JP5886873B2 - Ｎ置換アゼチジン誘導体 - Google Patents
Ｎ置換アゼチジン誘導体 Download PDFInfo
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- JP5886873B2 JP5886873B2 JP2013545218A JP2013545218A JP5886873B2 JP 5886873 B2 JP5886873 B2 JP 5886873B2 JP 2013545218 A JP2013545218 A JP 2013545218A JP 2013545218 A JP2013545218 A JP 2013545218A JP 5886873 B2 JP5886873 B2 JP 5886873B2
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- Prior art keywords
- compound
- alkyl
- scheme
- phenyl
- general procedure
- Prior art date
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- -1 N-substituted azetidine Chemical class 0.000 title claims description 113
- 150000001875 compounds Chemical class 0.000 claims description 213
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 206010006187 Breast cancer Diseases 0.000 claims description 54
- 208000026310 Breast neoplasm Diseases 0.000 claims description 53
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 53
- 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 claims description 53
- 229910052731 fluorine Inorganic materials 0.000 claims description 45
- 239000011737 fluorine Substances 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- 239000000460 chlorine Substances 0.000 claims description 36
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 35
- 229910052801 chlorine Inorganic materials 0.000 claims description 34
- 150000002825 nitriles Chemical class 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 229960001603 tamoxifen Drugs 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 8
- 201000009273 Endometriosis Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
- 206010014733 Endometrial cancer Diseases 0.000 claims description 7
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 7
- 208000001132 Osteoporosis Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 230000004064 dysfunction Effects 0.000 claims description 7
- 238000001794 hormone therapy Methods 0.000 claims description 7
- 230000016087 ovulation Effects 0.000 claims description 7
- 206010046766 uterine cancer Diseases 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims 3
- 238000000034 method Methods 0.000 description 114
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 111
- 230000015572 biosynthetic process Effects 0.000 description 87
- 238000003786 synthesis reaction Methods 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
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- 239000000203 mixture Substances 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 235000019000 fluorine Nutrition 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 41
- 239000000243 solution Substances 0.000 description 36
- 108010038795 estrogen receptors Proteins 0.000 description 34
- 102100038595 Estrogen receptor Human genes 0.000 description 33
- 108010007005 Estrogen Receptor alpha Proteins 0.000 description 30
- 102000007594 Estrogen Receptor alpha Human genes 0.000 description 30
- 239000011734 sodium Substances 0.000 description 29
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
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- 125000004432 carbon atom Chemical group C* 0.000 description 20
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- 239000012299 nitrogen atmosphere Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
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- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000012634 fragment Substances 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 12
- 229940119564 Selective estrogen receptor downregulator Drugs 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- WTDFFADXONGQOM-UHFFFAOYSA-N formaldehyde;hydrochloride Chemical compound Cl.O=C WTDFFADXONGQOM-UHFFFAOYSA-N 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 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 11
- 239000012267 brine Substances 0.000 description 11
- 229960002258 fulvestrant Drugs 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 9
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 9
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical group C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 6
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- 150000003839 salts Chemical class 0.000 description 6
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 5
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- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
