JP2017519025A - チオフェン−２−イル−ピリジン−２−イル−１ｈ−ピラゾール−４−カルボン酸誘導体、および可溶性グアニル酸シクラーゼ活性化剤としてのその使用 - Google Patents
チオフェン−２−イル−ピリジン−２−イル−１ｈ−ピラゾール−４−カルボン酸誘導体、および可溶性グアニル酸シクラーゼ活性化剤としてのその使用 Download PDFInfo
- Publication number
- JP2017519025A JP2017519025A JP2016574921A JP2016574921A JP2017519025A JP 2017519025 A JP2017519025 A JP 2017519025A JP 2016574921 A JP2016574921 A JP 2016574921A JP 2016574921 A JP2016574921 A JP 2016574921A JP 2017519025 A JP2017519025 A JP 2017519025A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- alkyl
- trifluoromethyl
- mmol
- pyrazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 title description 42
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 title description 42
- ADKNNQOWOFNISC-UHFFFAOYSA-N 1-pyridin-2-yl-3-thiophen-2-ylpyrazole-4-carboxylic acid Chemical class OC(=O)C1=CN(C=2N=CC=CC=2)N=C1C1=CC=CS1 ADKNNQOWOFNISC-UHFFFAOYSA-N 0.000 title 1
- 229940126514 guanylate cyclase activator Drugs 0.000 title 1
- 239000003119 guanylate cyclase activator Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 339
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- -1 C 1 -C 4 alkyl Chemical group 0.000 claims description 108
- 238000000034 method Methods 0.000 claims description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 239000001257 hydrogen Substances 0.000 claims description 58
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
- 150000002431 hydrogen Chemical group 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 230000004410 intraocular pressure Effects 0.000 claims description 32
- 208000010412 Glaucoma Diseases 0.000 claims description 31
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 230000000699 topical effect Effects 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 239000000556 agonist Substances 0.000 claims description 4
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 4
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 claims description 3
- 239000002876 beta blocker Substances 0.000 claims description 3
- 229940097320 beta blocking agent Drugs 0.000 claims description 3
- 239000004090 neuroprotective agent Substances 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 150000003180 prostaglandins Chemical class 0.000 claims description 3
- 210000003786 sclera Anatomy 0.000 claims description 3
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005002 aryl methyl group Chemical group 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 229960003310 sildenafil Drugs 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 229960000835 tadalafil Drugs 0.000 claims description 2
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims description 2
- 229960002381 vardenafil Drugs 0.000 claims description 2
- 230000000394 mitotic effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 239000013543 active substance Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 296
- 239000000203 mixture Substances 0.000 description 290
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
- 235000019439 ethyl acetate Nutrition 0.000 description 128
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 92
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 88
- 239000000460 chlorine Substances 0.000 description 87
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 86
- 239000000741 silica gel Substances 0.000 description 68
- 229910002027 silica gel Inorganic materials 0.000 description 68
- 238000003818 flash chromatography Methods 0.000 description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 55
- 239000012044 organic layer Substances 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 239000002904 solvent Substances 0.000 description 48
- 238000011282 treatment Methods 0.000 description 43
- 239000011541 reaction mixture Substances 0.000 description 42
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 41
- 239000011734 sodium Substances 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 37
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 34
- 235000002639 sodium chloride Nutrition 0.000 description 34
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 32
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000007858 starting material Substances 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- 201000010099 disease Diseases 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- 229940125526 sGC activator Drugs 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- MCLKZJLGDFGFLI-UHFFFAOYSA-N 1-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound OC(=O)C=1C=NN(C(F)(F)F)C=1 MCLKZJLGDFGFLI-UHFFFAOYSA-N 0.000 description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
- 238000004007 reversed phase HPLC Methods 0.000 description 15
- 239000012190 activator Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 11
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 11
- 238000005984 hydrogenation reaction Methods 0.000 description 11
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000010348 incorporation Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 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 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000011591 potassium Substances 0.000 description 8
- 229910052700 potassium Inorganic materials 0.000 description 8
- 238000007127 saponification reaction Methods 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 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 7
- 239000000284 extract Substances 0.000 description 7
- 150000003278 haem Chemical class 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000009466 transformation Effects 0.000 description 7
- RTMMSCJWQYWMNK-UHFFFAOYSA-N 2,2,2-trifluoroethyl trifluoromethanesulfonate Chemical compound FC(F)(F)COS(=O)(=O)C(F)(F)F RTMMSCJWQYWMNK-UHFFFAOYSA-N 0.000 description 6
- IWJGMJHAIUBWKT-UHFFFAOYSA-N 4-bromo-2-methylphenol Chemical compound CC1=CC(Br)=CC=C1O IWJGMJHAIUBWKT-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- PSGHZLMVOUCELD-UHFFFAOYSA-N ethyl 1-[6-[3-[(2-methyl-4-piperidin-4-ylphenoxy)methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC(=C1)C1CCNCC1 PSGHZLMVOUCELD-UHFFFAOYSA-N 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- OZMLUMPWPFZWTP-UHFFFAOYSA-N 2-(tributyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CCCCP(CCCC)(CCCC)=CC#N OZMLUMPWPFZWTP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000007821 HATU Substances 0.000 description 5
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 5
- 101150003085 Pdcl gene Proteins 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 201000006366 primary open angle glaucoma Diseases 0.000 description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 5
- 229940127296 soluble guanylate cyclase stimulator Drugs 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- CUUQNEXFGPWNPJ-UHFFFAOYSA-N tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(O)C=C1 CUUQNEXFGPWNPJ-UHFFFAOYSA-N 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- LZMHWZHOZLVYDL-UHFFFAOYSA-N 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one Chemical compound C1=CC=C2N3C(=O)ON=C3C=NC2=C1 LZMHWZHOZLVYDL-UHFFFAOYSA-N 0.000 description 4
- ZPWPMAAPQZXPDD-UHFFFAOYSA-N 2-bromo-3-(bromomethyl)thiophene Chemical compound BrCC=1C=CSC=1Br ZPWPMAAPQZXPDD-UHFFFAOYSA-N 0.000 description 4
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 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 4
- 241000124008 Mammalia Species 0.000 description 4
- 206010030043 Ocular hypertension Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 210000001742 aqueous humor Anatomy 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000003889 eye drop Substances 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- 230000036542 oxidative stress Effects 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- ZPHGMBGIFODUMF-UHFFFAOYSA-N thiophen-2-ylmethanol Chemical class OCC1=CC=CS1 ZPHGMBGIFODUMF-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 230000004382 visual function Effects 0.000 description 4
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 description 3
- WJUBBZGKAIMZBR-UHFFFAOYSA-N 1-[6-[3-[2-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]ethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C WJUBBZGKAIMZBR-UHFFFAOYSA-N 0.000 description 3
- CIPNFRLWJBKZJA-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]-5-propan-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)(C)C1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C CIPNFRLWJBKZJA-UHFFFAOYSA-N 0.000 description 3
- XYEMKCOHHAXZCO-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(pyrrolidine-3-carbonyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(=O)C1CNCC1 XYEMKCOHHAXZCO-UHFFFAOYSA-N 0.000 description 3
- ZDFBKZUDCQQKAC-UHFFFAOYSA-N 1-bromo-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1 ZDFBKZUDCQQKAC-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 3
- VHKMTORCXXPIFI-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole-4-carboxylic acid Chemical compound OC(=O)C=1C=NNC=1C(F)(F)F VHKMTORCXXPIFI-UHFFFAOYSA-N 0.000 description 3
- MMARFGDTMJBIBK-UHFFFAOYSA-N 5-bromo-2-methoxy-1,3-dimethylbenzene Chemical compound COC1=C(C)C=C(Br)C=C1C MMARFGDTMJBIBK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 206010067013 Normal tension glaucoma Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 description 3
- IXKCRTQEEQPAKY-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC IXKCRTQEEQPAKY-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 201000002978 low tension glaucoma Diseases 0.000 description 3
- 235000001055 magnesium Nutrition 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000003590 rho kinase inhibitor Substances 0.000 description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- MLMJILGYEYTGNT-UHFFFAOYSA-N tert-butyl 4-(3-methyl-4-nitrophenyl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1=C([N+]([O-])=O)C(C)=CC(C=2CCN(CC=2)C(=O)OC(C)(C)C)=C1 MLMJILGYEYTGNT-UHFFFAOYSA-N 0.000 description 3
