CN114957148A - Fumaric acid derivative and preparation method and medical application thereof - Google Patents
Fumaric acid derivative and preparation method and medical application thereof Download PDFInfo
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- CN114957148A CN114957148A CN202210167160.XA CN202210167160A CN114957148A CN 114957148 A CN114957148 A CN 114957148A CN 202210167160 A CN202210167160 A CN 202210167160A CN 114957148 A CN114957148 A CN 114957148A
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- fumaric acid
- acid derivative
- compound
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- condensing agent
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- 150000002237 fumaric acid derivatives Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 31
- NKHAVTQWNUWKEO-NSCUHMNNSA-N monomethyl fumarate Chemical compound COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 claims description 29
- NKHAVTQWNUWKEO-UHFFFAOYSA-N fumaric acid monomethyl ester Natural products COC(=O)C=CC(O)=O NKHAVTQWNUWKEO-UHFFFAOYSA-N 0.000 claims description 27
- 229940005650 monomethyl fumarate Drugs 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical group CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 230000002884 effect on inflammation Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 24
- 229960004419 dimethyl fumarate Drugs 0.000 description 22
- 239000003814 drug Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- 230000003110 anti-inflammatory effect Effects 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 6
- 229960003151 mercaptamine Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 238000000465 moulding Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical compound O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 229920003045 dextran sodium sulfate Polymers 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- -1 Dimethyl Fumarate Chemical compound 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IHDKBHLTKNUCCW-UHFFFAOYSA-N 1,3-thiazole 1-oxide Chemical compound O=S1C=CN=C1 IHDKBHLTKNUCCW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000004440 column chromatography Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- TWYIPMITVXPNEM-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidine-2,5-dione Chemical group OCCN1C(=O)CCC1=O TWYIPMITVXPNEM-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-M 4-methoxy-4-oxobutanoate Chemical group COC(=O)CCC([O-])=O JDRMYOQETPMYQX-UHFFFAOYSA-M 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 description 1
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-N butanedioic acid monomethyl ester Natural products COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 1
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- 230000007302 negative regulation of cytokine production Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- 150000003573 thiols Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a novel fumaric acid derivative, which has a structural formula shown as a formula (I):
wherein R is 1 Or R 2 Each independently selected from: hydrogen, C1-C6 linear or branched alkyl, benzyl, phenyl or mixtures containingPhenyl as a substituent; x, Y are each independently selected from: o or S. The derivatives have good intervention effect on inflammation-related diseases. The invention also provides a preparation method of the derivative and an intermediate thereof, a pharmaceutical composition and medical application thereof.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to fumaric acid derivatives, a preparation method of the compounds and medical application of the compounds in treating inflammation-related diseases.
Background
Dimethyl Fumarate (DMF), namely Dimethyl Fumarate, is a marketed drug
(Biogen), which has been approved for the treatment of autoimmune disease multiple sclerosis. DMF metabolizes in vivo to Monomethyl Fumarate (MMF) to function. DMF and MMF have been shown to have the potential to modulate the body's immunity and to interfere with inflammation. For example, DMF, which can ameliorate colitis caused by dextran sodium sulfate by activating Nrf2 and/or inhibiting NLRP3, is a candidate for the treatment of anti-inflammatory bowel disease (Biochemical Pharmacology, 2016, 37-49. FUMADERM, a drug with DMF and MMF as the main active ingredients, has been approved in Germany for the treatment of psoriasis as early as 1994. however, FUMADERM exhibits a high inter-patient variability and food significantly reduces its efficacy. the site of absorption of this drug reaches a peak level in the small intestine about 5-6 hours after administration, but significant side effects occur in 70-90% of the patients administered.
Desloximate fumarate (DRF) is a novel fumaric acid derivative, and clinical studies have shown that the rate of patients whose treatment was discontinued due to gastrointestinal adverse events is less than 1%. Which can improve the above-mentioned side effects of dimethyl fumarate. Compared with DMF, DRF can maintain lower and more stable plasma peak value, prolong the action time of the medicine and reduce the degree and incidence of side effects.
