US 12,559,465 B2Granted

Substituted benzotriazinone metabolites of a GPR139 agonist

AssigneeTakeda Pharmaceutical Company Limited

InventorsStephen Uriah Bowlin, Amin Mohamed Kamel

Life of this patent

Estimating the term…

Abstract

Compounds that are mammalian metabolites of an agonist of G-protein-coupled receptor 1.39 (GPR139), intermediates used in the synthesis of such metabolites, pharmaceutical compositions comprising such metabolites, and the use of such metabolites as biomarkers and agents in the treatment of schizophrenia, for example, negative and/or cognitive symptoms of schizophrenia, disorders associated with social and cognitive dysfunction, as well as several other disorders related to modulated of GPR139.

Claims1

Dependent claims

A compound selected from:

(S)-2-(6-hydroxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy) phenyl) ethyl) acetamide;
(S)-2-(5-hydroxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy) phenyl) ethyl) acetamide;
(S)-2-(7-hydroxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy) phenyl) ethyl) acetamide;
(S)-2-(8-hydroxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo [d][1,2,3]triazin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;
(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl hydrogen sulfate;
(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl hydrogen sulfate;
(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl hydrogen sulfate;
(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl hydrogen sulfate;
N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)thio)propan-2-yl)glutamine;
N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)thio)propan-2-yl)glutamine;
N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)thio)propan-2-yl)glutamine;
N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)thio)propan-2-yl)glutamine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)cysteinylglycine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteinylglycine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteinylglycine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteinylglycine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4 dihydrobenzo[d][1,2,3]triazin-6-yl)cysteine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteine;
S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteine;
N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)cysteine;
N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteine;
N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteine;
N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteine;
(S)-2-(6-mercapto-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(5-mercapto-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(7-mercapto-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(8-mercapto-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(6-(methylthio)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(5-(methylthio)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(7-(methylthio)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(8-(methylthio)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
2-(6-(methylsulfinyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl acetamide;
2-(5-(methylsulfinyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
2-(7-(methylsulfinyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
2-(8-(methylsulfinyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(6-(methylsulfonyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(5-(methylsulfonyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(7-(methylsulfonyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-(8-(methylsulfonyl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)thio)propanoic acid;
(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)thio)propanoic acid;
(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)thio)propanoic acid;
(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)thio)propanoic acid;
(S)-N-(1-(2-hydroxy-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;
(S)-N-(1-(3-hydroxy-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;
(R)-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;
N-(1-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin -3 (4H)-yl)acetamide;
(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(5-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin -3 (4H)-yl)acetamido)ethyl)-2-(trifluoromethoxy)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(2-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin -3 (4H)-yl)acetamido)ethyl)-5-(trifluoromethoxy)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin-3(4H) -yl) acetamido)-1-(4-(trifluoromethoxy)phenyl)ethoxy)tetrahydro-2H-pyran-2-carboxylic acid;
(2R,3R,4R,5S,6S)-3,4,5-trihydroxy-6-((R)-2-(2-(4-oxobenzo[d][1,2,3]triazin-3(4H) -yl) acetamido)-2-(4-(trifluoromethoxy)phenyl)ethoxy)tetrahydro-2H-pyran-2-carboxylic acid;
2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;
2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetic acid;
(S)-2-hydroxy-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;
(S)-2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)acetic acid;
(S)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1,2,3-oxadiazol-5-amine, and pharmaceutically acceptable salts of any of the foregoing.

58 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/998,131Filed 6 May 2021 · us provisional application
Priority: 8 May 2020
Published: US 2023/0227416 A120 Jul 2023
Granted: 24 Feb 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 253/08
Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61P 25/00
Drugs for disorders of the nervous system
C07C 201/00
Preparation of esters of nitric or nitrous acid or of compounds containing
C07H 17/02
Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals: heterocyclic radicals containing only…

Family

Application63/021,895Us provisional application · filed 8 May 2020
US 2023/0227416 A1Pre-grant publication · published 20 Jul 2023
US 12,559,465 B2This patent

From the US filing history. Foreign family members aren’t listed.

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