- ZFZSPLFKSLVQAX-UHFFFAOYSA-N tert-butyl 4-(4-hydroxy-3-methylphenyl)piperidine-1-carboxylate Chemical compound OC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C ZFZSPLFKSLVQAX-UHFFFAOYSA-N 0.000 description 3
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- NAVPHGRFAKSAOL-UHFFFAOYSA-N (2-chloro-6-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(Cl)=N1 NAVPHGRFAKSAOL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- HYXMHAHVUFTVFZ-UHFFFAOYSA-N (3-formylthiophen-2-yl)boronic acid Chemical compound OB(O)C=1SC=CC=1C=O HYXMHAHVUFTVFZ-UHFFFAOYSA-N 0.000 description 2
- QNIVKTTWBMFSBR-UHFFFAOYSA-J 1,2,3,4,5-pentamethylcyclopentane;rhodium(2+);tetrachloride Chemical compound Cl[Rh]Cl.Cl[Rh]Cl.C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C QNIVKTTWBMFSBR-UHFFFAOYSA-J 0.000 description 2
- NCADHSLPNSTDMJ-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(C(O)=O)C1 NCADHSLPNSTDMJ-UHFFFAOYSA-N 0.000 description 2
- HRMRQBJUFWFQLX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)C1 HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 2
- WDFNDIYLWSYHKB-UHFFFAOYSA-N 1-[4-(4-hydroxy-3,5-dimethylphenyl)piperidin-1-yl]propan-1-one Chemical compound OC1=C(C=C(C=C1C)C1CCN(CC1)C(CC)=O)C WDFNDIYLWSYHKB-UHFFFAOYSA-N 0.000 description 2
- JIXSYCMWYPBHSP-UHFFFAOYSA-N 1-[6-[3-[2-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]ethyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C JIXSYCMWYPBHSP-UHFFFAOYSA-N 0.000 description 2
- FTKYPWRMPVNWFB-UHFFFAOYSA-N 1-[6-[3-[2-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]phenyl]ethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(CCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1 FTKYPWRMPVNWFB-UHFFFAOYSA-N 0.000 description 2
- VGSHLDMSRPXBDM-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]-5-propylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC(=C2)CCC)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)CC(F)(F)F VGSHLDMSRPXBDM-UHFFFAOYSA-N 0.000 description 2
- RFXYOJDMMPINFS-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)CC(F)(F)F RFXYOJDMMPINFS-UHFFFAOYSA-N 0.000 description 2
- JTOBYTIJKSQNDN-UHFFFAOYSA-N 1-[6-[3-[[4-(1-methoxycarbonylpiperidin-4-yl)-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound COC(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C JTOBYTIJKSQNDN-UHFFFAOYSA-N 0.000 description 2
- OTTWDFAXZUNFEG-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2,3-dihydroxypropanoyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound OC(C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC)CO OTTWDFAXZUNFEG-UHFFFAOYSA-N 0.000 description 2
- YGKMOWMXAIFLOV-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(azetidine-3-carbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound N1CC(C1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C YGKMOWMXAIFLOV-UHFFFAOYSA-N 0.000 description 2
- KZJMTLAPNGLEFJ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)O)C KZJMTLAPNGLEFJ-UHFFFAOYSA-N 0.000 description 2
- AIRIZDWADNYHJQ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C AIRIZDWADNYHJQ-UHFFFAOYSA-N 0.000 description 2
- RDRNSWXCVKPZHA-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylanilino]methyl]-4-(trifluoromethyl)thiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)NCC1=C(SC=C1C(F)(F)F)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)O)CC RDRNSWXCVKPZHA-UHFFFAOYSA-N 0.000 description 2
- GHZGBBPCTNNUCH-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylanilino]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)NCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)CC GHZGBBPCTNNUCH-UHFFFAOYSA-N 0.000 description 2
- FCZLWWFGTIZQSN-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylanilino]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)NCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)O)CC FCZLWWFGTIZQSN-UHFFFAOYSA-N 0.000 description 2
- HZLAHOYQWOBKGM-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]anilino]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(C=C1)NCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O HZLAHOYQWOBKGM-UHFFFAOYSA-N 0.000 description 2
- KYAYGYYFCXFDGS-UHFFFAOYSA-N 1-[6-[5-methyl-3-[2-[2-methyl-4-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]phenyl]ethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)C1=CC(=C(CCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C KYAYGYYFCXFDGS-UHFFFAOYSA-N 0.000 description 2
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 2
- KRTVZBZIKULDNU-UHFFFAOYSA-N 1-bromo-2-ethenyl-3-fluoro-4-phenylmethoxybenzene Chemical compound C(C1=CC=CC=C1)OC1=C(C(=C(C=C1)Br)C=C)F KRTVZBZIKULDNU-UHFFFAOYSA-N 0.000 description 2
- WOWNZZYJCUUIFC-UHFFFAOYSA-N 1-bromo-4-methoxy-2,3-dimethylbenzene Chemical compound COC1=CC=C(Br)C(C)=C1C WOWNZZYJCUUIFC-UHFFFAOYSA-N 0.000 description 2
- ITADIVACIVJFJF-UHFFFAOYSA-N 1-bromo-4-methoxy-2-propan-2-ylbenzene Chemical compound COC1=CC=C(Br)C(C(C)C)=C1 ITADIVACIVJFJF-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- OZPFVBLDYBXHAF-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid Chemical compound CC1(C)OCC(C(O)=O)O1 OZPFVBLDYBXHAF-UHFFFAOYSA-N 0.000 description 2
- WSNAMSQNHCXVSZ-UHFFFAOYSA-N 2-bromo-3-methoxythiophene Chemical compound COC=1C=CSC=1Br WSNAMSQNHCXVSZ-UHFFFAOYSA-N 0.000 description 2
- SCRQAWQJSSKCFN-UHFFFAOYSA-N 2-bromo-5-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C(C=O)=C1 SCRQAWQJSSKCFN-UHFFFAOYSA-N 0.000 description 2
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- FICXHNUJLDDMGP-UHFFFAOYSA-N 2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]aniline Chemical compound CC1=C(N)C=CC(=C1)C1CCN(CC1)CC(F)(F)F FICXHNUJLDDMGP-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- ONZQYZKCUHFORE-UHFFFAOYSA-N 3-bromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)CBr ONZQYZKCUHFORE-UHFFFAOYSA-N 0.000 description 2
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- PAHAIHXVVJMZKU-UHFFFAOYSA-N 4-bromo-2-methyl-1-nitrobenzene Chemical compound CC1=CC(Br)=CC=C1[N+]([O-])=O PAHAIHXVVJMZKU-UHFFFAOYSA-N 0.000 description 2
- FQEYHIPPYOSPLF-UHFFFAOYSA-N 4-bromo-3-chlorophenol Chemical compound OC1=CC=C(Br)C(Cl)=C1 FQEYHIPPYOSPLF-UHFFFAOYSA-N 0.000 description 2
- KWQNNOZROOJVJB-UHFFFAOYSA-N 4-bromo-3-ethylaniline Chemical compound CCC1=CC(N)=CC=C1Br KWQNNOZROOJVJB-UHFFFAOYSA-N 0.000 description 2
- DVKVZPIRWWREJC-UHFFFAOYSA-N 4-chloro-3-ethylphenol Chemical compound CCC1=CC(O)=CC=C1Cl DVKVZPIRWWREJC-UHFFFAOYSA-N 0.000 description 2
- LRFIHWGUGBXFEC-UHFFFAOYSA-N 4-methylthiophene-3-carboxylic acid Chemical compound CC1=CSC=C1C(O)=O LRFIHWGUGBXFEC-UHFFFAOYSA-N 0.000 description 2
- RMWYQKVGQWYCBR-UHFFFAOYSA-N 4-piperidin-4-yl-3-propan-2-ylphenol Chemical compound C(C)(C)C=1C=C(C=CC=1C1CCNCC1)O RMWYQKVGQWYCBR-UHFFFAOYSA-N 0.000 description 2
- GRIVHAIKQQBTIY-UHFFFAOYSA-N 6-bromo-2-fluoro-3-phenylmethoxybenzaldehyde Chemical compound C1=CC(Br)=C(C=O)C(F)=C1OCC1=CC=CC=C1 GRIVHAIKQQBTIY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010002388 Angina unstable Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 244000303965 Cyamopsis psoralioides Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VHDLBVBQAINTOW-UHFFFAOYSA-N OC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O Chemical compound OC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O VHDLBVBQAINTOW-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007718 Stable Angina Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 2
- 102100023118 Transcription factor JunD Human genes 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- VCCRAEOWYNDZJL-UHFFFAOYSA-M [2-methyl-4-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]phenyl]methyl-triphenylphosphanium bromide Chemical compound [Br-].C(C)(C)(C)OC(=O)N1CCC(CC1)C1=CC(=C(C[P+](C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)C=C1)C VCCRAEOWYNDZJL-UHFFFAOYSA-M 0.000 description 2
- FQKOKQKXLBWJKK-UHFFFAOYSA-N [4-(4-aminophenyl)piperidin-1-yl]-cyclopropylmethanone Chemical compound C1=CC(N)=CC=C1C1CCN(C(=O)C2CC2)CC1 FQKOKQKXLBWJKK-UHFFFAOYSA-N 0.000 description 2
- QQDRLKRHJOAQDC-FBHGDYMESA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 QQDRLKRHJOAQDC-FBHGDYMESA-N 0.000 description 2
- IKQCKJSWVAERRG-UHFFFAOYSA-M [Br-].CC(C)[Zn+] Chemical compound [Br-].CC(C)[Zn+] IKQCKJSWVAERRG-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 229960003679 brimonidine Drugs 0.000 description 2
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 2
- 229960000722 brinzolamide Drugs 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- XNGGOXOLHQANRB-WAYWQWQTSA-N ethyl (2z)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate Chemical compound CCO\C=C(C(=O)C(F)(F)F)/C(=O)OCC XNGGOXOLHQANRB-WAYWQWQTSA-N 0.000 description 2
- QYLMLIKWOSITQG-UHFFFAOYSA-N ethyl 1-(6-bromopyridin-2-yl)-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound FC(F)(F)C1=C(C(=O)OCC)C=NN1C1=CC=CC(Br)=N1 QYLMLIKWOSITQG-UHFFFAOYSA-N 0.000 description 2
- VNZPXEMLXFCTOV-UHFFFAOYSA-N ethyl 1-(6-bromopyridin-2-yl)-5-ethylpyrazole-4-carboxylate Chemical compound BrC1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)OCC VNZPXEMLXFCTOV-UHFFFAOYSA-N 0.000 description 2
- KXMNHMKUWUGBEI-UHFFFAOYSA-N ethyl 1-[6-(3-methoxythiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound COC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC KXMNHMKUWUGBEI-UHFFFAOYSA-N 0.000 description 2
- FMCYJKBGRXBSHT-UHFFFAOYSA-N ethyl 1-[6-[3-(1,2,3,4-tetrahydroisoquinolin-6-yloxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1NCCC2=CC(=CC=C12)OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC FMCYJKBGRXBSHT-UHFFFAOYSA-N 0.000 description 2
