WO2016074684A1

WO2016074684A1 - Fumaric acid derivatives for medical use

Info

Publication number: WO2016074684A1
Application number: PCT/DK2015/050344
Authority: WO
Inventors: Zsolt Laszlo ILLÉS; Kate Lykke LAMBERTSEN; Bente FINSEN; Helle Hvilsted NIELSEN; Bettina Hjelm CLAUSEN
Original assignee: Syddansk Universitet; Region Syddanmark
Priority date: 2014-11-11
Filing date: 2015-11-11
Publication date: 2016-05-19

Abstract

An object of the present invention relates to fumaric acid derivatives which are useful in the protection of 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. Thus, 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 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.

Description

FUMARIC ACID DERIVATIVES FOR MEDICAL USE

Technical field of the invention

The present invention relates to novel medical uses of fumaric acid derivatives. In particular the present invention relates to 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.

Background of the invention

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 (primary prevention) or prevention of recurrent stroke (secondary prevention) 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. Likewise, hypoperfusion to the brain due to low blood pressure or hypoglycemia can cause ischemic stroke.

Hence, there is a need for new therapies for the prevention and treatment neuronal cell damage and inflammation, particularly during stroke. There is a need for treatments which reduce the extent of tissue and especially neuronal cell death in general or e.g. during stroke, which are non-invasive, have different mechanism of action, and have fewer and/or less severe side effects than currently used treatments.

Summary of the invention

Thus, 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. The present inventors have surprisingly found that the administration of fumaric acid derivatives to a mouse model where ischemic stroke is induced results in maintained or elevated levels of HSP72 protein as compared to untreated controls, indicating a protective effect against neuronal necrosis in the brain. Also an increase in anti-inflammatory cytokines and a decrease in pro-inflammatory cytokines in brain tissue and blood was observed as compared to untreated controls indicating an anti-inflammatory effect. Thus, 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 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 comprising a fumaric acid derivative, a medicament for use in the prevention or treatment of stroke, hypoxia or vasoconstriction and a

pharmaceutically acceptable carrier.

Brief description of the figures

Figure 1 shows a proposed mechanism of action of methyl fumarate.

Figure 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.

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. *P<0.05, **P<0.01. 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. *P<0.05, **P<0.01. Figure 5E and 5F shows how MMF treatment protects mice against muscle weakness (hemiparesis). Grip strength is assymetric in untreated animals while there is no asymmetry in treated animals after 48 h (L = left side , R = right side). 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 present invention will now be described in more detail in the following.

Detailed description of the invention

Definitions

Prior to discussing the present invention in further details, the following terms and conventions will first be defined :

In the present context, 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. Despite not causing identifiable symptoms, 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. 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

inflammation, which causes aggregation of thrombocytes (thrombosis) or can be sources of emboli. In the acute phase of subarachnoid haemorrhage,

vasoconstriction may contribute to tissue damage through ischemia. In the present context "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), which is a specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells. Another subtype is vascular inflammation also called vasculitis.

In the present context "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

inflammation. They are abbreviated IL, and various types exist, such as IL2, IL5, IL12 (pro-inflammatory) and IL10 (anti-inflammatory).

In the present context "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. 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. In addition, 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". Thus, neurodegeneration is a chronic process, and

neurodegenerative diseases are chronic disorders. In for example acute ischemic stroke, there is acute neuronal loss due to hypoxia, but this is not

neurodegeneration. In the broadest sense "Fumaric acid derivatives" include all derivatives of fumaric acid, said fumaric acid having the formula H02CCH=CHC02H. Fumaric acid is considered to be the trans-isomer ((£)-Butenedioic acid), but herein the cis- isomer is also included, although the trans-isomer is preferred. Derivatives may particularly include mono- and di-esters of fumaric acid, while particular oligomers are also known. A well-known derivative is dimethylfumarate which is approved for the treatment of multiple sclerosis under the trade name Tecfidera^®.

Medical uses of the invention

As mentioned, there is a need for new therapies for the treatment and prevention of stroke, and for treatments of stroke that have fewer and/or less severe side effects than currently used therapies. Furthermore, there is a need for new therapies for reducing the extent of tissue death and/or inflammation in general and particularly as a result of a stroke. 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.

Monomethyl fumarate (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.

