JP7384903B2 - フルベストラントのプロドラッグ - Google Patents
フルベストラントのプロドラッグ Download PDFInfo
- Publication number
- JP7384903B2 JP7384903B2 JP2021515306A JP2021515306A JP7384903B2 JP 7384903 B2 JP7384903 B2 JP 7384903B2 JP 2021515306 A JP2021515306 A JP 2021515306A JP 2021515306 A JP2021515306 A JP 2021515306A JP 7384903 B2 JP7384903 B2 JP 7384903B2
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- JP
- Japan
- Prior art keywords
- optionally substituted
- aryl
- group
- cycloalkyl
- heteroaryl
- 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.)
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- 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 title description 145
- 229960002258 fulvestrant Drugs 0.000 title description 143
- 229940002612 prodrug Drugs 0.000 title description 77
- 239000000651 prodrug Substances 0.000 title description 77
- 125000003118 aryl group Chemical group 0.000 claims description 121
- 150000001875 compounds Chemical class 0.000 claims description 104
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 102
- 125000001072 heteroaryl group Chemical group 0.000 claims description 100
- 239000001257 hydrogen Substances 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 98
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 92
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 78
- 125000000304 alkynyl group Chemical group 0.000 claims description 75
- 125000003342 alkenyl group Chemical group 0.000 claims description 74
- 239000012453 solvate Substances 0.000 claims description 69
- 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 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 229910019142 PO4 Inorganic materials 0.000 claims description 39
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 38
- 239000010452 phosphate Substances 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000002252 acyl group Chemical group 0.000 claims description 29
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 229920006395 saturated elastomer Polymers 0.000 claims description 29
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 28
- 125000004414 alkyl thio group Chemical group 0.000 claims description 28
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 238000006467 substitution reaction Methods 0.000 claims description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 14
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 14
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 238000006116 polymerization reaction Methods 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 210000005000 reproductive tract Anatomy 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical class C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical class C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001541 aziridines Chemical class 0.000 claims description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical class C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 2
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 claims 2
- 210000000056 organ Anatomy 0.000 claims 2
- 230000001850 reproductive effect Effects 0.000 claims 2
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 179
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 156
- 239000011541 reaction mixture Substances 0.000 description 148
- 238000006243 chemical reaction Methods 0.000 description 119
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 110
- 239000000243 solution Substances 0.000 description 86
- 238000002360 preparation method Methods 0.000 description 79
- 239000012043 crude product Substances 0.000 description 68
- -1 isobutenyl Chemical group 0.000 description 64
- 238000004809 thin layer chromatography Methods 0.000 description 58
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 54
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000007787 solid Substances 0.000 description 50
- 238000002953 preparative HPLC Methods 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 36
- 239000000047 product Substances 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 235000021317 phosphate Nutrition 0.000 description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 21
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 21
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 21
- 239000001099 ammonium carbonate Substances 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 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 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 9
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229910001873 dinitrogen Inorganic materials 0.000 description 8
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 8
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 7
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 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 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- JAAMSBWLRYVTFZ-UHFFFAOYSA-N phenanthren-3-yl dihydrogen phosphate Chemical compound C1=CC(=CC=2C3=CC=CC=C3C=CC1=2)OP(=O)(O)O JAAMSBWLRYVTFZ-UHFFFAOYSA-N 0.000 description 6
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- IPXNXMNCBXHYLQ-UHFFFAOYSA-N 2-pyrrolidin-1-ylacetic acid Chemical compound OC(=O)CN1CCCC1 IPXNXMNCBXHYLQ-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- VIWZVFVJPXTXPA-UHFFFAOYSA-N N-(2-Carboxymethyl)-morpholine Chemical compound OC(=O)CN1CCOCC1 VIWZVFVJPXTXPA-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 4
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- YUYHRSGXZZVNMS-UHFFFAOYSA-N 3-morpholin-4-ylpropanoic acid Chemical compound OC(=O)CCN1CCOCC1 YUYHRSGXZZVNMS-UHFFFAOYSA-N 0.000 description 4
- FDEQQCOTLPPCAO-UHFFFAOYSA-N Cl.OC(O)=O Chemical compound Cl.OC(O)=O FDEQQCOTLPPCAO-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- 239000006187 pill Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 201000003437 pleural cancer Diseases 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- AUIVQIHTTVPKFS-FJXQXJEOSA-N tert-butyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.CC(C)[C@H](N)C(=O)OC(C)(C)C AUIVQIHTTVPKFS-FJXQXJEOSA-N 0.000 description 1
- QOISWWBTZMFUEL-NSHDSACASA-N tert-butyl (2s)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-NSHDSACASA-N 0.000 description 1
- FDMCEXDXULPJPG-MERQFXBCSA-N tert-butyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 FDMCEXDXULPJPG-MERQFXBCSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。
Rは、下記:
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。)
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。
Rは、下記:
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。
Rは、下記:
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。
Rは、下記:
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
各試験化合物の50mモルのストック溶液を、ジメチルスルホキシドを使用して調製した。このストック溶液から、ジメチルスルホキシドで希釈して1mモルの使用溶液を調製した。次に、1mモルの使用溶液を、ジメチルスルホキシドを使用して段階希釈した。次いで、5~20μlのストック溶液を、1mlのpH7.4のリン酸緩衝液に添加した。次に、平衡状態にするため、溶液を25℃で4時間撹拌した。このインキュベーション時間の後、溶液を、0.45ミクロンのPVDFインジェクターフィルターを使用してろ過し、化合物の不溶性画分を除去した後、ろ液を、UV検出器による定量に使用した。試験サンプルの濃度は、線形の検量線を使用して計算した。
表1:試験化合物とフルベストラントの動的溶解度
試験化合物及びフルベストラントのストック溶液を、リン酸緩衝生理食塩水(PBS)pH7.4及び酢酸ナトリウム緩衝液pH4.0で調製し、同一チューブ内にて100rpmで定速混合しながら室温で24時間インキュベートした。インキュベーション後、チューブを20分間10000rpmで遠心分離した。その後、200μLのサンプルを採取してろ過した。ろ液を、0.0012mg/ml、0.037mg/ml、0.3mg/ml、0.1mg/ml、及び1mg/mlのジメチルスルホキシド(DMSO)ストックに対してHPLC-UVで分析した。更に、データ分析を、次の式にしたがって行った。
溶解度(μg/ml)=[サンプルのピーク面積/標準品のピーク面積]×標準品の濃度
%水溶解度:[試験溶解度(μg/ml)/インキュベーション濃度(μg/ml)]×100
表2:試験化合物とフルベストラントの熱力学的溶解度
EDCI:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド
HOBt:ヒドロキシベンゾトリアゾール
DCM:ジクロロメタン
CHCl3:クロロホルム
ACN:アセトニトリル
NMM:N-メチルモルホリン
DIEA:N,N-ジイソプロピルエチルアミン
TEA:トリエチルアミン
DBU:1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
K2CO3:炭酸カリウム
NaOH:水酸化ナトリウム
DMAP:4-ジメチルアミノピリジン
TBAB:臭化テトラ-n-ブチルアンモニウム
DCC:N,N’-ジシクロヘキシルカルボジイミド
TLC:薄層クロマトグラフィー
LCMS:液体クロマトグラフィー質量分析
HPLC:高速液体クロマトグラフィー
1H-NMR (400 MHz, DMSO): δ 2.269 (s, 6H), 2.591-2.556 (t, 2H), 3.313 -3.280 (t, 2H), 3.735 (s, 2H), 3.822 (s, 2H), 5.310 (s, 2H), 7.413 (s, 1H) 及び 8.639-8.627 (s, 1H).
