US 7,741,332 B2Granted

Fused ring heterocycles as potassium channel modulators

AssigneeIcagen, Inc.

InventorsGrant Andrew McNaughton-Smith, George Salvatore Amato, James Barnwell Thomas, Jr.

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Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides quinazolinone, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases, maintaining bladder control or treating urinary incontinence) and as neuroprotective agents (e.g., to prevent stroke and the like) by modulating potassium channels associated with the onset or recurrence of the indicated conditions.

Claims45

Dependent claims

A compound of the formula:

in which
A is a member selected from the group consisting of substituted phenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted 1,2,3,-oxadiazolyl, and six-membered substituted or unsubstituted heteroaryl, substituted or unsubstituted C4-C8 cycloalkyl, and substituted or unsubstituted 5-8 membered heterocyclyl;
X is a member selected from CO and CS;
W is N;
Z is a member selected from the group consisting of —CH2—, —CHF—, —CF2—, and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
and
R2 is a member selected from the group consisting of CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl;
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-7-membered heterocyclyl,
such that when X is C(O), A is a substituted phenyl forming a 1,3-benzodioxolyl ring;
and Y—R2 is unsubstituted acyclic alkyl, acyclic alkyl substituted with an amide or unsubstituted phenyl, then Z-R1 is other than acyclic alkyl substituted with unsubstituted phenyl, and acyclic alkyl substituted with 4-phenyl- 1-halo.

13 more elements

A compound of the formula:

in which
X is a member selected from CO and CS;
W is N;
Z is a member selected from —CH2—, —CHF—, —CF2— and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R2 is a member selected from CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-oxtyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted 3-7 membered saturated heterocyclyl;
R8 and R9 are independently selected from H, halo, CF3, CF3O, NO2, CN, S(O)mR10, COOR11, CONR12R13, SO2NR12R13, S(O)mCF3, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl, with the proviso that R8 and R9 are not both H;
or R8 and R9 are taken together with the atoms to which they are attached to form a dioxolyl ring;
wherein R10 and R11 are independently selected from substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
m is an integer from 0 to 2;
and
R12 and R13 are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or R12 and R13, together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring,
such that when X is C(O), R8is halogen and R9 is H or R8 and R9 taken together with the carbon atoms to which they are joined form a dioxolyl ring, and Y—R2 is unsubstituted acyclic alkyl, acyclic alkyl substituted with an amide or unsubstituted phenyl, then Z-R1 is other than acyclic alkyl substituted with unsubstituted phenyl, and acyclic alkyl substituted with 4-phenyl-1-halo.

15 more elements

A compound of the formula:

in which
X is a member selected from CO and CS;
W is N;
Z is a member selected from —CH2—, —CHF—, —CF2— and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, substituted or unsubstituted C1-C8 alkyl;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R2 is a member selected from CF3, substituted or unsubstituted C1-C8 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-7 membered saturated heterocyclyl;
R8 and R9 are independently selected from H, halo, CF3O, NO2, CN, S(O)mR10, COOR11, CONR12R13, SO2NR12R13, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl, with the proviso that R8 and R9 are not both H;
wherein R10 is a member selected from CF3 and substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
and R11 is a member selected from substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
m is an integer from 0 to 2;
and
R12 and R13 are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or R12 and R13, taken together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring.

14 more elements

A composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

in which
A is a member selected from substituted phenyl;
substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted 1,2,3,-oxadiazolyl, and six-membered substituted or unsubstituted heteroaryl, substituted or unsubstituted C4-C8 cycloalkyl, and substituted or unsubstituted 5-8 membered heterocyclyl;
X is a member selected from CO and CS;
W is N;
Z is a member selected from the group consisting of —CH2—, —CHF—, —CF2—, and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
and
R2 is a member selected from the group consisting of CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (chclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 -7-membered heterocyclyl,
such that when X is C(O), A is a substituted phenyl forming a 1,3-benzodioxolyl ring;
and Y—R2 is unsubstituted acyclic alkyl, acyclic alkyl substituted with an amide or unsubstituted phenyl, then Z-R1 is other than acyclic alkyl substituted with unsubstituted phenyl, and acyclic alkyl substituted with 4-phenyl-1-halo.

