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8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer

An aryl and heteroaryl technology, applied in nervous system diseases, medical preparations containing active ingredients, drug combinations, etc.

Inactive Publication Date: 2014-02-19
AFRAXIS HLDG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, cancer and neurological disorders pose a huge health care burden to society

Method used

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  • 8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer
  • 8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer
  • 8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0837] Embodiment 1: synthetic 6-(2-chloro-4-[1,3,4] oxadiazol-2-yl-phenyl)-8-ethyl-2-[4-(4-methyl-piper Azin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (8)

[0838] Preparation of intermediate compounds :

[0839] Intermediate 1: Synthesis of 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3).

[0840]

[0841] Step 1: Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2)

[0842] Dissolve 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1, 1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) at room temperature To a solution of N-bromosuccinimide (0.99 g, 5.59 mmol) was added portionwise, and the reaction mixture was stirred for 18 hours. The mixture was concentrated and the solid was triturated with hot water (1 x 20 mL), filtered and washed with isopropanol to give the title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m / z272(M+H) + ; 1 H NMR (400MHz, DMSO-d 6 ) δppm 12.88 (broad singlet, 1H), 8.84...

Embodiment 2

[0857] Embodiment 2: synthetic 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)

[0858]

[0859] Preparation of intermediate compounds :

[0860] Intermediate 2: Synthesis of ethyl 4-bromo-2-chlorophenylacetate (19)

[0861]

[0862] Step 1: Synthesis of (4-bromo-2-chlorophenyl)methanol (15)

[0863] 4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in anhydrous 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 at -15°C for 10 minutes, cooled to -25°C and the precipitated N-methylmorpholine hydrochloride 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 while keeping the temperature below 0°C. After stirring at 0 °C for 1 h, th...

Embodiment 3

[0886] The following compounds were prepared by the method of Example 2 using the appropriate aryl acetate in step 1 and aniline in step 3. Examples containing a secondary amino group on the aniline were synthesized with the appropriate Boc-protected aminoaniline and treated with hydrogen chloride in an organic solvent in the final step to yield the example compound, usually isolated as the hydrochloride salt come out. In this way, Example 3 is made with 2-[5-methyl-2-(N-tert-butoxycarbonylpiperidine)-1,3-thiazol-4-yl]acetic acid methyl ester and 4-(4- Methylpiperazino) aniline prepared. Example 4a and Example 4b were prepared from Example 3 by reductive methylation and treatment with acetic anhydride, respectively.

[0887]

[0888]

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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 or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.

Description

[0001] cross reference [0002] This application claims the benefit of US Provisional Application 61 / 473,683, filed April 8, 2011, the entire contents of which are incorporated herein by reference. Background technique [0003] Neurological disorders are characterized by a variety of debilitating affective and cognitive deficits and can be categorized as central nervous system (CNS) disorders and peripheral nervous system (PNS) disorders. [0004] Neurofibromatosis type 1 (NF1) affects the nerves in the peripheral nervous system. Neurofibromas are benign nerve sheath tumors in the PNS and can cause a variety of symptoms ranging from body deformation and pain to cognitive impairment. Neurofibromatosis type 2 (NF2) affects the CNS and can cause tumors in the brain and spinal cord. [0005] Cancer (also called malignancy) is characterized by abnormal growth of cells. There are more than 100 types of cancer, including breast cancer, skin cancer, lung cancer, colon cancer, brain...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D413/14A61K31/519A61P25/00
CPCC07D519/00C07D471/04C07D413/14A61K31/519A61K45/06A61K9/0014A61K9/0019A61K9/0031A61K9/0043A61K9/0048A61K9/0056A61K9/0078A61K9/06A61K9/2054A61K9/4866A61P25/00A61P25/18A61P25/24A61P25/28A61P35/00A61P35/02A61P43/00
Inventor D.坎贝尔S.G.杜隆
Owner AFRAXIS HLDG
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