1H-NMR (400 MHz, DMSO): δ 7.337 (d, 1H), 6.863-6.842 (m, 1H), 6 881 (s, 1H), 4.543 (s, 1H), 3.587-3.536 (m, 5H), 3.50 (s, 2H), 2.898-2.687 (m, 11H), 2.546-2.325 (m, 7H), 2.01-1.75 (m, 4H), 1.78-1.48 (m, 4H), 1.48-1.08 (m, 22H), 0.90 (dd, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 10.315 (s, 1H-HCl salt), 7.337 (d, 1H), 6.863-6.842 (m, 1H), 6.881 (s, 1H), 4.543 (s, 1H), 3.587-3.536 (m, 5H), 3.50 (s, 2H), 2.898-2.687 (m, 11H), 2.546-2.325 (m, 7H), 2.01-1.75 (m, 4H), 1.78-1.48 (m, 4H), 1.48-1.08 (m, 22H), 0.90 (dd, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.281 (d, 1H), 6.857-6.804 (m, 2H), 4.541 (d, 1H), 3.560-3.363 (m, 6H), 2.900-2.648 (m, 7H), 2.541 (s, 7H), 2.521-2.351 (m, 4H), 2.291 (s, 3H), 1.901-1.861 (m, 1H), 1.852-1.218 (m, 20 H), 0.90 (dd, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 9.074 (s, 1H), 7.061 (d, 1H), 6.527-6.441 (m, 2H), 4.531 (d, 1H), 2.900-2.648 (m, 9H), 2.564- 2.491 (m, 4H), 2.481-2.109 (m, 7H), 2.011-1.952 (m, 3H), 1.901-1.102 (m, 26H), 0.90 (dd, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 10.423 (s, 1H), 7.987(d, 1H), 7.601 (t, 1H), 7.395 (d, 1H), 7.071-6.995 (m, 3H), 4.554 (d, 1H), 3.587 (d, 2H), 3.587-3.536 (m, 5H), 3.50 (s, 2H), 2.873-2.660 (m, 6H), 2.453-2.338 (m, 4H), 1.995-1.883 (m, 4H), 1.863-1.831 (m, 2H), 1.734-1.601 (m, 5H), 1.525-1.262 (m, 16H), 0.90 (dd, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.312 (d, 1H), 6.945 (d, 1H), 6.890 (s, 1H), 4.545 (d, 1H), 4.185-4.111 (m, 4H), 3.560 (d, 1H), 3.587-3.536 (m, 5H), 3.50 (s, 2H), 2.880-2.784 (m, 2H), 2.759-2.645 (m, 4H), 2.459-2.279 (m, 4H), 1.996-1.885 (m, 4H), 1.872 (d, 1H), 1.771-1.514 (m, 2H), 1.734-1.601 (m, 5H), 1.525-1.262 (m, 18H), 0.90 (dd, 2H) 及び 0.69 (s, 3H)
1H-NMR (400 MHz, DMSO): δ 7.336 (d, 1H), 6.865 (d, 1H), 6.813 (s, 1H), 4.544 (d, 1H), 3.575 (s, 3H), 2.893-2.633 (m, 10H), 2.477-2.269 (m, 5H), 1.954-1.492 (m, 13H), 1.392-1.205 (m, 18H), 0.901 (m, 2H) 及び 0.695 (s, 3H)
1H-NMR (400 MHz, DMSO): δ 7.272 (d, 1H), 6.821 (d, 1H), 6.781 (s, 1H), 4.559 (s, 1H), 4.131 (s, 1H), 4.047 (s, 1H), 3.558 (m, 2H), 3.501-3.486 (m, 5H), 2.961 (s, 2H), 2.892-2.623 (m, 10H), 2.446-2.279 (m, 12H), 1.996-1.885 (m, 4H), 1.835-1.746 (m, 5H), 1.771-1.514 (m, 4H), 1.734-1.601 (m, 8H), 1.525-1.262 (m, 24H), 0.901 (dd, 2H) 及び 0.684 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.342 (d, 1H), 6.871 (d, 1H), 6.823 (s, 1H), 4.549 (d, 1H), 3.681-3.544 (m, 5H), 3.503 (s, 2H), 2.895-2.867 (m, 2H), 2.841-2.726 (m, 4H), 2.596 (t, 4H), 2.444-2.157 (m, 4H), 2.019-1.756 (m, 5H), 1.787-1.487 (m, 4H), 1.448-1.087 (m, 18H), 0.903 (d, 2H) 及び 0.669 (s, 3H).
