WO2005027899A1 - Utilisation de derives d'acide fumarique pour prevenir et traiter des endommagements du genome - Google Patents

Utilisation de derives d'acide fumarique pour prevenir et traiter des endommagements du genome Download PDF

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Publication number
WO2005027899A1
WO2005027899A1 PCT/EP2004/010203 EP2004010203W WO2005027899A1 WO 2005027899 A1 WO2005027899 A1 WO 2005027899A1 EP 2004010203 W EP2004010203 W EP 2004010203W WO 2005027899 A1 WO2005027899 A1 WO 2005027899A1
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WIPO (PCT)
Prior art keywords
fumaric acid
treatment
acid derivatives
prophylaxis
age
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PCT/EP2004/010203
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German (de)
English (en)
Inventor
August Heidland
Original Assignee
August Heidland
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Publication date
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Publication of WO2005027899A1 publication Critical patent/WO2005027899A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of fumaric acid and its derivatives, individually or in mixtures, for the preparation of an agent for the prophylaxis and / or for the treatment of AGE-induced genome damage.
  • the invention relates to the prophylactic use and the treatment of genome damage occurring in renal failure or diabetes mellitus with fumaric acid derivatives, individually or in mixtures.
  • AGEs can trigger the formation of oxygen radicals in the cell by binding to the so-called RAGE receptor.
  • the radicals mentioned are in turn able to damage the DNA.
  • AGEs have been chemically characterized and identified in the serum or tissue. These include, for example, N ⁇ - carboxymethyllysine (CML), pentosidine (PENT), vesperlysine, pyrraline, imidazolone, glyoxallysine dimer and the methylglyoxallysine dimer.
  • AGEs Interactions of the AGEs with their receptors (RAGEs) and / or binding proteins could result in cell activation, the increased formation of oxygen radicals and consecutively also the activation of NF- ⁇ B.
  • RAGEs receptors
  • cytokines, growth factors and adhesion molecules as well as cell proliferation or programmed cell death, depending on the cell type, could be triggered.
  • AGEs have been associated with the pathogenesis of many complications in diabetes (nephropathy, retinopathy, neuropathy and atherosclerosis), in renal failure, and in the newly rodegenerative amyloid disease (Alzheimer's disease).
  • Receptors for AGEs were found on the surfaces of diverse cells, such as endothelial cells, mesangial cells, monocyte macrophages and neurons.
  • the best characterized receptor is RAGE, a member of the immunoglobulin superfamily.
  • the concentration of AGEs in serum and tissue is influenced by a variety of factors. These include dietary AGE intake, glycemic control (for diabetes), protein turnover, oxidative and carbonyl stress, inflammation, liver function, age and tobacco smoke. Kidney function has a very decisive influence.
  • the AGE peptides are removed via the kidney, by glomerular filtration with subsequent tubular reabsorption and by their excretion in the urine.
  • the AGE levels in the serum and - even more pronounced - in the tissue are increased, depending on the extent of the renal function impairment.
  • the serum AG E level therefore correlates directly with the serum creatinine and reciprocally with the creatinine clearance.
  • AGE-BSA AGE-bovine serum albumin
  • CML-BSA carboxymethyllysine-BSA
  • MG-BSA methylglyoxal-BSA
  • kidney transplantation is still the most effective therapy for reducing the increased AGE values in blood and tissue in diabetic and non-diabetic renal failure, it becomes clear that the kidney plays a central role in the regulation of AGE metabolism.
  • the object of the invention is to provide a pharmaceutical agent for the prophylaxis and also for the treatment of genome damage, which is more common in renal insufficiency. So far, no active ingredient is known that can reduce the genome damage induced by AGEs. It is known that certain fumaric acid derivatives have an antipsoriatic and antimicrobial effect. The treatment of psoriasis with various fumaric acid derivatives is already known from EP 188 749, DE 2 530 372, DE 2 621 214 and EP 312 697.
  • WO 01/51047 discloses the use of fumaric acid derivatives for the treatment of mitochondrial diseases.
  • the solution to the problem according to the invention lies in the use of fumaric acid and its derivatives for the production of an agent for the prophylaxis and treatment of genome damage.
  • Dimethyl fumarate is preferably used for prophylactic use and for the treatment of AGE-induced genome damage in renal failure and / or diabetes mellitus.
  • fumaric acid monoethyl ester is also preferred.
  • salts in particular the calcium, magnesium and zinc salts of monoethyl hydrogen fumarate, is particularly preferred.
  • Alternative fumaric acid derivatives can be all physiologically compatible mono- or diesters and all physiologically compatible salts of fumaric acid or fumaric acid monoesters.
  • the mono- and bifunctional fumaric acid derivatives that can be metabolized in the body are also preferred.
  • Fumaric acid and fumaric acid dialkyl esters in which the carboxyl groups may be substituted identically or differently and may be substituted independently of one another with a linear, branched, cyclic, saturated or unsaturated C1-6-alkyl radical.
  • Fumaric acid monoalkyl esters and salts of fumaric acid monoalkyl esters in which one of the two carboxyl groups can be substituted with a linear, branched, cyclic, saturated or unsaturated C1-6-alkyl radical and the other carboxyl group in each case can be substituted with a proton or as a carboxylate ion with one and form salts corresponding to multivalent cations.
