JP2015155480A - Fumaric acid derivative-containing medicament for treating cardiac failure and asthma - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: what is presented is using fumaric acid derivatives specified in a group consisting of dialkylfumarates, monoalkylhydrofumarates, fumaric acid monoalkyl ester salts, fumaric acid monoamides, fumaric acid monoamide salts, fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic and oxacarbocyclic oligomers of these compounds or their mixtures for preparing a drug for treatment or prevention of cardiac failure, particularly left-ventricular failure, myocardial infarction and angina. ^ EFFECT: dimethylfumarate has appeared to reduce considerably an area of infarction caused by ischemia followed by reperfusion. ^ 19 cl, 4 dwg, 7 ex

Description

  The present invention relates to the use of fumaric acid derivatives for treating heart failure and asthma.

  Fumaric acid dialkyl esters and fumaric acid monoalkyl esters, and salts thereof have been used effectively for the treatment of psoriasis over a long period of time. Examples of use thereof include, for example, specifications such as Patent Document 1 (German Patent No. 25 30 372), Patent Document 2 (German Patent No. 26 21 214) or Patent Document 3 (European Patent No. 0 312 697). Have been described.

  Furthermore, only as a therapeutic agent for autoimmune diseases such as multiple arthritis or multiple sclerosis (Patent Document 4: German Patent Application No. 197 21 099.6 and Patent Document 5: German Patent Application No. 198 53 487.6). Instead, it is also mentioned that fumaric acid mono- and diesters are used for transplantation drugs (Patent Document 6: German Patent Application No. 198 53 487.6 and Patent Document 7: German Patent Application No. 198 39 566.3). . Further, the use of fumaric acid mono- and dialkyl esters for the treatment of mitochondrial diseases and NF-kappa B-mediated diseases and / or as NF-kappa B inhibitors is described in Patent Document 8 (German Patent Application No. 10101). No. 307.8) and Patent Document 9 (German Patent Application No. 100 00 577.2). These publications all describe fumaric acid mono- and diesters, and optionally certain salts.

   The use of fumaric acid mono- and diimide to treat these symptoms is known from Patent Document 10 (German Patent Application No. 10 1 33 004.9). These amides are formed using amino acids and preferably specific peptides. Furthermore, fumaric acid oligomers and the use of these oligomers for the treatment of the aforementioned diseases are known from patent document 11 (German Patent Application No. 102 17 314.1).

  Severe dyspnea with marked seizures is understood by asthma (bronchial asthma), which is troubled by almost 4 to 5% of the population in developed countries. This dyspnea is due to indefinite and reversible obstruction in the airways by the hyperreactive bronchial system, which is induced by exogenous and / or intrinsic stimuli. These include chemical or physical triggers, infectious diseases, physical effort and / or mental factors. After long-term illness, sequelae such as chronic bronchitis, emphysema, bronchiectasis, pulmonary diastolic or pulmonary heart disease or respiratory heart failure usually occur.

    Due to its cause, it is differentiated between different asthma, ie allergy, infection, analgesics, asthma caused by working conditions or physical effort, mixed asthma or cardiac asthma, nasal asthma and uremic asthma. In particular, cardiac asthma can cause dyspnea due to increased clogging in the small circulation in the case of left ventricular failure.

    In addition to measures that are still accepted to simply avoid triggering stimuli, for example, beta-2 sympathomimetics, corticosteroids, parasympatholytics, theophylline, anti-inflammatory drugs, anti-allergic drugs, It is administered for drug therapy and / or alleviation of asthma.

    At the molecular level, asthma is characterized by increased Th2 activity in lung lymphocytes, resulting in increased release of certain Th2 cytokines and ultimately IgE isotype switching, mucus production, favorable Causes known features of asthma such as acid sphere recruitment and activation. Furthermore, Th2 cytokines appear to undergo further differentiation in Th2 cells through a signaling pathway known as JAK-STAT, resulting in a self-promoting circle. Promotion of proliferation of mesenchymal cells, especially bronchial smooth muscle cells, is observed.

So-called JAK-STAT signal transduction pathway (JA nus K inase S ignal T transducer and A ctivator of T ranscription) , for example, the path for transmitting the information by the information proteins such as cytokines are transmitted cells and / or the nucleus inside It is. Signal transduction occurs through the STAT protein present in the cytoplasm and is initially inactive. Seven STAT proteins are known in the human body. As a result of the binding of receptor ligands on the cell surface, these STAT proteins are rapidly activated, for example by phosphorylation by Janus kinase. Phosphorylation results in homo or heterodimerization of the STAT protein, which dimer rapidly translocates into the nucleus, binds to the target promoter, and rapidly increases the transcription rate of this promoter.

  The heart cannot deliver the blood output required for metabolism and / or receive venous return, acutely or chronically, during stress (stress failure) and / or at rest (resting failure) Is understood as heart failure. This failure can not only cause pure left or right ventricular failure, but can affect both ventricles.

  The clinical picture of heart failure is thought to be due to various factors from the viewpoint of causation, in particular, inflammatory and degenerative changes of the myocardium and endocardium, coronary artery circulatory disorder, myocardial infarction, injury and the like. Subsequently, heart failure causes peripheral circulation changes, respiratory diseases, in particular cardiac asthma, renal failure, electrolyte metabolism diseases as well as edema, a disease that reduces the functional capacity of skeletal muscle.

  Regarding signs, acute heart failure, energetic heart failure, energetic heart failure, hypoactive heart failure (so-called Heglin syndrome II), stimulated heart failure (excitometric heart rhythm) Differentiated between heart failure and / or left ventricular failure as a result of hypoxic, latent, primary, compensatory, relative or stressful failure.

  At present, constriction-promoting substances are used in pharmacotherapy for heart failure, and golicosides (particularly digoxin as well as digigoxin) are still used in chronic treatments today. However, defect extenders (nitro compounds, dihydrazines, alpha blockers, calcium antagonists, especially ACE inhibitors) have gained in importance over the last few years. ACE inhibitors are most important for long-term treatment. In addition, diuretics are used. The acute form is being treated with catecholamines (although amrinone is also possible).