工程2:ジクロロメタン(2ml)中のtert-ブチル4-(((((7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル)オキシ)カルボニル)オキシ)ピペリジン-1-カルボキシレート(0.280g)の攪拌溶液に、メタンスルホン酸(0.023g)を0℃で添加し、2時間撹拌した。反応を、TLC及びLCMSでモニターした。反応完了後、反応混合物を真空下蒸発させて、粗生成物を得た。得られた粗生成物を、移動相A)0.1%ギ酸水溶液及びB)アセトニトリルを使用する分取HPLCを使用して精製した。画分を凍結乾燥して、(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルピペリジン-4-イルカーボネート(0.010g,5.36%)を白色固体として得た。
1H-NMR (400 MHz, DMSO): δ 8.399 (s, 0.5H-formic salt), 7.345 (d, 1H), 6.945(s, 1H), 6.908 (s, 1H), 4.701 (s, 1H), 4.536 (s, 1H), 3.525 (q, 2H), 2.998-2.981 (m, 4H), 2.752-2.714 (m, 5H), 2.664-2.599 (m, 4H), 2.398-2.385 (m, 4H), 1.927-1.888 (m, 5H), 1.827-1.669 (m, 4H), 1.604-1.550 (m, 7H), 1.358-1.257 (m, 21H), 0.881 (s, 1H) 及び 0.677 (s, 3H).
工程1:1-メチルピペリジン-4-イル(4-ニトロフェニル)カーボネートの調製
1H-NMR (400 MHz, DMSO): δ 8.356 (d, 2H), 7.612 (d, 2H), 5.101 (m, 1H), 2.724-2.682 (m, 4H), 1.938-1.894 (m, 2H) 及び 1.741-1.612 (m, 2H).
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル(1-メチルピペリジン-4-イル)カーボネートの調製
1H-NMR (400 MHz, DMSO): δ 7.234 (d, 1H), 6.954 (d, 1H), 6.912 (s, 1H), 4.639 (s, 1H), 4.543 (s, 1H), 3.561 (m, 1H), 2.876-2.841 (s, 2H), 2.743-2.623 (m, 4H), 2.407-2.229 (m, 4H), 2.217 (s, 4H), 1.919 (t, 5H), 1.823 (d, 2H), 1.651-1562 (m, 9H), 1.364-1.242 (m, 18H), 0.905 (dd, 1H) 及び 0.684 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.337 (d, 1H), 6.856 (d, 1H), 6.801 (s, 1H) 4.545 (d, 1H), 3.596 (t, 4H), 3.523-3.501 (m, 4H), 2.892-2.624 (m, 10H), 2.42-2.296 (m, 9H), 1.953-1.816 (m, 4H), 1.717-1.515 (m, 5H), 1.372-1.104 (m, 20H), 0.914 (d, 2H) 及び 0.697 (s, 3H).
1H-NMR (400 MHz, DMSO): 7.334 (d, 1H), 6.898 (d, 1H), 6.852 (s, 1H), 4.542 (d, 1H), 4.401 (s, 2H), 3.687-3.544 (m, 7H), 3.465-3.445 (m, 2H), 3.259 (s, 3H), 2.891-2.823 (m, 2H), 2.781-2.716 (m, 4H), 2.441-2.271 (m, 4H), 2.011-1.891 (m, 5H), 1.842 (d, 2H), 1.781-1.482 (m, 4H), 1.480-1.081 (m, 18H), 0.90 (d, 1H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.321 (d, 1H), 6.835 (d, 1H), 6.81 (s, 1H), 4.542 (d, 1H), 3.564 (s, 1H), 2.89-2.86 (m, 4H), 2.84-2.72 (m, 4H), 2.59 (t, 2H), 2.44-2.15 (m, 4H), 2.01-1.75 (m, 2H), 1.78-1.48 (m, 11H), 1.48-1.08 (m, 18H), 0.90 (d, 1H) 及び 0.69 (s, 3H).
HPLC純度:100%
1H-NMR (400 MHz, DMSO): δ 7.321 (d, 1H), 6.856 (d, 1H), 6.813 (s, 1H), 4.541 (d, 1H), 3.563 (d, 1H), 3.487-3.423 (m, 2H), 2.876-2.219 (m, 19H), 2.01-1.75 (m, 6H), 1.78-1.48 (m, 4H), 1.48-1.08 (m, 18H), 0.90 (d, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.321 (d, 1H), 6.843-6.542 (m, 2H), 4.542 (d, 1H), 3.551 (t, 1H), 2.896-2.726 (m, 6H), 2.691-2.581 (m, 5H), 2.441-2.261 (m, 4H), 2.194 (s, 6H), 1.951-1.895 (m, 4H), 1.841-1.491 (m, 6H), 1.448-1.081 (m, 19H), 0.90 (d, 2H) 及び 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.883 (d, 1H), 7.361-7.312 (m, 2H), 6.945 (d, 1H), 6.903 (s, 1H), 6.823 (d, 1H), 6.726 (s, 2H), 6.597 (t, 1H), 4.535 (s, 1H), 2.875-2.614 (m, 9H), 2.401-2.345 (m, 5H), 1.923-1.815 (m, 5H), 1.772 (s, 1H), 1.623-1.523 (m, 5H), 1.376-1. 248 (m, 22H), 0.914 (dd, 1H) 及び 0.696 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.267 (d, 1H), 6.831(d, 1H), 6.783 (s, 1H), 4.523 (d, 1H), 3.58 (s, 3H), 3.465 (m, 3H), 2.834-2.501 (m, 10H), 2.391-2.283 (m, 4H), 1.923-1.834 (m, 6H), 1.693-1.499 (m, 4H), 1.357-1.341 (m, 23H), 0.90 (d, 1H) 及び 0.69 (s, 3H).
工程1:ジベンジル((7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル)ホスフェートの調製
1H-NMR (400 MHz, DMSO): δ 7.384 (s, 10H), 7.291 (d, 1H), 6.921 (d, 1H), 6.827 (s, 1H), 5.168 (s, 2H), 5.148 (s, 2H), 4.559 (s, 1H), 4.534 (s, 1H), 3.558 (m, 2H), 2.891-2.871 (s, 2H), 2.832-2.623 (m, 4H), 2.456-2.249 (m, 4H), 1.956-1.801 (m, 5H), 1.694 (s, 1H), 1.632-1.492 (m, 4H), 1.525- 1.102 (m, 22H), 0.865 (dd, 1H) 及び 0.684 (s, 3H).
