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Benzopyranone compounds, compositions thereof, and methods of treatment therewith

a technology of benzopyranone and compounds, applied in the field ofbenzopyranone compounds, can solve the problems of limited treatment, increased cancer risk, fragile bones,

Inactive Publication Date: 2004-05-13
SIGNAL PHARMA LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

0019] In recent years a number of both steroidal and nonsteroidal compounds which interact with ER have been developed. For example, Tamoxifen was originally developed as an anti-estrogen and used for the treatment of breast cancer, but more recently has been found to act as a partial estrogen agonist in the uterus, bone and cardiovascular system. Raloxifene is another compound that has been proposed as a SERM, and has been approved for treatment of osteoporosis. 2

Problems solved by technology

However, in addition to its positive effects, estrogen also is a potent growth factor in the breast and endometrium that increases the risk of cancer.
Bone-resorbing diseases, such as osteoporosis, are debilitating conditions which affect a wide population, and to which there is only limited treatment.
In individuals with osteoporosis, increased loss of bone mass results in fragile bones and, as a result, increased risk of bone fractures.
In individuals suffering from a bone-resorbing disease, there is an imbalance in the function of these two types of cells.
However, the mechanism of how the loss of estrogen results in increased bone resorption has long been debated.
These compounds, however, are generally used for long-term treatments, and have undesirable side effects.
es. Some of these results, however, are controversial, which may be attributable to the method used for measuring ER, the species analyzed (rat, mouse, human) and / or the differentiation state of isolated primary ce

Method used

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  • Benzopyranone compounds, compositions thereof, and methods of treatment therewith
  • Benzopyranone compounds, compositions thereof, and methods of treatment therewith
  • Benzopyranone compounds, compositions thereof, and methods of treatment therewith

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-(2-CHLORO-4-TRIFLUOROMETHYLPHENYL)-7-HYDROXY-4-(4-(2-PYRROLIDIN-1-YL-ETH-OXY)-BENZYL)-CHROMEN-2-ONE

[0115] A. (2-Chloro-4-trifluoromethylphenyl)-acetic Acid 10

[0116] A solution of LiHMDS in toluene was prepared by the addition of n-BuLi (357 mL of a 1.6 M solution in hexanes, 571 mmol) to a cold (-78.degree. C.) solution of HMDS (120.5 mL, 571 mmol) in toluene (700 mL). After 30 min, the reaction mixture was allowed to warm up to 10.degree. C. over 1 h. The solution was then transferred via a cannula to a flame-dried, three-neck flask under N.sub.2 containing Pd.sub.2 dba.sub.3 (4.18 g, 4.57 mmol) and (2'-dicyclohexylphosphanylbiphenyl-2-yl-)-dimethylamine (3.77 g, 9.59 mmol). The mixture was stirred for 15 min at 15.degree. C., cooled to -10.degree. C. and t-butylacetate (70.5 mL, 525.4 mmol) was added dropwise. After 10 min, 3-chloro-4-iodobenzotrifluo-ride (70 g, 228.4 mmol) was added and the reaction mixture was warmed up to 28.degree. C. After stirring at this temperature for ...

example 2

3-(4-CHLORO-2-TRIFLUOROMETHYLPHENYL)-7-HYDROXY-4-(4-(2-PYRROLIDIN-1-YL-ETH-OXY)-BENZYL)-CHROMEN-2-ONE

[0124] A. (4-Chloro-2-trifluoromethylphenyl)-acetic Acid 14

[0125] A solution containing 4-chloro-1-iodo-2-trifluoromethylbenzene (14.98 g, 48.9 mmol), Bu.sub.3SnCH.dbd.CH.sub.2 (15.7 mL, 53.7 mmol) and (Ph.sub.3P).sub.4Pd (2.26 g, 1.955 mmol) in anhyd toluene (200 mL) was deoxygenated using vacuum-N.sub.2 flush (3.times.). After refluxing the reaction mixture for 17 h, it was cooled to 0.degree. C. and a solution of disiamylborane-methyl sulfide complex in toluene (.about.1.95 M, 47 mL) was added dropwise over a period of 5 min. The disiamylborane-methyl sulfide complex solution was prepared by adding 2-methyl-2-butene (26 mL, 245 mmol) to a cold (0.degree. C.) solution of borane-methyl sulfide complex (11.6 mL, 122.3 mmol) in anhyd toluene (25 mL) and stirring the resultant mixture at r.t. for 2 h. The bath was removed and the reaction mixture was stirred at r.t. for 3 h. After that...

example 3

3-(2,4-BIS-TRIFLUOROMETHYLPHENYL)-7-HYDROXY-4-(4-(2-PYRROLIDIN-1-YL-ETHOXY-)-BENZYL)-CHROMEN-2-ONE

[0133] A. 3-(2,4-bistrifluoromethylphenyl)-4-(4-hydroxybenzyl)-7-methoxych-romen-2-one 18

[0134] This compound was prepared using the methodology described above in Example 1B. The resultant residue was purified using flash chromatography (silica gel, 1:1 to 3:2 Et.sub.2O:hexanes) to provide the title compound as a yellow foam showing: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.03 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=2.5 Hz), 6.84 (d, 2H, J=8.5 Hz), 6.78 (dd, 1H, J=2.5, 8.8 Hz), 6.70 (d, 2H, J=8.5 Hz), 4.76 (s, 1H), 4.01 (d, 1H, J=16.0 Hz), 3.88 (s, 3H), 3.57 (d, 1H, J=16.0 Hz).

[0135] B. 3-(2,4-bistrifluoromethylphenyl)-7-methoxy-4-(4-(2-pyrrolidin-1--yl-ethoxy)benzyl)-chromen-2-one 19

[0136] This compound was prepared using the methodology described above in Example 1C. The resultant brown foam was purified using flash chromatog...

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Abstract

Benzopyranone compounds having the following structure: wherein R1, X, Y and n are as defined here, are disclosed. The compounds of formula (I), wherein R1 is H, can be prepared by demethylation of the corresponding phenolic methyl ether. The compounds are useful for treating a bone-resorbing disease, cancer, arthritis or an estrogen-related condition such as breast cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, and adverse reproductive effects associated with exposure to environmental chemicals or natural hormonal imbalances.

Description

[0001] This application is a continuation-in-part of U.S. application Ser. No. 10 / 125,965 filed Apr. 19, 2002 which is incorporated by reference herein in its entirety.1. FIELD OF THE INVENTION[0002] This invention is generally directed to benzopyranone compounds, compositions comprising the benzopyranone compounds and methods for treating a bone-resorbing disease, cancer, arthritis or an estrogen-related condition, comprising administering an effective amount of a benzopyranone compound to a patient in need thereof.2. BACKGROUND OF THE INVENTION[0003] The estrogen hormone has a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous system (CNS) function, and the protection of organ systems from the effects of aging. However, in addition to its positive effects, estrogen also is a potent growth factor in the breast and endometrium that increases t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D311/16
CPCC07D311/16A61P13/00A61P17/10A61P19/02A61P19/08A61P19/10A61P25/00A61P25/28A61P27/12A61P3/04A61P35/00A61P35/04A61P5/18A61P9/00C07D405/12
Inventor RENAUD, JOHANNEMISSBACH, MARTINMCKIE, JEFFREY A.BHAGWAT, SHRIPAD S.
Owner SIGNAL PHARMA LLC
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