Alpha-7 nicotinic acetylcholine receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9994518-B2
Application number	US-201515318207-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 13, 2014
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Disclosed are compounds of Formula (IVA), or a salt thereof, and pharmaceutical formulations (pharmaceutical compositions) comprising those compounds, or a salt thereof: Formula (IVA), wherein “R Ia ”, “R Ib ”, “R Ic ”, “R Id ”, “R Ie ”, are defined herein above, which compounds are believed suitable for use in positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR) receptors, for example, those found in the cerebral cortex and the hippocampus. Such compounds and pharmaceutical formulations are believed to be useful in treatment or management of neurodegenerative diseases, for example, Alzheimer's disease (AD), schizophrenia, and Parkinson's disease (PD), or movement disorders arising from use of certain medications used in the treatment or management of Parkinson's disease.

First claim

What is claimed is:

1. A compound of Formula IVA:

or a salt thereof,
wherein:
R Ia is a moiety of the formula: (a) NH 2 —SO 2 —; (b) NR′ 2 —SO 2 NR″—, wherein R′ is independently for each occurrence: (i) —H; (ii) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or (iii) one of R′ is —H and the other is t-BOC; and R″ is: (a) —H; or (b) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or (iv) one of R′ is —H and the other R′ together with R″ and the —N—SO 2 —N— moiety to which they are attached form a heterocycle of up to 6 ring atoms;
R Ib has the formula: —CH 2 —X—, wherein X is —O—, —S—, CH 2 —;
R Id and R Ie are independently for each occurrence —H or linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or
R Id and R Ie together with the cyclopropyl moiety to which they are attached from a spirocycle of up to 8 carbon atoms;
R Ic is:
(a) a heteroaryl of the formula:

wherein:
n=0, 1, or 2;
one of R IIa or R IIb is a bond to the cyclopropyl core of Formula IVA and the other is —H or —R IIc , wherein,
R IIc is: (i) linear-, branched-, or cyclic-alkoxy of up to 6 carbon, which may optionally be substituted with one or more halogen; (ii) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms, which may optionally be substituted with halogen or linear-, branched-, or cyclic-alkoxy of up to 6 carbon atoms;

(b) heteroaryl of the formula

wherein:
R IId is —H or linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or
(c) aryl of the formula

wherein:
n=1 or 2;
R IIIa is: (i) halogen; (ii) —CN; (iii) linear-, branched-, or cyclic-alkoxy of up to 6 carbon atoms which may optionally be substituted with one or more (1) halogen; or (2) linear-, branched-, or cyclic alkoxy of up to 6 carbon atoms; (iv) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms which may optionally be substituted with one or more: (1) halogen; or (2) linear-, branched-, or cyclic alkoxy of up to 6 carbon atoms.

2. A compound of claim 1 , or a salt thereof, wherein, R Id and R Ie are independently for each occurrence: (a) —H, or (b) methyl.

3. A compound of claim 2 , or a salt thereof, wherein R Id and R Ie are joined together to form, together with the cyclopropyl moiety to which they are attached, a spirocyclo moiety of 7 carbon atoms.

4. A compound, or a salt thereof, of claim 1 wherein, —R Ib -R Ic is —CH 2 —X—R AH , wherein:
X is —CH 2 —, —S—, or —O—; and
R AH is:

5. A compound which is:
±trans 4-{3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
±trans 4-{2-[(5-chloro-2-methoxyphenoxy)methyl]spiro[2.4]hept-1-yl}benzenesulfonamide;
±trans 4-[(1R,3R)-3-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-2,2-dimethylcyclopropyl]-benzene sulfonamide;
±trans 4-{(1R,2R)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]spiro[2.4]hept-1-yl}benzene-sulfonamide;
N-(4-{(1S,3S)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-methanesulfonamide;
N-{4-[(1S,3S)-3-{[(6-methoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]phenyl}-methanesulfonamide;
N-(4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-methanesulfonamide;
N-(4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl) sulfuric diamide;
N-(4-{(1S,3S)-3-[(5-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl) sulfuric diamide;
4-[(1S,3S)-3-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;
4-{(1S,3S)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1R,3R)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-[(1S,3S)-2,2-dimethyl-3-{[(4-methylphenyl)sulfanyl]methyl}cyclopropyl]benzene-sulfonamide;
4-[(1R,3R)-3-{[(5-chloro-2-methoxyphenyl)sulfanyl]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;
4-[(1R,3R)-2,2-dimethyl-3-{[(4-methylphenyl)sulfanyl]methyl}cyclopropyl]benzene-sulfonamide;
4-[(1S,3S)-3-{[(5-chloro-2-methoxyphenyl)sulfanyl]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;
N-{4-[(1S,3S)-3-{[(6-methoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]phenyl}-sulfuric diamide;
N-{4-[(1S,3S)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}sulfuric diamide;
N-{4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}-methanesulfonamide;
N-{4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}sulfuric diamide;
4-[(1R,3R)-3-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;
4-[(1R,3R)-3-{[2-(difluoromethoxy)-5-fluorophenoxy]methyl}-2,2-dimethylcyclopropyl]-benzenesulfonamide;
N-(4-{(1S,3S)-3-[(4-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-sulfuric diamide;
N-(4-{(1S,3S)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-sulfuric diamide;
4-{(1S,3S)-2,2-dimethyl-3-[(pyridin-3-yloxy)methyl]cyclopropyl}benzenesulfonamide;
4-[(1S,3S)-3-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]-benzenesulfonamide;
4-[(1R,3R)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;
4-{(1R,3R)-3-[(2-cyano-4-fluorophenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1R,3R)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1S,3S)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1S,3S)-3-[(2-cyano-4-fluorophenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-[(1S,3S)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;
4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;
4-{(1R,3R)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1S,3S)-3-[(5-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1R,2R)-2-[(2-cyano-4-fluorophenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-[(1R,2R)-2-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}cyclopropyl]benzenesulfonamide;
4-[(1R,2R)-2-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}cyclopropyl]benzenesulfonamide;
4-{(1R,2R)-2-[(5-chloro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-{(1R,2R)-2-[(4-fluoro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-[(1R,3R)-3-{[2-(difluoromethoxy)phenoxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;
4-{(1R,3R)-3-[(5-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;
4-{(1S,2S)-2-[(4-fluoro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-{(1S,2S)-2-[(2-cyano-4-fluorophenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-[(1S,2S)-2-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}cyclopropyl]benzene sulfonamide;
4-{(1S,2S)-2-[(5-chloro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;
4-{(1R,3R)-3-[2-(2-methoxyphenyl)ethyl]-2,2-dimethylcyclopropyl}benzenesulfonamide;
4-{(1R,2R)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]spiro[2.4]hept-1-yl}benzenesulfonamide;
4-{(1S,2S)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]sp

Assignees

• Merck Sharp & Dohme

Inventors

• Leavitt Kenneth
• Crowley Brendan
• Bell Ian M
• Harvey Andrew
• Avery Thomas
• Paul Dharam
• Ripper Justin
• Huff Belinda
• Singh Rajinder
• Schaeffer Laurent
• Joseph Christophe
• Morice Christophe
• Giethlen Bruno
• Bazzini Patrick
• Fromeyer Aurelie

Classifications

• A61P25/28

  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 title

• C07C311/29 Primary

  having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D239/34

  One oxygen atom · CPC title

• C07C323/67

  containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton · CPC title

• C07D213/69

  Two or more oxygen atoms · CPC title