CN104370842B - The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use - Google Patents
The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use Download PDFInfo
- Publication number
- CN104370842B CN104370842B CN201410582801.3A CN201410582801A CN104370842B CN 104370842 B CN104370842 B CN 104370842B CN 201410582801 A CN201410582801 A CN 201410582801A CN 104370842 B CN104370842 B CN 104370842B
- Authority
- CN
- China
- Prior art keywords
- compound
- present
- sulphonyl
- triazole
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title abstract description 5
- -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 8
- 150000001875 compounds Chemical class 0.000 claims description 42
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000000460 chlorine Substances 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
- 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 5
- 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
- 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 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
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 12
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 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
- 238000000605 extraction 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
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 229960003838 lesinurad Drugs 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
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 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 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 241001415342 Ardea Species 0.000 description 2
- 108010078791 Carrier Proteins Proteins 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
- 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
- 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
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-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
- 239000000176 sodium gluconate Substances 0.000 description 2
- 235000012207 sodium gluconate Nutrition 0.000 description 2
- 229940005574 sodium gluconate Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 108010092464 Urate Oxidase Proteins 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 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
- 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 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
- 229960001338 colchicine Drugs 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
- 208000035475 disorder Diseases 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
- 239000008103 glucose Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000011534 incubation Methods 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
- 210000004185 liver Anatomy 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
- 230000002503 metabolic effect Effects 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
- 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
- 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the drug world relevant to hyperuricemia and gout.Specifically, the present invention relates to uric acid transporter body 1 inhibitor of triazole sulphonyl malonic acid structure that a class replaces, its preparation method and containing their pharmaceutical composition and their application in preparing diabetes medicament containing phenyl.
Description
Technical field
The present invention relates to the drug world that treatment hyperuricemia is relevant with gout.Specifically, the present invention relates to hyperuricemia and gout medicative one class phenyl replace uric acid transporter body 1 (uratetransporter1, the URAT1) inhibitor of triazole sulphonyl malonic acid structure, preparation method, containing they pharmaceutical composition and in purposes pharmaceutically.
Background technology
Gout is a kind of chronic metabolic disease, and the pain being deposited on the positions such as joint and causing with hyperuricemia and monosodium urate salt (MSU) is for principal character, and main cause is purine metabolic disturbance and/or uric acid excretion disorder.According to estimates, whole world patient with gout has more than 2,000 ten thousand at present.The medicine being currently used for treatment gout includes for lenitive anti-inflammatory drug (such as colchicine etc.), suppresses uricopoiesis medicine (xanthine oxidase inhibitor being representative with allopurinol and Febuxostat), thick urate excretion medicine (the urate excretion medicine being representative with probenecid, sulphinpyrazone, benzbromarone and losartan) and uricase (with pegloticase for representative).There is the toxic and side effects of different degree in these medicines, as benzbromarone has the danger causing explosive hepatitis, allopurinol has liver and the untoward reaction such as bone marrow toxicity and allergy, etc..
Lesinurad (RDEA594) a kind of can be suppressed uric acid transporter body (uratetransporter1 in kidney by what Ardea company developed, URAT1) discharged the oral drugs of uric acid in blood by the approach of urine, be currently in III phase clinical stage.The antiviral drugs RDEA806 that Lesinurad is researched and developed by Valeant company the earliest develops.The proprietary rights of present Lesinurad is purchased due to Ardea company at present and is belonged to AstraZeneca.
The invention discloses the URAT1 inhibitor of the triazole sulphonyl malonic acid structure that a class replaces containing phenyl, these compounds can be used for the medicine of preparation treatment hyperuricemia and 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 the compound of formula I.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of formula (I) and has following structural formula:
Wherein, R is selected from halogenic substituent.
The compound of preferred formula (I) has following structure,
Formula of the present invention (I) compound is synthesized by following route:
Compound II per and alpha-brominated dimethyl malenate react in the presence of a base, obtain compound IV；Compound IV is obtained by reacting compound V with sodium nitrite and dichloroacetic acid in bromofom；Compound V is hydrolyzed 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 as effective ingredient for preparing the medicine of hyperuricemia and gout.The activity of compound of Formula I of the present invention is to be 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, within the scope of 1mg-500mg/ people, is divided into once or is administered for several times.The actual dosage taking compound of Formula I of the present invention can be determined according to relevant situation by doctor.
