CA2956045C - Carboxylic acid compound, method for preparation thereof, and use thereof - Google Patents
Carboxylic acid compound, method for preparation thereof, and use thereof Download PDFInfo
- Publication number
- CA2956045C CA2956045C CA2956045A CA2956045A CA2956045C CA 2956045 C CA2956045 C CA 2956045C CA 2956045 A CA2956045 A CA 2956045A CA 2956045 A CA2956045 A CA 2956045A CA 2956045 C CA2956045 C CA 2956045C
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- CA
- Canada
- Prior art keywords
- carboxylic acid
- acceptable salt
- acid compound
- mmol
- disease
- 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.)
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- -1 Carboxylic acid compound Chemical class 0.000 title claims abstract description 95
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000012453 solvate Substances 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims description 92
- 229940116269 uric acid Drugs 0.000 claims description 56
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 54
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 40
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 36
- 201000005569 Gout Diseases 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 210000004369 blood Anatomy 0.000 claims description 17
- 239000008280 blood Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 11
- 230000029142 excretion Effects 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 210000000056 organ Anatomy 0.000 claims description 9
- 229910052721 tungsten Inorganic materials 0.000 claims description 9
- 229910052727 yttrium Inorganic materials 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 201000001431 Hyperuricemia Diseases 0.000 claims description 8
- 108010093894 Xanthine oxidase Proteins 0.000 claims description 8
- 230000002159 abnormal effect Effects 0.000 claims description 8
- 206010003246 arthritis Diseases 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 102000005773 Xanthine dehydrogenase Human genes 0.000 claims description 7
- 108010091383 Xanthine dehydrogenase Proteins 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 230000001737 promoting effect Effects 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical group OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 claims description 6
- 229960003459 allopurinol Drugs 0.000 claims description 6
- 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 claims description 6
- 229960005101 febuxostat Drugs 0.000 claims description 6
- 125000000466 oxiranyl group Chemical group 0.000 claims description 6
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 208000000913 Kidney Calculi Diseases 0.000 claims description 5
- 206010029148 Nephrolithiasis Diseases 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- 125000003566 oxetanyl group Chemical group 0.000 claims description 5
- 208000008281 urolithiasis Diseases 0.000 claims description 5
- 206010007027 Calculus urinary Diseases 0.000 claims description 4
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 claims description 4
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 4
- 108700017799 HPRT-Related Gout Proteins 0.000 claims description 4
- 208000027408 HRPT-related hyperuricemia Diseases 0.000 claims description 4
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 4
- 208000009625 Lesch-Nyhan syndrome Diseases 0.000 claims description 4
- 229940122272 Oxidoreductase inhibitor Drugs 0.000 claims description 4
- 208000035318 Partial hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 208000035317 Total hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 claims description 4
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 claims description 4
- 150000003863 ammonium salts Chemical group 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 208000018937 joint inflammation Diseases 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 208000008127 lead poisoning Diseases 0.000 claims description 4
