TWI794205B - 化合物 - Google Patents

Info

Publication number

TWI794205B

TWI794205B TW107103088A TW107103088A TWI794205B TW I794205 B TWI794205 B TW I794205B TW 107103088 A TW107103088 A TW 107103088A TW 107103088 A TW107103088 A TW 107103088A TW I794205 B TWI794205 B TW I794205B

Authority

TW

Taiwan

Prior art keywords

methyl

compound

formula

tetrahydro

pyrido

Prior art date

2017-01-30

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 472
• 150000003839 salts Chemical class 0.000 claims abstract description 222
• 238000002360 preparation method Methods 0.000 claims abstract description 57
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 119
• 206010028980 Neoplasm Diseases 0.000 claims description 94
• 229910052739 hydrogen Inorganic materials 0.000 claims description 82
• 201000011510 cancer Diseases 0.000 claims description 58
• 241001465754 Metazoa Species 0.000 claims description 46
• 239000003814 drug Substances 0.000 claims description 44
• 206010006187 Breast cancer Diseases 0.000 claims description 43
• 208000026310 Breast neoplasm Diseases 0.000 claims description 42
• HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 30
• 241000282414 Homo sapiens Species 0.000 claims description 29
• 239000002253 acid Substances 0.000 claims description 23
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 22
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• JMHAEPDWKOSCPH-RYUVBPIJSA-N (2R)-3-[(1R,3R)-1-[5-fluoro-2-[2-(3-fluoropropylamino)ethoxy]-3-methylpyridin-4-yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@H](CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(OCCNCCCF)=NC=C1F)C(O)=O JMHAEPDWKOSCPH-RYUVBPIJSA-N 0.000 claims description 4
• KNSMOAXIFSMQRE-HQWTYURQSA-N (2S)-3-[(1R,3R)-1-[6-fluoro-3-[2-(3-fluoropropylamino)ethoxy]-2-methylphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@@H](CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(OCCNCCCF)=CC=C1F)C(O)=O KNSMOAXIFSMQRE-HQWTYURQSA-N 0.000 claims description 3
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
• BTJWAAQFFCCLEV-DDWQGHIRSA-N (2R)-3-[(1R,3R)-1-[3-[2-(3,3-difluoropropylamino)ethoxy]-6-fluoro-2-methylphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@H](CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(OCCNCCC(F)F)=CC=C1F)C(O)=O BTJWAAQFFCCLEV-DDWQGHIRSA-N 0.000 claims description 2
• KNSMOAXIFSMQRE-KMVLGAPJSA-N (2R)-3-[(1R,3R)-1-[6-fluoro-3-[2-(3-fluoropropylamino)ethoxy]-2-methylphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@H](CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(OCCNCCCF)=CC=C1F)C(O)=O KNSMOAXIFSMQRE-KMVLGAPJSA-N 0.000 claims description 2
• JOFYCYZGTXIWEJ-DDWQGHIRSA-N (2R)-3-[(1R,3R)-6-fluoro-1-[6-fluoro-3-[2-(3-fluoropropylamino)ethoxy]-2-methylphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@H](CN1[C@H](C)CC2=C(NC3=CC=C(F)C=C23)[C@H]1C1=C(C)C(OCCNCCCF)=CC=C1F)C(O)=O JOFYCYZGTXIWEJ-DDWQGHIRSA-N 0.000 claims description 2
• JMHAEPDWKOSCPH-RJYGXOMWSA-N (2S)-3-[(1R,3R)-1-[5-fluoro-2-[2-(3-fluoropropylamino)ethoxy]-3-methylpyridin-4-yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoic acid Chemical compound C[C@@H](CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(OCCNCCCF)=NC=C1F)C(O)=O JMHAEPDWKOSCPH-RJYGXOMWSA-N 0.000 claims description 2
• WXZYOKABAPSHMB-AYPCSJHXSA-N FC=1C(=C(C(=NC=1)OCCN(C([2H])([2H])[2H])CCCF)C)[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)C[C@H](C(=O)O)C Chemical compound FC=1C(=C(C(=NC=1)OCCN(C([2H])([2H])[2H])CCCF)C)[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)C[C@H](C(=O)O)C WXZYOKABAPSHMB-AYPCSJHXSA-N 0.000 claims 1
• KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 101
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• 239000000543 intermediate Substances 0.000 abstract description 4
• 230000002062 proliferating effect Effects 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 195
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 121
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 119
• 239000002585 base Substances 0.000 description 118
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 107
• 238000006243 chemical reaction Methods 0.000 description 104
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 102
• 235000019439 ethyl acetate Nutrition 0.000 description 88