German Patent No. 25 30 372 German Patent No. 26 21 214 EP 0 312 697 German Patent Application No. 197 21 099.6 German Patent Application No. 198 53 487.6 German Patent Application No. 198 53 487.6 German Patent Application No. 198 39 566.3 German Patent Application No. 101 01 307.8 German Patent Application No. 100 00 577.2 German Patent Application No. 101 33 004.9 German Patent Application No. 102 17 314.1

  The object of the present invention is to provide further therapeutic agents for heart failure as well as asthma. In particular, an object of the present invention is to provide a therapeutic agent for cardiac asthma and left ventricular failure that overlap each other. It is a further object of the present invention to provide a therapeutic agent that is suitable for long-term treatment due to its tolerability and can be applied to either individual or mutually overlapping areas.

  The object of the present invention is achieved in particular by using fumaric acid derivatives in the manufacture or formulation of drugs for the treatment of human asthma and / or heart failure.

  The first invention of the present application relates to dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocycle of these compounds and Use of a fumaric acid derivative selected from the group consisting of an oxacarbocyclic oligomer and a mixture of the aforementioned compounds in the manufacture of a medicament for the treatment or prevention of heart failure, in particular left ventricular failure, myocardial infarction and angina. It is.

The second invention relates to dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocycle and oxacarbon of these compounds A fumaric acid derivative selected from the group consisting of a ring oligomer and a mixture of said compounds, asthma, chronic obstructive pulmonary disease, in particular asthma caused by allergies, infections, analgesics, work conditions or physical effort, mixed type It is used for the manufacture of a medicament for the treatment of asthma or cardiac asthma.
About the use of.

The present invention also relates to a method for inhibiting ³ H-thymidine uptake by bronchial smooth muscle cells and a method for preventing the proliferation of these cells as described below and in the claims.
Furthermore, the present invention relates to the use of the fumaric acid derivative described above for blocking PDGF-induced STAT1 activity.
For example, the present invention provides the following items.
(Item 1)
Dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and An agent for treating or preventing heart failure, in particular left ventricular failure, myocardial infarction and angina pectoris, comprising a fumaric acid derivative selected from the group consisting of a mixture of compounds.
(Item 2)
Dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and Asthma, chronic obstructive pulmonary disease in general, especially asthma caused by allergies, infections, analgesics, work conditions or physical effort, mixed asthma, or containing a fumaric acid derivative selected from the group consisting of compounds Drugs for treating heart asthma.
(Item 3)
The fumaric acid derivative is preferably dexamethasone, cortisone, hydrocortisone, prednisolone, prednisone, methylprednisolone, methylprednisolone, methylprednisolone, methylprednisolone. , Beclomethasone, budenoside, flunisonide, fluticasone, betamethasone, and therapeutically acceptable salts and derivatives thereof Drug Attribute 2 wherein containing in combination with-option glucocorticoid.
(Item 4)
4. The drug according to any one of items 1 to 3, wherein the fumaric acid derivative is selected from one or more dialkyl esters of fumaric acid represented by formula I.
(Chemical formula 1)

(Wherein R ₁ and R ₂ may be the same or different from each other, and may be linear, branched or cyclic, saturated or unsaturated, C _1-24 alkyl group or _Represents a C _5-20 aryl group, and these groups are halogen (F, Cl, Br, I), hydroxyl group, C _1-4 alkoxy group, C _1-4 alkyl group, nitro group or cyano group. It may be optionally substituted.)
(Item 5)
4. The drug according to any one of items 1 to 3, wherein the fumaric acid derivative is selected from one or more fumaric acid monoalkyl esters represented by formula II.
(Chemical formula 2)

(Wherein R ₁ represents a linear, branched or cyclic, saturated or unsaturated, C _1-24 alkyl group or C _5-20 aryl group, and A represents hydrogen, alkali or alkali. Represents earth metal cations or physiologically acceptable transition metal cations, preferably selected from Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ , Zn ²⁺ , Fe ²⁺ and Mn ²⁺ , n is 1 Or 2 and corresponds to the valence of A.)
(Item 6)
Item 6. The drug according to any one of Items 1 to 5, wherein the fumaric acid derivative is selected from one or more of a compound represented by Formula I, a compound represented by Formula II, and a mixture thereof.
(Item 7)
The fumaric acid derivative is fumaric acid dimethyl ester, fumaric acid diethyl ester, fumaric acid methyl ethyl ester, monomethyl fumarate, monoethyl fumarate, methyl fumarate calcium salt, ethyl fumarate calcium salt, magnesium salt of methyl fumarate, Item 7. The drug according to item 6, selected from the group consisting of ethyl fumarate magnesium salt, methyl fumarate zinc salt, ethyl fumarate zinc salt, methyl fumarate iron salt, and ethyl fumarate iron salt.
(Item 8)
4. The drug according to any one of items 1 to 3, wherein the fumaric acid derivative is selected from one or more fumaric acid amides represented by general formula III.
(Chemical formula 3)

