EA030634B1 - Индановые и индолиновые производные и их применение в качестве активаторов растворимой гуанилатциклазы - Google Patents
Индановые и индолиновые производные и их применение в качестве активаторов растворимой гуанилатциклазы Download PDFInfo
- Publication number
- EA030634B1 EA030634B1 EA201692542A EA201692542A EA030634B1 EA 030634 B1 EA030634 B1 EA 030634B1 EA 201692542 A EA201692542 A EA 201692542A EA 201692542 A EA201692542 A EA 201692542A EA 030634 B1 EA030634 B1 EA 030634B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- mmol
- ethyl
- alkyl
- compound
- methyl
- Prior art date
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- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 title claims description 4
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 title claims description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 title 2
- 239000003119 guanylate cyclase activator Substances 0.000 title 1
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 536
- 238000000034 method Methods 0.000 claims abstract description 79
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- -1 C 1 -C 4 -alkyl Chemical group 0.000 claims description 429
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 103
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 208000010412 Glaucoma Diseases 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 230000004410 intraocular pressure Effects 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 238000002513 implantation Methods 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 210000003786 sclera Anatomy 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 5
- 150000002367 halogens Chemical class 0.000 claims 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 4
- 125000005842 heteroatom Chemical group 0.000 claims 3
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical group [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000006413 ring segment Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 210000000795 conjunctiva Anatomy 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 398
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 323
- 239000000203 mixture Substances 0.000 description 289
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 244
- 238000005481 NMR spectroscopy Methods 0.000 description 175
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 150
- 239000000243 solution Substances 0.000 description 137
- 235000019439 ethyl acetate Nutrition 0.000 description 120
- 239000011541 reaction mixture Substances 0.000 description 100
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 93
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 85
- 239000000460 chlorine Substances 0.000 description 84
- 239000012044 organic layer Substances 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- 239000011734 sodium Substances 0.000 description 73
- 238000007127 saponification reaction Methods 0.000 description 71
- 238000003818 flash chromatography Methods 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 67
- 238000000926 separation method Methods 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 62
- 230000015572 biosynthetic process Effects 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 58
- 239000000741 silica gel Substances 0.000 description 57
- 229910002027 silica gel Inorganic materials 0.000 description 57
- 235000002639 sodium chloride Nutrition 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 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 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 53
- 239000002904 solvent Substances 0.000 description 50
- 238000004808 supercritical fluid chromatography Methods 0.000 description 50
- 239000007864 aqueous solution Substances 0.000 description 49
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- 239000012267 brine Substances 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000126 substance Substances 0.000 description 42
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 40
- 239000002253 acid Substances 0.000 description 35
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
- 238000004007 reversed phase HPLC Methods 0.000 description 31
- 239000012071 phase Substances 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 239000010410 layer Substances 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 22
