JP2016533355A - アルドステロン合成酵素の阻害剤としてのフェニル−ジヒドロピリジン誘導体 - Google Patents
アルドステロン合成酵素の阻害剤としてのフェニル−ジヒドロピリジン誘導体 Download PDFInfo
- Publication number
- JP2016533355A JP2016533355A JP2016521350A JP2016521350A JP2016533355A JP 2016533355 A JP2016533355 A JP 2016533355A JP 2016521350 A JP2016521350 A JP 2016521350A JP 2016521350 A JP2016521350 A JP 2016521350A JP 2016533355 A JP2016533355 A JP 2016533355A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- fluoro
- trifluoromethyl
- pyridin
- dihydro
- 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.)
- Granted
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- 239000003112 inhibitor Substances 0.000 title description 12
- 108010009911 Cytochrome P-450 CYP11B2 Proteins 0.000 title description 2
- 102100024329 Cytochrome P450 11B2, mitochondrial Human genes 0.000 title description 2
- MOKUQYSJYISPJS-UHFFFAOYSA-N 1-phenyl-2h-pyridine Chemical class C1C=CC=CN1C1=CC=CC=C1 MOKUQYSJYISPJS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 238000000034 method Methods 0.000 claims abstract description 62
- -1 R 21 Chemical compound 0.000 claims description 102
- 238000011282 treatment Methods 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 230000002265 prevention Effects 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 206010019280 Heart failures Diseases 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 206010020772 Hypertension Diseases 0.000 claims description 21
- 208000020832 chronic kidney disease Diseases 0.000 claims description 19
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 17
- 208000016998 Conn syndrome Diseases 0.000 claims description 17
- 208000013846 primary aldosteronism Diseases 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 12
- 208000014311 Cushing syndrome Diseases 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- HKQQXHGIRUXNIE-UHFFFAOYSA-N 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-N-methylacetamide Chemical compound CNC(=O)CC1CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F HKQQXHGIRUXNIE-UHFFFAOYSA-N 0.000 claims description 9
- IRMQTDOAIYOFIP-UHFFFAOYSA-N 4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound C=12C(O)(C=3C=CC=CC=3)CCC2=CN=CC=1C1=CC=C(C(F)(F)F)C=C1F IRMQTDOAIYOFIP-UHFFFAOYSA-N 0.000 claims description 9
- GTYKECURALXPMJ-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound OC1(CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F)c1ccccc1 GTYKECURALXPMJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 7
- FHQKPJFBDORYAG-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound CC1(O)CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F FHQKPJFBDORYAG-UHFFFAOYSA-N 0.000 claims description 6
- SXPIIQUKRKSQRQ-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol Chemical compound OC1CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F SXPIIQUKRKSQRQ-UHFFFAOYSA-N 0.000 claims description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- CMTVGYIJELKEGA-UHFFFAOYSA-N 4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-propan-2-yl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound CC(C)C1(O)CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F CMTVGYIJELKEGA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004858 cycloalkoxyalkyl group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- YEXNNFBDDRRSBF-UHFFFAOYSA-N 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-1-pyrrolidin-1-ylethanone Chemical compound Fc1cc(ccc1-c1cncc2CCC(CC(=O)N3CCCC3)c12)C(F)(F)F YEXNNFBDDRRSBF-UHFFFAOYSA-N 0.000 claims description 3
