Tocopherol and tocopheryl quinone derivatives as correctors of lysosomal storage disorders

Patent metadata

Field	Value
Publication number	US-2016207902-A1
Application number	US-201314442637-A
Country	US
Kind code	A1
Filing date	Nov 14, 2013
Priority date	Nov 16, 2012
Publication date	Jul 21, 2016
Grant date	—

Abstract

The subject invention relates to improved tocopheryl quinone derivatives and tocopherol derivatives having improved pharmacokinetics in vivo that can, in some embodiments, be useful in the treatment of Lysosomal Storage Disorders, restoration of normal mitochondrial ATP production, modulation of intracellular calcium ion concentration and other treatments or therapies. The tocopheryl quinone derivatives and tocopherol derivatives have side chains that have terminally halogenated carbon atoms.

First claim

1 . A tocopheryl quinone derivative comprising a compound having the structure [1]:

wherein the dotted line bonds indicate single or double bonds;
R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, wherein R 7 =H or a single or double bond, and X=a halogen.

2 . The quinone derivative of claim 1 having the structure [2]:

wherein R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
n=20;
R 4 , R 5 =alkyl, fluoroalkyl, hydroxyl, alkoxy, or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

3 . A pharmaceutical composition comprising a tocopheryl quinone derivative having the structure [1]:

wherein the dotted line bonds indicate single or double bonds;
R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, wherein R 7 =H or a single or double bond and X=a halogen; and
a pharmaceutically acceptable vehicle.

4 . The pharmaceutical composition of claim 3 , wherein the tocopheryl quinone derivative has the structure [4]:

wherein R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
n=20;
R 4 , R 5 =alkyl, fluoroalkyl, hydroxyl, alkoxy, or H; and
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

5 . A method of treating a lysosomal storage disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a tocopheryl quinone having the structure [1]:

wherein the dotted line bonds indicate single or double bonds;
R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, wherein R 7 =H or a single or double bond, and X=a halogen; and
a pharmaceutically acceptable vehicle.

6 . The method of treatment of claim 5 , wherein the pharmaceutical composition comprises the quinone derivative of claim 5 having the structure [2]:

wherein R 1 , R 2 and R 3 =alkyl, fluoroalkyl, halogen or H;
n=20;
R 4 , R 5 =alkyl, fluoroalkyl, hydroxyl, alkoxy, or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

7 . The method of claim 5 , further comprising the step of administering to said patient a cyclodextrin.

8 . A method for improving mitochondrial ATP production comprising:
contacting mitochondria with a compound having the structure [1]:

wherein the dotted line bonds indicate single or double bonds;
R 1 , R 2 , R 3 =alkyl, fluoroalkyl, halogen or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, wherein R 7 =H or a single or double bond, and X=a halogen.

9 . The method of claim 8 wherein said compound has the structure [2]:

wherein R 1 , R 2 , R 3 =alkyl, fluoroalkyl, halogen or H;
n=1-20;
R 4 , R 5 =alkyl, fluoroalkyl, hydroxyl, alkoxy or H;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

10 . A tocopherol derivative having the structure [3]:

wherein R 1 -R 3 =alkyl, fluoroalkyl, halogen or H;
R 6 =alkyl, fluoroalkyl, alkenyl or H;
R 8 =a lower alkyl having C 1 to C 6 ;
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, wherein R 7 =H or a single or double bond, and X=a halogen.

11 . The tocopherol derivative of claim 10 having the structure [4]:

wherein R 1 -R 3 =alkyl, fluoroalkyl, halogen or H;
n=1-20,
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

12 . The tocopherol derivative of claim 10 having the structure:

13 . A pharmaceutical composition comprising the tocopherol derivative of claim 10 ; and
a pharmaceutically acceptable vehicle.

14 . The pharmaceutical composition of claim 13 , wherein said tocopherol derivative has the structure [4]:

wherein R 1 -R 3 =alkyl, fluoroalkyl, halogen or H;
n=1-20,
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

15 . The pharmaceutical composition of claim 13 , wherein said tocopherol derivative has the structure:

16 . A method for treating a lysosomal storage disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 13 ;
wherein R 8 =lower alkyl having C 1 -C 5 .

17 . The method of claim 16 , wherein the composition comprises the tocopherol derivative having the structure [4]:

wherein R 1 -R 3 =alkyl, fluoroalkyl, halogen or H;
n=1-20,
wherein the side chain is an alkyl, alkenyl, or alkynyl chain, straight or branched, and X=a halogen.

18 . The method of claim 16 , wherein the composition comprises the tocopherol derivative having the structure:

19 . The method of claim 16 , wherein the treatment with the composition comprising the tocopherol derivative substantially increases Ca 2+ influx to the cells and/or cholesterol exocytosis from the cells of the patient.

20 . The method of claim 16 , wherein the lysosomal storage disorder is selected from the group consisting of Niemann Pick Type C (NPC), Wolman, Niemann Pick Type A, Farber, Tay-Saches, MSIIIB and CLN2 (Batten) diseases.

21 . The method of claim 16 , further comprising the step of administering to said patient a therapeutically effective amount of a cyclodextrin.

Assignees

• Us Health

Inventors

• Marugan Juan Jose
• Zheng Wei
• Xiao Jingbo
• Mckew John

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title

• A61K31/355

  Tocopherols, e.g. vitamin E · CPC title