UA85862C2 - Селективні модулятори рецепторів естрогену для лікування вазомоторних симптомів - Google Patents
Селективні модулятори рецепторів естрогену для лікування вазомоторних симптомів Download PDFInfo
- Publication number
- UA85862C2 UA85862C2 UAA200607867A UAA200607867A UA85862C2 UA 85862 C2 UA85862 C2 UA 85862C2 UA A200607867 A UAA200607867 A UA A200607867A UA A200607867 A UAA200607867 A UA A200607867A UA 85862 C2 UA85862 C2 UA 85862C2
- Authority
- UA
- Ukraine
- Prior art keywords
- phenyl
- mmol
- ethoxy
- mixture
- dichloromethane
- Prior art date
Links
- 208000024891 symptom Diseases 0.000 title abstract description 15
- 230000001457 vasomotor Effects 0.000 title abstract description 10
- 229940095743 selective estrogen receptor modulator Drugs 0.000 title abstract 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 title abstract 2
- 238000011282 treatment Methods 0.000 title description 7
- 150000003839 salts Chemical class 0.000 abstract description 26
- 239000002253 acid Substances 0.000 abstract description 25
- 206010060800 Hot flush Diseases 0.000 abstract description 5
- 208000033830 Hot Flashes Diseases 0.000 abstract description 3
- 206010029410 night sweats Diseases 0.000 abstract description 2
- 230000036565 night sweats Effects 0.000 abstract description 2
- 230000009245 menopause Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 780
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 565
- 239000000203 mixture Substances 0.000 description 300
- 150000001875 compounds Chemical class 0.000 description 241
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 195
- 239000000243 solution Substances 0.000 description 187
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 150
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 143
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 137
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 133
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 129
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 125
- 239000012044 organic layer Substances 0.000 description 121
- 239000011541 reaction mixture Substances 0.000 description 119
- 239000000741 silica gel Substances 0.000 description 116
- 229910002027 silica gel Inorganic materials 0.000 description 116
- 238000003756 stirring Methods 0.000 description 90
- 238000001819 mass spectrum Methods 0.000 description 89
- 239000000047 product Substances 0.000 description 89
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 78
- 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
- -1 for example Chemical group 0.000 description 74
- 239000002904 solvent Substances 0.000 description 74
- 150000002500 ions Chemical class 0.000 description 73
- 239000010410 layer Substances 0.000 description 73
- 238000004544 sputter deposition Methods 0.000 description 73
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 72
- 239000012141 concentrate Substances 0.000 description 67
- 235000008504 concentrate Nutrition 0.000 description 67
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 61
- 235000017557 sodium bicarbonate Nutrition 0.000 description 61
- 239000007864 aqueous solution Substances 0.000 description 59
- 229920006395 saturated elastomer Polymers 0.000 description 57
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- 229910052938 sodium sulfate Inorganic materials 0.000 description 56
- 235000011152 sodium sulphate Nutrition 0.000 description 56
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- 239000012071 phase Substances 0.000 description 52
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 51
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 50
- 239000012458 free base Substances 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 48
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 43
- 238000004587 chromatography analysis Methods 0.000 description 39