(Wherein R _a represents a D- or L-amino acid group —NH—CHR ₄ —COOH linked via OR ₃ or an amide bond , R ₃ is hydrogen, linear or branched, optionally alkyl C _{1 to 24} having a substituent, an aryl group or an aralkyl group having a phenyl group or a C _{6 to 10,} the side chain of R ₄ is a natural or synthetic amino acid, R _b is via an amide bond Shown are peptide groups having 2 to 100 amino acids, which may be the same or different, linked via a linked D- or L-amino acid group -NH-CHR ₅ -COOH or an amide bond. , R ₅ is a side chain of a natural or synthetic amino acid which may be the same as or different from R _4. )
(Item 9)
The side chain of a natural or synthetic amino acid is Ala, Val, Leu, Ile, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp 9. The agent according to item 8, selected from the group consisting of, Hyl, Orn, Sar, Me-Gly side chains, preferably the group consisting of Gly, Ala, Val, Ile, Leu, and Me-Gly side chains.
(Item 10)
9. The drug according to item 8 , wherein R _a is —OR ₃ , R _b is L-amino acid group —NH—CHR ₅ —COOH or a peptide group, and R ₅ is as defined in item 8.
(Item 11)
The fumaric acid derivative is a carbocyclic oligomer composed of 2 to 10 fumaric acid moieties as repeating units, and the fumaric acid moiety is fumaric acid, dialkyl fumarate, monoalkyl fumarate, fumaric acid monoamide, fumaric acid diamide, mono 4. The agent according to any one of items 1 to 3, which is derived from a monomer selected from the group consisting of alkyl monoamide fumarate, and salts and mixtures thereof.
(Item 12)
An alkyl group having 1 to 24 carbon atoms is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl Hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2 Selected from the group consisting of a -methoxyethyl group, a methoxymethyl group, a 2-methoxypropyl group, a 3-methoxypropyl group or a 2,3-dimethoxypropyl group, and preferably a methyl group or an ethyl group The drug according to any one of the above.
(Item 13)
13. A medicament according to any of items 1 to 12, provided in a dosage form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary or parenteral administration.
(Item 14)
Tablets, coated tablets, capsules, granules, liquid drinks, liposomes, nanoparticles, nanocapsules, microcapsules, microtablets, pellets, powders, as well as granules, capsules or sachets filled in capsules or sachets 14. The medicine according to item 13, which is a microtablet, a pellet filled in a capsule or a sachet, a nanoparticle filled in a capsule or a sachet, or a powder medicine filled in a capsule or sachet.
(Item 15)
Item 15. The drug of item 14, wherein the drug is a nanoparticle, pellet, or microtablet dosage form, optionally packed in a sachet or capsule.
(Item 16)
Item 16. The drug according to Item 14 or 15, wherein an enteric coating is applied to the solid oral dosage form.
(Item 17)
The medicine in any one of the items 1-16 containing the fumaric acid derivative equivalent to 1-500 mg fumaric acid.
(Item 18)
Culturing the cells in the presence of a sufficient amount of a fumaric acid derivative to inhibit thymidine incorporation into bronchial smooth muscle cells, wherein the fumaric acid derivative is a dialkyl fumarate, monoalkyl fumarate, monofumarate Selected from the group consisting of alkyl ester salts, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and mixtures of the foregoing compounds. A method of blocking thymidine incorporation into bronchial smooth muscle cells induced by PDGF.
(Item 19)
Dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and A method for inhibiting bronchial smooth muscle cell proliferation comprising the step of bringing bronchial smooth muscle cells into direct or indirect contact with a growth inhibitory amount of a fumaric acid derivative selected from the group consisting of a mixture of compounds.
(Item 20)
20. A method according to item 18 or 19, wherein the fumaric acid derivative is selected from one or more fumaric acid dialkyl esters of formula I.
(Chemical formula 1)

Wherein R ₁ and R ₂ may be the same or independently different, linear, branched or cyclic, saturated or unsaturated, C _1-24 alkyl group or C _5-20 represents an aryl group, these groups, halogen (F, Cl, Br, I ), a hydroxyl _group, an alkoxy group of _{C 1 to 4,} alkyl group of _{C 1 to 4,} optionally substituted with a nitro group or a cyano group May be.)
(Item 21)
20. The method according to any of items 18 or 19, wherein the fumaric acid derivative is selected from one or more fumaric acid monoalkyl esters of formula II.
(Chemical formula 2)

(Wherein R ₁ represents a linear, branched or cyclic, saturated or unsaturated, C _1-24 alkyl group or C _5-20 aryl group, and A represents hydrogen, alkali or alkali. Represents earth metal cations or physiologically acceptable transition metal cations, preferably selected from Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ , Zn ²⁺ , Fe ²⁺ and Mn ²⁺ , n is 1 Or 2 and corresponds to the valence of A.)
(Item 22)
Item 22. The method according to Item 20 or 21, wherein the fumaric acid derivative is selected from one or more of a compound represented by formula (I), a compound represented by formula (II), and a mixture thereof.
(Item 23)
Item 20. The method according to Item 19, which is performed in the body by administering a fumaric acid derivative to a subject.
(Item 24)
24. The method according to item 23, wherein the administration is oral administration.
(Item 25)
Dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and An agent for inhibiting bronchial smooth muscle cell proliferation, comprising a fumaric acid derivative selected from the group consisting of a mixture of compounds.
(Item 26)
Dialkyl fumarate, monoalkyl fumarate, fumaric acid monoalkyl ester salt, fumaric acid monoamide, monoamide fumarate, fumaric acid diamide, monoalkyl monoamide fumarate, carbocyclic and oxacarbocyclic oligomers of these compounds, and An agent that inhibits PDGF-induced STATI activity, comprising a fumaric acid derivative selected from the group consisting of a mixture of compounds.

It is a bar graph which shows the infarct degree about after DMF administration, after ischemia, and a comparison control. ³ is the inhibition rate of ³ H-thymidine uptake in PDGF-induced smooth muscle cells when DMF is added. It is a bar graph which shows the cell proliferation rate of the smooth muscle cell by PDGF irritation | stimulation in the case where DMF and / or dexamethasone exists, and when it does not exist. 6 is a bar graph showing the left ventricular end-diastolic diameter of Dahl rats before a high salt meal or after 8 weeks of a high salt meal with or without DMF.

  One aspect of the present invention relates to the use of fumaric acid derivatives in the manufacture of a medicament for the treatment of asthma as well as chronic obstructive pulmonary disease in general. It is preferred if this asthma is caused by allergies, infections, analgesics, working conditions or physical effort, in particular cardiac asthma.

  Another aspect of the present invention relates to the use of a fumaric acid derivative in the manufacture of a medicament for the treatment or prevention of heart failure, myocardial infarction, angina. The subject heart failure may be of any type regardless of its form / etiology. Examples of heart failure treated with the agents of the present invention include acute heart failure, energetic heart failure, energetic heart failure and hypoactive heart failure, so-called HEGGLIN syndrome II, exercise-promoting heart failure, cardiac arrhythmia, hypoxia, latent Heart failure as a result of sex, primary, compensatory, decompensated, relative, or stressful and / or left ventricular failure, most optimally left ventricular failure. The composition is also effective as a preventive agent for these diseases and / or myocardial infarction including first, second and further infarcts.

  These uses are based on the discovery that fumaric acid derivatives inhibit PDGF (platelet derived growth factor) induced STAT1 activity. As described above, in asthma, STAT activity was predicted to shift the cytokine pattern, eventually resulting in vicious cycle and mucus secretion, promotion of Th2 cell activity, IgE production, and eosinophil recruitment ( A. B. Pernis, P. B. Rothman, “JAK-STAT signaling in asthma”: The J. of Clin. Investigation, Vol. 10, No. 1, May 2002).

