Inhibitors of D-amino acid oxidase

Patent metadata

Field	Value
Publication number	US-9505753-B2
Application number	US-201314420236-A
Country	US
Kind code	B2
Filing date	Aug 8, 2013
Priority date	Aug 8, 2012
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

D-amino acid oxidase (DAAO) inhibitors and methods of their use, either alone or in combination with D-serine or D-alanine, to facilitate allosteric activation of NMDA receptor-mediated neurotransmission and methods of their use as therapeutic agents for treating a subject afflicted with one or more cognitive-disorders, such as schizophrenia, including subjects suffering from negative symptoms and cognitive impairments, post-traumatic stress disorder (PTSD), or pain, are disclosed.

First claim

That which is claimed:

1. A compound of formula (I):

wherein:
n is an integer selected from the group consisting of 1, 2, and 3;
X is oxygen or sulfur;
R 1 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, substituted cyclopropyl, amino, carboxyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted carbazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thienyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzo[b]thiophenyl, substituted or unsubstituted 1H-benzo[d]imidazolyl, substituted or unsubstituted 1H-pyrrolo[2,3-b]pyridinyl, and substituted or unsubstituted 1H-pyrrol[2,3-b]pyridinyl; and
each occurrence of R 2 and R 3 is independently selected from the group consisting of H, hydroxyl, and halogen, or R 2 and R 3 together can be oxygen;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of isopentyl, 3,3-dimethylbutyl, dimethylamino, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,2-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, perfluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-phenoxyphenyl, 2-fluorophenoxyphenyl, 2-oxo-phenyl, 4-morpholinophenyl, naphthyl, 2-methylnaphthyl, 4-methylnaphthyl, 4-fluoronaphthyl, 5-fluoronaphthyl, 6-bromonaphthyl, 6-fluoronaphthyl, biphenyl, 2′-fluorobiphenyl, pyridinyl, morpholino, quinolinyl, isoquinolinyl, 1H-pyrrolyl, 1H-indolyl, 1H-indazolyl, 9H-carbazolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[b]thiophenyl, 4-isopropylpiperazinyl, (2-fluorophenyl)piperazinyl, 3,4-dihydroisoquinolinyl, and phenylcyclopropyl.

3. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of: 6-hydroxy-2-phenethyl-1,2,4-triazine-3,5(2H,4H)-dione; 2-(4-fluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3-fluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-fluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(4-chloropisohenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3-chlorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-chlorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(4-methylphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-methylphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-methylphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(4-(trifluoromethyl)phenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-(trifluoromethyl)phenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2,4-dichlorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-(naphthalen-1-yl)ethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(biphenyl-4-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-isopentyl-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,3-dimethylbutyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-phenylpropyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-benzyl-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-methoxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-hydroxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-methoxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-hydroxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(4-methoxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(4-hydroxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,4-dichlorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3-chloro-4-fluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(naphthalen-2-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 24(6-fluoronaphthalen-2-yl)methyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(4-methoxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(3-phenoxyphenethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(4-(2-fluorophenoxy)benzyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(biphenyl-4-ylmethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2,2-Difluoro-2-phenylethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,4-difluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-pyrrol-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-pyrazol-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-indol-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(1H-indazol-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(9H-carbazol-9-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-morpholinoethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(1-phenylpropan-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-(pyridin-2-yl)ethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-((perfluorophenyl)ethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(((1R,2R)-2-phenylcyclopropyl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-((1H-indol-4-yl)methyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(isoquinolin-5-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(benzo[b]thiophen-7-ylmethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-difluorophenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-((5-fluoronaphthalen-1-yl)methyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(4-ethoxyphenethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-((2-methylnaphthalen-1-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(dimethylamino)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-(4-isopropylpiperazin-1-yl)ethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-phenethyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one; 6-hydroxy-2-(2-oxo-2-phenylethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(2-hydroxy-2-phenylethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-(quinolin-8-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-((4-fluoronaphthalen-1-yl)methyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 6-hydroxy-2-((4-methylnaphthalen-1-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-((6-bromonaphthalen-1-yl)methyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; 2-(2-(2′-fluorobiphenyl-4-yl)ethyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione; and 6-hydroxy-2-(4-morpholinophenethyl)-1,2,4-triazine-3,5(2H,4H)-dione.

4. A composition comprising a pharmaceutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The composition of claim 4 , further comprising a therapeutically effective combination of D-serine or D-alanine and a compound of formula (I).

Assignees

• Univ Johns Hopkins

Inventors

• Tsukamoto Takashi
• Slusher Barbara Stauch
• Ferraris Dana V
• Rojas Camilo
• Hin Niyada
• Duvall Bridget

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

• C07D253/075

  Two hetero atoms, in positions 3 and 5 · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/198

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title