T-type calcium channel modulator and uses thereof

Patent metadata

Field	Value
Publication number	US-10227332-B2
Application number	US-201515518473-A
Country	US
Kind code	B2
Filing date	Oct 15, 2015
Priority date	Oct 15, 2014
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

The present invention provides T-type calcium channel modulators and methods for producing and using the same. In some embodiments, compounds of the invention are of the formula:

where
R 1 is selected from the group consisting of alkyl, alkenyl, polyether, alkoxy and cycloalkyl; X is selected from the group consisting of methylene, —C(═O)—[NR 4 ] a —, —C(═S)—, and —S(═O) b ; R 2 is selected from the group consisting of heterocycloalkyl and heteroaryl; R 3 is selected from the group consisting of alkyl, alkenyl, polyether, alkoxy, cycloalkyl, —NR 5 R 6 , —C(═O)NR 5 R 6 , —C(═O)OR a (where R a is alkyl, typically C 1 -C 8 alkyl, often C 2 -C 6 alkyl, and in one particular embodiment R a is tert-butyl), and —SO 2 NR 5 R 6 ; R 4 is hydrogen, alkyl, or a nitrogen protecting group; each of R 5 and R 6 are independently selected from the group consisting of hydrogen and alkyl; a is 0 or 1; b is 1 or 2; n=1 to 3; and m=0 to 1.

First claim

What is claimed is:

1. A compound of the formula:

wherein
R 1 is alkyl;
X is selected from the group consisting of —C(═O)—[NR 4 ] a —, —C(═S)—, and —S(═O) b —;
R 2 is selected from the group consisting of piperidinyl and pyrrolidinyl;
R 3 is selected from the group consisting of —C(═O)NH-tBu and 3,3-dimethylbutyl;
R 4 is hydrogen, alkyl, or a nitrogen protecting group;
a is 0 or 1;
b is 1 or 2;
n=1 to 3; and
m=0 to 1.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of C 1 -C 10 alkyl.

3. The compound of claim 2 , wherein R 1 is propyl, butyl, or pentyl.

4. The compound of claim 1 , wherein X is —C(═O)—NH—.

5. The compound of claim 4 , wherein n is 1.

6. The compound of claim 1 , wherein R 2 is selected from the group consisting of

7. The compound of claim 4 , wherein m is 1.

8. The compound of claim 4 , wherein R 3 is —C(═O)NH-tBu.

9. The compound of claim 8 , wherein R 3 is 3,3-dimethylbutyl.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of propyl, butyl and pentyl.

11. A method for treating a clinical condition associated with T-type calcium channel activation, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of claim 1 wherein treating does not embrace preventing.

12. The method of claim 11 , wherein said clinical condition associated with T-type calcium channel activation comprises acute inflammatory pain, tactile allodynia, diabetic neuropathy, pulmonary hypertension, chemotherapeutic induced neuropathy, chronic pain, diabetes, epilepsy, visceral pain, cancer pain, cardiac hypertrophy, or a combination thereof.

13. A method for treating a clinical condition associated with T-type calcium channel activation, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound selected from the group consisting of:

wherein treating does not embrace preventing.

Assignees

• Uti Lp
• Univ Of Montana
• The Univ Of Montana

Inventors

• Zamponi Gerald Werner
• Diaz Philippe

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D209/88

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title