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Unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors

a technology of unsaturated nitrogen and heterocyclic compounds, applied in the field of unsaturated nitrogen heterocyclic compounds, can solve the problem that a large amount of information cannot be obtained by other means

Inactive Publication Date: 2014-07-31
INC AMGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention includes compounds that have been labeled with different isotopes of atoms that have the same atomic number but different atomic mass. This allows for the creation of isotopically-labeled compounds that can be used in pharmaceutical applications.

Problems solved by technology

Much of this information cannot be obtained by other means.

Method used

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  • Unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors
  • Unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors
  • Unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1.1

(1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDIN-1-YL]-METHANONE

[0561]To a mixture of 1H-benzoimidazole-2-carboxylic acid (124 mg, 0.76 mmol) in DMF (5 mL) was added TEA (152 mg, 1.5 mmol) and HATU (347 mg, 0.92 mmol). The reaction mixture was stirred for 5 min and 2-azetidin-3-yl-3-phenyl-pyridine hydrochloride (100 mg, 0.76 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give (1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone (100 mg, 0.28 mmol, 59% yield) as a light yellow solid.

[0562]The following Table 13A lists compounds of Examples 1.1 to 1.17, which were made analogous to Scheme 1 by using the appropriate materials and reaction conditions, w...

example 2.1

(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANONE

[0563]To a stirred solution of [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (100 mg, 0.30 mmol) in dioxane (10 mL) was added phenylboronic acid (87 mg, 0.71 mmol), Na2CO3 (152 mg, 1.4 mmol) and H2O (2 mL). The reaction mixture was degassed with N2 and then PdCl2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (20 mL×3). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography to give the desired compound (60 mg, 0.17 mmol, yield 70%)

[0564]The following Table 14A lists compounds of Examples 2.1 to 2.30, which were made analogous to Scheme 2 by using the appropriate materials and reaction conditions, which are listed in Table 14B. The NMR data of the Example...

example 3.1

(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PIPERIDIN-1-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANONE

[0565]To a mixture of [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (0.10 g, 0.30 mmol), piperidine (0.052 g, 0.60 mmol) and triethylamine (0.091 g, 0.90 mmol) was added DMSO (4 mL). The solution was heated to 120° C. for 5 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give (1-methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone (0.072 g, 0.19 mmol, 63% yield) as white solid.

[0566]The following Table 15A lists compounds of Examples 3.1 to 3.54, which were made analogous to Scheme 3 by using the appropriate materials and r...

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Abstract

Unsaturated nitrogen heterocyclic compounds of formula (I):as defined in the specification, compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, Huntington's Disease, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 13 / 105,860, filed May 11, 2011, which claims the benefit of U.S. Provisional Application No. 61 / 334,525, filed May 13, 2010, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]Provided herein are certain unsaturated nitrogen heterocyclic compounds that are PDE10 inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, Huntington's disease, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.BACKGROUND[0003]Neurotransmitters and hormones, as well as other types of extracellular signals such as light and odors, create intracellular signals by altering the amounts of cyclic nucleotide monophosphates (cAMP...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D403/14C07D417/14C07D409/14C07D413/14C07D487/08C07D487/10C07D405/14C07D487/04C07D491/08C07D401/14C07D491/107
CPCC07D403/14C07D401/14C07D417/14C07D409/14C07D413/14C07D491/107C07D487/10C07D405/14C07D487/04C07D491/08C07D487/08C07D471/04C07D471/08C07D491/056C07D513/04A61P25/00A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P25/30A61P25/36A61P3/04A61P43/00A61P7/12A61P3/10C07C53/18
Inventor ALLEN, JENNIFER R.CHEN, JIAN J.FROHN, MICHAEL J.HARRINGTON, ESSA HULIU, QINGYIANPICKRELL, ALEXANDER J.RUMFELT, SHANNONRZASA, ROBERT M.ZHONG, WENGE
Owner INC AMGEN
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