- HWIOZPDPPZYVKL-UHFFFAOYSA-N 2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-N-methyl-N-propan-2-ylacetamide Chemical compound CC(C)N(C)C(=O)CC1CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F HWIOZPDPPZYVKL-UHFFFAOYSA-N 0.000 claims description 3
- ZBGYDQQWZZZKHK-UHFFFAOYSA-N 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-1-morpholin-4-ylethanone Chemical compound Fc1cc(ccc1C(F)(F)F)-c1cncc2CCC(CC(=O)N3CCOCC3)c12 ZBGYDQQWZZZKHK-UHFFFAOYSA-N 0.000 claims description 3
- WFURBWGYSWMXMW-UHFFFAOYSA-N 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-1-piperidin-1-ylethanone Chemical compound Fc1cc(ccc1C(F)(F)F)-c1cncc2CCC(CC(=O)N3CCCCC3)c12 WFURBWGYSWMXMW-UHFFFAOYSA-N 0.000 claims description 3
- JYBSZMIURPAQHG-UHFFFAOYSA-N 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-N-propylacetamide Chemical compound CCCNC(=O)CC1CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F JYBSZMIURPAQHG-UHFFFAOYSA-N 0.000 claims description 3
- HXUAAUPPFPJIJG-UHFFFAOYSA-N 4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound CC1(O)CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F HXUAAUPPFPJIJG-UHFFFAOYSA-N 0.000 claims description 3
- IZYTXEGTLYORLP-UHFFFAOYSA-N 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol Chemical compound OC1CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F IZYTXEGTLYORLP-UHFFFAOYSA-N 0.000 claims description 3
- NCSWZWPSAUEQRN-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine Chemical compound NC1CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F NCSWZWPSAUEQRN-UHFFFAOYSA-N 0.000 claims description 3
- BTKHYONHXBNKFR-UHFFFAOYSA-N N-(cyclopropylmethyl)-2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetamide Chemical compound Fc1cc(ccc1C(F)(F)F)-c1cncc2CCC(CC(=O)NCC3CC3)c12 BTKHYONHXBNKFR-UHFFFAOYSA-N 0.000 claims description 3
- KLKAVRQVRLAVIG-UHFFFAOYSA-N N-cyclopropyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-N-methylacetamide Chemical compound CN(C1CC1)C(=O)CC1CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F KLKAVRQVRLAVIG-UHFFFAOYSA-N 0.000 claims description 3
- TUXMJNRBRICPNR-UHFFFAOYSA-N N-ethyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]-N-methylacetamide Chemical compound CCN(C)C(=O)CC1CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F TUXMJNRBRICPNR-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- OQFDAZAKJXDUCB-UHFFFAOYSA-N ethyl 2-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetate Chemical compound CCOC(=O)CC1CCc2cncc(c12)-c1ccc(c(F)c1)C(F)(F)F OQFDAZAKJXDUCB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- IRMQTDOAIYOFIP-HXUWFJFHSA-N (5R)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound O[C@]1(CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F)c1ccccc1 IRMQTDOAIYOFIP-HXUWFJFHSA-N 0.000 claims description 2
- IRMQTDOAIYOFIP-FQEVSTJZSA-N (5S)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-phenyl-6,7-dihydrocyclopenta[c]pyridin-5-ol Chemical compound O[C@@]1(CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F)c1ccccc1 IRMQTDOAIYOFIP-FQEVSTJZSA-N 0.000 claims description 2
