PHARMACOLOGICAL AGENTS FOR TREATING CONDITIONS OF THE EYE

Abstract

Provided are compounds useful for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye, including COMT inhibitors and pro-drugs thereof, and methods of using these compounds.

Claims

1. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering to the subject in need a compound of Formula (I), ##STR00040## or a solvate or a pharmaceutically acceptable salt thereof, wherein: R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00041## R.sub.2 is selected from the group consisting of: hydrogen, NO.sub.2, and (C.sub.1-C.sub.6)alkyl; R.sub.3 and R.sub.4 are the same or different, and each of R.sub.3 and R.sub.4 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, and halo(C.sub.3-C.sub.6)cycloalkyl; and R.sub.5 is selected from the group consisting of: ##STR00042## R.sup.6a, R.sup.6b, R.sup.7 are the same or different and are each independently hydrogen or a (C.sub.1-C.sub.6)alkyl; R.sup.8 is selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, and ##STR00043## R.sup.9 is selected from the group consisting of: (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, and haloaryl; R.sub.10a and R.sub.10b are the same or different, and each of R.sub.10a and R.sub.10b is a halogen; R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27, are the same or different, and each is independently 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, and halo(C.sub.3-C.sub.6)cycloalkyl; R.sub.22 is CH.sub.3 or CF.sub.3; R.sub.24 and R.sub.25 are the same or different, and each of R.sub.24 and R.sub.25 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00044## Rc, R.sub.D, R.sub.E, and R.sub.F are each the same or different, and each independently are selected from the group consisting of: hydrogen, (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; X is a C.sub.1 alkyl, O, or a direct bond; m and z are each independently a number from 0 to 3; n and p are each independently a number from 0 to 10; and q is a number from 1 to 10.

2. The method of any of the preceding claims, wherein R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00045##

3. The method of any of the preceding claims, wherein R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, ##STR00046##

4. The method of any of the preceding claims, wherein one of R.sub.1a and R.sub.1b is hydrogen, and the other is. ##STR00047##

5. The method of any of the preceding claims, wherein: (a) if R.sub.5 is ##STR00048## then at least one of R.sub.1a, R.sub.1b, R.sub.24, and R.sub.25 is not hydrogen, and (b) is R.sub.5 is not ##STR00049## then at least one of R.sub.1a and R.sub.1b is not hydrogen.

6. The method of any of claims 1-5, wherein R.sub.2 is NO.sub.2.

7. The method of any of claims 1-5, wherein the condition is presbyopia, cataract, or transthyretin (TTR)-associated amyloidosis.

8. The method of any of claims 1-5, wherein the condition is high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM), or lens induced myopia (LIM).

9. A compound of Formula (I) ##STR00050## or a solvate or a pharmaceutically acceptable salt thereof, wherein: R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00051## R.sub.2 is selected from the group consisting of: hydrogen, NO.sub.2, and (C.sub.1-C.sub.6)alkyl; R.sub.3 and R.sub.4 are the same or different, and each of R.sub.3 and R.sub.4 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, and halo(C.sub.3-C.sub.6)cycloalkyl; and R.sub.5 is selected from the group consisting of: ##STR00052## R.sup.6a, R.sup.6b, R.sup.7 are the same or different and are each independently hydrogen or a (C.sub.1-C.sub.6)alkyl; R.sup.8 is selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, and ##STR00053## R.sup.9 is selected from the group consisting of: (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, and haloaryl; R.sub.10a and R.sub.10b are the same or different, and each of R.sub.10a and R.sub.10b is a halogen; R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27, are the same or different, and each is independently 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, and halo(C.sub.3-C.sub.6)cycloalkyl; R.sub.22 is CH.sub.3 or CF.sub.3; R.sub.24 and R.sub.25 are the same or different, and each of R.sub.24 and R.sub.25 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00054## Rc, R.sub.D, R.sub.E, and R.sub.F are each the same or different, and each independently are selected from the group consisting of: hydrogen, (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; X is a C.sub.1 alkyl, O, or a direct bond; m and z are each independently a number from 0 to 3; n and p are each independently a number from 0 to 10; q is a number from 1 to 10; and wherein: (a) if R.sub.5 is ##STR00055## then at least one of R.sub.1a, R.sub.1b, R.sub.24, and R.sub.25 is not hydrogen, and (b) is R.sub.5 is not ##STR00056## then at least one of R.sub.1a and R.sub.1b is not hydrogen.

10. The compound of claim 9, wherein R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00057##

11. The compound of claim 9 or 10, wherein R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, ##STR00058##

12. The compound of claim 9, 10, or 11, wherein one of R.sub.1a and R.sub.1b is hydrogen, and the other is. ##STR00059##

13. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering to the subject in need a compound of Formula (II), ##STR00060## or a solvate or a pharmaceutically acceptable salt thereof, wherein, R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, R.sub.GCO, ##STR00061## Rc, R.sub.D, R.sub.E, and R.sub.F 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.G 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.H and R.sub.J are each the same or different, and independently a branched or linear (C.sub.1-C.sub.6)alkyl, ##STR00062## R.sub.K is branched or linear (C.sub.1-C.sub.6)alkyl, aryl, or X is a C, O, or a direct bond; n is a number from 0 to 10; p is a number from 0 to 10; and q is a number from 1 to 10.

14. The method of claim 13, wherein R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, ##STR00063##

15. The method of claim 13 or 14, wherein only one of R.sub.A and R.sub.B is hydrogen

16. The method of any of claims 13-15, wherein the condition is presbyopia, cataract, or transthyretin (TTR)-associated amyloidosis.

17. The method of any of claims 13-15, wherein the condition is high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM), or lens induced myopia (LIM).

18. A compound of Formula (II) ##STR00064## or a solvate or a pharmaceutically acceptable salt thereof, wherein, R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, R.sub.GCO, ##STR00065## Rc, R.sub.D, R.sub.E, and R.sub.F 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.G 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.H and R.sub.J are each the same or different, and independently a branched or linear (C.sub.1-C.sub.6)alkyl, R.sub.K is branched or linear (C.sub.1-C.sub.6)alkyl, aryl, or ##STR00066## X is a C, O, or a direct bond; n is a number from 0 to 10; p is a number from 0 to 10; and q is a number from 1 to 10, and wherein at least one of R.sub.A and R.sub.B is not hydrogen.

