CN104341362B - Triazole sulphonyl malonic acid compounds, Preparation Method And The Use - Google Patents
Triazole sulphonyl malonic acid compounds, Preparation Method And The Use Download PDFInfo
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- CN104341362B CN104341362B CN201410582690.6A CN201410582690A CN104341362B CN 104341362 B CN104341362 B CN 104341362B CN 201410582690 A CN201410582690 A CN 201410582690A CN 104341362 B CN104341362 B CN 104341362B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 Triazole sulphonyl malonic acid compounds Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 12
- 201000005569 Gout Diseases 0.000 claims abstract description 10
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 42
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 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 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 9
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 7
- 229940116269 uric acid Drugs 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 11
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 229960003838 lesinurad Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- ASUMVAPLXCRBMA-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydro-1,4-benzoxazin-4-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2OCC1 ASUMVAPLXCRBMA-UHFFFAOYSA-N 0.000 description 2
- 241001415342 Ardea Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229940083914 URAT1 inhibitor Drugs 0.000 description 2
- 235000009392 Vitis Nutrition 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960002529 benzbromarone Drugs 0.000 description 2
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- YLWAQARRNQVEHD-PBZHRCKQSA-N tazettine Chemical compound O([C@]1(O)CN2C)CC3=CC=4OCOC=4C=C3[C@]31[C@@H]2C[C@H](OC)C=C3 YLWAQARRNQVEHD-PBZHRCKQSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108010068701 Pegloticase Proteins 0.000 description 1
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 102100030935 Solute carrier family 2, facilitated glucose transporter member 9 Human genes 0.000 description 1
- XEEPVFFWNATEGX-IUHNQTRMSA-N Tazettadiol Natural products C1=C(CO)C([C@]23[C@H](O)CN(C)[C@H]2C[C@@H](C=C3)OC)=CC2=C1OCO2 XEEPVFFWNATEGX-IUHNQTRMSA-N 0.000 description 1
- 108010092464 Urate Oxidase Proteins 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- IDAGXRIGDWCIET-SDFKWCIISA-L disodium;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IDAGXRIGDWCIET-SDFKWCIISA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical class [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229960001376 pegloticase Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- ZVIWEYTXPYNLGB-UHFFFAOYSA-M potassium;4-[[2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-chlorobenzoate Chemical compound [K+].ClC1=CC(C(=O)[O-])=CC=C1NC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 ZVIWEYTXPYNLGB-UHFFFAOYSA-M 0.000 description 1
- KLJOYDMUWKSYBP-SLEMLFNQSA-N pretazettine Natural products CO[C@H]1C[C@@H]2N(C)C[C@@H]3O[C@@H](O)c4cc5OCOc5cc4[C@]23C=C1 KLJOYDMUWKSYBP-SLEMLFNQSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- YLWAQARRNQVEHD-UHFFFAOYSA-N sekisanoline Natural products CN1CC2(O)OCC3=CC=4OCOC=4C=C3C32C1CC(OC)C=C3 YLWAQARRNQVEHD-UHFFFAOYSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Abstract
The present invention relates to the drug world relevant to hyperuricemia and gout.Specifically, the present invention relates to a class containing uric acid transporter body 1 inhibitor of triazole sulphonyl malonic acid structure, its preparation method and pharmaceutical composition and their application in preparing diabetes medicament containing them.Wherein, R is selected from H, C1‑C8Alkyl, C3‑C6Cycloalkyl.
Description
Technical field
The present invention relates to treat the drug world that hyperuricemia is relevant with gout.Specifically, the present invention relates to height
Hyperuricemia and the gout medicative class uric acid transporter body 1 (urate containing triazole sulphonyl malonic acid structure
Transporter 1, URAT1) inhibitor, preparation method, containing they pharmaceutical composition and in purposes pharmaceutically.