  The shift of cytokine from Th1 to Th2 for the class of fumaric acid derivatives described in that document (see previously published patent specifications) rather predicts that this vicious circle is enhanced. Therefore, they cannot be said to be suitable for the treatment of asthma. Surprisingly, however, it has been found that fumaric acid derivatives can inhibit the proliferation of airway smooth muscle cells. This appears to be through the inhibition of the PDGF-induced transcription factor STAT1. It could clearly be shown that the fumaric acid derivative can block PDGF-induced STAT1 activity as well as PDGF-stimulated thymidine incorporation into BSM (bronchial smooth muscle cells). Although not limited by these, it can be said that this growth inhibitory effect is due to both effects of the fumaric acid derivative in the treatment of asthma.

The fumaric acid derivatives used in the present invention are dialkyl fumarate (each of the dialkyl esters of fumaric acid), monoalkyl fumarate (each of the monoalkyl esters of fumaric acid), physiologically acceptable cations, in particular Li ⁺ , Monoalkyl ester fumarate salt of alkali or alkaline earth metal cations or transition metal cations such as Na ⁺ , K ⁺ , NH ₄ ⁺ , Mg ²⁺ , Ca ²⁺ , Fe ²⁺ , Mn ²⁺ , Zn ^2+, etc. Each of alkyl ester salts), fumaric acid monoamides, fumaric acid diamides and their salts, carbocyclic and oxacarbocyclic oligomers of these compounds, and one or more selected from the group consisting of the foregoing There may be several.

  In a preferred embodiment, the fumaric acid derivative is selected from the group consisting of optionally substituted fumaric acid dialkyl esters, free acid form fumaric acid monoalkyl esters, and mixtures thereof.

  Particularly in this case, it is preferable to use a dialkyl ester of the fumaric acid of the formula (I) as described in Patent Document 5 (German Patent Application No. 198 53 487.6).

In the formula, R ₁ and R ₂ may be the same or independently different, and represent a C _1-24 alkyl group or a C _5-20 aryl group, and these groups are halogen (F, Cl, Br, I), a hydroxyl group, a C _1-4 alkoxy group, a nitro group, or a cyano group may be optionally substituted. In particular, the dialkyl fumarate is dimethyl fumarate, diethyl fumarate and / or methyl ethyl fumarate.
In general, an alkyl group in the present invention is a saturated or unsaturated linear, branched, or cyclic hydrocarbon group having 1 to 24 carbon atoms, and these are optionally substituted with one or more substituents. It must be understood that it may be substituted. The alkyl group is preferably a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, pentyl group, cyclopentyl group, or 2-ethylhexyl group. Hexyl group, cyclohexyl group, heptyl group, cycloheptyl group, octyl group, vinyl group, allyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 2 -A methoxyethyl group, a methoxymethyl group, a 2-methoxypropyl group, a 3-methoxypropyl group, or a 2,3-dimethoxypropyl group, and most preferably a methyl group or an ethyl group.

  In the present invention, an aryl group is an optionally substituted aryl group, an alkyl-substituted aryl group, or an aralkyl group having 5 to 20 carbon atoms, preferably an alkyl having 6 to 10 carbon atoms. It should be understood as a substituted aryl or aralkyl group. Examples of these groups include phenyl group, benzyl group, phenethyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, t-butylphenyl group, and in particular, phenyl group and benzyl group. preferable.

Substituents of these groups, halogen (F, Cl, Br, I ), a hydroxyl _group, an alkoxy group of _{C 1 to 4,} alkyl group of _{C 1 to 4,} be selected from the group consisting of a nitro group and a cyano group preferable.

  A fumaric acid monoalkyl ester of the formula (II) as described in patent document 4 (German Patent Application No. 197 21 099.6) can be used effectively.

In the formula, R ₁ is the same as described above, A is hydrogen, an alkali or alkaline earth metal cation or a physiologically acceptable transition metal cation, and Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , It is preferably selected from Ca ²⁺ , Zn ²⁺ , Fe ²⁺ and Mn ²⁺ , where n is 1 or 2 and corresponds to the valence of A.

  Examples of compounds of formula (I) and (II) include 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 There are fumarate, magnesium ethyl fumarate, zinc methyl fumarate, zinc ethyl fumarate, iron methyl fumarate and iron ethyl fumarate. These can be used individually or mixed.

  The fumaric acid monoamides used in the present invention are preferably those described in Patent Document 10 (German Patent Application No. 101 33 004.9). These correspond to general formula (III).

In which R _a represents a D- or L-amino acid group —NH—CHR ₄ —COOH bonded via OR ₃ or an amide bond, R ₃ is hydrogen, linear or branched, and alkyl C _{1 to 24} having a substituent group with an aryl group or an aralkyl group having a phenyl group or a C _{6 to 10,} bond R ₄ is the side chain of a natural or synthetic amino acid, R _b is via an amide bond D- or L-amino acid group —NH—CHR ₅ —COOH (R ₅ is a side chain of a natural or synthetic amino acid) or a peptide group having 2 to 100 amino acids linked via an amide bond (the amino acids are identical) But may be different).

The side chains of natural or synthetic amino acids are typically Ala, Val, Leu, Ile, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy. , Hse, Hyp, Hyl, Orn, Sar, Me-Gly are side chains selected from the group consisting of side chains. The side chains of Gly, Ala, Val, Ile, Leu, and Me-Gly are preferred. When R _a is L-amino acid group —NH—CHR ₄ —COOH and R _b is L-amino acid group —NH—CHR ₅ —COOH, R ₄ and R ₅ may be the same or different. May be. R ₄ and R ₅ are more preferably the same. Most preferably, R _a and R _b are each glycine.

R _a may be —OR ₃ , R _b may be L-amino acid group —NH—CHR ₅ —COOH or a peptide, and R ₅ is as described above. In this case, the fumaric acid derivative is a monoalkyl monoamide fumarate.

Peptide groups are linked via amide bonds and have 2 to 100, preferably 2 to 30, and most preferably 2 to 15 amino acids that may be the same or different. The peptide group R _b is most preferably a peptide group selected from the group consisting of peptide hormones, growth factors, cytokines, neurotransmitters, neuropeptides, antibody fragments, blood coagulation factors, cyclosporine, and derivatives and fragments thereof. preferable. R _a is preferably _a methoxy group or an ethoxy group, and R _b is preferably Gly, Ala, Val, Ile, Leu, or Me-Gly.

  The fumaric acid amides defined above may be used individually, mixed and further mixed with a monoalkyl or dialkyl ester of fumaric acid as defined above.

