EA012262B1 - Селективные модуляторы рецепторов эстрогена для лечения вазомоторных симптомов - Google Patents

Info

Publication number

EA012262B1

EA012262B1 EA200601353A EA200601353A EA012262B1 EA 012262 B1 EA012262 B1 EA 012262B1 EA 200601353 A EA200601353 A EA 200601353A EA 200601353 A EA200601353 A EA 200601353A EA 012262 B1 EA012262 B1 EA 012262B1

Authority

EA

Eurasian Patent Office

Prior art keywords

mmol

added

ethoxy

phenyl

piperidin

Prior art date

2004-01-22

Links

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• Global Dossier
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• 208000024891 symptom Diseases 0.000 title claims abstract description 30
• 230000001457 vasomotor Effects 0.000 title claims abstract description 20
• 238000011282 treatment Methods 0.000 title claims description 18
• 229940095743 selective estrogen receptor modulator Drugs 0.000 title abstract description 3
• 239000000333 selective estrogen receptor modulator Substances 0.000 title abstract description 3
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• 239000002253 acid Substances 0.000 claims abstract description 26
• 150000001875 compounds Chemical class 0.000 claims description 248
• -1 ΝΚ 5 Β 5α Chemical group 0.000 claims description 115
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
• 229910052757 nitrogen Inorganic materials 0.000 claims description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 206010060800 Hot flush Diseases 0.000 claims description 17
• 238000002360 preparation method Methods 0.000 claims description 17
• 208000033830 Hot Flashes Diseases 0.000 claims description 16
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical group 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims 5
• 230000000996 additive effect Effects 0.000 claims 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 4
• 229910052731 fluorine Inorganic materials 0.000 claims 4
• 239000011737 fluorine Substances 0.000 claims 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
• 229910052760 oxygen Inorganic materials 0.000 claims 2
• GMBXBKNMMIWUED-UHFFFAOYSA-N n-(2,2,6,6-tetramethylpiperidin-4-yl)-3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]propanamide Chemical compound C1C(C)(C)NC(C)(C)CC1NCCC(=O)NC1CC(C)(C)NC(C)(C)C1 GMBXBKNMMIWUED-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 774
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 615
• 239000000203 mixture Substances 0.000 description 197
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• 239000011541 reaction mixture Substances 0.000 description 134
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• 150000002500 ions Chemical class 0.000 description 98
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• 238000004544 sputter deposition Methods 0.000 description 90
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 81
• XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 78
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 76
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 76
• 238000005341 cation exchange Methods 0.000 description 70
• 239000002904 solvent Substances 0.000 description 69
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
• 239000000047 product Substances 0.000 description 58
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
• 229910052938 sodium sulfate Inorganic materials 0.000 description 54
• 235000011152 sodium sulphate Nutrition 0.000 description 54
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 53
• 239000012071 phase Substances 0.000 description 52
• 239000010410 layer Substances 0.000 description 50
• 229920006395 saturated elastomer Polymers 0.000 description 49
• 239000012458 free base Substances 0.000 description 47
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 45
• 235000017557 sodium bicarbonate Nutrition 0.000 description 45
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 43
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 43
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 41
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
• 229910021529 ammonia Inorganic materials 0.000 description 39
• 238000000034 method Methods 0.000 description 35
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
• 239000012267 brine Substances 0.000 description 32
• 239000000460 chlorine Substances 0.000 description 32
• 239000003921 oil Substances 0.000 description 32
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 239000012141 concentrate Substances 0.000 description 28
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
• 235000019341 magnesium sulphate Nutrition 0.000 description 28
• 239000012299 nitrogen atmosphere Substances 0.000 description 28
• 239000007787 solid Substances 0.000 description 28
• 238000003756 stirring Methods 0.000 description 28
• YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 27
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 24
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
• 239000007864 aqueous solution Substances 0.000 description 23
• 239000002808 molecular sieve Substances 0.000 description 23
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 22
• 238000007792 addition Methods 0.000 description 21
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 21
• 239000012047 saturated solution Substances 0.000 description 21
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 20
• 238000005160 1H NMR spectroscopy Methods 0.000 description 19
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 18
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 18
• 239000000725 suspension Substances 0.000 description 18
• NRPNUEPMRUIRMD-UHFFFAOYSA-N [2-(2,5-difluorophenyl)-6-hydroxynaphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C=1C(F)=CC=C(F)C=1C=1C=CC2=CC(O)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 NRPNUEPMRUIRMD-UHFFFAOYSA-N 0.000 description 16
• 238000004587 chromatography analysis Methods 0.000 description 16
• YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 235000019270 ammonium chloride Nutrition 0.000 description 15
• 229940011871 estrogen Drugs 0.000 description 15
• 239000000262 estrogen Substances 0.000 description 15
• 239000000284 extract Substances 0.000 description 15
• 241000700159 Rattus Species 0.000 description 14
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 14
• 229910052763 palladium Inorganic materials 0.000 description 14
• 239000012043 crude product Substances 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 13
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 12
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
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• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• 238000003818 flash chromatography Methods 0.000 description 12
• 239000012312 sodium hydride Substances 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 11
• 238000002156 mixing Methods 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 10
• 238000004458 analytical method Methods 0.000 description 10
• 238000003821 enantio-separation Methods 0.000 description 10
• 229910052744 lithium Inorganic materials 0.000 description 10
• 229910000160 potassium phosphate Inorganic materials 0.000 description 10
• 235000011009 potassium phosphates Nutrition 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
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• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
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• 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 8
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• 206010048010 Withdrawal syndrome Diseases 0.000 description 8
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• QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 8
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
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• 238000012360 testing method Methods 0.000 description 8
• QQLRSCZSKQTFGY-UHFFFAOYSA-N (2,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1F QQLRSCZSKQTFGY-UHFFFAOYSA-N 0.000 description 7
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 7
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• JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 description 7
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• LKUMXVRHPHWJPN-UHFFFAOYSA-N [6-hydroxy-2-(2,3,5-trifluorophenyl)naphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C=1C(F)=CC(F)=C(F)C=1C=1C=CC2=CC(O)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 LKUMXVRHPHWJPN-UHFFFAOYSA-N 0.000 description 6
• TWIGSNOBRLPNEM-UHFFFAOYSA-N [6-hydroxy-2-(2,4,6-trifluorophenyl)naphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound FC=1C=C(F)C=C(F)C=1C=1C=CC2=CC(O)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 TWIGSNOBRLPNEM-UHFFFAOYSA-N 0.000 description 6
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
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• BNMVVSDCDYQUDB-UHFFFAOYSA-N [2-(2,4-difluorophenyl)-6-methoxynaphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C=1C=C(F)C=C(F)C=1C=1C=CC2=CC(OC)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 BNMVVSDCDYQUDB-UHFFFAOYSA-N 0.000 description 5
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• UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 5
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