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルリン酸二水素の調製
1H-NMR (400 MHz, DMSO): δ 7.165 (d, 1H), 6.911 (d, 1H), 6.857 (s, 1H), 4.559 (s, 1H), 3.558-3.532 (m, 2H), 2.881-2.591 (m, 6H), 2.406-2.249 (m, 6H), 1.956-1.901 (m, 3H), 1.823-1.501 (m, 8H), 1.525-1.102 (m, 22H), 0.905 (dd, 1H) 及び 0.684 (s, 3H).
HPLC純度:93.06%
1H-NMR (400 MHz, DMSO): δ 7.05-6.80 (m, 3H), 4.47 (s, 1H), 3.52 (s, 1H), 2.83-2.63 (m, 5H), 2.36-2.19 (m, 4H), 1.89-1.77 (m, 4H), 1.59-1.23 (m, 25H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
1H-NMR (400 MHz, DMSO): δ 7.245 (d, 1H), 6.801 (d, 1H), 6.764 (s, 1H), 5.434 (s, 2H), 4.542 (d, 1H), 3.554(s, 1H), 2.846-2.812 (m, 2H), 2.751-2.716 (m, 5H), 2.331-2.201 (m, 6H), 2.011-1.891 (m, 6H), 1.842 (d, 2H), 1.781-1.482 (m, 4H), 1.480-1.281 (m, 33H), 0.901 (d, 1H) 及び 0.692 (s, 3H).
工程1:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル(tert-ブトキシカルボニル)-L-バリネートの調製
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルL-バリネート塩酸塩の調製
HPLC純度:97.12%
1H-NMR (400 MHz, DMSO): δ 8.59 (s, 3H), 7.38 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 4.52 (d, 1H), 4.17 (s, 1H), 3.56 (t, 1H), 2.77 (m, 6H), 2.37 (m, 5H), 1.91 (m, 4H), 1.57 (m, 4H), 1.23 (m, 25H), 0.89 (d, 1H) 及び 0.69 (s, 3H).
工程1:tert-ブチル4-(((((7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル)オキシ)カルボニル)オキシ)ピペリジン-1-カルボキシレート
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルピペリジン-4-イルカーボネート塩酸塩の調製
HPLC純度:99.85%
1H-NMR (400 MHz, DMSO): δ 8.56 (s, 2H), 7.31 (d, 1H), 6.96 (dd, 1H), 6.91 (d,1H), 4.93-4.87 (m, 1H), 4.50 (d, 1H), 3.57-3.52 (m, 1H), 3.21-3.19 (m, 2H), 3.13-3.07 (m, 2H), 2.88-2.80 (m, 2H), 2.76-2.62 (m, 4H), 2.42-2.22 (m, 4H), 2.13-2.07 (m, 2H), 19.4-1.79 (m, 6H), 1.71 (d, 1H), 1.64-1.46 (m, 4H), 1.38-1.16 (m, 18H), 0.80 (m,1 H) 及び 0.67 (s, 3H).
工程1:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル(4-ニトロフェニル)カーボネートの調製
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル4-メチル-1,4-ジアゼパン-1-カルボキシレート塩酸塩の調製
HPLC純度:99.06%
1H NMR (400 MHz, DMSO): δ 10.22 (s, 1H), 7.29 (d, 1H), 6.90-6.82 (m, 2H), 4.49 (s, 1H), 4.0-3.86 (m, 1H), 3.65-3.45 (m, 6H), 3.27-3.16 (m, 2H), 2.88-2.81 (m, 5H), 2.76-2.60 (m, 4H), 2.45-2.25 (m, 4H), 2.17-2.07 (m, 2H), 1.94-1.70 (m, 5H), 1.64-1.48(m, 4H), 1.38-1.19 (m, 18H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:97.14%
1H-NMR (400 MHz, DMSO): δ 10.1 (s, 1H), 7.36 (d, 1H), 6.94 (dd, 1H), 6.90 (d, 1H), 4.51 (s, 1H), 4.35 (s, 2H), 3.55 (t, 1H), 2.88-2.64 (m, 12H), 2.37-2.32 (m, 4H), 2.80-1.80 (m, 4H), 1.72 (d, 1H), 1.64-1.49 (m, 4H), 1.38-1.23 (m, 18H), 0.80 (m,1H) 及び 0.67 (s, 3H).
HPLC純度:95.43%。
1H-NMR (400 MHz, DMSO): δ 10.8 (s, 1H), 7.35 (d, 1H), 6.92 (d, 1H), 6.88 (s, 1H), 4.43 (s, 3H), 3.76 (s, 4H), 3.54 (d, 1H), 3.12 (s, 4H), 2.88-2.81 (m, 2H), 2.76-2.60 (m, 4H), 2.39-2.26 (m, 4H), 1.94-1.80 (m, 4H), 1.71 (d, 1H), 1.64-1.48 (m, 4H), 1.38-1.23 (m, 18H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:97.85%
1H-NMR (400 MHz, DMSO): δ 10.08 (s, 1H), 7.29 (d, 1H), 6.86 (dd, 1H), 6.82 (d, 1H), 4.50 (d, 1H), 4.13 (s, 2H) 3.54 (s, 1H), 3.41 (s, 2H), 3.1 (s, 2H), 2.88-2.59 (m, 8H), 2.50 (s, 3H), 2.40-2.38 (m, 4H), 1.94-1.80 (m, 4H), 1.71 (d, 1H), 1.62-1.48 (m, 4H), 1.38-1.19 (m, 18H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:92.30%
1H-NMR (400 MHz, DMSO): δ 9.45 (s, 1H), 7.29 (d, 1H), 6.83 (dd, 1H), 6.79 (s, 1H), 4.49-4.15 (m, 3H), 3.55 (t, 1H), 3.41-3.37 (m, 4H), 2.98-2.80 (m, 6H), 2.76-2.57 (m, 3H), 2.37-2.24 (m, 4H), 2.08 (d, 2H), 1.94-1.48 (m, 16H), 1.38-1.19 (m, 19H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:99.40%
1H-NMR (400 MHz, DMSO): δ 10.29 (s, 1H), 7.34 (d, 1H), 6.98 (d, 1H), 6.92 (s, 1H), 5.33 (s, 1H), 4.50 (s, 1H), 3.84-3.81 (m, 2H),3.55 (s, 1H), 3.16(s, 2H), 2.86-2.81 (m, 5H), 2.76-2.60 (m, 4H), 2.33-2.26 (m, 6H), 1.94-1.79 (m, 4H), 1.70 (s, 1H), 1.64-1.54 (m, 4H), 1.38-1.19 (m, 18H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:90.09%
1H-NMR (400 MHz, DMSO): δ 9.35 (s, 1H), 7.32 (d, 1H), 6.82 (dd, 1H), 6.80 (d, 1H), 4.50 (d, 1H), 3.53 (d, 1H), 3.32 (s, 2H), 2.88-2.81 (m, 4H), 2.76-2.62 (m, 8H), 2.42-2.25 (m, 5H), 1.96-1.46 (m, 14H), 1.38-1.19 (m, 18H), 0.80(m, 1H) 及び 0.67(s, 3H).
