JP7241542B2 - テトラヒドロイソキノリン エストロゲン受容体モジュレーター及びその使用 - Google Patents
テトラヒドロイソキノリン エストロゲン受容体モジュレーター及びその使用 Download PDFInfo
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- JP7241542B2 JP7241542B2 JP2018552850A JP2018552850A JP7241542B2 JP 7241542 B2 JP7241542 B2 JP 7241542B2 JP 2018552850 A JP2018552850 A JP 2018552850A JP 2018552850 A JP2018552850 A JP 2018552850A JP 7241542 B2 JP7241542 B2 JP 7241542B2
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- compound
- phenyl
- azetidin
- ethoxy
- fluoromethyl
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- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title description 5
- 239000002834 estrogen receptor modulator Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 381
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 147
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 140
- -1 1-methylazetidin-3-yl Chemical group 0.000 claims description 133
- 206010028980 Neoplasm Diseases 0.000 claims description 100
- 238000000034 method Methods 0.000 claims description 70
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 56
- 239000003814 drug Substances 0.000 claims description 55
- 201000011510 cancer Diseases 0.000 claims description 53
- 108010038795 estrogen receptors Proteins 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 229940124597 therapeutic agent Drugs 0.000 claims description 30
- 206010006187 Breast cancer Diseases 0.000 claims description 29
- 208000026310 Breast neoplasm Diseases 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 229910020008 S(O) Inorganic materials 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 229940127089 cytotoxic agent Drugs 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 9
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 6
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- BKBDCKCPOHJNMA-WAIKUNEKSA-N (1R,3R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N([C@@H](CC2=CC(=CC=C12)O)C)CC(F)(F)F BKBDCKCPOHJNMA-WAIKUNEKSA-N 0.000 claims description 4
- DABPJEVISFOUNE-QMHKHESXSA-N (1R,4R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-4-methyl-2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(C[C@@H](C2=CC(=CC=C12)O)C)S(=O)(=O)C DABPJEVISFOUNE-QMHKHESXSA-N 0.000 claims description 4
- DABPJEVISFOUNE-WAIKUNEKSA-N (1R,4S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-4-methyl-2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(C[C@H](C2=CC(=CC=C12)O)C)S(=O)(=O)C DABPJEVISFOUNE-WAIKUNEKSA-N 0.000 claims description 4
- DABPJEVISFOUNE-MWTRTKDXSA-N (1S,4S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-4-methyl-2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N(C[C@H](C2=CC(=CC=C12)O)C)S(=O)(=O)C DABPJEVISFOUNE-MWTRTKDXSA-N 0.000 claims description 4
- IWCNMGHVEYTYJN-YHAMSUFESA-N FC1=C(C(=CC(=C1)OCCN1CC(C1)CF)F)[C@@H]1N([C@H](CC2=C3C(=CC=C12)NN=C3)C)CC(C)(C)F Chemical compound FC1=C(C(=CC(=C1)OCCN1CC(C1)CF)F)[C@@H]1N([C@H](CC2=C3C(=CC=C12)NN=C3)C)CC(C)(C)F IWCNMGHVEYTYJN-YHAMSUFESA-N 0.000 claims description 4