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 22
- 239000011591 potassium Substances 0.000 description 22
- 229910052700 potassium Inorganic materials 0.000 description 22
- 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 21
- 229940125526 sGC activator Drugs 0.000 description 21
- 229910052708 sodium Inorganic materials 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 239000011575 calcium Substances 0.000 description 20
- 229910052791 calcium Inorganic materials 0.000 description 20
- 201000010099 disease Diseases 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 18
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 18
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 18
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 17
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 16
- 229910052805 deuterium Inorganic materials 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 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 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 14
- SWKIUGNKACYPSN-UHFFFAOYSA-N ethyl 5-methyl-1-[6-[3-(2-methyl-4-piperidin-4-ylanilino)-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)NC1=C(C=C(C=C1)C1CCNCC1)C)C(=O)OCC SWKIUGNKACYPSN-UHFFFAOYSA-N 0.000 description 14
- 229910052763 palladium Inorganic materials 0.000 description 14
- 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 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 229940124597 therapeutic agent Drugs 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 12
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 12
- 239000011777 magnesium Substances 0.000 description 12
- 229910052749 magnesium Inorganic materials 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 10
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 10
- 239000004472 Lysine Substances 0.000 description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 10
- 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 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 10
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 10
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 10
- 229960003646 lysine Drugs 0.000 description 10
- 159000000003 magnesium salts Chemical class 0.000 description 10
- 229960003194 meglumine Drugs 0.000 description 10
- 235000019371 penicillin G benzathine Nutrition 0.000 description 10
- 229960005141 piperazine Drugs 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229910052709 silver Inorganic materials 0.000 description 10
- 239000004332 silver Substances 0.000 description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 10
- 229960000281 trometamol Drugs 0.000 description 10
- 229910052725 zinc Inorganic materials 0.000 description 10
- 239000011701 zinc Substances 0.000 description 10
- NBLYSDQTFQPHCS-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CC2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)O)C=C1)C NBLYSDQTFQPHCS-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 229910052742 iron Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 9
- 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 8
- 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 8
- ZWEODBMKCBWTTQ-UHFFFAOYSA-N 7-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=CC2=C1C(=O)CC2 ZWEODBMKCBWTTQ-UHFFFAOYSA-N 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- 239000007821 HATU Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- SISJOFILSYHKFK-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-(2-methyl-2,3-dihydro-1H-indol-7-yl)pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1C=CC=C2CC(NC=12)C)C(=O)OCC SISJOFILSYHKFK-UHFFFAOYSA-N 0.000 description 8
- 150000002357 guanidines Chemical class 0.000 description 8
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- JRHWHSJDIILJAT-BYPYZUCNSA-N (2s)-2-hydroxypentanoic acid Chemical compound CCC[C@H](O)C(O)=O JRHWHSJDIILJAT-BYPYZUCNSA-N 0.000 description 7
- VKTDEPYGHZYWDJ-UHFFFAOYSA-N 5-methyl-1-[6-[3-[2-methyl-4-[1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl]anilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylic acid Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)NC1=C(C=C(C=C1)C1CCN(CC1)C=1OC(=NN=1)C)C)C(=O)O VKTDEPYGHZYWDJ-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 239000012190 activator Substances 0.000 description 7