There is still a need to develop novel fumaric acid derivatives having a long-lasting pharmacological effect, an ideal anti-inflammatory activity and a small gastrointestinal side effect. Therefore, a series of novel fumaric acid derivatives are designed and synthesized based on monomethyl fumarate, and the derivatives are found to have outstanding in-vivo and in-vitro anti-inflammatory effects.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides a novel fumaric acid derivative which has good intervention effect on inflammation-related diseases. The invention also provides a preparation method of the derivative and an intermediate thereof, a pharmaceutical composition and medical application thereof.
The technical scheme is as follows:
the first object of the present invention is to provide a fumaric acid derivative represented by the following formula (I):
wherein R is 1 Or R 2 Each independently selected from: hydrogen, straight or branched chain alkyl of 1-6 carbons, benzyl, phenyl or substituted phenyl;
x, Y are each independently selected from: o or S.
Further, R 1 Or R 2 Each independently selected from: hydrogen, methyl, ethyl, isopropyl, benzyl, phenyl.
Further, the fumaric acid derivative is any one of the following compounds:
a second object of the present invention is to provide a process for producing the aforementioned fumaric acid derivative, which comprises: mixing a compound II and monomethyl fumarate (MMF) with a solvent, a condensing agent and an alkali according to any proportion, and carrying out condensation reaction to obtain a compound I, wherein the structural formula of the compound II is shown in the specification
Wherein R is 1 Or R 2 Each independently selected from: hydrogen, straight or branched chain alkyl of 1-6 carbons, benzyl, phenyl or substituted phenyl;
x, Y are each independently selected from: o or S.
Further, R 1 Or R 2 Each independently selected from: hydrogen, methyl, ethyl, isopropyl, benzyl, phenyl.
The synthetic route of the method for preparing the derivative of the formula (I) is shown as follows:
further, the solvent is selected from one or more of acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water and dichloromethane, and the concentration of the monomethyl fumarate in the solvent is 0.005-5 mol/L.
Further, the condensing agent is pivaloyl chloride, isobutyl chloroformate, DCC, (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU or HBTU, preferably, the condensing agent is pivaloyl chloride, and the molar ratio of the condensing agent to monomethyl fumarate is 1:1 to 10: 1.
Further, the base is triethylamine, diisopropylethylamine, DMAP or DBU, preferably, the base is triethylamine, and the molar ratio of the base to the condensing agent is 1:1 to 10: 1.
Further, the preparation method also comprises the step of adding an additive, wherein the additive is lithium chloride, magnesium bromide or copper chloride, and the molar ratio of the additive to the monomethyl fumarate is 0.1: 1-10: 1.
Further, the reaction temperature is-50 ℃ to 80 ℃, and preferably, the reaction temperature is-20 ℃ to 50 ℃.
The third purpose of the invention is to provide the application of the fumaric acid derivative in preparing anti-inflammatory medicines.
In the invention, the following steps:
EDCI refers to: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (CAS: 25952-53-8)
DMAP means: 4-dimethylaminopyridine (CAS: 1122-58-3)
DCC means: dicyclohexylcarbodiimide (CAS: 538-75-0)
HATU means: 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (CAS: 148893-10-1)
HBTU means: o-benzotriazole-tetramethylurea hexafluorophosphate (CAS: 94790-37-1)
DBU means: 1, 8-diazabicyclo [5.4.0] undec-7-ene (6674-22-2)
Compared with the prior art, the invention has the following beneficial effects:
the fumaric acid derivative provided by the invention has ideal anti-inflammatory activity; desirable in vitro metabolic properties; less gastrointestinal side effects.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1.
FIG. 2 is a graph showing the change in colon length after the administration of a dry dose in an ulcerative colitis test.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Example 1
This example shows that Compound II is 1, 3-thiazolidin-2-one
Monomethyl fumarate (260mg,2mmol), EDCI (767mg, 4mmol) and DMAP (488mg, 4mmol) were dissolved in dichloromethane (10mL), and a solution of 1, 3-thiazolidin-2-one (240mg, 2.3mmol) in dichloromethane (2mL) was added dropwise and stirred at room temperature for 18 hours. Purification by column chromatography gave compound 1 as a white solid, 53.3mg, 11% yield. 1 H NMR(300MHz,Chloroform-d)δ7.93(d,J＝15.5 Hz,1H),6.88(d,J＝15.5Hz,1H),4.24(t,J＝7.2Hz,2H),3.82(s,3H),3.37(t,J＝7.2Hz,2H).