19. The compound of claim 18, wherein R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, ##STR00067##

20. The compound of claim 18 or 19, wherein R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, ##STR00068##

21. The compound of claim 18, 19, or 20, wherein: R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, ##STR00069##

22. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering a compound of Formula (III), (IV), (V), (VI), (VII), (VIII), or (IX), or a solvent or salt thereof to the subject: ##STR00070##

23. The method of claim 22, wherein the condition is presbyopia, cataract, or transthyretin (TTR)-associated amyloidosis.

24. The method of claim 22, wherein the condition is high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM), or lens induced myopia (LIM).

25. The method of any of claims 22-24, wherein the compound of Formula (III) or salt thereof.

26. A compound of Formula (Ma), (IVa), (Va), (VIa), (VIIa), (VIIIa), or (IXa) or a solvent or salt thereof: ##STR00071## wherein Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 are the same or different, and each of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO, ##STR00072## wherein: R.sup.6a, R.sup.6b, R.sup.7 are the same or different and are each independently hydrogen or a (C.sub.1-C.sub.6)alkyl; R.sup.8 is selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, and ##STR00073## R.sup.9 is selected from the group consisting of: (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, and haloaryl; X is a C.sub.1-alkyl, O, or a direct bond; m is a number from 0 to 3; n and p are each independently a number from 0 to 10; q is a number from 1 to 10; and wherein at least one of Z.sub.1 and Z.sub.2 is not hydrogen.

27. The compound of claim 26, wherein the compound is Formula (IIIa), and wherein one of Z.sub.1 and Z.sub.2 is hydrogen and the other is selected from the group consisting of: ##STR00074##

28. The compound of claim 26 or 27, wherein Z.sub.2 is hydrogen.

29. The compound of any of claims 26-28, wherein Z.sub.1 or Z.sub.2 is ##STR00075##

30. The compound of any of claims 26-28, wherein one of Z.sub.1 or Z.sub.2, and the other is ##STR00076##

31. A compound selected from the group consisting of: ##STR00077## or a salt or solvate thereof.

32. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering a compound of any of claims 26-31 to the subject.

33. The method of claim 32, wherein the condition is presbyopia, cataract, or transthyretin (TTR)-associated amyloidosis.

34. The method of claim 32, wherein the condition is high non-pathologic-myopia, pathological myopia, pseudomyopia, form deprived myopia (FDM), or lens induced myopia (LIM).

35. A pharmaceutical composition comprising a compound of any one of claims 9-12, 18-21, and 26-31, and one or more pharmaceutically acceptable excipients.

36. The pharmaceutical composition of any one of claims 9-12, 18-21, and 26-31, further comprising an additional agent.

37. The pharmaceutical composition of claim 36, wherein the additional agent is selected from the group consisting of: COMT inhibitors, MAOI inhibitors, atropine, L-dopa, carbidopa, and non-steroidal anti-inflammatory agents.

38. The method of any of claims 1-8, 13-17, 22-25, further comprising administering an additional agent.

39. The method of claim 38, wherein the additional agent is selected from the group consisting of: COMT inhibitors, MAOI inhibitors, atropine, L-dopa, carbidopa, and non-steroidal anti-inflammatory agents.

40. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye, comprising administering to the subject compound of any one of claims 9-12, 18-21, and 26-31 and one or more of: atropine, L-Dopa, and carbidopa.

41. A method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with myopia in a subject in need thereof, comprising administering to the subject: a compound of any of 9-12, 18-21, and 26-31, atropine, and optionally L-Dopa and/or carbidopa.

Description

DESCRIPTION OF THE FIGURES

[0019] FIG. 1 depicts synthesis and metabolism of dopamine. The enzymes, COMT and MAO are enzymes involved in the metabolism of dopamine.

[0020] FIG. 2 represents data relating to UVC/H.sub.2O.sub.2-induced aggregation of bovine lens extracts, as described in Example 4.

[0021] FIG. 3 and FIG. 4 represents data relating to Example 5.

DETAILED DESCRIPTION

[0022] The present disclosure related to compounds useful for the treatment of conditions of the eye, and methods using COMT inhibitors and prodrugs thereof. The inhibitors of COMT and prodrugs can be used as standalone (monotherapy) or in combination with inhibitors of monoamine oxidase for the treatment and/or management of conditions of the eye. In addition, the COMT inhibitors can be used in combination with L-Dopa and/or carbidopa. Further, the COMT inhibitors can also be used in combination with atropine. In some aspects, the COMT inhibitors can be used in combination with one or more of: L-Dopa, carbidopa, and atropine. Described herein are use of COMT inhibitors and their prodrugs for the treatment of conditions of the eye. These compounds may be delivered using one or a combination of following approaches: (i) topical; (ii) intravitreal; (iii) systemic; (iv) formulated as a device; (v) nanoparticle; (vi) formulated as gel; (vi) coated on to a device (such as glasses and/or contact lenses).

[0023] The present disclosure provides compounds of Formula (I) and methods of using these compounds:

##STR00001##

or a solvate or a pharmaceutically acceptable salt thereof, wherein: [0024] R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO,

##STR00002## [0025] R.sub.2 is selected from the group consisting of: hydrogen, NO.sub.2, and (C.sub.1-C.sub.6)alkyl; [0026] R.sub.3 and R.sub.4 are the same or different, and each of R.sub.3 and R.sub.4 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, and halo(C.sub.3-C.sub.6)cycloalkyl; and [0027] R.sub.5 is selected from the group consisting of:

##STR00003##

[0028] R.sub.6a, R.sub.6b, R.sub.7 are the same or different and are each independently hydrogen or a (C.sub.1-C.sub.6)alkyl; [0029] R.sup.8 is selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, and

##STR00004## [0030] R.sup.9 is selected from the group consisting of: (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, and haloaryl; [0031] R.sub.10a and R.sub.10b are the same or different, and each of R.sub.10a and R.sub.10b is a halogen; [0032] R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27, are the same or different, and each is independently 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, and halo(C.sub.3-C.sub.6)cycloalkyl; [0033] R.sub.22 is CH.sub.3 or CF.sub.3; [0034] R.sub.24 and R.sub.25 are the same or different, and each of R.sub.24 and R.sub.25 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO,

##STR00005## [0035] Rc, R.sub.D, R.sub.E, and R.sub.F are each the same or different, and each independently are selected from the group consisting of: hydrogen, (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; [0036] X is a C.sub.1-alkyl, O, or a direct bond; [0037] m and z are each independently a number from 0 to 3, or any range of numbers within 0 to 3; [0038] n and p are each independently a number from 0 to 10, or any range of numbers within 0 to and [0039] q is a number from 1 to 10, or any range of numbers within 1 to 10.