- SKAZGZQHXXMMGA-UHFFFAOYSA-N N-cyclopropyl-N-ethyl-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]acetamide Chemical compound CCN(C1CC1)C(=O)CC1CCc2cncc(c12)-c1ccc(cc1F)C(F)(F)F SKAZGZQHXXMMGA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 28
- 238000000746 purification Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 25
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 25
- 229960002478 aldosterone Drugs 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 19
- 230000002441 reversible effect Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 16
- 239000011877 solvent mixture Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 10
- 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 9
- 230000002526 effect on cardiovascular system Effects 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 206010016654 Fibrosis Diseases 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 208000017169 kidney disease Diseases 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 8
- 102100024332 Cytochrome P450 11B1, mitochondrial Human genes 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 108010049356 Steroid 11-beta-Hydroxylase Proteins 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 239000008346 aqueous phase Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
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- 208000033679 diabetic kidney disease Diseases 0.000 description 6
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
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- 150000002576 ketones Chemical class 0.000 description 6
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- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
- NNRZTJAACCRFRV-UHFFFAOYSA-N 2-(2-cyclopentenyl)-ethanoic acid Chemical compound OC(=O)CC1CCC=C1 NNRZTJAACCRFRV-UHFFFAOYSA-N 0.000 description 5
- CKOLJUFPFUEZJP-UHFFFAOYSA-N 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,7-dihydro-5h-cyclopenta[c]pyridine Chemical compound C1=C(C(F)(F)F)C(F)=CC(C=2C=3CCCC=3C=NC=2)=C1 CKOLJUFPFUEZJP-UHFFFAOYSA-N 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
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- 229910052786 argon Inorganic materials 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 230000009787 cardiac fibrosis Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000003821 enantio-separation Methods 0.000 description 5
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 150000003431 steroids Chemical class 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
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 description 4
- 108010037778 Cytochrome P450 Family 11 Proteins 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
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Abstract
Description
[式中、
R1、R2、R3、R4及びR5は、独立に、H、ハロゲン、シアノ、ニトロ、アルキル、ハロアルキル、シクロアルキル、アルコキシ、ハロアルコキシ及びシクロアルコキシより選択され;
R6、R7、R8、R9、R10及びR11は、独立に、H、ハロゲン、アルキル及びハロアルキルより選択され;
R12は、H、アルキル、ハロアルキル、シクロアルキル、置換アリール又は置換ヘテロアリール(ここで、置換アリール又は置換ヘテロアリールは、R18、R19及びR20で置換されている)であり;
A1は、−(CR14R15)p−NR16R17、−(CR14R15)p−OR17、−(CR14R15)p−C(O)NR16R17又は−(CR14R15)p−C(O)OR17であり;
R14及びR15は、独立に、H、アルキル、ハロアルキル、シクロアルキル及びハロシクロアルキルより選択され;
R16は、H、アルキル、ハロアルキル、シクロアルキル、ヒドロキシアルキル、アルコキシアルキル又はハロアルコキシアルキルであり;
R17は、H、アルキル、ハロアルキル、シクロアルキル、シクロアルキルアルキル、アルコキシアルキル、シクロアルコキシアルキル、置換アリール又は置換ヘテロアリール(ここで、置換アリール及び置換ヘテロアリールは、R21、R22及びR23で置換されている)であるか;
あるいは、R16及びR17は、それらが結合している窒素と一緒になって、置換ヘテロシクロアルキル又は置換ヘテロアリール(ここで、置換ヘテロシクロアルキル及び置換ヘテロアリールは、R21、R22及びR23で置換されている)を形成し;
