CN104415026A - Application of deuterated fumaric acid-enriched derivative in treatment of multiple sclerosis - Google Patents
Application of deuterated fumaric acid-enriched derivative in treatment of multiple sclerosis Download PDFInfo
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- CN104415026A CN104415026A CN201310389730.0A CN201310389730A CN104415026A CN 104415026 A CN104415026 A CN 104415026A CN 201310389730 A CN201310389730 A CN 201310389730A CN 104415026 A CN104415026 A CN 104415026A
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- deuterium
- fumarate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The invention relates to application of a deuterated fumaric acid-enriched derivative in preparation of medicaments for treating or preventing multiple sclerosis. The deuterated fumaric acid-enriched derivative is selected from the following components: 2,3-dideuterium- or 2-deuterium- or 3-deuterium-dialkyl fumarate, 2,3-dideuterium- or 2-deuterium- or 3-deuterium-hyrogen monoalkyl fumarate, 2,3-dideuterium- or 2-deuterium- or 3-deuterium-salt monoalkyl fumarate, 2,3-dideuterium- or 2-deuterium- or 3-deuterium-monoamide fumarate, 2,3-dideuterium- or 2-deuterium- or 3-deuterium-salt monoamide fumarate, 2,3-dideuterium- or 2-deuterium- or 3-deuterium-diamide fumarate and 2,3-dideuterium- or 2-deuterium- or 3-deuterium-monoalkyl monoamide fumarate as well as the mixture of the compounds. The application is found based on the fact that cellular pathways of Nrf2 in cells can be activated by the deuterated fumaric acid derivative.
Description
Technical field
The present invention relates to the application of deuterated fumaric acid derivatives in the medicine for the preparation for the treatment of or prevention multiple sclerosis.
Background technology
Dialkyl fumarate and monoalkyl esters and salt thereof have been successfully used to treat the psoriasis longer time.This application has been recorded in numerous patents, see, such as, DE2530372, DE2621214 or EP-B-0312697.
In addition, the application (see DE19721099.6 and DE19853487.6) in treatment immune disease such as polyarthritis or multiple sclerosis of fumaric monoalkylester and diester and the application in transplant medicine (see DE19853487.6 and DE19839566.3) has been recorded.And, can know that from DE10101307.8 and DE10000577.2 fumaric monoalkylester and diester are being treated the disease of NF κ B-mediation and treating mitochondriopathy and/or the application as NF kB inhibitor.All publications mentioned describe fumaric monoalkylester and diester, and it optionally exists with the form of certain salt.
In addition, fumaric acid monoamides and the application of diamides the described indication for the treatment of can be known from DE10133004.0.There is aminoacid to be formed during these amide, and preferably have particular peptide to be formed.Finally, the application described disease is being treated from DE10217314.1 known fumaric acid oligomer and they.
Multiple sclerosis becomes feature with central nervous system's white matter demyelinating disease, the individual autoimmune disease occurred with environmental factors effect of inheritance susceptible, is a kind of central nervous system disease of chronic, struvite, demyelination.Can cause various symptom, comprise sensation change, visual disorder, muscle weakness, melancholy, coordination and difficulty speaking, serious fatigue, cognitive disorder, disequilibrium, body heat and pain etc., serious can cause activeness obstacle and deformity.Have 2 in world wide, 500,000 people suffers from multiple sclerosis, and average age of onset is generally at 20 to 40 years old, and women's number of the infected doubles male.Be successfully used to treat multiple sclerosis from the known dialkyl fumarate of US8399514 and monoalkyl esters and salt thereof.
Research proves, activating nuclear factor E2-related factor 2 (Nrf2) cell pathway is one of effective means for the treatment of multiple sclerosis.Nrf2 is the transcription factor that responsible a series of important antioxidase is expressed.Improve the content of Nrf2, the expression of its downstream gene can be raised, comprise antioxidase quinone oxidoreductase 1 (NQO1), regulate cellular stress, play the effect of neuroprotective.
Deuterium is the hydrogen isotope that nature exists.Deuterium is nontoxic, "dead", to human-body safety.Carbon-deuterium bond is more stable than carbon-hydrogen link, therefore, in the molecule hydrogen is changed to deuterium, may stablize the metabolism site in drug molecule, the prolong drug half-life, does not affect pharmacologically active simultaneously.
