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Pyrimidinedione derivative capable of inhibiting monocarboxylate transporter

A compound and solvate technology, applied in the field of cancer and autoimmune diseases, can solve problems such as rapid cell division cannot be maintained

Active Publication Date: 2019-03-05
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

MCT1 inhibitors block lactate transport, leading to intracellular lactate accumulation, inhibiting glycolytic feedback, and ultimately making rapid cell division unsustainable

Method used

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  • Pyrimidinedione derivative capable of inhibiting monocarboxylate transporter
  • Pyrimidinedione derivative capable of inhibiting monocarboxylate transporter

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0305] (S)-5-(4-Hydroxyisoxazolidine-2-carbonyl)-1-ethyl-3-methyl-6-(naphthalen-1-ylmethyl)-1,6-dihydro-2H -Pyrrolo[3,4-d]pyrimidine-2,4(3H)-dione (1).

[0306] .

[0307] Step A

[0308] 1-ethyl-3-methyl-6-(naphthalen-1-ylmethyl)-2,4-dioxo-2,3,4,6-tetrahydro-1 H -pyrrolo[3,4- d ] Pyrimidine-5-carbaldehyde (1a).

[0309] Intermediate A (210mg, 0.63mmol) was dissolved in anhydrous tetrahydrofuran (2.5ml), cooled to -78 degrees in a liquid nitrogen acetone bath, and then dropped into 2.5M n-butyllithium solution (378μl, 0.95mmol) to activate After 10 minutes, add 400 μl of anhydrous dimethylformamide, then slowly rise to room temperature, dilute with water, extract three times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography (washing Removal of cyclohexane:ethyl acetate=10:1 to 8:1 and then 7:1) to obtain a yellow product (155.1 mg, yield 68%), namely 1-ethy...

Embodiment 2

[0321] ( S )-5-(4-Hydroxyisoxazolidine-2-carbonyl)-1-isobutyl-3-methyl-6-(naphthalen-1-ylmethyl)-1,6-dihydro-2 H -pyrrolo[3,4- d ]pyrimidine-2,4(3 H ) - diketone (2).

[0322] .

[0323] Example 2 is to prepare the title compound (2) according to the method of Example 1, replacing intermediate A in step A with intermediate B. MS-ESI (m / z): 477.0[M+H] + .

[0324] 1 H NMR (600MHz, CHLOROFORM-d) δ = 7.96 (br s, 1H), 7.92 - 7.88 (m, 1H), 7.87 - 7.84 (m, 1H), 7.58 - 7.50 (m, 2H), 7.44 (s, 1H), 7.19 - 7.13 (m, 1H), 6.25 (br s, 1H), 5.74 (br d, J=16.5 Hz, 2H), 4.77 - 4.64 (m, 1H), 4.57 -4.39 (m, 1H) , 4.24 - 4.12 (m, 1H), 4.08 - 3.95 (m, 1H), 3.64 - 3.43 (m, 3H), 3.37 (s, 3H), 2.14 - 2.05 (m, 1H), 0.94 - 0.78 (m, 6H).

Embodiment 3

[0326] ( S )-5-(4-Hydroxyisoxazolidine-2-carbonyl)-1-cyclopropylmethyl-3-methyl-6-(naphthalen-1-ylmethyl)-1,6-dihydro-2 H -pyrrolo[3,4- d ]pyrimidine-2,4(3 H )-diketones (3).

[0327] .

[0328] Example 3 is to prepare the title compound (3) according to the method of Example 1, replacing intermediate A in step A with intermediate C. MS-ESI (m / z): 475.0[M+H] + .

[0329] 1 H NMR (600MHz, CHLOROFORM-d) δ = 8.00 - 7.94 (m, 1H), 7.92 - 7.84 (m, 2H), 7.58 - 7.49 (m, 2H), , 7.48 - 7.41 (m, 1H), 7.20 ( br d, J=6.6 Hz,1H), 6.24 (br s, 1H), 5.71 - 5.62 (m, 1H), 5.00 - 4.89 (m, 1H), 4.72 (br s,1H), 4.53 - 4.45 (m , 1H), 4.19 (br d, J=7.7 Hz, 1H), 4.07 - 4.00 (m, 1H),3.82 - 3.68 (m, 2H), 3.52 (br s, 1H), 3.37 (s, 3H), 2.41 - 2.30 (m, 1H), 1.60 (br d, J=7.0 Hz, 1H), 1.28 - 1.21 (m, 3H).

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Abstract

The invention relates to a pyrimidinedione derivative capable of inhibiting a monocarboxylate transporter, the pyrimidinedione derivative is a formula (I) compound and / or a pharmaceutically acceptablesalt thereof, and / or a stereoisomer thereof, and / or a solvate thereof, the compound has the effect of inhibiting the activity of the monocarboxylate transporter, and also comprises a pharmaceutical composition containing the formula (I) compound and the use of the pharmaceutical composition in treatment.

Description

technical field [0001] The present invention relates to a class of compounds and / or pharmaceutically acceptable salts capable of inhibiting the activity of monocarboxylate transporters (MCT1s), pharmaceutical compositions containing them and their use in therapy, such as cancer and autoimmune diseases. Background technique [0002] Monocarboxylate transporter proteins (MCTs) are a class of transmembrane transport proteins widely distributed on human cell membranes. They are a family of proteins that transport lactic acid and other small monocarboxylic acids. Very important. Upon activation of T lymphocytes or cancer cells, the expression of MCT1 is rapidly upregulated to meet the demand for lactate efflux caused by increased glycolytic rates. MCT1 inhibitors block lactate transport, leading to intracellular lactate accumulation, inhibiting glycolytic feedback, and ultimately making rapid cell division unsustainable. Therefore, such inhibitors have immunosuppressive and ant...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04A61K31/519A61P11/00A61P35/00A61P37/06A61P29/00A61P31/18A61P11/06A61P11/02A61P19/02A61P19/08A61P17/06A61P31/22A61P17/14A61P17/00A61P17/08A61P1/00A61P25/06A61P1/04A61P9/10A61P37/02A61P5/14A61P3/10A61P13/12
CPCC07D471/04C07D487/04
Inventor 徐立炎廖勇刘才平雷皇书邓杰邹艳冶雷文波周昌兵何志琴吴坤灿袁泉樊斌
Owner CHONGQING PHARMA RES INST
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