Background technology
Gout is a kind of chronic metabolic disease, is deposited on the portions such as joint with hyperuricemia and monosodium urate salt (MSU)
Position and the pain that causes is principal character, main cause is purine metabolic disturbance and/or uric acid excretion disorder.According to estimates, at present
Whole world patient with gout has more than 2,000 ten thousand.The medicine being currently used for treating gout includes for lenitive anti-inflammatory drug (such as the autumn
Tazettine etc.), suppression uricopoiesis medicine (xanthine oxidase inhibitor as representative with allopurinol and Febuxostat), slightly urinate
Acid excretion medicine (the urate excretion medicine with probenecid, sulphinpyrazone, benzbromarone and losartan as representative) and uricase (with
Pegloticase is representative).There is the toxic and side effects of different degree in these medicines, causes explosive liver as benzbromarone has
Scorching danger, allopurinol has liver and the untoward reaction such as bone marrow toxicity and allergy, etc..
Lesinurad (RDEA 594) is a kind of can be suppressed uric acid transporter body in kidney by what Ardea company developed
(urate transporter 1, URAT1) and discharged the oral drugs of uric acid in blood by the approach of urine, locate at present
In III phase clinical stage.Antiviral drugs RDEA806 that Lesinurad is researched and developed by Valeant company the earliest develops.Existing
Proprietary rights at Lesinurad is purchased due to Ardea company at present and is belonged to Astra Zeneca.
The invention discloses the class URAT1 inhibitor containing triazole sulphonyl malonic acid structure, these compounds can be used for
Preparation treatment hyperuricemia and the medicine of gout.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, there is a compounds of formula I.
It is a further object to provide the method that preparation has compounds of formula I.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of logical formula (I) and has a following structural formula:
Wherein, R is selected from H, C1-C8Alkyl, C3-C6Cycloalkyl.
Preferably: R is selected from H, C1-C4Alkyl, C3-C4Cycloalkyl.
The compound more preferably leading to formula (I) has following structure,
Logical formula (I) compound of the present invention is synthesized by following route:
Compound II reacts in the presence of a base with alpha-brominated dimethyl malenate, obtains compound IV；Compound IV is at bromine
React with sodium nitrite and dichloroacetic acid in Fang and obtain compound V；Compound V hydrolyzes in the basic conditions and obtains compound VI；
Compound VI and 2 equivalents and above oxidizing obtain compound I.
Compound of Formula I of the present invention has the inhibitory action of URAT1, can be used for preparing metabolic arthritis as effective ingredient
Mass formed by blood stasis and the medicine of gout.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes is about
In the range of 1mg-500mg/ people, it is divided into once or is administered for several times.The actual dosage taking compound of Formula I of the present invention can be by curing
Take root and determine according to relevant situation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various changes that the teachings of the present invention is made
Within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I-1
A. the synthesis of compound IV-1
5.65g (20mmol) compound II-1 and 4.22g (20mmol) compound III is dissolved in the DMF that 100mL is dried,
Stir under room temperature, add 8.29g (60mmol) solid K2CO3, then reactant mixture is stirred at room temperature, and sends out until TLC follows the tracks of
Now react (within general 12h).Reactant mixture pours in 400mL frozen water, stirring, uses the CH of 100mL × 32Cl2
Extraction, merges extraction phase, uses the saline washing of 100mL 5%, and anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate exists
Being evaporated on Rotary Evaporators, the residue obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/
Z=435 ([M+Na]+)。
B. the synthesis of compound V-1
5.23g (12mmol) compound IV-1 is dissolved in 30mL bromofom, stirs under room temperature, adds 3.45g (50mmol)
NaNO2With 3.00g benzyl triethyl ammonium bromide, then add 6.45g (50mmol) dichloroacetic acid.Gained mixture is at room temperature
Stirring, until TLC follows the tracks of finds that reaction completes (within general 12h).Reactant mixture pours in 300mL frozen water, stirring, makes
With the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses the Na of 100mL 2% successively2S2O3Solution and the salt of 100mL 5%
Water washs, and anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses
Column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=499 ([M+Na]+)。
C. the synthesis of compound VI-1
3.81g (8mmol) compound V-1 is dissolved in 30mL methanol, stirs under room temperature, adds the LiOH solution of 3mL10%,
Stir under gained mixture room temperature, until TLC follows the tracks of finds that reaction completes (within general 3h).Reactant mixture pours into
In 200mL frozen water, stirring, use concentrated hydrochloric acid regulation pH=2-3, the CH of 100mL × 32Cl2Extraction, merges extraction phase, uses
The saline washing of 100mL 5%, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, obtains
Residue use column chromatography purification, obtain compound VI-1, white solid, ESI-MS, m/z=446,448 ([M-H]-)。
D.The synthesis of compound I-1
2.69g (6mmol) compound VI-1 is dissolved in 20mL CH2Cl2In, stirring, add 2.40g (14mmol) m-chloro peroxide
Benzoic acid (mCPBA), stirs 5h hour under room temperature.Reactant mixture pours in 200mL frozen water, stirring, 100mL × 3
CH2Cl2Extraction, merges extraction phase, uses 100mL 2%Na successively2S2O3The saturated NaHCO of solution, 100mL3With 100mL's 5%
Saline washs, and anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained makes
Purify with column chromatography, obtain compound I-1, white solid, ESI-MS, m/z=478,480 ([M-H]-).。
Embodiment 2-6
With reference to embodiment 1 operating procedure, synthesize compound listed in Table.