- 238000004296 chiral HPLC Methods 0.000 description 7
- 150000001879 copper Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- AQAOFBMIZJAKRZ-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenyl]methyl]-3-methyl-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(CN2CC(C3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C)C=C1)CC AQAOFBMIZJAKRZ-UHFFFAOYSA-N 0.000 description 7
- MIAUPPMLWMSIER-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclobutanecarbonyl)piperidin-4-yl]-2-methylanilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CCC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC)C MIAUPPMLWMSIER-UHFFFAOYSA-N 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- BDANRHYZJFBCQQ-UHFFFAOYSA-N 7-bromo-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC(Br)=C2C(O)CCC2=C1 BDANRHYZJFBCQQ-UHFFFAOYSA-N 0.000 description 6
- 150000001448 anilines Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229960004217 benzyl alcohol Drugs 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 6
- FBLLIFABVUGMPF-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)OCC)C FBLLIFABVUGMPF-UHFFFAOYSA-N 0.000 description 6
- UWUSQHKNRWMOQC-UHFFFAOYSA-N ethyl 1-[6-[3-[[5-[1-(cyclopropanecarbonyl)piperidin-4-yl]-6-ethylpyridin-2-yl]amino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C=1C=CC(=NC=1CC)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)OCC UWUSQHKNRWMOQC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 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 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- BDKXLYMWMJIYHU-UHFFFAOYSA-N 1-[3-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]methyl]-2,3-dihydro-1H-inden-4-yl]phenyl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CC2CCC3=CC=CC(=C23)C=2C=C(C=CC=2)N2N=CC(=C2C)C(=O)O)C=C1)C BDKXLYMWMJIYHU-UHFFFAOYSA-N 0.000 description 5
- HAMFJJDEDZILSJ-UHFFFAOYSA-N 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)CC HAMFJJDEDZILSJ-UHFFFAOYSA-N 0.000 description 5
- NCRQOOBGNGBFFE-UHFFFAOYSA-N 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OC2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)C NCRQOOBGNGBFFE-UHFFFAOYSA-N 0.000 description 5
- KMZIJZGAFPSODO-UHFFFAOYSA-N 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]anilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)O KMZIJZGAFPSODO-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 235000019445 benzyl alcohol Nutrition 0.000 description 5
- 235000011089 carbon dioxide Nutrition 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 5
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 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 5
- LDYSSCUEVWRJRL-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenyl]methyl]-3-methyl-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(CN2CC(C3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)OCC)C)C=C1)CC LDYSSCUEVWRJRL-UHFFFAOYSA-N 0.000 description 5
- WFHLUVNJWMERGW-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]-2,3-dihydro-1-benzofuran-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC1COC2=C1C(=CC=C2)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC)C WFHLUVNJWMERGW-UHFFFAOYSA-N 0.000 description 5
- XCUPVSJVKAIPQH-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-(3-methyl-2,3-dihydro-1H-indol-7-yl)pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1C=CC=C2C(CNC=12)C)C(=O)OCC XCUPVSJVKAIPQH-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 description 4
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 4
- UJPZBWRMNIMCKD-UHFFFAOYSA-N 1-[3-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylanilino]-2,3-dihydro-1H-inden-4-yl]phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(C=C1)NC1CCC2=CC=CC(=C12)C=1C=C(C=CC=1)N1N=CC(=C1C(F)(F)F)C(=O)O)C UJPZBWRMNIMCKD-UHFFFAOYSA-N 0.000 description 4
- QVJLUAJGAWEJMU-UHFFFAOYSA-N 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-(trifluoromethyl)phenoxy]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OC2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)O)C=C1)C(F)(F)F QVJLUAJGAWEJMU-UHFFFAOYSA-N 0.000 description 4
- HHHIJZSWPMQHSU-UHFFFAOYSA-N 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylic acid Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CC2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)O)C=C1)C HHHIJZSWPMQHSU-UHFFFAOYSA-N 0.000 description 4
