WO2023127853A1 - 化合物、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 - Google Patents
化合物、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 Download PDFInfo
- Publication number
- WO2023127853A1 WO2023127853A1 PCT/JP2022/048117 JP2022048117W WO2023127853A1 WO 2023127853 A1 WO2023127853 A1 WO 2023127853A1 JP 2022048117 W JP2022048117 W JP 2022048117W WO 2023127853 A1 WO2023127853 A1 WO 2023127853A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- pharmaceutically acceptable
- acceptable salt
- mmol
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 107
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 20
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 title claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
- 150000002367 halogens Chemical class 0.000 claims abstract description 24
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 11
- -1 patch Substances 0.000 claims description 50
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 230000008816 organ damage Effects 0.000 claims description 11
- 206010019280 Heart failures Diseases 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 208000017169 kidney disease Diseases 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 claims description 8
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 8
- 208000003947 Knee Osteoarthritis Diseases 0.000 claims description 8
- 208000001826 Marfan syndrome Diseases 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 206010030043 Ocular hypertension Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 201000000708 eosinophilic esophagitis Diseases 0.000 claims description 8
- 208000019622 heart disease Diseases 0.000 claims description 8
- 208000019423 liver disease Diseases 0.000 claims description 8
- 230000002792 vascular Effects 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 201000008482 osteoarthritis Diseases 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 6
- 206010020718 hyperplasia Diseases 0.000 claims description 6
- 208000015114 central nervous system disease Diseases 0.000 claims description 4
- 239000003889 eye drop Substances 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 45
- 239000000203 mixture Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 238000004519 manufacturing process Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 229910052938 sodium sulfate Inorganic materials 0.000 description 24
- 235000011152 sodium sulphate Nutrition 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 230000002401 inhibitory effect Effects 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 201000010099 disease Diseases 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 101150059573 AGTR1 gene Proteins 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 102000005862 Angiotensin II Human genes 0.000 description 10
- 101800000733 Angiotensin-2 Proteins 0.000 description 10
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 10
- 229950006323 angiotensin ii Drugs 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 6
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 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 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 102000017914 EDNRA Human genes 0.000 description 4
- 108010090549 Endothelin A Receptor Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 4
- 201000001119 neuropathy Diseases 0.000 description 4
- 230000007823 neuropathy Effects 0.000 description 4
- 208000033808 peripheral neuropathy Diseases 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- IKXAQUWRNLFKGW-UHFFFAOYSA-N 2-bromo-n-(4,5-dimethyl-1,2-oxazol-3-yl)-n-(methoxymethyl)benzenesulfonamide Chemical compound C=1C=CC=C(Br)C=1S(=O)(=O)N(COC)C1=NOC(C)=C1C IKXAQUWRNLFKGW-UHFFFAOYSA-N 0.000 description 3
- VFPWGZNNRSQPBT-UHFFFAOYSA-N 2-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1Br VFPWGZNNRSQPBT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102000002045 Endothelin Human genes 0.000 description 3
- 108050009340 Endothelin Proteins 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WDBHYTAEQAWRCQ-UHFFFAOYSA-N 1-nonen-4-one Chemical compound CCCCCC(=O)CC=C WDBHYTAEQAWRCQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LMHPPPZOKWWMJN-UHFFFAOYSA-N 2-bromo-n-(3-methoxy-5-methylpyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CC=C1Br LMHPPPZOKWWMJN-UHFFFAOYSA-N 0.000 description 2
- AEHZMTLXZJYRCA-UHFFFAOYSA-N 2-bromo-n-(4,5-dimethyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound CC1=C(C)ON=C1NS(=O)(=O)C1=CC=CC=C1Br AEHZMTLXZJYRCA-UHFFFAOYSA-N 0.000 description 2
- IWKWOYOVCXHXSS-UHFFFAOYSA-N 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one Chemical compound O=C1NC(CCCC)=NC11CCCC1 IWKWOYOVCXHXSS-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- ODIBGDLEXHFRCR-UHFFFAOYSA-N 7-bromo-1,3-dihydro-2-benzofuran-4-carbaldehyde Chemical compound BrC1=CC=C(C=2COCC1=2)C=O ODIBGDLEXHFRCR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010003130 Arrhythmia supraventricular Diseases 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 206010007556 Cardiac failure acute Diseases 0.000 description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 208000031229 Cardiomyopathies Diseases 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 206010003668 atrial tachycardia Diseases 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 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 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000013677 cerebrovascular dementia Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 238000007887 coronary angioplasty Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 206010061989 glomerulosclerosis Diseases 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002608 intravascular ultrasound Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- CLKNENGMHCINTB-UHFFFAOYSA-N (7-bromo-1,3-dihydro-2-benzofuran-4-yl)methanol Chemical compound BrC=1C=CC(=C2COCC=12)CO CLKNENGMHCINTB-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- AYTUUHSVCDKHBB-UHFFFAOYSA-N 2-bromo-n-(3-methoxy-5-methylpyrazin-2-yl)-n-(2-trimethylsilylethoxymethyl)benzenesulfonamide Chemical compound COC1=NC(C)=CN=C1N(COCC[Si](C)(C)C)S(=O)(=O)C1=CC=CC=C1Br AYTUUHSVCDKHBB-UHFFFAOYSA-N 0.000 description 1
- FPLJQLCKZBEBDK-UHFFFAOYSA-N 2-bromo-n-(4-chloro-5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound ClC1=C(C)ON=C1NS(=O)(=O)C1=CC=CC=C1Br FPLJQLCKZBEBDK-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- NIQNPTQRAGJGPS-UHFFFAOYSA-N 3-methoxy-5-methylpyrazin-2-amine Chemical compound COC1=NC(C)=CN=C1N NIQNPTQRAGJGPS-UHFFFAOYSA-N 0.000 description 1
- VPANVNSDJSUFEF-UHFFFAOYSA-N 4,5-dimethyl-1,2-oxazol-3-amine Chemical compound CC=1ON=C(N)C=1C VPANVNSDJSUFEF-UHFFFAOYSA-N 0.000 description 1
- DWTDMSYCNGIYGE-UHFFFAOYSA-N 4,7-dibromo-1,3-dihydro-2-benzofuran Chemical compound BrC1=C2COCC2=C(C=C1)Br DWTDMSYCNGIYGE-UHFFFAOYSA-N 0.000 description 1
- DWVOVXRNQIXUEE-UHFFFAOYSA-N 4-chloro-5-methyl-1,2-oxazol-3-amine Chemical compound CC=1ON=C(N)C=1Cl DWVOVXRNQIXUEE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 101150116411 AGTR2 gene Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010000239 Aequorin Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005485 Azilsartan Substances 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000690425 Homo sapiens Type-1 angiotensin II receptor Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 108010062475 Type 2 Angiotensin Receptor Proteins 0.000 description 1
- 102100040372 Type-2 angiotensin II receptor Human genes 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960002731 azilsartan Drugs 0.000 description 1
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 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
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002315 pressor effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 230000006438 vascular health Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/02—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 containing two hetero rings
- C07D405/06—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 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/14—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 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- the present invention relates to compounds, angiotensin II type 1 receptor antagonists and pharmaceutical compositions.
- Receptors for angiotensin II include angiotensin II type 1 receptor (AT1 receptor) and angiotensin II type 2 receptor (AT2 receptor), and various diseases related (mediated) by AT1 receptor have been reported. It is believed that AT1 receptor is angiotensin II type 1 receptor (AT1 receptor) and angiotensin II type 2 receptor (AT2 receptor), and various diseases related (mediated) by AT1 receptor have been reported. It is believed that AT1 receptorsin II type 1 receptor (AT1 receptor) and angiotensin II type 2 receptor (AT2 receptor), and various diseases related (mediated) by AT1 receptor have been reported. It is
- AT1 receptor-related diseases include hypertension (Patent Document 1), heart disease (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, diastolic failure, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, and myocardial infarction) (Non-Patent Documents 1 and 2), progression of heart failure after myocardial infarction (Non-Patent Document 3), renal diseases (e.g., nephritis, glomerulonephritis, glomerulosclerosis) , renal failure, thrombotic microangiopathy, complications of dialysis, and organ damage including nephropathy due to irradiation) (Non-Patent Documents 4 and 5), interventions (e.g., percutaneous coronary angioplasty, stent placement, Vascular thickening, occlusion and organ damage after coronary artery endoscopy
- An object of the present invention is to provide a compound having AT1 receptor antagonistic activity, or an AT1 receptor antagonist or pharmaceutical composition containing said compound.