Example 2
This example Compound II is a thiazolone derivative
Monomethyl fumarate (260mg,2mmol), triethylamine (400mg, 4mmol) were dissolved in anhydrous tetrahydrofuran (10mL) followed by the addition of pivaloyl chloride (480. mu.L, 4mmol) and stirring at-20 ℃ for 2 h. Anhydrous lithium chloride (157mg, 3.7mmol) and thiazolone derivative (260mg,2mmol) were added successively, and stirred at-20 ℃ for 4 hours. The reaction solution was adjusted to pH with 0.1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and purified by column chromatography to give compound 2 as a white solid 298mg, 61% yield. And Mp: 142 ℃ and 143 ℃; [ M + H ]] + ：244.0655。
Example 3
With reference to the method of example 2, the charged amount of monomethyl fumarate was (260mg,2mmol), and the compound II in this example was
(300mg, 2.1mmol) to give Compound 3
212mg of white solid, yield 41%. [ M + Na ]] + ：280.0606。
Example 4
Referring to example 2, the charge of monomethyl fumarate (130mg, 0.5mmol) was determined as compound II
(400mg, 2,1mmol) to give Compound 4
142mg of a white solid, yield 47%. [ M + H ]] + ：306.0801。
Example 5
Referring to example 2, the charge of monomethyl fumarate (130mg, 0.5mmol) was determined as compound II
(275mg, 1.5mmol) at a reaction temperature of 50 ℃ to give Compound 5
192mg of a white solid, yield 66%. And Mp: 150 ℃ and 151 ℃; [ M + H ]] + ：292.0641。
Example 6
According to the method of reference example 1, monomethyl fumarate was charged (390mg, 1.5mmol), and Compound II of this example was 1, 3-oxazolidin-2-one
(261mg, 3mmol) at a reaction temperature of 80 ℃ to give 104mg of a colorless oil in a yield of 16%. 1 H NMR(300MHz,Chloroform-d)δ8.17(d,J＝15.5Hz,1H),6.98(d,J＝15.7Hz, 1H),4.50(t,J＝7.9Hz,2H),4.21–4.06(m,2H),3.84(s,3H).
Example 7 preparation of negative control
By the method in reference example 1, monomethyl fumarate was replaced with monomethyl succinate (369mg) and the charge of 1, 3-thiazolidin-2-one was 309mg, to give Compound 7
518mg of colorless crystals, yield 86%. 1 H NMR (300MHz,Chloroform-d)δ4.15(t,J＝7.3Hz,2H),3.67(s,3H),3.29(t,J＝7.3Hz,2H),3.16(t,J ＝6.4Hz,2H),2.63(t,2H).
EXAMPLE 8 preparation of Positive control
Referring to the method of example 1, the charged amount of monomethyl fumarate was 260mg, the amount of monomethyl fumarateThe 1, 3-thiazolidin-2-one was replaced with 1- (2-hydroxyethyl) pyrrolidine-2, 5-dione (286.8mg) to give compound 8
198mg of white powder, 39% yield. 1 H NMR(300MHz,Chloroform-d)δ6.84(s,1H),4.39(t,J＝5.3Hz,2H),3.82(s,3H), 2.75(s,4H).
Example 9
In vitro thiol binding assay
The experimental principle is as follows: since dimethyl fumarate/monomethyl fumarate exerts its pharmacological effects in vivo by binding to sulfhydryl groups on proteins or other residues in the organism, we have designed an in vitro sulfhydryl group binding capacity test based on the literature (J.Med.chem.2017,60, 3656-.
The experimental method comprises the following steps: evaluation of the binding ability of the synthesized compound was carried out by designing the following experiment.