An object of the present invention is to provide the medicine of another kind for the treatment of multiple sclerosis.Another object of the present invention is on the basis of original medicine, introduce deuterated technology, provides a kind of drug metabolism to stablize, the medicine of the treatment multiple sclerosis that drug effect is suitable.
By the application of deuterated fumaric acid derivatives in the medicine for the preparation for the treatment of or prevention multiple sclerosis, reach object of the present invention.
Summary of the invention
The present invention relates to the application of deuterated fumaric acid derivatives in the medicine for the preparation for the treatment of or prevention multiple sclerosis be selected from following group: 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-dialkyl fumarate, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid hydrogen mono alkyl ester, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-monoalkyl esters salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid monoamides, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid monoamides salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid diamides, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-monoalkyl esters monoamides, and the mixture of these compounds.
The present invention relates to above-mentioned deuterated fumaric acid derivatives and activate the application in Nrf2 cell pathway.
Accompanying drawing explanation
Figure 1 shows that 2-deuterium dimethyl fumarate (d-DMF) and 2,3-bis-deuterium dimethyl fumarate (d, d-DMF) Nrf2 and NQO1 protein content in elevate cellular at a given concentration.
Detailed description of the invention
Present invention relates in general to the application of deuterated fumaric acid derivatives in the medicine for the preparation for the treatment of or prevention multiple sclerosis.These application are based on following discovery, i.e. Nrf2 cell pathway in deuterated fumaric acid derivatives energy active cell.As mentioned above, activating Nrf2 cell pathway is one of effective means for the treatment of multiple sclerosis.Nrf2 is the transcription factor that responsible a series of important antioxidase is expressed.Improve the content of Nrf2, the expression of its downstream gene can be raised, comprise antioxidase quinone oxidoreductase 1 (NQO1), regulate cellular stress, play the effect of neuroprotective.
Want deuterated fumaric acid derivatives used according to the invention can be selected from following group one or more: 2,3-bis-deuterium-or 2-deuterium-or 3-deuterium-dialkyl fumarate, 2,3-bis-deuteriums-or 2-deuterium-or 3-deuterium-fumaric acid hydrogen mono alkyl ester, the acceptable cation of physiology, especially alkali metal or alkaline earth metal cation or transition-metal cation such as Li
+, Na
+, K
+, NH
4 +, Mg
2+, Ca
2+, Fe
2+, Mn
2+and Zn
2+2,3-bis-deuteriums-or 2-deuterium-or 3-deuterium-monoalkyl esters salt, 2,3-bis-deuteriums-or 2-deuterium-or 3-deuterium-fumaric acid monoamides and 2,3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid diamides and their salt.
In a preferred embodiment, deuterated fumaric acid derivatives is selected from 2, the 3-bis-deuterium dialkyl fumarates be optionally substituted and 2, the 3-bis-deuterium monoalkyl esters of free acid or its salt and their form of mixtures.
In this case, particularly preferably be the application of formula (I) deuterated dialkyl fumarate,
Wherein X represents hydrogen or deuterium, and at least one X is deuterium, R1 and R2 can be identical or different, and represents straight chain, side chain or ring-type, saturated or unsaturated C independently
1-24alkyl or C
5-20aryl, and wherein said group can optionally by halogen, hydroxyl, C
1-14alkoxyl, C
1-4alkyl, nitro or cyano group replace.Particularly preferably, this deuterated dialkyl fumarate is 2,3-bis-deuterium dimethyl fumarate, 2-deuterium dimethyl fumarate, 2,3-bis-deuterium DEF and 2-deuterium DEF.
Usually, according to the present invention, alkyl should be understood to the alkyl with the saturated or unsaturated, straight chain, side chain of 1-24 carbon atom or ring-type, and it can optionally be replaced by one or more substituent group.Preferably, alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, cyclopenta, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, suberyl, octyl group, vinyl, pi-allyl, 2-ethoxy, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxy, 2-methoxy-propyl, 3-methoxy-propyl or 2,3-dimethoxypropyl.Methyl or ethyl are most preferred.
According to the present invention, aryl should be understood to have the aryl be optionally substituted of 5-20 carbon atom, the aryl or aralkyl of alkyl replacement, preferably has the aryl or aralkyl of the aryl of 6-10 carbon atom, alkyl replacement.Exemplary groups is phenyl, benzyl, phenethyl, tolyl, ethylbenzene, propyl phenyl and butylbenzene base, tert-butyl-phenyl.Phenyl and benzyl are particularly preferred.