- 239000012299 nitrogen atmosphere Substances 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 36
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 35
- 238000000034 method Methods 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 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 33
- 238000010828 elution Methods 0.000 description 32
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- 239000003921 oil Substances 0.000 description 31
- 238000010992 reflux Methods 0.000 description 31
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
- 239000012267 brine Substances 0.000 description 30
- 239000002808 molecular sieve Substances 0.000 description 29
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 29
- 239000000284 extract Substances 0.000 description 27
- 239000012047 saturated solution Substances 0.000 description 27
- 229910021529 ammonia Inorganic materials 0.000 description 25
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000000725 suspension Substances 0.000 description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 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 16
- 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 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 15
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 239000012074 organic phase Substances 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 11
- 238000000889 atomisation Methods 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 229940011871 estrogen Drugs 0.000 description 9
- 239000000262 estrogen Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 229910000160 potassium phosphate Inorganic materials 0.000 description 9
- 235000011009 potassium phosphates Nutrition 0.000 description 9
- 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 9
- 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
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 238000003821 enantio-separation Methods 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 229960005181 morphine Drugs 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229910000085 borane Inorganic materials 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000011068 loading method Methods 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000002604 ultrasonography Methods 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- DBZAICSEFBVFHL-UHFFFAOYSA-N (2,6-difluorophenyl)boronic acid Chemical compound OB(O)C1=C(F)C=CC=C1F DBZAICSEFBVFHL-UHFFFAOYSA-N 0.000 description 4
- XSMLLZPSNLQCQU-UHFFFAOYSA-N 1-bromo-2,3,5-trifluorobenzene Chemical compound FC1=CC(F)=C(F)C(Br)=C1 XSMLLZPSNLQCQU-UHFFFAOYSA-N 0.000 description 4
- CNAXDCSHYHIOGW-UHFFFAOYSA-N 2-bromo-1,3,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(Br)=C1F CNAXDCSHYHIOGW-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- DMPWMEXBCMEKDA-UHFFFAOYSA-N 4-[2-(azepan-1-yl)ethoxy]phenol Chemical compound C1=CC(O)=CC=C1OCCN1CCCCCC1 DMPWMEXBCMEKDA-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- CDEIGFNQWMSEKG-UHFFFAOYSA-M chloro-[4-[(2-hydroxynaphthalen-1-yl)diazenyl]phenyl]mercury Chemical compound OC1=CC=C2C=CC=CC2=C1N=NC1=CC=C([Hg]Cl)C=C1 CDEIGFNQWMSEKG-UHFFFAOYSA-M 0.000 description 4
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 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 4
- 229960004127 naloxone Drugs 0.000 description 4
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 4
- 229940117969 neopentyl glycol Drugs 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 210000004291 uterus Anatomy 0.000 description 4
- IPEIGKHHSZFAEW-UHFFFAOYSA-N (2,4,6-trifluorophenyl)boronic acid Chemical compound OB(O)C1=C(F)C=C(F)C=C1F IPEIGKHHSZFAEW-UHFFFAOYSA-N 0.000 description 3
- QQLRSCZSKQTFGY-UHFFFAOYSA-N (2,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1F QQLRSCZSKQTFGY-UHFFFAOYSA-N 0.000 description 3
- KTOJGSDLJNUAEP-UHFFFAOYSA-N (2,5-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC=C1F KTOJGSDLJNUAEP-UHFFFAOYSA-N 0.000 description 3