- IWCNMGHVEYTYJN-DXPJPUQTSA-N FC1=C(C(=CC(=C1)OCCN1CC(C1)CF)F)[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC(C)(C)F Chemical compound FC1=C(C(=CC(=C1)OCCN1CC(C1)CF)F)[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC(C)(C)F IWCNMGHVEYTYJN-DXPJPUQTSA-N 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000014951 hematologic disease Diseases 0.000 claims description 4
- 208000019423 liver disease Diseases 0.000 claims description 4
- JWUOZESJFTULNI-AREMUKBSSA-N (1R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2-fluoro-2-methylpropyl)-1-methyl-3,4-dihydroisoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@]1(N(CCC2=CC(=CC=C12)O)CC(C)(C)F)C JWUOZESJFTULNI-AREMUKBSSA-N 0.000 claims description 3
- GYPXHXYCRMGLOU-HSZRJFAPSA-N (1R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3,3-dimethyl-2-(2,2,2-trifluoroethyl)-1,4-dihydroisoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(C(CC2=CC(=CC=C12)O)(C)C)CC(F)(F)F GYPXHXYCRMGLOU-HSZRJFAPSA-N 0.000 claims description 3
- KTLXJZWWYPXZBP-UZUQRXQVSA-N (1R,3R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N([C@@H](CC2=CC=CC=C12)C)CC(F)(F)F KTLXJZWWYPXZBP-UZUQRXQVSA-N 0.000 claims description 3
- VOYGBWDJGBJHDH-WAIKUNEKSA-N (1R,3R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline-6-carboxylic acid Chemical compound C[C@@H]1CC2=C(C=CC(=C2)C(O)=O)[C@H](N1CC(F)(F)F)C1=CC=C(OCCN2CC(CF)C2)C=C1 VOYGBWDJGBJHDH-WAIKUNEKSA-N 0.000 claims description 3
- JMKZMWGLYQTHCM-MZNJEOGPSA-N (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FC(CN1[C@@H](C2=CC=C(C=C2C[C@H]1C)O)C1=CC=C(C=C1)OCCN1CC(C1)CF)(CO)F JMKZMWGLYQTHCM-MZNJEOGPSA-N 0.000 claims description 3
- PTNXVMQCPOSHGP-MZNJEOGPSA-N (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinolin-8-ol Chemical compound C[C@@H]1CC2=C([C@H](N1CC(F)(F)CO)C1=CC=C(OCCN3CC(CF)C3)C=C1)C(O)=CC=C2 PTNXVMQCPOSHGP-MZNJEOGPSA-N 0.000 claims description 3
- KUSGGKASIHPZQJ-MZNJEOGPSA-N (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinoline-6-sulfonamide Chemical compound C[C@@H]1CC2=C(C=CC(=C2)S(N)(=O)=O)[C@H](N1CC(F)(F)CO)C1=CC=C(OCCN2CC(CF)C2)C=C1 KUSGGKASIHPZQJ-MZNJEOGPSA-N 0.000 claims description 3
- JWUOZESJFTULNI-SANMLTNESA-N (1S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2-fluoro-2-methylpropyl)-1-methyl-3,4-dihydroisoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@]1(N(CCC2=CC(=CC=C12)O)CC(C)(C)F)C JWUOZESJFTULNI-SANMLTNESA-N 0.000 claims description 3
- YJLADFAOINOYCZ-QFIPXVFZSA-N (1S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N(CCC2=CC(=CC=C12)O)S(=O)(=O)C YJLADFAOINOYCZ-QFIPXVFZSA-N 0.000 claims description 3
- BKBDCKCPOHJNMA-HJPURHCSSA-N (1S,3S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N([C@H](CC2=CC(=CC=C12)O)C)CC(F)(F)F BKBDCKCPOHJNMA-HJPURHCSSA-N 0.000 claims description 3
- KTLXJZWWYPXZBP-SBUREZEXSA-N (1S,3S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N([C@H](CC2=CC=CC=C12)C)CC(F)(F)F KTLXJZWWYPXZBP-SBUREZEXSA-N 0.000 claims description 3
- JMKZMWGLYQTHCM-XDHUDOTRSA-N (1S,3S)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound C[C@H]1CC2=C(C=CC(O)=C2)[C@@H](N1CC(F)(F)CO)C1=CC=C(OCCN2CC(CF)C2)C=C1 JMKZMWGLYQTHCM-XDHUDOTRSA-N 0.000 claims description 3
- PTNXVMQCPOSHGP-XDHUDOTRSA-N (1S,3S)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinolin-8-ol Chemical compound FC(CN1[C@H](C2=C(C=CC=C2C[C@@H]1C)O)C1=CC=C(C=C1)OCCN1CC(C1)CF)(CO)F PTNXVMQCPOSHGP-XDHUDOTRSA-N 0.000 claims description 3