- the present invention includes the following embodiments.
- [4] The following compounds: The compound of [1] or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [5] An angiotensin II type 1 receptor antagonist comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4]. [6] A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4].
- the present invention also includes the following embodiments.
- [A1] A method for inhibiting angiotensin II type 1 receptor, comprising administering an effective amount of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof to a patient in need thereof. How to include.
- [A2] A method for preventing or treating a disease, comprising administering an effective amount of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof to a patient in need thereof.
- the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, post-intervention vascular hyperplasia, post-intervention occlusion, post-intervention organ damage, glaucoma, ocular hypertension, Alzheimer's disease, central The method of [A2], which is neuropathy, dementia, liver disease, eosinophilic esophagitis, knee osteoarthritis, epidermolysis bullosa, Marfan's syndrome, or cancer.
- [B1] A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], for use in inhibiting angiotensin II type 1 receptor.
- [B2] A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], for use in the prevention or treatment of diseases.
- the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, post-intervention vascular hyperplasia, post-intervention occlusion, post-intervention organ damage, glaucoma, ocular hypertension, Alzheimer's disease, central
- [C1] Use of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof for inhibiting angiotensin II type 1 receptor.
- [C2] Use of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof for preventing or treating diseases.
- [C3] The disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, post-intervention vascular hyperplasia, post-intervention occlusion, post-intervention organ damage, glaucoma, ocular hypertension, Alzheimer's disease, central
- [C2] which is neuropathy, dementia, liver disease, eosinophilic esophagitis, knee osteoarthritis, epidermolysis bullosa, Marfan's syndrome, or cancer.
- [D1] Use of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof in the manufacture of an angiotensin II type 1 receptor antagonist.
- [D2] Use of the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing or treating diseases.
- [D3] The disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, post-intervention vascular hyperplasia, post-intervention occlusion, post-intervention organ damage, glaucoma, ocular hypertension, Alzheimer's disease, central
- [D2] which is neuropathy, dementia, liver disease, eosinophilic esophagitis, knee osteoarthritis, epidermolysis bullosa, Marfan's syndrome, or cancer.
- a compound having AT1 receptor antagonistic activity or an AT1 receptor antagonist or pharmaceutical composition containing the compound can be provided.
- Ar is represented by the following formula (Ar1) or (Ar2): (In the formula, R 1 and R 2 are each independently alkyl, haloalkyl or halogen; each R3 is independently alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy; m is an integer from 0 to 3) is] It relates to a compound represented by or a pharmaceutically acceptable salt thereof.
- the compound according to this embodiment or a pharmaceutically acceptable salt thereof has AT1 receptor antagonistic activity.
- alkyl (including alkyl in haloalkyl) may be linear or branched.
- the alkyl moiety contained in alkoxy (including alkoxy in haloalkoxy) may be linear or branched.
- Ar is formula (Ar1) or formula (Ar2), preferably formula (Ar1).
- R 1 is alkyl, haloalkyl or halogen, preferably alkyl or halogen, more preferably alkyl.
- Alkyl of R 1 is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and still more preferably alkyl having 1 or 2 carbon atoms. and particularly preferably methyl.
- Halogen in R 1 and halo in haloalkyl are preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.
- R 2 is alkyl, haloalkyl or halogen, preferably alkyl or halogen, more preferably alkyl.
- Alkyl for R 2 is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and still more preferably alkyl having 1 or 2 carbon atoms. and particularly preferably methyl.
- Halogen in R 2 and halo in haloalkyl are preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.
- each R3 is independently alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably alkyl or alkoxy.
- Alkyl of R 3 is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and still more preferably alkyl having 1 or 2 carbon atoms. and particularly preferably methyl.
- Halogen in R 3 and halo in haloalkyl and haloalkoxy are preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.
- Alkoxy of R 3 (including alkoxy in haloalkoxy) is preferably alkoxy having 1 to 6 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, still more preferably alkoxy having 1 or 2 carbon atoms. and particularly preferably methoxy.
- m is an integer of 0 to 3, preferably 1 or 2, more preferably 2.
- the pharmaceutically acceptable salt of the compound represented by formula (1) is not particularly limited as long as it can be used as a medicine, and examples include hydrochloride, sulfate, nitrate, phosphate, hydrobromic acid Inorganic acid salts such as salts; fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, lactate, palmitic acid organic acid salts such as salts; inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, ammonium salts; diethylamine salts, diethanolamine salts, meglumine salts, N,N'-dibenzylethylenediamine salts Organic base salts may be mentioned.
- the compound represented by formula (1) or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate.
- a solvate is intended to be included in the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.
- stereoisomers e.g. enantiomers and diastereomers
- individual stereoisomers and mixtures thereof e.g. racemates
- One embodiment of the present invention relates to an AT1 receptor antagonist comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.
- the AT1 receptor antagonist of the present embodiment is preferably capable of selectively inhibiting the AT1 receptor with respect to the endothelin A receptor (ETA receptor).
- ETA receptor endothelin A receptor
- the ETA receptor inhibitory concentration (IC 50 )/AT1 receptor inhibitory concentration (IC 50 ) is preferably 100 or more, more preferably 200 or more, and further preferably 500 or more. It is preferably 1,000 or more, and particularly preferably 1,000 or more.
- the upper limit of ETA receptor inhibitory concentration (IC 50 )/AT1 receptor inhibitory concentration (IC 50 ) is not particularly limited, it may be, for example, 10,000, 8,000, 6,000, 4,000, and the like. ETA receptor inhibitory concentration and AT1 receptor inhibitory concentration can be measured by the method described in Examples.
- the AT1 receptor inhibitory concentration (IC 50 ) of the AT1 receptor antagonist of the present embodiment is preferably 1.0 nM or less, more preferably 0.5 nM or less, and 0.2 nM or less. More preferably, it is particularly preferably 0.1 nM or less.
- the lower limit of the AT1 receptor inhibitory concentration (IC 50 ) is not particularly limited, but may be, for example, 0.0025 nM, 0.005 nM, 0.01 nM, 0.02 nM.
- the ETA receptor inhibitory concentration (IC 50 ) of the AT1 receptor antagonist of the present embodiment is preferably 10 nM or higher, more preferably 20 nM or higher, even more preferably 50 nM or higher, and 100 nM or higher. It is particularly preferred to have The upper limit of ETA receptor inhibitory concentration (IC 50 ) is not particularly limited, but may be, for example, 1,000 nM, 800 nM, 600 nM, 400 nM, and the like.
- AT1 receptor-related (mediated) diseases can be treated and/or prevented.
- diseases include the diseases described in the section ⁇ Pharmaceutical composition> below.
- the subject of administration of the AT1 receptor antagonist of this embodiment and the pharmaceutical composition described later is preferably mammals, more preferably humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs and Rabbit, more preferably human.
- ⁇ Pharmaceutical composition> One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.
- Diseases to be prevented or treated by the pharmaceutical composition of the present embodiment include, for example, the following. high blood pressure; heart disease (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure, including congestive heart failure, diastolic failure, cardiomyopathy, angina, myocarditis, atrial fibrillation, arrhythmia, tachycardia, and myocardial infarction); progression of heart failure after myocardial infarction; kidney disease (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, and organ damage including nephropathy due to radiation); Vascular thickening, occlusion and organ damage after interventions (e.g., percutaneous coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, and coronary thrombolysis); eye diseases (eg, glaucoma, and ocular hypertension); neurodegenerative diseases
- Alzheimer's disease central nervous system disorders (e.g., disorders such as cerebral hemorrhage and cerebral infarction, and sequelae and complications); dementia (e.g. cerebrovascular dementia); liver disease (e.g., non-alcoholic fatty liver disease); eosinophilic esophagitis; bone diseases (e.g. osteoarthritis of the knee); skin diseases (e.g. epidermolysis bullosa); systemic diseases (eg, Marfan's syndrome); and cancer.