HPLC純度:97.43%
1H-NMR (400 MHz, DMSO): δ 9.77 (s, 1H), 7.32 (d, 1H), 6.86 (dd, 1H), 6.82 (d, 1H), 3.65 (s, 2H), 3.55(t, 1H), 3.32(s, 2H), 3.05 (d, 4H), 2.86-2.66 (m, 11H), 2.35-2.31 (m, 4H), 1.94-1.80 (m, 4H), 1.71 (d, 1H), 1.64-1.48 (m, 4H), 1.38-1.16 (m, 18H), 0.80 (m, 1H) 及び 0.67 (s, 3H).
工程1:ジベンジル((((7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル)オキシ)メチル)ホスフェートの調製
工程2:(((7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル)オキシ)メチル二水素ホスフェートの調製
HPLC純度:66.6%
工程1:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル2-((tert-ブトキシカルボニル)アミノ)-2-メチルプロパノエートの調製
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル2-アミノ-2-メチルプロパノエート塩酸塩の調製
HPLC純度:96.43%
1H-NMR (400 MHz, DMSO): δ 8.61(s, 3H), 7.38 (d, 1H), 6.94 (d, 1H), 6.87 (s, 1H),4.51 (d, 1H), 3.58-3.53 (m, 1H), 2.88 2.61 (m, 6H),2.42-2.25 (m, 4H), 1.94-1.79 (m, 4H), 1.71 (s, 1H), 1.62-1.46 (m, 10H), 1.38-1.18 (m, 18H), 0.89 (m, 1H) 及び 0.68 (s, 3H).
HPLC純度:97.27%
1H NMR (400 MHz, DMSO): δ 12.983 (bs, 1H), 9.026 (bs, 1H), 7.068 (d, 1H), 6.532-6.300 (m, 2H), 4.701 (t, 1H), 2.898-2.608 (m, 6H), 2.456-2.344 (m, 3H), 2.277-2.129 (m, 3H), 1.959-1.883 (m, 2H), 1.831-1.803 (m, 1H), 1.679-1.487 (m, 6H), 1.459-1.385 (m, 14H), 0.983-0.896 (m, 1H) 及び 0.853 (s, 3H).
HPLC純度:98.56%
1H NMR (400 MHz, DMSO): δ 7.32 (d, 1H), 6.83 (dd, 2H), 4.53 (s, 1H), 3.56 (s, 1H), 2.89-2.82 (m, 2H), 2.78-2.64 (m, 6H), 2.61-2.57 (m, 3H), 2.33-2.30 (m, 6H), 1.93 (t, 3H), 1.89-1.82 (m, 3H), 1.71 (bs, 1H), 1.63-1.51 (m, 3H), 1.51 (bs, 1H), 1.36-1.25 (m, 20H), 0.89 (s, 1H) 及び 0.68 (s, 3H).
HPLC純度:99.86%
1H NMR (400 MHz, DMSO): δ 7.32 (d, 1H), 6.95 (d, 1H), 6.90 (s, 1H), 5.08 (m, 1H), 4.50 (d, 1H), 3.54 (m, 1H), 2.86-2.76 (m, 2H), 2.76-2.59 (m, 7H), 2.35-2.31 (m, 9H), 1.92-1.79 (m, 5H), 1.71 (s, 1H), 1.62-1.46 (m, 4H), 1.38-1.16 (m, 18H), 0.89 (m, 1H) 及び 0.67 (s, 3H).
工程1:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル(4-ニトロフェニル)カーボネートの調製
工程2:(7R,8R,9S,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-((4,4,5,5,5-ペンタフルオロペンチル)スルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イル(1-メチルピペリジン-4-イル)カルバメートの調製
HPLC純度:99.25%
1H NMR (400 MHz, DMSO): δ 7.65 (d, 1H), 7.25 (d, 1H), 6.80 (q, 1H), 6.75 (d, 1H), 4.49 (d, 1H), 3.55 (m, 1H), 3.23 (S, 1H) 2.88-2.60 (m, 7H), 2.43-2.23 (m, 4H), 2.13 (s, 3H), 1.93-1.67 (m, 10H), 1.63-1.15 (m, 24H), 0.90 (m, 1H) 及び 0.67 (s, 3H).
HPLC純度:98.95%
1H NMR (400 MHz, DMSO): δ 10.51 (s, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 6.90 (s, 1H), 4.50 (s, 3H), 3.56 (m, 3H), 3.21 (d, 2H), 2.76 (m, 6H), 2.35 (m, 4H), 1.88 (m, 8H), 1.72 (d, 1H), 1.57 (m, 4H), 1.28 (m, 18H), 0.89 (t, 1H) 及び 0.68 (s, 3H).