[0040] In some aspects, at least one of R.sub.1a, and R.sub.1b is not hydrogen. In some aspects, at least one of R.sub.1a, and R.sub.1b is hydrogen. In some aspects, both R.sub.1a and R.sub.1b are not hydrogen. In some aspects, R.sub.1b is hydrogen. In some aspects, R.sub.1a, and R.sub.1b are the same. In some aspects, R.sub.1a, and R.sub.1b are different.

[0041] In some aspects, R.sub.2, is NO.sub.2. In some aspects, R.sub.2 is NO.sub.2, R.sub.1b is hydrogen, and R.sub.1a is not hydrogen.

[0042] In some aspects, n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1.

[0043] In some aspects, the compound is a compound of Formula (I), wherein: (a) if R.sub.5 is

##STR00006##

then at least one of R.sub.1a, R.sub.1b, R.sub.24, and R.sub.25 is not hydrogen, and

(b) is R.SUB.5 .is not

[0044] ##STR00007##

then at least one of R.sub.1a and R.sub.1b is not hydrogen.

[0045] In some aspects, R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO,

##STR00008##

In some embodiments, R.sup.6a, R.sup.6b, and R.sup.7 are each independently hydrogen, (C.sub.1-C.sub.6)alkyl, a (C.sub.1-C.sub.5)alkyl, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.2)alkyl, or a (Ci)alkyl.

[0046] In some aspects, R.sub.1a and R.sub.1b are the same or different, and each of R.sub.1a and R.sub.1b is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO,

##STR00009##

[0047] In some aspects, one of R.sub.1a and R.sub.1b is hydrogen, and the other is

##STR00010##

[0048] In some aspects, R.sub.5 is

##STR00011##

and wherein one or both of R.sub.11 and R.sub.12 is C.sub.2H.sub.5 or CH.sub.3. In some aspects, the one of R.sub.11 and R.sub.12 is C.sub.2H.sub.5 or CH.sub.3 and the other is hydrogen.

[0049] In some aspects, R.sub.5 is

##STR00012##

and wherein one or both of R.sub.13 and R.sub.14 is C.sub.2H.sub.5 or CH.sub.3.

[0050] In some aspects, R.sub.5 is

##STR00013##

and wherein one or more of R.sub.4, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27 is hydrogen. In some aspects, n is a number from 0 to 3.

[0051] In some aspects, R.sub.5 is

##STR00014##

and wherein one or more of R.sub.4, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27 is hydrogen.

[0052] In some aspects, R.sub.5 is

##STR00015##

and one or more of R.sub.4, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.23, R.sub.26, and R.sub.27 is hydrogen. In some aspects m is a number from 0 to 3.

[0053] In some aspects, R.sub.5 is

##STR00016##

and one or more of R.sub.4, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, Rn, R.sub.26, and R.sub.27 is hydrogen. In some aspects, z is a number from 0 to 5, or 0 to 3.

[0054] In some aspects, X is a direct bond or a C.sub.1-alkyl. In some aspects n and p are each independently 0 or 1. In some aspects, R.sup.6a and R.sup.6b are the same. In some aspects, R.sub.H, and R.sub.J are each independently a (C.sub.1-C.sub.3)alkyl.

[0055] In some aspects, at least one of R.sub.1a and R.sub.1b is

##STR00017##

and the other is hydrogen. In some aspects, each of R.sub.1a and R.sub.1b are independently is

##STR00018##

[0056] In some aspects, when one or both of R.sub.1a and R.sub.1b is not hydrogen, the compound is obtained by a process comprising reacting a compound wherein both R.sub.1a and R.sub.1b are hydrogen to obtain the compound wherein one or both of R.sub.1a and R.sub.1b is not hydrogen.

[0057] The present disclosure provides compounds of Formula (II):

##STR00019##

or a solvate or a pharmaceutically acceptable salt thereof,
wherein, [0058] R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen, R.sub.GCO,

##STR00020## [0059] Rc, R.sub.D, R.sub.E, and R.sub.F 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; [0060] R.sub.G 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 [0061] R.sub.H and R.sub.J are each the same or different, and independently a branched or linear (C.sub.1-C.sub.6)alkyl, [0062] R.sub.K is branched or linear (C.sub.1-C.sub.6)alkyl, aryl, or

##STR00021## [0063] X is a C.sub.1-alkyl, O, or a direct bond; [0064] n is a number from 0 to 10, or any range of numbers within 0 to 10; [0065] p is a number from 0 to 10, or any range of numbers within 0 to 10; and [0066] q is a number from 1 to 10, or any range of numbers within 0 to 10; and

[0067] In some aspects, n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1.

[0068] In some aspects, the compound is a compound of Formula (II), wherein at least one of R.sub.A and R.sub.B is not hydrogen. In some aspects, both R.sub.A and R.sub.B are not hydrogen. In some aspects, R.sub.B is hydrogen. In some aspects. R.sub.A and R.sub.B are the same. In some aspects. R.sub.A and R.sub.B are different.

[0069] In some aspects, R.sub.A and R.sub.B are the same or different, and each of R.sub.A and R.sub.B is independently selected from the group consisting of: hydrogen,

##STR00022##

[0070] In some aspects, X is a direct bond or a C.sub.1-alkyl. In some aspects n and p are each independently 0 or 1. In some aspects. R.sub.H and R.sub.J are the same. In some aspects, R.sub.H and R.sub.J are each independently a (C.sub.1-C.sub.3)alkyl.

[0071] In some aspects, when one or both of R.sub.A and R.sub.B is not hydrogen, the compound is obtained by a process comprising reacting a compound wherein both R.sub.A and R.sub.B are hydrogen, to obtain the compound wherein one or both of R.sub.A and R.sub.B1b is not hydrogen.