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- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
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- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 4
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
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| EP10196960.8 | 2010-12-24 | ||
| PCT/EP2011/073041 WO2012084711A1 (en) | 2010-12-24 | 2011-12-16 | N-substituted azetidine derivatives |
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| JP2014503537A5 JP2014503537A5 (cg-RX-API-DMAC10.html) | 2014-08-21 |
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| ES (1) | ES2586908T3 (cg-RX-API-DMAC10.html) |
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Families Citing this family (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3205648A1 (en) | 2010-06-10 | 2017-08-16 | Seragon Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
| US8853423B2 (en) | 2010-06-17 | 2014-10-07 | Seragon Pharmaceuticals, Inc. | Indane estrogen receptor modulators and uses thereof |
| EP2791132A4 (en) | 2011-12-14 | 2015-08-05 | Seragon Pharmaceuticals Inc | ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
| NZ710385A (en) | 2013-02-19 | 2016-10-28 | Novartis Ag | Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders |
| TWI784255B (zh) | 2014-12-18 | 2022-11-21 | 瑞士商赫孚孟拉羅股份公司 | 四氫-吡啶并[3,4-b]吲哚雌激素受體調節劑及其用途 |
| WO2016174551A1 (en) * | 2015-04-27 | 2016-11-03 | Pfizer Inc. | Anti-estrogenic compounds |
| WO2017059139A1 (en) | 2015-10-01 | 2017-04-06 | Olema Pharmaceuticals, Inc. | TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS |
| JP6920295B2 (ja) * | 2015-11-09 | 2021-08-18 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | テトラヒドロナフタレンエストロゲン受容体モジュレーター及びその使用 |
| DK3386500T3 (da) | 2015-12-09 | 2022-12-12 | Univ Illinois | Benzothiophen-baserede selektive østrogenreceptor ned-regulatorer |
| SG11201806829TA (en) * | 2016-02-15 | 2018-09-27 | Sanofi Sa | 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators |
| EP3440067B1 (en) * | 2016-04-08 | 2021-05-26 | F. Hoffmann-La Roche AG | Tetrahydroisoquinoline estrogen receptor modulators and uses thereof |
| WO2017197046A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
| CN109562107A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的杂环降解决定子体 |
| CN109562113A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的螺环降解决定子体 |
| CN121974842A (zh) | 2016-05-10 | 2026-05-05 | C4医药公司 | 用于靶蛋白降解的胺连接的c3-戊二酰亚胺降解决定子体 |
| CN109789143A (zh) | 2016-07-01 | 2019-05-21 | G1治疗公司 | 基于嘧啶的抗增殖剂 |
| UA125824C2 (uk) * | 2016-10-24 | 2022-06-15 | Астразенека Аб | 6,7,8,9-ТЕТРАГІДРО-3H-ПІРАЗОЛО[4,3-f]ІЗОХІНОЛІНОВІ ПОХІДНІ, ЗАСТОСОВНІ В ЛІКУВАННІ РАКУ |
| WO2018081168A2 (en) | 2016-10-24 | 2018-05-03 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
| EP3541809B1 (en) | 2016-11-17 | 2025-06-25 | Sanofi | Novel substituted n-(3-fluoropropyl)-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof |
| JP7229162B2 (ja) | 2017-01-06 | 2023-02-27 | ジー１ セラピューティクス， インコーポレイテッド | 癌の治療に対する併用療法 |
| WO2018138739A1 (en) | 2017-01-27 | 2018-08-02 | Sun Pharma Advanced Research Company Limited | Novel antiestrogenic heterocyclic compounds |
| KR20190117582A (ko) | 2017-02-10 | 2019-10-16 | 쥐원 쎄라퓨틱스, 인크. | 벤조티오펜 에스트로겐 수용체 조정제 |
| GB201706806D0 (en) | 2017-04-28 | 2017-06-14 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| EP4717317A3 (en) | 2017-06-20 | 2026-06-03 | C4 Therapeutics, Inc. | N/o-linked degrons and degronimers for protein degradation |
| EP3645001B1 (en) | 2017-06-29 | 2024-07-03 | G1 Therapeutics, Inc. | Morphic forms of git38 and methods of manufacture thereof |
| EP3434272A1 (en) | 2017-07-25 | 2019-01-30 | Sanofi | Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid |
| KR102765922B1 (ko) * | 2018-02-06 | 2025-02-11 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | 선택적인 에스트로겐 수용체 분해제로서의 치환된 벤조티오펜 유사체 |
| LT3810283T (lt) | 2018-06-21 | 2023-08-25 | F. Hoffmann-La Roche Ag | 3-((1r,3r)-1-(2,6-difluor-4-((1-(3-fluorpropil)azetidin-3- il)amino) fenil)-3-metil-1,3,4,9-tetrahidro-2h-pirido[3,4-b]indol-2-il)- 2,2- difluorpropan-1-olio tartrato druskos kietosios formos, jų paruošimo procesas ir jų naudojimo būdai vėžiui gydyti |
| DK3847157T3 (da) | 2018-09-07 | 2022-08-08 | Sanofi Sa | Fremgangsmåde til fremstilling af methyl-[6-(2,4-dichlorphenyl)-5-[4-[(3s)-1-(3-fluorpropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulen-2-carboxylat] og salt deraf |