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IPPIMDIVVBVFRT-UHFFFAOYSA-N 5-ethyl-1-[6-[3-[[3-ethyl-4-(1-methoxycarbonylpiperidin-4-yl)phenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylic acid Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)CC1=CC(=C(C=C1)C1CCN(CC1)C(=O)OC)CC)C(=O)O IPPIMDIVVBVFRT-UHFFFAOYSA-N 0.000 description 4
- YYGCGAGADIUFIL-KEPYVBBOSA-N 5-ethyl-1-[6-[3-[[3-ethyl-4-[1-[(2S)-2-hydroxypentanoyl]piperidin-4-yl]phenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylic acid Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)CC1=CC(=C(C=C1)C1CCN(CC1)C([C@H](CCC)O)=O)CC)C(=O)O YYGCGAGADIUFIL-KEPYVBBOSA-N 0.000 description 4
- NHLAUQQVKIVACU-UHFFFAOYSA-N 5-ethyl-1-[6-[3-[[4-(1-methoxycarbonylpiperidin-4-yl)-2-methylphenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylic acid Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)CC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC)C)C(=O)O NHLAUQQVKIVACU-UHFFFAOYSA-N 0.000 description 4
- NNHOFIYUZHKOFD-UHFFFAOYSA-N 7-bromo-3-methyl-1h-indole Chemical compound C1=CC=C2C(C)=CNC2=C1Br NNHOFIYUZHKOFD-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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 229920002413 Polyhexanide Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- UIOUTAYHWYPCGP-UHFFFAOYSA-N [4-[4-(bromomethyl)-2-ethylphenyl]piperidin-1-yl]-cyclopropylmethanone Chemical compound BrCC1=CC(=C(C=C1)C1CCN(CC1)C(=O)C1CC1)CC UIOUTAYHWYPCGP-UHFFFAOYSA-N 0.000 description 4
- WTMMHMLWJSCGEN-UHFFFAOYSA-N [4-[4-[(7-bromo-2,3-dihydro-1H-inden-1-yl)amino]-3-methylphenyl]piperidin-1-yl]-cyclopropylmethanone Chemical compound BrC=1C=CC=C2CCC(C=12)NC1=C(C=C(C=C1)C1CCN(CC1)C(=O)C1CC1)C WTMMHMLWJSCGEN-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000005336 allyloxy group Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 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 4
- 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 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- QYFOPNJSIOLIGR-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]methyl]-3-methyl-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CN2CC(C3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)OCC)C)C=C1)C QYFOPNJSIOLIGR-UHFFFAOYSA-N 0.000 description 4
- OHWDRLYQSCVBSJ-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(2-cyclopropylacetyl)piperidin-4-yl]-3-fluoro-2-methylanilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)CC(=O)N1CCC(CC1)C1=C(C(=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC)C)F OHWDRLYQSCVBSJ-UHFFFAOYSA-N 0.000 description 4
- FJRMHFWDYHSEHH-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylanilino]-2,3-dihydro-1-benzofuran-4-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)NC1COC2=C1C(=CC=C2)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CC FJRMHFWDYHSEHH-UHFFFAOYSA-N 0.000 description 4
- TVMPJAVDMDUABN-UHFFFAOYSA-N ethyl 1-[6-[3-[[2-(pyridin-2-ylmethyl)-3,4-dihydro-1H-isoquinolin-6-yl]oxy]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound N1=C(C=CC=C1)CN1CC2=CC=C(C=C2CC1)OC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC TVMPJAVDMDUABN-UHFFFAOYSA-N 0.000 description 4
- RJGYGTYCRBAOGZ-CXRNNAKRSA-N ethyl 5-ethyl-1-[6-[(3S)-3-[3-ethyl-4-[1-(4-hydroxy-2-methylbutanoyl)piperidin-4-yl]phenoxy]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C1=C2[C@H](CCC2=CC=C1)OC1=CC(=C(C=C1)C1CCN(CC1)C(C(CCO)C)=O)CC)C(=O)OCC RJGYGTYCRBAOGZ-CXRNNAKRSA-N 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
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- YVLUTHPDGDOXSK-UHFFFAOYSA-N ethyl 1-[6-(6-methyl-3-oxo-1,2-dihydroinden-4-yl)pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound CCOC(=O)C1=C(N(N=C1)C1=CC=CC(=N1)C1=CC(C)=CC2=C1C(=O)CC2)C(F)(F)F YVLUTHPDGDOXSK-UHFFFAOYSA-N 0.000 description 1
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- KWLVZZLXJPXYGV-UHFFFAOYSA-N ethyl 1-[6-[1-[(4-piperidin-4-ylphenyl)methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound N1CCC(CC1)C1=CC=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1 KWLVZZLXJPXYGV-UHFFFAOYSA-N 0.000 description 1