R18、R19、R20、R21、R22及びR23は、独立に、H、ハロゲン、アルキル、ハロアルキル、シクロアルキル、アルコキシ及びハロアルコキシより選択され;
nは、0、1又は2であり;
pは、0、1又は2である]で示される新規な化合物及びその薬学的に許容し得る塩を提供する。
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−アミン;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−イソプロピル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(+)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(−)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(R)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(S)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
エチル 2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセタート;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
N−(シクロプロピルメチル)−2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−プロピルアセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−(ピペリジン−1−イル)エタノン;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−モルホリノエタノン;
2−[4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−5H−[2]ピリンジン−5−イル]−N−イソオキサゾール−3−イル−アセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−(1H−ピラゾール−3−イル)アセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−(ピロリジン−1−イル)エタノン;
N−エチル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−イソプロピル−N−メチルアセトアミド;
N−シクロプロピル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
N−シクロプロピル−N−エチル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−((S)−2−メチルピロリジン−1−イル)エタノン
及びその薬学的に許容し得る塩。
BH3=ボラン、CDI=1,1−カルボニルジイミダゾール、DBU=2,3,4,6,7,8,9,10−オクタヒドロ−ピリミド[1,2−a]アゼピン、DCC=N,N’−ジシクロヘキシルカルボジイミド、DCM=ジクロロメタン、DMAP=4−ジメチルアミノピリジン、DMF=N,N−ジメチルホルムアミド、EDCI=1−(3−ジメチル−アミノプロピル)−3−エチルカルボジイミド塩酸塩、EtOAc=酢酸エチル、h=時間、HATU=1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム−3−オキシドへキサフルオロホスファート、HPLC=高速液体クロマトグラフィー、HOBT=1−ヒドロキシ−1,2,3−ベンゾトリアゾール、ヒューニッヒ(Huenig's)塩基=iPr2NEt=N−エチルジイソプロピルアミン、LiAlH4=水素化アルミニウムリチウム、LiBH4=水素化ホウ素リチウム、MeOH=メタノール、MPLC=中圧液体クロマトグラフィー、NaBH3CN=シアノ水素化ホウ素ナトリウム、NaBH4=水素化ホウ素ナトリウム、NaBH(OAc)3=トリアセトキシ水素化ホウ素ナトリウム、NH4OAc=酢酸アンモニウム、rt=室温、TBTU=O−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチル−ウロニウムテトラフルオロボラート、TosMIC=イソシアン化トルエンスルホニルメチル、THF=テトラヒドロフラン。
[式中、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R14、R15、R16、R17、n及びpは、本明細書で定義されたとおりであり、R24は、アルキルであり、そしてA1は、−(CR14R15)−C(O)NR16R17である]である。
本明細書において、本発明者らは、CYP11ファミリーの酵素を異所的に発現する(一過性に又は安定的に)宿主細胞としてG−402細胞株が使用できるかを確認した。具体的には、本発明者らは、ヒトCYP11B1、ヒトCYP11B2、ヒトCYP11A1、カニクイザル(cynomolgus)CYP11B1又はカニクイザルCYP11B2酵素活性を異所的に発現する安定なG−402細胞を開発した。重要なことに、確認した細胞株G−402は、CYP11ファミリーの活性に重要な補因子(アドレノドキシン及びアドレノドキシン還元酵素)を発現し、そして、CYP11ファミリーの無関係な酵素活性(H295R細胞と比較して)がこれらの細胞で検出された。したがって、G−402細胞株は、CYP11ファミリー由来の酵素の異所的発現の宿主細胞として独自に適する。G−402細胞は、ATCC(CRL−1440)から得ることができ、これは腎平滑筋芽腫由来のものであった。
(式中、Aは、最大y値であり、Bは、XLFitを使用して決定されるEC50因子であり、Cは、最少y値であり、そして、Dは、傾斜値である)
MeOH(100mL)中の3−フルオロ−4−(トリフルオロメチル)ベンズアルデヒド(1.40g、7.07mmol)及びp−トルエンスルホニルメチルイソシアニド(1.53g、7.68mmol; TosMIC)の溶液を、炭酸カリウム(1.97g、14.14mmol)で処理し、懸濁液を14時間加熱還流した。室温に冷やした後、溶媒を減圧下で除去し、粗生成物を、水を用いて0℃でトリチュレートした(2×25mL)。僅かに橙色の沈殿物を濾過により回収し、減圧下で乾燥させた(4.46g、92%)。MS: 232.0 (M+H)+。
o−ジクロロベンゼン(12mL)中の5−[3−フルオロ−4−(トリフルオロメチル)フェニル]オキサゾール(0.50g、2.16mmol)、シクロペンテン(2.95g、43.3mmol)及びトリフルオロ酢酸(0.49g、4.33mmol)の溶液を、マイクロ波照射下で220℃に6時間加熱した。反応混合物に、トリエチルアミン(5mL)を加え、溶媒混合物を減圧下で除去した。0〜50%EtOAc − n−ヘプタンの勾配で溶離するMPLC(SiO2 70g、Telos−カートリッジ)による精製により、標記化合物(0.27g、44%)を僅かに褐色の固体として与えた。MS: 282.5 (M+H)+。