1. Three secondary wells were set for each sample on a 96-well plate at time points of 0, 5, 10, 15, 20, 30, 45, 60, 90 minutes.
2. Preparing a solution: preparing 10mM DMSO (dimethyl sulfoxide) solution of a sample to be detected, and diluting the DMSO solution to 0.5mM by using PBS (phosphate buffered saline);
0.014mol of DTNB (5,5' -dithiobis (2-nitrobenzoic acid)) was dissolved in 25mL of PBS;
③ an ultra-pure aqueous solution (10mM) of mercaptoethylamine was prepared and subsequently diluted to 0.5mM with PBS.
3. Adding mercaptoethylamine and a sample solution to be detected in equal volume into a 96-well plate, reacting at 37 ℃ to a corresponding time point, adding 150 mu L of DTNB solution to terminate the reaction, and reading corresponding absorbance at 405nm after reacting for 1 minute
4. While cysteamine standard curves were formulated with reference to the above literature.
The experimental results are as follows: DMF (dimethyl fumarate), MMF (monomethyl fumarate) and a compound 8 are set as positive controls in the experiment, samples to be detected are compounds 1 to 6, and a compound 7 is a negative control; the final results were as follows:
table 1: reaction Rate constant k of Compound with cysteamine 2 (×10 -5 ·μM -1 ·min -1 )
And (4) checking and concluding: in the reaction of the tested compound with cysteamine, compound 1 showed stronger reactivity than the control drug DMF. The reactivity of the compound 1, the compound 2, the compound 3, the compound 4, the compound 5 and the compound 6 with the cysteamine is better than that of the MMF. The compound disclosed by the invention has better mercaptan binding force and potential to play an anti-inflammatory role by influencing free sulfydryl in vivo.
Example 10
Evaluation of anti-inflammatory Activity of Compounds (LPS-induced in vitro model of inflammation)
The experimental principle is as follows: LPS is adopted to induce a mouse mononuclear macrophage leukemia cell RAW264.7 cell inflammation model.
The experimental method comprises the following steps: selecting RAW264.7 cells (8 × 10) with good growth state 4 /mL) were inoculated into 48-well plates, 6 wells per group, and cultured for 24 hours. Blank group (+ DMEM culture medium), LPS-stimulated group (+0.5 μ g/mL), and administration group (LPS + drug) were set, and the administration group drugs included: compounds 1 to 6, positive control DMF (dimethyl fumarate), MMF (monomethyl fumarate). Each group was 3 replicates (5 μ M drug/blank pre-incubated with cells for 2 hours before LPS stimulation for 24 h). Supernatants were taken for ELISA for TNF-. alpha.and IL-6.
Table 2: inhibition of inflammatory cytokine production by compounds
The experimental conclusion is that: compound 1 showed the best inhibition of cytokine production, better than the positive drug DMF; more remarkably, the compound 1, the compound 2, the compound 3, the compound 4, the compound 5 and the compound 6 have better effects than MMF; whereas MMF is considered to be an active metabolite in DMF in vivo. Therefore, the compound reported in the technical scheme has excellent anti-inflammatory related drug effect.
Example 11 in vivo efficacy test in mice
The experimental principle is as follows: whether the compounds can alleviate the ulcerative colitis induced by Dextran Sodium Sulfate (DSS) was investigated by an acute model of mouse ulcerative colitis. Dimethyl fumarate (positive control), a compound 1 and a compound 6 are selected for in vivo activity study.
Experimental animals: c57BL/6Slac mice, 6-8 weeks old, n-8.
The experimental scheme is as follows: the preventive administration is carried out for 7 days (0.3mmol/kg, solvent is 0.5 percent of CMC-Na, the intragastric administration is carried out once a day); molding and dosing: the 3% DSS solution was drunk freely and molded from day 0; molding and continuing to administer the medicament in the same manner; the drug is administered 7 days after molding. ③ on day 8, water and food were prohibited, and on day nine, sacrifice was done, and blood and colon samples were taken.
Grouping experiments: (A) a model group; (B) blank group; (C) DMF; (D) compound 1; (E) compound 6.