- RIXAOJFHDHZWPK-UHFFFAOYSA-N ethyl 1-[6-[1-[[2-(pyridin-2-ylmethyl)-3,4-dihydro-1H-isoquinolin-6-yl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound N1=C(C=CC=C1)CN1CC2=CC=C(C=C2CC1)CN1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC RIXAOJFHDHZWPK-UHFFFAOYSA-N 0.000 description 1
- GDXVSKDUFLCAGW-UHFFFAOYSA-N ethyl 1-[6-[1-[[3-ethyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C(C)C=1C=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC=1C1CCN(CC1)CC(F)(F)F GDXVSKDUFLCAGW-UHFFFAOYSA-N 0.000 description 1
- GLBCOWBQNFVDPN-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)CC GLBCOWBQNFVDPN-UHFFFAOYSA-N 0.000 description 1
- RTSVMBHLJIRYJP-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylphenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-ethylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2CC)C(=O)OCC)C=C1)CC RTSVMBHLJIRYJP-UHFFFAOYSA-N 0.000 description 1
- PGSRRVRIRGIAHE-UHFFFAOYSA-N ethyl 1-[6-[1-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]phenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(CN2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1 PGSRRVRIRGIAHE-UHFFFAOYSA-N 0.000 description 1
- NMGPRRYEEKWGDO-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-3-ethylanilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=C(C=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC)CC NMGPRRYEEKWGDO-UHFFFAOYSA-N 0.000 description 1
- JQUGKFDENUITAU-UHFFFAOYSA-N ethyl 1-[6-[3-[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]anilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC=C(C=C1)NC1CCC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1C)C(=O)OCC JQUGKFDENUITAU-UHFFFAOYSA-N 0.000 description 1
- TVWZPKRKXMTWHY-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenyl]methyl]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(CC2CCC3=CC=CC(=C23)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)OCC)C=C1)C TVWZPKRKXMTWHY-UHFFFAOYSA-N 0.000 description 1
- NMEXYXQPNGTWOR-UHFFFAOYSA-N ethyl 2-(dimethylaminomethylidene)-5,5,5-trifluoro-3-oxopentanoate Chemical compound CN(C)C=C(C(=O)OCC)C(CC(F)(F)F)=O NMEXYXQPNGTWOR-UHFFFAOYSA-N 0.000 description 1
- QRBAKKYXCOHFDJ-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-(1H-indol-7-yl)pyridin-2-yl]pyrazole-4-carboxylate Chemical compound N1C=CC2=CC=CC(=C12)C1=CC=CC(=N1)N1N=CC(=C1CC)C(=O)OCC QRBAKKYXCOHFDJ-UHFFFAOYSA-N 0.000 description 1
- VVRSJVDBZPGFOY-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-[1-[[3-ethyl-4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl]methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C=1C=CC=C2CCN(C=12)CC1=CC(=C(C=C1)C1CCN(CC1)CC(F)(F)F)CC)C(=O)OCC VVRSJVDBZPGFOY-UHFFFAOYSA-N 0.000 description 1
- NUOQCIRFGHHKHX-UHFFFAOYSA-N ethyl 5-ethyl-1-[6-[3-(3-ethyl-4-piperidin-4-ylanilino)-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound C(C)C1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)NC1=CC(=C(C=C1)C1CCNCC1)CC)C(=O)OCC NUOQCIRFGHHKHX-UHFFFAOYSA-N 0.000 description 1
- CUJLKQPYRLVMBY-UHFFFAOYSA-N ethyl 5-methyl-1-[6-(3-oxo-1,2-dihydroinden-4-yl)pyridin-2-yl]pyrazole-4-carboxylate Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)=O)C(=O)OCC CUJLKQPYRLVMBY-UHFFFAOYSA-N 0.000 description 1
- RRFOAFYWIBQTMM-UHFFFAOYSA-N ethyl 5-methyl-1-[6-[1-[(2-methyl-4-piperidin-4-ylphenyl)methyl]-2,3-dihydroindol-7-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C=1C=CC=C2CCN(C=12)CC1=C(C=C(C=C1)C1CCNCC1)C)C(=O)OCC RRFOAFYWIBQTMM-UHFFFAOYSA-N 0.000 description 1
- KSIWQCLCRPZLHQ-UHFFFAOYSA-N ethyl 5-methyl-1-[6-[3-(2-methyl-4-piperidin-4-ylanilino)-2,3-dihydro-1-benzofuran-4-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C1=CC=CC2=C1C(CO2)NC1=C(C=C(C=C1)C1CCNCC1)C)C(=O)OCC KSIWQCLCRPZLHQ-UHFFFAOYSA-N 0.000 description 1
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- XDEAUSRHVZGLDC-UHFFFAOYSA-N ethyl 5-methyl-1-[6-[3-[2-methyl-4-[1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl]anilino]-2,3-dihydro-1H-inden-4-yl]pyridin-2-yl]pyrazole-4-carboxylate Chemical compound CC1=C(C=NN1C1=NC(=CC=C1)C1=C2C(CCC2=CC=C1)NC1=C(C=C(C=C1)C1CCN(CC1)C=1OC(=NN=1)C)C)C(=O)OCC XDEAUSRHVZGLDC-UHFFFAOYSA-N 0.000 description 1
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- 230000003176 fibrotic effect Effects 0.000 description 1
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- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 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