- KUSGGKASIHPZQJ-XDHUDOTRSA-N (1S,3S)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinoline-6-sulfonamide Chemical compound FC(CN1[C@H](C2=CC=C(C=C2C[C@@H]1C)S(=O)(=O)N)C1=CC=C(C=C1)OCCN1CC(C1)CF)(CO)F KUSGGKASIHPZQJ-XDHUDOTRSA-N 0.000 claims description 3
- DABPJEVISFOUNE-HJPURHCSSA-N (1S,4R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-4-methyl-2-methylsulfonyl-3,4-dihydro-1H-isoquinolin-6-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N(C[C@@H](C2=CC(=CC=C12)O)C)S(=O)(=O)C DABPJEVISFOUNE-HJPURHCSSA-N 0.000 claims description 3
- QCHUCQIQMVKSPC-WXTAPIANSA-N 1-[(1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-3,4-dihydro-1H-isoquinolin-6-yl]ethanone Chemical compound C[C@@H]1CC2=C(C=CC(=C2)C(C)=O)[C@H](N1CC(F)(F)CO)C1=CC=C(OCCN2CC(CF)C2)C=C1 QCHUCQIQMVKSPC-WXTAPIANSA-N 0.000 claims description 3
- ZKQHQMPYZQYLCG-BVZFJXPGSA-N 2,2-difluoro-3-[(1S,3S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-6-(hydroxymethyl)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl]propan-1-ol Chemical compound FC(CO)(CN1[C@H](C2=CC=C(C=C2C[C@@H]1C)CO)C1=CC=C(C=C1)OCCN1CC(C1)CF)F ZKQHQMPYZQYLCG-BVZFJXPGSA-N 0.000 claims description 3
- RNWOGOMXTBTLNW-BVZFJXPGSA-N 2-[(1S,3S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinolin-6-yl]propan-2-ol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N([C@H](CC2=CC(=CC=C12)C(C)(C)O)C)CC(F)(F)F RNWOGOMXTBTLNW-BVZFJXPGSA-N 0.000 claims description 3
- HAWGBQHBOGNATE-HSZRJFAPSA-N 2-fluoro-1-[(1R)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl]-2-methylpropan-1-one Chemical compound FC(C(=O)N1[C@@H](C2=CC=C(C=C2CC1)O)C1=CC=C(C=C1)OCCN1CC(C1)CF)(C)C HAWGBQHBOGNATE-HSZRJFAPSA-N 0.000 claims description 3
- HAWGBQHBOGNATE-QHCPKHFHSA-N 2-fluoro-1-[(1S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl]-2-methylpropan-1-one Chemical compound CC(C)(F)C(=O)N1CCC2=C(C=CC(O)=C2)[C@@H]1C1=CC=C(OCCN2CC(CF)C2)C=C1 HAWGBQHBOGNATE-QHCPKHFHSA-N 0.000 claims description 3
- LPSWHJANNYROHR-SANMLTNESA-N FC([C@]1(N(CCC2=CC(=CC=C12)O)CC(C)(C)F)C1=CC=C(C=C1)OCCN1CC(C1)CF)F Chemical compound FC([C@]1(N(CCC2=CC(=CC=C12)O)CC(C)(C)F)C1=CC=C(C=C1)OCCN1CC(C1)CF)F LPSWHJANNYROHR-SANMLTNESA-N 0.000 claims description 3
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- IJLPCRAVOLBSOO-JOCHJYFZSA-N FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(CCC2=CC(=CC=C12)O)CC(F)(F)F Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(CCC2=CC(=CC=C12)O)CC(F)(F)F IJLPCRAVOLBSOO-JOCHJYFZSA-N 0.000 claims description 3
- GJTGISRLQSHKNA-HSZRJFAPSA-N FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(CCCC2=C1C=CC(=C2)O)CC(F)(F)F Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@H]1N(CCCC2=C1C=CC(=C2)O)CC(F)(F)F GJTGISRLQSHKNA-HSZRJFAPSA-N 0.000 claims description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 3
- BSUFGZPLIVGYCD-UHFFFAOYSA-N OC1=CC2=C(C=C1)C(N(CC2)C1=CC=CC=C1)C1=CC=C(OC2CN(CCCF)C2)C=C1 Chemical compound OC1=CC2=C(C=C1)C(N(CC2)C1=CC=CC=C1)C1=CC=C(OC2CN(CCCF)C2)C=C1 BSUFGZPLIVGYCD-UHFFFAOYSA-N 0.000 claims description 3