Without wanting to be bound thereby, it is believed that pro-inflammatory changes in the atherosclerotic plaque (vascular inflammation) 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. The expression of endothelial VCAM-1, ICAM-1, TNF-alpha and iNOS are tightly regulated by the activation of NF-κΒ in endothelial cells. 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.

Figure 1 shows a proposed mechanism of action of methyl fumarate. Reactive oxygen species (ROS) activate NF-κΒ, which is a master regulator of

vascularinflammation in endothelial cells, resulting in increased expression of integrins/adhesions and production of pro-inflammatory cytokines. 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. These enzymes constitute major pathways of suppressing intracellular generation of ROS and facilitating increased ROS removal, thus preventing activation of the down-stream NF-κΒ pathway.

Considering the activation of the major anti-oxidant and anti-inflammatory pathway in the stroke tissue/penumbra, and also the role of oxidation and inflammation in atherosclerotic plaque formation, it is speculated that agents interfering with the Keapl/Nrf2 pathway may be powerful drugs to prevent stroke (atherosclerosis) or treat stroke. The present inventors have surprisingly found that 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.

Thus 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

inflammatory condition.

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

inflammation.

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. Thus, in a preferred embodiment 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.

Thus in a preferred embodiment 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. 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,

Benzodiazepines, Renin Inhibitors, Aldosterone receptor antagonists, Alpha-2 adrenergic receptor agonists, Endothelin receptor blockers. Further agents are mentioned under compositions below. 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. Preferably, 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⁺, Mg₂ ⁺, Ca₂ ⁺, Fe₂ ⁺, Mn₂ ⁺, and Zn₂ ⁺, fumaric acid monoamides and fumaric acid diamides and their salts, carbocyclic and oxacarbocyclic oligomers of these compounds and mixtures thereof. Preferred embodiments of the active fumaric acid derivatives are described below. 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.

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

monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.

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.

Compounds of the invention

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. In one embodiment, 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

Formula I)

wherein Ri, and R₂, 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.

In one embodiment, 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. In a preferred embodiment, Ri and/or R2 represent an alkyl radical selected from the group consisting of methyl and ethyl.

In the present context, the term "aryl radical" is to be understood as an optionally substituted aryl, alkyl substituted aryl or aralkyl group having 5 to 20 carbon atoms. Preferably an aryl, alkyl substituted aryl or aralkyl group have 6 to 10 carbon atoms.

In a preferred embodiment, 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.

In a preferred embodiment, 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.

In one embodiment, the fumaric acid derivative is selected from one or more fumaric acid monoalkyl 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 C5-20 aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci-4 alkoxy, Ci-4-alkyl, nitro or cyano;

wherein 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. Such compounds are described in EP0980242.

In one embodiment, 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. Specifically the preparation of such products requires protective measures such as the use of breathing masks, gloves, protective clothing. Fumaric acid esters are absorbed in the gastro-intestinal tract after oral administration and taken up unspecifically from the bloodstream by all body cells. Therefore, it is necessary to administer relatively high dosages in order to provide a therapeutically effective level of the active ingredient on or in the target cells. Such high dosages in turn lead to the known side effects of a fumaric acid therapy like flush symptoms (reddening) or gastrointestinal irritation (nausea, diarrhoea, winds). Even though such side effects may be reduced considerably by

administering the active ingredient in the form of micro-tablets as described in the above-cited prior art, they cannot be avoided altogether. At the same time, the fumaric acid diesters are rapidly hydrolysed in the blood. In order to maintain therapeutically effective levels, repeated and frequent administration is therefore necessary.

These problems may be solved by certain fumaric acid mono- and diamides or monoamido fumaric acid monoesters. Such compounds are described in

US2004038889. In one embodiment, the fumaric acid derivative is selected from one

fumaric acid amides of the general formula III

(Formula III)

wherein R_a represents OR3 or a D- or L-amino acid radical -NH-CHR₄-COOH bonded via an amide bond, wherein R3 is hydrogen, 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; wherein R₄ is a side chain of a natural or synthetic amino acid; wherein Rb represents a D- or L-amino acid radical -NH-CHR5-COOH bonded via an amide bond, wherein R5 is a side chain of a natural or synthetic amino acid which may be the same as or different from R₄, or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different.

In one embodiment, 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.

In a preferred embodiment, 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.