- central nervous system disorders e.g., disorders such as cerebral hemorrhage and cerebral infarction, and sequelae and complications
- dementia e.g. cerebrovascular dementia
- liver disease e.g., non-alcoholic fatty liver disease
- eosinophilic esophagitis e.g. osteoarthritis of the knee
- skin diseases e.g. epidermolysis bullosa
- systemic diseases eg, Marfan's syndrome
- the pharmaceutical composition of this embodiment can be administered orally or parenterally.
- Dosage forms for oral administration include, for example, tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions.
- Dosage forms for parenteral administration include, for example, injections, infusions, drops, eye drops, patches and suppositories.
- the pharmaceutical composition of this embodiment is preferably an injection. By making it into an injection, it can be suitably used for diseases with high urgency. Diseases of high urgency include, for example, acute hypertension accompanied by organ damage such as cerebral hemorrhage and myocardial infarction.
- the injection may contain a second active ingredient in addition to the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.
- the second active ingredient include compounds having AT1 receptor antagonistic activity other than the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, specifically losartan, valsartan, candesartan, telmisartan, olmesartan, irbesartan, azilsartan and the like.
- the pharmaceutical composition of this embodiment may optionally contain excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, coloring agents, preservatives, and fragrances. , flavoring agents, stabilizers, thickening agents and the like.
- the dosage of the pharmaceutical composition of the present embodiment varies depending on the patient's condition and weight, type of compound, type of disease, route of administration, etc., and the appropriate amount can be determined by a doctor.
- One embodiment of the present invention relates to intermediate compounds that can be used in the synthesis of compounds of formula (1) or pharmaceutically acceptable salts thereof.
- Examples of intermediate compounds include compounds represented by the following formulas (2) to (4) or salts thereof.
- the salts of the compounds represented by formulas (2) to (4) are not particularly limited, and examples thereof include those exemplified as pharmaceutically acceptable salts of the compound represented by formula (1).
- solvates are intended to be included in compounds represented by formulas (2) to (4) or salts thereof.
- R 4 is a leaving group, boronic acid (-B(OH) 2 ), boronate ester, or -BF 3 M 1 ; M 1 is an alkali metal] It relates to a compound represented by or a salt thereof.
- Leaving groups for R 4 include, for example, halogen (eg, fluorine, chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.
- halogen eg, fluorine, chlorine, bromine, or iodine
- a boronate ester of R 4 can be represented, for example, by —B(OR 4A ) 2 .
- R 4A include alkyl (eg, alkyl having 1 to 6 carbon atoms or alkyl having 1 to 3 carbon atoms).
- two R 4A of —B(OR 4A ) 2 may form a 5- or 6-membered heterocyclic ring together with the oxygen and boron to which they are directly or indirectly bonded; good.
- a heterocyclic ring may have a substituent.
- Heterocyclic substituents include, for example, alkyl (eg, alkyl having 1 to 3 carbon atoms), cycloalkyl (eg, cycloalkyl having 5 or 6 carbon atoms), or aryl (eg, phenyl).
- -B(OR 4A ) 2 is, for example, the following structure: A group having
- alkyl metals for M 1 examples include lithium, sodium, or potassium.
- Ar is represented by the following formula (Ar1) or (Ar2):
- R 1 and R 2 are each independently alkyl, haloalkyl or halogen; each R3 is independently alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy; m is an integer from 0 to 3) and R 5 is a leaving group, or —OR 5A ;
- R 5A is hydrogen or a protecting group,
- R 6 is hydrogen or a protecting group
- It relates to a compound represented by or a salt thereof.
- Leaving groups for R 5 include, for example, halogen (eg, fluorine, chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.
- halogen eg, fluorine, chlorine, bromine, or iodine
- the protective group for R 5A is not particularly limited as long as it is a hydroxyl protective group, and examples include methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), benzyl (Bn), benzoyl (Bz), and acetyl (Ac). , trimethylsilyl (TMS), or triethylsilyl (TES).
- MOM methoxymethyl
- TBS tert-butyldimethylsilyl
- Bn benzyl
- Bz benzoyl
- Ac acetyl
- TMS trimethylsilyl
- TES triethylsilyl
- the protecting group for R 6 is not particularly limited as long as it is a protecting group for an amino group. Examples include methoxymethyl (MOM), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy A carbonyl group (Fmoc) or an allyloxycarbonyl group (Alloc) can be mentioned.
- R 7 is a boronic acid (-B(OH) 2 ), boronate ester, or -BF 3 M 2 ; M2 is an alkali metal, R 8 is -OR 8A ; R 8A is hydrogen or a protecting group] It relates to a compound represented by or a salt thereof.
- a boronate ester of R 7 can be represented, for example, by —B(OR 7A ) 2 .
- R 7A include alkyl (eg, alkyl having 1 to 6 carbon atoms or alkyl having 1 to 3 carbon atoms).
- two R 7A of —B(OR 7A ) 2 may form a 5- or 6-membered heterocyclic ring together with the oxygen and boron to which they are directly or indirectly bonded; good.
- a heterocyclic ring may have a substituent.
- Heterocyclic substituents include, for example, alkyl (eg, alkyl having 1 to 3 carbon atoms), cycloalkyl (eg, cycloalkyl having 5 or 6 carbon atoms), or aryl (eg, phenyl).
- -B(OR 7A ) 2 includes, for example, the following structures: A group having
- Alkylmetals for M2 include, for example, lithium, sodium, or potassium.
- the protective group for R 8A is not particularly limited as long as it is a hydroxyl protective group, and examples include methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), benzyl (Bn), benzoyl (Bz), and acetyl (Ac). , trimethylsilyl (TMS), or triethylsilyl (TES).
- MOM methoxymethyl
- TBS tert-butyldimethylsilyl
- Bn benzyl
- Bz benzoyl
- Ac acetyl
- TMS trimethylsilyl
- TES triethylsilyl
- a compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be synthesized by appropriately using a known method.
- An example of the synthetic method is Scheme A below.
- compound (A2) is reacted with a metal hydride (eg, sodium hydride) and then reacted with compound (A1) to obtain compound (A3) (step A1).
- a metal hydride eg, sodium hydride
- the amino group of compound (A4) is protected with a protecting group (for example, methoxymethyl group) to obtain compound (A5) (step A2).
- Compound (A3) and compound (A5) are reacted to give compound (A6) (step A3), and compound (A6) is deprotected to give compound (A7) (step A4).
- the method for synthesizing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is not limited to Scheme A above, and an appropriate synthetic route and reaction conditions may be applied depending on the structure of the final compound. The trader can set it as appropriate.
- reaction mixture was stirred at 50° C. for 16 hours.
- the reaction mixture was brought to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (55 mg).
- the adduct (130 mg, 0.159 mmol) was added and the reaction mixture was stirred at 100° C. for 16 hours.
- the reaction mixture was brought to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (300 mg).
- the reaction mixture was warmed to room temperature and stirred for 2 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (250 mg).
- reaction mixture was stirred at 0° C. for 10 minutes.
- the reaction mixture was concentrated under reduced pressure, ice-cold water and saturated aqueous sodium bicarbonate were added to the resulting residue to neutralize the pH, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (38 mg).
- reaction mixture was stirred at 50° C. for 2 hours.
- the reaction mixture was concentrated under reduced pressure, ice-cold water and saturated aqueous sodium bicarbonate were added to the resulting residue to neutralize the pH, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (48 mg).
