Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes

• US 9,580,434 B2
• Filed: 10/26/2015
• Issued: 02/28/2017
• Est. Priority Date: 11/02/2006
• Status: Active Grant

• Current Assignee: Attenua, Inc.
• Original Assignee: Attenua, Inc.
• Inventors: Mazurov, Anatoly, Miao, Lan, Xiao, Yunde, Hammond, Philip S., Miller, Craig H., Akireddy, Srinivasa Rao, Murthy, Srinivasa V., Whitaker, Regina C., Breining, Scott R., Melvin, Matt S.
• Primary Examiner(s): RICCI, CRAIG D
• Application Number:
  US14/922,473
• Publication Number:
  US 20160039833A1
• Time in Patent Office: 491 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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

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

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.