In one embodiment, 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 R₄, or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different. In this case, the fumaric acid derivative is a monoalkyl monoamido fumarate. In a preferred embodiment 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 above mentioned problems may alternatively be solved by certain carbocyclic or oxacarbocyclic fumaric acid oligomers. Such compounds are described in US2005148664. They contain 2 to 10, preferably 2 to 6 and most preferably 2 to 3 units derived from fumaric acid and/or its esters and/or amides as defined above as repetitive units.

In one embodiment, 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.

These 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). Preferably, 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. More preferably, 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.

In the present context, the term "oligomer" refers to a number of at least two fumaric acid monomer units. Customarily, the carboxyclic fumaric acid oligomer contains 2 to 10, preferably 2 to 6 and most preferably 2 to 3 units derived from fumaric acid. Preferably, the carboxylic acid and/or carboxylic acid amide groups as substituents of the cycle are all in a transposition to each other.

In a preferred embodiment, a carbocyclic fumaric acid oligomer corresponding to the following formula (IVa)

(Formula IVa)

is used, wherein the 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, R₂ and Rs being as defined above and n being an integer from 2 to 10 inclusive, preferably 2 to 6 inclusive. Preferably, 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. Thus, the monomer(s) is(are) preferably one or several monoalkyl hydrogen fumarate(s). In another embodiment both radicals R_c and Rd may represent an alkoxy radical - ORI which, still more preferred, is identical. In this case, the monomer(s) is(are) dialkyl fumarates. Very preferably, 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.

In a preferred embodiment, the oxacarbocylic oligomer of the formula (IVb)

is used, wherein Ri and R₂ are as defined above and n is an integer from 2 to 10 inclusive, more preferably 2 to 6 inclusive.

In another embodiment, 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

incorporated herein by reference.

Pharmaceutical compositions and dosages of the invention

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 neuronal necrosis and/or inflammation. Thus, an interesting aspect of the present invention is 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.

Another aspect is pharmaceutical 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.

Benzodiazepines, Renin Inhibitors, Aldosterone receptor antagonists, Alpha-2 adrenergic receptor agonists, Endothelin receptor blockers. Anti-hypertensive agents may preferably be selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, epitizide,

hydrochlorothiazide, chlorothiazide, bendroflumethiazide, indapamide,

chlorthalidone, metolazone, amiloride, triamterene, spironolactone, amlodipine, cilnidipine, felodipine, isradipine, lercanidipine, levamlodipine, nicardipine, nifedipine, nimodipine, nitrendipine, diltiazem, verapamil, captopril, enalapril, fosinopril, Lisinopril, perindopril, quinapril, Ramipril, trandolapril, benazepril, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, atenolol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, timolol, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolol, carvedilol, labetalol, Aliskiren, eplerenone, spironolactone, clonidine, guanabenz, guanfacine, methyldopa, moxonidine.

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 combination of the above drugs may also be used. The pharmaceutical preparation may be present in a form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary, intracisternal or parenteral application. Preferably, the pharmaceutical preparation is suited for oral administration. It may then be present 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 granulate 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. Preferably, the drug is present in the form of nano-particles, pellets or micro-tablets, which may optionally be filled in sachets or capsules.

Preferably, 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. If desired, 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. Preferably, 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.

In the case of a parenteral administration via an injection (iv, im, sc, ip, intracisternal) the preparation is present in a form suitable for this. All customary liquid carriers suitable for the injection can be used.

According to a preferred embodiment, 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. According to an especially preferred embodiment, 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. Presumably, this is based on the fact that the micro-tablets, preferably enteric coated 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.

In one embodiment, 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

pharmaceutical composition 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.

In yet another embodiment, 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.

In still another embodiment, the solid oral dosage forms are provided with an enteric coating. Items of the invention

The following items are interesting aspects and embodiments of the present invention :

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

monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyi monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof. Item 2. 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.

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.

Item 4. The use according to any one of the items 1-3, wherein the fumaric acid derivative is selected from one or more fumaric acid dialkyl esters of the formula I

(Formula I) wherein Ri, and R₂, 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 use according to any one of the items 1-3, wherein 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;

wherein 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 6. The use according to any one of the items 1-5, wherein the fumaric acid derivative is selected from one or more compounds of the formulae (I) and (II) and mixtures thereof.