- 239000002457 oxidoreductase inhibitor Substances 0.000 claims description 4
- 230000000306 recurrent effect Effects 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 229940075420 xanthine Drugs 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 14
- 239000000651 prodrug Substances 0.000 abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 309
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 141
- 238000006243 chemical reaction Methods 0.000 description 132
- 239000000243 solution Substances 0.000 description 116
- 230000015572 biosynthetic process Effects 0.000 description 105
- 238000003786 synthesis reaction Methods 0.000 description 105
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 150000001875 compounds Chemical class 0.000 description 86
- 239000012074 organic phase Substances 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 70
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 65
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 50
- 239000012267 brine Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- 239000003208 petroleum Substances 0.000 description 36
- 239000012265 solid product Substances 0.000 description 36
- 229910000027 potassium carbonate Inorganic materials 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 30
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 27
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
- 235000017550 sodium carbonate Nutrition 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 235000011181 potassium carbonates Nutrition 0.000 description 20
- 229910052979 sodium sulfide Inorganic materials 0.000 description 20
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 239000005457 ice water Substances 0.000 description 15
- 235000015320 potassium carbonate Nutrition 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 14
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 125000002993 cycloalkylene group Chemical group 0.000 description 10
- JRHLVNAWLWIHDN-UHFFFAOYSA-N methyl 2-[1-(sulfanylmethyl)cyclopropyl]acetate Chemical compound COC(=O)CC1(CS)CC1 JRHLVNAWLWIHDN-UHFFFAOYSA-N 0.000 description 10
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 9
- 101150041968 CDC13 gene Proteins 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- QADXKWUCCGPQNR-UHFFFAOYSA-N 3-bromo-4-chloropyridine Chemical compound ClC1=CC=NC=C1Br QADXKWUCCGPQNR-UHFFFAOYSA-N 0.000 description 7
- 150000001450 anions Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910052705 radium Inorganic materials 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 6
- 108091006146 Channels Proteins 0.000 description 6
- 102000034573 Channels Human genes 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000009103 reabsorption Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229960002529 benzbromarone Drugs 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229910052701 rubidium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- CHIFTAQVXHNVRW-UHFFFAOYSA-N 1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 4
- VEKIYFGCEAJDDT-UHFFFAOYSA-N 2-pyridin-3-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CN=C1 VEKIYFGCEAJDDT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 241000282320 Panthera leo Species 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 150000001555 benzenes Chemical group 0.000 description 4
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- XAESVDCYDOTHKP-UHFFFAOYSA-N ethyl 2-[1-[(3-bromopyridin-4-yl)oxymethyl]cyclopropyl]acetate Chemical compound BrC=1C=NC=CC=1OCC1(CC1)CC(=O)OCC XAESVDCYDOTHKP-UHFFFAOYSA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- GPFGVZAQKJPYAT-UHFFFAOYSA-N methyl 1-(bromomethyl)cyclopropane-1-carboxylate Chemical compound COC(=O)C1(CBr)CC1 GPFGVZAQKJPYAT-UHFFFAOYSA-N 0.000 description 4
- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 4
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- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
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Classifications