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 illustrating, and it is not intended to limit the present invention.Those skilled in the art all should within the protection domain required by the application claim according to the various changes that the teachings of the present invention is made.
The synthesis of embodiment 1 compound I-1
A. the synthesis of compound IV-1
Compound II per is prepared with reference to patent documentation WO2011085009.5.96g (20mmol) Compound II per-1 and 4.22g (20mmol) Compound II per I are dissolved in the 100mL DMF dried, and stir under room temperature, add 8.29g (60mmol) solid K2CO3, then reactant mixture at room temperature stirs, until TLC follows the tracks of finds that reaction completes (within general 12h).Reactant mixture pours in 400mL frozen water, stirring, uses the CH of 100mL × 32Cl2Extracting, merge extraction phase, use the salt water washing of 100mL5%, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=551 ([M+Na]+)。
B. the synthesis of compound V-1
6.33g (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 at room temperature stirs, until TLC follows the tracks of finds that reaction completes (within general 12h).Reactant mixture pours in 300mL frozen water, stirring, uses the CH of 100mL × 32Cl2Extract, merge extraction phase, use the Na of 100mL2% successively2S2O3The salt water washing of solution and 100mL5%, anhydrous sodium sulfate dries.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=613 ([M+Na]+)。
C. the synthesis of compound VI-1
4.72g (8mmol) compound V-1 is dissolved in 30mL methanol, stirs under room temperature, adds the LiOH solution of 3mL10%, stirs under gained mixture room temperature, until TLC follows the tracks of finds that reaction completes (within general 3h).Reactant mixture pours in 200mL frozen water, stirring, uses concentrated hydrochloric acid to regulate the CH of pH=2-3,100mL × 32Cl2Extracting, merge extraction phase, use the salt water washing of 100mL5%, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound VI-1, white solid, ESI-MS, m/z=562,564,560 ([M-H]-)。
D.The synthesis of compound I-1
3.38g (6mmol) compound VI-1 is dissolved in 10mLCH2Cl2In, stirring, add 2.40g (14mmol) metachloroperbenzoic acid (mCPBA), stir 5h hour under room temperature.Reactant mixture pours in 200mL frozen water, stirring, the CH of 100mL × 32Cl2Extract, merge extraction phase, use 100mL2%Na successively2S2O3The saturated NaHCO of solution, 100mL3With the salt water washing of 100mL5%, anhydrous sodium sulfate dries.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification, obtains compound I-1, white solid, ESI-MS, m/z=594,596,592 ([M-H]-)。
Embodiment 2-8
With reference to embodiment 1 operating procedure, synthesize compound listed in Table.
Embodiment 9
Compound of the present invention and related compound are to the URAT1 IC suppressed50It is worth the similar method recorded according to document and measures (in US2014/0005136 embodiment 12).
