IP Library › Patent Application 17715401

Patent Application

App. No. 17/715,401

ALDOSE REDUCTASE INHIBITORS FOR TREATMENT OF PHOSPHOMANNOMUTASE 2 DEFICIENCY

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Patent No.: US None
App. No.: 17/715,401

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Abstract

The disclosure relates to methods for treating PMM2-CDG using aldose reductase inhibitors.

Claims (86)

1 . A method of treating PMM2-CDG, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof.

2 . A method of increasing PMM2 enzymatic activity in a subject with PMM2-CDG, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to the subject.

3 . The method of claim 1 , wherein the aldose reductase inhibitor is a compound of Formula (III):

or a 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 through 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 )-alkylsulfonyl; 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 , wherein the aldose reductase inhibitor is selected from the group consisting of:

and salts thereof.

5 . The method of claim 1 , wherein the aldose reductase inhibitor is

or a salt thereof.

6 . The method of claim 1 , wherein the aldose reductase inhibitor is a compound of Formula (II):

or a salt thereof, wherein:

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

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

R 7 through R 10 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 )-alkylsulfonyl; or two of R 7 through R 10 taken together are (C 1 -C 4 )-alkylenedioxy.

7 . The method of claim 6 , wherein the aldose reductase inhibitor is selected from the group consisting of:

and salts thereof.

8 . The method of claim 7 , wherein the aldose reductase inhibitor is

or a salt thereof.

9 . (canceled)

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

11 - 19 . (canceled)

20 . The method of claim 2 , wherein the aldose reductase inhibitor is a compound of Formula (III):

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

21 . The method of claim 20 , wherein the aldose reductase inhibitor is selected from the group consisting of:

and salts thereof.

22 . The method of claim 2 , wherein the aldose reductase inhibitor is

or a salt thereof.

23 . The method of claim 2 , wherein the aldose reductase inhibitor is a compound of Formula (II):

or a salt thereof, wherein:

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

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

24 . The method of claim 23 , wherein the aldose reductase inhibitor is selected from the group consisting of:

and salts thereof.

25 . The method of claim 24 , wherein the aldose reductase inhibitor is

or a salt thereof.

26 . The method of claim 1 , wherein the aldose reductase inhibitor is a compound of Formula (I):

or a salt thereof, wherein:

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

X 1 is N or CR 3 ;

X 2 is N or CR 4 ;

X 3 is N or CR 5 ;

X 4 is N or CR 6 ; with the proviso that two or three of X 1 , X 2 , X 3 , or X 4 are N;

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

Z is

A 1 is NR 11 , O, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 11 , O, or S;

R 3 through R 10 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 )-alkylsulfonyl; or two of R 3 through R 6 or two of R 7 through R 10 taken together are (C 1 -C 4 )-alkylenedioxy; and

R 11 is hydrogen, C 1 -C 4 alkyl, or C(O)O-(C 1 -C 4 )-alkyl.

27 . The method of claim 2 , wherein the aldose reductase inhibitor is a compound of Formula (I):

or a salt thereof, wherein:

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

X 1 is N or CR 3 ;

X 2 is N or CR 4 ;

X 3 is N or CR 5 ;

X 4 is N or CR 6 ; with the proviso that two or three of X 1 , X 2 , X 3 , or X 4 are N;

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

Z is

A 1 is NR 11 , o, S or CH 2 ;

A 2 is N or CH;

A 3 is NR 11 , O, or S;

R 11 is hydrogen, C 1 -C 4 alkyl, or C(O)O-(C 1 -C 4 )-alkyl.

28 . The method of claim 2 , wherein the subject is a human.

Assignments (2)

SECURITY INTEREST Recorded May 22, 2026

From: APPLIED THERAPEUTICS, INC.

To: BARCLAYS BANK PLC

Reel/Frame 074740/0446 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 22, 2023

From: PERFETTI, RICCARDO; SHENDELMAN, SHOSHANA

To: APPLIED THERAPEUTICS, INC.

Reel/Frame 063719/0723 →