  • Possible cations can be alkali metal cations, alkaline earth metal cations or physiologically compatible transition metal cations, preferably Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ .
  • the salts are formed with a corresponding number of fumaric acid monoalkyl esters present in the form of monocarboxylate ions.
  • Salts of fumaric acid in which one or both carboxyl groups are present as carboxylate and the fumarates with alkali metal cations, alkaline earth metal cations or physiologically compatible transition metal cations, preferably Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , according to their value, form salts.
  • the esters of fumaric acid derivatives can be formed with physiologically compatible C1-6 alkyl radicals, which can be linear, branched, cyclic, saturated or unsaturated.
  • C1-6 alkyl radicals which can be linear, branched, cyclic, saturated or unsaturated.
  • here are the methyl, ethyl, propyl, isopropyl, n-butyl, / so-butyl, te / r-butyl, 1-methylpropyl, cyclopentyl-r? -Hexyl, and
  • cyclohexyl esters which can be present as mono-, diester or as mixed esters of fumaric acid as well as in the form of salts of fumaric acid monoesters.
  • Suitable ester derivatives are not only the abovementioned ones, but all those which are physiologically tolerable and can be absorbed for absorption in cells (intestinal resorption, skin absorption, mucosal absorption, etc.).
  • the foregoing is not to be understood as limited with regard to the fumaric acid derivatives to be used, nor with regard to the cells mentioned, it is only intended to present a small, illustrated section.
  • the salts of the fumaric acid derivatives can be formed from physiologically compatible aikali metal cations, alkaline earth metal cations or physiologically compatible transition metal cations, in particular with Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ .
  • One or more compounds from the group of the salts of the fumaric acid monoalkyl esters and the fumaric acid dialkyl esters can be used to prepare the pharmaceutical preparation.
  • one or more compounds from the group of the salts of fumaric acid, fumaric acid, salts of fumaric acid monoesters, fumaric acid monoesters and also fumaric acid diesters, which can also be present as mixed esters, can be used for the production of pharmaceutical preparations.
  • Oral dosage forms are particularly preferred pharmaceutical preparations.
  • Further dosage forms can be parenteral, percutaneous and dermal applications of the derivatives of fumaric acid and / or fumaric acid, in particular also ointments and / or sprays for cosmetic and / or medical purposes.
  • These preparations can be used for the treatment and / or prophylaxis of AGE-induced genome damage, which include AGE-induced skin damage can also be understood.
  • fumaric acid derivatives according to the invention has proven to be particularly suitable for the prophylactic use and treatment of genome damage caused by AGEs.
  • the effect of the fumaric acid derivatives according to the invention is shown below on the basis of the result of a comet assay study which is shown in FIG. 1.
  • FIG. 1 Relative DNA damage in the comet assay in LLC-PK1 cells after treatment with CML-BSA or MGO-BSA.
  • LLC-PK1 cells were treated with 200 ⁇ g / ml CML-BSA (CML) and MGO-BSA (MGO) with and without pretreatment of the cells with dimethyl fumaric acid ester (DMF) 30 ⁇ M.
  • CML CML-BSA
  • MGO MGO-BSA
  • DMF dimethyl fumaric acid ester
  • Untreated LLC-PK1 cells Co1 and Co2 served as controls. Treatment of the LLC-PK1 cells with CML and MGO causes significant genome damage. The strong, positive influence of the co-incubation of dimethyl fumaric acid ester (DMF) and CML or MGO can be clearly seen. Genome damage has largely failed to materialize.
  • DMF dimethyl fumaric acid ester
  • the comet assay is carried out with slight modifications according to Singh et al: A 0.5% agarose solution (SEA Plaque GTG, low melting point) in PBS-CMF is prepared. The agarose is boiled before use and placed in a 37 ° C water bath. The cells to be examined are taken up in a ratio of 1:10 (cell suspension: agarose) in the 37 ° C. warm agarose solution and mixed gently. Then apply 45 ⁇ l of this suspension to a slide and cover with a cover glass (24x24mm). To consolidate the agarose, the slides are stored for 3-5 minutes at room temperature (in the summer in the refrigerator).
  • the cover slip is then removed and the specimens are placed in a lysis solution (4 ° C) for at least 1 hour (refrigerator).
  • a lysis solution (4 ° C) for at least 1 hour (refrigerator).
  • 1% Triton, 10% DMSO, 89% 10 mmol / L Tris; 1% Na Sarcosinate; 2.5 mol / L NaCI; 0.1 mol / L EDTA [pH 10]
  • the preparations are placed for 20 min in the electrophoresis chamber with 4 ° C cold alkali buffer for partial winding.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'acide fumarique et de ses dérivés, de manière individuelle ou dans des mélanges, afin de produire un médicament utilisé pour prévenir ou traiter des endommagements du génome provoqués par des produits terminaux de glycation avancée (AGE). Cette invention concerne notamment l'utilisation de dérivés d'acide fumarique chez des patients présentant une insuffisance rénale ou un diabète sucré.
PCT/EP2004/010203 2003-09-13 2004-09-13 Utilisation de derives d'acide fumarique pour prevenir et traiter des endommagements du genome WO2005027899A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10342423.7 2003-09-13
DE10342423A DE10342423A1 (de) 2003-09-13 2003-09-13 Verwendung von Fumarsäurederivaten zur Prophylaxe und zur Behandlung von Genomschäden