  Furthermore, carbocyclic and oxacarbocyclic fumaric acid oligomers as described in Patent Document 11 (German Patent Application No. 102 17 314.1) can also be used. These contain 2 to 10, preferably 2 to 6, most preferably 2 to 3 units derived from fumaric acid and / or its esters and / or amides as defined in the above application. .

  These fumaric acid oligomers are preferably (olefinic) polymerization of C and C double bonds (of carbocyclic oligomers) and / or C and C double bonds of units (of oxacarbocyclic oligomers) and carbonyl oxygen. (Olefinic) polymerization of Preferably, the units derived from fumaric acid are fumaric acid and dialkyl fumarate, monoalkyl fumarate, fumaric acid monoamide, fumaric acid diamide, monoalkyl monoamide fumarate, and salts and mixtures thereof as defined above. Is derived from a monomer selected from the group consisting of: More preferably, it contains only units derived from one or two monomers, most preferably the oligomer contains only units of the same monomer.

  The carbocyclic oligomer is composed of units derived from fumaric acid, and the units are linked to the 2nd and 3rd positions of the fumaric acid skeleton by a covalent C—C bond to produce a carbocyclic oligomer. The oligomer backbone has an even number of carbon atoms and does not contain other monomers and / or heteroatoms. The skeleton is substituted at each carbon atom with one of the carboxylic acid or carboxylic amide groups that make up the fumaric acid monomer unit.

The oxa carbocyclic oligomer of the present invention is composed of units of fumaric acid monomers, and the units are linked by carbon at the 1-position and 3-position by ether crosslinking. At the same time, the ethylene unsaturation moves from the C ₂ and C ₃ positions to the C ₁ and C ₂ positions. Thus, in the case of the oxacarbocyclic oligomer of the present invention, the ring contains a polyoxypropene unit.

  As used herein, the term “oligomer” means a unit of at least two fumaric acid monomers. The carbocyclic fumaric acid oligomer usually contains 2 to 10 units, preferably 2 to 6, most preferably 2 to 3 units derived from fumaric acid. Preferably, all of the carboxylic acid and / or carboxylic amide groups as ring substituents are in trans to each other.

  In a preferred embodiment, carbocyclic fumaric acid oligomers corresponding to the following formula (IVa) are used.

In the formula, residues R _c and R _d are the same or different groups, and have an amine group (—NR ₁ R ₂ ), an amino acid group —NH—C (COOH) —R ₅ , and a peptide having 2 to 100 amino acids. Selected from a group, an alkoxy group (—OR ₁ ) and a hydroxyl group, R ₁ , R ₂ and R ₅ are as defined above, and n is an integer of 2 to 10 (including 10), preferably 2 to 6 It is an integer (including 6).

R _c and R _d are preferably each independently alkoxy or hydroxyl, and most preferably R _c and R _d are not hydroxyl at the same time. Thus, the monomer is preferably one or several monoalkyl fumarate. In other embodiments, the residues R _c and R _d may both be an alkoxy group —OR ₁ , more preferably the same. In this case, the monomer is a dialkyl fumarate.

  Particularly preferably, r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane or r-1, t-2, c-3, t-4, c-5, t-6. Hexa (alkoxycarbonyl) cyclohexane, preferably r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane and / or r-1, t-2, c-3, t -4, c-5, t-6-hexa (methoxycarbonyl) cyclohexane is used in this embodiment.

In addition, an oxacarbocyclic oligomer of formula (IVb) is used, wherein R _c and R _d are defined as above, n is 2 to 10 (including 10), more preferably 2 to 6 ( 6).

  Examples of the fumaric acid derivative used in the present invention include Patent Document 4 (German Patent Application No. 197 21 099.6), Patent Document 10 (German Patent Application No. 101 33 004.9) or Patent Document 11 (German Patent Application No. 102 17). It can be produced by a known method as described in No. 314.1). The contents of these publications are hereby incorporated by reference.

  The pharmaceutical preparation is obtained in a dosage form suitable for oral, rectal, transdermal, dermal, ophthalmological, nasal, pulmonary or parenteral administration. Preferably, the pharmaceutical preparation is adapted for oral administration. It was filled into tablets, coated tablets, capsules, granules, liquid drinks, liposomes, nanoparticles, nanocapsules, microcapsules, microtablets, pellets, powder dosage forms, and even capsules or sachets Present in granules, microtablets filled into capsules or sachets, pellets filled into capsules or sachets, nanoparticles filled into capsules or sachets, powders filled into capsules or sachets. Preferably, the drug is in the form of nanoparticles, pellets or microtablets which may be filled in capsules or sachets.

  Preferably, any solid oral dosage form may be provided with an enteric coating. Such a coating is applied to the surface of tablets, microtablets, pellets, etc., for example, but may also be applied to the capsule surface containing them.

  Oral dosage forms according to the invention may be prepared as solid dispersions, basically by conventional compression methods or direct compression methods, as well as by melt methods or by spray drying methods. If desired, the enteric coating can be dropped or sprayed onto the tablet core surface in a conventional coating pan or applied in a fluid bed apparatus according to known formulations. . Subsequently, drying may be completed and film coating may be applied in the same apparatus.

  The fumaric acid derivative for the production of the pharmaceutical preparation according to the invention is preferably one or more equivalents of fumaric acid corresponding to 1-500 mg, preferably 10-300 mg, most preferably 10-200 mg of fumaric acid per dosage unit. The fumaric acid derivative of

  In the case of parenteral administration by injection (intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection), the drug is in a suitable dosage form. Any conventional liquid carrier suitable for injection can be used.

  In a preferred embodiment, the medicament produced according to the present invention may comprise the following, individually and in admixture. 10-500 mg dialkyl fumarate, especially dimethyl fumarate and / or diethyl fumarate, 10-500 mg calcium alkyl fumarate, especially calcium methyl fumarate and / or calcium ethyl fumarate, 0-250 mg zinc alkyl fumarate Zinc methyl fumarate and / or zinc ethyl fumarate, 0 to 250 mg monoalkyl fumarate, especially monomethyl fumarate and / or monoethyl fumarate, 0 to 250 mg magnesium alkyl fumarate, especially magnesium methyl Fumarate and / or magnesium ethyl fumarate, the total amount of which corresponds to 1-500 mg, preferably 10-300 mg, optimally 10-200 mg of fumaric acid.

  The pharmaceutical preparation according to the invention used with particular preference contains only 10 to 300 mg of dimethyl fumarate.