• -1 tetrahydro-1H-pyrido[3,4-b]indol-1-yl ring Chemical group 0.000 description 81
• 238000005481 NMR spectroscopy Methods 0.000 description 78
• 230000002829 reductive effect Effects 0.000 description 78
• 239000000243 solution Substances 0.000 description 75
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• 210000004027 cell Anatomy 0.000 description 65
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• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 61
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
• 102100038595 Estrogen receptor Human genes 0.000 description 55
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 51
• 108010038795 estrogen receptors Proteins 0.000 description 50
• 108010007005 Estrogen Receptor alpha Proteins 0.000 description 49
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 47
• 239000000047 product Substances 0.000 description 47
• 239000000460 chlorine Substances 0.000 description 46
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
• 150000007523 nucleic acids Chemical class 0.000 description 43
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 41
• 229910052801 chlorine Inorganic materials 0.000 description 40
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• 239000012043 crude product Substances 0.000 description 39
• 230000035772 mutation Effects 0.000 description 38
• 238000003199 nucleic acid amplification method Methods 0.000 description 37
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
• 230000003321 amplification Effects 0.000 description 36
• 102000007594 Estrogen Receptor alpha Human genes 0.000 description 35
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• 238000003556 assay Methods 0.000 description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 34
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• 239000011737 fluorine Substances 0.000 description 33
• 229920006395 saturated elastomer Polymers 0.000 description 33
• 125000000217 alkyl group Chemical group 0.000 description 32
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• CIJJUIJARCPGCV-QUVIJQCPSA-N methyl (2S)-3-[(1R,3R)-1-(3-bromo-6-fluoro-2-methylphenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methylpropanoate Chemical compound COC(=O)[C@@H](C)CN1[C@H](C)CC2=C(NC3=CC=CC=C23)[C@H]1C1=C(C)C(Br)=CC=C1F CIJJUIJARCPGCV-QUVIJQCPSA-N 0.000 description 29
• 239000011541 reaction mixture Substances 0.000 description 28
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• 229940034982 antineoplastic agent Drugs 0.000 description 27
• 239000010410 layer Substances 0.000 description 27
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 26
• CVLLAKCGAFNZHJ-UHFFFAOYSA-N ditert-butyl-[6-methoxy-3-methyl-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(C)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C(C)(C)C)C(C)(C)C CVLLAKCGAFNZHJ-UHFFFAOYSA-N 0.000 description 25
• 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 25
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
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• 238000004458 analytical method Methods 0.000 description 19
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• 229910000024 caesium carbonate Inorganic materials 0.000 description 19
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 19
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• NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 18
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• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
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• PORUFPRURWGFMV-WGDIFIGCSA-N 3-[(1R,3R)-1-[5-fluoro-2-[2-[3-fluoropropyl(methyl)amino]ethoxy]-3-methylpyridin-4-yl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]propanoic acid Chemical compound C[C@@H]1CC2=C(NC3=CC=CC=C23)[C@H](N1CCC(O)=O)C1=C(C)C(OCCN(C)CCCF)=NC=C1F PORUFPRURWGFMV-WGDIFIGCSA-N 0.000 description 1
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• DJOJMGVIZNWNIP-WAIKUNEKSA-N 3-fluoro-N-[2-[2-[(1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyridin-4-yl]oxyethyl]propan-1-amine Chemical compound FCCCNCCOC1=CC(=NC=C1)[C@H]1N([C@@H](CC2=C1NC1=CC=CC=C21)C)CC(F)(F)F DJOJMGVIZNWNIP-WAIKUNEKSA-N 0.000 description 1
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