[0072] In some aspects, at least one of R.sub.A and R.sub.B is

##STR00023##

and the other is hydrogen. In some aspects, each of R.sub.A and R.sub.B are independently is

##STR00024##

[0073] The present disclose provides compounds of Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or solvates or salts there:

##STR00025## ##STR00026##

[0074] The present disclosure provides compounds of Formula (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), or (IXa) or a solvent or salt thereof

##STR00027##

wherein each of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is the same or different, and each of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is independently selected from the group consisting of: hydrogen, (C.sub.1-C.sub.3)alkyl, halo(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl, R.sup.9CO,

##STR00028## [0075] R.sup.6a, R.sup.6b, R.sup.7 are the same or different and are each independently hydrogen or a (C.sub.1-C.sub.6)alkyl; [0076] R.sup.8 is selected from the group consisting of: hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, and

##STR00029## [0077] R.sup.9 is selected from the group consisting of: (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, and haloaryl; [0078] X is a C.sub.1-alkyl, O, or a direct bond; [0079] m is a number from 0 to 3; [0080] n and p are each independently a number from 0 to 10; and [0081] q is a number from 1 to 10,

[0082] In some aspects, at least one of Z.sub.1 and Z.sub.2 is not hydrogen. In some aspects, at least one of Z.sub.1 and Z.sub.2 is hydrogen. In some aspects, both Z.sub.1 and Z.sub.2 are not hydrogen. In some aspects, Z.sub.2 is hydrogen. In some aspects, Z.sub.2 are the same. In some aspects, Z.sub.1 and Z.sub.2 are different.

[0083] In some aspects, Z.sub.1 and Z.sub.2 are each independently selected from the group consisting of:

##STR00030##

[0084] In some aspects, one of Z.sub.1 and Z.sub.2 is hydrogen and the other is selected from the group consisting of:

##STR00031##

[0085] In some aspects, In some aspects, n and p are each independently a number from 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2, or 0 to 1.

[0086] In some aspects, wherein the compound is a compound of Formula (IXa), at least one of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is not hydrogen. In some aspects, at least one Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is hydrogen. In some aspects, one, two, or three of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is hydrogen. In some aspects, none of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is hydrogen. In some aspects, one, two, three, or four of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is the same. In some aspects, one, two, three, or four of Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 is different.

[0087] In some aspects, the compounds of Formula (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), or (IXa) or a solvent or salt are obtained by reacting the compounds of Formulas (III), (IV), (V), (VI), (VII), (VIII), or (IX), respectively:

##STR00032##

or a solvent or salt there. In some aspects, the compounds of Formulas (III), (IV), (V), (VI), (VII), (VIII), or (IX), can be used as a starting material to prepare the compounds of Formula (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), or (IXa), respectively. The compounds may be obtained as described in any of the following, or obtained using starting compounds described in the following, which are each incorporated by reference in their entirety: Canadian Patent No. 2,342,634; Learmonth et al. Synthesis and biological evaluation of a novel series of ortho-nitrated inhibitors of catechol-O-methyltransferase. J Med Chem. 2005 Dec. 15; 48(25):8070-8; Backstrom et al. Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors. J Med Chem. 1989 April; 32(4):841-6; Ma et al. Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders. Br J Clin Pharmacol. 2014; 77(3):410-420; and Bailey et al. Synthesis and evaluation of bifunctional nitrocatechol inhibitors of pig liver catechol-O-methyltransferase. Bioorg Med Chem. 2005 Oct. 15; 13(20):5740-9.

[0088] In some aspects, compounds of the present disclosure that are pro-drugs may be made by a process, such as the one shown below, which is a representative scheme. The starting materials and reagents used for reacting with the OH group are merely examples and each may be selected as appropriate based on the desired end product.

##STR00033##

[0089] The present disclosure provides the following compounds, or a salt or solvate thereof:

##STR00034## ##STR00035##

The present disclosure provides pharmaceutical compositions comprising the above compound and a pharmaceutically acceptable excipient. The present disclosure also provides methods of using the above compounds, comprising administration to a subject in need thereof.

[0090] The present disclosure provides a pharmaceutical composition comprising any of the compounds, or solvents of salts thereof, in the disclosure, and a pharmaceutically acceptable excipient. In some aspects, the pharmaceutical composition comprises a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), or (IXa). In some aspects, the pharmaceutical composition further comprises one or more additional agents, and the methods discussed herein provide for co-administration of one or more additional agents. In some aspects, the additional agent is a compound suitable for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition or disorder associated with the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia, and any other condition that would benefit from administration of a COMT inhibitor or a compound that has an inhibitory effect on COMT.. In some aspects, the additional agent is a monoamine oxidase inhibitor (MAOI). Examples of MAOIs include, but are not limited to: isocarboxazid, selegiline, moclobemide, rasagiline, clorgyline, benmoxin, echinopsidine, mebanazine, metralindole, paragyline, phenelzine, and tranylcyclopramine. In some aspects, the COMT inhibitor or compound having an additional effect on COMT, or the additional agent, is L-Dopa and/or carbidopa. In some aspects, the additional agent is a COMT inhibitor or a further COMT inhibitor or any compound having an inhibitory effect on COMT. In some aspects, the additional agent is nitecapone, entacapone, nebicapone, tolcapone, BIA 3-3335 (1-(3,4-Dihydroxy-5-nitrophenyl)-3-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}-1-propanone dihydrochloride), or bifunctional inhibitor compounds such as N,N-(propane-1,3-diyl)bis(3,4-dihydroxybenzamide). In some aspects, the additional agent is atropine. In some aspects, the additional agent is a non-steroidal anti-inflammatory agent.

[0091] In some aspects, the present disclosure provides a pharmaceutical composition comprising: a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa); atropine; and one or more pharmaceutically acceptable excipients. In some aspects, the additional agent is in pro-drug form or not in pro-drug form.

[0092] The present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering any of the compounds, or solvents of salts thereof, in the disclosure, to the subject. In some aspects, the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye in a subject in need thereof, comprising administering any of compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), or a solvent or salt thereof to the subject. In some aspects, the present disclosure provides methods of reducing or inhibiting the formation of, or dissolving high molecular weight aggregates of human -A-crystallin, or to treat, prevent, or reduce the occurrence of or to reduce, ameliorate, or alleviated symptoms associated with conditions relating to human -A-crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Strussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, comprising administering an effective amount of any of the compounds of the present disclosure.

[0093] In some aspects, myopia includes but is not limited to high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM) and lens induced myopia (LIM).