DCM(0.5mL)中の4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン(76.0mg、0.27mmol)及びジロジウム(II, III)テトラキスカプロラクタマート(1.8mg、0.0027mmol; 合成については、M. P. Doyle et al., J. Am. Chem. Soc. 1993, 115, 958-964に記載されている)の溶液に、重炭酸ナトリウム(22.7mg、0.27mmol)及びtert−ブチルヒドロペルオキシド(0.25mL、1.35mmol)を加えた。反応混合物を室温で48時間撹拌した。この間に、更に等量のtert−ブチルヒドロペルオキシド(1.25mL、6.75mmol)を少しずつ加えた。溶媒を減圧下で除去し、粗反応混合物を、0〜50%EtOAc − n−ヘプタンの勾配で溶離するMPLC(SiO2 20g、Telos−カートリッジ)により精製して、4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−5,6−ジヒドロシクロペンタ[c]ピリジン−7−オン[15.5mg、19%;MS: 296.1(M+H)+]及び標記化合物[17.4mg、22%;MS: 296.4(M+H)+]をいずれも僅かに黄色の固体として与えた。
4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン(中間体A−1、工程B、フロー手法)の調製に関して記載された手順と同様にするが、5−[3−フルオロ−4−(トリフルオロメチル)フェニル]オキサゾールを5−[2−フルオロ−4−(トリフルオロメチル)フェニル]オキサゾール(CAS[1146694-91-8])に置き換える。フロー方法を、250℃にてtR,eff=120分間の有効滞留時間で実行した。標記化合物を明褐色の固体(54%)として得た。MS: 282.1(M+H)+。
4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−1)及び4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−5,6−ジヒドロシクロペンタ[c]ピリジン−7−オン(中間体A−2)の調製に関して記載された手順と同様にするが、4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジンを4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジンに置き換える。標記化合物[20%;MS: 296.1(M+H)+]及び4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5,6−ジヒドロシクロペンタ[c]ピリジン−7−オン[30%;MS: 296.1(M+H)+]をオフホワイトの固体として得た。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−アミン
MeOH(7mL)中の酢酸アンモニウム(1.57g、20.4mmol)の溶液を、4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−1)(0.20g、0.68mmol)で処理し、反応混合物を室温で1時間撹拌した。シアノ水素化ホウ素ナトリウム(0.15g、2.39mmol)を加え、撹拌を室温で続けた。15分後、反応混合物を90分間加熱還流した。溶媒を減圧下で除去し、塩化アンモニウムの飽和水溶液(2mL)及びHClの1M 溶液(2mL)を加え、水相をDCM(3×5mL)で洗浄した。水相に、NaOHの1M 溶液(4mL)を加え、DCM(3×5mL)で抽出した。合わせた有機相をMgSO4で乾燥させ、減圧下で濃縮した。標記化合物を明褐色の固体(74mg、37%)として単離した。MS: 297.4(M+H)+。
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール
メタノール(1mL)中の4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)(15.9mg、0.054mmol)の溶液を、0℃にて水素化ホウ素ナトリウム(2.0mg、0.954mmol)で処理した。10分後、反応混合物を酢酸(0.43mL)の添加によりクエンチし、粗反応混合物を減圧下で濃縮した。重炭酸ナトリウムの飽和水溶液(5mL)を加え、水相をEtOAc(3×10mL)で抽出した。合わせた有機相をNa2SO4で乾燥させ、減圧下で濃縮した。DCM−イソプロパノールの勾配で溶離するMPLCによる精製により、標記化合物をオフホワイトの固体(14mg、88%)として与えた。MS: 298.1(M+H)+。
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール
ジエチルエーテル(3mL)中の4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)(25mg、0.085mmol)及びリチウムクロリド(10.9mg、0.25mmol)の溶液を、アルゴン下、メチルリチウム(0.063mL、0.10mmol;ジエチルエーテル中1.6M 溶液)で処理し、反応混合物を0℃で撹拌した。1時間後、撹拌を室温で3時間続けた。反応混合物を塩化アンモニウムの飽和水溶液(10mL)の添加によりクエンチし、水相をEtOAc(3×10mL)で抽出した。合わせた有機相をMgSO4で乾燥させ、減圧下で濃縮した。アセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物をオフホワイトの固体(12mg、46%)として与えた。MS: 312.1(M+H)+。
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール
ジエチルエーテル(3mL)中の4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)(25mg、0.085mmol)及びリチウムクロリド(10.9mg、0.25mmol)の溶液を、アルゴン下、フェニルリチウム(0.050mL、0.10mmol;ジブチルエーテル中2.0M 溶液)で処理し、反応混合物を0℃で撹拌した。1時間後、反応混合物を塩化アンモニウムの飽和水溶液(10mL)の添加によりクエンチし、水相をEtOAc(3×10mL)で抽出した。合わせた有機相をMgSO4で乾燥させ、減圧下で濃縮した。アセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の油状物(3.3mg、10%)として与えた。MS: 374.2(M+H)+。
(rac)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール(実施例2)の調製に関して記載された手順と同様にするが、4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)を4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−2)に置き換える。標記化合物を白色の固体(10.6mg、66%)として得た。MS: 298.1(M+H)+。
(rac)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5−メチル−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オール