HPLC:97.06%
1H NMR (400 MHz, DMSO): δ 7.33 (d, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 4.50 (d, 1H), 4.38 (s, 2H), 3.68.3.66 (m, 2H), 3.58-3.49 (m, 9H), 3.43-3.41 (m, 2H), 3.23 (s, 3H), 2.87-2.62 (m, 6H), 2.42-2.25 (m, 4H), 1.94-1.79 (m,4H), 1.71 (s, 1H), 1.63-1.48 (m, 4H), 1.38-1.18 (m, 18H), 0.90 (m, 1H) 及び 0.67 (s, 3H).
HPLC:97.74%
1H NMR (400 MHz, DMSO): δ 7.31 (d, 1H), 6.84 (d, 1H), 6.77 (s, 1H),4.50 (d, 1H), 3.72 (t, 2H), 3.54-3.48 (m, 15H), 3.42-3.41 (m, 2H), 3.22 (s, 3H), 2.87-2.67 (m, 8H), 2.37-2.38 (m, 4H), 1.94-1.79 (m, 4H), 1.71 (s, 1H), 1.63-1.48 (m, 4H), 1.38-1.1 8 (m, 18H), 0.90 (m, 1H) 及び 0.67 (s, 3H).
HPLC:96.83%
1H NMR (400 MHz, DMSO): δ 7.31 (d, 1H), 6.84 (d, 1H), 6.77 (s, 1H), 4.50 (d, 1H), 3.74 (t, 2H), 3.55-3.48 (m, 22 H), 3.42-3.40 (m,2H), 3.23 (s, 3H), 2.88-2.64 (m, 8H), 2.39-2.25 (m, 5H), 1.94-1.79 (m, 4H), 1.71 (s, 1H), 1.62-1.48 (m ,4H), 1.38-1.18 (m, 18H), 0.90 (m, 1H) 及び 0.67 (s, 3H).
HPLC:99.91%
1H NMR (400 MHz, DMSO): δ 7.31 (d, 1H), 6.84 (d, 1H), 6.77 (s, 1H),4.49 (d, 1H), 3.74 (t, 2H), 3.55-3.48 (m, 18H), 3.42-3.40 (m, 2H), 3.23 (s, 3H), 2.88-2.62 (m, 8H), 2.37-2.28 (m, 5H), 1.94-1.79 (m, 4H), 1.72 (s, 1H), 1.62-1.48 (m, 4H), 1.38-1.16 (m, 18H), 0.90 (m, 1H) 及び 0.67 (s, 3H).
テトラヒドロフラン(10.0ml)中のフルベストラント(1.0g)の攪拌溶液に、窒素ガス雰囲気下、カリウムtert-ブトキシド(0.28g)を室温で添加し、この反応混合物を70℃に5分間で加熱した。テトラヒドロフラン(1ml)中のジ-tert-ブチルクロロメチルホスフェート(0.60g)を滴下し、この反応混合物を70℃で3~4時間撹拌した。反応を、TLCでモニターした。反応混合物を室温に冷却し、反応混合物をブライン溶液(10ml)、酢酸エチル(20ml)で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下濃縮した。このようにして、ジ-tert-ブチル((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)メチルホスフェートをゴム状固体として(1.3g,95.58%)粗生成物を単離した。LCMS:81.63%(m/z:830.6、831.6、[M+1]+、[M+2]+)。粗生成物を次工程に使用した。
工程2:((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)メチル二水素ホスフェート
HPLC純度:96.33%
1H NMR (400 MHz , DMSO-d6): 1H NMR (400 MHz, DMSO) δ 7.13 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 5.30 (d, J = 4.6 Hz, 2H), 3.61 - 3.47 (m, 2H), 2.89 - 2.59 (m, 6H), 2.39 - 2.16 (m, 4H), 1.90 (dd, J = 15.5, 7.9 Hz, 3H), 1.78 (d, J = 11.5 Hz, 1H), 1.70 - 1.41 (m, 5H), 1.21 (t, J = 25.0 Hz, 14H), 0.88 (s, 1H), 0.65 (s, 3H).
テトラヒドロフラン(10.0ml)中の(S)-tert-ブチル2-アミノ-3-メチルブタノエート塩酸塩(0.38g)の撹拌溶液に、窒素ガス雰囲気下、室温で、炭酸ビス(4-ノトロフェニル)(0.56g)を添加し、この反応混合物を0℃に冷却した。N,N-ジイソプロピルエチルアミン(0.7g)を滴下し、この反応混合物を室温で一晩撹拌した。この反応混合物に、フルベストラント(1.0g)、N,N-ジイソプロピルエチルアミン(0.7g)を添加し、この反応混合物を再度室温で一晩撹拌した。反応を、TLCでモニターした。反応混合物をブライン溶液(10ml)及び酢酸エチル(20ml)で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下濃縮した。単離した粗生成物を、移動相A)10mモル重炭酸アンモニウム水溶液及びB)100%アセトニトリルを使用する分取HPLCで精製した。生成物画分を凍結乾燥して、(2S)-tert-ブチル2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-メチルブタノエートを白色固体として得た(0.65g,48.8%)。
HPLC純度:99.13%
工程2:(2S)-2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-メチルブタン酸の調製
HPLC純度:99.32%
1H NMR (400 MHz , DMSO-d6): 1H NMR (400 MHz, DMSO) δ 7.64 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 4.50 (s, 1H), 3.78 (s, 1H), 3.53 (s, 1H), 2.80 (d, J = 8.4 Hz, 2H), 2.76 - 2.58 (m, 4H), 2.39 - 2.20 (m, 5H), 2.08 (d, J = 6.2 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.79 (d, J = 12.4 Hz, 1H), 1.66 (s, 1H), 1.54 (dd, J = 25.2, 16.4 Hz, 4H), 1.41 - 1.07 (m, 17H), 1.01 (d, J = 6.1 Hz, 2H), 0.88 (d, J = 5.8 Hz, 7H), 0.65 (s, 3H).
