RET inhibitor, pharmaceutical composition and application thereof

A technology of compounds and solvates, applied in the field of RET inhibitors, their pharmaceutical compositions and their uses, can solve problems such as administration and toxicity, and achieve the effects of promoting side effects, good inhibitory effect, and good inhibitory selectivity

Pending Publication Date: 2021-03-30
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs cannot always be administered at levels sufficient to inhibit RET, due to toxicity from inhibition of targets other than RET
Furthermore, one of the greatest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment

Method used

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  • RET inhibitor, pharmaceutical composition and application thereof
  • RET inhibitor, pharmaceutical composition and application thereof
  • RET inhibitor, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0491]Example 1: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine -3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1, Synthesis of 5-a]pyridine-3-carbonitrile

[0492]

[0493] Step 1: Hexahydro-2H-[1,4]dioxine[2,3-c]pyrrole hydrochloride

[0494] Add tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrole-6(3H)-tert-butyl carboxylate (2230mg, 9.73mmol), HCl / EA(4N) in sequence to 100mL one-mouth bottle (18 mL), stirred at rt for 8 hours. TLC monitors the complete reaction of raw materials, spins dry and directly puts into the next reaction. LC-MS: (ESI-MS): m / z=130.1[M+H] + .

[0495] Step 2: 6-(2-Chloroethyl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

[0496] Add hexahydro-2H-[1,4]dioxine[2,3-c]pyrrole hydrochloride (4.5mmol, 740mg, acetone (15mL), K 2 CO 3 (2030 mg, 14.7 mmol), stirred overnight at rt. The reaction liquid was filtered with celite, washed with EA (15mL×3), concentrated, and subjected to silica gel colum...

Embodiment 2

[0499] Example 2: 6-(2-(5-hydroxyl-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethoxy)-4-(6-(6-((6 -Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazole[1,5-a] Synthesis of Pyridine-3-carbonitrile

[0500]

[0501] Step 1: tert-butyl N-formate-5-hydroxy-5-methylhexahydrocyclopentane[c]pyrrole

[0502] 0°C, N-tert-butyl formate-hexahydro-5-oxocyclopenta[c]pyrrole (1.00g, 4.44mmol) was dissolved in anhydrous THF (10mL), slowly added THF solution of methylmagnesium bromide (3mL, 9mmol, 3mol / L), naturally rose to room temperature and stirred for 1h. The reaction was monitored by TLC (PE / EA (v / v)=1 / 1, Rf=0.32), and the reaction of the starting material was complete. saturated NH 4 Quench the reaction with Cl solution, stop the reaction, filter with suction, concentrate, perform silica gel column chromatography, eluent PE / EA (v / v)=10 / 1-3 / 1, and obtain 0.71 g of a yellow-brown solid, which is the target product , yield 66%. 1 H NMR (400MHz,...

Embodiment 3

[0509] Example 3: 6-(2-(5-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethoxy)-4-(6-(6-((6-methoxy Basepyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazol[1,5-a]pyridine-3 -Synthesis of forminonitrile

[0510]

[0511] Step 1: tert-butyl N-formate-5-hydroxyhexahydrocyclopentane[c]pyrrole

[0512] In an ice-water bath, LiAlH 4 (0.35g, 9.2mmol) was slowly added to anhydrous THF (15mL), after stirring at low temperature for 15min, slowly added N-tert-butyl formate-hexahydro-5-oxocyclopenta[c]pyrrole (1.03g, 4.57 mmol), naturally rose to room temperature and stirred for 2h. The reaction was monitored by TLC (PE / EA (v / v)=4 / 1, iodine fumigation, Rf=0.18), and the reaction of the raw material was complete. saturated Na 2 SO 4 The solution was quenched, filtered with suction, and concentrated to obtain 0.89 g of brown-yellow viscous liquid (yield 86%). 1 H NMR (400MHz, CDCl 3 )δ4.34-4.23(m,1H),3.54-3.45(m,2H),3.38-3.28(m,2H),2.81-2.64(m,1H),2.62-2.52...

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Abstract

The invention belongs to the field of medicines, and relates to an RET inhibitor, a pharmaceutical composition and application thereof, specifically to a compound as shown in a formula (I), or a stereoisomer, a geometrical isomer, a tautomer, nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I). The invention also relates to a pharmaceutical composition comprising the compound, and use of the compound and the pharmaceutical composition thereof in manufacture of medicine, wherein the medicine is particularly used for treatment and prevention of diseases and disorders associated with available RET, including cancers, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

Description

technical field [0001] The present invention belongs to the field of medicine, specifically, the present invention relates to a new compound exhibiting inhibition of transfection phase rearrangement (RET) kinase, a pharmaceutical composition comprising the compound, and the use of the compound or its pharmaceutical composition in the preparation of medicines. The medicament is especially useful in the treatment and prevention of RET-related diseases and conditions, including cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome. Background technique [0002] Re-arranged during transfection (RET) is one of the receptor-type tyrosine kinases belonging to the cadherin superfamily, which activates multiple downstream pathways involved in cell proliferation and survival. [0003] It has been reported that the result of RET gene abnormality (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) is involved in carcinog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/444A61P35/00A61P1/00
CPCC07D519/00A61P35/00A61P1/00A61K31/444A61K31/437C07D471/04
Inventor 谢洪明罗明张英俊寇玉辉胡扬校何锦
Owner SUNSHINE LAKE PHARM CO LTD
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