Embodiment 7
The IC50 value that URAT1 is suppressed by compound of the present invention and related compound according to document record similar
Method measures (embodiment 12 in US2014/0005136).
Build stably express humanization URAT1 transporter cell strain: by humanization URAT1 gene (SLC22A112) from
Plasmid pCMV6-XL-5 (Origene) is subcloned on the plasmid pCMV6/neo (Origene) of eukaryotic expression.Gene sequencing is demonstrate,proved
Real humanization URAT1 and the information consistent (NM_144585.2) recorded in gene bank.HEK293 human embryonic kidney cell (ATCC#
CRL-1573) in EMEM tissue culture medium 5% CO2Cultivate with in the air atmosphere of 95%.Use L2000 type transfection agents
(Invitrogene) pCMV6/Neo/URAT1 is transfected on HEK293 cell.After 24 hours, transfected cell is assigned to
In the tissue culture dishes of a diameter of 10cm, continued growth one day, then culture medium is replaced by containing 0.5mg/mL G418
(Gibco) fresh culture medium.After 8 days, select and collect drug resistance bacterium colony, and right with its test14The uric acid of C-labelling
Transport activity.HEK293/URAT1 cell is planted on 96 orifice plates that poly-D-Lys covers with the density in 75,000/ hole.
These cells grow overnight at 37 DEG C in incubator, are then cooled under room temperature, and culture fluid therein uses 250
The cleanout fluid in μ L/ hole washed once (125mM sodium gluconate, the 10mMHEPES of pH=7.3).By testing compound or sky
White comparison is added to containing 40 μMs14In the buffer of C-labelling uric acid (54mCi/mmol), described buffer contains 125mM Fructus Vitis viniferae
Sodium saccharate, 4.8mM potassium gluconate, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconate, 5.6mM Fructus Vitis viniferae
Sugar, 25mM HEPES, final pH=7.3.96 orifice plates are at room temperature cultivated 10 minutes, the most successively with 50 μ L/ holes and 250 μ L/
The above-mentioned cleanout fluid in hole respectively cleans three times.Adding Microscint 20 type liquid on 96 orifice plates and dodge agent, plank is cultivated at 45 DEG C
Overnight, then reading on TopCount Plate Reader, and calculate IC accordingly50。
Shown in the following list of result:
The part of compounds of the present invention IC to URAT150Value
| Compound | IC50(hURAT1,nM) |
| Lesinurad | 22.4 |
| I-1 | 13.1 |
| I-2 | 32.8 |
| I-3 | 25.7 |
| I-4 | 28.2 |
| I-5 | 21.5 |
| I-6 | 16.7 |
Above-mentioned IC50Measurement result show, the compounds of this invention is strong URAT1 inhibitor, can be used to preparation treatment
Hyperuricemia and the medicine of gout.
Claims (3)
1. following compounds,
2. the method for compound described in synthesis claim 1:
Compound II reacts in the presence of a base with alpha-brominated dimethyl malenate, obtains compound IV；Compound IV is in bromofom
React with sodium nitrite and dichloroacetic acid and obtain compound V；Compound V hydrolyzes in the basic conditions and obtains compound VI；Chemical combination
Thing VI and 2 equivalents and above oxidizing obtain compound I；Wherein R is cyclopropyl or the tert-butyl group.
3. the application in terms of preparation treatment hyperuricemia and gout medicine of the compound described in claim 1.
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