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール(実施例3)の調製に関して記載された手順と同様にするが、4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)を4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−2)に置き換える。分取TLC(EtOAc − n−ヘプタン=1:1)による精製により、標記化合物を白色の固体(6.1mg、23%)として与えた。MS: 312.1(M+H)+。
(rac)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5−イソプロピル−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オール
THF(1mL)中のイソプロピルマグネシウムクロリド(0.044mL、0.088mmol; THF中の2.0M 溶液)の溶液を、アルゴン下、イソプロピルマグネシウムクロリド(0.044mL、0.088mmol; THF中の2.0M 溶液)で室温にて1時間処理した。反応混合物を0℃に冷却し、THF(2mL)中の4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−2)(20mg、0.068mmol)の溶液を加えた。2時間後、反応混合物を塩化アンモニウムの飽和水溶液(10mL)の添加によりクエンチし、水相をEtOAc(3×10mL)で抽出した。合わせた有機相をMgSO4で乾燥させ、減圧下で濃縮した。アセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物をオフホワイトの固体(5.0mg、22%)として与えた。MS: 340.1(M+H)+。
(rac)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5−フェニル−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オール
(rac)−4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール(実施例4)の調製に関して記載された手順と同様にするが、4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−[2]ピリンジン−5−オン(中間体A−1)を4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オン(中間体A−2)に置き換える。アセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(5.0mg、15%)として与えた。MS: 374.1(M+H)+。
(+)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5−フェニル−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オール及び(−)−4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−5−フェニル−6,7−ジヒドロシクロペンタ[c]ピリジン−5−オール
(rac)−エチル 2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]アセタート
DMF(0.4mL)及びエタノール(0.4mL)中の(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸 オン(中間体A−3)(67.9mg、0.20mmol)、及びN,N−ジイソプロピルエチルアミン(0.17mL、1.0mmol)の溶液を、アルゴン下、HATU(98.9mg、0.26mmol)で室温にて2時間処理した。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(6.2mg、17%)として与えた。MS: 368.1(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド
DMF(0.4mL)中の(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸 オン(中間体A−3)(50mg、0.15mmol)及びN,N−ジイソプロピルエチルアミン(0.13mL、0.74mmol)の溶液を、アルゴン下、HATU(72.9mg、0.19mmol)で処理した。この溶液に、メチルアミン(0.22mL、0.44mmol; THF中2.0M 溶液)を加え、反応混合物を室温で16時間撹拌した。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(8.0mg、30%)として与えた。MS: 353.1(M+H)+。
(rac)−N−(シクロプロピルメチル)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]アセトアミド
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンをシクロプロピルメチルアミンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明黄色の固体(6.0mg、20%)として与えた。MS: 393.2(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−プロピル−アセトアミド
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンをプロピルアミンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(2.0mg、4%)として与えた。MS: 381.6(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−(1−ピペリジル)エタノン
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンをピペリジンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(4.8mg、16%)として与えた。MS: 407.6(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−モルホリノ−エタノン
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンをモルホリンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(4.2mg、14%)として与えた。MS: 409.6(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−イソオキサゾール−3−イル−アセトアミド
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンをイソオキサゾール−3−アミンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(6.6mg、22%)として与えた。MS: 406.1(M+H)+。
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−(1H−ピラゾール−3−イル)アセトアミド
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、メチルアミンを1H−ピラゾール−3−アミンに置き換える。溶媒混合物の蒸発そしてアセトニトリル−水の勾配で溶離する逆相分取HPLCによる精製により、標記化合物を明褐色の固体(10.4mg、34%)として与えた。MS: 405.1(M+H)+。
