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Phenyl naphthol ligands for thyroid hormone receptor

a thyroid hormone receptor and phenyl naphthol technology, applied in the field of phenyl naphthol compounds, can solve the problems of limited development of thyroid agonists and antagonists for treatment, slow discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism, and weight gain

Inactive Publication Date: 2005-03-10
HANGELAND JON J
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow.
This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression.
However, replacement therapy, particularly in older individuals, may be restricted by certain detrimental effects from thyroid hormones.
Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.

Method used

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  • Phenyl naphthol ligands for thyroid hormone receptor
  • Phenyl naphthol ligands for thyroid hormone receptor
  • Phenyl naphthol ligands for thyroid hormone receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-3-amino-3-oxopropanoic acid

6-Methoxynaphth-1-ol (0.5 g, 2.8 mmol) and triethylamine (313 mg, 3.1 mmol) were dissolved in anhyd dichloromethane (28 mL) under a blanket of argon and cooled to −400° C. Triflic anhydride (891 mg, 3.1 mmol) was added dropwise. The reaction was warmed to −10° C. and stirred for an additional 1.5 h. Additional triflic anhydride (291 mg, 0.3 mmol) was added to complete the reaction. The reaction was quenched with water. The layers were separated and the organic layer washed with water and brine, dried over magnesium sulfate, filtered and dried in vacuo to yield 877 mg (99%) of an oil which solidifies upon standing. 1H-NMR is consistent with the proposed structure.

The triflate of Compound 1a (857 mg, 2.8 mmol), bis-picolinatodi-borane (1.07 g, 4.2 mmol) and anhyd potassium acetate (824 mg, 8.4 mmol) were placed in a one necked flask equipped with an argon inlet. The solids were suspended in anhyd DMS...

example 2

2-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-2-amino-2-oxoacetic acid

Compound 1f (397 mg, 1.0 mmol) and triethyl amine (120 mg, 1.2 mmol) were dissolved in anhyd dichloromethane (5 mL) and cooled to 0° C. Ethyl chlorooxolate (163 mg, 1.2 mmol) was added dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhyd magnesium sulfate, filtered and dried in vacuo. Flash chromatography (30 g silica gel, elute with 15% ethyl acetate in hexanes) provided pure product (298 mg, 60%). 1H-NMR was consistent with the proposed structure.

The ester formed by Compound 2a (60 mg, 0.12 mmol) was deprotected using the protocol described for Compound 1h yielding 25 mg, (55%) of the title compound of Example 2. 1H-NMR and mass spec were consistent with the proposed structure of Example 2.

example 3

N-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-glycine

Compound 1f (50 mg, 0.126 mmol) was dissolved in anhyd acetonitrile (1 mL) and treated with potassium carbonate (19 mg, 0.139 mmol) and ethyl bromoacetate (23 mg, 0.139 mmol). The reaction was heated to 80° C. for 2 h. Very little reaction was evident. Additional ethyl bromoacetate (112 mg, 0.68 mmol) was added. Heating was continued overnight. The reaction was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine, dried over anhyd magnesium sulfate, filtered and evaporated in vacuo. The crude product was carried onto the next step without further purification.

The ester formed by Compound 3a (60 mg, 0.12 mmol) was deprotected using the protocol described for compound 1 hr yielding 45 mg (55%) of the title Compound of Example 3. 1H-NMR and mass spec were consistent with the proposed structure.

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Abstract

New thyroid receptor ligands are provided which have the general formula I wherein R1 is halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-7 cycloalkyl; R2 and R3 are each independently hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, wherein at least one of R2 and R3 is other than hydrogen; R4 is a carboxylic acid selected from the group consisting of (CH2)nCOOH, (CH)2COOH, NHCO(CH2)nCOOH, CONH(CH2)nCOOH and NH(CH2)mCOOH; n is an integer from 0 to 4; and m is an integer from 1 to 4. In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T3 regulated gene, wherein a compound as described above is administered in a therapeutically effective amount.

Description

FIELD OF THE INVENTION The present invention relates to novel phenyl naphthol compounds which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor β. Further, the present invention relates to methods for using such compounds and to pharmaceutical compositions containing such compounds. BACKGROUND OF THE INVENTION While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias. Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence blood levels of serum low de...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/195A61K31/198A61K45/06C07C59/56C07C229/18C07C233/25C07C233/56
CPCA61K31/195A61K31/198A61K45/06C07C59/56C07C229/18C07C233/25C07C233/56A61K2300/00
Inventor HANGELAND, JON J.
Owner HANGELAND JON J
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