KR100487647B1 - 벤조피란함유화합물및이들의사용방법 - Google Patents
벤조피란함유화합물및이들의사용방법 Download PDFInfo
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- KR100487647B1 KR100487647B1 KR1019970705813A KR19970705813A KR100487647B1 KR 100487647 B1 KR100487647 B1 KR 100487647B1 KR 1019970705813 A KR1019970705813 A KR 1019970705813A KR 19970705813 A KR19970705813 A KR 19970705813A KR 100487647 B1 KR100487647 B1 KR 100487647B1
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- salt
- phenyl
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- 150000001875 compounds Chemical class 0.000 title claims description 87
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 22
- 229940011871 estrogen Drugs 0.000 claims abstract description 24
- 239000000262 estrogen Substances 0.000 claims abstract description 24
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 17
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 238000001727 in vivo Methods 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 7
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- -1 pivaloyloxy group Chemical group 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 55
- 230000001833 anti-estrogenic effect Effects 0.000 abstract description 32
- 229940002612 prodrug Drugs 0.000 abstract description 30
- 239000000651 prodrug Substances 0.000 abstract description 30
- 239000000328 estrogen antagonist Substances 0.000 abstract description 29
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- 238000011282 treatment Methods 0.000 abstract description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
- DUYNJNWVGIWJRI-UHFFFAOYSA-N 3-(4-hydroxyphenyl)-4-methyl-2-[4-(2-piperidin-1-ylethoxy)phenyl]-2h-chromen-7-ol Chemical compound O1C2=CC(O)=CC=C2C(C)=C(C=2C=CC(O)=CC=2)C1C(C=C1)=CC=C1OCCN1CCCCC1 DUYNJNWVGIWJRI-UHFFFAOYSA-N 0.000 description 34
- 230000000694 effects Effects 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- DUYNJNWVGIWJRI-LJAQVGFWSA-N acolbifene Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(O)C=C3O2)C)C=2C=CC(O)=CC=2)=CC=C1OCCN1CCCCC1 DUYNJNWVGIWJRI-LJAQVGFWSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- OEKMGABCSLYWOP-DHUJRADRSA-N [4-[(2s)-7-(2,2-dimethylpropanoyloxy)-4-methyl-2-[4-(2-piperidin-1-ylethoxy)phenyl]-2h-chromen-3-yl]phenyl] 2,2-dimethylpropanoate Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(OC(=O)C(C)(C)C)C=C3O2)C)C=2C=CC(OC(=O)C(C)(C)C)=CC=2)=CC=C1OCCN1CCCCC1 OEKMGABCSLYWOP-DHUJRADRSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 14
- 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 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
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- 239000012153 distilled water Substances 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 150000003431 steroids Chemical class 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 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
- 150000001412 amines Chemical class 0.000 description 6
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- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 4
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
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- 210000004291 uterus Anatomy 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
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Abstract
Description
Claims (13)
- 아래의 분자 구조식 (I)을 갖는, 광학 활성 화합물로서,R1과 R2는 독립적으로 하이드록실기 및 생체 내에서 하이드록실기로 전환되는 모이어티로 구성된 군에서 선택되는 것이고, R3은 -CH2CH2-이며,분자 구조 (I)이 지배적이고, 2R 입체 이성질체가 실질적으로 존재하지 않는 정도의 순도를 갖는 화합물 또는 약학적으로 허용되는 이들의 염.
- 제 4 항에 있어서, 상기 화합물 또는 이들의 염은 2S 배열을 갖는 입체 이성질체를 총 입체 이성질체에 대한 상대 중량으로 50% 이상 포함하는 것인 화합물 또는 이들의 염.
- 제 7 항에 있어서, R1 또는 R2 중의 어느 하나가 입체적인 장애를 갖는 지방족 아실옥시기인 화합물 또는 이들의 염.
- 제 7 항에 있어서, R1과 R2 중의 어느 하나가 피발로일옥시기인 것인 화합물 또는 이들의 염.
- 치료학적 유효량의 제 1 항 내지 제 10항 중의 어느 한 항에 따른 화합물 또는 이들의 염을, 약학적으로 허용되는 담체 또는 희석제와 함께 또는 이들 없이, 함유하는, 에스트로젠-센시티브 질병 치료용 약학 조성물.
- 제 11 항에 있어서, 상기 에스트로젠-센시티브 질병이 유방암 또는 자궁암인 것인 약학 조성물.
- 아래의 분자 구조식 (I)을 갖는, 광학 활성 화합물로서,R1과 R2는 독립적으로 하이드록실기 및 생체 내에서 하이드록실기로 전환되는 모이어티로 구성된 군에서 선택되는 것이고, R3은 -CH2- 인 것으로서,분자 구조 (I)이 지배적이고, 2R 입체 이성질체가 실질적으로 존재하지 않는 정도의 순도를 갖는 화합물 또는 약학적으로 허용되는 이들의 염.
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US8/388,207 | 1995-02-21 | ||
US08/388207 | 1995-02-21 | ||
US08/388,207 US6060503A (en) | 1991-12-02 | 1995-02-21 | Benzopyran-containing compounds and method for their use |
Publications (2)
Publication Number | Publication Date |
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KR19980702414A KR19980702414A (ko) | 1998-07-15 |
KR100487647B1 true KR100487647B1 (ko) | 2005-09-14 |
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KR1019970705813A KR100487647B1 (ko) | 1995-02-21 | 1996-02-20 | 벤조피란함유화합물및이들의사용방법 |
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US (1) | US6060503A (ko) |
EP (2) | EP0811006B1 (ko) |
JP (1) | JPH11500133A (ko) |
KR (1) | KR100487647B1 (ko) |
CN (1) | CN1158274C (ko) |
AR (1) | AR004167A1 (ko) |
AT (2) | ATE240951T1 (ko) |
AU (1) | AU4660696A (ko) |
BR (1) | BR9607259A (ko) |
CA (1) | CA2212856C (ko) |
DE (2) | DE69627831T2 (ko) |
DK (2) | DK0811006T3 (ko) |
ES (2) | ES2197232T3 (ko) |
FI (1) | FI120940B (ko) |
HK (1) | HK1009440A1 (ko) |
HU (1) | HU227762B1 (ko) |
IL (2) | IL150767A (ko) |
MX (1) | MX9706345A (ko) |
MY (1) | MY117248A (ko) |
NO (2) | NO317055B1 (ko) |
NZ (1) | NZ301231A (ko) |
PL (1) | PL188076B1 (ko) |
PT (2) | PT1167364E (ko) |
RU (1) | RU2220143C2 (ko) |
TR (1) | TR199600144A2 (ko) |
TW (1) | TW434238B (ko) |
WO (1) | WO1996026201A1 (ko) |
ZA (1) | ZA961316B (ko) |
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1995
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- 1996-02-20 CN CNB961932392A patent/CN1158274C/zh not_active Expired - Fee Related
- 1996-02-20 PT PT01123569T patent/PT1167364E/pt unknown
- 1996-02-20 BR BR9607259A patent/BR9607259A/pt not_active Application Discontinuation
- 1996-02-20 EP EP01123569A patent/EP1167364B1/en not_active Expired - Lifetime
- 1996-02-20 WO PCT/CA1996/000097 patent/WO1996026201A1/en active IP Right Grant
- 1996-02-20 AU AU46606/96A patent/AU4660696A/en not_active Abandoned
- 1996-02-20 HU HU9801230A patent/HU227762B1/hu not_active IP Right Cessation
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WO1993010741A2 (en) * | 1991-12-02 | 1993-06-10 | Endorecherche Inc. | Sex steroid activity inhibitors |
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