -alkyl, nitro or cyano. Item 5.
  • the fumaric acid derivative is selected from one or more fumaric acid monoalkyi esters of the formula II n (Formula II) wherein Ri represents a linear, branched or cyclic, saturated or unsaturated Ci- 24 alkyl radical or a Cs zo aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci- 4 alkoxy, Ci- 4 -alkyl, nitro or cyano;
  • A represents hydrogen, an alkaline or alkaline earth metal cat ion or a physiologically acceptable transition metal cat ion, and wherein n equals 1 or 2.
  • Item 7 The use according to item 6, wherein the fumaric acid derivative is selected from the group consisting of fumaric acid dimethyl ester, fumaric acid diethyl ester, fumaric acid methyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate, calcium methyl fumarate, calcium ethyl fumarate, magnesium methyl fumarate, magnesium ethyl fumarate, zinc methyl fumarate, zinc ethyl fumarate, iron methyl fumarate, iron ethyl fumarate and mixtures thereof.
  • the fumaric acid derivative is selected from one or more fumaric acid amides of the general formula III
  • R a represents OR3 or a D- or L-amino acid radical -NH-CHR 4 -COOH bonded via an amide bond
  • R3 is hydrogen, linear, branched or cyclic, saturated or unsaturated Ci-2 4 alkyl radical or a Cs-2o aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci- 4 alkoxy, Ci-4- alkyl, nitro or cyano
  • R 4 is a side chain of a natural or synthetic amino acid
  • Rb represents a D- or L-amino acid radical -NH-CHR5-COOH bonded via an amide bond
  • R5 is a side chain of a natural or synthetic amino acid which may be the same as or different from R 4 , or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different.
  • Item 9 The use according to item 8, wherein the side chain of a natural or synthetic amino acid is selected from the group consisting of the side chains of Ala, Val, Leu, He, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrulline, Hey,Hse, Hyp, Hyl, Orn, Sar, and Me-Gly, preferably Gly, Ala, Val, He, Leu, and Me-Gly.
  • Item 10 The use according to item 8, wherein R a is the radical -OR3 and Rb is an L-amino acid radical -NH-CHR5-COOH or a peptide radical, R5 being as defined in item 8.
  • Item 11 The use according to any one of the items 1-3, wherein the fumaric acid derivative is a carbocyclic oligomer consisting of 2 to 10 fumaric acid moieties as repetitive moieties, wherein the fumaric acid moieties are derived from monomers selected from the group consisting of fumaric acid, dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid monoamides, fumaric acid diamides, monoalkyl monoamido fumarates and salts and mixtures thereof.
  • alkyl radicals having 1 to 24 carbon atoms are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2- or 3- hydroxy propyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxy methyl, 2-methoxy propyl, 3-methoxy propyl or 2,3-dimethoxy propyl.
  • Item 13 The use according to any of the previous items, wherein the fumaric acid derivative is provided in a form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary or parenteral application.
  • Item 14 The use according to item 13, wherein the fumaric acid derivative is provided in a pharmaceutical composition in the form of tablets, coated tablets, capsules, granulate, solutions for drinking, liposomes, nano-particles, nano- capsules, micro-capsules, micro-tablets, pellets or powders and in the form of granules filled in capsules or sachets, micro-tablets filled in capsules or sachets, pellets filled in capsules or sachets, nano-particles filled in capsules or sachets or powder filled in capsules or sachets.
  • Item 15 The use according to item 14, wherein the fumaric acid derivative is present in the form of nano-particles, pellets or micro-tablets which may optionally be filled in sachets or capsules
  • Item 16 The use according to any of the items 14 to 15, wherein the solid oral dosage forms are provided with an enteric coating. It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.
  • Example 1 preparation of preferred pharmaceutical preparations are given below. The examples are for illustrations purposes only, but not to restrict the invention. Example 1
  • the active ingredient is added to the entire powder mixture, mixed, homogenized by means of a sieve 200 and processed with a 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon® 25) in the usual manner into binder granules, and then mixed with the outer phase in a dry state.
  • PVP polyvinyl pyrrolidone
  • the latter consists of 2 kg of a so- called FST complex containing 80% of talcum, 10% of silicic acid and 10% of magnesium stearate.
