Compositions and methods for treating galactosemia

1. A method of treating galactosemia or preventing complications associated with galactosemia, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof, wherein the aldose reductase inhibitor is a compound of Formula (III) or pharmaceutically acceptable salt thereof:

wherein,

R 1 is CO 2 R 2 ;

R 2 is H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;

X 1 is H or halogen;

X 2 is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;

Z is

A 1 is NR 7 , O, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 7 , O, or S;

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkyl sulfonyl; and

R 7 is hydrogen, C 1 -C 4 -alkyl, or C(O)O—(C 1 -C 4 )-alkyl.

2. A method of reducing the amount or level of galactitol in a subject with galactosemia, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to the subject, wherein the aldose reductase inhibitor is a compound of Formula (III) or pharmaceutically acceptable salt thereof:

wherein,

R 1 is CO 2 R 2 ;

R 2 is H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;

X 1 is H or halogen;

X 2 is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;

Z is

A 1 is NR 7 , O, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 7 , O, or S;

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkyl sulfonyl; and

R 7 is hydrogen, C 1 -C 4 -alkyl, or C(O)O—(C 1 -C 4 )-alkyl.

3. A method for treating cataracts, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof, wherein the aldose reductase inhibitor is a compound of Formula (III) or pharmaceutically acceptable salt thereof:

wherein,

R 1 is CO 2 R 2 ;

R 2 is H, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;

X 1 is H or halogen;

X 2 is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;

Z is

A 1 is NR 7 , O, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 7 , O, or S;

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkyl sulfonyl; and

R 7 is hydrogen, C 1 -C 4 -alkyl, or C(O)O—(C 1 -C 4 )-alkyl.

4. The method of claim 3 , where the subject in need thereof has galactosemia.

5. A method for treating or preventing cognitive or neurological deficiency associated with galactosemia, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject with galactosemia, wherein the aldose reductase inhibitor is a compound of Formula (III) or pharmaceutically acceptable salt thereof:

wherein,

R 1 is CO 2 R 2 ;

R 2 is H, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;

X 1 is H or halogen;

X 2 is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;

Z is

A 1 is NR 7 , O, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 7 , O, or S;

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkyl sulfonyl; and

R 7 is hydrogen, C 1 -C 4 -alkyl, or C(O)O—(C 1 -C 4 )-alkyl.

6. The method of claim 5 , wherein the cognitive or neurological deficiency associated with galactosemia is speech dysfunction.

7. The method of claim 5 , wherein the cognitive or neurological deficiency associated with galactosemia is motor ataxia.

8. The method of claim 5 , wherein the cognitive or neurological deficiency associated with galactosemia is cognitive dysfunction.

9. The method of claim 5 , wherein the cognitive or neurological deficiency associated with galactosemia is pseudomotor cerebrii.

10. The method of claim 5 , wherein the cognitive or neurological deficiency associated with galactosemia is seizure.

11. The method of claim 1 , wherein the aldose reductase inhibitor is a compound of Formula (III-1) or pharmaceutically acceptable salt thereof:

wherein, R 1 is CO 2 R 2 ;

R 2 is H;

X 1 is H;

X 2 is H;

Y is C═O;

A 1 is S;

A 2 is N; and

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, or haloalkyl.

12. The method of claim 2 , wherein the aldose reductase inhibitor is a compound of Formula (III-1) or pharmaceutically acceptable salt thereof:

wherein, R 1 is CO 2 R 2 ;

R 2 is H;

X 1 is H;

X 2 is H;

Y is C═O;

A 1 is S;

A 2 is N; and

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, or haloalkyl.

13. The method of claim 3 , wherein the aldose reductase inhibitor is a compound of Formula (III-1) or pharmaceutically acceptable salt thereof:

wherein, R 1 is CO 2 R 2 ;

R 2 is H;

X 1 is H;

X 2 is H;

Y is a C═O;

A 1 is S;

A 2 is N; and

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, or haloalkyl.

14. The method of claim 5 , wherein the aldose reductase inhibitor is a compound of Formula (III-1) or pharmaceutically acceptable salt thereof:

wherein, R 1 is CO 2 R 2 ;

R 2 is H;

X 1 is H;

X 2 is H;

Y is C═O;

A 1 is S;

A 2 is N; and

R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, or haloalkyl.

15. The method of claim 1 , wherein the aldose reductase inhibitor is selected from the group consisting of

and pharmaceutically acceptable salts thereof.

16. The method of claim 1 , wherein the subject is a human.

17. The method of claim 1 , wherein the galactosemia is manifested in the subject as increased alditol levels in blood, urine or intraocular fluid.

18. The method of claim 17 , wherein the alditol is galactitol, myoinositol or sorbitol.

19. The method of claim 1 , wherein the galactosemia is manifested in the subject as increased liver cirrhosis, retinal disorder, macular edema, eye cataract, ovarian dysfunction, muscle or nerve dysfunction, retinopathy, neuropathy, impaired neural conduction or mental retardation.

20. The method of claim 1 , wherein the galactosemia is Type I Galactosemia (GALT deficiency).

21. The method of claim 1 , wherein the galactosemia is Type II Galactosemia (GALK deficiency).

22. The method of claim 1 , wherein the galactosemia is Type III Galactosemia (GALE deficiency).

23. The method of claim 1 , wherein the aldose reductase inhibitor is Compound B:

or a pharmaceutically acceptable salt thereof.

24. The method of claim 2 , wherein the aldose reductase inhibitor is selected from the group consisting of

and pharmaceutically acceptable salts thereof.

25. The method of claim 3 , wherein the aldose reductase inhibitor is selected from the group consisting of

and pharmaceutically acceptable salts thereof.

26. The method of claim 5 , wherein the aldose reductase inhibitor is selected from the group consisting of

and pharmaceutically acceptable salts thereof.

27. The method of claim 2 , wherein the aldose reductase inhibitor is Compound B:

or a pharmaceutically acceptable salt thereof.

28. The method of claim 3 , wherein the aldose reductase inhibitor is Compound B:

or a pharmaceutically acceptable salt thereof.

29. The method of claim 5 , wherein the aldose reductase inhibitor is Compound B:

or a pharmaceutically acceptable salt thereof.