WO2005007104A2

WO2005007104A2 - Novel compositions, pharmaceutical compositions, and methods for the treatment and prevention of heart disease

Info

Publication number: WO2005007104A2
Application number: PCT/US2004/022066
Authority: WO
Inventors: Jason P. Mcdevitt
Original assignee: Emory University
Priority date: 2003-07-07
Filing date: 2004-07-07
Publication date: 2005-01-27
Also published as: WO2005007104A3

Abstract

The invention provides the following formula (I) and uses thereof: wherein each Ak is independently selected from the group consisting of alkyl; Cy is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle; and A is selected from the group consisting of alkyl, substituted alkyl, C(O)R, and C(O)NHR.

Description

TITLE OF INVENTION

Novel Compositions, Pharmaceutical Compositions, and Methods for the Treatment and Prevention of Heart Disease

CROSS-REFERENCE TO RELATED APPLICATIONS Not Applicable

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

BACKGROUND

The invention describes a novel class of compounds suitable for treatment of coronary heart disease (atherosclerosis), There are several drugs that indirectly target atherosclerosis by reducing risk factors such as cholesterol. Many people now believe that inflammation of the arteries is the underlying cause of atherosclerosis. AtheroGenics Inc. has progressed into Phase III clinical trials with its lead drug candidate, AGI-1067, AGI-1067 is an anti-inflammatory compound that may act on the molecular level by inhibiting oxidation of polyunsaturated fatty acids,

AGI-1067 is a probucol analog (probucol monoester) having the following structure:

wherein a = R = Me and R 3^J = _ (CH₂CH_Z)

In general, attempts to make AGI-1067 analogs have focused on derivatives of probucol In other words, starting from the probucol skeleton, the two phenolic alcohols have been systematically modified. It is believed that AGI-1067 is metabolized in the body to probucol, and thus it has been desirable to leave the probucol skeleton intact.

However, great benefits may be obtained by altering the skeleton to provide enhanced rigidity. Introduction of a ring system into the center portion of the molecule may be particularly advantageous.

BRIEF SUMMARY OF THE INVENTION

The invention comprises novel compositions of matter, pharmaceutical compositions, and methods for treatment of heart disease using thiol etals selected from compounds having the following structural characteristics,

wherein A means any atom other than hydrogen, and Ak means any alkyl group, and Cy means any ring.

Accordingly, compounds of the structural class shown below are being synthesized,

wherein R is any atom or group other than hydrogen, and wherein the ring emanating from the thioketal can be any size from 3 to 7 members, preferably a 3-, 5-, or 6- membered ring. The ring can contain a heteroatom, and can be substituted. Obviously, the substitution pattern on the ring can result in a chiral molecule. Often, R will be derived from the reaction of the phenol with a cyclic anhydride, although R can be any alkyl, aryl, substituted alkyl, or anything else other than H. It is preferably that R contains a carboxylic acid group to improve solubility. Other functional groups providing substantially improved solubility relative to the parent phenol may also be preferred.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of these compounds is straightforward from the commercially available precursor ϊ shown below:

Condensation of 1 with a cyclic ketone, followed by reaction at one of the two phenolic groups, leads to the compounds of the present invention. In many cases, the second step will be an acylation, yielding an ester.

It should be pointed out that compounds described in this invention need not by synthesized using I as an intermediate. For example, synthesis of the thioketal 2 shown below is described in Hung. Teljes, 56815, 28 Oct 1991.

c

Monoesterification of the diphenol product 2 would yield the cyclic thioketal 3 offhe present invention.

Reaction of 1 tvith cyclopropsmone yields a cyclic thioketal intermediate 41. Reaction of the intermediate with succinic anhydride optionally catalyzed produces 5. Reaction of 4 with glutaric anhydride yields 6. Reaction of 4 with diglycolic anhydride yields 7.

4 R = OH 5 R = OC(0)(CH₂),COOH 6 R = OC(0)(CH₂)₃COOH 7 R = OC(0)CH₂θCH₂COOH In general, the same synthetic pathway can be used to make the analogous compounds described below. A simple, two-step synthesis can be used to make the compounds described herein. Both synthetic steps are standard reactions commonly used in functional group protection.

The initial reaction of 1 with a ketone proceeds under acid catalysis, often with additional heat supplied (see, for example, Greene, T.W, and uts, P.G.M., Protective Groups in Organic Synthesis. 2^nd Ed., (1991), p. 198-199). For example, thioketal 2 can be prepared from 1 by reacting 1 with cyclohexanone and concentrated HC1. Alternatively, 1 can be treated with cyclohexanone and TiCl in methylene chloride to give 2. Products can be purified by column chromatography or other methods known in the art.