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. Item 8. The use according to any one of the items 1-3, wherein the fumaric acid derivative is selected from one or more fumaric acid amides of the general formula III

(Formula III) wherein R_a represents OR3 or a D- or L-amino acid radical -NH-CHR₄-COOH bonded via an amide bond, wherein R3 is hydrogen, linear, branched or cyclic, saturated or unsaturated Ci-2₄ 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; wherein R₄ is a side chain of a natural or synthetic amino acid; wherein Rb represents a D- or L-amino acid radical -NH-CHR5-COOH bonded via an amide bond, wherein R5 is a side chain of a natural or synthetic amino acid which may be the same as or different from R₄, 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.

Item 12. The use according to any one of the previous items, wherein 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-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.

All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples. Examples

EXAMPLES OF PREPARATION

To explain the use according to the invention, various examples for the

preparation of preferred pharmaceutical preparations are given below. The examples are for illustrations purposes only, but not to restrict the invention. Example 1

Preparation of film tablets with an enteric coating containing 100.0 mg of monomethyl fumarate-Ca salt, which corresponds to 78 mg of fumaric acid.

Taking the necessary precautions (breathing mask, gloves, protective clothing, etc.), 10 kg of monomethyl fumarate-Ca salt are crushed, mixed intensely and homogenized by means of a sieve 800. Then an excipient mixture of the following composition is prepared : 21 kg of starch derivative (STA-RX 1500®), 2 kg of micro- crystalline cellulose (Avicel PH 101®), 0.6 kg of polyvinyl pyrrolidone (PVP, Kollidon® 25), 4 kg of Primogel®, 0.3 kg of colloidal silicic acid (Aerosil®).

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. 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.

Thereafter, the mixture is pressed into convex tablets with a weight of 400 mg and a diameter of 10.0 mm by the usual method. Instead of these classic compaction methods, other methods such as direct compaction or solid

dispersions according to the melting method and the spray drying method may also be used for preparing tablets. Enteric coating

A solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP® 50) is dissolved in 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.

After a corresponding drying, 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.

Example 2

Preparation of enteric coated capsules containing 86.5 mg of monoethyl fumarate- Ca salt and 110.0 mg of dimethyl fumarate, which corresponds to a total of 150 mg of fumaric acid.

Taking the necessary precautions (breathing mask, gloves, protective clothing, etc.), 8.65 kg of monoethyl fumarate-Ca salt and 11 kg of dimethyl fumarate are intensely mixed with a mixture consisting of 15 kg of starch, 6 kg of lactose Ph. Helv. VII, 2 kg of micro- crystalline cellulose (Avicelt®), 1 kg of polyvinyl pyrrolidone (Kollidon® 25) and 4 kg of Primogel® and homogenized by means of a sieve 800.

Together with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® 25) 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.

Example 3

Preparation of enteric micro-tablets in capsules containing 87.0 mg of monoethyl fumarate- Ca salt, 120 mg of dimethyl fumarate, 5.0 mg of monoethyl fumarate- Mg salt and 3.0 mg of monoethyl fumarate-Zn salt, which corresponds to a total of 164 mg of fumaric acid ("forte" tablets)

Taking the necessary precautions (breathing mask, gloves, protective clothing, etc.), 8.7 kg of monoethyl fumarate-Ca salt, 12 kg of dimethyl fumarate, 0.5 kg of monoethyl fumarate-Mg salt and 0.3 kg of monoethyl fumarate-Zn salt are crushed, intensely mixed and homogenized by means of an sieve 800. An excipient mixture of the following composition is prepared : 18 kg of starch derivative (STA-RX 1500), 0.3 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, 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.

The enteric (gastric acid-resistant) coating is applied in a fluidized-bed apparatus. In order to achieve resistance to gastric acid, 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.

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.

Example 4

Preparation of 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.

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.

To achieve resistance to gastric acid, portions of a solution of 2.25 kg hydroxy propyl methyl cellulose phthalate (HPMCP, Phannacoat® HP 50) are e.g. dissolved in 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.

After drying is completed, 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. Example 5

Preparation of 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. Then, 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.

Subsequently, 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.

Example 6

Preparation of 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.