- PCALQEVYUGIAEH-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-5-methyl-4-propan-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1C(C)C)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC PCALQEVYUGIAEH-UHFFFAOYSA-N 0.000 description 2
- PVHBKGHDPSUIKW-UHFFFAOYSA-N ethyl 1-[6-[3-[(2-chloro-4-piperidin-4-ylphenoxy)methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound ClC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC(=C1)C1CCNCC1 PVHBKGHDPSUIKW-UHFFFAOYSA-N 0.000 description 2
- XCXHRWKDSQQENR-UHFFFAOYSA-N ethyl 1-[6-[3-[(4-piperidin-4-ylphenoxy)methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound N1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1 XCXHRWKDSQQENR-UHFFFAOYSA-N 0.000 description 2
- KIXUDIDVUUMZTD-UHFFFAOYSA-N ethyl 1-[6-[3-[2-(4-bromophenyl)ethenyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC1=CC=C(C=CC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1 KIXUDIDVUUMZTD-UHFFFAOYSA-N 0.000 description 2
- XJJPICIFAYFZPY-UHFFFAOYSA-N ethyl 1-[6-[3-[[3-(hydroxymethyl)-4-piperidin-4-ylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC=1C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC=1C1CCNCC1 XJJPICIFAYFZPY-UHFFFAOYSA-N 0.000 description 2
- RTISTTFEYWGEMK-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-(trifluoromethyl)phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C(F)(F)F RTISTTFEYWGEMK-UHFFFAOYSA-N 0.000 description 2
- JZKVITFYVMPLNN-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-cyclopropyl-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2C2CC2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C JZKVITFYVMPLNN-UHFFFAOYSA-N 0.000 description 2
- ZBMWPABPSBRVAF-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-ethyl-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2CC)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C ZBMWPABPSBRVAF-UHFFFAOYSA-N 0.000 description 2
- VRCXMNUWXYAMDO-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C VRCXMNUWXYAMDO-UHFFFAOYSA-N 0.000 description 2
- NLOTXIZVZLUUHH-UHFFFAOYSA-N ethyl 1-[6-[4-bromo-3-(hydroxymethyl)-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO NLOTXIZVZLUUHH-UHFFFAOYSA-N 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- JOAQPMUQGGFQDE-UHFFFAOYSA-N methyl 1-[6-(3-hydroxythiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OC JOAQPMUQGGFQDE-UHFFFAOYSA-N 0.000 description 2
- DSVLFSAWVFGCEJ-UHFFFAOYSA-N methyl 5-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(C)=C1 DSVLFSAWVFGCEJ-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- QRPRIOOKPZSVFN-UHFFFAOYSA-M methyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 QRPRIOOKPZSVFN-UHFFFAOYSA-M 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000004452 microanalysis Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- XKMLYUALXHKNFT-UHFFFAOYSA-N rGTP Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O XKMLYUALXHKNFT-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- ANAVEQYVVUEPAF-UHFFFAOYSA-N tert-butyl 4-(2-chloro-4-hydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound ClC1=C(C=CC(=C1)O)C1=CCN(CC1)C(=O)OC(C)(C)C ANAVEQYVVUEPAF-UHFFFAOYSA-N 0.000 description 2
- GXSBBRJGBDDOGG-UHFFFAOYSA-N tert-butyl 4-(2-ethenyl-3-fluoro-4-phenylmethoxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC1=C(C(=C(C=C1)C1=CCN(CC1)C(=O)OC(C)(C)C)C=C)F GXSBBRJGBDDOGG-UHFFFAOYSA-N 0.000 description 2
- LOVKILUSQSZJSJ-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound C(C)C1=C(C=CC(=C1)O)C1CCN(CC1)C(=O)OC(C)(C)C LOVKILUSQSZJSJ-UHFFFAOYSA-N 0.000 description 2
- HKCXJSVPYCSVOR-UHFFFAOYSA-N tert-butyl 4-(3-chloro-5-hydroxypyridin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound ClC=1C(=NC=C(C=1)O)C1=CCN(CC1)C(=O)OC(C)(C)C HKCXJSVPYCSVOR-UHFFFAOYSA-N 0.000 description 2
- VSRPOQDOXMYYNF-UHFFFAOYSA-N tert-butyl 4-(4-amino-2-ethylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound NC1=CC(=C(C=C1)C1=CCN(CC1)C(=O)OC(C)(C)C)CC VSRPOQDOXMYYNF-UHFFFAOYSA-N 0.000 description 2
- YRLQFRXDWBFGMK-UHFFFAOYSA-N tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(N)C=C1 YRLQFRXDWBFGMK-UHFFFAOYSA-N 0.000 description 2
- PNWXNBIUASCWBN-UHFFFAOYSA-N tert-butyl 4-[4-(bromomethyl)-3-methylphenyl]piperidine-1-carboxylate Chemical compound BrCC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C PNWXNBIUASCWBN-UHFFFAOYSA-N 0.000 description 2
- KOUUZSVQZUIQNU-UHFFFAOYSA-N tert-butyl 4-[4-(hydroxymethyl)-3-methylphenyl]piperidine-1-carboxylate Chemical compound OCC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C KOUUZSVQZUIQNU-UHFFFAOYSA-N 0.000 description 2
- YPAVHCJZNOTJLF-UHFFFAOYSA-N tert-butyl 4-[4-(hydroxymethyl)phenyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(CO)C=C1 YPAVHCJZNOTJLF-UHFFFAOYSA-N 0.000 description 2
- IVHHZZKGSYGTKZ-UHFFFAOYSA-N tert-butyl 6-hydroxy-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound OC1=CC=C2CN(C(=O)OC(C)(C)C)CCC2=C1 IVHHZZKGSYGTKZ-UHFFFAOYSA-N 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 2
- 230000009424 thromboembolic effect Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 210000001585 trabecular meshwork Anatomy 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 208000014001 urinary system disease Diseases 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- DYWNLSQWJMTVGJ-UHFFFAOYSA-N (1-hydroxy-1-phenylpropan-2-yl)azanium;chloride Chemical compound Cl.CC(N)C(O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-UHFFFAOYSA-N 0.000 description 1
- RRZBXOSETANGLP-UHFFFAOYSA-N (2-bromo-4-methylthiophen-3-yl)methanol Chemical compound BrC=1SC=C(C=1CO)C RRZBXOSETANGLP-UHFFFAOYSA-N 0.000 description 1
- ZIRDZICIIVGANO-UHFFFAOYSA-N (2-bromo-5-methylthiophen-3-yl)methanol Chemical compound BrC=1SC(=CC=1CO)C ZIRDZICIIVGANO-UHFFFAOYSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- FQJYKXVQABPCRA-UHFFFAOYSA-M (4-bromophenyl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C1=CC(Br)=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FQJYKXVQABPCRA-UHFFFAOYSA-M 0.000 description 1
- NRQHBNNTBIDSRK-YRNVUSSQSA-N (4e)-4-[(4-methoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(OC)=CC=C1\C=C\1C(=O)OC(C)=N/1 NRQHBNNTBIDSRK-YRNVUSSQSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FMRFUKZPHGBWHF-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-1-ol Chemical class C1=CC=C2C(O)NCCC2=C1 FMRFUKZPHGBWHF-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- GGUSQTSTQSHJAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanol Chemical compound C=1C=C(Cl)C=CC=1C(O)CN(CC1)CCC1CC1=CC=C(F)C=C1 GGUSQTSTQSHJAH-UHFFFAOYSA-N 0.000 description 1
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- VPKYLEJROXEZNN-UHFFFAOYSA-N 1-[3-[3-[1-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]ethyl]thiophen-2-yl]phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC(C)C1=C(SC=C1)C=1C=C(C=CC=1)N1N=CC(=C1C(F)(F)F)C(=O)O)C VPKYLEJROXEZNN-UHFFFAOYSA-N 0.000 description 1
- LNSNOCOJSAPLPF-UHFFFAOYSA-N 1-[3-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C=2C=C(C=CC=2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C LNSNOCOJSAPLPF-UHFFFAOYSA-N 0.000 description 1
- HNEFHOAFNZETAQ-UHFFFAOYSA-N 1-[4-(4-hydroxy-3-methylphenyl)piperidin-1-yl]propan-1-one Chemical compound OC1=C(C=C(C=C1)C1CCN(CC1)C(CC)=O)C HNEFHOAFNZETAQ-UHFFFAOYSA-N 0.000 description 1
- VAWNNVUDSTYGEJ-UHFFFAOYSA-N 1-[4-(4-methoxy-3-methylphenyl)piperidin-1-yl]propan-1-one Chemical compound COC1=C(C=C(C=C1)C1CCN(CC1)C(CC)=O)C VAWNNVUDSTYGEJ-UHFFFAOYSA-N 0.000 description 1
- NVYJSCWBZJICKM-UHFFFAOYSA-N 1-[4-[4-[(2-bromo-5-methylthiophen-3-yl)methoxy]phenyl]piperidin-1-yl]propan-1-one Chemical compound BrC=1SC(=CC=1COC1=CC=C(C=C1)C1CCN(CC1)C(CC)=O)C NVYJSCWBZJICKM-UHFFFAOYSA-N 0.000 description 1
- SMHXMHQNTZGWPG-UHFFFAOYSA-N 1-[6-[3-[2-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]ethyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)CCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)O)C SMHXMHQNTZGWPG-UHFFFAOYSA-N 0.000 description 1
- QVEHPIVXTFUJHH-UHFFFAOYSA-N 1-[6-[3-[[2,6-dimethyl-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C(=CC(=C1)C1CCN(CC1)C(CC)=O)C QVEHPIVXTFUJHH-UHFFFAOYSA-N 0.000 description 1
- LOSDGAZQOXNIBL-UHFFFAOYSA-N 1-[6-[3-[[2-(pyridin-2-ylmethyl)-3,4-dihydro-1H-isoquinolin-6-yl]oxymethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound N1=C(C=CC=C1)CN1CC2=CC=C(C=C2CC1)OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O LOSDGAZQOXNIBL-UHFFFAOYSA-N 0.000 description 1
- WGZHISGEOJYPCV-UHFFFAOYSA-N 1-[6-[3-[[2-chloro-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound ClC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(CC)=O WGZHISGEOJYPCV-UHFFFAOYSA-N 0.000 description 1
- YGRXLFVDEJQOEP-UHFFFAOYSA-N 1-[6-[3-[[2-chloro-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound ClC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(=O)C1CC1 YGRXLFVDEJQOEP-UHFFFAOYSA-N 0.000 description 1
- AJONNHOEYKNDDH-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]-4-(trifluoromethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2C(F)(F)F)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(CC)=O AJONNHOEYKNDDH-UHFFFAOYSA-N 0.000 description 1
- FQTGLXVGVNWFCD-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(CC)=O FQTGLXVGVNWFCD-UHFFFAOYSA-N 0.000 description 1
- HCZKGPXSTMAQKA-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(oxetan-3-yl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C1COC1 HCZKGPXSTMAQKA-UHFFFAOYSA-N 0.000 description 1
- ZNSXMHSURUICCW-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(oxetane-3-carbonyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(=O)C1COC1 ZNSXMHSURUICCW-UHFFFAOYSA-N 0.000 description 1
- FLRMETBQJGWWGF-UHFFFAOYSA-N 1-[6-[3-[[2-methyl-4-[1-(oxolane-3-carbonyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC(=C1)C1CCN(CC1)C(=O)C1COCC1 FLRMETBQJGWWGF-UHFFFAOYSA-N 0.000 description 1