Build the cell strain of stably express humanization URAT1 transporter: be subcloned into the plasmid pCMV6/neo (Origene) of eukaryotic expression from plasmid pCMV6-XL-5 (Origene) by humanization URAT1 gene (SLC22A112).Gene sequencing confirms humanization URAT1 and the information consistent (NM_144585.2) of record in gene bank.HEK293 human embryonic kidney cell (ATCC#CRL-1573) in EMEM tissue culture medium at the CO of 5%2Cultivate with in the air atmosphere of 95%.L2000 type transfection agents (Invitrogene) is used to be transfected on HEK293 cell by pCMV6/Neo/URAT1.After 24 hours, transfected cell is assigned in the tissue culture dishes that diameter is 10cm, continued growth one day, then culture medium is replaced by the fresh culture medium containing 0.5mg/mLG418 (Gibco).After 8 days, select and collect drug resistance bacterium colony, and right with its test14The transport activity of the uric acid of C-labelling.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 the cleanout fluid in 250 μ L/ holes to wash once the 10mMHEPES of pH=7.3 (the 125mM sodium gluconate).Testing compound or blank are added to containing 40 μMs14In the buffer of C-labelling uric acid (54mCi/mmol), described buffer contains 125mM sodium gluconate, 4.8mM potassium gluconate, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconate, 5.6mM glucose, 25mMHEPES, final pH=7.3.96 orifice plates are at room temperature cultivated 10 minutes, then respectively clean three times with the above-mentioned cleanout fluid in 50 μ L/ holes and 250 μ L/ holes successively.Adding Microscint20 type liquid on 96 orifice plates and dodge agent, plank is overnight incubation at 45 DEG C, then reading on TopCountPlateReader, and calculates 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 | 7.7 |
| I-2 | 29.4 |
| I-3 | 12.5 |
| I-4 | 10.6 |
| I-6 | 31.0 |
| I-7 | 23.8 |
| I-8 | 18.2 |
Above-mentioned IC50Measurement result show, the compounds of this invention is strong URAT1 inhibitor, it is possible to be used for preparing treatment hyperuricemia and the medicine of gout.
Claims (3)
1. following compounds,
2. the method for compound described in synthesis claim 1:
Compound II per and alpha-brominated dimethyl malenate react in the presence of a base, obtain compound IV；Compound IV is obtained by reacting compound V with sodium nitrite and dichloroacetic acid in bromofom；Compound V is hydrolyzed in the basic conditions and obtains compound VI；Compound VI and 2 equivalents and above oxidizing obtain compound I；Wherein R is 3-fluorine, 3-chlorine, 3-bromine or 4-bromine.
3. the purposes in preparation treatment hyperuricemia and gout medicine of the compound described in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410582801.3A CN104370842B (en) | 2014-10-27 | 2014-10-27 | The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410582801.3A CN104370842B (en) | 2014-10-27 | 2014-10-27 | The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104370842A CN104370842A (en) | 2015-02-25 |
| CN104370842B true CN104370842B (en) | 2016-07-13 |
Family
ID=52550077
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410582801.3A Active CN104370842B (en) | 2014-10-27 | 2014-10-27 | The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104370842B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101083987A (en) * | 2004-08-25 | 2007-12-05 | 阿迪亚生命科学公司 | S-Triazolyl α-Mercaptoacetanilides as HIV Reverse Transcriptase Inhibitors |
| WO2010135530A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Compounds, compositions and methods for modulating uric acid levels |
| WO2010135536A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
| CN101918377A (en) * | 2007-11-27 | 2010-12-15 | 亚德生化公司 | Novel compounds and compositions and methods of use |
| CN102186832A (en) * | 2008-09-04 | 2011-09-14 | 亚德生化公司 | Compounds, compositions and methods of use for modulating uric acid levels |
-
2014
- 2014-10-27 CN CN201410582801.3A patent/CN104370842B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101083987A (en) * | 2004-08-25 | 2007-12-05 | 阿迪亚生命科学公司 | S-Triazolyl α-Mercaptoacetanilides as HIV Reverse Transcriptase Inhibitors |
| CN101918377A (en) * | 2007-11-27 | 2010-12-15 | 亚德生化公司 | Novel compounds and compositions and methods of use |
| CN103058944A (en) * | 2007-11-27 | 2013-04-24 | 亚德生化公司 | Novel compound and composition |
| CN102186832A (en) * | 2008-09-04 | 2011-09-14 | 亚德生化公司 | Compounds, compositions and methods of use for modulating uric acid levels |
| CN103819419A (en) * | 2008-09-04 | 2014-05-28 | 亚德生化公司 | Compounds, compositions and methods of using same for modulating uric acid levels |