60 kg of r-l,t-2,c-l,t-4-tetrakis (methoxy carbonyl) cyclobutane and 3.0 kg of r- l,t-2, c-3,t-4,c-5,t-6-hexa (methoxy carbonyl) cyclohexane are crushed, intensely mixed and homogenized by means of sieve 800. An excipient mixture of the following composition is prepared : 18 kg of starch derivative (STA-RX 1500®), 0.30 kg of micro-crystalline cellulose (Avicel® PH 101), 0.75 kg of PVP (Kollidon® 120), 4.00 kg of Primogel®, 0.25 kg of colloidal silicic acid (Aerosil®). 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. Thereafter, 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. In order to achieve resistance to gastric acid, 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 13.00 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.

Subsequently, the enteric micro-tablets are analyzed with respect to their active ingredients and filled into hard gelatine capsules at a corresponding net weight and sealed.

Example 7

Preparation of a suspension for parenteral application 60.0 mg of r-l,t-2,c-4,t-4- tetrakis (methoxy carbonyl) cyclobutane and 30.0 mg r-l,t-2,c-3,t-4,c-5,t-6-hexa (methoxy carbonyl) cyclohexane

Ingredients mg/ml r-l,t-2,c-3,t-4-tetrakis (methoxy carbonyl) cyclobutane 60.00 r-l,t-2,c-3,t-4,c-5,t-6-hexa (methoxy carbonyl) cyclohexane 30.00 Methyl cellulose 0.25

Sodium citrate, dihydrate 30.00

Benzyl alcohol 9.00

Methyl p-hydroxybenzoic acid 1.80

Propyl p-hydroxybenzoic acid 1.20

Water for injection purposes q. s. a. d. 1.00

The aforementioned ingredients are processed to a parenteral suspension using standard techniques.

EXAMPLES OF MEDICAL USE

The compounds of the present invention were tested on a mouse model. The materials and methods used where as follows. Materials and methods:

Ischemic stroke was induced by permanent left middle cerebral artery occlusion (pMCAO) in 7-8-week old C57BL/6 male mice. Thirty minutes after focal cerebral ischemia, 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). 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. Groups consisted of mice surviving either 6 hours (n=9/group) or 48 hours (n=20/group). A separate group of mice served a controls and were allowed to survive for 48 hours after drug administration (n= 10-ll/group). Physiological parameters (temperature, weight) 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. Example 8

An initial experiment involved the inducing ischemic stroke in mice and treating intravenously with monomethyl fumarate (MMF), the active metabolite of dimethyl fumarates (DMF).

Surgical procedure:

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. 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

dehydration, and the eyes were coated with ointment to protect drying. Mice were returned to their cages and were allowed to recover from anesthesia in a 28°C controlled environment. For postsurgical analgesia, mice were treated with

Temgesic (0.001 mg/20 g buprenorphinum; Reckitt & Colman).

Drug treatment:

Mono-methyl fumarate (MMF; 651419-1G from Sigma Aldrich)(10 mg/kg) dissolved in dimethyl sulfoxide (DMSO)(final concentration 0.8% DMSO) was administered intravenously 30 minutes after permanent MCA occlusion (n = 9) into the tail vein. Vehicle-treatment consisted of in saline containing 0.8% DMSO (n = 9).

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-μηι 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.

Results:

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.

Example 9

Measurement of heat shock protein levels in the brain were conducted on an experimental stroke mouse model as described under materials and methods. As shown in Figure 2 heat shock protein (HSP72) levels 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. Since HSP will protect against neuronal necrosis MMF has thus been shown to have a positive effect on neuronal survival.

These results are further confirmed in Figure 7 where it is shown that MMF treatment of mice, intravenously 30 minutes after ischemia, had a

neuroprotective effect and appears to decrease the penumbra : protein levels of Hsp72 were decreased in the untreated animals 6 hours after stroke, while it was maintained in the treated animals reflecting neuronal survival.

Example 10

Measurement of cytokine levels in the brain and serum where conducted on an experimental stroke mouse model as described under materials and methods.

As shown in figure 3 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. (*P<0.05, **P<0.01 in figure 3). Likewise, as shown in Figure 4 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).

Thus, MMF treatment reduced pro-inflammatory interleukin 12 (IL-12)

concentration in the brain and pro-inflammatory IL-5 and IL-2 in the serum.

Furthermore, serum concentration levels of anti-inflammatory IL-10 was increased. This indicates the usefulness of fumaric acid derivatives in the treatment of inflammatory conditions, both systemic and in brain tissue, particularly in connection with stroke.

