Lipoic acid prodrug

Patent metadata

Field	Value
Publication number	US-2022151989-A1
Application number	US-202017604054-A
Country	US
Kind code	A1
Filing date	Apr 16, 2020
Priority date	Apr 17, 2019
Publication date	May 19, 2022
Grant date	—

Abstract

The present disclosure provides and an agent for treating or preventing an eye disease such as presbyopia, comprising, as an active ingredient, a lipoic acid prodrug having a specified structure.

First claim

1 . (canceled)

2 . (canceled)

3 . (canceled)

4 . (canceled)

5 . (canceled)

6 . (canceled)

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . (canceled)

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . (canceled)

16 . (canceled)

17 . A compound of

or a pharmaceutically acceptable salt thereof.

18 . A method for treating or preventing presbyopia, comprising administering to a subject in need thereof an effective amount of a compound of Formula [I]:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from:
C 2-8 alkenyl, optionally substituted with the same or different 1 to 4 R 2 ,
C 2-8 alkynyl, optionally substituted with the same or different 1 to 4 R 2 ,
C 1-4 alkyl, substituted with the same or different one or two 4- to 7-membered saturated heteromonocyclic group, wherein the saturated heteromonocyclic group comprises a carbon atom and the same or different 1 to 3 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 , and
C 1-4 alkyl, substituted with the same or different one or two 9- to 10-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group comprises a carbon atom and the same or different 1 to 4 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 ;
R 2 , at each occurrence, is independently selected from —OH, halo, or C 1-3 alkoxy;
R 3 , at each occurrence, is independently selected from —OH, halo, C 1-3 alkyl, optionally substituted with the same or different 1 to 4 R 4 , or C 1-3 alkoxy, optionally substituted with the same or different 1 to 4 R 4 ; and
R 4 , at each occurrence, is independently selected from —OH or halo.

19 . The method according to claim 18 , wherein the compound of Formula [I] is a compound of Formula [I-a]:

wherein R 1 is as defined in claim 18 .

20 . The method according to claim 18 , wherein
R 1 is selected from: C 2-8 alkenyl, optionally substituted with the same or different 1 to 4 R 2 , C 2-8 alkynyl, optionally substituted with the same or different 1 to 4 R 2 , or —(CH 2 ) 1-4 -4- to 7-membered saturated heteromonocyclyl, wherein the saturated heteromonocyclyl comprises a carbon atom and the same or different 1 to 3 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 ; R 2 , at each occurrence, is independently selected from —OH, halo, or C 1-3 alkoxy; R 3 , at each occurrence, is independently selected from —OH, halo, C 1-3 alkyl, optionally substituted with the same or different 1 to 4 R 4 , or C 1-3 alkoxy, optionally substituted with the same or different 1 to 4 R 4 ; and R 4 , at each occurrence, is independently selected from —OH or halo.

21 . The method according to claim 18 , wherein
R 1 is selected from: C 2-8 alkenyl, optionally substituted with the same or different 1 to 4 R 2 , or C 2-8 alkynyl, optionally substituted with the same or different 1 to 4 R 2 ; and R 2 , at each occurrence, is independently selected from —OH, halo, or C 1-3 alkoxy.

22 . The method according to claim 18 , wherein
R 1 is C 1-4 alkyl substituted with the same or different one or two 4- to 7-membered saturated heteromonocyclic group, wherein the saturated heteromonocyclic group comprises a carbon atom and the same or different 1 to 3 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 ; R 3 , at each occurrence, is independently selected from —OH, halo, C 1-3 alkyl, optionally substituted with the same or different 1 to 4 R 4 , or C 1-3 alkoxy, optionally substituted with the same or different 1 to 4 R 4 ; and R 4 , at each occurrence, is independently selected from —OH or halo.

23 . The method according to claim 18 , wherein
R 1 is C 1-4 alkyl substituted with the same or different one or two 9- to 10-membered bicyclic fused heterocyclic group, wherein the bicyclic fused heterocyclic group comprises a carbon atom and the same or different 1 to 4 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 ; R 3 , at each occurrence, is independently selected from —OH, halo, C 1-3 alkyl, optionally substituted with the same or different 1 to 4 R 4 , or C 1-3 alkoxy, optionally substituted with the same or different 1 to 4 R 4 ; and R 4 , at each occurrence, is independently selected from —OH or halo.

24 . The method according to claim 18 , wherein
R 1 is —(CH 2 ) 1-4 -4- to 7-membered saturated heteromonocyclyl, wherein the saturated heteromonocyclyl comprises a carbon atom and the same or different 1 to 3 heteroatoms selected from N, O or S(O) 0-2 and may be substituted with the same or different 1 to 4 R 3 ; R 3 is selected from —OH, halo, C 1-3 alkyl, optionally substituted with the same or different 1 to 4 R 4 , or C 1-3 alkoxy, optionally substituted with the same or different 1 to 4 R 4 ; and R 4 , at each occurrence, is independently selected from —OH or halo.

25 . The method according to claim 18 , wherein the compound of Formula [I] is selected from:

26 . The method according to claim 18 , wherein the compound of Formula [I] or a pharmaceutically acceptable salt thereof is administered ophthalmically.

27 . The method according to claim 18 , wherein the compound of Formula [I] or a pharmaceutically acceptable salt thereof is administered as an eye drop or an eye ointment.

28 . The method according to claim 27 , wherein the amount of the compound of Formula [I] or a pharmaceutically acceptable salt thereof comprised in the eye drop or the eye ointment is 0.00001 to 10% (w/v).

29 . A method for treating or preventing an eye disease accompanied by a decrease in lens elasticity, comprising administering to a subject in need thereof an effective amount of a compound of Formula [I]:

wherein R 1 is as defined in claim 18
or a pharmaceutically acceptable salt thereof.

30 . A method for treating or preventing an eye disease accompanied by a decrease in accommodative function of the eye, comprising administering to a subject in need thereof an effective amount of a compound of Formula [I]:

wherein R 1 is as defined in claim 18
or a pharmaceutically acceptable salt thereof.

31 . A method for improving penetration of lipoic acid into lens comprising making lipoic acid into a compound of Formula [I]:

wherein R 1 is as defined in claim 18
or a pharm

Assignees

• Santen Pharmaceutical Co Ltd

Inventors

• Kato Masatomo
• Oda Tomoko
• Takaoka Shinji
• Honda Takahiro
• Hata Tatsuya

Classifications

• A61K31/385 Primary

  having two or more sulfur atoms in the same ring · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/381

  having five-membered rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title