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8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of CNS disorders

a technology of cns disorders and pyrimidins, which is applied in the field of 8ethyl6(aryl) pyrido2, 3dpyrimidin7 (8h)ones for the treatment of cns disorders, can solve the problems of imposing an enormous health care burden on society, the effects of cns disorders are devastating to the quality of life of those affected and their families, and the loss of synaptic function of neuronal withering and/

Inactive Publication Date: 2013-02-07
AFRAXIS HLDG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a group of compounds that can improve cognitive scores, reduce symptoms of Alzheimer's disease, and improve brain function in individuals with certain disorders. These compounds can also reduce or stabilize the loss of brain tissue and prevent the buildup of harmful proteins in the brain.

Problems solved by technology

The effects of CNS disorders are devastating to the quality of life of those afflicted as well as that of their families.
Moreover, CNS disorders impose an enormous health care burden on society.

Method used

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  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of CNS disorders
  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of CNS disorders
  • 8-ethyl-6-(ARYL)pyrido[2,3-d]pyrimidin-7(8H)-ones for the treatment of CNS disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 6-(2-chloro-4-[1,3,4]oxadiazol-2-yl-phenyl)-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (8)

[0556]Preparation of Intermediate Compounds:

Intermediate 1: Synthesis of 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3)

[0557]

Step 1: Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2)

[0558]To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1, 1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) was added N-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature, and the reaction mixture was stirred for 18 h. The mixture was concentrated, and the solid was triturated with hot water (1×20 mL), filtered, and washed with isopropanol to give title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m / z 272 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57 (s, 3H).

Step 2: Synthesis of 6-bromo-8-ethyl-2-(methylthio)pyrido[2...

example 2

Synthesis of 6-[2-chloro-4-(thiophen-2-yl)phenyl]-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (13)

[0566]

[0567]Preparation of Intermediate Compounds:

Intermediate 2: Synthesis of ethyl 4-bromo-2-chlorophenylacetate

[0568]

Step 1: Synthesis of (4-Bromo-2-chlorophenyl)methanol (15)

[0569]4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in dry tetrahydrofuran (920 mL) and cooled to −15° C. Isobutyryl choroformate (51.0 mL, 0.39 mol) was added followed by N-methylmorpholine (43.5 mL, 0.39 mol). The resulting mixture was stirred for 10 minutes at −15° C., cooled to −25° C. and the precipitated N-methylmorpholine hydrochloride salt was filtered off. The filtrate was warmed to −5° C. and a solution of sodium borohydride (22.19 g, 0.586 mol) in water (190 mL) was added dropwise to the mixture keeping the temperature below 0° C. After stirring for 1 h at 0° C., the volatiles were evaporated, and the residue was diluted with water (500 mL) and...

examples 3-5

[0581]The following compounds were made by the method of Example 2 using the appropriate arylacetic acid at Step 1 and aniline at Step 3. Examples containing secondary amines on the aniline were synthesized using the appropriate Boc protected aminoaniline and in the final step were treated with a solution of hydrogen chloride in an organic solvent to produce the example compound, usually isolated as the hydrochloride salt. In this manner, Example 3 was prepared using methyl 245-methyl-2-(n-tert-butoxycarbonylpiperidine)-1,3-thiazol-4-yl)acetate and 4-(4-methylpiperazino)aniline. Example 4 and Example 5 were prepared from Example 3 by reductive methylation and treatment with acetic anyhydride respectively.

LCMSLCMSEx.StructureMWMethodIonRt3544.7A5450.964558.8A5600.985586.8A5871.16

Examples 6-33

[0582]Preparation of Intermediate Compounds:

Intermediate 3: Synthesis of 2-(4-Amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester

[0583]

Step 1: Synthesis of 2-(4-nitro-phenyl)-oxirane (2)

[...

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Abstract

Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 250,262, filed Oct. 9, 2009, and U.S. Provisional Application No. 61 / 353,054, filed Jun. 9, 2010, which are both incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Central Nervous System (CNS) disorders are characterized by a variety of debilitating affective and cognitive impairments. For example, a clinical sign of individuals with Alzheimer's disease is progressive cognition deterioration. Worldwide, approximately 24 million people have dementia, 60% of these cases are due to Alzheimer's.[0003]Other CNS disorders include, e.g., mood disorders, age-related cognitive decline, and neurological disorders (e.g., epilepsy, schizophrenia, Fragile X mental retardation syndrome and Huntington's disease). The effects of CNS disorders are devastating to the quality of life of those afflicted as well as that of their families. Moreover, CNS disorders impose an enor...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K31/5377A61P25/00C12N9/99A61P25/18A61P25/24A61P35/00A61P35/02C07D471/04A61P25/28
CPCC07D471/04A61P25/00A61P25/18A61P25/24A61P25/28A61P35/00A61P35/02A61P43/00C07D403/12A61K31/519
Inventor VOLLRATH, BENEDIKTCAMPBELL, DAVIDDURÓN, SERGIO G.WADE, WARREN
Owner AFRAXIS HLDG
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