The substituent group of described group is preferably selected from following group: halogen (F, Cl, Br, I), hydroxyl, C1-4 alkoxyl, C1-4 alkyl, nitro and cyano group.
Advantageously can also use the monoalkyl esters of formula (II),
Wherein X represents hydrogen or deuterium, and at least one X is deuterium, and R1 represents straight chain, side chain or ring-type, saturated or unsaturated C
1-24alkyl or C
5-20aryl, and wherein said group can optionally by halogen, hydroxyl, C
1-14alkoxyl, C
1-4alkyl, nitro or cyano group replace, and A represents hydrogen, is selected from Li
+, Na
+, K
+, Mg
2+, Ca
2+, Zn
2+, Fe
2+, and Mn
2+alkali metal or alkaline earth metal cation or the acceptable transition-metal cation of physiology, n equals 1 or 2, and corresponding with the valence mumber of A.
The exemplary compounds of formula (I) and (II) is 2, 3-bis-deuterium-or 2-deuterium-dimethyl fumarate, 2, 3-bis-deuterium-or 2-deuterium-DEF, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid methyl ethyl ester, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-monomethyl fumarate, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-monomethyl ester, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl calcium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate calcium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl magnesium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate magnesium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl zinc salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate zinc salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl iron salt and 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate iron salt.They can use individually or as mixture.
Preferably, the corresponding general formula (III) of amides used according to the invention,
Wherein X represents hydrogen or deuterium, and at least one X is deuterium, and Ra represents OR
3or by D-or L-aminoacid group-NH-CHR that amido link combines
4-COOH, wherein R
3hydrogen, straight chain or side chain, the C that is optionally substituted
1-24alkyl, phenyl or C
6-10aralkyl, and R
4it is amino acid whose side chain that is natural or synthesis; And Rb represents D-or the L-aminoacid group-NH-CHR combined by amido link
5-COOH, wherein R
5be can with R
4identical or different amino acid whose side chain that is natural or synthesis, or representative by amido link combine have 2-100 can be identical or different amino acid whose peptide group.
Side chain that is natural or synthesizing amino acid is selected from the side chain in following group typically: the side chain of Ala, Val, Leu, Ile, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.The side chain of Gly, Ala, Val, Ile, Leu and Me-Gly is preferred.If Ra is L-amino acid group-NH-CHR
4-COOH, and Rb is L-amino acid group-NH-CHR
5-COOH, then R4 and R5 can be identical or different.More preferably, R
4and R
5identical.Most preferably, Ra and Rb is glycine.
Or Ra can be group OR
3, and Rb can be L-amino acid group-NH-CHR
5-COOH or peptide group, R
5there is implication defined above.In this case, deuterated fumaric acid derivatives is 2,3-bis-deuterium-or 2-deuterium-or 3-deuterium-monoalkyl esters monoamides.
Peptide group is combined by amido link, and has the aminoacid that 2-100, preferably 2-30, most preferably 2-15 can be identical or different.Peptide group Rb is most preferably selected from following group: peptide hormone, somatomedin, cytokine, neurotransmitter, neuropeptide, antibody fragment, thrombin and ciclosporin and its derivant and fragment.Preferably, Ra is methoxy or ethoxy, and Rb is Gly, Ala, Val, Ile, Leu and Me-Gly.
Above-mentioned 2 can be used individually or mixedly, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-amides, or also can with 2,3-bis-above-mentioned deuteriums-or 2-deuterium-or 3-deuterium-monoalkyl esters or 2,3-bis-deuterium-or 2-deuterium-or 3-deuterium-dialkyl used in combination.
Fumaric acid derivatives used according to the invention can be prepared according to the known method as described in DE19721099.6, DE10133004.9 or DE10217314.1.The content of these publications is incorporated by reference here.
The form that described pharmaceutical preparation can be used to be suitable for oral administration, rectal administration, transdermal administration, dermal administration, ocular administration, nasal administration, pulmonary administration or parenteral route exists.Preferably, this pharmaceutical preparation is applicable to oral administration.So, it can exist with following form: the tablet of tablet, coating, capsule, granule, solution for drinking, liposome, nanoparticle, Nano capsule, microcapsule, micro-tablet, pellet agent (pellet) or powder, can also following form exist: be filled in the granule in capsule or wafer, the micro-tablet be filled in capsule or wafer, the pellet agent be filled in capsule or wafer, the powder that is filled in the nano-particle in capsule or wafer or is filled in capsule or wafer.Preferably, medicine exists with the form of nanoparticle, pellet agent or microplate, and it can optionally load in wafer or capsule.