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53844204P | 2004-01-22 | 2004-01-22 | |
| US53834204P | 2004-01-22 | 2004-01-22 | |
| PCT/US2005/000020 WO2005073204A1 (en) | 2004-01-22 | 2005-01-18 | Selective estrogen receptor modulators for the treatment of vasomotor symptoms |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| UA85862C2 true UA85862C2 (uk) | 2009-03-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| UAA200607867A UA85862C2 (uk) | 2004-01-22 | 2005-01-18 | Селективні модулятори рецепторів естрогену для лікування вазомоторних симптомів |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US20090023917A1 (https=) |
| EP (1) | EP1709021B1 (https=) |
| JP (1) | JP4909086B2 (https=) |
| KR (2) | KR100849559B1 (https=) |
| CN (1) | CN102250042A (https=) |
| AT (1) | ATE476428T1 (https=) |
| AU (1) | AU2005207821B2 (https=) |
| BR (1) | BRPI0506721A (https=) |
| CA (1) | CA2551956C (https=) |
| CR (1) | CR8517A (https=) |
| DE (1) | DE602005022673D1 (https=) |
| EA (2) | EA012262B1 (https=) |
| EC (1) | ECSP066711A (https=) |
| ES (1) | ES2347973T3 (https=) |
| IL (1) | IL176738A0 (https=) |
| MA (1) | MA28436B1 (https=) |
| NO (1) | NO20063760L (https=) |
| SG (1) | SG149867A1 (https=) |
| UA (1) | UA85862C2 (https=) |
| WO (1) | WO2005073204A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008002490A2 (en) | 2006-06-23 | 2008-01-03 | Radius Health, Inc. | Treatment of vasomotor symptoms with selective estrogen receptor modulators |
| US10144736B2 (en) * | 2006-07-20 | 2018-12-04 | Gilead Sciences, Inc. | Substituted pteridines useful for the treatment and prevention of viral infections |
| WO2008009078A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| CA2738878C (en) * | 2008-09-29 | 2013-08-13 | Eli Lilly And Company | Selective estrogen receptor modulator for the treatment of osteoarthritis |
| US20100087402A1 (en) * | 2008-09-29 | 2010-04-08 | Vivus, Inc. | Methods and compositions for the treatment of estrogen-dependent hyperproliferative uterine disorders |
| US20100317635A1 (en) | 2009-06-16 | 2010-12-16 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
| HUE030072T2 (en) | 2010-05-12 | 2017-04-28 | Radius Health Inc | Therapeutic prescriptions |
| US9133182B2 (en) | 2010-09-28 | 2015-09-15 | Radius Health, Inc. | Selective androgen receptor modulators |
| FR3014437B1 (fr) * | 2013-12-05 | 2016-12-23 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
| FR3014434B1 (fr) * | 2013-12-05 | 2015-12-25 | Servier Lab | Nouveau procede de synthese du 7-methoxy-naphtalene-1-carbaldehyde et application a la synthese de l'agomelatine |
| US9421264B2 (en) | 2014-03-28 | 2016-08-23 | Duke University | Method of treating cancer using selective estrogen receptor modulators |
| ES3055185T3 (en) | 2014-03-28 | 2026-02-10 | Univ Duke | Treatment of an estrogen receptor positive breast cancer using a selective estrogen receptor modulator |
| US9670205B2 (en) | 2015-03-04 | 2017-06-06 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
| MX389702B (es) | 2016-06-22 | 2025-03-20 | Ellipses Pharma Ltd | Compuestos para usarse en el tratamiento de cancer de mama que expresa el receptor de androgenos (ar+). |
| WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
| AU2017318601B2 (en) | 2016-09-02 | 2020-09-03 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
| JP7481115B2 (ja) | 2017-01-05 | 2024-05-10 | ラジウス ファーマシューティカルズ，インコーポレイテッド | Ｒａｄ１９０１－２ｈｃｌの多形性形態 |
| CN108675999B (zh) * | 2018-05-09 | 2021-03-16 | 浙江农林大学暨阳学院 | 一种醋酸铜催化制备8-(9-亚砜基-10-二氢菲)喹啉类化合物的方法 |
| MX2020013713A (es) | 2018-07-04 | 2021-03-02 | Radius Pharmaceuticals Inc | Formas polimorficas de rad1901-2hcl. |
| CN112424205B (zh) * | 2018-07-12 | 2023-10-31 | 伊莱利利公司 | 选择性的雌激素受体降解剂 |
| TWI702219B (zh) * | 2018-07-12 | 2020-08-21 | 美商美國禮來大藥廠 | 選擇性雌激素受體降解劑 |
