PHARMACOLOGICAL AGENTS FOR PREVENTING AND TREATING CATARACTS AND PRESBYOPIA EYE DISEASES

Abstract

Methods of treating presbyopia or cataract in a subject in need thereof are provided. The methods require administering to the subject an effective amount of a composition comprising a compound that inhibits the formation or dissolves high molecular weight aggregates of human ?-A-crystallin. Compositions containing certain compounds are believed to be also effective in the treatment of transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Str?ussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome.

Claims

1. A compound, where in the compound is: ##STR00020## or a solvate or a pharmaceutically acceptable salt thereof, wherein, R.sub.1 and R.sub.2 are the same or different, and each of R.sub.1 and R.sub.2 is independently selected from the group consisting of: hydrogen, R.sub.4C?O, ##STR00021## R.sub.3a, R.sub.3b, R.sub.3c, and R.sub.3d are each the same or different, and each independently are selected from the group consisting of: hydrogen, branched or linear (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, and hydroxyl; R.sub.4 is selected from the group consisting of: branched or linear (C.sub.1-C.sub.6)alkyl; halo(C.sub.1-C.sub.6)alkyl; (C.sub.3-C.sub.6)cycloalkyl; halo(C.sub.3-C.sub.6)cycloalkyl; aryl; haloaryl; and R.sub.5a and R.sub.5b are each the same or different, and independently a branched or linear (C.sub.1-C.sub.6)alkyl, R.sub.6 is branched or linear (C.sub.1-C.sub.6)alkyl, aryl, or a polyethylene glycol group or ##STR00022## wherein q is 1 to 10; p is a number from 0 to 10, n is a number from 0 to 10, and X is a C or O;

2. The compound of claim 1, wherein at least one of R.sub.1 and R.sub.2 is selected from the group consisting of ##STR00023## wherein R.sub.5a is (C.sub.1-C.sub.6)alkyl and R.sub.6 is (C.sub.1-C.sub.6)alkyl, aryl, or, ##STR00024## wherein q is 1 to 10, or a solvate or a pharmaceutically acceptable salt thereof.

3. A compound of formula (Ia): ##STR00025## or a solvate or a pharmaceutically acceptable salt thereof; a compound of formula (Ib): ##STR00026## or a solvate or a pharmaceutically acceptable salt thereof; a compound of formula (Ic): ##STR00027## or a solvate or a pharmaceutically acceptable salt thereof; a compound of formula (Id); ##STR00028## or a solvate or a pharmaceutically acceptable salt thereof; a compound of formula (Ie): ##STR00029## or a solvate or a pharmaceutically acceptable salt thereof; or a compound of formula (If): ##STR00030## or a solvate or a pharmaceutically acceptable salt thereof.

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. A compound selected from: ##STR00031## or a solvate or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.

11. A method of treating, preventing, reducing the occurrence or, or reducing, ameliorating, or alleviating the symptoms associated with presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, or other conditions or disorders associated with the eye, comprising administering to a subject in need thereof a compound of claim 1.

12. A method of treating, preventing, reducing the occurrence or, or reducing, ameliorating, or alleviating the symptoms associated with presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, or other conditions or disorders associated with the eye, comprising administering to a subject in need thereof the pharmaceutical composition of claim 10.

Description

DESCRIPTION OF FIGURES

[0071] FIG. 1A shows various concentrations of CAP1160 exposed to UV.

[0072] FIG. 1B shows absorbance at 600 nm for various concentrations of CAP1160 exposed to UV.

EXAMPLES

Example 1: Prevention of UVC/H.SUB.2.O.SUB.2.-Induced Aggregation of Bovine Lens Extracts by CAP1160

[0073] Bovine lens lysates (2 mg/ml, 50 ?l) were incubated with various concentrations of CAP1160 (structure shown below) or a vehicle (0.5% DMSO), and then left unexposed (no exposure) or exposed to UV (UV-irradiated). See FIG. 1A. At various time points, wells-containing bovine lens lysates were pictured and the corresponding absorbance at 600 nm (A600) was measured. See FIGS. 1A and 1B. Representative brightfield images of wells taken 7 min after initial UV exposure (FIG. 1A) and corresponding A600 (FIG. 1B).

[0074] The results show that CAP1160 delays, in a dose-dependent manner, the opacification of bovine lens protein lysates induced by UV irradiation.

##STR00018##

Example 2: General Scheme for Making Prodrugs

[0075] Prodrugs described herein are prepared by the following general scheme.

##STR00019##

[0076] In the above scheme, starting compound 1 and the reagent used for reacting with the OH group are mere examples, and each may be selected as appropriate based on the desired end product.