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7320999B2 (en) 1998-11-19 2008-01-22 Fumapharm Ag Dimethyl fumarate for the treatment of multiple sclerosis
US8148414B2 (en) 2008-08-19 2012-04-03 Xenoport, Inc. Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
WO2013092269A1 (fr) 2011-12-19 2013-06-27 Ares Trading S.A. Compositions pharmaceutiques des glitazones et des activateurs de nrf2
WO2013119791A1 (fr) 2012-02-07 2013-08-15 Xenoport, Inc. Composés de fumarate de morpholinoalkyle, compositions pharmaceutiques et procédés d'utilisation
WO2014152494A1 (fr) 2013-03-14 2014-09-25 Alkermes Pharma Ireland Limited Promédicaments de fumarates et leur utilisation pour le traitement de diverses maladies
WO2014160633A1 (fr) 2013-03-24 2014-10-02 Xenoport, Inc. Compositions pharmaceutiques de fumarate de diméthyle
WO2014197860A1 (fr) 2013-06-07 2014-12-11 Xenoport, Inc. Procédé de production de monométhylfumarate
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
WO2016061393A1 (fr) 2014-10-15 2016-04-21 Xenoport, Inc. Composés de fumarate, compositions pharmaceutiques et procédés d'utilisation
WO2016124960A1 (fr) 2015-02-08 2016-08-11 Alkermes Pharma Ireland Limited Compositions de promédicaments à base de fumarate de monométhyle
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
WO2017060420A1 (fr) 2015-10-07 2017-04-13 Neurovive Pharmaceutical Ab Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects

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JPS52130924A (en) * 1976-04-22 1977-11-02 Keiko Kuroda Swelling and tumor suppressing agent
WO1998027970A2 (fr) * 1996-12-24 1998-07-02 National Research Council Of Canada Traitement de maladies ou prevention de dommages cellulaires causes par des radicaux libres contenant de l'oxygene
WO2002055067A2 (fr) * 2001-01-12 2002-07-18 Fumapharm Ag Derives de l'acide fumarique utilises comme inhibiteurs nf-kappab
US6509376B1 (en) * 1998-11-19 2003-01-21 Fumapharm Ag Utilization of dialkyfumarates

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JPS52130924A (en) * 1976-04-22 1977-11-02 Keiko Kuroda Swelling and tumor suppressing agent
WO1998027970A2 (fr) * 1996-12-24 1998-07-02 National Research Council Of Canada Traitement de maladies ou prevention de dommages cellulaires causes par des radicaux libres contenant de l'oxygene
US6509376B1 (en) * 1998-11-19 2003-01-21 Fumapharm Ag Utilization of dialkyfumarates
WO2002055067A2 (fr) * 2001-01-12 2002-07-18 Fumapharm Ag Derives de l'acide fumarique utilises comme inhibiteurs nf-kappab