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン
(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド(実施例12)の調製に関して記載された手順と同様にするが、(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[3−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸−オン(中間体A−3)を、(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]酢酸及び(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−7−イル]酢酸 オン(中間体A−4)に置き換え、ならびにメチルアミンをピロリジンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(2.2mg、8%)として与えた。MS: 393.2(M+H)+。
(rac)−N−エチル−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン(実施例19)の調製に関して記載された手順と同様にするが、ピロリジンをN−メチルエタンアミンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(2.4mg、9%)として与えた。MS: 381.2(M+H)+。
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−イソプロピル−N−メチル−アセトアミド
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン(実施例19)の調製に関して記載された手順と同様にするが、ピロリジンをN−メチルプロパン−2−アミンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(2.2mg、8%)として与えた。MS: 395.2(M+H)+。
(rac)−N−シクロプロピル−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−N−メチル−アセトアミド
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン(実施例19)の調製に関して記載された手順と同様にするが、ピロリジンをN−メチルシクロプロパンアミンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(1.4mg、5%)として与えた。MS: 393.2(M+H)+。
(rac)−N−シクロプロピル−N−エチル−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]アセトアミド
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン(実施例19)の調製に関して記載された手順と同様にするが、ピロリジンをN−エチルシクロプロパンアミンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(2.4mg、8%)として与えた。MS: 407.2(M+H)+。
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−[(2S)−2−メチルピロリジン−1−イル]エタノン
(rac)−2−[4−[2−フルオロ−4−(トリフルオロメチル)フェニル]−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル]−1−ピロリジン−1−イル−エタノン(実施例19)の調製に関して記載された手順と同様にするが、ピロリジンを(2S)−2−メチルピロリジンに置き換える。溶媒混合物の蒸発、そしてアセトニトリル−水の勾配で溶離する逆相分取HPLC及び順相分取TLC(DCM−MeOH=93:7)による精製により、標記化合物を白色の固体(2.3mg、7%)として与えた。MS: 407.2(M+H)+。
式(I)の化合物は、それ自体既知のやり方で、以下の組成の錠剤の製造用の活性成分として使用することができる:
1錠当たり
活性成分 200mg
微晶質セルロース 155mg
トウモロコシデンプン 25mg
タルク 25mg
ヒドロキシプロピルメチルセルロース 20mg
425mg
式(I)の化合物は、それ自体既知のやり方で、以下の組成のカプセル剤の製造用の活性成分として使用することができる:
1カプセル当たり
活性成分 100.0mg
トウモロコシデンプン 20.0mg
乳糖 95.0mg
タルク 4.5mg
ステアリン酸マグネシウム 0.5mg
220.0mg
Claims (26)
- 式(I):
[式中、
R1、R2、R3、R4及びR5は、独立に、H、ハロゲン、シアノ、ニトロ、アルキル、ハロアルキル、シクロアルキル、アルコキシ、ハロアルコキシ及びシクロアルコキシより選択され;
R6、R7、R8、R9、R10及びR11は、独立に、H、ハロゲン、アルキル及びハロアルキルより選択され;
R12は、H、アルキル、ハロアルキル、シクロアルキル、置換アリール又は置換ヘテロアリール(ここで、置換アリール又は置換ヘテロアリールは、R18、R19及びR20で置換されている)であり;
A1は、−(CR14R15)p−NR16R17、−(CR14R15)p−OR17、−(CR14R15)p−C(O)NR16R17又は−(CR14R15)p−C(O)OR17であり;
R14及びR15は、独立に、H、アルキル、ハロアルキル、シクロアルキル及びハロシクロアルキルより選択され;
R16は、H、アルキル、ハロアルキル、シクロアルキル、ヒドロキシアルキル、アルコキシアルキル又はハロアルコキシアルキルであり;
R17は、H、アルキル、ハロアルキル、シクロアルキル、シクロアルキルアルキル、アルコキシアルキル、シクロアルコキシアルキル、置換アリール又は置換ヘテロアリール(ここで、置換アリール及び置換ヘテロアリールは、R21、R22及びR23で置換されている)であるか;
あるいは、R16及びR17は、それらが結合している窒素と一緒になって、置換ヘテロシクロアルキル又は置換ヘテロアリール(ここで、置換ヘテロシクロアルキル及び置換ヘテロアリールは、R21、R22及びR23で置換されている)を形成し;
R18、R19、R20、R21、R22及びR23は、独立に、H、ハロゲン、アルキル、ハロアルキル、シクロアルキル、アルコキシ及びハロアルコキシより選択され;
nは、0、1又は2であり;
pは、0、1又は2である]で示される化合物及びその薬学的に許容し得る塩。 - R1、R2、R3、R4及びR5が、独立に、H、ハロゲン及びハロアルキルより選択される、請求項1記載の化合物。
- R1及びR2が、独立に、H及びハロゲンより選択される、請求項1及び2のいずれか一項記載の化合物。
- R3が、ハロアルキルである、請求項1〜3のいずれか一項記載の化合物。
- R4及びR5が、Hである、請求項1〜4のいずれか一項記載の化合物。
- nが、0であり、そしてR6、R7、R8及びR9が、Hである、請求項1〜5のいずれか一項記載の化合物。
- R12が、H、アルキル又は置換アリール(ここで、置換アリールは、R18、R19及びR20で置換されている)である、請求項1〜6のいずれか一項記載の化合物。