テトラヒドロフラン(8.0ml)中の(S)-tert-ブチル2-アミノ-3-フェニルプロパノエート(0.24g)の撹拌溶液に、窒素ガス雰囲気下、室温で、炭酸ビス(4-ノトロフェニル)(0.28g)を添加し、この反応混合物を0℃に冷却した。N,N-ジイソプロピルエチルアミン(0.35g)を滴下し、この反応混合物を室温で一晩撹拌した。この反応混合物に、フルベストラント(0.5g)、N,N-ジイソプロピルエチルアミン(0.35g)を添加し、この反応混合物を再度室温で一晩撹拌した。反応を、TLCでモニターした。反応混合物をブライン溶液(10ml)及び酢酸エチル(20ml)で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、減圧下濃縮した。単離した粗生成物を、移動相A)10mモル重炭酸アンモニウム水溶液及びB)100%アセトニトリルを使用する分取HPLCで精製した。生成物画分を凍結乾燥して、(2S)-tert-ブチル2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-フェニルプロパノエートを白色固体として得た(0.27g,33.96%)。
工程2:(2S)-2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-フェニルプロパン酸の調製
HPLC純度:98.16%
1H NMR (400 MHz , DMSO-d6): 1H NMR (400 MHz, DMSO) δ 7.37 (s, 1H), 7.23 (s, 5H), 7.19 - 7.14 (m, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.63 (s, 1H), 4.50 (s, 1H), 3.98 (s, 1H), 3.52 (s, 2H), 3.10 (d, J = 9.5 Hz, 1H), 2.92 - 2.78 (m, 3H), 2.77 - 2.59 (m, 6H), 2.39 - 2.19 (m, 3H), 1.95 - 1.83 (m, 3H), 1.78 (d, J = 12.1 Hz, 1H), 1.66 (s, 1H), 1.54 (dd, J = 25.2, 9.6 Hz, 4H), 1.23 (t, J = 35.2 Hz, 17H), 0.86 (s, 1H), 0.64 (s, 3H).
HPLC純度:99.12%
1H NMR (400 MHz , DMSO-d6): δ 7.106-7.085 (d, J = 8.3 Hz, 1H), 6.832-6.806 (d, J = 10.9 Hz, 2H), 4.866-4.843 (d, J = 9.2 Hz, 2H), 4.509-4.497 (d, J = 4.9 Hz, 1H), 3.568-3.543 (m, 4H), 3.205 (s, 3H), 2.873-2.632 (m, 7H), 2.428-2.191 (m, 5H), 1.948-1.889 (m, 4H), 1.815-1.784 (d, J = 12.3 Hz, 1H), 1.685 (s, 1H), 1.66-1.605 (m, 2H), 1.547-1.495 (d, J = 9.8 Hz, 2H), 1.462-1.32 (m, 4H), 1.374-1.243 (s, 11H), 1.174 (s, 2H), 0.920 (s, 1H), 0.670 (s, 3H).
HPLC純度:99.77%
1H NMR (400 MHz , DMSO-d6): δ 7.107-7.086 (d, J = 8.4 Hz, 1H), 6.788 (s, 1H), 6.759 (s, 1H), 5.383-5.353 (d, J = 12.8 Hz, 2H), 4.724-4.679 (m, 1H), 4.515 (s, 1H), 3.589-3.534 (m, 2H), 3.078-3.023 (q, J = 14.8 Hz, 1H), 2.856-2.784 (m, 1H), 2.758 - 2.621 (m, 6H), 2..381-2.170 (m, 5H), 1.925 - 1.863 (m, 3H), 1.781-1.752 (d, , J = 11.6 Hz, 1H), 1.633-1.587 (m, 1H), 1.589-1.553 (m, 2H), 1.49-1.144 (m, 2H), 1.324-1.289 (m, 4H), 1.222 - 1.19 (m, 16H), 1.01-1.123 (q, J = 6.4 Hz, 6H), 0.854 (s,1H), 0.621 (s, 3H).
N,N-ジメチルホルムアミド(1.0ml)中の((2S)-2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-メチルブタン酸(0.3g)の攪拌溶液に、窒素ガス雰囲気下、室温でヒドロキシベンゾトリアゾール(0.108g)、EDC-HCl(0.084g)を添加し、この反応混合物を0℃に冷却した。(S)-tert-ブチル2-アミノ-3-フェニルプロパノエート塩酸塩(0.113g)及びN,N-ジイソプロピルエチルアミン(0.155g)を滴下し、この反応混合物を室温で2日間撹拌した。反応を、TLC及びLCMSでモニターした。反応混合物を氷水(10ml)で希釈し、酢酸エチルで抽出した。有機層を無水Na2SO4で乾燥し、減圧下濃縮した。単離した粗生成物を、移動相A)10mモル重炭酸アンモニウム水溶液及びB)100%アセトニトリルを用いる分取HPLCで精製した。生成物画分を凍結乾燥して、(2S)-tert-ブチル2-((2S)-2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-メチルブタナミド)-3-フェニルプロパノエートを白色固体として得た(0.105g,27.56%)。
HPLC純度:99.23%
工程2:(2S)-2-((2S)-2-(((7R,8R,13S,14S,17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)カルボニルアミノ)-3-メチルブタナミド)-3-フェニルプロパン酸の調製
HPLC純度:95.27%
1H NMR (400 MHz , DMSO-d6): δ 7.942 (s, 1H), 7.775 (s, 1H), 7.268-7.249 (d, J = 8.3 Hz, 1H), 7.19 (bs, 5H), 6.811 (s, 1H), 6.747 (s, 1H), 4.527 (s, 1H), 4.271 (s, 1H), 3.796 (s, 1H), 3.543 (s, 1H), 3.040 (s, 1H), 2.932 (m, 1H), 2.823 (m, 2H), 2.726-2.672 (m, 4H), 2.395-2.263 (m, 5H), 1.958-1.878 (m, 4H), 1.815-1.789 (d, J = 10.2 Hz, 1H), 1.685 (s, 1H), 1.589 (s, 3H), 1.487 (s, 1H), 1.342 (s, 4H), 1.11-1.3 (m, 11H), 0.85 (s, 1H), 0.837-0.823 (d, J = 5.6 Hz, 6H), 0.666 (s, 3H).