The drug effect index is as follows:
DAI (disease Activity index) score
Table 3: scoring criteria
Wherein, the fecal occult blood determination adopts an o-toluidine-glacial acetic acid method. The principle of the method is as follows: the ferrohemoglobin in the hemoglobin has peroxidase-like activity, can catalyze hydrogen peroxide to release nascent oxygen, and oxidize o-toluidine into o-azobenzene, which is blue.
The experimental results are as follows:
table 4: day 7 DAI score after Molding
As shown in the colon length (figure 2) and DAI score table at 7 days after molding, the compounds 1 and 6 can better improve the colon length, and the effect is equivalent to that of the positive drug DMF. Whereas compound 1 outperformed DMF and compound 6 approached DMF on the DAI score.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that modifications and variations can be made by those skilled in the art in light of the above description, and these modifications and variations are within the scope of the appended claims.
Claims (10)
1. A fumaric acid derivative is characterized in that the structural formula is shown as the formula (I):
wherein R is 1 Or R 2 Each independently selected from: hydrogen, straight or branched chain alkyl of 1-6 carbons, benzyl, phenyl or substituted phenyl;
x, Y are each independently selected from: o or S.
2. The fumaric acid derivative according to claim 1, wherein R is 1 Or R 2 Each independently selected from: hydrogen, methyl, ethyl, isopropyl, benzyl, phenyl.
3. The fumaric acid derivative according to claim 1, wherein the fumaric acid derivative is any one of the following compounds:
4. a process for preparing the fumaric acid derivative according to claim 1, which comprises: reacting compound II with monomethyl fumarateMixing a solvent, a condensing agent and alkali, and carrying out condensation reaction to obtain a compound I, wherein the structural formula of the compound II is shown in the specification
Wherein R is 1 Or R 2 Each independently selected from: hydrogen, straight or branched chain alkyl of 1-6 carbons, benzyl, phenyl or substituted phenyl;
x, Y are each independently selected from: o or S.
5. The method according to claim 4, wherein the solvent is selected from one or more of acetonitrile, tetrahydrofuran, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water and dichloromethane, and the concentration of the monomethyl fumarate in the solvent is 0.005-5 mol/L.
6. The process of claim 4, wherein the condensing agent is pivaloyl chloride, isobutyl chloroformate, DCC, (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU or HBTU, and the molar ratio of the condensing agent to monomethyl fumarate is 1:1 to 10:1, and preferably the condensing agent is pivaloyl chloride.
7. The method of claim 4, wherein the base is triethylamine, diisopropylethylamine, DMAP or DBU, and the molar ratio of the base to the condensing agent is 1:1 to 10: 1; preferably, the base is triethylamine.
8. The method of claim 4, wherein the preparation method further comprises adding an additive, wherein the additive is lithium chloride, magnesium bromide or copper chloride, and the molar ratio of the additive to the monomethyl fumarate is 0.1:1 to 10: 1.
9. The process of claim 4, wherein the reaction temperature is from-50 ℃ to 80 ℃, preferably from-20 ℃ to 50 ℃.
10. Use of the fumaric acid derivative according to claim 1 for producing an anti-inflammatory agent.
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| JPWO2019208023A1 (en) * | 2018-04-27 | 2021-09-09 | 国立大学法人千葉大学 | An optically active rare earth complex, an asymmetric catalyst composed of this complex, and a method for producing an optically active organic compound using this asymmetric catalyst. |
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| WO2000051609A1 (en) * | 1999-03-02 | 2000-09-08 | Merck & Co., Inc. | 3-alkyl substituted pyrrolidine modulators of chemokine receptor activity |
| KR20110088623A (en) * | 2010-01-29 | 2011-08-04 | 순천향대학교 산학협력단 | Pharmaceutical compositions containing fumaryl oxazolidinone derivatives for treating and preventing of inflammatory diseases or immune diseases |
| JPWO2019208023A1 (en) * | 2018-04-27 | 2021-09-09 | 国立大学法人千葉大学 | An optically active rare earth complex, an asymmetric catalyst composed of this complex, and a method for producing an optically active organic compound using this asymmetric catalyst. |
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