[0094] In some aspects, the compound may be administered as monotherapy or with an additional agent. In some aspects, the present disclosure provides methods of administering a compound of the present disclosure and an additional agent, and methods of administrating a pharmaceutical composition comprising a compound of the present disclosure, an additional agent, and one or more pharmaceutically acceptable excipients. In some aspects, the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition of the eye, including but not limited to myopia, in a subject in need thereof, comprising administering to the subject any of the compounds of the present disclosure and one or more additional agents, including but not limited to atropine. In some aspects, the co-administration with one or more additional agents may provide synergistic effects. In some aspects, the co-administration with atropine may provide synergistic effects.

[0095] In some aspects, the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject a COMT inhibitor or any compound having an inhibitory effect on COMT. In some aspects, the condition is a condition of the eye. In some aspects, the condition of the eye is myopia, including but not limited to high non-pathologic-myopia, pathological myopia, pseudomyopia, deprived myopia (FDM) and lens induced myopia (LIM). In some aspects, the condition of the eye is presbyopia, cataract, transthyretin (TTR)-associated amyloidosis. In some aspects, the condition is a condition relating to human -A-crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Strussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome

[0096] In some aspects, the COMT inhibitor or compound having an inhibitory effect on COMT may or may not be a pro-drug. In some aspects, the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a COMT inhibitor or any compound having an inhibitory effect on COMT, and one or more pharmaceutically acceptable excipients.

[0097] In some aspects, the present disclosure provides a method for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition to a subject in need thereof, comprising administering to the subject L-dopa and/or carbidopa, or a pharmaceutical composition comprising L-dopa and/or carbidopa and one of more pharmaceutically acceptable excipients. In some aspects, the condition is a condition of the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia In some aspects, the condition is a condition relating to human -A-crystallin and conditions including but not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Strussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome.

[0098] In some aspects, the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition, such as a condition of the eye, including but not limited to presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, and myopia in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa); and atropine. In some aspects, the present disclosure provides a method of treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition of the eye, including but not limited to myopia, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising: a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIIa), (IVa), (Va), (VIa), (Vila), (VIIIa), (IXa); atropine; and one or more pharmaceutically acceptable excipients. In some aspects, the condition is myopia.

[0099] In some aspects, the present disclosure provides methods of administering any of the compounds of the present disclosure and one or more of: atropine, L-Dopa, and carbidopa. In some aspects, the present disclosure provides methods of administering any of the compounds of the present disclosure, atropine, and optionally L-Dopa and/or carbidopa. In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, one or more pharmaceutically acceptable exciepints, and further comprising one or more of: atropine, L-Dopa, and carbidopa. In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, atropine, one or more pharmaceutically acceptable excipients, and optionally L-Dopa and/or carbidopa. In some aspects, the combination of one or more of: atropine, L-Dopa, and/or carbidopa provide a synergistic effect. In some aspects, the combination of any of the compounds of the presently claimed invention and one or more of: atropine, L-Dopa, and/or carbidopa provide a synergistic effect. In some aspects, the combination of a compound of Formula (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa) with one or more of: atropine, L-Dopa, and/or carbidopa provide a synergistic effect.

[0100] In some aspects, the compounds of the present disclosure are administered in an amount effective for treating, preventing, reducing the occurrence of, slowing the progression of, or reducing, ameliorating, or alleviating the symptoms associated with a condition selected from the group consisting of: presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, myopia, or other conditions or disorders associated with the eye. In some aspects, pharmaceutical compositions comprise a compound of the present disclosure in an effective amount.

[0101] In some aspects, the compounds of the present disclosure may be administered through any route of administration, including but not limited to oral, nasal, intranasal, intramuscular, intravenous, subcutaneous, rectal, sublingual, intrathecal, transdermal, intraocularly, inhalation or other topical. In some aspects, the compounds of the present disclosure are administrated intraocularly or topically to the eye. In some aspects, the pharmaceutical composition is an ophthalmic solution or suspension comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients suitable for administration to the eye. In some aspects, an amount effective to reduce or inhibit the formation of, or dissolve high molecular weight aggregates of human -A-crystallin, or to treat, prevent, or reduce the occurrence of or to reduce, ameliorate, or alleviated symptoms associated with conditions relating to human -A-crystallin. In some aspects, the conditions include but are not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome

[0102] Methods used to deliver compounds described herein to the eye include, but are not limited to: (i) topical, (ii) (iii) subconjunctival, (iv) intravitreal, (v) systemic, (vi) using a device using a formulation suitable for the device (vii) as nanoparticles (vii) as a gel with suitable formulation, (viii) coated on to a device (such as contact lenses).

[0103] With regard to topical administration, such administration is typically accomplished using eye drops. Contact time on the eye surface is short, but can be prolonged using specific formulations, e.g., gels, gelifying formulations, ointments, and inserts. Typically, the basic nature of the solution containing the drug composition is aqueous and as such, agents designed to increase the viscosity of the solution may be employed. Such agents include, for example, hydroxypropyl methylcellulose, carbopol, polyvinyl alcohol, and the like.

[0104] Traditionally subconjunctival injections have been used to deliver drugs at increased levels to the uvea. This mode of administration can be used to deliver drugs in controlled release formulations to the posterior segment and to guide the healing process after surgery.

[0105] With regard to intravitreal administration, direct drug administration into the vitreous offers the advantage of more straightforward access to the vitreous and retina. Delivery from the vitreous to the choroid is more complicated, however, due to the hindrance by the RPE (Retinal Pigment Epithelium) barrier. Small molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules, particularly those that are positively charged, is restricted. An injectable composition suitable for intraocular injection typically comprises a solution of the drug or a fine particle suspension, which may enable sustained delivery to the eye. Formulations are usually aqueous and may commonly include solubilization enhancers such as, but not limited to, polyvinyl alcohol, Tween 80, solutel, cremophore, and cyclodextrin. These solubilization enhancers may be used in combination. The formulation is typically in the pH range of 3-8, which is regarded as acceptable for intravitreal formulations. To achieve an acceptable pH, buffering systems are sometimes used. These include but are not limited to citrate and phosphate based buffering systems. The tonicity of the intravitreal formulation may be adjusted to remain within a desirable range which typically would be 250-360 mOsm/kg. Adjustment of tonicity may be achieved for example by addition of sodium chloride. Typically, intravitreal formulations are produced by sterile manufacture for single use. Preserved formulations can be used, for example, formulations containing a preservative such as benzoyl alcohol. The dose of the active agent in the compositions of the invention will depend on the nature and degree of the condition, the age and condition of the patient and other factors known to those skilled in the art. Administration can be either as a single injection with no further dosing or multiple injections.