  • dispersions according to the melting method and the spray drying method may also be used for preparing tablets.
  • HPMCP hydroxy propyl methyl cellulose phthalate
  • a solvent mixture consisting of 2.50 litres of demineralised water, 13 I of acetone Ph. Helv. VII and 13 I of ethanol (94% by weight) and then 0.240 kg of castor oil (Ph. Eur. II) is added to the solution.
  • the solution is poured or sprayed in portions onto the tablet cores in a coating pan in a conventional manner.
  • the film coating is subsequently applied.
  • Said coating consists of a solution of Eudragit® E 12.5% 4.8 kg, talcum Ph. Eur. II 0.34 kg, titanium (VI) oxide Cronus RN 56® 0.52 kg, coloured lacquer ZLT-2 blue (Siegle) 0.21 kg, and polyethylene glycol 6000 Ph. Helv. VII 0.12 kg in a solvent mixture of 8.2 kg of 2-propanol Ph. Helv. VII, 0.06 kg of glycerine triacetate (Triacetin®), and 0.2 kg of demineralised water. Homogenous distribution in the coating pan or the fluidized bed is followed by drying and polishing in the usual manner.
  • the entire powder mixture is processed in the usual manner into a binder granulate and mixed with the outer phase in the dried state.
  • Said outer phase consists of 0.35 kg of colloidal silicic acid (Aerosil®), 0.5 kg of magnesium stearate and 1.5 kg of talcum Ph. Helv. VII.
  • the homogeneous mixture is then filled in portions of 500.0 mg into appropriate capsules which are then provided with an enteric (gastric-acid resistant) coating consisting of hydroxy propyl ethyl cellulose phthalate and castor oil as softening agent in a customary fashion.
  • the entire powder mixture is added to the active ingredient mixture, homogenized by means of a 200 sieve, and processed in the usual manner with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K25) to obtain a binder granulate and mixed in a dry state with the outer phase that consists of 0.5 kg of magnesium stearate and 1.5 kg of talcum. Then the powder mixture is pressed by the conventional method into convex micro-tablets with a gross mass of 10.0 mg and a diameter of 2.0 mm.
  • Kollidon® K25 polyvinyl pyrrolidone
  • the enteric (gastric acid-resistant) coating is applied in a fluidized-bed apparatus.
  • portions of a solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50) are dissolved in a mixture of the following solvents: acetone 13 I, ethanol 94% by weight denatured with 2% ketone 13.5 I and demineralized water 2.5 I.
  • 0.240 kg of castor oil are added as softening agent to the finished solution and applied in portions onto the tablet cores in the usual manner.
  • Film coat After drying is completed, a suspension of the following composition is then applied as a film coat in the same apparatus: talcum 0.340 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, coloured lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition : 2-propanol 8.17 kg, demineralised water 0.2 kg and glycerine triacetate (Triacetin®) 0.6 kg.
  • talcum 0.340 kg titanium (VI) oxide Cronus RN 56 0.4 kg, coloured lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition : 2-propanol 8.17 kg, demineralised water 0.2 kg and glycerine triacetate (Triacetin®) 0.6 kg.
  • the gastric acid-resistant micro-tablets are analyzed with respect to their ingredients and are then filled into hard gelatine capsules at, a corresponding net weight and sealed.
  • enteric micro-tablets in capsules containing 120.0 mg dimethyl fumarate, which corresponds to 96 mg fumaric acid. Taking the necessary precautions (breathing mask, gloves, protective clothing, etc.) 12 kg of dimethyl fumarate are crushed and homogenized by means of an 800 sieve.
  • An excipient mixture of the following composition is prepared : 17.5 kg of starch derivative (STA-RX ® 1500), 0.30 kg of micro-crystalline cellulose (Avicel® PH 101), 0.75 kg of PVP (Kollidon® 120), 4 kg of Primogel®, 0.25 kg of colloidal silicic acid (Aerosil®).
  • the entire powder mixture is added to the active ingredient mixture, mixed, homogenized by means of a 200 sieve, processed in the usual manner with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K25) to obtain a binder granulate and mixed in a dry state with the outer phase which consists of 0.5 kg of Mg stearate and 1.5 kg of talcum.