  In particularly preferred embodiments, the pharmaceutical preparation is in the form of a microtablet or pellet. These preferably have a size and / or average diameter of 5000 μm or less, preferably 300 to 2500 μm, in particular 300 to 1000 μm for micropellets and 1000 to 2500 μm for microtablets. Administration of the fumaric acid derivative in a microtablet dosage form, which is a preferred dosage form in the present invention, can further reduce gastrointestinal inflammation and / or side effects that cannot be excluded by administration with a normal single unit dosage tablet. Perhaps this effect is due to the fact that microtablets, preferably enteric-coated microtablets, are already dispersed in the stomach and enter the intestine like a bolus, and the active substance with the same total dose is applied locally. By being released in smaller doses. For this reason, local inflammation of the intestinal epithelial cells is avoided, thereby providing better gastrointestinal resistance with microtablets compared to conventional tablets.

Preparation Examples Various preparation examples of preferred pharmaceutical preparations are described below to illustrate the use according to the invention. The examples are merely illustrative and do not limit the invention.

Example 1
Production of a film tablet having an enteric coating and containing 100.0 mg monomethyl fumarate calcium salt corresponding to 78 mg fumaric acid:
Take necessary precautions (breathing mask, gloves, protective clothing, etc.), crush monomethyl fumarate Ca salt: 10 kg, mix vigorously and homogenize with 800 sieves. An excipient mixture of the following composition is prepared: Starch derivatives (STA-Rx 1500 ^®): 21 kg, microcrystalline cellulose (Avicel PH 101 ^®): 2 kg, polyvinylpyrrolidone (PVP, Kollidon ^® 25): 0.6kg, Primogel ^®: 4 kg, colloidal silicic acid ( Aerosil ^{registered trademark} ): 0.3 kg.

The active ingredient is added to the entire powder mixture, mixed, homogenized by sieve 200, polyvinyl pyrrolidone (PVP, Kollidon ^® 25) in a conventional manner by treatment with a 2% aqueous solution of a binder granules, the external phase in the dry state Mix with. The latter consists of 2 kg of so-called FST composite containing 80% talc powder, 10% silicic acid and 10% magnesium stearate.

Thereafter, the mixture is compressed into a convex tablet having a weight of 400 mg and a diameter of 10.0 mm by an ordinary method. Instead of these standard compression methods, tablets may be made using other methods such as direct compression or solid dispersion by melt and spray drying methods.
Enteric coating:
Hydroxypropylmethylcellulose phthalate (HPMCP, Pharmacoat HP ^® 50): 2.250kg A solution of pure water 2.50 liters acetone Ph. Helv. VII: 13 liters and ethanol (94% by weight): dissolved in a mixed solvent consisting of 13 liters, and castor oil (Ph. Eur. II): 0.240 kg is added to this solution. In a conventional manner, in a coated dish, the solution is aliquoted and poured into tablet cores or sprayed.

After corresponding drying, a film coating is formed. The coating is 2-propanol Ph.D. Helv. VII: 8.2 kg, glycerol triacetate (Triacetine ^TM): 0.06 kg and Eudragit ^® E12.5% in the mixed solvent of pure water 0.2 kg: 4.8 kg, talcum Ph. Eur. II: 0.34 kg, titanium oxide (VI) Cronus RN 56 ^{registered trademark} : 0.52 kg, colored lacquer ZLT-2 blue (Siegle): 0.21 kg and polyethylene glycol 6000 Ph. Helv. VII: consisting of 0.12 kg of solution. After uniform distribution in a coated dish or fluidized bed, the mixture is dried and smoothed in the usual way.

Example 2
Production of enteric cotting-treated capsules containing 86.5 mg of monoethyl fumarate Ca salt and 110.0 mg of dimethyl fumarate (corresponding to a total of 150 mg of fumaric acid):
Necessary precautions (breathing mask, gloves, protective clothing, etc.) were taken, monoethyl fumarate Ca salt: 8.65 kg and dimethyl fumarate: 11 kg, starch: 15 kg, lactose Ph. Helv. VII: 6 kg, microcrystalline cellulose (Avicel ^®): 2 kg, polyvinylpyrrolidone (Kollidon ^® 25): 1 kg and Primogel ^®: mixed vigorously with a mixture consisting of 4 kg, is homogenized by sieve 800.

With 2% aqueous solution of polyvinyl pyrrolidone (Kollidon ^® 25), the entire powder mixture is processed in the usual manner, as a binder granulate and mixed with the outer phase in a dry state. The external phase, colloidal silicic acid (Aerosil ^®): 0.35 kg, magnesium stearate: 0.5 kg and talcum Ph. Helv. VII: 1.5 kg. 500.0 mg of the uniform mixture was filled into appropriate capsules and an enteric (gastric acid-resistant) coating consisting of hydroxypropylethylcellulose stearate and castor oil as a softening agent was applied by known methods.

Example 3
Encapsulated enteric microcapsule containing monoethyl fumarate Ca salt 87.0 mg, dimethyl fumarate 120 mg, monoethyl fumarate Mg salt 5.0 mg and monoethyl fumarate Zn salt 3.0 mg (corresponding to 164 mg in total fumaric acid) Manufacture of tablets ("forte" tablets):
Take necessary precautions (breathing mask, gloves, protective clothing, etc.), monoethyl fumarate Ca salt: 8.7 kg, dimethyl fumarate: 12 kg, monoethyl fumarate Mg salt: 0.5 kg and monoethyl fumarate Zn salt: 0.3 kg is crushed and mixed vigorously to make it uniform with sieve 800. An excipient mixture with the following composition is prepared: Starch derivative (STA-RX 1500): 18 kg, microcrystalline cellulose (Avicel PH 101): 0.3 kg, PVP (Kollidon 120): 0.75 kg, Primogel: 4 kg, colloidal silicic acid (Aerosil): 0.25 kg. The whole powder mixture is added to the active ingredient mixture, homogenized with 200 sieves and treated with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon K25) in the usual manner to obtain binder granules, followed by magnesium stearate: 0.5 kg and Talc powder: mixed with an external phase consisting of 1.5 kg in a dry state. Next, the powder mixture is press-molded into a convex microtablet having a total weight of 10.0 mg and a diameter of 2.0 mm by an ordinary method.