[0106] With respect to systemic administration, systemic medication is required for posterior segment therapy and to complement topical therapy for the anterior segment. The posterior segment always requires systemic therapy, because most topical medications do not penetrate to the posterior segment Retrobulbar and orbital tissues are treated systemically.

[0107] In some aspects, the present disclosure provides a method of treating conditions of the eye that requires administration of an effective amount of a composition comprising a compound described herein, the compound being present in a prodrug form, or being converted to a prodrug form. Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are better able to penetrate the cornea (e.g., they are more lipophilic) than the standard formulation of the drug. See review by Brian G. Short, Toxicologic Pathology, 36:49-62, 2008. As described in the review and the references cited therein, within the cornea or after corneal penetration, the prodrug is either chemically or enzymatically metabolized to the active parent compound. Enzyme systems identified in ocular tissues include esterases, ketone reductase, and steroid 6-hydroxylase.

[0108] Most prodrugs are delivered conventionally by topical application such as antiviral prodrugs ganciclovir and acyclovir, although ganciclovir has also been delivered intravitreally by injection or as a nonbiodegradable reservoir. Delivery of a drug with a nonnatural enzyme system in the cornea has been achieved with topical 5-fturocytosine, a prodrug of 5-fluorouracil, administered after subconjunctival transplantation of cells containing the converting enzyme cytosine deaminase. Increased corneal penetration into the anterior segments can be achieved with the addition of permeability enhancers to the drug formulation. Surfactants, bile acids, chelating agents, and preservatives have all been used. Cyclodextrins, cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that form complexes with lipophilic drugs, are among the more popular permeability enhancers, They increase chemical stability and bioavailability and decrease local irritation, and they have been used with corticosteroids, choloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors. The present invention includes small molecule inhibitors that are synthesized as prodrugs such that they have a better ability to permeate the cornea.

[0109] The terms halo and halogen, as used herein refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I).

[0110] The term alkyl, used alone or as a part of a larger moiety such as e.g., haloalkyl, means a saturated monovalent straight or branched, substituted or unsubstituted hydrocarbon radical having, unless otherwise specified, 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, see-butyl, isobutyl, tert-butyl, n-pentyl n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. Monovalent means attached to the rest of the molecule at one point.

[0111] The terms cycloalkyl used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic, bicyclic or tricyclic substituted or unsubstituted ring system as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include. without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl cycloheptenyl, and cyclooctyl. Bicyclic cycloalkyl groups include e.g., cycloalkyl group fused to another cycloalkyl group, such as decalin or a cycloalkyl group fused to an and group (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline. An example of a tricyclic ring system is adamantane. It will be understood that the point of attachment for bicyclic cycloalkyl groups can be a tether on the cycloalkyl portion or on the aryl group (e.g., phenyl) or heteroaryl group that results in a stable structure. It will be further understood that when specified, optional substituents on a cyloalkyl may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.

[0112] The term heterocyclyl means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated substituted or unsubstituted heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms heterocycle, heterocyclyl, heterocyclyl ring, heterocyclic group, heterocyclic moiety, and heterocyclic radical may be used interchangeably. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. A heterocylyl group may be mono- or bi-cyclic. Unless otherwise specified, bicyclic heterocydyl groups include, e.g., unsaturated or saturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaryl ring, such as for example, chronmnyl, 2,3-dihydrobenzo[b][1,4]dioxioyl, tetrahydronaphthyridioyl, dihydropyrrolotriazolyl, imidazopynmidinyl, quinolinonyl, dioxaspirodecanyl. It will be understood that the point of attachment for bicyclic heterocydyl groups can be on the heterocyclyl group or aromatic ring that results in a stable structure. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

[0113] The term heteroaryl used alone or as part of a larger moiety as in heteroarylalkyl, heteroarylalkoxy, or heteroatylaminoalkyl, refers to a 5-10-membered substituted or unsubstituted aromatic radical containing 1-4 heteroatoms selected from N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazioyl, pyrimidinyl, pyrazinyl, indolizinyl purinyl, naphthyridinyl, and pteridinyl. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic. The terms heteroaryl and heteroar-, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, and quinoxalinyl. A heteroaryl group may be mono- or bicyclic. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached. As used herein, the term aryl, used done or in conjunction with other terms, refers to a 6-14 membered aromatic ring containing only ring carbon atoms. The aryl ring may be monocyclic, bicyclic or tricyclic. Non-limiting examples include phenyl, naphthyl or anthracenyl, and the like. It will also be understood that when specified, optional substituents on an aryl group may be present on any substitutable position. The aryl group may be unsubstituted or mono- or di-substituted.

[0114] As used herein the terms subject and patient may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, eats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0115] The compounds of the present disclosure may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic pharmaceutically acceptable salts.

[0116] For any structure disclosed herein, the scope of a compound also includes any tautomer which may be formed. Unless otherwise indicated, reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.

[0117] A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions). Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Pharmaceutically acceptable basic/cationic sate include, the sodium, potassium, calcium, magnesium, diethanolamine, romethyl-D-glneamlne, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

[0118] Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.

[0119] A prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by the removal of a biologically labile group. Prodrug preparation is well known in the art. For example, Prodrugs and Drug Delivery Systems, which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

[0120] Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.

[0121] Unless stereochemistry is explicitly depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture. Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.

[0122] Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.

[0123] When ranges of values are disclosed, and the notation from n1 . . . to n2 or n1 . . . to n2 is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range 3 to 11 membered cycloalkyl is intended to include cycloalkyl having three, four, five, six, seven, eight, nine, ten, or eleven ring atoms. When n is set at 0 in the context of 0 carbon atoms, it is intended to indicate a bond or null.