  • Kollidon® K25 polyvinyl pyrrolidone
  • the powder mixture is pressed by the conventional method into convex micro-tablets with a gross mass of 10.0 mg and a diameter of 2.0 mm.
  • HPMCP hydroxy propyl methyl cellulose phthalate
  • Phannacoat® HP 50 hydroxy propyl methyl cellulose phthalate
  • acetone 13 I a mixture of the following solvents: acetone 13 I, ethanol (94% by weight denatured with 2% ketone) 13.5 I and demineralised water 1.5 I.
  • Castor oil (0.24 kg) is added as softening agent to the finished solution and applied in portions onto the tablet cores in the usual manner.
  • a suspension of the following composition is then applied as a film coat in the same apparatus: talcum 0.34 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, coloured lacquer L red lacquer 86837: 0.324 kg, Eudragit E 12.5% 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition : 2-propanol 8.17 kg, demineralized water 0.2 kg and glycerine triacetate (Triacetin®) 0.6 kg.
  • the gastric acid-resistant micro-tablets are analyzed with respect to their ingredients and are then filled into hard gelatine capsules at a corresponding net weight and sealed.
  • enteric micro-tablets in capsules containing 120.0 mg of diglycine fumaric acid diamide which corresponds to 96 mg of fumaric acid.
  • 12 kg of diglycine fumaric acid diamide are crushed and homogenized as indicated above.
  • An excipient mixture of the following composition is prepared : 23.2 kg of micro- crystalline cellulose (Avicel® PH 200), 3 kg of croscarmelose sodium (AC- Di-SOL-SD-711), 2.5 kg of talcum, 0.1 kg of anhydrous silicic acid (Aerosil® 200) and 1kg Mg stearate.
  • the entire powder mixture is added to the active ingredient mixture and homogeneously mixed.
  • the powder mixture is pressed by the direct compaction into convex micro-tablets with a gross mass of 10.0 mg and a diameter of 2.0 mm.
  • a solution of 0.94 kg Eudragit® in isopropanol is prepared which, additionally, contains 0.07 kg dibutyl phthalate. This solution is sprayed onto the tablet cores. Then, a dispersion of 17.32 kg Eudragit® L D-55 and a mixture of 2.8 kg micro-talcum, 2 kg Macrogol 6000 and 0.07 kg Dimeticon in water is prepared and sprayed onto the cores. Subsequently, the enteric micro-tablets are analyzed with respect to their ingredients and filled into hard gelatine capsules at a corresponding net weight and sealed.
  • enteric micro-tablets in capsules containing 60.0 mg of r-1, t-2, c- 3, t-4-tetrakis (methoxy carbonyl) cyclobutane and 30.0 mg r-1, t-2, c-3, t-4, c-5, t-6-hexa (methoxy carbonyl) cyclohexane.
  • the active ingredient is added to the entire powder mixture and homogenized by means of a sieve 200 and processed with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K25) in the usual manner into binder granules, and then mixed with the outer phase in a dry state.
  • the latter consists of 0.50 kg of Mg stearate and 1.50 kg of talcum.
  • the powder mixture is pressed into convex micro- tablets with a gross mass of 10.0 mg and a diameter of 2.0 mm by the usual method.
  • the enteric (gastric acid-resistant) coating is poured onto the tablet cores in a classic coating pan.
  • Pharmacoat HP 50 are dissolved in a mixture of the following solvents: acetone 13.00 I, ethanol 94% by weight denatured with 2% ketone 13.50 I and
  • demineralised water 2.50 I. 0.240 kg of castor oil is added as softening agent to the finished solution and applied in portions to the tablet cores in the usual manner.
  • Film coat After drying is completed, a suspension of the following composition is applied as a film coat in the same apparatus: talcum 0.340 kg, titanium(VI) oxide Cronus RN 56 0.400 kg, coloured lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.800 kg and polyethylene glycol 6000 pH 11 XI 0.120 kg in a solvent mixture of the following composition : 2-propanol 8.170 kg, demineralised water 0.200 kg and glycerine triacetate (Triacetin®) 0.600 kg.