| EP3924328A1 (en) | 2019-02-12 | 2021-12-22 | Radius Pharmaceuticals, Inc. | Processes and compounds |
| TWI751516B (zh) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TW202212339A (zh) | 2019-04-17 | 2022-04-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TWI879779B (zh) | 2019-06-28 | 2025-04-11 | 美商基利科學股份有限公司 | 類鐸受體調節劑化合物的製備方法 |
| TWI894443B (zh) | 2021-03-16 | 2025-08-21 | 美商美國禮來大藥廠 | 選擇性雌激素受體降解劑 |
| CA3243621A1 (en) | 2022-02-01 | 2023-08-10 | Eli Lilly And Company | METHODS FOR PREPARING SELECTIVE ESTROGEN RECEPTOR DEGRADING AGENTS |
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|---|---|---|---|---|
| US5998401A (en) * | 1995-02-28 | 1999-12-07 | Eli Lilly And Company | Naphthyl compounds, intermediates, compositions, and methods |
| US5726186A (en) * | 1995-09-08 | 1998-03-10 | Eli Lilly And Company | Pentacyclic compounds, intermediates, processes, compositions, and methods |
| ID19392A (id) * | 1996-08-29 | 1998-07-09 | Lilly Co Eli | Senyawa naftil dan bahan pertengahan serta komposisi dan metode penggunaan |
| CA2213810C (en) * | 1996-08-29 | 2006-06-06 | Lewis Dale Pennington | Benzo¬b|thiophene compounds, intermediates, processes, compositions and methods |
| US5916916A (en) * | 1996-10-10 | 1999-06-29 | Eli Lilly And Company | 1-aryloxy-2-arylnaphthyl compounds, intermediates, compositions, and methods |
| CA2217810A1 (en) * | 1996-10-10 | 1998-04-10 | Eli Lilly And Company | 2-aryl-3-aminoaryloxynaphthyl compounds, intermediates, compositions and methods |
| CA2298651A1 (en) * | 1997-08-07 | 1999-02-18 | Jeffrey Alan Dodge | 1-¬4-(substituted alkoxy)benzyl|naphthalene compounds having estrogen inhibitory activity |
| EA008024B1 (ru) * | 2002-07-22 | 2007-02-27 | Эли Лилли Энд Компани | Селективные модуляторы эстрогенных рецепторов, содержащие фенилсульфонильную группу |
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2005
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- 2005-01-18 CN CN2011101337521A patent/CN102250042A/zh active Pending
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- 2005-01-18 EA EA200601353A patent/EA012262B1/ru not_active IP Right Cessation
- 2005-01-18 WO PCT/US2005/000020 patent/WO2005073204A1/en not_active Ceased
- 2005-01-18 DE DE602005022673T patent/DE602005022673D1/de not_active Expired - Lifetime
- 2005-01-18 US US10/597,241 patent/US20090023917A1/en not_active Abandoned
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- 2005-01-18 AU AU2005207821A patent/AU2005207821B2/en not_active Ceased
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- 2005-01-18 EP EP05704874A patent/EP1709021B1/en not_active Expired - Lifetime
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- 2006-08-18 MA MA29277A patent/MA28436B1/fr unknown
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| US20090023917A1 (en) | 2009-01-22 |
| KR101008804B1 (ko) | 2011-01-14 |
| CR8517A (es) | 2006-12-01 |
| EA012262B1 (ru) | 2009-08-28 |
| KR20060129277A (ko) | 2006-12-15 |
| KR100849559B1 (ko) | 2008-07-31 |
| US20110281847A1 (en) | 2011-11-17 |
| US8217032B2 (en) | 2012-07-10 |
| MA28436B1 (fr) | 2007-02-01 |
| BRPI0506721A (pt) | 2007-05-02 |
| CA2551956C (en) | 2013-05-07 |
| EA016613B1 (ru) | 2012-06-29 |
| ECSP066711A (es) | 2006-10-31 |
| SG149867A1 (en) | 2009-02-27 |
| AU2005207821A1 (en) | 2005-08-11 |
| EA200900586A1 (ru) | 2009-08-28 |
| AU2005207821B2 (en) | 2011-02-10 |
| CN102250042A (zh) | 2011-11-23 |
| KR20080016755A (ko) | 2008-02-21 |
| NO20063760L (no) | 2006-10-16 |
| CA2551956A1 (en) | 2005-08-11 |
| ATE476428T1 (de) | 2010-08-15 |
| WO2005073204A1 (en) | 2005-08-11 |
| DE602005022673D1 (de) | 2010-09-16 |
| JP4909086B2 (ja) | 2012-04-04 |
| JP2007519721A (ja) | 2007-07-19 |
| ES2347973T3 (es) | 2010-11-26 |
| IL176738A0 (en) | 2006-10-31 |
| EP1709021B1 (en) | 2010-08-04 |
| EA200601353A1 (ru) | 2007-02-27 |
| EP1709021A1 (en) | 2006-10-11 |
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