Esteπfication of the resulting dipheπol to produce the monoester can be performed in a number of ways known in the art (see, for example, Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis. 2^nd Ed., (1991), p. 88-89; 100- 102), including reaction of the diphenol in DMF with an anhydride and a base such as triethylamine. DMAP or other catalysts may be used. Frequently, one-half equivalent of the anhydride will be used; alternatively, higher concentrations of the anhydride can be used and the reaction can be stopped before proceeding to completion. Obviously, diesterification is a likely side product, and column chromatography or other purification measures will be used to purify the monoester product.

Reaction of cyclopentanone with thiophenol 1, followed by esterification of the product with succinic anhydride, yields cyclic thioketal 8:

Reaction of cyclohexanone with thiophenol 1, followed by esterification of the produc. with succinic anhydride, yields cyclic thioketal 3:

Reaction of norcamphor with thiophenol 1, followed by esterification of the product with succinic anhydride, yields a racemic mixture of cyclic thioketal 9. This racemic mixture can potentially be resolved into its component enantiomers using a number of different techniques, including HPLC.

Reaction of 2-chlorocyclopentanoπe with thiophenol 1, followed by esterification of the product with succinic anhydride, yields a mixture of four diastereomers 10-13 resulting from the two chiral centers, The diastereomers can be resolved or enriched using standard methods known in the art.

10 R, R isomer 11 R, S isomer 12 S, R isomer 13 S, S isomer

Other embodiments of the invention can be obtained via reaction of 1 wi h a ketone selected from the group consisting of camphor, 2-methylcyclopentanone, 2- methylcyclohexanone, 2-chlorocyclopentanone, tetrahydro-(4H)-pyran-4-one, and cycloheptanone, followed by reaction of the product with a cyclic anhydride selected from the group consisting of succinic anhydride, glutaric anhydride, methylsuccinic anhydride, and maleic anhydride.

Molecular modeling, in vitro assays, and in vivo assays will be used to predict and identify superior drug candidates. Many of these compounds will inhibit the expression of VCAM-1. Many of these compounds will reduce oxidation of polyunsaturated fatty acids in the body. Many of these compounds will reduce, prevent, or even reverse inflammation in the arteries that is often the underlying cause of heart disease. Many of these compounds will lower LDL cholesterol levels.

Many of these compounds will be useful therapeutics for treatment of atherosclerosis, restenosis, and heart disease. Many of these compounds may be useful to treat individuals considered to be at high risk of developing heart disease,

It is envisioned that these compounds will be most useful as pharmaceuticals when formulated as metal salts of the carboxylic acid. Therapeutic compounds may be formulated as capsules, tablets, pills, solutions, or any other standard medicinal formulation. It is envisioned that these compounds could be used in conjunction with other pharmaceuticals, particularly in combination with cholesterol-lowering drug^'s such as Lipitor®. The pharmaceutical compositions of the present invention may also be formulated into extended release formulations. It is envisioned that dosagts of the active compound will be between 0.001 g and 2 g. likely between 5 mg and 1 g when administered to a patient weighing 150 pounds.

Claims

I claim; 1. A compound of the formula:

wherein each Ak is independently selected from the group consisting of alkyl;

Cy is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle;

and A is selected from the group consisting of alkyl, substituted alkyl, C(0)R, and C(O)NHR.

2. A compound of the formula:

wherein R is selected from the group consisting of OH, OC(0)(CH₂).COOH, OC(0)(CH₂)₃COOH- and OC(0)CH₂OCH₂COOH.

3. A compound of the formula:

wherein each Ak is independently alkyl;

L is selected from the group consisting of CH₂, CH₂CH₂, CH₂CH₂CH₂, and CH₂OCH₂; each Q is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, halogen, ORi, or NHRi; and R is selected from the group consisting of alkyl, substituted alkyl, C(O)R, and C(O)NHR.

4. A compound of the formula:

wherein each Ak is tert-butyl;

L is selected from the group consisting of CH₂CH₂; each Q is hydrogen; and R is C(0) CH₂CH₂COOH.

5. A method of treating atherosclerosis in a subject, comprising administering to the subject an effective- amount of a compound of the formula of claim 1,

6. A method of treating atherosclerosis in a subject, comprising administering to the subject an effective amount of a compound of the formula of claim 2

7. A method of treating atherosclerosis in a subject, comprising administering to the subject an effective amount of a compound of the formula of claim 3.

8. A method of treating atherosclerosis in a subject, comprising administering to the subject an effective amount of a compound of the formula of claim 4.

9. A pharmaceutical formulation, comprising a compound of the formula of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A pharmaceutical formulation, comprising a compound of the formula of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.

11. A pharmaceutical formulation, comprising a compound of the formula of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A pharmaceutical formulation, comprising a compound of the formula of claim 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.