- BQUXOJLKBUYAFH-UHFFFAOYSA-N 1-[6-[3-[[3-ethyl-4-[1-(2-hydroxyacetyl)piperidin-4-yl]phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C=1C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC=1C1CCN(CC1)C(CO)=O BQUXOJLKBUYAFH-UHFFFAOYSA-N 0.000 description 1
- CBPWWNDKIQBBFY-UHFFFAOYSA-N 1-[6-[3-[[3-ethyl-4-[1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-4-yl]phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C=1C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=CC=1C1CCN(CC1)C(C(CO)(C)C)=O CBPWWNDKIQBBFY-UHFFFAOYSA-N 0.000 description 1
- JYVJPDONBQBCKM-IBGZPJMESA-N 1-[6-[3-[[3-ethyl-4-[1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl]phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CCC1=CC(OCC2=C(SC(C)=C2)C2=CC=CC(=N2)N2N=CC(C(O)=O)=C2C(F)(F)F)=CC=C1C1CCN(CC1)C(=O)[C@H](C)O JYVJPDONBQBCKM-IBGZPJMESA-N 0.000 description 1
- SGGQRGDBYCYMMV-UHFFFAOYSA-N 1-[6-[3-[[4-(1-methoxycarbonylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound COC(=O)N1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1 SGGQRGDBYCYMMV-UHFFFAOYSA-N 0.000 description 1
- ZMNWTMSBKKTLHF-UHFFFAOYSA-N 1-[6-[3-[[4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(CC)(=O)N1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1 ZMNWTMSBKKTLHF-UHFFFAOYSA-N 0.000 description 1
- MBPDVYSOFWADAX-UHFFFAOYSA-N 1-[6-[3-[[4-(1-propanoylpiperidin-4-yl)phenyl]methoxy]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(CC)(=O)N1CCC(CC1)C1=CC=C(COC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1 MBPDVYSOFWADAX-UHFFFAOYSA-N 0.000 description 1
- LPPBEDBWNCEYRD-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound FC(CN1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)(F)F LPPBEDBWNCEYRD-UHFFFAOYSA-N 0.000 description 1
- LROYNOKIZQFBHU-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2,2-dimethyl-1,3-dioxolane-4-carbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1(OCC(O1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C)C LROYNOKIZQFBHU-UHFFFAOYSA-N 0.000 description 1
- HCBWKHZPDCOFOU-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2-cyclopropylacetyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)CC(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C HCBWKHZPDCOFOU-UHFFFAOYSA-N 0.000 description 1
- XOBDRVIZCBYZLM-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2-cyclopropylacetyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)CC(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC XOBDRVIZCBYZLM-UHFFFAOYSA-N 0.000 description 1
- AKVHZTACUXZLDE-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(2-cyclopropylacetyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)CC(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)CC AKVHZTACUXZLDE-UHFFFAOYSA-N 0.000 description 1
- JISHTCNZCYCKSE-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(3-hydroxycyclobutanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound OC1CC(C1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C JISHTCNZCYCKSE-UHFFFAOYSA-N 0.000 description 1
- UTWGLVXHFVUDSQ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclobutanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CCC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C UTWGLVXHFVUDSQ-UHFFFAOYSA-N 0.000 description 1
- UOONXMUKMUDUKL-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)-2,2,6,6-tetramethylpiperidin-4-yl]-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1C(CC(CC1(C)C)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C)(C)C UOONXMUKMUDUKL-UHFFFAOYSA-N 0.000 description 1
- PYNGOYLLPJXMGO-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2,3-dimethylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C)C PYNGOYLLPJXMGO-UHFFFAOYSA-N 0.000 description 1
- YBAREVRZCUECPT-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-(trifluoromethyl)phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C(F)(F)F YBAREVRZCUECPT-UHFFFAOYSA-N 0.000 description 1
- QCSZYEDUCDOCRO-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-(trifluoromethyl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C(F)(F)F QCSZYEDUCDOCRO-UHFFFAOYSA-N 0.000 description 1
- YXVRJFDQWBMYQX-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC YXVRJFDQWBMYQX-UHFFFAOYSA-N 0.000 description 1
- KGYVDAZBIJZIRC-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-fluorophenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)F KGYVDAZBIJZIRC-UHFFFAOYSA-N 0.000 description 1
- PYZCPDVEFFDVEX-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]-4,5-dimethylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC(=C1C)C)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)O)C PYZCPDVEFFDVEX-UHFFFAOYSA-N 0.000 description 1
- PGNUHILZKGHBHG-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)C PGNUHILZKGHBHG-UHFFFAOYSA-N 0.000 description 1
- BQLRXXHXIIUTJY-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)O)C BQLRXXHXIIUTJY-UHFFFAOYSA-N 0.000 description 1
- YBPCKIJBCIKYCO-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)C YBPCKIJBCIKYCO-UHFFFAOYSA-N 0.000 description 1
- OUHMTWFSKWBCIU-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4,5-dimethylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2C)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C OUHMTWFSKWBCIU-UHFFFAOYSA-N 0.000 description 1
- UWHRLMNVFALIQM-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4,5-dimethylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2C)C)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)C UWHRLMNVFALIQM-UHFFFAOYSA-N 0.000 description 1
- VAMXMPCGSNCSQP-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-ethyl-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2CC)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C VAMXMPCGSNCSQP-UHFFFAOYSA-N 0.000 description 1
- XVAYAHBVMXBETC-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-ethylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2CC)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C XVAYAHBVMXBETC-UHFFFAOYSA-N 0.000 description 1
- AKIOCJUOEKYWLH-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C AKIOCJUOEKYWLH-UHFFFAOYSA-N 0.000 description 1
- TWCNQWJJXQBNNI-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-cyclopropylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C2CC2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C TWCNQWJJXQBNNI-UHFFFAOYSA-N 0.000 description 1
- NZXVVTFUXCIIOH-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-ethylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)CC)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C NZXVVTFUXCIIOH-UHFFFAOYSA-N 0.000 description 1
- LEWYYHUMXLPRNX-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-methyl-4-propan-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2C(C)C)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C LEWYYHUMXLPRNX-UHFFFAOYSA-N 0.000 description 1
- DQHUKHSBISNXAA-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)C DQHUKHSBISNXAA-UHFFFAOYSA-N 0.000 description 1
- IRJHSLTWVSXFKH-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)C IRJHSLTWVSXFKH-UHFFFAOYSA-N 0.000 description 1
- YLQBWVYWMSJOBK-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-5-propan-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2)C(C)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C YLQBWVYWMSJOBK-UHFFFAOYSA-N 0.000 description 1
- WXYIZQKSZUJVIC-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)C WXYIZQKSZUJVIC-UHFFFAOYSA-N 0.000 description 1
- FAAZWMQTZVQNAN-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-(hydroxymethyl)phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CO FAAZWMQTZVQNAN-UHFFFAOYSA-N 0.000 description 1
- SJEKQLLVAFHUAY-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethyl-2-fluorophenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C(=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)F)CC SJEKQLLVAFHUAY-UHFFFAOYSA-N 0.000 description 1
- DREQKOUZDXWKFZ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC=C2C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC DREQKOUZDXWKFZ-UHFFFAOYSA-N 0.000 description 1
- CNIRUZPSWFWFSU-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC CNIRUZPSWFWFSU-UHFFFAOYSA-N 0.000 description 1
- UCNSVPVNYRTKFQ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)CC UCNSVPVNYRTKFQ-UHFFFAOYSA-N 0.000 description 1
- VTYMYTWRESPCNP-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)CC VTYMYTWRESPCNP-UHFFFAOYSA-N 0.000 description 1
- VNKHAUHCXHUWCC-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)CC VNKHAUHCXHUWCC-UHFFFAOYSA-N 0.000 description 1
- NBQWVDXNJBVDFI-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)CC NBQWVDXNJBVDFI-UHFFFAOYSA-N 0.000 description 1
- ZGMSGQUPBOUNGK-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-fluorophenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)F ZGMSGQUPBOUNGK-UHFFFAOYSA-N 0.000 description 1
- GDYKTZMATSMXGO-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-methylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C GDYKTZMATSMXGO-UHFFFAOYSA-N 0.000 description 1
- NMBMIAGSWFAISW-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-propan-2-ylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C(C)C NMBMIAGSWFAISW-UHFFFAOYSA-N 0.000 description 1
- ZPVSTABQLJVPOY-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-propylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CCC ZPVSTABQLJVPOY-UHFFFAOYSA-N 0.000 description 1
- JRMDMCKYPAVPKZ-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]anilino]methyl]-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(C=C1)NCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O JRMDMCKYPAVPKZ-UHFFFAOYSA-N 0.000 description 1
- JXPDJWJXOFOQTK-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]anilino]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(C=C1)NCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)O JXPDJWJXOFOQTK-UHFFFAOYSA-N 0.000 description 1
