TW201625601A - 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 - Google Patents

Info

Publication number

TW201625601A

TW201625601A TW104121397A TW104121397A TW201625601A TW 201625601 A TW201625601 A TW 201625601A TW 104121397 A TW104121397 A TW 104121397A TW 104121397 A TW104121397 A TW 104121397A TW 201625601 A TW201625601 A TW 201625601A

Authority

TW

Taiwan

Prior art keywords

methyl

alkyl

trifluoromethyl

pyrazole

pyridin

Prior art date

2014-07-02

Links

• Espacenet
• Global Dossier
• Discuss

• 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 title description 41
• 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 title description 41
• 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
• 239000003119 guanylate cyclase activator Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 270
• 238000000034 method Methods 0.000 claims abstract description 86
• 150000003839 salts Chemical class 0.000 claims abstract description 44
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
• -1 C 1 -C 4 alkyl Chemical group 0.000 claims description 125
• 239000000460 chlorine Substances 0.000 claims description 88
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 83
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 239000001257 hydrogen Substances 0.000 claims description 59
• 150000002431 hydrogen Chemical group 0.000 claims description 36
• 208000010412 Glaucoma Diseases 0.000 claims description 34
• 230000004410 intraocular pressure Effects 0.000 claims description 32
• 229920006395 saturated elastomer Polymers 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 239000003795 chemical substances by application Substances 0.000 claims description 21
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 19
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 18
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
• 229910052760 oxygen Inorganic materials 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 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
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 125000005843 halogen group 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 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 230000000699 topical effect Effects 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 7
• 125000005842 heteroatom 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
• 125000004429 atom Chemical group 0.000 claims description 6
• 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
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 239000002590 phosphodiesterase V inhibitor Substances 0.000 claims description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 239000000556 agonist Substances 0.000 claims description 4
• 239000007943 implant Substances 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
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
• 125000003277 amino group Chemical group 0.000 claims description 3
• 239000002876 beta blocker Substances 0.000 claims description 3
• 229940097320 beta blocking agent Drugs 0.000 claims description 3
• 150000004820 halides Chemical class 0.000 claims description 3
• 239000004090 neuroprotective agent Substances 0.000 claims description 3
• 150000003180 prostaglandins Chemical class 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
• 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
• 239000003604 miotic agent Substances 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 238000007911 parenteral 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
• 102000003846 Carbonic anhydrases Human genes 0.000 claims 1
• 108090000209 Carbonic anhydrases Proteins 0.000 claims 1
• 239000004593 Epoxy Substances 0.000 claims 1
• 230000005764 inhibitory process Effects 0.000 claims 1
• 238000007914 intraventricular administration Methods 0.000 claims 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 abstract description 9
• 230000001225 therapeutic effect Effects 0.000 abstract description 5
• 239000013543 active substance Substances 0.000 abstract 1
• 239000000543 intermediate Substances 0.000 description 298
• 239000000203 mixture Substances 0.000 description 295
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 220
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 113
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 113
• 235000019439 ethyl acetate Nutrition 0.000 description 110
• 239000000243 solution Substances 0.000 description 93
• 238000006243 chemical reaction Methods 0.000 description 62
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 52
• 239000002904 solvent Substances 0.000 description 51
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 49
• 239000012044 organic layer Substances 0.000 description 47
• 239000011541 reaction mixture Substances 0.000 description 41
• 235000002639 sodium chloride Nutrition 0.000 description 39
• 239000007858 starting material Substances 0.000 description 39
• 239000011734 sodium Substances 0.000 description 37
• 238000002360 preparation method Methods 0.000 description 36
• 238000005481 NMR spectroscopy Methods 0.000 description 35
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
• 238000003786 synthesis reaction Methods 0.000 description 33
• 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
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 31
• 230000015572 biosynthetic process Effects 0.000 description 31
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
• 239000002253 acid Substances 0.000 description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 26
• 229940125526 sGC activator Drugs 0.000 description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 150000002148 esters Chemical class 0.000 description 22
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
• 201000010099 disease Diseases 0.000 description 21
• 239000000725 suspension Substances 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 19
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
• DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 18
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• 239000007864 aqueous solution Substances 0.000 description 18
• 239000002585 base Substances 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 150000001412 amines Chemical class 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 230000008569 process Effects 0.000 description 14
• 239000012190 activator Substances 0.000 description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
• 238000005160 1H NMR spectroscopy Methods 0.000 description 12
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 12
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 12
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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
• ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 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
• 239000004480 active ingredient Substances 0.000 description 10
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 10
• 239000010410 layer 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
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• 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
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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• 238000001914 filtration Methods 0.000 description 9
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• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• 230000008901 benefit Effects 0.000 description 8
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• 239000012071 phase Substances 0.000 description 8
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
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• 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
• 230000005526 G1 to G0 transition Effects 0.000 description 7
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• 230000003213 activating effect Effects 0.000 description 7
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
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• IWJGMJHAIUBWKT-UHFFFAOYSA-N 4-bromo-2-methylphenol Chemical compound CC1=CC(Br)=CC=C1O IWJGMJHAIUBWKT-UHFFFAOYSA-N 0.000 description 5
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• 101150003085 Pdcl gene Proteins 0.000 description 5
• AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
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• YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 5
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• 229910000027 potassium carbonate Inorganic materials 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
• WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 5
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• 239000007821 HATU Substances 0.000 description 4
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• 229910052799 carbon Inorganic materials 0.000 description 4
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• 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 1
• 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 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
• 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 1
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