Pantothenate derivatives for the treatment of neurologic disorders
View Patent ↗The present disclosure relates to pantothenate derivatives for the treatment of neurologic disorders (such as pantothenate kinase-associated neurodegeneration), pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
R (Amino Acid)
R′
R″
Me (L-Ala)
Me
Me
Me (L-Ala)
Et
Bn
Me (L-Ala)
MeCyPr
MeCyPr
MeIndole (L-Trp)
Bn
Et.
2. The compound of claim 1 , wherein R, R′ and R″ are methyl.
3. The compound of claim 1 , wherein R is methyl, R′ is ethyl and R″ is benzyl.
4. The compound of claim 1 , wherein R is methyl, and R′ and R″ are methylcyclopropyl.
5. The compound of claim 1 , wherein R is 1H-indol-3yl-methyl, R′ is benzyl and R″ is ethyl.
6. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is a dosage unit form.
8. A method of treating dystonia, extrapyramidal effects, dysphagia, rigidity and/or stiffness of limbs, choreoathetosis, tremor, dementia, spasticity, muscle weakness, or seizure in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1 .
9. The method of claim 8 , wherein the subject suffers from neurodegeneration with brain iron accumulation.
10. The method of claim 8 , wherein the subject is a child.
11. The method of claim 10 , wherein the child is 10 to 15 years old.
12. The method of claim 8 , wherein the subject is an adult.
13. A method of preparing a compound of claim 1 , the method comprising:
(a) protecting both hydroxyl groups of pantothenic acid;
(b) esterifying the acid moiety of the protected pantothenic acid to form a compound of formula:
wherein each Pg independently represent a protecting group, and R″ is as defined as in claim 1 ;
(c) deprotecting the hydroxyl groups;
(d) phosphorylating the deprotected compound with a compound of formula:
wherein L is a leaving group, and R and R′ are defined as in claim 1 ; and
(e) optionally, forming a salt of the compound formed in step (d).
14. A method of preparing a compound of claim 1 , the method comprising:
(a) esterifying pantothenic acid with an alcohol of the formula R″OH to form a compound of formula:
wherein R″ is defined as in claim 1 ;
(b) phosphorylating the esterified compound with a compound of formula:
wherein L is a leaving group, and R and R′ are defined as in claim 1 ; and
(c) optionally, forming a salt of the compound formed in step (b).
15. The method of claim 14 , wherein step (a) comprises subjecting pantothenic acid to Fischer esterification conditions.
16. The method of claim 8 , wherein the subject suffers from a deficiency of pantothenate kinase, 4′-phosphopantothenate, or Coenzyme A.
17. The method of claim 8 , wherein the subject suffers from dystonia.
18. The method of claim 8 , wherein the subject suffers from extrapyramidal effects.
19. The method of claim 8 , wherein the subject suffers from dysphagia.
20. The method of claim 8 , wherein the subject suffers from rigidity and/or stiffness of limbs.
21. The method of claim 8 , wherein the subject suffers from choreoathetosis.
22. The method of claim 8 , wherein the subject suffers from tremor.
23. The method of claim 8 , wherein the subject suffers from dementia.
24. The method of claim 8 , wherein the subject suffers from spasticity.
25. The method of claim 8 , wherein the subject suffers from muscle weakness.
26. The method of claim 8 , wherein the subject suffers from seizure.