- WKNNSQGFMSYJPF-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1 WKNNSQGFMSYJPF-UHFFFAOYSA-N 0.000 description 1
- JQOWBFLNGKVRQT-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(dimethylcarbamoyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CN(C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)CC)C JQOWBFLNGKVRQT-UHFFFAOYSA-N 0.000 description 1
- FLZOCUNCYOLZLM-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(dimethylcarbamoyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound CN(C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)CC)C FLZOCUNCYOLZLM-UHFFFAOYSA-N 0.000 description 1
- RFNKHHIPFYRKDR-UHFFFAOYSA-N 1-[6-[3-[[5-[1-(cyclopropanecarbonyl)piperidin-4-yl]pyridin-2-yl]oxymethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C=1C=CC(=NC=1)OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O RFNKHHIPFYRKDR-UHFFFAOYSA-N 0.000 description 1
- ATOYAEMJQZICIS-UHFFFAOYSA-N 1-[6-[3-[[5-methyl-2-(pyridin-2-ylmethyl)-3,4-dihydro-1H-isoquinolin-6-yl]oxymethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=C2CCN(CC2=CC=C1OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)CC1=NC=CC=C1 ATOYAEMJQZICIS-UHFFFAOYSA-N 0.000 description 1
- WDDKHWNMFXPGPS-UHFFFAOYSA-N 1-[6-[3-[[6-[1-(cyclopropanecarbonyl)piperidin-4-yl]-5-ethylpyridin-3-yl]oxymethyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=N1)OCC1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)CC WDDKHWNMFXPGPS-UHFFFAOYSA-N 0.000 description 1
- JXUDHTVIDDQRDC-UHFFFAOYSA-N 1-[6-[4,5-dimethyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C JXUDHTVIDDQRDC-UHFFFAOYSA-N 0.000 description 1
- HXENOXNYSIVNRZ-UHFFFAOYSA-N 1-[6-[4,5-dimethyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound CC=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C HXENOXNYSIVNRZ-UHFFFAOYSA-N 0.000 description 1
- GVHNMOAAPLPMMT-UHFFFAOYSA-N 1-[6-[4-cyclopropyl-5-methyl-3-[[2-methyl-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)C(CC)=O)C GVHNMOAAPLPMMT-UHFFFAOYSA-N 0.000 description 1
- CUCIGZUIGDJJCM-UHFFFAOYSA-N 1-[6-[4-ethyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C CUCIGZUIGDJJCM-UHFFFAOYSA-N 0.000 description 1
- OFQWNMLSAWPKQY-UHFFFAOYSA-N 1-[6-[4-ethyl-5-methyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C OFQWNMLSAWPKQY-UHFFFAOYSA-N 0.000 description 1
- DNKASVYKQIWJIB-UHFFFAOYSA-N 1-[6-[4-methyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]anilino]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)CNC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C DNKASVYKQIWJIB-UHFFFAOYSA-N 0.000 description 1
- RFBAYQVPIKOLJD-UHFFFAOYSA-N 1-[6-[4-methyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C RFBAYQVPIKOLJD-UHFFFAOYSA-N 0.000 description 1
- MCBUIULZXZTHMY-UHFFFAOYSA-N 1-[6-[5-chloro-3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound ClC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)C(=O)C1CC1)C MCBUIULZXZTHMY-UHFFFAOYSA-N 0.000 description 1
- UVIREOQNBARRRN-UHFFFAOYSA-N 1-[6-[5-ethyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C UVIREOQNBARRRN-UHFFFAOYSA-N 0.000 description 1
- OSMRSLHPFVQPIY-UHFFFAOYSA-N 1-[6-[5-ethyl-3-[[4-(1-methoxycarbonylpiperidin-4-yl)-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C(C)C1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC)C OSMRSLHPFVQPIY-UHFFFAOYSA-N 0.000 description 1
- YCWORTUVPSSRPT-UHFFFAOYSA-N 1-[6-[5-methyl-3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C YCWORTUVPSSRPT-UHFFFAOYSA-N 0.000 description 1
- DVLXBEHCUYYYCD-UHFFFAOYSA-N 1-[6-[5-methyl-3-[[4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound CC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)O)COC1=CC=C(C=C1)C1CCN(CC1)C(CC)=O DVLXBEHCUYYYCD-UHFFFAOYSA-N 0.000 description 1
- FQLLUPPDTXCICZ-UHFFFAOYSA-N 1-benzyl-4-(4-methoxy-3-methylphenyl)-3,6-dihydro-2H-pyridine Chemical compound C(C1=CC=CC=C1)N1CCC(=CC1)C1=CC(=C(C=C1)OC)C FQLLUPPDTXCICZ-UHFFFAOYSA-N 0.000 description 1
- IZMHBVDXCBPHTH-UHFFFAOYSA-N 1-benzyl-4-(4-methoxy-3-methylphenyl)piperidin-4-ol Chemical compound C(C1=CC=CC=C1)N1CCC(CC1)(O)C1=CC(=C(C=C1)OC)C IZMHBVDXCBPHTH-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- OUUCZGCOAXRCHN-UHFFFAOYSA-N 1-hexadecoxyoctadecane Chemical class CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC OUUCZGCOAXRCHN-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- YYKBFGMYHQMXIL-UHFFFAOYSA-N 1-phenyl-2,3,4-tri(propan-2-yl)benzene Chemical group CC(C)C1=C(C(C)C)C(C(C)C)=CC=C1C1=CC=CC=C1 YYKBFGMYHQMXIL-UHFFFAOYSA-N 0.000 description 1
- YYVIRFZZNQUTKP-UHFFFAOYSA-N 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydropyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(C)(C)NC(C)(C)C1 YYVIRFZZNQUTKP-UHFFFAOYSA-N 0.000 description 1
- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 description 1
- IWWLVWWEZSOTJH-UHFFFAOYSA-N 2,3-dihydroxy-4-(4-methylbenzoyl)oxy-4-oxobutanoic acid Chemical compound CC1=CC=C(C(=O)OC(=O)C(O)C(O)C(O)=O)C=C1 IWWLVWWEZSOTJH-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- DOSGEBYQRMBTGS-UHFFFAOYSA-N 2-(3,6-dihydro-2h-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CCOCC1 DOSGEBYQRMBTGS-UHFFFAOYSA-N 0.000 description 1
- JQDNCGRNPYKRAO-UHFFFAOYSA-N 2-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CC=N1 JQDNCGRNPYKRAO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- UHTQHHLSGVOGQR-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-4-ium-1-yl]ethanesulfonate Chemical compound OCCN1CCN(CCS(O)(=O)=O)CC1.OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 UHTQHHLSGVOGQR-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- UZGAFXRKFGZBRQ-UHFFFAOYSA-N 2-bromo-4-methylthiophene-3-carboxylic acid Chemical compound CC1=CSC(Br)=C1C(O)=O UZGAFXRKFGZBRQ-UHFFFAOYSA-N 0.000 description 1
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 1
- MHDFOXVWKGLZJX-UHFFFAOYSA-N 2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol Chemical compound CC1=C(C=CC(=C1)C1CCN(CC1)CC(F)(F)F)O MHDFOXVWKGLZJX-UHFFFAOYSA-N 0.000 description 1
- PQARDSOLYLHRQD-UHFFFAOYSA-N 2-methyl-4-piperidin-4-ylphenol Chemical compound C1=C(O)C(C)=CC(C2CCNCC2)=C1 PQARDSOLYLHRQD-UHFFFAOYSA-N 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- YIRNNHURQFNQDX-UHFFFAOYSA-N 3,6-dihydro-2h-pyridine-1-carboxylic acid Chemical compound OC(=O)N1CCC=CC1 YIRNNHURQFNQDX-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 1
- COPMASWDWLENMV-VOTSOKGWSA-N 4,4,5,5-tetramethyl-2-[(e)-prop-1-enyl]-1,3,2-dioxaborolane Chemical compound C\C=C\B1OC(C)(C)C(C)(C)O1 COPMASWDWLENMV-VOTSOKGWSA-N 0.000 description 1
- KAMGNFJZBIIAQE-UHFFFAOYSA-N 4-(3-methyl-4-phenylmethoxyphenyl)-1-(2,2,2-trifluoroethyl)piperidine Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1)C1CCN(CC1)CC(F)(F)F)C KAMGNFJZBIIAQE-UHFFFAOYSA-N 0.000 description 1
- LFSVHCZJBFRGKH-UHFFFAOYSA-N 4-(4-methoxy-3-methylphenyl)piperidine Chemical compound C1=C(C)C(OC)=CC=C1C1CCNCC1 LFSVHCZJBFRGKH-UHFFFAOYSA-N 0.000 description 1
- UDLRGQOHGYWLCS-UHFFFAOYSA-N 4-bromo-1-methoxy-2-methylbenzene Chemical compound COC1=CC=C(Br)C=C1C UDLRGQOHGYWLCS-UHFFFAOYSA-N 0.000 description 1
- CWOUYJWXWZFCMM-UHFFFAOYSA-N 4-bromo-2-[6-[4-ethoxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]pyridin-2-yl]thiophene-3-carboxylic acid Chemical compound BrC=1C(=C(SC=1)C1=NC(=CC=C1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)C(=O)O CWOUYJWXWZFCMM-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical class OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QJNLUNBGDFUULX-UHFFFAOYSA-N 4-n,4-n'-dimethyl-3h-pyridine-4,4-diamine Chemical compound CNC1(NC)CC=NC=C1 QJNLUNBGDFUULX-UHFFFAOYSA-N 0.000 description 1
- KAKYNGJFPXFCDD-PPHPATTJSA-N 5-bromo-n-(4,5-dihydro-1h-imidazol-2-yl)quinoxalin-6-amine;(4r)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1.CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 KAKYNGJFPXFCDD-PPHPATTJSA-N 0.000 description 1
- SCZFBZIEMXKKDS-UHFFFAOYSA-N 5-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol Chemical compound C1NCCC2=C1C=CC(O)=C2C SCZFBZIEMXKKDS-UHFFFAOYSA-N 0.000 description 1
- DHKTYYVUEJTFHF-UHFFFAOYSA-N 6-bromo-5-chloropyridin-3-ol Chemical compound OC1=CN=C(Br)C(Cl)=C1 DHKTYYVUEJTFHF-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- KXYKSKAFMRRNMS-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=C(C=C(C=C1)C1CCNCC1)C Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1)C1CCNCC1)C KXYKSKAFMRRNMS-UHFFFAOYSA-N 0.000 description 1
- JEBRKULJHOQDCN-WIOPSUGQSA-N C1(CC1)C(=O)N1C[C@H]([C@@H](CC1)C1=CC=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)O Chemical compound C1(CC1)C(=O)N1C[C@H]([C@@H](CC1)C1=CC=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)O JEBRKULJHOQDCN-WIOPSUGQSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 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
- 108020004635 Complementary DNA Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- UYUXSRADSPPKRZ-SKNVOMKLSA-N D-glucurono-6,3-lactone Chemical compound O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O UYUXSRADSPPKRZ-SKNVOMKLSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 102000005640 Myosin Type II Human genes 0.000 description 1
- 108010045128 Myosin Type II Proteins 0.000 description 1
- XPOPNAOUHJCNQU-UHFFFAOYSA-N N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]thiophene-3-carboxamide Chemical compound FC1=C(C(=C(C(=C1F)C(F)(F)F)F)F)NC(=O)C1=CSC=C1 XPOPNAOUHJCNQU-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 102000002451 NPR2 Human genes 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- MKRNVBXERAPZOP-UHFFFAOYSA-N Starch acetate Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OC(C)=O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 MKRNVBXERAPZOP-UHFFFAOYSA-N 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 206010047555 Visual field defect Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- CHPDCDRDTOQRAG-UHFFFAOYSA-N [2-(2,6-dimethoxyphenyl)phenyl]phosphane Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P CHPDCDRDTOQRAG-UHFFFAOYSA-N 0.000 description 1
