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Tetracyclic compounds as estrogen ligands

A compound and halogen technology, applied in the direction of steroids, drug combinations, organic chemistry, etc., can solve problems such as unsatisfied estrogen substances

Inactive Publication Date: 2007-07-04
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is a large unmet need in the art for estrogens to provide patients with more treatment options

Method used

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  • Tetracyclic compounds as estrogen ligands
  • Tetracyclic compounds as estrogen ligands
  • Tetracyclic compounds as estrogen ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0148] Synthesis of Example Compounds

[0149] The synthesis of the compounds described in the following examples is depicted in Reaction Schemes 1-9 below. The chemical preparation methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg UV-visible), and mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0150] Reaction scheme 1

[0151]

[0152] Reaction scheme 2

[0153]

[0154] Reaction Scheme 3 (preparation of stannane 13)

[0155]

[0156] Reaction scheme 4

[0157]

[0158] Reaction scheme 5

[0159]

[0160] Reaction scheme 6

[0161]

[0162] Reaction scheme 7

[0163]

[0164] Reaction Scheme 8 (Preparation of Precursor 30 Used in...

preparation Embodiment 1、2 and 3

[0169] Preparative Examples 1, 2 and 3 (from Reaction Scheme 1)

[0170] 2-Bromo-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (3)

[0171] Dissolve 6-methoxy-1-tetralone 1 (100 g, 0.567 mol) in ether (2 liters), and add Br dropwise over 1 hour 2 (30ml, 0.59mol) for treatment. The solution was stirred for an additional 2 hours, then heated by adding 10% Na 2 SO 3 solution, NaHCO 3 Wash with brine for workup. The solution was allowed to stand overnight and 30 g of crystals were filtered over the next day. Concentration of the remaining solution afforded an additional 98 g of product. Combined yield of desired product was 128 g (88%). The resulting product was used as it is in the following reaction.

[0172] 2-Bromo-6-methoxy-3,4-dihydro-naphthalen-1-yl acetate (5)

[0173] A solution of 3 (80 g, 0.325 mol) in THF (200 mL) was cooled to -78 °C and treated by slowly adding 0.65 L of a 0.53 molar solution of LiHMDS in THF. The reaction...

Embodiment 2

[0180] Mp=219-220°C; MS

[0181] m / z 253(M+H) + .

[0182] Benzo[B]naphtho[2,1-D]furan-3,9-diol (Example 2)

[0183] Example 1 (0.22 g, 0.00087 mol (based on 88% pure material)) was treated with DDQ (0.24 g, 0.001 mol) and heated to reflux in dioxane (20 mL) for 30 minutes. The reaction mixture was concentrated onto silica gel and purified by chromatography (EtOAc / hexanes; 3:7) to afford Example 2 (0.1 g, 46%):

[0184] Mp = 250-260°C; 1 H NMR (DMSO-d 6 )δ9.85(s, 1H), 9.80(s, 1H), 8.15(d, 1H, J=8.9Hz), 7.96(d, 1H, J=8.6Hz), 7.87(d, 1H, J=8.3 Hz), 7.63(d, 1H, J=8.6Hz), 7.30(d, 1H, J=1.9Hz), 7.23(dd, 1H, J=8.8Hz, 2.1Hz), 7.12(d, 1H, J= 1.9Hz), 6.88(dd, 1H, J=8.3Hz, J=1.9Hz).

[0185] 5-Bromo-benzo[B]naphtho[2,1-D]furan-3,9-diol (Example 3)

[0186] A solution of Example 2 (0.25 g, 10 mmol) and pyridine (0.79 g, 10 mmol) in dichloromethane (10 mL) was treated with acet...

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PUM

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Abstract

This invention provides estrogen receptor modulators having the structure (I), wherein R1, R2, R3, R4, Q, n, R8, R9, R10, and R11 have been defined in the specification; or a pharmaceutically acceptable salt thereof. The invention further provides methods for the preparation and use of the compounds.

Description

field of invention [0001] The present invention relates to tetracyclic compounds useful as estrogenic agents, methods of making said compounds, and methods of using said compounds. Background of the invention [0002] The pleiotropic effects of estrogen in mammalian tissues have been well reported (Dey, M., Lyttle, C.R., Pickar, J.H. Maturitas (2000), 34(S2): S25-S33, Speroff, L., Ann.N.Y. Acad. Sci. (2000), 900, 26-39, Nozaki, M., Ernst Schering Res. Found. Workshop (2000), Suppl. 4, 115-125). The estrogen receptor (ER), a member of the ER family of nuclear hormones, regulates transcription through its interaction with a variety of proteins, including coactivators and corepressors (collectively referred to as coregulators). ) and estrogen response element (ERE). In addition to its ability to affect the cellular transcriptional machinery through the action of the ERE, the ER can also affect transcriptional processes independent of its direct interaction with DNA. For exam...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77C07D493/04C07J69/00A61K31/343A61K31/352A61P19/10A61P3/06A61P25/00A61P15/18
CPCC07D307/77C07D307/93C07D493/04A61P1/04A61P11/00A61P11/06A61P13/02A61P13/08A61P15/00A61P15/02A61P15/08A61P15/18A61P17/02A61P17/18A61P19/02A61P19/08A61P19/10A61P25/00A61P25/22A61P25/28A61P27/02A61P29/00A61P31/04A61P35/00A61P3/06A61P39/06A61P43/00A61P5/30A61P7/10A61P7/12A61P9/00A61P9/10A61P3/10
Inventor C·P·米勒M·D·科利尼R·L·莫里斯R·R·小辛豪斯
Owner WYETH LLC
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