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- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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| CN201410398333.4A CN105439946B (zh) | 2014-08-13 | 2014-08-13 | 羧酸化合物及其制备方法和用途 |
| CN201410398333.4 | 2014-08-13 | ||
| PCT/CN2015/086605 WO2016023460A1 (zh) | 2014-08-13 | 2015-08-11 | 羧酸化合物及其制备方法和用途 |
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| CN105439946B (zh) * | 2014-08-13 | 2018-02-02 | 益方生物科技(上海)有限公司 | 羧酸化合物及其制备方法和用途 |
| KR20180112773A (ko) | 2015-12-28 | 2018-10-12 | 상하이 포천 파마슈티컬 씨오 엘티디 | 인돌리진 유도체, 조성물 및 사용 방법 |
| CN105884807A (zh) * | 2016-04-26 | 2016-08-24 | 昆药集团股份有限公司 | 硼酸频那醇酯衍生物的制备方法、硫代乙酸盐化合物的制备方法 |
| CN106748987B (zh) * | 2016-11-18 | 2019-05-31 | 昆药集团股份有限公司 | 2-((3-(4-氰基萘-1-基)吡啶-4-基)硫基)-2-甲基丙酸钠盐的晶型 |
| PE20200846A1 (es) * | 2017-10-04 | 2020-08-18 | Japan Tobacco Inc | Compuesto de heteroarilo con contenido de nitrogeno y su uso farmaceutico |
| CN108084153A (zh) * | 2017-12-20 | 2018-05-29 | 广东赛烽医药科技有限公司 | 吡啶基硫代乙酸化合物、组合物及其应用 |
| CN108069940B (zh) * | 2017-12-20 | 2021-04-30 | 广东赛烽医药科技有限公司 | 硫代乙酸化合物、组合物及其应用 |
| CN108440397B (zh) * | 2018-03-06 | 2020-06-05 | 南方医科大学 | 3-(萘-1-甲基取代)吡啶衍生物及其合成方法和应用 |
| WO2019183835A1 (en) | 2018-03-28 | 2019-10-03 | Inventisbio Shanghai Ltd. | Novel salt forms of urat-1 inhibitors |
| CN108484494B (zh) * | 2018-06-15 | 2021-07-30 | 沈阳药科大学 | 2-氧代-1,2-二氢吡啶-4-甲酸类化合物 |
| CN111943957B (zh) * | 2019-05-17 | 2023-01-06 | 中国医学科学院药物研究所 | 喹啉甲酰胺类化合物及其制备方法和用途 |
| CN113493407B (zh) * | 2020-04-03 | 2025-01-28 | 中国医学科学院药物研究所 | 一种吡啶类化合物及其制法和药物用途 |
| AR124985A1 (es) * | 2021-03-01 | 2023-05-24 | Orion Corp | Nuevas formas de sal de un inhibidor de cyp11a1 estructurado en 4h-piran-4-ona |
| MX2023010269A (es) * | 2021-03-01 | 2023-11-14 | Orion Corp | Formas solidas de un inhibidor de cyp11a1 estructurado en 4h-piran-4-ona. |
| CN113979931B (zh) * | 2021-10-08 | 2023-06-13 | 南方医科大学 | 一种吡啶3-胺衍生物及其制备方法和应用 |
| TWI870839B (zh) * | 2022-04-27 | 2025-01-21 | 大陸商杭州新元素藥業有限公司 | 可用於降尿酸的化合物 |
| WO2025060786A1 (zh) * | 2023-09-19 | 2025-03-27 | 湘北威尔曼制药股份有限公司 | 一种六元并五元稠环衍生物及其制备方法和应用 |
| WO2025060752A1 (zh) * | 2023-09-19 | 2025-03-27 | 湘北威尔曼制药股份有限公司 | 一种硫醚衍生物及其制备方法和应用 |
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| DE19541146A1 (de) * | 1995-10-25 | 1997-04-30 | Schering Ag | Imidazolderivate und deren Verwendung als Stickstoffmonoxid-Synthase-Inhibitoren |
| SE0301010D0 (sv) | 2003-04-07 | 2003-04-07 | Astrazeneca Ab | Novel compounds |
| FR2903984B1 (fr) * | 2006-07-24 | 2008-10-03 | Genfit Sa | Derives d'imidazolones substitues, preparation et utilisations |
| JP5597202B2 (ja) * | 2009-08-28 | 2014-10-01 | 第一三共株式会社 | 3−(ビアリールオキシ)プロピオン酸誘導体 |
| WO2011159840A2 (en) * | 2010-06-16 | 2011-12-22 | Ardea Biosciences, Inc. | Phenylthioacetate compounds, compositions and methods of use |
| AR081930A1 (es) * | 2010-06-16 | 2012-10-31 | Ardea Biosciences Inc | Compuestos de tioacetato |
| EP2776028B1 (en) * | 2011-11-03 | 2018-10-17 | Ardea Biosciences, Inc. | 3,4-di-substituted pyridine compound, methods of using and compositions comprising the same |
| JP6067031B2 (ja) * | 2012-01-04 | 2017-01-25 | ファイザー・リミテッドPfizer Limited | N−アミノスルホニルベンズアミド |
| WO2013158422A1 (en) * | 2012-04-17 | 2013-10-24 | E. I. Du Pont De Nemours And Company | Heterocyclic compounds for controlling invertebrate pests |
| CN105439946B (zh) * | 2014-08-13 | 2018-02-02 | 益方生物科技(上海)有限公司 | 羧酸化合物及其制备方法和用途 |
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| US20180022736A1 (en) | 2018-01-25 |
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| CA2956045A1 (en) | 2016-02-18 |
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| CN106573908B (zh) | 2021-02-05 |
| JP2017524704A (ja) | 2017-08-31 |
| EP3181557A4 (en) | 2018-05-30 |
| CN105439946A (zh) | 2016-03-30 |
| KR102474640B1 (ko) | 2022-12-05 |
| WO2016023460A1 (zh) | 2016-02-18 |
| EP3181557A1 (en) | 2017-06-21 |
| ES2942259T3 (es) | 2023-05-31 |
| IL250524B (en) | 2020-07-30 |
| KR20170042687A (ko) | 2017-04-19 |
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