Preferably, enteric coating can be provided for all solid oral dosage form.Such as, this enteric coating can impose on tablet, micro-tablet, pellet agent etc., but also can be applied to the capsule containing them.
Substantially, can prepare according to oral pharmaceutical form of the present invention according to the drawing method of classics and by direct pressing, and solid dispersion can be made according to fusion method or by spray drying process.If needed, can in the coating pan of classics, enteric coating be poured into step by step or be sprayed onto on label, or be used by fluidized bed plant according to known method.Subsequently, after completing drying, film coating can be used in identical device.
Preferably, the amount of one or more the deuterated fumaric acid derivatives this pharmaceutical preparation of every dosage unit being contained for the preparation of the use amount of the deuterated fumaric acid derivatives of pharmaceutical preparation according to the present invention correspond to and/or equals the amount of 1-500mg, the preferably deuterated fumaric acid of 10-300mg, most preferably 10-200mg.
Embodiment 1
The human colon cancer cell DLD1 that will obtain from American Tissue Culture Collection (Manassas, VA, USA) is with 5X10
5the density of individual cells/well be inoculated in 6 well culture plates containing in the DMEM of 10%FBS, process 24 hours with compound d-DMF or d, d-DMF with normal concentration (5,15, or 50uM).Be separated total cell lysate, SDS-PAGE be separated 50ug albumen, forwarded on nitrocellulose filter.Anti-Nrf2 and anti-NQO1 antibody is used to carry out Western Northern blot analysis, to detect the activation of Nrf2 cell pathway.Result display in Fig. 1: than undressed compared with control cells, the activation of Nrf2 significantly increases in the cell through compound d-DMF or d, d-DMF process.
Example of formulations
Embodiment 2
Prepare conventional tablet, it contains the deuterated dimethyl fumarate of 120.0mg.
Tabletting material is prepared than dry granulation according to following material:
| Material | Inventory |
| Dimethyl fumarate | 12kg |
| Microcrystalline Cellulose | 2kg |
| Cross-linking sodium carboxymethyl cellulose | 3kg |
| Pregelatinized Starch | 20kg |
| Micronized silica gel | 0.3kg |
| Magnesium stearate | 0.3kg |
Conveniently method for preparing tablet thereof prepare plain sheet, then namely coating solution coating obtains product.
Embodiment 3
Prepare conventional capsule agent, it contains the deuterated dimethyl fumarate of 120.0mg.
Tabletting material is prepared than dry granulation according to following material:
| Material | Inventory |
| Dimethyl fumarate | 12kg |
| Microcrystalline Cellulose | 2kg |
| Cross-linking sodium carboxymethyl cellulose | 3kg |
[0050]
| Pregelatinized Starch | 20kg |
| Micronized silica gel | 0.3kg |
The method preparation preparing capsule filling conveniently, then namely fill capsule obtains product.
Embodiment 4
Preparation has the film coated tablet of enteric coating, and it contains the deuterated dimethyl fumarate of 120.0mg.
Pulverize the deuterated dimethyl fumarate of 12kg, acutely mix, and by 800 mesh sieve homogenize.Then, 21kg starch derivatives, 2kg microcrystalline Cellulose, 0.6kg polyvinylpyrrolidone, 4kg carboxymethylstach sodium, 0.3kg colloid silicic acid mix homogeneously is for subsequent use.Deuterated dimethyl fumarate is added in whole mixture of powders, mixing, by 200 mesh sieve homogenize, then bonding particle is processed into according to a conventional method with the aqueous solution of 2% polyvinylpyrrolidone, and then in the dry state, add it and contain 80% Talcum, 10% silicic acid and 10% magnesium stearate, mix homogeneously.Then, by conventional method, this mixture being pressed into weight is 420mg, and diameter is the lug of 10.0mm.Except this typical drawing method, additive method also can be used to prepare tablet, such as direct compression or the solid dispersion method according to fusion method and spray drying method.