- KTYNIRXEEFFLOJ-UHFFFAOYSA-N [2-bromo-4-(trifluoromethyl)thiophen-3-yl]methanol Chemical compound BrC=1SC=C(C=1CO)C(F)(F)F KTYNIRXEEFFLOJ-UHFFFAOYSA-N 0.000 description 1
- ZJFOCFOLJFKHIL-UHFFFAOYSA-N [2-chloro-6-(2,6-dimethoxyphenyl)phenyl]-dicyclohexylphosphane Chemical group ClC=1C(=C(C=CC=1)C1=C(C=CC=C1OC)OC)P(C1CCCCC1)C1CCCCC1 ZJFOCFOLJFKHIL-UHFFFAOYSA-N 0.000 description 1
- IMTLECOSKPMJEX-UHFFFAOYSA-N [4-(4-amino-3-methylphenyl)piperidin-1-yl]-cyclopropylmethanone Chemical compound NC1=C(C=C(C=C1)C1CCN(CC1)C(=O)C1CC1)C IMTLECOSKPMJEX-UHFFFAOYSA-N 0.000 description 1
- BRGZNWYADAFVAK-UHFFFAOYSA-N [4-[4-[(2-bromo-4-methylthiophen-3-yl)methoxy]-3-methylphenyl]piperidin-1-yl]-cyclopropylmethanone Chemical compound BrC=1SC=C(C=1COC1=C(C=C(C=C1)C1CCN(CC1)C(=O)C1CC1)C)C BRGZNWYADAFVAK-UHFFFAOYSA-N 0.000 description 1
- LKBREHQHCVRNFR-UHFFFAOYSA-K [B+3].[Br-].[Br-].[Br-] Chemical compound [B+3].[Br-].[Br-].[Br-] LKBREHQHCVRNFR-UHFFFAOYSA-K 0.000 description 1
- XJQXCHHPKLIOBW-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)OCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC Chemical compound [Si](C)(C)(C(C)(C)C)OCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC XJQXCHHPKLIOBW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- JXYRIQRQKAUQIY-UHFFFAOYSA-N acetic acid;oxolane Chemical compound CC(O)=O.C1CCOC1 JXYRIQRQKAUQIY-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000012036 alkyl zinc reagent Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 1
- 230000004509 aqueous humor production Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 108010038664 atrial natriuretic factor receptor B Proteins 0.000 description 1
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 1
- 229960000307 avanafil Drugs 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 description 1
- QJKJIULTPCUPFN-UHFFFAOYSA-M bis(1-adamantyl)-butylphosphane chloropalladium(1+) 2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 QJKJIULTPCUPFN-UHFFFAOYSA-M 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- ZRFFGWCOKPCRGR-UHFFFAOYSA-N butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OCCCC)CCC(B2OC(C)(C)C(C)(C)O2)=C1 ZRFFGWCOKPCRGR-UHFFFAOYSA-N 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229940003871 calcium ion Drugs 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- XNRHTMDHGDWBGP-UHFFFAOYSA-N carbamic acid;hydrochloride Chemical compound Cl.NC(O)=O XNRHTMDHGDWBGP-UHFFFAOYSA-N 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
- 229940043234 carbomer-940 Drugs 0.000 description 1
- 229940031663 carbomer-974p Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000003181 co-melting Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- ZKWSXJLPBZLNMC-UHFFFAOYSA-N cyclohexyl-[1-cyclohexylphosphanyl-2-[2,4,6-tri(propan-2-yl)phenyl]cyclohexa-2,4-dien-1-yl]phosphane Chemical group C1(CCCCC1)PC1(C(=CC=CC1)C1=C(C=C(C=C1C(C)C)C(C)C)C(C)C)PC1CCCCC1 ZKWSXJLPBZLNMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- VXACHMDJVCSSCT-UHFFFAOYSA-N cyclopropyl-[4-(3-methyl-4-nitrophenyl)-3,6-dihydro-2H-pyridin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1CC=C(CC1)C1=CC(=C(C=C1)[N+](=O)[O-])C VXACHMDJVCSSCT-UHFFFAOYSA-N 0.000 description 1
- SUPXSLOYVLXQQP-UHFFFAOYSA-N cyclopropyl-[4-(4-hydroxy-2,3-dimethylphenyl)piperidin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C(=C(C=C1)O)C)C SUPXSLOYVLXQQP-UHFFFAOYSA-N 0.000 description 1
- SIPHCJREFROUKT-UHFFFAOYSA-N cyclopropyl-[4-(4-hydroxy-2-propan-2-ylphenyl)piperidin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)O)C(C)C SIPHCJREFROUKT-UHFFFAOYSA-N 0.000 description 1
- JQIZNMHBQPDBGC-UHFFFAOYSA-N cyclopropyl-[4-(4-hydroxy-3-methylphenyl)-2,2,6,6-tetramethylpiperidin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1C(CC(CC1(C)C)C1=CC(=C(C=C1)O)C)(C)C JQIZNMHBQPDBGC-UHFFFAOYSA-N 0.000 description 1
- XOCQYWKXKXKXSU-UHFFFAOYSA-N cyclopropyl-[4-(4-hydroxy-3-methylphenyl)piperidin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)O)C XOCQYWKXKXKXSU-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000036576 dermal application Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940119743 dextran 70 Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- UOPIRNHVGHLLDZ-UHFFFAOYSA-L dichlororhodium Chemical compound Cl[Rh]Cl UOPIRNHVGHLLDZ-UHFFFAOYSA-L 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- UMCMPZBLKLEWAF-UHFFFAOYSA-O dimethyl-(3-sulfopropyl)-[3-[4-(3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoylamino]propyl]azanium Chemical compound OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCC[N+](C)(C)CCCS(O)(=O)=O)C)C1(C)C(O)C2 UMCMPZBLKLEWAF-UHFFFAOYSA-O 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 229950005455 eliprodil Drugs 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- NUIWRMGOBPOIOY-UHFFFAOYSA-N ethanesulfonic acid;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCS(O)(=O)=O NUIWRMGOBPOIOY-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- AFECQUUSJNXMNL-BQYQJAHWSA-N ethyl (2e)-2-(dimethylaminomethylidene)-3-oxopentanoate Chemical compound CCOC(=O)C(=C\N(C)C)\C(=O)CC AFECQUUSJNXMNL-BQYQJAHWSA-N 0.000 description 1
- HKUSNFDWRQCFFK-UHFFFAOYSA-N ethyl 1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound FC(F)(F)C1=C(C(=O)OCC)C=NN1C1=CC=CC(Cl)=N1 HKUSNFDWRQCFFK-UHFFFAOYSA-N 0.000 description 1
- BLMAMPYPUAWKJI-UHFFFAOYSA-N ethyl 1-[3-(3-acetylthiophen-2-yl)phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(C)(=O)C1=C(SC=C1)C=1C=C(C=CC=1)N1N=CC(=C1C(F)(F)F)C(=O)OCC BLMAMPYPUAWKJI-UHFFFAOYSA-N 0.000 description 1
- SXGGKSWWPGBLFV-UHFFFAOYSA-N ethyl 1-[3-[3-(1-hydroxyethyl)thiophen-2-yl]phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OC(C)C1=C(SC=C1)C=1C=C(C=CC=1)N1N=CC(=C1C(F)(F)F)C(=O)OCC SXGGKSWWPGBLFV-UHFFFAOYSA-N 0.000 description 1
- ZRQZFLTZMYAOBY-UHFFFAOYSA-N ethyl 1-[3-[3-[1-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]ethyl]thiophen-2-yl]phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC(C)C1=C(SC=C1)C=1C=C(C=CC=1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)C ZRQZFLTZMYAOBY-UHFFFAOYSA-N 0.000 description 1
- GIRAKACFDUXQRI-UHFFFAOYSA-N ethyl 1-[6-(3-ethenyl-5-methylthiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)C=C GIRAKACFDUXQRI-UHFFFAOYSA-N 0.000 description 1
- IPIVDLMLUATSOV-UHFFFAOYSA-N ethyl 1-[6-(3-ethenylthiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound FC(C1=C(C=NN1C1=NC(=CC=C1)C=1SC=CC=1C=C)C(=O)OCC)(F)F IPIVDLMLUATSOV-UHFFFAOYSA-N 0.000 description 1
- ZMDYCKXINDYKNV-UHFFFAOYSA-N ethyl 1-[6-(3-formyl-5-methylthiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(=O)C1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC ZMDYCKXINDYKNV-UHFFFAOYSA-N 0.000 description 1
- QGXGIOCJXBSCFM-UHFFFAOYSA-N ethyl 1-[6-(3-formyl-5-methylthiophen-2-yl)pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C(=O)C1=C(SC(=C1)C)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC QGXGIOCJXBSCFM-UHFFFAOYSA-N 0.000 description 1
- OUWHIUJOIKIBKU-UHFFFAOYSA-N ethyl 1-[6-(3-formylthiophen-2-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(=O)C1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC OUWHIUJOIKIBKU-UHFFFAOYSA-N 0.000 description 1
- MQDLVKGCXLQUIY-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-4,5-dimethylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1C)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC MQDLVKGCXLQUIY-UHFFFAOYSA-N 0.000 description 1
- NVVDKUSPAMTMRO-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC NVVDKUSPAMTMRO-UHFFFAOYSA-N 0.000 description 1
- DFDWWQPREFKGAT-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-5-prop-1-en-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1)C(=C)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC DFDWWQPREFKGAT-UHFFFAOYSA-N 0.000 description 1
- OURHOXCYRSUCLW-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-5-propan-2-ylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1)C(C)C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC OURHOXCYRSUCLW-UHFFFAOYSA-N 0.000 description 1
- BXLPUVDMKGQHJD-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)-5-propylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC(=C1)CCC)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC BXLPUVDMKGQHJD-UHFFFAOYSA-N 0.000 description 1
- BVYPYWIYAOLALG-UHFFFAOYSA-N ethyl 1-[6-[3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC BVYPYWIYAOLALG-UHFFFAOYSA-N 0.000 description 1
- MSSLISPOGAWSAD-UHFFFAOYSA-N ethyl 1-[6-[3-[(4-bromo-3-formylphenoxy)methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C=O MSSLISPOGAWSAD-UHFFFAOYSA-N 0.000 description 1
- GIXZDGKXFZOVAY-UHFFFAOYSA-N ethyl 1-[6-[3-[[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]carbamoyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound FC1=C(C(=C(C(=C1F)C(F)(F)F)F)F)NC(=O)C1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC GIXZDGKXFZOVAY-UHFFFAOYSA-N 0.000 description 1
- YXOKJUKMTIFXRU-UHFFFAOYSA-N ethyl 1-[6-[3-[[2-(pyridin-2-ylmethyl)-3,4-dihydro-1H-isoquinolin-6-yl]oxymethyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound N1=C(C=CC=C1)CN1CC2=CC=C(C=C2CC1)OCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC YXOKJUKMTIFXRU-UHFFFAOYSA-N 0.000 description 1
- DLFRXZALXRAFGB-UHFFFAOYSA-N ethyl 1-[6-[3-[[2-chloro-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound ClC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC(=C1)C1CCN(CC1)C(CC)=O DLFRXZALXRAFGB-UHFFFAOYSA-N 0.000 description 1
- PDBVUEYIVYOHEI-UHFFFAOYSA-N ethyl 1-[6-[3-[[2-methyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC(=C1)C1CCN(CC1)CC(F)(F)F PDBVUEYIVYOHEI-UHFFFAOYSA-N 0.000 description 1
