Potassium channel modulators

Patent metadata

Field	Value
Publication number	US-8962639-B2
Application number	US-78974410-A
Country	US
Kind code	B2
Filing date	May 28, 2010
Priority date	May 29, 2009
Publication date	Feb 24, 2015
Grant date	Feb 24, 2015

Abstract

Disclosed herein are KCNQ potassium channels modulators of formula (I)

wherein ring G 1 , X, R 1 , and R 2 are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.

First claim

We claim:

1. A compound having formula (I-a):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, wherein
each T is independently G a , alkyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —S(O)R a , —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —C(O)R a , —(CR za R zb ) m —C(O)OR a , —(CR za R zb ) m —C(O)NR a R b , or —(CR za R zb ) m -G a ;
q is 0, 1, 2, 3, or 4;
X is C(O);
R 1 is G 1a or —(CR 1a R 1b ) n -G 1a ;
R 2 is alkyl;
G 1a is polycyclic cycloalkyl which is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G a , alkyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —SR a , —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —C(O)R a , and —(CR za R zb ) m —C(O)NR a R b ;
G a , at each occurrence, is independently aryl or C 3 —C 6 cycloalkyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, oxo, —CN, —NO 2 , —OR a , —NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —(CR za R zb ) m —CN, —(CR za R zb ) m —NO 2 , —(CR za R zb ) m —OR a , —(CR za R zb ) m —NR a R b , —(CR za R zb ) m —SR a , —(CR za R zb ) m —S(O)R a , —(CR za R zb ) m —S(O) 2 R a , —(CR za R zb ) m —C(O)R a , —(CR za R zb ) m —C(O)OR a , and —(CR za R zb ) m —C(O)NR a R b ;
R a and R b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl;
R 1a and R 1b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;
R za and R zb , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; and
m and n, at each occurrence, are each independently 1, 2, 3, or 4.

2. The compound or stereoisomer according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, wherein G 1a is optionally substituted hexahydro-2,5-methano-3a(1 H)-pentalene, optionally substituted adamantane, unsubstituted bicyclo[2.2.1]heptane, unsubstituted bicyclo[2.2.1]heptene, optionally substituted oxatricyclo[3.3.1.1 3,7 ]decane, unsubstituted bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane unsubstituted or substituted with one oxo group, or unsubstituted tricyclo[3.2.1.0 2,4 ]octane.

3. The compound or stereoisomer according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, wherein the compound or stereoisomer is selected from the group consisting of:
2-(2-adamantyl)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
2-(1-adamantyl)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
2-(1-adamantyl)-N-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide;
2-(1-adamantyl)-N-(2-ethyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(±)-exo-2-bicyclo[2.2.1]hept-2-yl-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
3-(1-adamantyl)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)propanamide;
(±)-endo-2-bicyclo[2.2.1]hept-5-en-2-yl-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
2-[3-chloro-1-adamantyl]-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(±)-endo-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)bicyclo[2.2.1]heptane-2-carboxamide;
(−)-exo-2-[bicyclo[2.2.1]hept-2-yl]-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(+)-exo2-[bicyclo[2.2.1]hept-2-yl]-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(±)-(endo)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)bicyclo[2.2.1]hept-5-ene-2-carboxamide;
(±)-(exo)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)bicyclo[2.2.1]hept-5-ene-2-carboxamide;
2-(1-adamantyl)-N-(7-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(±)-2-[(endo)-bicyclo[2.2.1]hept-2-yl]-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide;
(±)-2-[(endo)-bicyclo[2.2.1]hept-2-yl]-N-(2-ethyl-4-oxoguinazolin-3(4H)-yl)acetamide;
N-(2-ethyl-4-oxoguinazolin-3(4H)-yl)-2-oxatricyclo[3.3.1.1 3,7 ]decane-1-carboxamide;
endo 2-[bicyclo[3.2.1]oct-3-yl]-N-(2-ethyl-4-oxoguinazolin-3(4H)-ypacetamide;
2-bicyclo[3.3.1]non-9-yl-N-(2-isopropyl-4-oxoguinazolin-3(4H)-yl)acetamide;
2-bicyclo[3.3.1]non-9-yl-N-(2-ethyl-4-oxoguinazolin-3(4H)-yl)acetamide;
(exo,exo)-N-(2-ethyl-4-oxoquinazolin-3(4H)-yl)tricyclo[3 .2.1.0 2,4 ]octane-3-carboxamide;
(exo,exo)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)tricyclo[3.2.1.0 2,4 ]octane-3-carboxamide; and
endo-N-(2-isopropyl-4-oxoguinazolin-3(4H)-yl)-2-7-oxobicyclo[3.3.1]non-3-yl]acetamide.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound or stereoisomer of formula (I-a) according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, in combination with a pharmaceutically acceptable carrier.

5. A method for treating pain in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound or stereoisomer of formula (I-a) according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, alone or in combination with a pharmaceutically acceptable carrier.

6. A method for treating epilepsy, migraine, overactive bladder, schizophrenia, or anxiety in a subject in need thereof, said method comprises administering to the subject a therapeutically effective amount of a compound or stereoisomer of formula (I-a) according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, alone or in combination with a pharmaceutically acceptable carrier.

7. A method of activating KCNQ channels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or stereoisomer of formula (I-a) according to claim 1 , or a pharmaceutically acceptable salt of the compound or stereoisomer, alone or in combination with a pharmaceutically acceptable carrier.

Assignees

• Scanio Marc J
• Bunnelle William H
• Carroll William A
• Peddi Sridhar
• Perez-Medrano Arturo
• Shi Lei
• Abbvie Inc

Inventors

• Scanio Marc J
• Bunnelle William H
• Carroll William A
• Peddi Sridhar
• Perez-Medrano Arturo
• Shi Lei

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title