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Bicyclic heterocyclic derivatives

A technology of compounds and mixtures, applied in drug combination, organic active ingredients, organic chemistry, etc., can solve problems such as hyperglycemia

Active Publication Date: 2018-03-27
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, pyruvate formed by glycolysis cannot be oxidized, which can lead to hyperglycemia due to the ineffective use of glucose in the blood

Method used

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  • Bicyclic heterocyclic derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0261] (2R)-1-[1-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one ("A1")

[0262]

[0263] 1.1 tert-butyl 1-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate

[0264] 3-[1-Dimethylamino-methyl-(E)-ylidene]-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.786 mmol) and 4-chlorophenylhydrazine hydrochloride The salt (155 mg, 0.865 mmol) was suspended in methanol (4 mL) and water (1 mL). While stirring, glacial acetic acid (0.23 mL, 3.932 mmol) was added and an orange solution formed after a few minutes. The mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, water, saturated NaHCO 3 solution and brine, washed with Na 2 SO 4 Dry, filter and evaporate to dryness. The oily residue was purified by flash chromatography (Companion RF, 40 g Si50 silica gel column). Yield: 145.5 mg brown oil; LC / MS, Rt: 2.61 min; (M+H) 334.1.

[0265] 1.2 1-(4-Chloro-ph...

Embodiment 2

[0271] (2R)-1-[2-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one ("A2")

[0272] "A2" as the isomeric cyclization product of step 1.1 was isolated in step 1.3 by preparative HPLC (Agilent 1260, column: Waters SunFire C18, 5 μm, 30×150 mm). Yield: 7mg (4%) colorless powder; LC / MS, Rt: 2.26min; (M+H) 374.1; 1 H NMR (500MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 7.82-7.76(m, 2H), 7.55-7.50 (m, 2H), 7.21 (s, 1H), 5.16-4.94 (m, 1H), 4.69-4.50 (m,1H ), 4.28-4.02 (m, 1H), 3.94-3.68 (m, 1H), 2.93-2.68 (m, 2H), 1.66-1.45 (m, 3H).

Embodiment 3

[0274] (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(1-phenyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c ]pyridin-5-yl)-propan-1-one ("A3")

[0275]

[0276] Prepare as described in Example 1 (steps 1.1-1.3). Yield: 142mg (62%) colorless solid; LC / MS, Rt: 1.97min; (M+H) 340.1; 1 H NMR (400MHz, DMSO-d 6 ) δ 7.58-7.52 (m, 3H), 7.52-7.45(m, 2H), 7.38-7.31 (m, 1H), 6.87 (s, 1H), 4.73 (s, 2H), 4.09-3.90 (m, 2H ),2.91 (t, J =5.8Hz, 2H), 1.58 (s, 3H).

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Abstract

Compounds of the formula la or of the formula lb in which X, Y, R1 and R2 have the meanings indicated in Claim 1, are inhibitors of pyruvate dehydrogenase kinase (PDHK), and can be employed, inter alia, for the treatment of diseases such as cancer.

Description

technical field [0001] The present invention relates to novel bicyclic heterocyclic derivatives that inhibit pyruvate dehydrogenase kinase (PDHK), pharmaceutical compositions containing them, processes for their preparation and their use in cancer therapy. Background of the invention [0002] Pyruvate dehydrogenase kinase (also known as pyruvate dehydrogenase complex kinase, PDC kinase, or PDHK) is a kinase that acts to inactivate the enzyme (pyruvate dehydrogenase) by phosphorylating it with ATP . [0003] Thus, PDHK is involved in the regulation of the pyruvate dehydrogenase complex in which pyruvate dehydrogenase is the first component. Both PDHK and the pyruvate dehydrogenase complex are located in the mitochondrial matrix of eukaryotes. In the citric acid cycle, this complex functions to convert pyruvate (a product of glycolysis in the cytosol) to acetyl-CoA, which is subsequently oxidized in the mitochondria to generate energy. By downregulating the activity of this...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/437A61P35/00
CPCC07D487/04C07D471/04A61P35/00A61K31/437A61K31/4745
Inventor H-P.布赫施塔勒
Owner MERCK PATENT GMBH