  • Triacetin® Triacetin®
  • enteric micro-tablets are analyzed with respect to their active ingredients and filled into hard gelatine capsules at a corresponding net weight and sealed.
  • the aforementioned ingredients are processed to a parenteral suspension using standard techniques.
  • mice were injected i.v. with either saline (containing 0.8% dimethyl sulfoxide (DMSO) or MMF (dissolved in 0.9% saline containing 0.8% DMSO).
  • saline containing 0.8% dimethyl sulfoxide (DMSO)
  • MMF dissolved in 0.9% saline containing 0.8% DMSO.
  • mice with 6 hours survival were treated with 10 mg/kg MMF, whereas control mice and mice with 48 hours survival were treated with 20 mg/kg MMF.
  • Physiological parameters were measured and behavioural tests (grip strength, rung walk) were done 48 hours after stroke.
  • Blood, brain and spleen were collected 6 and 48 hours after stroke, and were analysed for the infarct size by toluidine blue staining; for the expression of HSP-72, Keapl by real-time RT-PCR; for the expression of pERK, pJNK, pp38, HSP72, and Nrf2 by Western blot; and for the concentration of pro- and anti- inflammatory cytokines by using Mesocale.
  • Real-time PCR and western blotting were analysed with one-way ANOVA followed by Tukey's test for multiple comparisons. For single comparisons, Student's t test was applied. P values equal to or less than 0.05 were considered statistically significant.
  • mice An initial experiment involved the inducing ischemic stroke in mice and treating intravenously with monomethyl fumarate (MMF), the active metabolite of dimethyl fumarates (DMF).
  • MMF monomethyl fumarate
  • DMF dimethyl fumarates
  • mice Male C57Black/6 (C57BL/6) mice (7-8 weeks old) were purchased from Taconic and allowed to acclimatize for 1 week prior to surgery. Mice were anesthetized by subcutaneous injection of a 1: 1 : 2 mixture of Hypnorm (fentanyl citrate 0.315 mg/mL and fluanisone 10 mg/mL, Jansen-Cilag), Stesolid (5 mg/mL Diazepamum, Dumex), and distilled H20 (0.18 mL/10 g). Mice were placed on a heating pad (37°C ⁇ 0.5°C) and a skin incision between the lateral part of the orbit and the external auditory meatus was made.
  • Hypnorm fuseditopril citrate 0.315 mg/mL and fluanisone 10 mg/mL, Jansen-Cilag
  • Stesolid 5 mg/mL Diazepamum, Dumex
  • distilled H20 distilled H20 (0.18 mL/10 g).
  • the superior pole of the parotid gland and the upper part of the temporal muscle were pushed aside after partial resection.
  • a burr-hole was drilled directly over the distal part of the middle cerebral artery (MCA), the dura mater was removed, and the MCA was coagulated by applying bipolar forceps coupled to an electrosurgical unit.
  • the incisions were closed and the mice were supplied with 1 mL of physiologic 0.9% saline to prevent
  • mice were returned to their cages and were allowed to recover from anesthesia in a 28°C controlled environment.
  • mice were treated with
  • Temgesic (0.001 mg/20 g buprenorphinum; Reckitt & Colman).
  • MMF Mono-methyl fumarate
  • DMSO dimethyl sulfoxide
  • Brain tissue processing
  • mice were decapitated after cervical dislocation 6 hours after permanent occlusion of the MCA, and the brains and livers were removed and rapidly frozen in C02- snow. Brains were cut into serial 30- ⁇ cryostat sections, mounted on gelatin- treated glass slides (1 series) or placed in eppendorf tubes (2 1/2 series), and stored at -80°C until further tissue processing. Every sixth section was stained with toluidine blue for determination of infarct volume using the Computer Assisted Stereological Test Grid System (Olympus, Denmark) and the Cavalieri principle for volume estimation.
  • mice 3 out of 9 mice were lost in the saline group after surgery. Since this is very rarely seen and none of the drug-treated mice died, this indicated a positive effect of the drug.