- UVIVDAKLZBCFCV-UHFFFAOYSA-N ethyl 1-[6-[3-[[2-methyl-4-[1-(oxetan-3-yl)piperidin-4-yl]phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CC1=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC(=C1)C1CCN(CC1)C1COC1 UVIVDAKLZBCFCV-UHFFFAOYSA-N 0.000 description 1
- VVUSPYARRPSYOG-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(CC)(=O)N1CCC(CC1)C1=CC=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1 VVUSPYARRPSYOG-UHFFFAOYSA-N 0.000 description 1
- WLWZDAZYOXETQM-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(2,3-dihydroxypropanoyl)piperidin-4-yl]-3-ethylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OC(C(=O)N1CCC(CC1)C1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)CC)CO WLWZDAZYOXETQM-UHFFFAOYSA-N 0.000 description 1
- WYYCFURSQJWGOL-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(2-cyclopropylacetyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)CC(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C WYYCFURSQJWGOL-UHFFFAOYSA-N 0.000 description 1
- BFYILRPOLUSHTI-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]-4-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC=C1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)C BFYILRPOLUSHTI-UHFFFAOYSA-N 0.000 description 1
- IXHITDUJCORAGP-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NCC1=C(SC=C1)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC)C IXHITDUJCORAGP-UHFFFAOYSA-N 0.000 description 1
- QAHJGTYAYAKLPT-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)OCC)C=C1)C QAHJGTYAYAKLPT-UHFFFAOYSA-N 0.000 description 1
- ZUWIPAITRPREJH-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-bromo-3-(hydroxymethyl)phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)CO ZUWIPAITRPREJH-UHFFFAOYSA-N 0.000 description 1
- CKFKKTUCENQBCO-UHFFFAOYSA-N ethyl 1-[6-[4-bromo-3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO CKFKKTUCENQBCO-UHFFFAOYSA-N 0.000 description 1
- DPOHYGZDWVIMFB-UHFFFAOYSA-N ethyl 1-[6-[4-bromo-3-[[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]carbamoyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)C(NC1=C(C(=C(C(=C1F)F)C(F)(F)F)F)F)=O DPOHYGZDWVIMFB-UHFFFAOYSA-N 0.000 description 1
- JLSZQTSCVGIGKF-UHFFFAOYSA-N ethyl 1-[6-[4-cyclopropyl-5-methyl-3-[(2-methyl-4-piperidin-4-ylphenoxy)methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)COC1=C(C=C(C=C1)C1CCNCC1)C JLSZQTSCVGIGKF-UHFFFAOYSA-N 0.000 description 1
- LXXSRZICFKSNDH-UHFFFAOYSA-N ethyl 1-[6-[4-ethyl-3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(C)C=1C(=C(SC=1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO LXXSRZICFKSNDH-UHFFFAOYSA-N 0.000 description 1
- JDSREQZHJDCHJN-UHFFFAOYSA-N ethyl 1-[6-[5-bromo-3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO JDSREQZHJDCHJN-UHFFFAOYSA-N 0.000 description 1
- HMKAOWUGFFMHAI-UHFFFAOYSA-N ethyl 1-[6-[5-chloro-3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound ClC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO HMKAOWUGFFMHAI-UHFFFAOYSA-N 0.000 description 1
- WMGXGPWORPDOTD-UHFFFAOYSA-N ethyl 1-[6-[5-cyclopropyl-3-(hydroxymethyl)thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO WMGXGPWORPDOTD-UHFFFAOYSA-N 0.000 description 1
- XCWITETYZSBJPQ-UHFFFAOYSA-N ethyl 1-[6-[5-methyl-3-[[2-methyl-4-(1-propanoylpiperidin-4-yl)phenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CC1=CC(=C(S1)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)COC1=C(C=C(C=C1)C1CCN(CC1)C(CC)=O)C XCWITETYZSBJPQ-UHFFFAOYSA-N 0.000 description 1
- AFECQUUSJNXMNL-UHFFFAOYSA-N ethyl 2-(dimethylaminomethylidene)-3-oxopentanoate Chemical compound CCOC(=O)C(=CN(C)C)C(=O)CC AFECQUUSJNXMNL-UHFFFAOYSA-N 0.000 description 1
- RGKAODVRJJBFKW-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-(3-formyl-5-methylthiophen-2-yl)pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1SC(=CC=1C=O)C)C(=O)OCC RGKAODVRJJBFKW-UHFFFAOYSA-N 0.000 description 1
- KNKLMFDEULYLFH-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-[3-(hydroxymethyl)-4-(trifluoromethyl)thiophen-2-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1SC=C(C=1CO)C(F)(F)F)C(=O)OCC KNKLMFDEULYLFH-UHFFFAOYSA-N 0.000 description 1
- NODHPPXKIFIWAI-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-[3-(hydroxymethyl)-5-methylthiophen-2-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1SC(=CC=1CO)C)C(=O)OCC NODHPPXKIFIWAI-UHFFFAOYSA-N 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical class OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- VFTZKSMAJVLWOV-UHFFFAOYSA-N methyl 1h-pyrazole-4-carboxylate Chemical compound COC(=O)C=1C=NNC=1 VFTZKSMAJVLWOV-UHFFFAOYSA-N 0.000 description 1
- DSXCCQZUWIGHJW-UHFFFAOYSA-N methyl 2-bromo-4-(trifluoromethyl)thiophene-3-carboxylate Chemical compound BrC=1SC=C(C=1C(=O)OC)C(F)(F)F DSXCCQZUWIGHJW-UHFFFAOYSA-N 0.000 description 1
- ROKSORSRSUAPHR-UHFFFAOYSA-N methyl 2-bromo-5-methylthiophene-3-carboxylate Chemical compound COC(=O)C=1C=C(C)SC=1Br ROKSORSRSUAPHR-UHFFFAOYSA-N 0.000 description 1
- ISMJVGFYZAMASD-UHFFFAOYSA-N methyl 4-[4-[(2-bromo-5-methylthiophen-3-yl)methoxy]-3-methylphenyl]piperidine-1-carboxylate Chemical compound BrC=1SC(=CC=1COC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC)C)C ISMJVGFYZAMASD-UHFFFAOYSA-N 0.000 description 1
- CYEXEOXALMJXDI-UHFFFAOYSA-N methyl 4-bromo-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1C CYEXEOXALMJXDI-UHFFFAOYSA-N 0.000 description 1
- GCHTVSJQOZUHSH-UHFFFAOYSA-N methyl 5-amino-3-hydroxy-3-(trifluoromethyl)-2h-thiophene-4-carboxylate Chemical compound COC(=O)C1=C(N)SCC1(O)C(F)(F)F GCHTVSJQOZUHSH-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 1
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 description 1
- RQNMYNYHBQQZSP-UHFFFAOYSA-M methylmagnesium chloride Chemical compound C[Mg]Cl RQNMYNYHBQQZSP-UHFFFAOYSA-M 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 230000003547 miosis Effects 0.000 description 1
- 239000003604 miotic agent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- SQMJDLXORYKZGJ-UHFFFAOYSA-N n',n'-bis(methylamino)ethane-1,2-diamine Chemical compound CNN(NC)CCN SQMJDLXORYKZGJ-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000004493 normal intraocular pressure Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-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
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 150000003169 prostaglandin F2α derivatives Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 210000003994 retinal ganglion cell Anatomy 0.000 description 1
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960000529 riociguat Drugs 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003478 serotonin 5-HT2 receptor agonist Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 229940015676 simbrinza Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- ZNKXTIAQRUWLRL-UHFFFAOYSA-M sodium;sulfane;hydroxide Chemical compound O.[Na+].[SH-] ZNKXTIAQRUWLRL-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- MSIRZXLJORDERI-UHFFFAOYSA-N tert-butyl 4-(2-chloro-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound ClC1=C(C=CC(=C1)O)C1CCN(CC1)C(=O)OC(C)(C)C MSIRZXLJORDERI-UHFFFAOYSA-N 0.000 description 1
- IYNLFTHNQLCXAS-UHFFFAOYSA-N tert-butyl 4-(2-chloro-6-methoxypyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound ClC1=NC(=CC=C1C1=CCN(CC1)C(=O)OC(C)(C)C)OC IYNLFTHNQLCXAS-UHFFFAOYSA-N 0.000 description 1
- JDFDFVCIRJHZAW-UHFFFAOYSA-N tert-butyl 4-(2-cyclopropyl-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound C1(CC1)C1=C(C=CC(=C1)O)C1CCN(CC1)C(=O)OC(C)(C)C JDFDFVCIRJHZAW-UHFFFAOYSA-N 0.000 description 1
- ZNOFGLQGCIKRNL-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound C(C)C1=C(C=CC(=C1F)O)C1CCN(CC1)C(=O)OC(C)(C)C ZNOFGLQGCIKRNL-UHFFFAOYSA-N 0.000 description 1
- GASMIAYYKCUENM-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-4-hydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CCN(CC1)C(=O)OC(C)(C)C GASMIAYYKCUENM-UHFFFAOYSA-N 0.000 description 1
- USBGQDLNSJEGEN-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-6-methoxypyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C)C1=NC(=CC=C1C1=CCN(CC1)C(=O)OC(C)(C)C)OC USBGQDLNSJEGEN-UHFFFAOYSA-N 0.000 description 1
- MODOGKRTFTXVLG-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-6-methoxypyridin-3-yl)piperidine-1-carboxylate Chemical compound C(C)C1=NC(=CC=C1C1CCN(CC1)C(=O)OC(C)(C)C)OC MODOGKRTFTXVLG-UHFFFAOYSA-N 0.000 description 1
- NOLPZKMKZPRBEZ-UHFFFAOYSA-N tert-butyl 4-(3-chloro-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound ClC=1C=C(C=CC=1O)C1CCN(CC1)C(=O)OC(C)(C)C NOLPZKMKZPRBEZ-UHFFFAOYSA-N 0.000 description 1
- DYIXRLOWAQEDDL-UHFFFAOYSA-N tert-butyl 4-(3-ethyl-5-hydroxypyridin-2-yl)piperidine-1-carboxylate Chemical compound C(C)C=1C(=NC=C(C=1)O)C1CCN(CC1)C(=O)OC(C)(C)C DYIXRLOWAQEDDL-UHFFFAOYSA-N 0.000 description 1
- GNLMUOBRTDOQID-UHFFFAOYSA-N tert-butyl 4-(4-amino-2-ethylphenyl)piperidine-1-carboxylate Chemical compound NC1=CC(=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)CC GNLMUOBRTDOQID-UHFFFAOYSA-N 0.000 description 1
- CZGMDLYFBULKGX-UHFFFAOYSA-N tert-butyl 4-(4-hydroxy-2-propylphenyl)piperidine-1-carboxylate Chemical compound OC1=CC(=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)CCC CZGMDLYFBULKGX-UHFFFAOYSA-N 0.000 description 1
- GKBNVJLJNRKSAF-UHFFFAOYSA-N tert-butyl 4-(4-hydroxy-3-methylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound OC1=C(C=C(C=C1)C1=CCN(CC1)C(=O)OC(C)(C)C)C GKBNVJLJNRKSAF-UHFFFAOYSA-N 0.000 description 1
- XKQQXMJVWLOPDH-UHFFFAOYSA-N tert-butyl 4-[4-[(2-bromothiophen-3-yl)methoxy]phenyl]piperidine-1-carboxylate Chemical compound BrC=1SC=CC=1COC1=CC=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C XKQQXMJVWLOPDH-UHFFFAOYSA-N 0.000 description 1
- POCDUGZQMXWOAO-UHFFFAOYSA-N tert-butyl 4-[4-[2-[2-[6-[4-ethoxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]pyridin-2-yl]thiophen-3-yl]ethenyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C)OC(=O)C=1C=NN(C=1C(F)(F)F)C1=CC=CC(=N1)C=1SC=CC=1C=CC1=CC=C(C=C1)C1=CCN(CC1)C(=O)OC(C)(C)C POCDUGZQMXWOAO-UHFFFAOYSA-N 0.000 description 1
