IP Library › Granted Patent US 9,580,434
Granted Patent B2
US 9,580,434 · App. 14/922,473 · Granted Feb 28, 2017

Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes

Inventors: Anatoly Mazurov (Greensboro, NC); Lan Miao (Advance, NC); Yunde Xiao (Clemmons, NC); Philip S. Hammond (Pinnacle, NC); Craig H. Miller (Winston-Salem, NC); Srinivasa Rao Akireddy (Winston-Salem, NC); Srinivasa V. Murthy (Lewisville, NC); Regina C. Whitaker (Mocksville, NC); Scott R. Breining (Winston-Salem, NC); Matt S. Melvin (Winston-Salem, NC)
Assignee: Attenua, Inc.
C07D487/04C07D471/08
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Quick Facts
Patent No.
US 9,580,434
App. No.
14/922,473
Granted
Feb 28, 2017
Kind
B2
Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are amide compounds which can be prepared from certain heteroaryl carboxylic acids and certain diazabicycloalkanes. The compounds exhibit selectivity for, and bind with high affinity to, neuronal nicotinic receptors of the α4β2 subtype in the central nervous system (CNS). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly CNS disorders. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects, and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g. side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastrointestinal tract, and significant effects upon skeletal muscle).

Claims (75)

1. A method of synthesizing compounds represented as Formula I:

wherein n has a value of 0 or 1, and Cy is a heteroaryl group selected from the group consisting of 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,4-thiadiazol-5-yl and 4-pyridinyl, which heteroaryl groups are optionally substituted with up to two non-hydrogen substituents independently selected from halo, —CN, —SO 2 NH 2 , —C(O)NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, furan, and phenyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, furan and phenyl groups are each optionally substituted with 1 to 3 halogen atoms and/or phenyl.

2. The method according to claim 1 , wherein:

n has a value of 0 or 1, and Cy is a C 5-10 heteroaryl group selected from the group consisting of 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl and 4-pyridinyl, which heteroaryl groups are optionally substituted with up to two non-hydrogen substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkyl substituted with 1 to 3 halogen atoms and/or phenyl, and C 2-6 alkynyl substituted with phenyl.

3. The method according to claim 1 , wherein n is 0.

4. The method according to claim 1 , wherein n is 0 and Cy is 2-furanyl.

5. The method according to claim 1 , wherein Cy is 2-furanyl substituted with halo.

6. The method according to claim 1 , wherein the compound prepared is selected from the group consisting of:

N-(furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(3-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(5-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(3-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(3-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(5-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(4-phenylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(5-(2-pyridinyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(5-(phenylethynyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(furan-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(oxazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(oxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(oxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isoxazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isoxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(3-bromoisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(3-methoxyisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,2,4-oxadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,2,4-oxadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,3,4-oxadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(thiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(thiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(thiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isothiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isothiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(isothiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,2,4-thiadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,2,4-thiadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(1,3,4-thiadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,

N-(pyridin-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, and pharmaceutically acceptable salts thereof.

7. The method according to claim 1 , wherein the compound prepared is selected from the group consisting of:

N-(furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(3-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(5-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(3-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(3-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(5-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(4-phenylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(5-(2-pyridinyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(5-(phenylethynyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(furan-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(oxazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(oxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(oxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isoxazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isoxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(3-bromoisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(3-methoxyisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,2,4-oxadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,2,4-oxadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,3,4-oxadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(thiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(thiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(thiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isothiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isothiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(isothiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,2,4-thiadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,2,4-thiadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(1,3,4-thiadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,

N-(pyridin-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane, and pharmaceutically acceptable salts thereof.

8. The method according to claim 1 , wherein the compound prepared is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, or pharmaceutically acceptable salts thereof.

9. The method according to claim 1 , wherein the compound prepared is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane, or pharmaceutically acceptable salts thereof.

Assignments (2)
CHANGE OF NAME Recorded Sep 1, 2016
From: TARGACEPT, INC.
To: CATALYST BIOSCIENCES, INC.
Reel/Frame 039897/0053 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 30, 2016
From: CATALYST BIOSCIENCES, INC.
To: ATTENUA, INC.
Reel/Frame 039585/0675 →
Continuity (6)
Continuation 14551498 · Nov 24, 2014
Continuation 13555458 · Jul 23, 2012
Continuation 13342635 · Jan 3, 2012
Division 12447850
Provisional Application 60856079 · Nov 2, 2006
Related Publication 20160039833A1 · Feb 11, 2016