- IJLPCRAVOLBSOO-QFIPXVFZSA-N OC1=CC2=C(C=C1)[C@@H](N(CC(F)(F)F)CC2)C1=CC=C(OCCN2CC(CF)C2)C=C1 Chemical compound OC1=CC2=C(C=C1)[C@@H](N(CC(F)(F)F)CC2)C1=CC=C(OCCN2CC(CF)C2)C=C1 IJLPCRAVOLBSOO-QFIPXVFZSA-N 0.000 claims description 3
- APHXUUHZAZJKAK-QHCPKHFHSA-N [(1S)-1-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinolin-6-yl]methanol Chemical compound FCC1CN(C1)CCOC1=CC=C(C=C1)[C@@H]1N(CCC2=CC(=CC=C12)CO)CC(F)(F)F APHXUUHZAZJKAK-QHCPKHFHSA-N 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 102000015694 estrogen receptors Human genes 0.000 claims description 3
- 230000000508 neurotrophic effect Effects 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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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
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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
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| PCT/EP2017/058313 WO2017174757A1 (en) | 2016-04-08 | 2017-04-07 | Tetrahydroisoquinoline estrogen receptor modulators and uses thereof |
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| US10125135B2 (en) | 2016-04-20 | 2018-11-13 | Astrazeneca Ab | Chemical compounds |
| WO2018019793A1 (en) | 2016-07-25 | 2018-02-01 | Astrazeneca Ab | N-(2-(4-((1r,3r)-3-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine derivatives and related compounds as selective down-regulators of the estrogen receptor for treating cancer |
| WO2018077630A1 (en) | 2016-10-24 | 2018-05-03 | Astrazeneca Ab | 6,7,8,9-tetrahydro-3h-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer |
| EA037533B9 (ru) * | 2016-12-16 | 2021-05-27 | Астразенека Аб | 6,7,8,9-ТЕТРАГИДРО-3H-ПИРАЗОЛО[4,3-f]ИЗОХИНОЛИНОВЫЕ ПРОИЗВОДНЫЕ, ПРИМЕНИМЫЕ В ЛЕЧЕНИИ РАКА |
| ES2766249T3 (es) | 2017-01-30 | 2020-06-12 | Astrazeneca Ab | Moduladores del receptor de estrógeno |
| WO2019002442A1 (en) * | 2017-06-29 | 2019-01-03 | Astrazeneca Ab | CHEMICAL COMPOUNDS |
| WO2019002441A1 (en) * | 2017-06-29 | 2019-01-03 | Astrazeneca Ab | CHEMICAL COMPOUNDS |
| ES2912740T3 (es) * | 2017-11-14 | 2022-05-27 | Kind Pharmaceutical | Compuesto heterocíclico y aplicación del mismo en medicina |
| JP2021503448A (ja) * | 2017-11-16 | 2021-02-12 | ノバルティス アーゲー | Lsz102及びリボシクリブを含む医薬組合せ |
| DK3820874T3 (da) * | 2018-07-12 | 2022-12-12 | Lilly Co Eli | Selektive estrogenreceptornedbrydere |
| CN111499614A (zh) * | 2019-01-31 | 2020-08-07 | 江苏恒瑞医药股份有限公司 | 四氢异喹啉类衍生物、其制备方法及其在医药上的应用 |
| BR112022013322A2 (pt) | 2020-01-10 | 2022-09-20 | Jiangsu Hengrui Medicine Co | Derivado de tetra-hidroisoquinolina tricíclico, método de preparação para o mesmo e aplicação do mesmo em medicina |
| WO2021213358A1 (zh) * | 2020-04-21 | 2021-10-28 | 江苏先声药业有限公司 | 含硼化合物及其应用 |
| AU2021260109B2 (en) | 2020-04-24 | 2024-07-11 | Astrazeneca Ab | Pharmaceutical formulations |
| EP4138834A1 (en) | 2020-04-24 | 2023-03-01 | Astrazeneca AB | Dosage regimen for the treatment of cancer |
| CN111825613B (zh) * | 2020-08-17 | 2022-02-15 | 上海勋和医药科技有限公司 | 作为选择性雌激素受体下调剂的四氢异喹啉类化合物、合成方法及用途 |
| CN114105977B (zh) * | 2020-08-28 | 2023-09-01 | 先声再明医药有限公司 | 雌激素受体调节剂化合物及其用途 |
| CN116669729A (zh) * | 2021-02-08 | 2023-08-29 | 贝达药业股份有限公司 | 杂芳基并哌啶类衍生物及其药物组合物和应用 |