  An enteric (gastric acid resistant) coating is applied in a fluid bed apparatus. To obtain resistance to gastric acid, a portion of a solution of hydroxypropylmethylcellulose phthalate (HPMCP, Phrmacoat HP 50): 2.250 kg, 94% by weight of ethanol denatured with acetone: 13 liters, 2% ketone: 13 50 liters and pure water: Dissolve in 2.5 liters of mixed solvent. Castor oil: 0.240 kg is added to the final solution as a softener, and is subdivided by a conventional method and applied to the tablet core.

  Film coat: After complete drying, a suspension of the following composition is applied as a film coating in the same apparatus. 2-propanol: 8.17 kg, pure water: 0.2 kg and glycerin triacetate (Triacetin) in a mixed solvent of 0.6 kg, talc powder: 0.340 kg, titanium oxide (VI) Cronus RN 56: 0.4 kg, colored 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.

  The ingredients of the gastric acid-resistant microtablets are analyzed and filled into hard gelatin capsules with the corresponding net weight and sealed.

Example 4
Production of enteric microtablets in capsules containing 120.0 mg of dimethyl fumarate corresponding to 96 mg of fumaric acid:
Take necessary preventive measures (breathing mask, gloves, protective clothing, etc.), pulverize 12 kg of dimethyl fumarate and homogenize with sieve 800. Then preparing an excipient mixture of the following composition: starch derivative (STA-RX ^® 1500): 17.5 kg, microcrystalline cellulose (Avicel ^® PH101): 0.30kg, PVP (Kollidon ^® 120): 0.75kg, Primogel ^{registered trademark:} 4kg, colloidal silicic acid (Aerosil ^{registered trademark):} 0.25kg. The active ingredient is added to the total powder mixture, mixed, homogenized by sieve 200, processed in a conventional manner using a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon ^TM K25) to obtain a binder granulate and then the other in the dry state Mix with the phase. This other phase consists of magnesium stearate: 0.5 kg and talc powder: 1.50 kg.

  Next, this powder mixture is press-molded by a conventional method to form a convex tablet having a total weight of 10.0 mg and a diameter of 2.0 mm.

As an example to obtain the gastric acid, hydroxypropylmethylcellulose phthalate (HPMCP, Pharmacoat ^® HP50): a solution of 2.25kg of dissolved in portions in the following solvent mixture: acetone: 14 liters of ethanol (94 wt% Modified with 2% ketone): 13.5 liters, pure water: 1.50 liters. Castor oil (0.24 kg) as a softening agent is added to the final solution and applied to tablet cores in small portions by conventional methods.

  After completion of drying, a suspension having the following composition is applied as a film coating as a film coating in the same apparatus. 2-Propanol: 8.17 kg, pure water: 0.2 kg, glycerin triacetate (triacetin): talc powder in a mixed solvent having a composition of 0.6 kg: 0.34 kg, titanium (VI) Cronus RN 56: 0. 4 kg, colored lacquer L red lacquer 86837: 0.324 kg, Eudragit E 12.5%: 4.8 kg, polyethylene glycol 6000 pH 11 XI: 0.12 kg.

  Thereafter, the components of the gastric acid-resistant microtablet are analyzed, and the hard gelatin capsule is filled with a substantial net weight and sealed.

Example 5
Production of enteric microtablets in capsules containing 120.0 mg of diglycine fumaric acid diamide corresponding to 96 mg of fumaric acid:
Diglycine fumaric acid: 12 kg is pulverized and homogenized in the same manner as above. Then make excipient mixture of the following composition: microcrystalline cellulose (Avicel ^® PH 200): 23.2 kg, Sodium Croscarmelose (AC-Di-SOL- SD-711): 3kg, talcum: 2.5 kg , anhydrous silica (Aerosil ^® 200): 0.1 kg, magnesium stearate: 1.00 kg. The whole powder mixture is then added to the active ingredient mixture and mixed uniformly. The powder mixture is then pressed into a convex tablet having a total weight of 10.0 mg and a diameter of 2.0 mm by a direct compression method.

After this, Eudragit ^{registered trademark} L: make a solution of isopropanol containing 0.94kg. This solution contains 0.07 kg of dibutyl phthalate. Spray this solution onto the tablet core. Thereafter, a dispersion was prepared by dispersing a mixture of Eudragit ^{registered trademark} LD-55: 17.32 kg, microtalc powder: 2.8 kg, Macrogol 6000: 2 kg and dimethicone: 0.07 kg in water, Spray onto the core.

  The enteric microtablet components are then analyzed and filled into hard gelatin capsules with substantial net weight and sealed.

Example 6
r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane 60.0 mg, r-1, t-2, c-3, t-4, c-5, t-6 -Preparation of encapsulated enteric microtablets containing 30.0 mg of hexa (methoxycarbonyl) cyclohexane:
6.0 kg r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane and 3.0 kg r-1, t-2, c-3, t-4, c- 5, t-6-hexa (methoxycarbonyl) cyclohexane is crushed, mixed well, and homogenized by sieve 800. Next, an excipient mixture having the following composition is prepared. Starch derivatives (STA-Rx 1500 ^®): 18.00kg, microcrystalline cellulose (Avicel PH101): 0.30kg, PVP (Kollidon 120): 0.75kg, gum tragacanth (Primogel): 4.00kg, colloidal silicic acid (Aerosil ): 0.25 kg. The active ingredient is added to the whole powder mixture, mixed, homogenized by sieve 200, treated with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon K25) in the usual way to form binder granules, then dried, Mix with phase. The external phase consists of 0.50 kg magnesium stearate and 1.5 kg talc powder. Thereafter, the mixture is pressed into a convex microtablet having a total weight of 10.0 mg and a diameter of 2.0 mm by a usual method.

  An enteric (gastric acid-resistant) coating is poured onto the tablet core in a conventional coating pan. Hydroxypropyl methylcellulose phthalate (HPMCP, Pharmacoat HP50): 2.250 kg of acetone modified with acetone: 13.00 liters, 2% ketone: 94 wt% ethanol: 13.50 liters, pure Dissolve in a mixed solvent consisting of 2.50 liters of water. As a softening agent, 0.240 kg of castor oil is added to the obtained solution, divided by a usual method, and applied to the tablet core.

