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Novel heterocyclic analogs of diphenylethylene compounds

a diphenylethylene and heterocyclic technology, applied in the field of new heterocyclic analogs of diphenylethylene compounds, can solve the problems of morbidity and mortality, undesirable side effects of gastrointestinal pathology, and the ineffectiveness of known thiazolidinediones for a significant portion of the patient population

Inactive Publication Date: 2006-10-19
THERAKOS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0068] These compounds are useful for treating diabetes, hyperlipidemia and other diseases linked to insulin resistance, such as coronary artery disease and peripheral vascular disease, and also for treating or inhibiting inflammation or inflammatory diseases such as inflammatory arthritides and collagen vascular diseases, which are caused by, for example, cytokines or cyclooxygenase such as TNF-alpha, IL-1, IL-6 and/or COX-2. The compounds are also useful for treating or preventing other diseases mediated by cytokines and/or cyclooxygenase, such as cancer.
[0069] Accordingly, the invention also provides a method of treating diabetes and related diseases comprising the step of administering to a s

Problems solved by technology

However, type II diabetes, the more common form, is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced.
However, the known thiazolidinediones are not effective for a significant portion of the patient population.
In addition, the first drug in this class to be approved by the FDA, troglitazone, was withdrawn from the market due to problems of liver toxicity.
However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality.
They can be effective in reducing inflammatory pain and swelling, but since they hamper the protective action of COX-1, they produce undesirable side effects of gastrointestinal pathology.

Method used

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  • Novel heterocyclic analogs of diphenylethylene compounds
  • Novel heterocyclic analogs of diphenylethylene compounds
  • Novel heterocyclic analogs of diphenylethylene compounds

Examples

Experimental program
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example 1

[0117] General Methods. Melting points were measured on a Mel-Temp melting point apparatus and are uncorrected. The 1H NMR and 13C NMR spectra were recorded on a JEOL Eclipse (400 MHz) or Nicolet NT 36 (360 MHz) spectrometer and are reported as parts per million (ppm) downfield from TMS. The infrared spectra were recorded on a Nicolet Impact 410 FT-IR spectrophotometer. The mass spectra were recorded on Fison VG Platform II of HP 1100 MDS 1964A mass spectrophotometer. UV spectra were recorded on a Beckman DU650 spectrophotometer. TLC was done on Merck silica gel F254 precoated plates. The silica gel used for column chromatography was ‘Baker’ silica gel (40 μm) for flash chromatography.

[0118] 3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid (7). To a mixture of 3,5-dimethoxybenzaldehyde, 5, (500 g, 3.0 mol) and 4-hydroxyphenyl acetic acid, 6, (457 g, 3.0 mol) was added acetic anhydride (1.0 L, 10.60 mole) and triethylamine (420 mL, 3.0 mol). After stirring at 130-140° C. for...

example 2

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylamide (24)

[0157] Compound 24, which may be represented by the formula:

was prepared as follows from compound 14. A clean dry flask with stirbar was charged with compound 14 (0.423 g, 0.837 mmol) and dry DMF (10 mL). Then with stirring carbonyldiimidazole (0.271 g, 1.67 mmol) was added and the reaction was heated to 60° C. for 1 h. while vented through an oil-bubbler. The reaction mixture was then cooled to 0° C. and 2M ammonia in methanol (2.1 mL, 4.2 mmol) was added. The reaction was worked up by partitioning the mixture with 10% citric acid (10 mL), ethyl acetate (50 mL), and water (40 mL). The organic phase was then rinsed sequentially with water (2×30 mL), brine (1×20 mL) and dried with anhydrous MgSO4. Concentration of the organics afforded crude product. The crude product was purified by silica gel chromatography using ethyl acetate-hexanes (1:1) containing 1% acetic acid to ethyl acetat...

example 3

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5ylmethyl)-phenoxy]-phenyl}-N,N-dimethylacrylamide (25)

[0158] Compound 25, represented by the formula:

was prepared as follows: A clean dry flask with stirbar was charged with compound 14 (0.422 g, 0.835 mmol) and dry DMF (1 mL). Then with stirring carbonyldiimidazole (0.271 g, 1.67 mmol) was added and the reaction was heated to 60° C. for 1 h. while vented through an oil-bubbler. The reaction mixture was then cooled to 0° C. and a 2M dimethylamine in THF (2.1 mL, 4.2 mmol) solution was added. The reaction was worked up by partitioning the mixture with 10% citric acid (10 mL), ethyl acetate (50 mL), water (40 mL). The organic phase was then rinsed sequentially with water (2×30 mL), brine (1×20 mL) and dried with anhydrous MgSO4. Concentration of the organics afforded crude product. The crude product was purified by silica gel chromatography using ethyl acetate-hexanes (3:2) containing 1% acetic acid elution. Concentration of t...

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Abstract

Novel diphenylethylene compounds and derivatives thereof containing thiazolidinedione or oxazolidinedione moieties are provided which are effective in lowering blood glucose level, serum insulin, triglyceride and free fatty acid levels in animal models of Type II diabetes. The compounds are disclosed as useful for a variety of treatments including the treatment of inflammation, inflammatory and immunological diseases, insulin resistance, hyperlipidemia, coronary artery disease, cancer and multiple sclerosis.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This is a continuation-in-part of U.S. patent application Ser. No. 10 / 265,902, filed Oct. 8, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 843,167, filed Apr. 27, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 785,554, filed Feb. 20, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 591,105, filed on Jun. 9, 2000, and which further is a continuation-in-part of U.S. patent application Ser. No. 09 / 287,237, filed on Apr. 6, 1999.BACKGROUND OF THE INVENTION [0002] The present application is directed to novel compounds formed by chemically coupling diphenylethylene compounds and derivatives thereof with thiazolidine or oxazolidine intermediates. These compounds are effective for providing a variety of useful pharmacological effects. For example, the compounds are useful in lowering blood glucose, serum insulin and triglyceride levels in animal models of t...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/421A61K31/4166A61P3/10C07D277/20C07D277/24C07D277/34
CPCC07D277/20C07D277/34C07D277/24A61P3/06A61P3/10A61P9/10A61P25/00A61P29/00A61P35/00A61P37/02
Inventor NEOGI, PARTHADEY, DEBENBDRANATHMEDICHERLA, SATYANARAYANANAG, BISHWAJITLEE, ARTHUR
Owner THERAKOS INC
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