LCMS:27.87%(m/z:799.5、[M+1]+、821.5、[M+23]+
HPLC純度:27.89%
工程2:(2S)-1-(ヒドロキシ((7R、8R、13S、14S、17S)-17-ヒドロキシ-13-メチル-7-(9-(4,4,5,5,5-ペンタフルオロペンチルスルフィニル)ノニル)-7,8,9,11,12,13,14,15,16,17-デカヒドロ-6H-シクロペンタ[a]フェナントレン-3-イルオキシ)ホスホリル)ピロリジン-2-カルボン酸の調製
LCMS:43.11%(m/z:785.5、[M+1]+、807.5、[M+23]+
HPLC:43.11%
LCMS:20.79%(m/z:730.3、[M+1]+、752.3、[M+23]+
HPLC:20.79%
プロドラッグのフルベストラントへのインビボ変換について、プロドラッグを経口投与されたマウスのマウス薬物動態研究で評価した。比較のため、経口用フルベストラントを用いたマウスの薬物動態研究を実施した。研究デザイン及び測定したフルベストラントへの曝露を、表3にまとめる。簡潔に述べると、3頭の雄のスイスアルビノマウスの群に(1)90%PBS(pH7.4)、10%エタノール中の化合物(I-t)又は(2)90%PBS(pH7.4)、10%エタノール中のフルベストラントを経口投与した。血液サンプルを、ヘパリンを含む回収チューブに24時間に亘って複数の時点で回収した。血漿を血液から分離し、内部標準を含むアセトニトリルでタンパク質を沈殿させ、ボルテックスし、遠心分離した。これから、上清を分離し、メタノール:水(1:1)で希釈し、化合物(I-t)とフルベストラントの定量のためにLC-MS分析を行った。化合物(I-t)は、所定用量でマウス血漿に検出されなかった。
表3:マウスにおけるインビボ曝露
Claims (23)
- 式I-Aの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれかである化合物。
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。) - 式IIの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれかである化合物。
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
- 下記式で表される化合物III、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物IV、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物V、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物VI、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物VII、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。) - 下記式で表される化合物VIII、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物XV、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物III、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物IV、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物V、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物VI、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物VII、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物VIII、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記式で表される化合物XV、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物のいずれか、を含む請求項1又は2に記載の化合物。
- 下記からなる群から選択されることを特徴とする化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩又は溶媒和物。
- 請求項1に定義される式I-Aの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩及び溶媒和物の少なくともいずれかと;
薬学的に許容される賦形剤と;を含むことを特徴とする医薬組成物。 - 請求項2に定義される式IIの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩及び溶媒和物の少なくともいずれかと;
薬学的に許容される賦形剤と;を含むことを特徴とする医薬組成物。 - 式I-Aの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩及び溶媒和物の少なくともいずれかを含むことを特徴とする、***又は生殖器官の良性又は悪性疾患治療薬。
Aは、水素、及び下記
Rは、下記:
但し、Aが水素であり、R12置換の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
h)水素(但し、Rが水素である場合、Aは水素ではない)からなる群から選択される。) - 式IIの化合物、それらのエナンチオマー、ジアステレオマー、ラセミ体、薬学的に許容される塩及び溶媒和物の少なくともいずれかを含むことを特徴とする、***又は生殖器官の良性又は悪性疾患治療薬。
Rは、下記:
但し、R12の1つがアルキル及びアリールから選択される場合、他のR12置換は水素である。);
- 請求項20に定義される式I-Aの化合物の少なくともいずれかと;
薬学的に許容される賦形剤と;を含むことを特徴とする***又は生殖管の良性又は悪性疾患治療用組成物。 - 請求項21に定義される式IIの化合物の少なくともいずれかと;
薬学的に許容される賦形剤と;を含むことを特徴とする***又は生殖管の良性又は悪性疾患治療用組成物。
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WO2022034587A1 (en) * | 2020-08-10 | 2022-02-17 | Tnik Therapeutics Ltd | Traf2- AND Nck-INTERACTING KINASE (TNIK) INHIBITORS AND USES THEREOF |
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JP2003528919A (ja) | 2000-04-05 | 2003-09-30 | アストラゼネカ アクチボラグ | 抵抗性乳癌の治療におけるフルベストラントの使用 |
CN103421069A (zh) | 2013-05-23 | 2013-12-04 | 中国海洋大学 | 氟维司群磷酸酯衍生物及其制备方法和应用 |
JP2015511606A (ja) | 2012-03-31 | 2015-04-20 | リポント ファーマシューティカルズ インコーポレイテッド | 乳酸エステルをベースとするフルベストラント又はその誘導体の油性製剤およびその製造方法 |
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WO2019050850A1 (en) | 2017-09-05 | 2019-03-14 | Primetime Life Sciences, Llc | BIGUANIDINE DERIVATIVES OF THERAPEUTIC AGENTS, AND PREPARATION METHODS AND METHODS OF USING SAME |
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CN104936971B (zh) * | 2013-04-18 | 2017-10-13 | 西安力邦医药科技有限责任公司 | 具有抗癌活性的7‑α‑[9‑(4,4,5,5,5‑五氟戊基亚硫酰基)壬基]‑雌甾‑1,3,5(10)‑三烯‑3,17β‑二醇的酯类衍生物及其制备方法 |
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JP2003528919A (ja) | 2000-04-05 | 2003-09-30 | アストラゼネカ アクチボラグ | 抵抗性乳癌の治療におけるフルベストラントの使用 |
JP2015511606A (ja) | 2012-03-31 | 2015-04-20 | リポント ファーマシューティカルズ インコーポレイテッド | 乳酸エステルをベースとするフルベストラント又はその誘導体の油性製剤およびその製造方法 |
CN103421069A (zh) | 2013-05-23 | 2013-12-04 | 中国海洋大学 | 氟维司群磷酸酯衍生物及其制备方法和应用 |
WO2019050850A1 (en) | 2017-09-05 | 2019-03-14 | Primetime Life Sciences, Llc | BIGUANIDINE DERIVATIVES OF THERAPEUTIC AGENTS, AND PREPARATION METHODS AND METHODS OF USING SAME |
CN108159055A (zh) | 2018-01-04 | 2018-06-15 | 西安力邦医药科技有限责任公司 | 治疗乳腺癌的长效递药***、其制备方法及应用 |
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JP2021525278A (ja) | 2021-09-24 |
AU2019274815A1 (en) | 2021-01-21 |
JP2024016210A (ja) | 2024-02-06 |
CA3101421C (en) | 2024-06-18 |
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