- Angiotensin II type 1 receptor inhibitory action was examined by the following method. CHO-K1-mt aequorin-G ⁇ 16 cells forced to express human angiotensin II type 1 receptor (Accession Number NP — 000676.1) were cultured in an antibiotic-free medium for 18 hours, and then treated with PBS-EDTA (5 mM EDTA). After processing and centrifugation (2 minutes, 405 ⁇ g, room temperature), the cells were suspended in assay buffer (DMEM/HAM's F12 with HEPES+0.1% BSA protease free).
- IC50 values were calculated using XLfit (IDBS).
- Endothelin A receptor inhibitory action The inhibitory activity of endothelin A receptor was examined by the following method. CHO-K1-mt aequorin cells forcibly expressing human Endothelin A receptor (Accession Number NP_001948.1) were cultured in an antibiotic-free medium for 18 hours, treated with PBS-EDTA (5 mM EDTA), and centrifuged. After separation (2 minutes, 405 ⁇ g, room temperature), they were suspended in assay buffer (DMEM/HAM's F12 with HEPES+0.1% BSA protease free).
- assay buffer DMEM/HAM's F12 with HEPES+0.1% BSA protease free
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Gastroenterology & Hepatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
[1]
下記式(1):
[式中、
Arは、下記式(Ar1)、又は(Ar2):
(式中、
R1及びR2は、それぞれ独立して、アルキル、ハロアルキル又はハロゲンであり、
R3は、それぞれ独立して、アルキル、ハロアルキル、ハロゲン、アルコキシ、又はハロアルコキシであり、
mは、0~3の整数である)
である]
で表される化合物又はその医薬上許容可能な塩。
[2]
Arが、式(Ar1)である、[1]に記載の化合物又はその医薬上許容可能な塩。
[3]
R1及びR2が、それぞれ独立して、アルキルである、[1]又は[2]に記載の化合物又はその医薬上許容可能な塩。
[4]
下記化合物:
からなる群から選択される、[1]に記載の化合物又はその医薬上許容可能な塩。
[5]
[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩を含む、アンジオテンシンIIタイプ1受容体拮抗剤。
[6]
[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩を含む、医薬組成物。
[7]
高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんを予防又は治療するための、[6]に記載の医薬組成物。
[8]
注射剤、貼付剤、又は点眼剤である、[6]又は[7]に記載の医薬組成物。
[9]
下記式(2):
[式中、
R4は、脱離基、ボロン酸、ボロン酸エステル、又は-BF3M1であり、
M1は、アルカリ金属である]
で表される化合物又はその塩。
[10]
下記式(3):
[式中、
Arは、下記式(Ar1)、又は(Ar2):
(式中、
R1及びR2は、それぞれ独立して、アルキル、ハロアルキル又はハロゲンであり、
R3は、それぞれ独立して、アルキル、ハロアルキル、ハロゲン、アルコキシ、又はハロアルコキシであり、
mは、0~3の整数である)
であり、
R5は、脱離基、又は-OR5Aであり、
R5Aは、水素、又は保護基であり、
R6は、水素、又は保護基である]
で表される化合物又はその塩。
[11]
下記式(4):
[式中、
R7は、ボロン酸、ボロン酸エステル、又は-BF3M2であり、
M2は、アルカリ金属であり、
R8は、-OR8Aであり、
R8Aは、水素、又は保護基である]
で表される化合物又はその塩。
[A1]
アンジオテンシンIIタイプ1受容体を阻害する方法であって、その必要のある患者に有効量の[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩を投与することを含む方法。
[A2]
疾患を予防又は治療する方法であって、その必要のある患者に有効量の[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩を投与することを含む方法。
[A3]
前記疾患が、高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんである、[A2]に記載の方法。
アンジオテンシンIIタイプ1受容体の阻害に使用するための、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩。
[B2]
疾患の予防又は治療に使用するための、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩。
[B3]
前記疾患が、高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんである、[B2]に記載の化合物又はその医薬上許容可能な塩。
アンジオテンシンIIタイプ1受容体を阻害するための、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩の使用。
[C2]
疾患を予防又は治療するための、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩の使用。
[C3]
前記疾患が、高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんである、[C2]に記載の使用。
アンジオテンシンIIタイプ1受容体拮抗剤の製造における、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩の使用。
[D2]
疾患を予防又は治療するための医薬組成物の製造における、[1]~[4]のいずれかに記載の化合物又はその医薬上許容可能な塩の使用。
[D3]
前記疾患が、高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんである、[D2]に記載の使用。
本発明の一実施形態は、下記式(1):
[式中、
Arは、下記式(Ar1)、又は(Ar2):
(式中、
R1及びR2は、それぞれ独立して、アルキル、ハロアルキル又はハロゲンであり、
R3は、それぞれ独立して、アルキル、ハロアルキル、ハロゲン、アルコキシ、又はハロアルコキシであり、
mは、0~3の整数である)
である]
で表される化合物又はその医薬上許容可能な塩に関する。
本明細書において、アルコキシ(ハロアルコキシにおけるアルコキシを含む。)に含まれるアルキル部分は、直鎖状であってもよいし、分岐状であってもよい。
R1のハロゲン、及びハロアルキルにおけるハロは、好ましくはフッ素、塩素、臭素又はヨウ素であり、より好ましくは塩素である。
R2のハロゲン、及びハロアルキルにおけるハロは、好ましくはフッ素、塩素、臭素又はヨウ素であり、より好ましくは塩素である。
R3のハロゲン、並びにハロアルキル及びハロアルコキシにおけるハロは、好ましくはフッ素、塩素、臭素又はヨウ素であり、より好ましくは塩素である。
R3のアルコキシ(ハロアルコキシにおけるアルコキシを含む。)は、好ましくは炭素数1~6のアルコキシであり、より好ましくは炭素数1~3のアルコキシであり、更に好ましくは炭素数1又は2のアルコキシであり、特に好ましくはメトキシである。
本発明の一実施形態は、式(1)で表される化合物又はその医薬上許容可能な塩を含む、AT1受容体拮抗剤に関する。本実施形態のAT1受容体拮抗剤は、好ましくは、エンドセリンA受容体(ETA受容体)を対照として、AT1受容体を選択的に阻害することができる。AT1受容体を選択的に阻害することによって、ETA受容体の阻害による副作用(例えば催奇形性)のリスクを低減することができる。
本発明の一実施形態は、式(1)で表される化合物又はその医薬上許容可能な塩を含む、医薬組成物に関する。
高血圧症;
心疾患(例えば、心肥大、急性心不全、うっ血性心不全を含む慢性心不全、拡張不全、心筋症、狭心症、心筋炎、心房細動、不整脈、頻脈、及び心筋梗塞);
心筋梗塞後の心不全進行;
腎疾患(例えば、腎炎、糸球体腎炎、糸球体硬化症、腎不全、血栓性微小血管症、透析の合併症、及び放射線照射による腎症を含む臓器障害);
インターベンション(例えば、経皮的冠動脈形成術、ステント留置、冠動脈内視鏡、血管内超音波、及び冠注血栓溶解療法)後の血管肥厚、閉塞及び臓器障害;
眼疾患(例えば、緑内障、及び高眼圧症);
神経変性疾患(例えば、アルツハイマー病);
中枢神経障害(例えば、脳出血及び脳梗塞等の障害、並びにその後遺症及び合併症);
認知症(例えば、脳血管性認知症);
肝臓疾患(例えば、非アルコール性脂肪性肝疾患);
好酸球性食道炎;
骨疾患(例えば、変形性膝関節炎);
皮膚疾患(例えば、表皮水疱症);
全身疾患(例えば、マルファン症候群);並びに
がん。
本発明の一実施形態は、式(1)で表される化合物又はその医薬上許容可能な塩の合成に使用することができる中間体化合物に関する。中間体化合物としては、例えば、下記式(2)~式(4)で表される化合物又はその塩が挙げられる。
本発明の一実施形態は、下記式(2):
[式中、
R4は、脱離基、ボロン酸(-B(OH)2)、ボロン酸エステル、又は-BF3M1であり、
M1は、アルカリ金属である]
で表される化合物又はその塩に関する。
また、-B(OR4A)2の2つのR4Aは、それらが直接的に又は間接的に結合する酸素及びホウ素と一緒になって、5員若しくは6員の複素環を形成していてもよい。複素環は置換基を有していてもよい。複素環の置換基としては、例えば、アルキル(例えば炭素数1~3のアルキル)、シクロアルキル(例えば、炭素数5又は6のシクロアルキル)、又はアリール(例えば、フェニル)が挙げられる。-B(OR4A)2としては、例えば、下記の構造:
を有する基が挙げられる。
本発明の一実施形態は、下記式(3):
[式中、
Arは、下記式(Ar1)、又は(Ar2):
(式中、
R1及びR2は、それぞれ独立して、アルキル、ハロアルキル又はハロゲンであり、
R3は、それぞれ独立して、アルキル、ハロアルキル、ハロゲン、アルコキシ、又はハロアルコキシであり、
mは、0~3の整数である)
であり、
R5は、脱離基、又は-OR5Aであり、
R5Aは、水素、又は保護基であり、
R6は、水素、又は保護基である]
で表される化合物又はその塩に関する。