  Film coat: After the drying is completed, a suspension having the following composition is coated as a film coat in the same apparatus. Talc powder: 0.340 kg, titanium (VI) Cronus RN56: 0.400 kg, color lacquer L red lacquer 86837: 0.324 kg, Eudragit E 12.5%: 4.800 kg, and polyethylene glycol 6000 pH 11 XI: 0 Suspension suspended in a mixed solvent of 120 kg, 2-propanol: 8.170 kg, pure water: 0.200 kg, glycerin triacetate (Triacetin): 0.600 kg.

  Then, the active ingredient in the enteric microtablets is analyzed, and the enteric microtablets are filled and sealed in a hard gelatin capsule with a considerable net weight.

Example 7
r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane 60.0 mg, r-1, t-2, c-3, t-4, c-5, t-6 -Preparation of a parenteral suspension containing 30.0 mg of hexa (methoxycarbonyl) cyclohexane:

Ingredient: mg / ml

r-1, t-2, c-3, t-4-tetrakis (methoxycarbonyl) cyclobutane: 60.0

r-1, t-2, c-3, t-4, c-5, t-6-hexa (methoxycarbonyl) cyclohexane: 30.0
Methylcellulose: 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 above ingredients are processed into a parenteral suspension according to a standard formulation.

Application examples
Example A
In vivo data for treatment of heart failure with DMF using a rat model:
In this study, the effect of dimethyl fumarate was examined in a model of rat ischemia / reperfusion. For this purpose, healthy male rats were divided into 3 groups with 17 animals in each group. In the test, ischemia was caused by arterial occlusion for 45 minutes with the heart exposed and then perfused for 120 minutes. Finally, myocardial infarction was induced by re-occlusion and the risk area was determined by staining with phthalocyanine blue.

  The test article was administered iv at the beginning of the first occlusion. The control group received 0.02% DMSO (0.5 ml / kg body weight) and the DMF group received 10 mg dimethyl fumarate in 0.02% DMSO (0.5 ml / kg body weight). In the second group, the animals were ischemic conditioned (2 occlusions and 2 perfusions each 5 minutes).

  The results are shown in FIG. Obviously, in this experiment, the risk range is similar in all three groups, but the dimethyl fumarate (DMF) group and the ischemic preconditioning (IPC) group are limited in infarct size to a statistically significant extent. It was. This data therefore demonstrates that the dimethyl fumarate used significantly reduces infarct size and prevents heart failure.

Example B
Prevention of PDGF-induced thymidine incorporation:
There are three different pathways for successful asthma treatment. (1) small release of inflammatory mediators in allergic reactions; (2) inhibition of T lymphocyte invasion; and (3) inhibition of mesenchymal cell proliferation. Glucocorticoids, which are considered to be the preferred treatment for asthma, have been demonstrated to inhibit mesenchymal cell proliferation. The test can then be used to investigate other active substances that are considered possible for the treatment of asthma.

BSM (bronchial smooth muscle) cells were prepared in the presence of 0, 1, 5, 10, 20 ng / ml PDG in the presence or absence of 10 ⁻⁵ M dimethyl fumarate, RPMI, 0.3% albumin and 0.1% DMSO. Medium was cultured at 37 ° C.

After a predetermined time, 5 μCi of ³ H-thymidine was added to the culture medium, and the culture was continued for another 24 hours. Uptake was terminated by suspension centrifugation, washing, and cell lysis. ³ H-thymidine incorporation was determined by radioactivity in the lysate compared to the control in a liquid scintillation apparatus. The results are shown in FIG. 2 as a percentage with the control as 100%. Addition of PDGF clearly increases ³ H-thymidine incorporation and cell proliferation, but this growth is significantly reduced by the addition of dimethyl fumarate.

Example C
Bronchial smooth muscle cells were grown in 96 well plates until they were 60-70% confluent. The cells were then starved for 48 hours in RPMI serum-free medium containing 0.3% albumin. One hour prior to stimulation of cell growth with 10 ng / ml PDGF, cells were either (a) 10 ⁻⁵ M DMF, (b) 10 ⁻⁸ M dexamethasone (dexa), or (c) 10 ⁻⁵ M DMF and 10 ⁻ Treated with ⁸ M dexa. As a control, untreated cells (buffer only) were used. Cells were treated for 36 hours and 4 μCi of ³ H-thymidine was added for an additional 8 hours. Cells were lysed, ³ H-thymidine incorporated into DNA was bound to a filter membrane, and incorporated cpm was measured with a liquid scintillation apparatus. The results are shown in FIG. 3 as a ratio relative to the control (100%), comparing PDGF-induced proliferation.

Treatment with dexa (10 ⁻⁸ M) alone, a therapeutically relevant dose, reduced cell proliferation to approximately 117 ± 11%. A comparable reduction was observed with ^10-5 M DMF (116 ± 4%). The combined administration of DMF and dexa at the above concentrations resulted in a synergistic reduction of cell proliferation at approximately baseline levels (95 ± 11%). These results indicate that DMF is effective in treating asthma alone or in combination with normal dexamethasone or glucocorticoid.

  In the treatment of asthma and chronic obstructive pulmonary disease in a particularly preferred embodiment, such treatment is performed in combination with a glucocorticoid. It may be administered in the same dosing unit or in separate dosing units. Furthermore, administration may be performed in parallel or sequentially. Preferably, the glucocorticoid is dexamethasone, cortisone, hydrocortisone, prednisolone, prednisolone, methylprednisolone, methylprednisolone, methylprednisolone, methylprednisolone, methylprednisolone. , Betamethasone, beclomethasone, budenoside, flunisonide, fluticasone and the therapeutically usable salts and derivatives thereof It is selected from.

Example D
Different doses of DMF were administered daily to salt-sensitive Dahl rats and fed a high salt diet. Eight weeks after such treatment, the left ventricular end-diastolic diameter was measured for the test group and the control group by echocardiographic analysis. The measured groups were: control group (0 mg DMF; n = 9); group 1 (2 × 5 mg DMF / kg / d; n = 9); and group 2 (2 × 15 mg DMF / kg / d; n = 11).

  In echocardiographic analysis, DMF inhibited dilatation of the left ventricle with an 8-week high-salt diet, depending on its dose. That is, in the DMF group, the inner diameter of the left ventricle was maintained in the same range as the baseline (FIG. 4). In contrast, the control group of animals showed an enlarged left ventricle that was left ventricular dilation. Importantly, left ventricular dilation is the transition from compensatory hypertrophy to decompensated heart failure. As a result, DMF delays the transition to heart failure and prevents myocardial infarction.

Claims (1)

The invention described herein.