| WO2010135530A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Compounds, compositions and methods for modulating uric acid levels |
| WO2010135536A2 (en) * | 2009-05-20 | 2010-11-25 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104370842A (en) | 2015-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104292123B (en) | The succinamide derivative of phenyl naphthalene nucleus, Preparation Method And The Use | |
| CN104262277B (en) | Containing nitro and the tetrazoleacetic acid compounds of halobenzene replacement, Preparation Method And The Use | |
| CN104311442B (en) | The succinamide derivative of halo naphthalene nucleus, Preparation Method And The Use | |
| CN104370842B (en) | The triazole sulphonyl malonic acid compounds of phenyl replacement, Preparation Method And The Use | |
| CN104292178B (en) | Containing tetrazoleacetic acid compounds, Preparation Method And The Use | |
| CN104326998B (en) | Phenyl substituted triazole malonic acid compounds, Preparation Method And The Use | |
| CN104326999B (en) | Alkoxy-substituted triazole sulfinyl malonate type compound, and preparation method and application thereof | |
| CN104311498B (en) | Triazole sulphonyl propanedioic acid compounds, Preparation Method And The Use that alkoxyl group replaces | |
| CN104292175B (en) | Tetrazoleacetic acid compounds containing nitro, Preparation Method And The Use | |
| CN104341361B (en) | Cyano-substituted triazolesulfonylmalonic acid compounds as well as preparation method and application thereof | |
| CN104326997B (en) | Alkoxyl substituted triazole malonic acid compounds, Preparation Method And The Use | |
| CN104341362B (en) | Triazole sulphonyl malonic acid compounds, Preparation Method And The Use | |
| CN104341364A (en) | Triazole malonic acid compounds as well as preparation method and application thereof | |
| CN104341363B (en) | A kind of nitro substituted triazole sulphonyl malonic acid compounds, Preparation Method And The Use | |
| CN104292177B (en) | Nitrile group-containing and halobenzene substituted tetrazoleacetic acid compounds, Preparation Method And The Use | |
| CN104370841B (en) | Triazole sulfenyl malonic acid compounds, Preparation Method And The Use | |
| CN104262276B (en) | Tetrazoleacetic acid compounds containing halogeno-benzene, Preparation Method And The Use | |
| CN104193644B (en) | The succinamide derivative of methoxy naphthalene nucleus, Preparation Method And The Use | |
| CN104230833B (en) | The tetrazoleacetic acid compounds of nitrile group-containing, Preparation Method And The Use | |
| CN104311445B (en) | Naphthalene-ring containing succinamide derivative, Preparation Method And The Use | |
| CN104326995A (en) | Nitrile-substituted triazole malonate type compound, and preparation method and application thereof | |
| CN104356078A (en) | Halogenated triazole sulfuryl malonic acid compound, as well as preparation method and application thereof | |
| CN104327000B (en) | Phenyl substituted triazole sulfenyl malonic acid compounds, Preparation Method And The Use | |
| CN104341365A (en) | Halogenated triazole malonic acid compounds as well as preparation method and application thereof | |
| CN104326994A (en) | Nitrile-substituted triazole sulfonyl malonate type compound, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20181211 Address after: 225300 Pearl River Road, Yongan Town, Taizhou, Jiangsu Province, 108 Patentee after: Wang Yajun Address before: 528000 floor 5, Pu Lan Road, Chancheng District, Foshan, Guangdong. Patentee before: Zhang Yuanqiang |
|
| CP02 | Change in the address of a patent holder |
Address after: 273500 University Student Science Park, No. 80 Xiwaihuan Road, Zoucheng City, Jining City, Shandong Province Patentee after: Wang Yajun Address before: 225300 Pearl River Road, Yongan Town, Taizhou, Jiangsu Province, 108 Patentee before: Wang Yajun |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 261061 Blue Intellectual Valley Park, Healthy East Street, Weifang High-tech Zone, Shandong Province Patentee after: Wang Yajun Address before: 273500 University Student Science Park, No. 80 Xiwaihuan Road, Zoucheng City, Jining City, Shandong Province Patentee before: Wang Yajun |
|
| CP02 | Change in the address of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191105 Address after: 314100 room 427, No.16 Fuxing Avenue, Xitang Town, Jiashan County, Jiaxing City, Zhejiang Province Patentee after: Zhejiang Xitang Industry Co., Ltd Address before: 261061 Blue Intellectual Valley Park, Healthy East Street, Weifang High-tech Zone, Shandong Province Patentee before: Wang Yajun |
|
| TR01 | Transfer of patent right |