| EP3897631A4 (en) | 2018-12-20 | 2022-11-23 | C4 Therapeutics, Inc. | TARGETED PROTEIN BREAKDOWN |
| CA3144791A1 (en) | 2019-07-07 | 2021-01-14 | Olema Pharmaceuticals, Inc. | Regimens of estrogen receptor antagonists |
| WO2021063967A1 (en) | 2019-10-01 | 2021-04-08 | Sanofi | Novel substituted 6,7-dihydro-5h-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof |
| CA3160897A1 (en) | 2019-12-09 | 2021-06-17 | Sanofi | Crystalline form of a 7h-benzo[7]annulene-2-carboxylic acid derivative |
| EP4681715A3 (en) | 2019-12-20 | 2026-01-28 | C4 Therapeutics, Inc. | Isoindolinone and indazole compounds for the degradation of egfr |
| TW202146007A (zh) | 2020-02-27 | 2021-12-16 | 法商賽諾菲公司 | 包含阿培利司（ａｌｐｅｌｉｓｉｂ）與６－（２，４－二氯苯基）－５－［４－［（３ｓ）－１－（３－氟丙基）吡咯啶－３－基］氧苯基］－８，９－二氫－７ｈ－苯并［７］輪烯－２－羧酸之組合 |
| CN119823124A (zh) | 2020-03-05 | 2025-04-15 | C4医药公司 | 用于brd9的靶向降解的化合物 |
| MX2022010425A (es) | 2020-03-06 | 2022-09-07 | Olema Pharmaceuticals Inc | Metodos de tratamiento de enfermedades asociadas a los receptores de estrogenos. |
| EP4164653A4 (en) | 2020-06-15 | 2024-06-19 | G1 Therapeutics, Inc. | MORPHIC FORMS OF TRILACICLIB AND METHODS OF PREPARING THE SAME |
| CN116490186B (zh) | 2020-08-05 | 2025-10-31 | C4医药公司 | 用于ret的靶向降解的化合物 |
| GB202015187D0 (en) | 2020-09-25 | 2020-11-11 | Sentinel Oncology Ltd | A pharmaceutical salt |
| IL302152B1 (en) | 2020-10-19 | 2026-07-01 | Sanofi Sa | 6,7-DIHYDRO-5H-BENZO[7]ANNULENE COMPOUNDS AND THEIR DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR THERAPEUTIC USES |
| IL302153B1 (en) | 2020-10-19 | 2026-07-01 | Sanofi Sa | 6,7-DIHYDRO-5H-BENZO[7]ANNULENE COMPOUNDS AND THEIR DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR THERAPEUTIC USES |
| CN113248455A (zh) * | 2021-05-25 | 2021-08-13 | 湖北科技学院 | 一种3,5-二取代异噁唑类衍生物及其合成方法 |
| BR112023024507A2 (pt) | 2021-05-26 | 2024-02-15 | C4 Therapeutics Inc | Método para tratar um câncer mediado por receptor do fator de crescimento epidérmico mutante que sofreu metástase para o cérebro ou sistema nervoso central |
| AU2022290851A1 (en) | 2021-06-08 | 2023-11-23 | C4 Therapeutics, Inc. | Therapeutics for the degradation of mutant braf |
| WO2023059714A1 (en) * | 2021-10-06 | 2023-04-13 | Olema Pharmaceuticals, Inc. | Methods of treating estrogen receptor-mediated disorders |
| KR20250055538A (ko) | 2022-08-03 | 2025-04-24 | 브리스톨-마이어스 스큅 컴퍼니 | Ret 단백질을 조정하기 위한 화합물 |
| CN117924262A (zh) * | 2022-10-14 | 2024-04-26 | 中国科学院上海药物研究所 | 二氢苯并噻喃类衍生物及其制备方法和用途 |
| JP2025540906A (ja) | 2022-11-04 | 2025-12-17 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｅｔ－ｌｄｄタンパク質阻害剤 |
| KR20250117789A (ko) | 2022-11-04 | 2025-08-05 | 브리스톨-마이어스 스큅 컴퍼니 | Ret-ldd 단백질 분해제 |
| CN116813603B (zh) * | 2023-06-02 | 2024-10-22 | 成都市第三人民医院 | 一种选择性雌激素受体α降解化合物及其制备方法和应用 |
| CN122206684A (zh) | 2023-06-30 | 2026-06-12 | 默克专利有限公司 | 用于kras蛋白降解的异双功能化合物 |
| WO2026139448A1 (en) | 2024-12-23 | 2026-07-02 | Merck Patent Gmbh | Heterobifunctional compounds for the degradation of kras protein |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3983245A (en) * | 1975-02-06 | 1976-09-28 | Smithkline Corporation | Certain 4-(3-azacycloalkoxy or azacycloalkylmethoxy)benzoylbenzofurans or benzothiophenes |
| US6750213B2 (en) | 2000-10-19 | 2004-06-15 | Merck & Co., Inc. | Estrogen receptor modulators |
| DOP2002000467A (es) * | 2001-10-10 | 2003-04-15 | Pfizer Prod Inc | 2-amino-6 (fenilo sustituido en las posiciones 2,4,5)-piridinas |
| TW200304371A (en) * | 2002-02-22 | 2003-10-01 | Akzo Nobel Nv | Substituted 10-ary1-11H-benzo [b] fluorenes and 7-ary1-5, 6-dihydro-benz [a] anthracenes for selective effects on estrogen receptors |
| US20030225132A1 (en) | 2002-04-11 | 2003-12-04 | Dininno Frank P. | Estrogen receptor modulators |
| ATE481397T1 (de) | 2002-04-24 | 2010-10-15 | Merck Sharp & Dohme | Modulatoren des östrogenrezeptors |
| CA2512000C (en) * | 2002-12-26 | 2011-08-09 | Eisai Co., Ltd. | Selective estrogen receptor modulator |
| EP2222638A2 (en) * | 2007-11-21 | 2010-09-01 | Decode Genetics EHF | Biaryl pde4 inhibitors for treating inflammation |
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| EP2655367A1 (en) | 2013-10-30 |
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| ES2586908T3 (es) | 2016-10-19 |
| US9540361B2 (en) | 2017-01-10 |
| JP2014503537A (ja) | 2014-02-13 |
| CA2819299A1 (en) | 2012-06-28 |
| US20160130262A1 (en) | 2016-05-12 |
| AU2011347718A1 (en) | 2013-05-30 |
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