These results are further confirmed by the data in Figures 8 and 9. Herein it is shown that MMF treatment of mice, intravenously 30 minutes after ischemia, had an effect on the inflammatory response in the brain : the levels of proinflammatory cytokine IL-12 is decreased in the brain 24 and 48 hours after stroke in the treated animals (Figure 8B - brain). In contrast, the antiinflammatory IL-10 is increased in the brain 6 hours after stroke (Figure 91 - brain).

Also 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) is also increased at early time points. These cytokines also have a neuroprotective effect.

Example 11

Measurement of grip strength was performed using the Grip strength test. 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. We analyzed the grip strength in individual (left and right) front paws prior to (baseline) and one, three and five days after pMCAO. The unit of force measured is presented as grams (g). Asymmetry between paws in individual mice following pMCAO were calculated and

are presented as delta (Δ) grip strength measured in grams (g). Mice that were allowed to survive for 24 hours were tested on day one, and mice that were allowed to survive for five days were tested on day three and five. The data shows that MMF treatment of mice, intravenously 30 minutes after ischemia, protected animals against muscle weakness (hemiparesis) : the grips strength was asymmetric in untreated animals as expected (hemiparesis), while no asymmetry was observed in the treated animals (Figure 5E and 5F).

Example 12

Keapl and Nrf2 mRNA expression, along with Nrf2 protein levels were measured as provided under material and methods.

The data shows that MMF treatment of mice, intravenously 30 minutes after ischemia, was able to influence the Keapl-Nrf2 pathway within the ischemic brain area via reduced Keapl mRNA (Figure 6A) and increased Nrf2 protein (Figure 6B). Conclusion on examples

These experiments confirms the functional effect (protection against hemiparesis), and beneficial effects on Hsp72 and cytokine levelss. In addition, these

experiments provide evidence of early effect on the Keapl-Nrf2 pathway within the infarct area (see also Figure 1).

In summary, 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

compartment. References

• EP0980242

• US2004038889

• US20051486

Claims

1. Fumaric acid derivatives for use in the prevention or treatment of a condition selected from the group consisting of an inflammatory condition and neuronal necrosis.

2. The fumaric acid derivatives according to claim 1, for use in the prevention or treatment of an inflammatory condition and neuronal necrosis.

3. The fumaric acid derivatives according to any one of claims 1-2, wherein the inflammatory condition or neuronal necrosis occurs in connection with a further condition selected from the group consisting of stroke, hypoxia or

vasoconstriction.

4. The fumaric acid derivatives according to any one of claims 1-3, wherein said fumaric acid derivatives are selected from the group consisting of dialkyi fumarates, monoalkyl hydrogen fumarates, fumaric acid monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures thereof.

5. The fumaric acid derivatives according to any one of claims 1-4, wherein the fumaric acid derivative is selected from one or more fumaric acid dialkyi esters of the formula I

(Formula I) wherein Ri, and R₂, 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.

6. The fumaric acid derivatives according to any one of claims 1-4, wherein the fumaric acid derivative is selected from one or more fumaric acid monoalkyi esters of the formula II

n fFnrm ula in 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; wherein 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.

7. The fumaric acid derivatives according to any one of claims 1-6, wherein the fumaric acid derivative is selected from one or more compounds of the formulae

(I) and (II) and mixtures thereof.

8. The fumaric acid derivatives according to any one of claims 1-7, 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.

9. The fumaric acid derivatives according to any one of claims 1-4, wherein the fumaric acid derivative is selected from one or more fumaric acid amides of the general formula III

(Formula III) wherein R_a represents OR3 or a D- or L-amino acid radical -NH-CHR₄-COOH bonded via an amide bond, wherein R3 is hydrogen, linear, branched or cyclic, saturated or unsaturated Ci-2₄ alkyl radical or a Cs-2o aryl radical, and wherein said radicals may optionally be substituted with halogen, hydroxy, Ci-₄ alkoxy, C1-4- alkyl, nitro or cyano; wherein R₄ is a side chain of a natural or synthetic amino acid; wherein Rb represents a D- or L-amino acid radical -NH-CHR5-COOH bonded via an amide bond, wherein R5 is a side chain of a natural or synthetic amino acid which may be the same as or different from R₄, or a peptide radical with 2 to 100 amino acids bonded via an amide bond, which amino acids may be the same or different.