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KURODA K ET AL: "INHIBITORY EFFECT OF FUMARIC ACID ON FORESTOMACH AND LUNG CARCINOGENESIS BY A 5-NITROFURAN NAPHTHYRIDINE DERIVATIVE IN MICE", JOURNAL OF THE NATIONAL CANCER INSTITUTE, US DEPT. OF HEALTH, EDICATIONAND WELFARE, PUBLIC HEALTH, US, vol. 69, no. 6, December 1982 (1982-12-01), pages 1317 - 1320, XP008017434, ISSN: 0027-8874 *
RAO C V ET AL: "CHEMOPREVENTION OF AZOXYMETHANE-INDUCED COLON CANCER BY ASCORBYLPALMITATE, CARBENOXOLONE, DIMETHYLFUMARATE AND P-METHOXYPHENOL IN MALE F344 RATS", ANTICANCER RESEARCH, HELENIC ANTICANCER INSTITUTE, ATHENS,, GR, vol. 15, no. 4, July 1995 (1995-07-01), pages 1199 - 1204, XP008017443, ISSN: 0250-7005 *

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8524773B2 (en) 1998-11-19 2013-09-03 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7612110B2 (en) 1998-11-19 2009-11-03 Biogen Idec International Ag Utilization of dialkylfumarates
US7619001B2 (en) 1998-11-19 2009-11-17 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7803840B2 (en) 1998-11-19 2010-09-28 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7915310B2 (en) 1998-11-19 2011-03-29 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7320999B2 (en) 1998-11-19 2008-01-22 Fumapharm Ag Dimethyl fumarate for the treatment of multiple sclerosis
US8759393B2 (en) 1998-11-19 2014-06-24 Biogen Idec International Gmbh Utilization of dialkylfumarates
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US8778991B2 (en) 2008-08-19 2014-07-15 Xenoport, Inc. Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use
US8785443B2 (en) 2008-08-19 2014-07-22 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
EP2650279A2 (fr) 2008-08-19 2013-10-16 XenoPort, Inc. Promédicaments de fumarate de méthyle-hydrogène, compositions pharmaceutiques à base de ceux-ci, et procédés d'utilisation
US8148414B2 (en) 2008-08-19 2012-04-03 Xenoport, Inc. Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use
US10426763B2 (en) 2011-12-19 2019-10-01 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and NRF2 activators
WO2013092269A1 (fr) 2011-12-19 2013-06-27 Ares Trading S.A. Compositions pharmaceutiques des glitazones et des activateurs de nrf2
US11484530B2 (en) 2011-12-19 2022-11-01 Bjoern Colin Kahrs Pharmaceutical compositions comprising the PPAR agonist INT-131 and Nrf2 activators
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US8952006B2 (en) 2012-02-07 2015-02-10 Xenoport, Inc. Morpholinoalkyl fumarate compounds, pharmaceutical compositions, and methods of use
WO2013119791A1 (fr) 2012-02-07 2013-08-15 Xenoport, Inc. Composés de fumarate de morpholinoalkyle, compositions pharmaceutiques et procédés d'utilisation
US10716760B2 (en) 2012-08-22 2020-07-21 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10940117B2 (en) 2012-08-22 2021-03-09 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
EP3366668A1 (fr) 2013-03-14 2018-08-29 Alkermes Pharma Ireland Limited Promédicaments de fumarates et leur utilisation pour le traitement de diverses maladies
EP4230264A2 (fr) 2013-03-14 2023-08-23 Alkermes Pharma Ireland Limited Promédicaments de fumarates et leur utilisation pour le traitement de diverses maladies
WO2014152494A1 (fr) 2013-03-14 2014-09-25 Alkermes Pharma Ireland Limited Promédicaments de fumarates et leur utilisation pour le traitement de diverses maladies
US10179118B2 (en) 2013-03-24 2019-01-15 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
US11938111B2 (en) 2013-03-24 2024-03-26 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of dimethyl fumarate
WO2014160633A1 (fr) 2013-03-24 2014-10-02 Xenoport, Inc. Compositions pharmaceutiques de fumarate de diméthyle
WO2014197860A1 (fr) 2013-06-07 2014-12-11 Xenoport, Inc. Procédé de production de monométhylfumarate
US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9682057B2 (en) 2013-09-06 2017-06-20 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US11135296B2 (en) 2014-03-24 2021-10-05 Arbor Pharmaceuticals, Llc Pharmaceutical compositions of fumaric acid esters
WO2016061393A1 (fr) 2014-10-15 2016-04-21 Xenoport, Inc. Composés de fumarate, compositions pharmaceutiques et procédés d'utilisation
WO2016124960A1 (fr) 2015-02-08 2016-08-11 Alkermes Pharma Ireland Limited Compositions de promédicaments à base de fumarate de monométhyle
WO2017060420A1 (fr) 2015-10-07 2017-04-13 Neurovive Pharmaceutical Ab Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes

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