Calcium channel agonists

Patent metadata

Field	Value
Publication number	US-2018009810-A1
Application number	US-201715711715-A
Country	US
Kind code	A1
Filing date	Sep 21, 2017
Priority date	May 20, 2013
Publication date	Jan 11, 2018
Grant date	—

Abstract

Embodiments of calcium channel agonists, as well as methods of making and using the calcium channel agonists, are disclosed. The disclosed calcium channel agonists and corresponding salt forms have a structure according to general formula I:

wherein each bond depicted as “ ” is a single bond or a double bond as needed to satisfy valence requirements; Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 independently are nitrogen or carbon; R 1 and R 3 are alkyl; R 2 is alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; and R 4 is alkyl or hydroxyalkyl.

First claim

We claim:

1 . A method for treating a condition mediated by calcium channel dysfunction, comprising:
administering to a subject having, or suspected of having, a condition mediated by calcium channel dysfunction a therapeutically effective amount of a compound having a structure according to general formula I or a pharmaceutically acceptable salt thereof:

wherein each bond depicted as “ ” is a single bond or a double bond as needed to satisfy valence requirements;
Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 independently are nitrogen or carbon;
R 1 and R 3 are alkyl;
R 2 is alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; and
R 4 is alkyl or hydroxyalkyl, provided that:

when Z 1 and Z 3 are nitrogen, Z 2 , Z 4 , and Z 5 are carbon, R 1 is 2-propyl, R 3 is methyl, and R 4 is —CH2OH, then R 2 is not benzyl or 2-hydroxybenzyl.

2 . The method of claim 1 , wherein the condition produces neuromuscular weakness.

3 . The method of claim 1 , wherein the condition is Lambert-Eaton Myasthenic Syndrome, congenital myasthenic syndrome, myasthenia gravis, botulism, botulinum toxin overdose, a peripheral demyelinating disorder, a motor neuron disease, or a combination thereof.

4 . The method of claim 3 , wherein the myasthenia gravis is MuSK myasthenia gravis.

5 . The method of claim 3 , wherein the peripheral demyelinating disorder is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease, copper deficiency, or a combination thereof.

6 . The method of claim 3 , wherein the motor neuron disease is spinal muscular atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive bulbar palsy, pseudobulbar palsy, or a combination thereof.

7 . The method of claim 1 , wherein the compound has a Ca 2+ channel activity half maximal effective concentration, EC 50 , of <50 μM.

8 . The method of claim 1 , wherein the compound has a cyclin-dependent kinase 2 EC 50 of at least 0.2 μM.

9 . The method of claim 1 , wherein the compound has an N-type and/or P/Q-type Ca 2+ channel activity EC 50 that is at least 10-fold less than an L-type Ca 2+ channel activity EC 50 of the compound.

10 . The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of an acetylcholinesterase inhibitor, an immunosuppressant, intravenous immunoglobulins, a glucocorticoid, ascorbic acid, an anti-cancer agent, a potassium channel blocker, a copper supplement, an analgesic, an antidepressant, a muscle relaxant, or a combination thereof.

11 . The method of claim 10 , wherein the condition is Lambert Eaton Myasthenic Syndrome, and the method further comprises administering to the subject a therapeutically effective amount of 3,4-diaminopyridine.

12 . The method of claim 1 , wherein two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are nitrogen.

13 . The method of claim 1 , wherein Z 1 and Z 3 are nitrogen, and Z 2 , Z 4 , and Z 5 are carbon.

14 . The method of claim 1 , wherein R 3 is ethyl.

15 . The method of claim 1 , wherein R 4 is —CH 2 OH.

16 . The method of claim 1 , wherein R 1 is n-alkyl.

17 . The method of claim 1 , wherein R 1 is C 1 -C 3 alkyl.

18 . The method of claim 1 , wherein R 2 is substituted or unsubstituted thiophenyl methyl.

19 . The method of claim 1 , wherein R 2 is:

20 . The method of claim 1 , wherein Z 3 and Z 4 are nitrogen, and Z 1 , Z 2 and Z 5 are carbon.

21 . The method of claim 1 , wherein R 1 is substituted alkyl.

22 . The method of claim 1 , wherein R 1 is cyclic alkyl.

23 . The method of claim 1 , wherein Z 1 , Z 2 and Z 3 are nitrogen, and Z 4 and Z 5 are carbon.

24 . The method of claim 19 , wherein R 4 is —CH 2 OH.

25 . The method of claim 24 , wherein R 3 is ethyl.

26 . The method of claim 19 , wherein Z 1 and Z 3 are nitrogen, and Z 2 , Z 4 , and Z 5 are carbon.

27 . The method of claim 19 , wherein Z 3 and Z 4 are nitrogen, and Z 1 , Z 2 and Z 5 are carbon.

28 . The method of claim 19 , wherein Z 1 , Z 2 and Z 3 are nitrogen, and Z 4 and Z 5 are carbon.

29 . The method of claim 19 , wherein the condition is Lambert-Eaton Myasthenic Syndrome, congenital myasthenic syndrome, myasthenia gravis, botulism, botulinum toxin overdose, a peripheral demyelinating disorder, a motor neuron disease, or a combination thereof.

Assignees

• Univ Of Pittsburgh - Of The Commonwealth System Of Higher Education

Inventors

• Wipf Peter
• Meriney Stephen D
• Liang Mary

Classifications

• C07D473/16 Primary

  two nitrogen atoms · CPC title

• A61K31/375

  Ascorbic acid, i.e. vitamin C; Salts thereof · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title