EXAMPLES

Example 1: Inhibition of Catechol-O-Methyl Transferase (COMT)

[0124] Unless already known, the ability of a compound to act as an inhibitor of COMT is determined using a fluorescence polarization assay (Graves, T. L., et al. 2008). Compounds exhibit activity in the assay based on their ability to inhibit the production of S-adenosyl homocysteine (SAH). Any compound exhibiting an IC.sub.50 below 1 M is considered a COMT inhibitor. To determine IC.sub.50 values, a 10 mM compound stock in DMSO is used to prepare a 10-point 3-fold dilution series of the compound. 1 L of an appropriate dilution of the compound is plated into assay wells (black 96-well, round-bottom, polystyrene plates from Corning Inc., Corning, NY, Costar #3792). Recombinant enzyme is diluted in Assay Buffer (100 mM Na.sub.2HPO.sub.4 pH 7.4, 1 mM DTT, 0.005% Tween-20), and 35 L of the diluted enzyme is added to the assay wells containing 1 L of the diluted compound. The final amount of enzyme in the assay is varied between 1 and 6 ng depending on the preparation of COMT utilized. COMT and the compound are preincubated for about 2 h at room temperature. Enzyme reactions are initiated by the addition of 5 L of an 8 mix prepared in Assay Buffer containing 8 M S-adenosyl methionine (SAM) (USB Corporation, Cleveland, OH, #US10601), 16 M dopamine (Sigma-Aldrich, St. Louis, MO, #H8502), and 40 mM MgCl.sub.2. After a 25 min incubation at room temperature, reactions are quenched with 5 L of 250 mM EDTA, pH 8.2. A 20 L of a preformed complex containing a 1:80 000 dilution of S-adenosyl-L-cysteine (SAC) TAMRA tracer (2 mM from AnaSpec, Fremont, CA) and a 1:20 dilution of anti-S-adenosyl-L-homocysteine antibody (mouse monoclonal from IMX Homocysteine Reagent Pack, Abbott Laboratories, Abbott Park, Ill., #7D29-20) was prepared in Assay Buffer B (Na2HPO4 pH 7.2). The SAH antibody/SAC TAMRA tracer complex discussed above was pre-formed at room temperature for 30 min while protected from light. Addition of 20 l of pre-formed complex to 40 l of the quenched reaction mix resulted in a final dilution of the SAH antibody and SAC TAMRA mix to be 1:60 and 1:240 000, respectively. After a 2.5 h incubation at room temperature, while being protected from light, fluorescence polarization was measured using a Tecan Safire2plate reader using an excitation of 530 nm and an emission of 595 nm (Tecan US, Durham, NC). Titration curves and IC.sub.50 values were calculated using standard protocols.

Example 2: General Scheme for Making Prodrugs

[0125] Prodrugs described herein are prepared by the following general scheme.

##STR00036##

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. In some aspects, n is a number from 1 to 10.

Example 3: Evaluation the Efficacy of CAP4196 in Myopia Chick Model

[0126] The Myopia chick model, developed more than 35 years ago, is one of the major models for Myopia today. Major advantages of this model include: (1) relatively large eyes (8 to 14 mm), (2) rapid eye growth of about 100 m per day, (3) highly sensitive control of refractive state by retinal image quality and focus, (4) excellent optics (diffraction-limited at 2.0 mm pupils), (5) Active accommodation (about 17 D), (6) high visual acuity (7 cycles/degree), (7) easy drug delivery by intravitreal injection, (8) Friendly and co-operative nature, and (9) inexpensive and easy to keep

[0127] Three compounds, quinpirole, CAP4196, and L-DOPA (see structures below), are tested in chicks for their effects on scleral proteoglycan synthesis as a measure of scleral growth, axial elongation, and myopia.

##STR00037##

[0128] Ten to thirteen chicks are tested for each of the following conditions (sample size provided in parentheses): [0129] Group 1: Normal (n=13), Vehicle (n=13), quinpirole (n=13) [0130] Group 2: Vehicle (n=13), CAP4196 low dose (n=13), CAP4196 high dose (n=13) [0131] Group 3: Vehicle (n=10), L-DOPA (n=10), L-DOPA+CAP4196 low dose (n=10), L-DOPA+CAP4196 high dose (n=10).

[0132] The amount of the compound injected and the vehicle are as shown below. [0133] Quinpirole (n=13): 10 nmoles in 20 l injection [0134] L-DOPA: 7.5 mM in 20 l injection [0135] CAP4196: low dose 0.75 mM in 20 l injection [0136] CAP4196: high dose 2.25 mM in 20 l injection [0137] Vehicle for quinpirole: Saline (20 l, 0.75% NaCl w/v) (vehicle for quinpirole) [0138] Vehicle for L-DOPA and CAP4196: 0.1% w/v ascorbic acid in 1 phosphate-buffered saline_(PBS) [0139] Vehicle for L-DOPA and CAP4196: Phosphate buffered saline

[0140] Form deprivation myopia is induced in the right eyes of 4-5 days old chicks by the application of translucent occluders. Chicks receive intravitreal injections of the compound or vehicle in the form deprived eye (20 l/eye) daily for a total of five days. Additionally, a group of normal chicks receive intravitreal injections of vehicle in their right eye, to control for changes associated with intravitreal injections (Normal, n=13). At the end of the treatment period, chicks are sacrificed, their sclera labelled in organ culture with .sup.35SO.sub.4, and scleral proteoglycan synthesis measured by CPC-precipitation of newly synthesized glycosaminoglycans. Radioactivity is measured using scintillation counting, and the amount of radioactivity is compared (as CPM) between right and left eyes of all groups of animals by paired t-tests and between different groups using ANOVA. Animals are raised in the Oklahoma University Health Science Center (OUHSC) Animal facility.

Example 4: Prevention of UVC/H.SUB.2.O.SUB.2.-Induced Aggregation of Bovine Lens Extracts by CAP 1160

[0141] As shown in FIG. 4 (with 7 minutes exposure), CAP1160 prevents UVC/H.sub.2O.sub.2-induced aggregation of bovine lens extracts. The structure of CAP1160 is:

##STR00038##

Example 5: Evaluation the Efficacy of CAP4719 in Myopia Check Model

[0142] Three compounds (quinpirole, CAP4719, and L-DOPA) were tested in chicks for their effects on scleral proteoglycan synthesis, as a measure of scleral growth, axial elongation and myopia. CAP4719 has the following structure:

##STR00039##

[0143] A sample size of 15 chicks for each of the following conditions (sample size in parentheses) is tested: [0144] Group 1: Normal (n=15), Vehicle (n=15), quinpirole (n=15) [Positive control] [0145] Group 2: Vehicle (n=15), CAP4719 low dose (n=15), CAP4719 high dose (n=15) [0146] Group 3: Vehicle (n=15), L-DOPA (n=15), L-DOPA+CAP4719 low dose (n=L-DOPA+CAP4719 high dose (n=15). [0147] Saline (20 l, 0.75% NaCl w/v) (vehicle for quinpirole) [0148] 0.1% w/v ascorbic acid in 1phosphate-buffered saline (PBS) (vehicle for L-DOPA and CAP4719) [0149] Quinpirole (n=15), 10 nmoles in 20 ul injection [0150] L-DOPA 7.5 mM in 20 ul injection [0151] CAP4719 low dose 0.75 mM in 20 ul injection [0152] CAP4719 high dose 2.25 mM in 20 ul injection

[0153] Form deprivation myopia is induced in the right eyes of 4-5 days old chicks by the application of translucent occluders. Chicks receive intravitreal injections of the compound or vehicle in the form deprived eye (20 ul/eye) daily for a total of seven days. Additionally, a group of normal chicks receive intravitreal injections of vehicle in their right eye, to control for changes associated with intravitreal injections (Normal, n=15). At the end of the treatment period, chicks are sacrificed, their sclera labelled in organ culture with 35SO4, and scleral proteoglycan synthesis measured by CPC-precipitation of newly synthesized glycosaminoglycans. Radioactivity is measured using scintillation counting, and the amount of radioactivity compared (as CPM) between right and left eyes of all groups of animals by paired t-tests and between different groups using ANOVA. Animals are raised in an approved Animal facility and all experimental procedures will be carried out under an institutionally approved IACUC protocol.

[0154] In addition, the tissue is used for further evaluation using analytical methods to quantify levels of dopamine, metabolites (HVA & DOPAC) and CAP4719 by liquid chromatography mass spectrometry (LC/MS).

[0155] Results

[0156] The right eyes were goggled (myopic) and injected with either the high dose, low dose, or vehicle of the CAP4719 compound. Proteoglycan synthesis was measured as the amount of 35SO4 (cpm) incorporated into glycosaminoglycans four hours after the final dose. It is expected that the right eye has a higher rate of proteoglycan synthesis. The higher rate of proteoglycan synthesis is related to the increased growth rate of the myopic eye. Application of the high and low doses of the compound did not completely block the increase in proteoglycan synthesis, but the percentage increase over the left (control) eye appears to be lower in the CAP4719 treated eyes compared with the vehicle. The lower rate of proteoglycan synthesis in the right eyes of the treated eyes would be expected to cause a slower rate of elongation (and less myopia) compared with the vehicle treated eyes. Results are shown in FIG. 3 and FIG. 4.

REFERENCES

[0157] Axelrod, J., and Tomchick, R.: Enzymatic O-methylation of epinephrine and other catechols, J Biol. Chem. 233: 702, (1958) [0158] Bergen, M. A. et al. Altered Refractive Development in Mice With Reduced Levels of Retinal Dopamine. Invest Ophthalmol Vis Sci 57, 4412-4419 (2016) [0159] Feldkaemper, M. & Schaeffel, F. An updated view on the role of dopamine in myopia. Exp Eye Res 114, 106-119 (2013) [0160] Graves, T. L., Zhang, Y., and Scott, J. E. A universal competitive fluorescence polarization activity assay for S-adenosylmethionine utilizing methyltransferases. Anal. Biochem. 373,296-306 (2008) [0161] Holden, B. A. et al. Nearly 1 billion myopes at risk of myopia-related sight-threatening conditions by 2050time to act now. Clin Exp Optom, 98, 491-493 (2015) [0162] Holden B, Fricke T R, Wilson D A, Jong M, Naidoo K S, Sankaridurg P et al. Global prevalence of myopia, high myopia, and temporal trends from 2000 to 2050, Ophthalmology, 123(5):1036-42 (2016) [0163] Iuvone, P. M., Tigges, M., Fernandes, A. & Tigges, J. Dopamine synthesis and metabolism in rhesus monkey retina: development, aging, and the effects of monocular visual deprivation. Vis Neurosci 2, 465-471 (1989) [0164] Kate Thomson, Cindy Karouta, Ian Morgan, Tamsin Kelly, and Regan Ashby; Effectiveness and safety of topical levodopa in a chick model of myopia, Sci Rep. 9: 18345 (2019) [0165] Mao J, Liu S, Qin W, Li F, Wu X, Tan Q; Optom Vis Sci. 87(1):53-60 (2010) [0166] McCarthy, C. S., Megaw, P., Devadas, M. & Morgan, I. G. Dopaminergic agents affect the ability of brief periods of normal vision to prevent form-deprivation myopia. Exp Eye Res 84, 100-107 (2007) [0167] Morgan, I. G., Ohno-Matsui, K. & Saw, S. M. Myopia. Lancet, 379, 1739-1748 (2012) [0168] Morgan, I. G., He, M. & Rose, K. A. Epidemic of pathologic myopia: what can laboratory studies and epidemiology tell us? Retina, 37, 989-997 (2017) [0169] Ohno-Matsui K, Yoshida T, Futagami S, Yasuzumi K, Shimada N, Kojima A. Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularization in pathological myopia. Br J Ophthalmol, 87:570-3 (2013) [0170] Ohno-Matsui, K. What Is the Fundamental Nature of Pathologic Myopia? Retina, 37, 1043-1048 (2017) [0171] Rein, D. B. Vision problems are a leading source of modifiable health expenditures. Invest Ophthalmol Vis Sci 54, ORSF18-22 (2013) [0172] Tosini, G and Iuvone, P M, Role of Melatonin and Dopamine in the Regulation of Retinal Circadian Rhythms, from The Retina and Circadian Rhythms, Springer Series in Vision Research, Eds. Marshall, M J & Collin, S P (eds.) 2014 10.1007/978-1-4614-9613-7 0 Springer Science+Business Media New York 2014 [0173] Waltman S and Sears M, Catechol-O-Methyl Transferase and Monoamine Oxidase Activity in the Ocular Tissues of Albino Rabbits, Invest Ophthalmol., 3:601-5 (1964) [0174] Witkovsky, P. Dopamine and retinal function. Doc Ophthalmol 108, 17-40 (2004) [0175] Wu, X. H. et al. The Role of Retinal Dopamine in C57BL/6 Mouse Refractive Development as Revealed by Intravitreal Administration of 6-Hydroxydopamine. Invest Ophthalmol Vis Sci 57, 5393-5404 (2016)

[0176] Other Equivalents

[0177] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0178] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.