| WO2022178139A1 (en) * | 2021-02-19 | 2022-08-25 | The University Of Chicago | Estrogen receptor alpha antagonists and uses thereof |
| CN113024460B (zh) * | 2021-03-10 | 2022-11-08 | 中国药科大学 | 作为雌激素受体与组蛋白去乙酰化酶双靶点化合物的四氢异喹啉类化合物、合成方法及用途 |
| JP7605536B2 (ja) * | 2021-03-15 | 2024-12-24 | 深▲せん▼福沃薬業有限公司 | エストロゲン受容体モジュレーター |
| WO2023280309A1 (zh) * | 2021-07-09 | 2023-01-12 | 江苏恒瑞医药股份有限公司 | 一种三环四氢异喹啉类衍生物的盐型 |
| WO2023284837A1 (zh) * | 2021-07-15 | 2023-01-19 | 四川海思科制药有限公司 | 芳氨基衍生物雌激素受体调节剂及其用途 |
| JP2025529875A (ja) * | 2022-08-25 | 2025-09-09 | サノフイ | 新規の置換テトラヒドロイソキノリン-6-カルボン酸誘導体、この誘導体を調製する方法、及びこの誘導体の治療的使用 |
| CN115252606B (zh) * | 2022-09-29 | 2023-02-03 | 北京市神经外科研究所 | 化合物在制备用于治疗肿瘤的药物中的应用 |
| WO2025209455A1 (zh) * | 2024-04-01 | 2025-10-09 | 山东盛迪医药有限公司 | 一种选择性雌激素受体降解剂的制备方法 |
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| JP2014503537A (ja) | 2010-12-24 | 2014-02-13 | メルク・シャープ・エンド・ドーム・ベー・フェー | N置換アゼチジン誘導体 |
| WO2015092634A1 (en) | 2013-12-16 | 2015-06-25 | Novartis Ag | 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders |
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| WO2018077630A1 (en) | 2016-10-24 | 2018-05-03 | Astrazeneca Ab | 6,7,8,9-tetrahydro-3h-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer |
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| US5552412A (en) * | 1995-01-09 | 1996-09-03 | Pfizer Inc | 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis |
| US5981521A (en) * | 1998-11-13 | 1999-11-09 | Abbott Laboratories | Tetrahydroisoquinoline derivatives as LHRH antagonists |
| US6436923B1 (en) * | 1999-03-17 | 2002-08-20 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
| DE60115227T2 (de) * | 2000-05-11 | 2006-08-24 | Bristol-Myers Squibb Co. | Tetrahydroisochinolin-analoga als wachstumshormon-sekretagoga |
| AU2002222853A1 (en) * | 2000-12-07 | 2002-06-18 | Astrazeneca Ab | Therapeutic compounds |
| CN102875466A (zh) * | 2012-04-23 | 2013-01-16 | 中国药科大学 | 异喹啉酮衍生物,其制备方法及其医药用途 |
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2017
- 2017-04-07 EP EP17715939.9A patent/EP3440067B1/en active Active
- 2017-04-07 CN CN201780034424.1A patent/CN109219604B/zh active Active
- 2017-04-07 WO PCT/EP2017/058313 patent/WO2017174757A1/en not_active Ceased
- 2017-04-07 US US15/481,757 patent/US9969732B2/en active Active
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| WO2015092634A1 (en) | 2013-12-16 | 2015-06-25 | Novartis Ag | 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders |
| WO2016097071A1 (en) | 2014-12-18 | 2016-06-23 | F. Hoffmann-La Roche Ag | Estrogen receptor modulators and uses thereof |
| WO2017182493A1 (en) | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Indazole derivatives for use in down-regulation of the estrogen receptor for the treatment of cancer |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP3440067A1 (en) | 2019-02-13 |
| US20170320871A1 (en) | 2017-11-09 |
| JP2019510799A (ja) | 2019-04-18 |
| CN109219604B (zh) | 2021-09-24 |
| EP3440067B1 (en) | 2021-05-26 |
| CN109219604A (zh) | 2019-01-15 |
| US9969732B2 (en) | 2018-05-15 |
| WO2017174757A1 (en) | 2017-10-12 |
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