- 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
- 229960002381 vardenafil Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- 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
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- 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
- A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
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- 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
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| 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 |
| US10364256B2 (en) | 2015-10-06 | 2019-07-30 | Glaxosmithkline Intellectual Property Development Limited | Biaryl pyrazoles as NRF2 regulators |
| JP2018537488A (ja) * | 2015-12-18 | 2018-12-20 | ノバルティス アーゲー | 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 |
| WO2017201683A1 (en) * | 2016-05-25 | 2017-11-30 | Merck Sharp & Dohme Corp. | Substituted tetrahydroisoquinoline compounds useful as gpr120 agonists |
| EP3489219B1 (en) | 2016-07-22 | 2020-12-16 | TOA Eiyo Ltd. | Therapeutic agent for glaucoma |
| EP3525778A1 (de) | 2016-10-11 | 2019-08-21 | Bayer Pharma Aktiengesellschaft | Kombination enthaltend sgc aktivatoren und mineralocorticoid-rezeptor-antagonisten |
| 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) |
| JP7314173B2 (ja) | 2018-04-30 | 2023-07-25 | バイエル アクチェンゲゼルシャフト | 認知障害の治療のためのsGC活性化薬及びsGC刺激薬の使用 |
| BR112020022340A2 (pt) | 2018-05-15 | 2021-02-02 | Bayer Aktiengesellschaft | benzamidas substituídas por 1,3-tiazol-2-il para o tratamento de doenças associadas com sensibilização de fibras nervosas |
| US11508483B2 (en) | 2018-05-30 | 2022-11-22 | 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 |
| KR102836746B1 (ko) | 2018-08-06 | 2025-07-21 | 니콕스 에스아 | 산화질소 방출 포스포디에스테라제 타입 5 억제제 |
| 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 |
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| WO2008073452A1 (en) * | 2006-12-11 | 2008-06-19 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors |
| WO2010099054A2 (en) * | 2009-02-26 | 2010-09-02 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
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| 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 |
| DE10110750A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| DE10110749A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte Aminodicarbonsäurederivate |
| DE10216145A1 (de) | 2002-04-12 | 2003-10-23 | Bayer Ag | Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Glaukom |
| CA2514733A1 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| DE102007015035A1 (de) | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Substituierte Dibenzoesäure-Derivate und ihre Verwendung |
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| UY31507A1 (es) | 2007-12-03 | 2009-07-17 | Derivados de piridina activadores de 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 |
| WO2010015653A1 (en) | 2008-08-07 | 2010-02-11 | Smithkline Beecham Corporation | Pyrimidine derivatives as activators of soluble guanylate cyclase |
| 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 |
| WO2011095553A1 (en) | 2010-02-05 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft | Sgc stimulators or sgc activators in combination with pde5 inhbitors for the treatment of erectile dysfunction |
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| WO2015095515A1 (en) | 2013-12-20 | 2015-06-25 | Novartis Ag | Sgc activators for the treatment of glaucoma |
| TW201625601A (zh) | 2014-07-02 | 2016-07-16 | 諾華公司 | 噻吩-2-基-吡啶-2-基-1h-吡唑-4-羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 |
| 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 |
| TW201625586A (zh) | 2014-07-02 | 2016-07-16 | 諾華公司 | 環己烯-1-基-吡啶-2-基-1h-吡唑-4-羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 |
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| WO2008073452A1 (en) * | 2006-12-11 | 2008-06-19 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors |
| WO2010099054A2 (en) * | 2009-02-26 | 2010-09-02 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
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| AP2016009609A0 (en) | 2016-12-31 |
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| ES2732758T3 (es) | 2019-11-25 |
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