  • HSP72 heat shock protein
  • MMF monomethyl fumarate
  • MMF treatment induced elevation of anti-inflammatory IL-10 in the sera in contrast to untreated controls.
  • the concentration of proinflammatory IL-12 was reduced in the brain after 48 hours in contrast to untreated controls.
  • the concentration of pro-inflammatory IL-5 and IL-2 was reduced in the sera after 6 and 48 hours, respectively, in contrast to untreated animals. (*P ⁇ 0.05, **P ⁇ 0.01 in Figure 4).
  • MMF treatment reduced pro-inflammatory interleukin 12 (IL-12)
  • the treatment had an effect on early systemic inflammatory responses: the level of anti-inflammtory IL-10 is increased in the serum (Figure 91 - serum).
  • Proinflammatory IL-6 Figure 8F - serum
  • TNF-alpha Figure 8G -serum
  • cytokines also have a neuroprotective effect.
  • the grip strength meter (BIO-GT-3, BIOSEB, Vitrolles, France) was used to study neuromuscular function in mice subjected to pMCAO and sham surgery. The peak amount of force was recorded in five sequential trials and the highest grip value was recorded as the score.
  • Keapl and Nrf2 mRNA expression, along with Nrf2 protein levels were measured as provided under material and methods.
  • MMF treatment in the acute phase of experimental stroke may influence both neuronal survival resulting in protection against functional deficit, and also inflammatory responses in both the brain and the systemic

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Abstract

L'invention concerne des dérivés d'acide fumarique qui sont utilisés dans la protection contre la nécrose neuronale et l'inflammation, en particulier dans le cerveau. L'invention permet en particulier de protéger contre de tels états pendant ou en liaison avec un accident vasculaire cérébral, l'hypoxie ou une vasoconstriction. Ainsi, selon un aspect, l'invention concerne les dérivés d'acide fumarique utilisés pour prévenir ou traiter une affection choisie dans le groupe constitué par la nécrose neuronale et un état inflammatoire. Selon autre aspect, l'invention concerne une composition pharmaceutique comprenant un dérivé d'acide fumarique, un médicament choisi dans le groupe constitué par des agents thrombolytiques, des agents fibrinolytiques, des agents anti-thrombotiques, des agents anti-agrégation plaquettaire, des anticoagulants, des agents anti-hypertenseurs, des agents anti-diabétiques, des agents anti-dyslipidémie, des agents réduisant le cholestérol, des statines et un support pharmaceutiquement acceptable.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016153957A3 (fr) * 2015-03-20 2016-11-10 Biogen Ma Inc. Procédés et compositions pour l'administration intraveineuse de fumarates pour le traitement de maladies neurologiques
CN111617255A (zh) * 2019-02-28 2020-09-04 北京强新生物科技有限公司 用于治疗中枢神经系统紊乱的组合疗法
US11484530B2 (en) 2011-12-19 2022-11-01 Bjoern Colin Kahrs Pharmaceutical compositions comprising the PPAR agonist INT-131 and Nrf2 activators
US12083107B2 (en) 2011-12-19 2024-09-10 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0980242A2 (fr) 1997-05-20 2000-02-23 Fumapharm AG Utilisation de derives d'acide fumarique
US20040038889A1 (en) 2001-01-12 2004-02-26 Joshi Rajendra Kumar Fumaric acid amides
US20050001486A1 (en) 2001-08-09 2005-01-06 Astropower, Inc. Power and/or energy monitor, method of using, and display device
WO2005023241A1 (fr) * 2003-09-09 2005-03-17 Fumapharm Ag Utilisation de derives d'acide fumarique pour traiter l'insuffisance cardiaque et l'asthme
US20050148664A1 (en) 2002-04-18 2005-07-07 Joshi Rajendra K. Carbocyclic and oxacarbocyclic fumaric acid oligomers
US20080233185A1 (en) * 2001-01-12 2008-09-25 Fumapharm Ag Fumaric Acid Derivatives as NF-kappaB Inhibitor
