CN104292178B - Containing tetrazoleacetic acid compounds, Preparation Method And The Use - Google Patents
Containing tetrazoleacetic acid compounds, Preparation Method And The Use Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical class OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 12
- 201000005569 Gout Diseases 0.000 claims abstract description 11
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000002585 base Substances 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 4
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 2
- -1 compound 2-halogenated acetic acids Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 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
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 206010012601 diabetes mellitus Diseases 0.000 abstract 1
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 10
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 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
- 238000001816 cooling 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 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 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000011734 sodium 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
- 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241001415342 Ardea Species 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 239000004615 ingredient Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 229960003838 lesinurad Drugs 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 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
- 235000019270 ammonium chloride Nutrition 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 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
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 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
- 239000003085 diluting agent 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
- 239000003937 drug carrier Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-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
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 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
- 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 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
- 238000012163 sequencing technique Methods 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
- 238000010792 warming Methods 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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 class uric acid transporter body 1 inhibitor containing tetrazoleacetic acid structure, its preparation method and pharmaceutical composition and their application in preparing diabetes medicament containing them。Wherein, R1Selected from H, C1-C5Alkyl, C3-C6Cycloalkyl。
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 class uric acid transporter body 1 (uratetransporter1, the URAT1) inhibitor containing tetrazoleacetic 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 class URAT1 inhibitor containing tetrazoleacetic acid structure, 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。
It is also another object of the present invention to provide the compound containing formula I as effective ingredient, and the Pharmaceutical composition of one or more pharmaceutically acceptable carriers, excipient or diluent, and the application in treatment gout。
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, R1Selected from H, C1-C5Alkyl, C3-C6Cycloalkyl。
Preferably, R1Selected from H, C1-C3Alkyl, C3-C4Cycloalkyl。
Further, it is preferable that below general formula (I) compound,
Formula of the present invention (I) compound is synthesized by following route:
Compound II per reacts in the presence of a base with 4-halo butyronitrile III, obtains compound IV；Compound IV in the presence of a base with R2X (V) is obtained by reacting compound VI；Compound VI and NaN3At NH4There is lower reaction in Cl, obtains product VII；VII and compound 2-halogenated acetic acids VIII is obtained by reacting product I in the presence of a base。X is selected from Cl, Br and I, and described alkali is selected from various organic bases, inorganic base etc.。Described R1Defined as described above。
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 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
3.66g (20mmol) Compound II per-1 and 2.96g (20mmol) Compound II per I-1 are dissolved in the 40mL DMF dried, stirring, add 3.32g (20mmol) potassium iodide and 6.91g (50mmol) potassium carbonate, nitrogen atmosphere reacts at 100 DEG C, until having reacted (TLC follows the tracks of, general 5h)。After reactant mixture cooling, pour in 300mL frozen water, stirring, use 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=283 ([M+Na]+)。
B. the synthesis of compound VI-1
3.00g (12mmol) compound IV-1 and 1.12g (12mmol) Celfume V-1 is dissolved in the 30mL DMF dried, stirring, adds 4.98g (36mmol) potassium carbonate, reacts in nitrogen atmosphere at 100 DEG C, until having reacted。After reactant mixture cooling, pour in 300mL frozen water, stirring, use 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 VI-1, white solid, ESI-MS, m/z=287 ([M+Na]+)。
C. the synthesis of compound VII-1
2.11g (8mmol) compound VI-1 is dissolved in the 20mL DMF dried, stirring, adds 1.30g (20mmol) NaN3With 1.07g (20mmol) ammonium chloride, then reaction at 120 DEG C in nitrogen atmosphere, until having reacted。After reactant mixture cooling, pour in 200mL frozen water, stirring, use 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 VII-1, white solid, ESI-MS, m/z=330 ([M+Na]+)。
D. the synthesis of compound I-1
1.54g (5mmol) compound VII-1 and 1.39g (10mmol) bromoacetic acid is dissolved in 15mL ethanol, stir under room temperature, the slowly dropping 3mL aqueous solution containing 1.20g (30mmol) NaOH, gained mixture is warming up to 50 DEG C of heating, until having reacted。After reactant mixture cooling, pouring in 100mL frozen water, stirring, concentrated hydrochloric acid regulates pH=2-3, uses the CH of 50mL × 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=364 ([M-H]-)。
Embodiment 2-5
With reference to embodiment 1 operating procedure, it is prepared for compound listed in Table。
Embodiment 6
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 IC50 value to URAT1
| Compound | IC50(hURAT1,nM) |
| Embodiment 1 compound | 6.7 |
| Embodiment 2 compound | 8.5 |
| Embodiment 3 compound | 15.8 |
| Embodiment 4 compound | 11.3 |
| Embodiment 5 compound | 12.9 |
Above-mentioned IC50Measurement result show, the compound of the present invention is strong URAT1 inhibitor, it is possible to be used for preparing treatment hyperuricemia and the medicine of gout。
Claims (5)
1. there is the compound of general formula I,
Wherein, R1Selected from H, C1-C5Alkyl, C3-C6Cycloalkyl。
2. the compound with formula I that claim 1 is defined,
Wherein, R1Selected from H, C1-C3Alkyl, C3-C4Cycloalkyl。
3. the compound of Formula I that claim 2 is defined, is selected from:
4. the method synthesizing the compound of the arbitrary defined formula I of claim 1-3:
Compound II per reacts in the presence of a base with 4-halo butyronitrile III, obtains compound IV；Compound IV in the presence of a base with R1X (V) is obtained by reacting compound VI；Compound VI and NaN3At NH4There is lower reaction in Cl, obtains product VII；VII and compound 2-halogenated acetic acids VIII is obtained by reacting product I in the presence of a base；X is selected from Cl, Br and I, and described alkali is selected from organic base, inorganic base；Described R1As described in definition is corresponding as arbitrary in claim 1-3。
5. the compound of Formula I defined for one of claim 1-3 application in preparation treatment hyperuricemia and gout medicine。
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| CN1356977A (en) * | 1999-05-17 | 2002-07-03 | 诺沃挪第克公司 | Glucagon antagonists/inverse agonists |
| WO2008021804A2 (en) * | 2006-08-09 | 2008-02-21 | Allergan, Inc. | Therapeutic amides and related compounds |
| EP1985297A1 (en) * | 2006-01-27 | 2008-10-29 | Japan Tobacco, Inc. | Carboxylic acid compound and use thereof |
| US20100056542A1 (en) * | 2008-09-04 | 2010-03-04 | Ardea Biosciences | Compounds, compositions and methods of using same for modulating uric acid levels |
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| CN1356977A (en) * | 1999-05-17 | 2002-07-03 | 诺沃挪第克公司 | Glucagon antagonists/inverse agonists |
| EP1985297A1 (en) * | 2006-01-27 | 2008-10-29 | Japan Tobacco, Inc. | Carboxylic acid compound and use thereof |
| WO2008021804A2 (en) * | 2006-08-09 | 2008-02-21 | Allergan, Inc. | Therapeutic amides and related compounds |
| US20100056542A1 (en) * | 2008-09-04 | 2010-03-04 | Ardea Biosciences | Compounds, compositions and methods of using same 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 |
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