13 more elements

A composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

in which
X is a member selected from CO and CS;
W is N;
Z is a member selected from —CH2—, —CHF—, —CF2— and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R2 is a member selected from CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-7 membered saturated heterocyclyl;
R8 and R9 are independently selected from H, halo, CF3, CF3O, NO2, CN, S(O)mR10, COOR11, CONR12R13, SO2NR12R13, S(O)mCF3, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl, with the proviso that R8 and R9are not both H;
or R8 and R9 are taken together with the atoms to which they are attached to form a dioxolyl ring;
wherein R10 and R11 are independently selected from substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
m is an integer from 0 to 2;
and
R12 and R13 are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or R12 and R13, together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring,
such that when X is C(O), R8 is halogen and R9 is H or R8 and R9 taken together with the carbon atoms to which they are joined form a dioxolyl ring, and Y—R2 is unsubstituted acyclic alkyl, acyclic alkyl substituted with an amide or unsubstituted phenyl, then Z- R1 is other than acyclic alkyl substituted with unsubstituted phenyl, and acyclic alkyl substituted with 4-phenyl-1-halo.

15 more elements

A composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

in which
X is a member selected from CO and CS;
W is N;
Z is a member selected from —CH2—, —CHF—, —CF2— and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, substituted or unsubstituted C1-C8 alkyl;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8alkyl;
R2 is a member selected from CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-7 membered saturated heterocyclyl;
R8 and R9 are independently selected from H, halo, CF3O, NO2, CN, S(O)mR10, COOR11, CONR12R13, SO2NR12R13, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl, with the proviso that R8 and R9 are not both H;
wherein R10 is a member selected from CF3 and substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
and R11 is a member selected from substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
m is an integer from 0 to 2;
and
R12 and R13 are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or R12 and R13, taken together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring.

14 more elements

A compound of the formula:

in which wherein A has the formula:
in which E is selected from CR9 and N, and G is selected from O and S,
X is a member selected from CO and CS;
W is N;
Z is a member selected from the group consisting of —CH2—, —CHF—, —CF2—, and —NR4(CR4aR4b)s—
wherein R4 is a member selected from H and a substituted or unsubstituted C1-C5 alkyl group;
R4a and R4b are members independently selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
s is an integer from 1 to 3;
Y is (CR5R6)n, wherein n is an integer from 0-4;
and R5 and R6 are members independently selected from H, F, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
R1 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclyl, and substituted or unsubstituted C1-C8 alkyl;
and
R2 is a member selected from the group consisting of CF3, substituted or unsubstituted C1-C8 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl;
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted 3-7-membered heterocyclyl,
R8 and R9 are independently selected from:
H, halo, CF3, CF3O, NO2, CN, S(O)mR10, COOR11, CONR12R13, SO2NR12R13, S(O)mCF3, CH2CF3, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl, wherein
R10 and R11 are independently selected from substituted or unsubstituted C1-C5 alkyl, and substituted or unsubstituted C3-C7 cycloalkyl;
m is an integer from 0 to 2;
and
R12 and R13 are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, or R12 and R13, together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/740,831Filed 26 Apr 2007 · continuation
Priority: 10 Sep 2003
Published: US 2008/0058319 A16 Mar 2008
Granted: 22 Jun 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification29 codes

C04B 35/632
Using additives specially adapted for forming the products , e.g.. binder binders: organic additives
A61P 3/12
Drugs for disorders of the metabolism: for electrolyte homeostasis
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system

Family

Application60/502,109Us provisional application · filed 10 Sep 2003
Application10/937,958Parent of this continuation · filed 10 Sep 2004
US 2008/0058319 A1Pre-grant publication · published 6 Mar 2008
US 7,223,768 B2Parent of this continuation
US 2005/0059823 A1Published application
US 7,741,332 B2This patent

From the US filing history. Foreign family members aren’t listed.