US20130158077A1 (en) * 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
US20140275048A1 (en) * 2013-03-14 2014-09-18 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0980242A2 (fr) 1997-05-20 2000-02-23 Fumapharm AG Utilisation de derives d'acide fumarique
US20040038889A1 (en) 2001-01-12 2004-02-26 Joshi Rajendra Kumar Fumaric acid amides
US20080233185A1 (en) * 2001-01-12 2008-09-25 Fumapharm Ag Fumaric Acid Derivatives as NF-kappaB Inhibitor
US20050001486A1 (en) 2001-08-09 2005-01-06 Astropower, Inc. Power and/or energy monitor, method of using, and display device
US20050148664A1 (en) 2002-04-18 2005-07-07 Joshi Rajendra K. Carbocyclic and oxacarbocyclic fumaric acid oligomers
WO2005023241A1 (fr) * 2003-09-09 2005-03-17 Fumapharm Ag Utilisation de derives d'acide fumarique pour traiter l'insuffisance cardiaque et l'asthme
US20130158077A1 (en) * 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
US20140275048A1 (en) * 2013-03-14 2014-09-18 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ALFIERI ALESSIO ET AL: "Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke", JOURNAL OF PHYSIOLOGY (OXFORD), vol. 589, no. 17, September 2011 (2011-09-01), pages 4125 - 4136, XP002753603 *
CLAUSEN BETTINA H ET AL: "Effect of monomethyl-fumarate on experimental stroke", JOURNAL OF NEUROIMMUNOLOGY, vol. 275, no. 1, 15 October 2014 (2014-10-15), pages 221, XP029083513, ISSN: 0165-5728, DOI: 10.1016/J.JNEUROIM.2014.08.594 *
HOUMAN ASHRAFIAN ET AL: "Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway", CELL METABOLISM, CELL PRESS, UNITED STATES, vol. 15, no. 3, 18 January 2012 (2012-01-18), pages 361 - 371, XP028466139, ISSN: 1550-4131, [retrieved on 20120206], DOI: 10.1016/J.CMET.2012.01.017 *
LINKER RALF A ET AL: "Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.", BRAIN : A JOURNAL OF NEUROLOGY MAR 2011, vol. 134, no. Pt 3, March 2011 (2011-03-01), pages 678 - 692, XP002753604, ISSN: 1460-2156 *
SCANNEVIN ROBERT H ET AL: "Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway.", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS APR 2012, vol. 341, no. 1, April 2012 (2012-04-01), pages 274 - 284, XP002753605, ISSN: 1521-0103 *
SCHILLING S ET AL: "Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, WILEY-BLACKWELL PUBLISHING LTD, GB, vol. 145, no. 1, 1 July 2006 (2006-07-01), pages 101 - 107, XP009105979, ISSN: 0009-9104, DOI: 10.1111/J.1365-2249.2006.03094.X *
SHIH A Y ET AL: "A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylais against cerebral ischemia in vivo", JOURNAL OF NEUROSCIENCE, SOCIETY FOR NEUROSCIENCE, US, vol. 25, no. 44, 2 November 2005 (2005-11-02), pages 10321 - 10335, XP002553422, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.4014-05.2005 *
WILMS HENRIK ET AL: "Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1Î, TNF-Î+- and IL-6 in an in-vitro model of brain inflammation", JOURNAL OF NEUROINFLAMMATION, BIOMED CENTRAL LTD., LONDON, GB, vol. 7, no. 1, 19 May 2010 (2010-05-19), pages 30, XP021079507, ISSN: 1742-2094, DOI: 10.1186/1742-2094-7-30 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11484530B2 (en) 2011-12-19 2022-11-01 Bjoern Colin Kahrs Pharmaceutical compositions comprising the PPAR agonist INT-131 and Nrf2 activators
US12083107B2 (en) 2011-12-19 2024-09-10 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
WO2016153957A3 (fr) * 2015-03-20 2016-11-10 Biogen Ma Inc. Procédés et compositions pour l'administration intraveineuse de fumarates pour le traitement de maladies neurologiques
CN111617255A (zh) * 2019-02-28 2020-09-04 北京强新生物科技有限公司 用于治疗中枢神经系统紊乱的组合疗法
CN111617255B (zh) * 2019-02-28 2023-08-18 北京强新生物科技有限公司 用于治疗中枢神经系统紊乱的组合疗法

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