- R18、R19及びR20が、Hである、請求項1〜7のいずれか一項記載の化合物。
- A1が、−(CR14R15)p−OR17又は−(CR14R15)p−C(O)NR16R17である、請求項1〜8のいずれか一項記載の化合物。
- A1が、−(CR14R15)p−OR17である、請求項1〜9のいずれか一項記載の化合物。
- R16が、Hである、請求項1〜10のいずれか一項記載の化合物。
- R17が、H、アルキル、アルコキシアルキル又は置換ヘテロアリール(ここで、置換ヘテロアリールは、R21、R22及びR23で置換されている)であるか、あるいは、R16及びR17が、それらが結合している窒素と一緒になって、置換ヘテロシクロアルキル(ここで、置換ヘテロシクロアルキルは、R21、R22及びR23で置換されている)を形成する、請求項1〜11のいずれか一項記載の化合物。
- R17が、H、アルキル、アルコキシアルキル又は置換ヘテロアリール(ここで、置換ヘテロアリールは、R21、R22及びR23で置換されている)である、請求項1〜12のいずれか一項記載の化合物。
- R21、R22及びR23が、独立に、H及びアルキルより選択される、請求項1〜13のいずれか一項記載の化合物。
- R14及びR15が、Hである、請求項1〜14のいずれか一項記載の化合物。
- pが、0又は1である、請求項1〜15のいずれか一項記載の化合物。
- 4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−アミン;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−イソプロピル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(+)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(−)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(R)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
(S)−4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−5−フェニル−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−オール;
エチル 2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセタート;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
N−(シクロプロピルメチル)−2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−プロピルアセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−(ピペリジン−1−イル)エタノン;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−モルホリノエタノン;
2−[4−(3−フルオロ−4−トリフルオロメチル−フェニル)−6,7−ジヒドロ−5H−[2]ピリンジン−5−イル]−N−イソオキサゾール−3−イル−アセトアミド;
2−(4−(3−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−(1H−ピラゾール−3−イル)アセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−(ピロリジン−1−イル)エタノン;
N−エチル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−イソプロピル−N−メチルアセトアミド;
N−シクロプロピル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−N−メチルアセトアミド;
N−シクロプロピル−N−エチル−2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)アセトアミド;
2−(4−(2−フルオロ−4−(トリフルオロメチル)フェニル)−6,7−ジヒドロ−5H−シクロペンタ[c]ピリジン−5−イル)−1−((S)−2−メチルピロリジン−1−イル)エタノン
より選択される、請求項1〜16のいずれか一項記載の化合物及びその薬学的に許容し得る塩。 - 治療活性物質として使用するための、請求項1〜17のいずれか一項記載の化合物。
- 請求項1〜17のいずれか一項記載の化合物及び治療上不活性な担体を含む、医薬組成物。
- 慢性腎疾患、うっ血性心不全、高血圧、原発性アルドステロン症及びクッシング症候群の治療又は予防のための、請求項1〜17のいずれか一項記載の化合物の使用。
- 慢性腎疾患、うっ血性心不全、高血圧、原発性アルドステロン症及びクッシング症候群の治療又は予防のための、請求項1〜17のいずれか一項記載の化合物。
- 慢性腎疾患、うっ血性心不全、高血圧、原発性アルドステロン症及びクッシング症候群の治療又は予防用の医薬の製造のための、請求項1〜17のいずれか一項記載の化合物の使用。
- 慢性腎疾患、うっ血性心不全、高血圧、原発性アルドステロン症及びクッシング症候群の治療又は予防のための方法であって、有効量の請求項1〜17のいずれか一項記載の化合物を投与することを含む、方法。
- 請求項18の方法に従って製造される、請求項1〜17のいずれか一項記載の化合物。
- 本明細書に上記のとおりの発明。
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WO2013041591A1 (en) * | 2011-09-23 | 2013-03-28 | F. Hoffmann-La Roche Ag | New bicyclic dihydroquinoline-2-one derivatives |
WO2013156423A1 (en) * | 2012-04-17 | 2013-10-24 | F. Hoffmann-La Roche Ag | New phenyl-tetrahydroisoquinoline derivatives |
WO2015055604A1 (en) * | 2013-10-17 | 2015-04-23 | F. Hoffmann-La Roche Ag | New phenyl-dihydropyridine derivatives as aldosterone synthase inhibitors |
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JP2008501000A (ja) * | 2004-05-28 | 2008-01-17 | シュペーデル・エクスペリメンタ・アーゲー | アルドステロンシンターゼ阻害剤としてのテトラヒドロ−イミダゾ[1,5−a]ピリジン誘導体 |
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WO2013156423A1 (en) * | 2012-04-17 | 2013-10-24 | F. Hoffmann-La Roche Ag | New phenyl-tetrahydroisoquinoline derivatives |
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