本発明の一実施形態は、下記式(4):
[式中、
R7は、ボロン酸(-B(OH)2)、ボロン酸エステル、又は-BF3M2であり、
M2は、アルカリ金属であり、
R8は、-OR8Aであり、
R8Aは、水素、又は保護基である]
で表される化合物又はその塩に関する。
また、-B(OR7A)2の2つのR7Aは、それらが直接的に又は間接的に結合する酸素及びホウ素と一緒になって、5員若しくは6員の複素環を形成していてもよい。複素環は置換基を有していてもよい。複素環の置換基としては、例えば、アルキル(例えば炭素数1~3のアルキル)、シクロアルキル(例えば、炭素数5又は6のシクロアルキル)、又はアリール(例えば、フェニル)が挙げられる。-B(OR7A)2としては、例えば、下記の構造:
を有する基が挙げられる。
7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-アミン ヒドロクロリド
tert-ブチル(7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)カルバマート(4.90g、15.6mmol)、ジクロロメタン(50.0mL)の混合物に塩化水素・1,4-ジオキサン溶液(4mol/L、15.0mL)を0℃でゆっくり加え、室温で6時間攪拌した。反応混合物を減圧下溶媒留去し、残渣をジエチルエーテルで洗浄し、標記化合物(2.90g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.05 (bs, 2H), 4.89 (bs, 2H).
4,7-ジブロモ-1,3-ジヒドロイソベンゾフラン
アルゴン雰囲気下、7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-アミン ヒドロクロリド(2.90g、11.64mmol)、アセトニトリル(40.0mL)の混合物に、臭化銅(II)(3.03g、13.5mmol)、亜硝酸tert-ブチル(1.54g、14.9mmol)、アセトニトリル(20.0mL)の混合物を0℃でゆっくり加え、80℃で6時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(1.70g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 7,45 (bs, 1H), 5.09 (s, 4H).
7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-カルバルデヒド
アルゴン雰囲気下、4,7-ジブロモ-1,3-ジヒドロイソベンゾフラン(1.70g、6.12mmol)、ジエチルエーテル(20.0mL)の混合物に、n-ブチルリチウム(2.3Mヘキサン溶液、5.65mL、7.34mmol)を-78℃でゆっくり加え、同温で1時間攪拌した。反応混合物にN,N-ジメチルホルムアミド(0.95mL、12.2mmol)をゆっくり加え、-78℃で30分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.80g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.87-7.79 (m, 2H), 5.37 (s, 2H), 5.01 (s, 2H).
(7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)メタノール
7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-カルバルデヒド(800mg、3.52mmol)、メタノール(10mL)の混合物に水素化ほう素ナトリウム(379mg、10.6mmol)を0℃で加え、反応混合物を室温で1時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.75g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 5.14 (s, 2H), 4.96 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H).
4-ブロモ-7-(クロロメチル)-1,3-ジヒドロイソベンゾフラン
(7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)メタノール(750mg、3.27mmol)、ジクロロメタン(15mL)の混合物に塩化チオニル(584mg、4.91mmol)を0℃でゆっくり加え、同温で30分間攪拌した。反応混合物に少量のN,N-ジメチルホルムアミドを加え、同温で2時間攪拌した。反応混合物に氷冷水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.63g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 5.00 (s, 2H), 4.73 (s, 2H).
3-((7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-2-ブチル-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン
2-ブチル-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(494mg、2.55mmol)とDMF(10mL)の混合物に、50%水素化ナトリウム(153mg、6.36mmol)を0℃でゆっくり加え、同温で30分間攪拌した。反応混合物に4-ブロモ-7-(クロロメチル)-1,3-ジヒドロイソベンゾフラン(630mg、2.55mmol)、DMF(5mL)の混合物をゆっくり加え、同温で2時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.90g)を得た。
ESI-MS: m/z 405.10 [M+1]+, 407.12 [M+3]+
2-ブチル-3-((7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン
アルゴン雰囲気下、3-((7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-2-ブチル-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(500mg、1.23mmol)、ビス(ピナコラト)ジボロン(471mg、1.85mmol)、酢酸カリウム(245mg、2.47mmol)、1,4-ジオキサン(10mL)の混合物に、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(50.3mg、0.0617mmol)を加え、反応混合物を100℃で16時間攪拌した。反応混合物を室温とし、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.35g)を得た。
ESI-MS: m/z 453.26 [M+1]+.
2-ブロモ-N-(4,5-ジメチルイソオキサゾール-3-イル)ベンゼンスルホンアミド
4,5-ジメチルイソオキサゾール-3-アミン(500mg、4.46mmol)とピリジン(10.0mL)との混合物に、4-ジメチルアミノピリジン(54.5mg、0.446mmol)、2-ブロモベンゼンスルホニル クロリド(1.71g、6.69mmol)を0℃でゆっくり加え、反応混合物を50℃で16時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を2mol/L塩酸、および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させた。減圧下溶媒留去し、標記化合物(1.20g)を粗体として得た。得られた粗体は、これ以上の精製をすることなく次の反応に用いた。
ESI-MS: m/z 330.91 [M+1]+, 332.93 [M+3]+
2-ブロモ-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
2-ブロモ-N-(4,5-ジメチルイソオキサゾール-3-イル)ベンゼンスルホンアミドの粗体(1.20g、3.62mmol)とDMF(20.0mL)の混合物に、50%水素化ナトリウム(217mg、4.53mmol)を0℃でゆっくり加え、同温で30分間攪拌した。反応混合物にクロロメチルメチルエーテル(583mg、7.25mmol)をゆっくり加え、室温で3時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.90g)を得た。
1H NMR (400 MHz, CDCl3) δ 8.02-8.00 (m, 1H), 7.76-7.74 (m, 1H), 7.40-7.38 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H), 2.30 (s, 3H), 1.99 (s, 3H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
アルゴン雰囲気下、2-ブロモ-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(347mg、0.92mmol)、2-ブチル-3-((7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(350mg、0.77mmol)、1,4-ジオキサン(5.0mL)、水(0.5mL)、炭酸カリウム(314mg、1.54mmol)の混合物に、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(63mg、0.07mmolを加え、反応混合物を100℃で16時間攪拌した。反応混合物を室温とし、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(0.25g)を得た。
ESI-MS: m/z 621.31 [M+1]+
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)ベンゼンスルホンアミド
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(250mg、0.40mmol)、メタノール(3mL)の混合物に6mol/L塩酸(1.5mL)を0℃で加え、反応混合物を50℃で16時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(55mg)を得た。
ESI-MS: m/z 577.30 [M+1]+
1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.06 (dd, J = 7.6, 1.6 Hz, 1H), 7.67-7.60 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.99-4.97 (m, 2H), 4.73-4.67 (m, 3H), 4.50-4.47 (m, 1H), 2.34 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.89-1.84 (m, 6H), 1.71-1.69 (m, 2H), 1.63 (s, 3H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 3H), 0.82 (t, J = 7.2 Hz, 3H).
