Opsin-Binding Ligands, Compositions and Methods of Use

摘要

Compounds and compositions are disclosed that are useful for treating ophthalmic conditions caused by or related to production of toxic visual cycle products that accumulate in the eye, such as dry adult macular degeneration, as well as conditions caused by or related to the misfolding of mutant opsin proteins and/or the mis-localization of opsin proteins. Compositions of these compounds alone or in combination with other therapeutic agents are also described, along with therapeutic methods of using such compounds and/or compositions. Methods of synthesizing such agents are also disclosed.

主权项

1. A compound having the structure of Formula I,wherein A is: R1 and R2 are independently:
1) hydrogen,2) —CH3, or3) —CH2CH3; R3 is:
1) hydrogen,2) —CH3,3) —CH2CH3, or4) deuteron; R4 is:
1) hydrogen,2) lower alkyl,3) lower haloalkyl, or4) deuteron; Ra and Rb are each independently:
1) hydrogen, or2) —CH3; T is:
1) —CH2—,2) —CH2CH2—, or3) absent; Ri and Rj are each independently:
1) hydrogen,2) hydroxyl, or3) lower alkyl; Ri and Rj taken together are oxo (═O); B is:
1) oxygen,2) S(O)n 3) NR5, or4) CRqRs; wherein n is 0, 1 or 2;
Rq and Rs are each independently:1) hydrogen,2) hydroxyl, or3) lower alkyl; wherein Rg and Rs can be combined as oxo (═O); R5 is:
1) hydrogen, or2) lower alkyl; Re, Rf Rg, Rh and Rk are each independently:
1) hydrogen;2) lower alkyl;3) lower haloalkyl4) halogen;5) nitro;6) hydroxy7) alkoxy;8) nitrile;9) carboxamido;10) arylcarbonyl;11) carbamoyl;12) amidyl;13) amino;14) alkylcarbonyl; or15) urea; Re and Rf taken together are:
1) —OCH2O—, or2) —OCF2O—; and provided that if R1 and/or R2 are hydrogen then each of Ra and Rb must be selected from methyl or ethyl including all pharmaceutically acceptable salts, solvates and hydrates thereof, and provided that said compound does not include a member of the Excluded Compound Group.