Enteric coating:
2.250kg hydroxypropyl methyl cellulose phthalate solution is dissolved in the solvent mixture be made up of 2.50 liters of deionized waters, 13 liters of acetone and 13 liters of ethanol (94 % by weight), then the Oleum Ricini of 0.240kg is added in solution.In conventional manner, solution poured into step by step or be sprayed onto on the label in coating pan.After corresponding drying, carry out film coating subsequently.Described coating solution composition is by polyacrylic resin 12.5%4.8kg, Talcum 0.34kg, titanium oxide (VI) 0.52kg, coloring agent 0.21kg and the solution composition of polyethylene glycol 6000 0.12kg in the solvent mixture be made up of 8.2kg2-propanol, 0.06kg glyceryl triacetate and 0.2kg deionized water.After being evenly distributed in coating pan or fluid bed, conventionally carry out drying and polishing.
Embodiment 5
Prepare enteric-coated capsule, it contains the deuterated dimethyl fumarate of 120mg.
12kg dimethyl fumarate is acutely mixed with the mixture be made up of 15kg starch, 6kg lactose, 2kg microcrystalline Cellulose, 1kg polyvinylpyrrolidone and 4kg carboxymethylstach sodium, and by 800 mesh sieve mix homogeneously.Together with the aqueous solution of 2% polyvinylpyrrolidone, according to a conventional method whole mixture of powders is processed into bonding particle, and mixes with following materials in the dry state, comprise 0.35kg colloid silicic acid, 0.5kg magnesium stearate and 1.5kg Talcum composition.This uniform every part, mixture 500.0mg is filled in suitable capsule, then in accordance with known methods, for described capsule provides by Cellulose ethyl hydroxypropyl ether phthalate ester and the enteric coating that forms as the Oleum Ricini of softening agent.
Claims (15)
1. be selected from the application of deuterated fumaric acid derivatives in the medicine for the preparation for the treatment of or prevention multiple sclerosis in following group.
2. application according to claim 1, wherein said deuterated fumaric acid derivatives is selected from the deuterated dialkyl fumarate of one or more formula I
Wherein
X represents hydrogen or deuterium, and at least one X is deuterium,
R1 and R2 can be identical or different, and represent straight chain, side chain or ring-type, saturated or unsaturated C independently
1-24alkyl or C
5-20aryl, and wherein said group can optionally by halogen, hydroxyl, C
1-14alkoxyl, C
1-4alkyl, nitro or cyano group replace.
3. application according to claim 1, wherein said deuterated fumaric acid derivatives is selected from the deuterated monoalkyl esters of one or more formula II
Wherein
X represents hydrogen or deuterium, and at least one X is deuterium,
R1 represents straight chain, side chain or ring-type, saturated or unsaturated C
1-24alkyl or C
5-20aryl, and wherein said group can optionally by halogen, hydroxyl, C
1-14alkoxyl, C
1-4alkyl, nitro or cyano group replace,
A represents hydrogen, or is selected from Li
+, Na
+, K
+, Mg
2+, Ca
2+, Zn
2+, Fe
2+, and Mn
2+alkali metal or alkaline earth metal cation or the acceptable transition-metal cation of physiology,
N equals 1 or 2, and corresponding with the valence mumber of A.
4. application according to claim 1, the compound that wherein said deuterated fumaric acid derivatives is selected from one or more formulas (I) and (II) with and composition thereof.
5. application according to claim 4, wherein said deuterated fumaric acid derivatives is selected from following group: 2, 3-bis-deuteriums-dimethyl fumarate, 2-deuterium-dimethyl fumarate, 2, 3-bis-deuteriums-DEF, 2-deuterium-DEF, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumaric acid methyl ethyl ester, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-methyl hydrogen fumarate, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl hydrogen fumarate, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl calcium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate calcium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl magnesium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate magnesium salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl zinc salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate zinc salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-fumarate dimethyl iron salt, 2, 3-bis-deuterium-or 2-deuterium-or 3-deuterium-ethyl fumarate iron salt with and composition thereof.
6. application according to claim 1, wherein said deuterated fumaric acid derivatives is selected from the deuterated amides of one or more general formula III
Wherein
X represents hydrogen or deuterium, and at least one X is deuterium,
Ra represents OR
3or by D-or L-aminoacid group-NH-CHR that amido link combines
4-COOH, wherein R
3hydrogen, straight chain or side chain, the C that is optionally substituted
1-24alkyl, phenyl or C
6-10aralkyl, and R
4it is amino acid whose side chain that is natural or synthesis; And
Rb represents D-or the L-aminoacid group-NH-CHR combined by amido link
5-COOH, wherein R
5be can with R
4identical or different amino acid whose side chain that is natural or synthesis, or representative by amido link combine have 2-100 can be identical or different amino acid whose peptide group.