4-ブロモ-7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン
(7-ブロモ-1,3-ジヒドロイソベンゾフラン-4-イル)メタノール(3.0g、13.1mmol)、ジクロロメタン(30mL)の混合物に3,4-ヒドロ-2H-ピラン(2.1g、26.2mmol)及び少量のp-トルエンスルホン酸を0℃でゆっくり加え、室温で3時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(2.9g)を得た。
1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.27 (d, J = 1.6 Hz, 2H), 5.11 (t, J = 4.0 Hz, 2H), 4.69 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4Hz, 1H), 3.90 - 3.85 (m, 1H), 3.59 - 3.54 (m, 1H), 1.88 - 1.84 (m, 1H), 1.79 -1.73 (m, 1H), 1.68 -1.57 (m, 4H).
4,4,5,5-テトラメチル-2-(7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-1,3,2-ジオキサボロラン
アルゴン雰囲気下、4-ブロモ-7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン(1.0g、3.19mmol)、ビス(ピナコラト)ジボロン(969mg、3.38mmol)、酢酸カリウム(937mg、9.57mmol)、1,4-ジオキサン(10mL)の混合物に、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(130mg、0.159mmol)を加え、反応混合物を100℃で16時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(300mg)を得た。
1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.07- 5.02 (m, 4H), 4.64 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4Hz, 1H), 3.77 - 3.72 (m, 1H), 3.49 - 3.45 (m, 1H), 1.67 - 1.64 (m, 2H), 1.52 -1.56 (m, 4H), 1.28 (s, 12H).
N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)-2-(7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)ベンゼンスルホンアミド
アルゴン雰囲気下、4,4,5,5-テトラメチル-2-(7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-1,3,2-ジオキサボロラン(600mg、1.66mmol)、2-ブロモ-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(749mg、1.99mmol)、1,4-ジオキサン(7.0mL)、水(0.5mL)、炭酸カリウム(687mg、4.98mmol)の混合物に、[1,1‘-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(135mg、0.166mmol)を加え、反応混合物を100℃で16時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(400mg)を得た。
1H NMR (400 MHz, DMSO): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.15 (s, 2H), 4.84 - 4.78 (m, 2H), 4.75 - 4.67 (m, 2H), 4.51 - 4.47 (m, 1H), 4.31 - 4.23 (m, 2H), 3.80 - 3.76 (m, 1H), 3.50 - 3.47 (m, 1H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H), 1.68 - 1.65 (m, 2H), 1.51 -1.48 (m, 4H).
N-(4,5-ジメチルイソオキサゾール-3-イル)-2-(7-(ヒドロキシメチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)-2-(7-(((テトラヒドロ-2H-ピラン-2-イル)オキシ)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)ベンゼンスルホンアミド(500mg、0.946mmol)、メタノール(8.0mL)の混合物にp-トルエンスルホン酸(35.2mg、0.189mmol)を0℃で加え、室温で3時間攪拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を飽和重曹水および飽和食塩水で洗浄、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(300mg)を得た。
1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.28 - 5.25 (m, 1H), 5.13 - 5.06 (m, 2H), 4.82- 4.72 (m, 2H), 4.53 - 4.51 (m, 2H), 4.33 - 4.23 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).
2-(7-(ブロモメチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
N-(4,5-ジメチルイソオキサゾール-3-イル)-2-(7-(ヒドロキシメチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(300mg、0.675mmol)、ジクロロメタン(7.0mL)溶液にテトラブロモメタン(290mg、0.877mmol)を0℃で加え、10分後にトリフェニルホスフィン(176mg、0.675mmol)を同温で加えた。反応混合物を室温に昇温し2時間攪拌した。反応混合物に氷冷水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(250mg)を得た。
1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.41 - 7.39 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 5.19 - 5.14 (m, 2H), 4.81 - 4.74 (m, 4H), 4.33- 4.21 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
2-ブチル-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(108mg、0.473mmol)のDMF(2.0mL)溶液に、60%水素化ナトリウム(31.5mg、0.788mmol)を0℃でゆっくり加え、室温で30分間攪拌した。反応混合物に2-(7-(ブロモメチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4,5-ジメチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(200mg、0.394mmol)、DMF(1.0mL)の混合物をゆっくり加え、室温で2時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(80mg)を得た。
1H NMR (400 MHz, DMSO): 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 4.80 - 4.69 (m, 4H), 4.30 - 4.21 (m, 2H), 3.18 (s, 3H), 2.30 (s, 4H), 1.85 - 1.80 (m, 9H), 1.70 - 1.68 (m, 2H), 1.53 - 1.49 (m, 2H), 1.31 - 1.23 (m, 3H), 0.84 - 0.81 (m, 3H).
2-ブロモ-N-(3-メトキシ-5-メチルピラジン-2-イル)ベンゼンスルホンアミド
3-メトキシ-5-メチルピラジン-2-アミン(500mg、3.5mmol)とピリジン(5.0mL)との混合物に、4-ジメチルアミノピリジン(128mg、1.05mmol)、2-ブロモベンゼンスルホニル クロリド(1.1g、4.3mmol)を室温で加え、反応混合物を50℃で12時間攪拌した。反応混合物を室温とし、2mol/L塩酸(5.0mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させた。減圧下溶媒留去し、標記化合物(1.20g)を粗体として得た。得られた粗体はシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(1.0g)を得た。
1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 0.8 Hz, 1H), 7.59-7.51 (m, 3H), 3.86 (s, 3H), 2.26 (s, 3H).
2-ブロモ-N-(3-メトキシ-5-メチルピラジン-2-イル)-N-((2-(トリメチルシリル)エトキシ)メチル)ベンゼンスルホンアミド
2-ブロモ-N-(3-メトキシ-5-メチルピラジン-2-イル)ベンゼンスルホンアミド(500mg、1.39mmol)とDMF(5.0mL)の混合物に、炭酸カリウム(380mg、2.79mmol)を0℃で加え、同温で30分間攪拌した。反応混合物に2-(トリメチルシリル)エトキシメチルクロリド(350mg、2.08mmol)を0℃でゆっくり加え、室温で1時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(500mg)を得た。
1H NMR (400 MHz, DMSO-d6): δ 8.09-8.07 (m, 1H), 7.99 (s, 1H), 7.87-7.85 (m, 1H), 7.57-7.54 (m,2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.62-3.58(m, 2H), 2.42(s, 3H), 0.76-0.72(m, 2H), 0.065(s, 9H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(3-メトキシ-5-メチルピラジン-2-イル)-N-((2-(トリメチルシリル)エトキシ)メチル)ベンゼンスルホンアミド
アルゴン雰囲気下、2-ブロモ-N-(3-メトキシ-5-メチルピラジン-2-イル)-N-((2-(トリメチルシリル)エトキシ)メチル)ベンゼンスルホンアミド(400mg、0.78mmol)、2-ブチル-3-((7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(445mg、0.98mmol)、1,4-ジオキサン(4.5mL)、水(0.5mL)、炭酸カリウム(340mg、2.71mmol)の混合物に、[1,1‘-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(67mg、0.09mmol)を加え、反応混合物を100℃で12時間攪拌した。反応混合物を室温とし、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(170mg)を得た。
1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J = 7.6 Hz, 1H), 7.796(s, 1H), 7.69-7.58 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.11 (d, , J = 8 Hz, 1H), 6.91 (d, , J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.74-4.67 (m, 6H), 3.76 (s, 3H), 3.45(t, J = 8 Hz, 2H), 2.42 (s, 3H), 2.28(t, J = 7.2 Hz, 2H), 1.86-183 (m, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.28-1.23 (m, 4H), 0.81 (m, 3H), 0.095(s, 9H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(3-メトキシ-5-メチルピラジン-2-イル)ベンゼンスルホンアミド
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(3-メトキシ-5-メチルピラジン-2-イル)-N-((2-(トリメチルシリル)エトキシ)メチル)ベンゼンスルホンアミド(170mg、0.231mmol)、メタノール(2mL)の混合物に50%硫酸(2.0mL)を0℃で加え、反応混合物を0℃で10分間攪拌した。反応混合物を減圧下濃縮し得られた残渣に氷冷水、飽和重曹水を加えpHを中性にしたのち酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(38mg)を得た。
ESI-MS: m/z 604.67 [M+1]+1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 10.04 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.60-7.52 (m, 3H), 7.26-6.90 (m, 2H), 6.78-6.78 (m, 1H), 4.96 (s, 1H), 4.77-4.68 (m, 2H), 4.58-4.44 (m, 2H), 3.82-3.79(m, 3H), 2.32-2.26 (m, 5H), 1.86 (s, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.26-1.25 (m, 2H), 0.79 (s, 3H).