10. The fumaric acid derivatives according to claim 9, 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.

11. The fumaric acid derivatives according to any one of claims 9- 10, wherein R_a is the radical -OR3 and Rb is an L-amino acid radical -NH-CHR5-COOH or a peptide radical, R3 and R5 being as defined in claim 9.

12. The fumaric acid derivatives according to any one of claims 1-4, wherein the fumaric acid derivative is a carbocyciic 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.

13. The fumaric acid derivatives according to any one of claims 5-12, wherein the Ci-2₄alkyl radical 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.

14. The fumaric acid derivatives according to any one of claims 1-13, wherein the fumaric acid derivative is selected from the group consisting of dimethylfumarate and monomethylfumarate.

15. The fumaric acid derivatives according to any one of claims 1-14, wherein the inflammatory condition is vascular inflammation.

16. The fumaric acid derivatives according to any one of claims 1-15, wherein the inflammatory condition is systemic.

17. The fumaric acid derivatives according to any one of claims 1-15, wherein the inflammatory condition is in brain tissue.

18. The fumaric acid derivatives according to any one of claims 1-17, wherein the inflammatory condition is atherosclerosis.

19. The fumaric acid derivatives according to any one of claims 1-18, wherein 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, antihypertensive agents, anti-diabetic agents, anti-dyslipidemia agents, cholesterol reducing agents, statins.

20. The fumaric acid derivatives according to claim 19, wherein the thrombolytic agents are selected from the group consisting of tissue plasminogen activators including alteplase, reteplase, and tenecteplase, anistreplase, streptokinase, and urokinase.

21. The fumaric acid derivatives according to claim 19, wherein the anti-platelet aggregation agents are 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.

22. The fumaric acid derivatives according to claim 19, wherein the statins are selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bezafibrat, and gemfibrozil.

23. The fumaric acid derivatives according to claim 19, wherein the antihypertensive agents are selected from the group consisting of Diuretics, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor antagonists, Adrenergic receptor antagonists, Vasodilators, Benzodiazepines, Renin Inhibitors, Aldosterone receptor antagonists, Alpha-2 adrenergic receptor agonists, Endothelin receptor blockers.

24. The fumaric acid derivatives according to claim 19, wherein the anti-diabetic agents are selected from the group consisting of insulin derivatives, glyburide, glimepiride, glipizide, metformin, acarbose, miglitol, voglibose, Pioglitazone, and Rosiglitazone.

25. The fumaric acid derivatives according to any one of claims 3-24, wherein said stroke is an ischemic stroke.

26. The fumaric acid derivatives according to any one of claims 1-25, wherein said fumaric acid derivative is administered in connection with a thrombectomy.

27. 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.

5 28. A pharmaceutical composition comprising a fumaric acid derivative, a

medicament for use in the prevention or treatment of a condition selected from the group consisting of stroke, hypoxia or vasoconstriction and a pharmaceutically acceptable carrier.

10 29. The pharmaceutical composition according to any one of claims 27-28,

wherein the thrombolytic agents are selected from the group consisting of tissue plasminogen activators including alteplase, reteplase, and tenecteplase, anistreplase, streptokinase, and urokinase.

15 30. The pharmaceutical composition according to claim 27, wherein the antiplatelet aggregation agents are 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

20 (PAR-1) antagonists including Vorapaxar, Glycoprotein IIB/IIIA inhibitors including Abciximab, Eptifibatide, Tirofiban, Adenosine reuptake inhibitors including

Dipyridamole, Thromboxane inhibitors, Thromboxane synthase inhibitors,

25

31. The pharmaceutical composition according to claim 27, wherein the statins are selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bezafibrat, and gemfibrozil.

30 32. The pharmaceutical composition according to claim 27, wherein the antihypertensive agents are selected from the group consisting of Diuretics, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor antagonists, Adrenergic receptor antagonists, Vasodilators, Benzodiazepines, Renin Inhibitors, Aldosterone receptor antagonists, Alpha-2 adrenergic receptor agonists, Endothelin receptor

35 blockers.

33. The pharmaceutical composition according to claim 27, wherein the antidiabetic agents are selected from the group consisting of insulin derivatives, glyburide, glimepiride, glipizide, metformin, acarbose, miglitol, voglibose, Pioglitazone, and Rosiglitazone.