Flouro-naphthyl derivatives

Patent metadata

Field	Value
Publication number	US-9708302-B2
Application number	US-201615216435-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jan 22, 2014
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention relates to compounds of formula

wherein
R 1 is C 4-6 -cycloalkyl or C 4-6 -heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl;
A is phenyl, pyridinyl or piperidinyl;
R 2 is hydrogen, halogen, lower alkyl, cyano, C 4-6 -cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl;
n is 1 or 2;
or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof.

The compounds may be used for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

First claim

The invention claimed is:

1. A compound of formula I

 wherein
R 1 is C 4-6 -cycloalkyl or C 4-6 -heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl;
A is phenyl, pyridinyl or piperidinyl;
R 2 is hydrogen, halogen, lower alkyl, cyano, C 4-6 -cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl; n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. A compound of formula I according to claim 1 , wherein A is phenyl and the other substituents are as described in claim 1 .

3. A compound of formula I according to claim 2 , which compounds are
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-methylbenzyl)-2-naphthamide
4-benzyl-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-(4-chlorobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-(4-cyanobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
1-fluoro-4-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)benzyl)-2-naphthamide or
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2-naphthamide.

4. A compound of formula I according to claim 1 , wherein A is pyridinyl and the other substituents are as described in claim 1 .

5. A compound of formula I according to claim 4 , wherein the compounds are
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclopentyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2R)-2-hydroxycyclopentyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxycyclohexyl)-2-naphthamide
1-fluoro-N-((1S,2 S)-2-hydroxycyclhexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide
1-fluoro-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide
1-fluoro-N-((3S,4 S)-4-hydroxytetrahydro-2H-pyran-3-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-4-((6-methylpyridin-3-yl)methyl)-2-naphthamide
4-((6-cyclopropylpyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide
or 4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(3S,4R)-3-hydroxyoxan-4-yl]naphthalene-2-carboxamide.

6. A compound of formula I according to claim 1 , wherein A is piperidinyl and the other substituents are as described above.

7. A compound of formula I according to claim 6 , wherein the compound is 4-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-1-fluoro-N-((1S,2 S)-2-hydroxycyclohexyl)-2-naphthamide.

8. A process for the manufacture of a compound of formula I as defined in claim 1 , which process comprises reacting a compound of formula 1:

 with a compound of formula 2:
R 1 NH 2   (2)

in the presence of an activating agent, selected from BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride, to a compound of formula I:

wherein the substituents are as defined in claim 1 ,
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

9. A compound manufactured by the process of claim 8 .

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant.

11. Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

12. A method for the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders, which method comprises administering an effective amount of a compound as defined in claim 1 .

Assignees

• Hoffmann La Roche
• Hoffmann-La-Roche Inc

Inventors

• Groebke Zbinden Katrin
• Pinard Emmanuel
• Ryckmans Thomas

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• 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

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/18

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

• A61P25/04

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