2-ブロモ-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)ベンゼンスルホンアミド
4-クロロ-5-メチルイソオキサゾール-3-アミン(1.0g、7.6mmol)とピリジン(5.0mL)との混合物に、4-ジメチルアミノピリジン(91mg、0.75mmol)、2-ブロモベンゼンスルホニル クロリド(2.3g、9.1mmol)を室温で加え、反応混合物を80℃で6時間攪拌した。反応混合物を室温とし、氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。得られた粗体はシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(850mg)を得た。
1H NMR (400 MHz, DMSO-d6): δ 11.68(s, 1H), 8.00 (dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz 1H), 7.63-7.59 (m, 2H), 3.34(s, 3H).
2-ブロモ-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
2-ブロモ-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)ベンゼンスルホンアミド(850mg、2.42mmol)とDMF(5.0mL)の混合物に、60%水素化ナトリウム(194mg、4.87mmol)を0℃でゆっくり加え、同温で30分間攪拌した。反応混合物にクロロメチルメチルエーテル(292mg、3.63mmol)をゆっくり加え、室温で1時間攪拌した。反応混合物に氷冷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(800mg)を得た。
1H NMR (400 MHz, DMSO-d6): δ 8.01(dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 1H), 7.63-7.59 (m, 2H), 5.19(s, 2H), 3.38(s, 3H), 2.42(s, 3H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド
アルゴン雰囲気下、2-ブロモ-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(400mg、1.01mmol)、2-ブチル-3-((7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1,3-ジヒドロイソベンゾフラン-4-イル)メチル)-1,3-ジアザスピロ[4.4]ノナ-1-エン-4-オン(549mg、1.21mmol)、1,4-ジオキサン(4.5mL)、水(0.5mL)、炭酸カリウム(419mg、3.03mmol)の混合物に、[1,1‘-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(82.5mg、0.10mmol)を加え、反応混合物を100℃で12時間攪拌した。反応混合物を室温とし、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(150mg)を得た。
1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J =8 Hz, 1H), 7.74 (t, J =7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 5.02 (s, 2H), 4.76-4.70 (m, 4H), 4.45-4.34 (m, 2H), 3.22 (s, 3H), 2.41 (s, 3H), 2.32-2.28 (m, 2H), 1.85-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.53-1.49 (m, 2H), 1.31-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)ベンゼンスルホンアミド
2-(7-((2-ブチル-4-オキソ-1,3-ジアザスピロ[4.4]ノナ-1-エン-3-イル)メチル)-1,3-ジヒドロイソベンゾフラン-4-イル)-N-(4-クロロ-5-メチルイソオキサゾール-3-イル)-N-(メトキシメチル)ベンゼンスルホンアミド(150mg、0.23mmol)、メタノール(2mL)の混合物に50%硫酸(2.0mL)を0℃でゆっくり加え、反応混合物を50℃で2時間攪拌した。反応混合物を減圧下濃縮し、得られた残渣に氷冷水、飽和重曹水を加えpHを中性にしたのち酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、標記化合物(48mg)を得た。
ESI-MS: m/z 597.67 [M+1]+
1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.97 (t, J = 3.6 Hz, 1H), 7.39 (bs, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 8 Hz, 1H), 4.91 (s, 2H), 4.63 (s, 2H), 4.52 (s, 2H), 2.36-2.32 (m, 2H), 2.12 (s, 3H), 1.88-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).
アンジオテンシンII type1受容体の阻害作用を以下の方法で検討した。
ヒトAngiotensin II type 1受容体(Accession Number NP_000676.1)を強制発現させたCHO-K1-mt aequorin-Gα16細胞を抗生剤無添加の培地で18時間培養した後、PBS-EDTA(5mM EDTA)で処理し、遠心分離後(2分、405×g、室温)、アッセイバッファー(DMEM/HAM‘s F12 with HEPES+0.1% BSA protease free)に懸濁させた。
1×106個/mLの細胞を終濃度5μMのCoelenterazin h(Molecular Probes)存在下4時間以上室温でインキュベートし、Angiotensin IIによるアゴニスト反応を確認し、EC80に相当するAngiotensin II濃度を求めた。
続いて96穴プレートに10000個/wellのCoelenterazin h処置した細胞懸濁液を50μLと被験物質(終濃度0.5%DMSO)を含むアッセイバッファー50μL添加し、15分後に終濃度がEC80濃度になるようにAngiotensin II溶液を100μL添加し、FDSS6000(浜松ホトニクス)にて受容体活性を発光量で測定した。IC50値はXLfit(IDBS)を用いて算出した。
エンドセリンA受容体の阻害作用を以下の方法で検討した。
ヒトEndothelin A受容体(Accession Number NP_001948.1)を強制発現させたCHO-K1-mt aequorin細胞を抗生剤無添加の培地で18時間培養した後、PBS-EDTA(5mM EDTA)で処理し、遠心分離後(2分、405×g、室温)、アッセイバッファー(DMEM/HAM‘s F12 with HEPES+0.1% BSA protease free)に懸濁させた。
1×106個/mLの細胞を終濃度5μMのCoelenterazin h(Molecular Probes)存在下4時間室温でインキュベートし、Endothelinによるアゴニスト反応を確認し、EC80に相当するEndothelin濃度を求めた。
続いて96穴プレートに10000個/wellのCoelenterazin h処置した細胞懸濁液を50μLと被験物質(終濃度0.5%DMSO)を含むアッセイバッファー50μL添加し、15分後に終濃度がEC80濃度になるようにEndothelinを添加し、FDSS6000(浜松ホトニクス)にて受容体活性を発光量で測定した。IC50値はXLfit(IDBS)を用いて算出した。
8~12週齢の雄性Wistarラットに、鎮痛剤処置とウレタン麻酔下にて、気管へ気道確保用カテーテル処置、頸動脈へ血圧測定用カテーテル処置、大腿静脈へアンジオテンシンII(ATII)投与用カテーテル処置を行った。血圧および心拍数が安定したことを確認後、溶媒(PBS)または溶媒で調整した被験物質(実施例1の化合物)1mg/kg(15mL/kg)を10分間かけて静脈内投与した。続いてATII(300ng/kg)を静脈内投与し、投与10分後まで血圧をモニタリングした。各群n=3で実施し、解析はATII投与2分前をプレ値とし、プレ値と血圧が最大となるATII投与直後の20秒間の収縮期血圧、拡張期血圧を求め、プレ値からの差分(デルタ値)を算出した。溶媒投与群と被験物質投与群のデルタ値の比較にはStudentのt検定を用いた。
Claims (11)
- Arが、式(Ar1)である、請求項1に記載の化合物又はその医薬上許容可能な塩。
- R1及びR2が、それぞれ独立して、アルキルである、請求項1又は2に記載の化合物又はその医薬上許容可能な塩。
- 請求項1~4のいずれか一項に記載の化合物又はその医薬上許容可能な塩を含む、アンジオテンシンIIタイプ1受容体拮抗剤。
- 請求項1~4のいずれか一項に記載の化合物又はその医薬上許容可能な塩を含む、医薬組成物。
- 高血圧症、心疾患、心筋梗塞後の心不全進行、腎疾患、インターベンション後の血管肥厚、インターベンション後の閉塞、インターベンション後の臓器障害、緑内障、高眼圧症、アルツハイマー病、中枢神経障害、認知症、肝臓疾患、好酸球性食道炎、変形性膝関節炎、表皮水疱症、マルファン症候群、又はがんを予防又は治療するための、請求項6に記載の医薬組成物。
- 注射剤、貼付剤、又は点眼剤である、請求項6又は7に記載の医薬組成物。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3231724A CA3231724A1 (en) | 2021-12-28 | 2022-12-27 | Compound, angiotensin ii type 1 receptor antagonist and pharmaceutical composition |
AU2022428746A AU2022428746A1 (en) | 2021-12-28 | 2022-12-27 | Compound, angiotensin II type 1 receptor antagonist and pharmaceutical composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021-213587 | 2021-12-28 | ||
JP2021213587 | 2021-12-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023127853A1 true WO2023127853A1 (ja) | 2023-07-06 |
Family
ID=86999006
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2022/048117 WO2023127853A1 (ja) | 2021-12-28 | 2022-12-27 | 化合物、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR128112A1 (ja) |
AU (1) | AU2022428746A1 (ja) |
CA (1) | CA3231724A1 (ja) |
TW (1) | TW202340183A (ja) |
