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Thioketals and thioethers for inhibiting the expression of VCAM-1

a technology of thioketals and thioethers, which is applied in the direction of sugar derivatives, aminosugars, biocides, etc., can solve the problems of limited expression of icam-1 and vcam-1 in normal cardiac tissu

Inactive Publication Date: 2005-08-04
ATHEROGENICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The thioketal and thioether compounds effectively inhibit VCAM-1 expression, thereby treating various disorders mediated by VCAM-1, including inflammatory, cardiovascular, and ocular diseases, as well as hypercholesterolemia, by reducing inflammation and cholesterol levels, thus addressing the limitations of existing treatments.

Problems solved by technology

Expression on VCAM-1 and ICAM-1 in normal cardiac tissue is very limited in vascular endothelium.

Method used

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  • Thioketals and thioethers for inhibiting the expression of VCAM-1
  • Thioketals and thioethers for inhibiting the expression of VCAM-1

Examples

Experimental program
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Effect test

example 1

Thioketal Synthetic Methods

[0144] The thioketal compounds of formula (I) wherein Z forms an ether group can be prepared by known procedures and techniques, or routine modifications thereof. General procedures for preparing compounds of formula (I) wherein Z forms an ether group are set forth in General Procedures A and B, wherein all substituents, unless otherwise indicated, are previously defined.

[0145] Compounds of the present invention can be readily prepared by someone skilled in the art of organic synthesis using a standard ether coupling procedure known as the Mitsunobu reaction (Hughes, D. L. Org. Prep. Proced. Int., 28, 127-64 (1996)). For example, to a solution of probucol in a suitable aprotic solvent such as tetrahydrofuran (THF) are added triphenylphosphine, diethyl azodicarboxylate, and an appropriate alcohol moiety optionally containing the additional substituents described above for Z. The resultant mixture is stirred under nitrogen at reflux for 2 to 8 hours and t...

example 4

Thioether Synthetic Methods

[0158] The thioethers of formula (II) can be prepared by utilizing known procedures and techniques, or routine modifications thereof. See, for example, the synthetic methods disclosed in PCT / US98 / 09781 published as WO 98 / 51662. A general synthetic method for preparing compounds of formula (II) is set forth in General Procedure C, wherein all substituents, unless otherwise indicated, are previously defined.

[0159] General Procedure C

[0160] The synthesis of the starting thiol, 4-mercapto-2,6-di-t-butylphenol, is described in the literature (U.S. Pat. No. 3,129,262 to Laufer, incorporated herein by reference in its entirety). The starting alkyl halides are commercially available or made from commercially available starting materials by methods known to one of ordinary skill in the art.

[0161] A quantity of the 4-mercapto-2,6-di-t-butylphenol is dissolved in ethanol to make a 0.5 M solution and treated with 1.2 equivalents of sodium hydroxide (5 N aqueous so...

example 6

2,6-Di-tert-butyl-[4′-(N,N-diethylaminocarbonyl)benzyl]thiophenol

[0170] Same as Example 3, but substitute diethylamine for dimethylamine.

[0171] The following examples illustrate the use of thioketals and thioethers according to the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

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Abstract

Thioketals and thioethers are provided that inhibit the expression of VCAM-1, and which can be used in the treatment of VCAM-1 mediated diseases including inflammatory disorders, cardiovascular diseases, occular diseases, autoimmune diseases, neurological disorders, and cancer. The compounds also can be used to treat hyperlipidemia and / or hypercholesterolemia.

Description

RELATIONSHIP TO PRIOR APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 191,046, filed on Mar. 21, 2000. This application also claims priority to pending U.S. application Ser. No. 09 / 370,046, filed Aug. 6, 1999, and U.S. patent application Ser. No. 09 / 079,213, filed May 14, 1998, and granted Nov. 14, 2000 as U.S. Pat. No. 6,147,250.FIELD OF THE INVENTION [0002] This invention is in the area of compounds, compositions and methods for inhibiting the expression of VCAM-1 and, in particular, for treating diseases mediated by VCAM-1, including inflammatory disorders, cardiovascular diseases, occular diseases, autoimmune diseases, neurological disorders, and cancer. The invention is further in the area of compounds, compositions and for treating hypercholesterolemia and hyperlipidemia. BACKGROUND OF THE INVENTION Expression of VCAM-1 [0003] Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C323/20C07C323/60C07H15/203
CPCA61K31/222A61K31/225C07C323/20C07C323/21C07H15/203C07C323/56C07C323/60C07C323/66C07C323/67C07C323/25
Inventor MENG, CHARLES Q.HOONG, LEE K.SOMERS, PATRICIA K.SIKORSKI, JAMES A.
Owner ATHEROGENICS PHARMA
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