- GFJXOPGTBDCOCW-UHFFFAOYSA-N tert-butyl 4-[4-[[2-bromo-4-(trifluoromethyl)thiophen-3-yl]methoxy]-3-methylphenyl]piperidine-1-carboxylate Chemical compound BrC=1SC=C(C=1COC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C)C(F)(F)F GFJXOPGTBDCOCW-UHFFFAOYSA-N 0.000 description 1
- QELOANLIBNLHHH-UHFFFAOYSA-N tert-butyl 4-[4-[[2-bromo-4-(trifluoromethyl)thiophen-3-yl]methoxy]phenyl]piperidine-1-carboxylate Chemical compound BrC=1SC=C(C=1COC1=CC=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C(F)(F)F QELOANLIBNLHHH-UHFFFAOYSA-N 0.000 description 1
- PQILACDFDBWRNK-UHFFFAOYSA-N tert-butyl 4-bromo-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(Br)=CC1 PQILACDFDBWRNK-UHFFFAOYSA-N 0.000 description 1
- VBGLHBOXTRXGBZ-UHFFFAOYSA-N tert-butyl 6-[(2-bromothiophen-3-yl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate Chemical compound BrC=1SC=CC=1COC=1C=C2CCN(CC2=CC=1)C(=O)OC(C)(C)C VBGLHBOXTRXGBZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- VNVAUIHQJKDHBN-UHFFFAOYSA-N thiophene;hydrobromide Chemical compound Br.C=1C=CSC=1 VNVAUIHQJKDHBN-UHFFFAOYSA-N 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960000438 udenafil Drugs 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462020182P | 2014-07-02 | 2014-07-02 | |
| US62/020,182 | 2014-07-02 | ||
| US201562168640P | 2015-05-29 | 2015-05-29 | |
| US62/168,640 | 2015-05-29 | ||
| PCT/IB2015/055007 WO2016001876A1 (en) | 2014-07-02 | 2015-07-02 | Thiophen-2-yl-pyridin-2-yl-1h-pyrazole-4-carboxylic acid derivatives and the use thereof as soluble guanylate cyclase activators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2017519025A true JP2017519025A (ja) | 2017-07-13 |
| JP2017519025A5 JP2017519025A5 (cg-RX-API-DMAC7.html) | 2018-08-09 |
Family
ID=53724403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016574921A Withdrawn JP2017519025A (ja) | 2014-07-02 | 2015-07-02 | チオフェン−２−イル−ピリジン−２−イル−１ｈ−ピラゾール−４−カルボン酸誘導体、および可溶性グアニル酸シクラーゼ活性化剤としてのその使用 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US9765067B2 (cg-RX-API-DMAC7.html) |
| EP (1) | EP3164399A1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2017519025A (cg-RX-API-DMAC7.html) |
| CN (1) | CN106470989A (cg-RX-API-DMAC7.html) |
| TW (1) | TW201625601A (cg-RX-API-DMAC7.html) |
| WO (1) | WO2016001876A1 (cg-RX-API-DMAC7.html) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201625584A (zh) | 2014-07-02 | 2016-07-16 | 諾華公司 | 茚滿及吲哚啉衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 |
| EP3371167A1 (en) | 2015-10-06 | 2018-09-12 | GlaxoSmithKline Intellectual Property Development Limited | Arylcyclohexyl pyrazoles as nrf2 regulators |
| WO2017060854A1 (en) | 2015-10-06 | 2017-04-13 | Glaxosmithkline Intellectual Property Development Limited | Biaryl pyrazoles as nrf2 regulators |
| KR20180095594A (ko) | 2015-12-18 | 2018-08-27 | 노파르티스 아게 | 인단 유도체 및 가용성 구아닐레이트 시클라제 활성화제로서의 그의 용도 |
| WO2017201683A1 (en) * | 2016-05-25 | 2017-11-30 | Merck Sharp & Dohme Corp. | Substituted tetrahydroisoquinoline compounds useful as gpr120 agonists |
| CN109476589A (zh) | 2016-07-22 | 2019-03-15 | 东亚荣养株式会社 | 青光眼治疗药 |
| CN109890379A (zh) | 2016-10-11 | 2019-06-14 | 拜耳制药股份公司 | 包含sGC活化剂和盐皮质激素受体拮抗剂的组合产品 |
| WO2019081456A1 (en) | 2017-10-24 | 2019-05-02 | Bayer Aktiengesellschaft | USE OF SGC ACTIVATORS AND STIMULATORS COMPRISING A BETA2 SUBUNIT |
| EP3498298A1 (en) | 2017-12-15 | 2019-06-19 | Bayer AG | The use of sgc stimulators and sgc activators alone or in combination with pde5 inhibitors for the treatment of bone disorders including osteogenesis imperfecta (oi) |
| CA3098475A1 (en) | 2018-04-30 | 2019-11-07 | Bayer Aktiengesellschaft | The use of sgc activators and sgc stimulators for the treatment of cognitive impairment |
| EA202092680A1 (ru) | 2018-05-15 | 2021-04-13 | Байер Акциенгезельшафт | 1,3-тиазол-2-ил-замещенные бензамиды для лечения заболеваний, ассоциированных с сенситизацией нервных волокон |
| EP3574905A1 (en) | 2018-05-30 | 2019-12-04 | Adverio Pharma GmbH | Method of identifying a subgroup of patients suffering from dcssc which benefits from a treatment with sgc stimulators and sgc activators in a higher degree than a control group |
| EP3911675A1 (en) | 2019-01-17 | 2021-11-24 | Bayer Aktiengesellschaft | Methods to determine whether a subject is suitable of being treated with an agonist of soluble guanylyl cyclase (sgc) |
| WO2023237577A1 (en) | 2022-06-09 | 2023-12-14 | Bayer Aktiengesellschaft | Soluble guanylate cyclase activators for use in the treatment of heart failure with preserved ejection fraction in women |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000002851A1 (en) | 1998-07-08 | 2000-01-20 | Aventis Pharma Deutschland Gmbh | Sulfur substituted sulfonylaminocarboxylic acid n-arylamides, their preparation, their use and pharmaceutical preparations comprising them |
| EP1420023B1 (en) | 2001-01-24 | 2006-12-06 | Yung Shin Pharmaceutical Ind. Co., Ltd. | Use of fused pyrazolyl compounds for the preparation of a medicament for treating hypertension |
| DE10110749A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte Aminodicarbonsäurederivate |
| DE10110750A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| DE10216145A1 (de) | 2002-04-12 | 2003-10-23 | Bayer Ag | Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Glaukom |
| JP2007524596A (ja) | 2003-02-28 | 2007-08-30 | トランスフォーム・ファーマシューティカルズ・インコーポレイテッド | 共結晶医薬組成物 |
| AU2007333586A1 (en) | 2006-12-11 | 2008-06-19 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors |
| DE102007015035A1 (de) | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Substituierte Dibenzoesäure-Derivate und ihre Verwendung |
| JP5298129B2 (ja) | 2007-09-06 | 2013-09-25 | メルク・シャープ・アンド・ドーム・コーポレーション | 可溶性グアニレートシクラーゼ活性化因子 |
| WO2009068652A1 (en) | 2007-11-30 | 2009-06-04 | Smithkline Beecham Corporation | 2, 6-disubstituted pyridines and 2, 4-disubstituted pyrimidines as soluble guanylate cyclase activators |
| PE20091258A1 (es) * | 2007-12-03 | 2009-09-12 | Smithkline Beecham Corp | Derivados de piridina como activadores de la guanilato ciclasa soluble |
| CA2720343A1 (en) | 2008-04-04 | 2009-10-08 | Takeda Pharmaceutical Company Limited | Heterocyclic derivative and use thereof |
| DE102008018675A1 (de) | 2008-04-14 | 2009-10-15 | Bayer Schering Pharma Aktiengesellschaft | Oxo-heterocyclisch substituierte Carbonsäure-Derivate und ihre Verwendung |
| WO2010099054A2 (en) | 2009-02-26 | 2010-09-02 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| DE102009012314A1 (de) | 2009-03-09 | 2010-09-16 | Bayer Schering Pharma Aktiengesellschaft | Oxo-heterocyclisch substituierte Alkylcarbonsäuren und ihre Verwendung |
| DE102009046115A1 (de) | 2009-10-28 | 2011-09-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 3-Phenylpropansäuren und ihre Verwendung |
| WO2012058132A1 (en) | 2010-10-28 | 2012-05-03 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
| MA34721B1 (fr) | 2010-12-07 | 2013-12-03 | Bayer Ip Gmbh | Acides carboxyliques 1-benzylcycloalkyle substitués et leur utilisation |
| WO2012122340A1 (en) | 2011-03-10 | 2012-09-13 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| DE102011007272A1 (de) | 2011-04-13 | 2012-10-18 | Bayer Pharma Aktiengesellschaft | Verzweigte 3-Phenylpropionsäure-Derivate und ihre Verwendung |
| US8815857B2 (en) | 2011-08-12 | 2014-08-26 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| JP5565645B1 (ja) | 2012-10-09 | 2014-08-06 | Ｄｉｃ株式会社 | バンプクッション |
| EP3024455A1 (en) | 2013-07-25 | 2016-06-01 | Bayer Pharma Aktiengesellschaft | Sgc stimulators or sgc activators and pde5 inhibitors in combination with additional treatment for the therapy of cystic fibrosis |
| US20160214956A1 (en) | 2013-09-05 | 2016-07-28 | Glaxosmithkline Intellectual Property Development Limited | Novel soluble guanylate cyclase activators and their use |
-
2015
- 2015-07-01 TW TW104121397A patent/TW201625601A/zh unknown
- 2015-07-02 EP EP15742104.1A patent/EP3164399A1/en not_active Withdrawn
- 2015-07-02 US US15/320,813 patent/US9765067B2/en not_active Expired - Fee Related
- 2015-07-02 JP JP2016574921A patent/JP2017519025A/ja not_active Withdrawn
- 2015-07-02 WO PCT/IB2015/055007 patent/WO2016001876A1/en not_active Ceased
- 2015-07-02 CN CN201580036308.4A patent/CN106470989A/zh not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016001876A1 (en) | 2016-01-07 |
| TW201625601A (zh) | 2016-07-16 |
| CN106470989A (zh) | 2017-03-01 |
| US9765067B2 (en) | 2017-09-19 |
| US20170197950A1 (en) | 2017-07-13 |
| EP3164399A1 (en) | 2017-05-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2017519025A (ja) | チオフェン−２−イル−ピリジン−２−イル−１ｈ−ピラゾール−４−カルボン酸誘導体、および可溶性グアニル酸シクラーゼ活性化剤としてのその使用 | |
| JP6289485B2 (ja) | Ｐｄｅ４のヘテロアリール阻害剤 | |
| US10550102B2 (en) | Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators | |
| EP3164396B1 (en) | Cyclohexen-1-yl-pyridin-2-yl-1h-pyrazole-4-carboxylic acid derivatives and the use thereof as soluble guanylate cyclase activators | |
| JP2021533093A (ja) | モノアシルグリセロールリパーゼ阻害剤としての新規複素環化合物 | |
| TW202346289A (zh) | 作為ｇｌｐ—１ｒ促效劑的化合物 | |
| US20250049772A1 (en) | Piperidinyl-3-(aryloxy)propanamides and propanoates | |
| KR20160121572A (ko) | 오렉신 수용체 길항제로서의 1,2-치환된 사이클로펜탄 | |
| KR20220141331A (ko) | P2x3 조정제 | |
| JP2018537488A (ja) | インダン誘導体、ならびに可溶性グアニル酸シクラーゼ活性化剤としてのその使用 | |
| CA3178447A1 (en) | N-heteroarylalkyl-2-(heterocyclyl and heterocyclylmethyl) acetamide derivatives as sstr4 agonists | |
| JP2002532480A (ja) | モルホリノン及びモルホリン誘導体、ならびにその使用 | |
| WO2025074305A1 (en) | N-(1-(aminomethyl)cyclopropyl)(aryl or heteroaryl) carboxamide derivatives | |
| HK40085749A (en) | P2x3 modulators |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180628 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180628 |
|
| A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20180830 |