WO (1) | WO2023127853A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024101440A1 (ja) * | 2022-11-11 | 2024-05-16 | 株式会社アークメディスン | 化合物、エンドセリンa受容体拮抗剤、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003520785A (ja) * | 1999-12-15 | 2003-07-08 | ブリストル−マイヤーズ スクイブ カンパニー | アンジオテンシン・エンドセリン受容体二重拮抗薬としてのビフェニルスルホンアミド類 |
WO2005080384A2 (en) | 2004-02-25 | 2005-09-01 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use as aii receptor antagonist |
JP2012522058A (ja) * | 2009-03-31 | 2012-09-20 | リガンド・ファーマシューティカルズ・インコーポレイテッド | 血圧上昇および糖尿病性腎症を処置するための、ジフェニルスルホンアミドエンドセリンおよびアンジオテンシンii受容体アゴニストの経口製剤 |
WO2020092383A1 (en) * | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
-
2022
- 2022-12-27 AR ARP220103593A patent/AR128112A1/es unknown
- 2022-12-27 CA CA3231724A patent/CA3231724A1/en active Pending
- 2022-12-27 WO PCT/JP2022/048117 patent/WO2023127853A1/ja active Application Filing
- 2022-12-27 TW TW111150073A patent/TW202340183A/zh unknown
- 2022-12-27 AU AU2022428746A patent/AU2022428746A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003520785A (ja) * | 1999-12-15 | 2003-07-08 | ブリストル−マイヤーズ スクイブ カンパニー | アンジオテンシン・エンドセリン受容体二重拮抗薬としてのビフェニルスルホンアミド類 |
WO2005080384A2 (en) | 2004-02-25 | 2005-09-01 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use as aii receptor antagonist |
JP2012522058A (ja) * | 2009-03-31 | 2012-09-20 | リガンド・ファーマシューティカルズ・インコーポレイテッド | 血圧上昇および糖尿病性腎症を処置するための、ジフェニルスルホンアミドエンドセリンおよびアンジオテンシンii受容体アゴニストの経口製剤 |
WO2020092383A1 (en) * | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
Non-Patent Citations (18)
Title |
---|
ANNALS OF PALLIATIVE MEDICINE, vol. 10, 2021, pages 8684 |
BIOCHEMICAL PHARMACOLOGY, vol. 151, 2018, pages 96 |
BLOOD PRESSURE, vol. 28, 2019, pages 358 |
BMC CARDIOVASCULAR DISORDERS, vol. 17, 2017, pages 278 |
DERMATOLOGIC THERAPY, 2020, pages e14279 |
EUROPEAN HEART JOURNAL, vol. 41, 2020, pages 4181 |
EXPERIMENTAL EYE RESEARCH, vol. 80, 2005, pages 629 |
EXPERT REVIEW OF CLINICAL IMMUNOLOGY, vol. 16, 2020, pages 421 |
HYPERTENSION RESEARCH, vol. 32, 2009, pages 738 |
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 13, 2012, pages 7739 |
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, vol. 36, 2000, pages 169 |
JOURNAL OF CLINICAL INVESTIGATION, vol. 117, 2007, pages 3393 |
JOURNAL OF ORTHOPAEDIC TRANSLATION, vol. 29, 2021, pages 30 |
ONCOTARGET, vol. 9, 2018, pages 24155 |
PHYSIOLOGICAL REPORTS, vol. 4, 2016, pages e13016 |
THE LANCET, vol. 360, 2002, pages 752 |
THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 345, 2001, pages 861 |
VASCULAR HEALTH AND RISK MANAGEMENT, vol. 4, 2008, pages 67 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024101440A1 (ja) * | 2022-11-11 | 2024-05-16 | 株式会社アークメディスン | 化合物、エンドセリンa受容体拮抗剤、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
AU2022428746A2 (en) | 2024-04-04 |
AU2022428746A1 (en) | 2024-04-04 |
TW202340183A (zh) | 2023-10-16 |
CA3231724A1 (en) | 2023-07-06 |
AR128112A1 (es) | 2024-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI436986B (zh) | 新穎之2環性雜環化合物 | |
EP3009426B1 (en) | 4-alkynyl imidazole derivative and medicine comprising same as active ingredient | |
ES2899937T3 (es) | Inhibidores de quinasa de pirazolilquinoxalina | |
ES2548228T3 (es) | Derivados de bencimidazol e imidazopiridina como moduladores de canal de sodio | |
RU2625303C2 (ru) | Хинолины в качестве модуляторов fgfr киназы | |
JP6308504B2 (ja) | タンパク質キナーゼ阻害薬 | |
RU2629194C2 (ru) | Производные 1,5- и 1,7-нафтиридина, полезные при лечении заболеваний, опосредованных fgfr | |
AU2014267974B2 (en) | Cycloalkyl acid derivative, preparation method thereof, and pharmaceutical application thereof | |
TWI586666B (zh) | Tetrahydrocarboline Derivatives (2) | |
JP2012504632A (ja) | C型肝炎ウイルス阻害剤 | |
BRPI0912878A2 (pt) | derivados de indazóis substituídos por fenila e benzodioxinila | |
TW201315727A (zh) | 尿嘧啶衍生物及其醫藥用途 | |
JP2024505732A (ja) | ピリドピリミジノン系誘導体及びその製造方法と使用 | |
WO2016088082A1 (en) | Amidomethyl-biaryl derivatives complement factor d inhibitors and uses thereof | |
CN111511720A (zh) | 用于治疗缺血性中风的芳族磺酰胺衍生物 | |
WO2023127853A1 (ja) | 化合物、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 | |
KR20210125471A (ko) | Apj 수용체 활성과 관련된 병태를 치료하기 위한 화합물 및 조성물 | |
JP2023520400A (ja) | アルファ-1-アンチトリプシン欠損症(aatd)を治療するためのアルファ-1-アンチトリプシンモジュレーターとしてのインドール誘導体 | |
WO2023085415A1 (ja) | 化合物、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 | |
CN118284605A (zh) | 化合物、血管紧张素ii第1型受体拮抗剂及医药组合物 | |
WO2021110076A1 (zh) | 草酰胺类衍生物、其制备方法及其在医药上的应用 | |
JP3116256B2 (ja) | (チオ)ウレア誘導体 | |
KR20130115311A (ko) | S1p 수용체의 조절제 | |
WO2024101440A1 (ja) | 化合物、エンドセリンa受容体拮抗剤、アンジオテンシンiiタイプ1受容体拮抗剤及び医薬組成物 | |
EP4353720A1 (en) | Novel piperidine derivative and pharmaceutical composition for inhibiting autotaxin comprising same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22916076 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023571043 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3231724 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022428746 Country of ref document: AU Ref document number: AU2022428746 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2022428746 Country of ref document: AU Date of ref document: 20221227 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112024010464 Country of ref document: BR |