7. application according to claim 6, wherein said amino acid whose side chain that is natural or synthesis is selected from the side chain in following group:: Ala, Val, Leu, Ile, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, citrulline, Hey, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.
8. application according to claim 6, wherein said amino acid whose side chain that is natural or synthesis is selected from the side chain in following group: Gly, Ala, Val, Ile, Leu and Me-Gly.
9. application according to claim 6, wherein Ra is group-OR
3, and Rb is L-amino acid group-NH-CHR
5-COOH or peptide group, R
5as claim 6 define.
10. according to the application of one of claim 2,3 and 6, wherein C
1-24alkyl is selected from following group: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, cyclopenta, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, suberyl, octyl group, vinyl, pi-allyl, 2-hydroxyethyl, 2 or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxy, 2-methoxy-propyl, 3-methoxy-propyl or 2,3-dimethoxypropyl.
11. application according to claim 10, wherein C
1-24alkyl is selected from methyl and ethyl.
12. according to the application of any one in foregoing Claims, and the form wherein used to be suitable for oral administration, rectal administration, transdermal administration, dermal administration, ocular administration, nasal administration, pulmonary administration or parenteral route provides described medicine.
13. application according to claim 12, wherein provide described medicine with following form: the tablet of tablet, coating, capsule, granule, solution for drinking, liposome, nanoparticle, Nano capsule, microcapsule, micro-tablet, pellet agent or powder, following form can also provide described medicine: be filled in the granule in capsule or wafer, the micro-tablet be filled in capsule or wafer, the pellet agent be filled in capsule or wafer, the powder that is filled in the nano-particle in capsule or wafer or is filled in capsule or wafer.
14. application according to claim 12, wherein said medicine exists with the form of nanoparticle, pellet agent or microplate, and they can optionally load in wafer or capsule, wherein solid oral ordinary preparation type, or have enteric coated formulation type.
15. application any one of foregoing Claims, wherein said medicine contains the deuterated fumaric acid derivatives of the amount being equivalent to the deuterated fumaric acid of 1-500mg.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310389730.0A CN104415026A (en) | 2013-08-31 | 2013-08-31 | Application of deuterated fumaric acid-enriched derivative in treatment of multiple sclerosis |
| PCT/CN2014/085636 WO2015027949A1 (en) | 2013-08-31 | 2014-08-30 | Application of deuterated fumaric acid derivatives in treatment of multiple sclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310389730.0A CN104415026A (en) | 2013-08-31 | 2013-08-31 | Application of deuterated fumaric acid-enriched derivative in treatment of multiple sclerosis |
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| Publication Number | Publication Date |
|---|---|
| CN104415026A true CN104415026A (en) | 2015-03-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310389730.0A Pending CN104415026A (en) | 2013-08-31 | 2013-08-31 | Application of deuterated fumaric acid-enriched derivative in treatment of multiple sclerosis |
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| Country | Link |
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| CN (1) | CN104415026A (en) |
| WO (1) | WO2015027949A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023045377A1 (en) * | 2021-09-27 | 2023-03-30 | 广州谷森制药有限公司 | Novel deuterated peg lipid compound, preparation method therefor, composition and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105142628A (en) | 2012-12-21 | 2015-12-09 | 比奥根玛公司 | Deuterium substituted fumarate derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19721099C2 (en) * | 1997-05-20 | 1999-12-02 | Fumapharm Ag Muri | Use of fumaric acid derivatives |
| DE19853487A1 (en) * | 1998-11-19 | 2000-05-25 | Fumapharm Ag Muri | Use of dialkyl fumarate for treating transplant rejection and autoimmune disease |
| CA2736091A1 (en) * | 2008-09-03 | 2010-03-11 | Teva Pharmaceutical Industries Ltd. | 2-oxo-1,2-dihydro-quinoline modulators of immune function |
| CN105142628A (en) * | 2012-12-21 | 2015-12-09 | 比奥根玛公司 | Deuterium substituted fumarate derivatives |
| CN103724198A (en) * | 2013-11-28 | 2014-04-16 | 镇江圣安医药有限公司 | Novel derivative of dimethyl fumarate and application of novel derivative |
-
2013
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023045377A1 (en) * | 2021-09-27 | 2023-03-30 | 广州谷森制药有限公司 | Novel deuterated peg lipid compound, preparation method therefor, composition and application thereof |
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| WO2015027949A1 (en) | 2015-03-05 |
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Application publication date: 20150318 |