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Pyrazolo compounds and uses thereof

Inactive Publication Date: 2014-09-18
CONSTELLATION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes compounds and compositions that can inhibit enzymes that remove a chemical group from DNA (histone demethylases). These compounds may be useful for treating diseases caused by abnormal activity of these enzymes. They may also be useful for studying the biological functions of these enzymes and for comparing the effects of different inhibitors.

Problems solved by technology

Packaging the 3 billion nucleotides of the human genome into the nucleus of a cell requires tremendous compaction.

Method used

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  • Pyrazolo compounds and uses thereof
  • Pyrazolo compounds and uses thereof
  • Pyrazolo compounds and uses thereof

Examples

Experimental program
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Effect test

example 1

Synthesis of ethyl 2-acetylpentanoate

[0159]

[0160]Ethyl 2-acetylpentanoate was synthesized according to Beddow et al, Org. Biomol. Chem. 5: 2812-2825 (2007). To a solution of t-BuOK (11.8 g, 0.11 mol) in THF (150 mL) was added ethyl 3-oxobutanoate (13 g, 0.1 mol) dropwise at 0° C., after stirred for 30 minutes, 1-bromopropane (12.3 g, 0.1 mmol) was added dropwise and the mixture was refluxed for 16 h. The reaction mixture was quenched by water, extracted with EtOAc (100 mL×2), combined organic layer was dried over anhydrous Na2SO4, evaporated, purified by column chromatography to give the expected compound ethyl 2-acetylpentaoate (8.5 g, 49%) as colorless oil. m / z (ESI) 173 [M+H]+.

example 2

[0161]By a similar method to Example 1, using the appropriate starting materials, the compounds in Table 2 were prepared.

TABLE 2Compound nameStructureDataethyl 2-acetyl-4- methylpentanoatem / z (ESI) 187 [M + H]+ethyl 2- acetylpent-4- enoatem / z (ESI) 171 [M + H]+ethyl 2-acetyl-4- methoxybutanoatem / z (ESI) 189 [M + H]+ethyl 2- acetylpent-4- ynoatem / z (ESI) 169 [M + H]+ethyl 2-ethyl- 4,4,4-trifluoro-3- oxobutanoatem / z (ESI) 213 [M + H]+ethyl 4-ethoxy-2- ethyl-3- oxobutanoatem / z (ESI) 203 [M + H]+ethyl 2-(2- methoxyacetyl) pent-4-enoatem / z (ESI) 201 [M + H]+ethyl 2- benzoylbutanoatem / z (ESI) 221 [M + H]+ethyl 2-(furan-2- carbonyl) butanoatem / z (ESI) 211 [M + H]+3-ethylpentane- 2,4-dionem / z (ESI) 129 [M + H]+

example 3

Synthesis of ethyl 2-ethyl-4-methoxy-3-oxobutanoate

[0162]

[0163]Ethyl 2-ethyl-4-methoxy-3-oxobutanoate was prepared according to WO 98 / 43968. Zinc (2 g, 30 mmol), methoxyacetonitrile (1.42 g, 20 mmol) and a catalytic amount of mercuric chloride in toluene (50 mL) were heated to reflux. Ethyl 2-bromobutanoate (5.85 g, 30 mmol) was added dropwise, then reflux continued for a hour, and cooled to a room temperature. 10% Aqueous sulfuric solution (16.5 mL) was added, and the organic layer was separated. The aqueous layer was further extracted with ethyl ether and the combined organic layers washed with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give the product as yellow oil (1.7 g, 45%). 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7.2 Hz, 2H), 4.07 (d, J=3.6 Hz, 2H), 3.45 (t, J=7.2 Hz, 1H), 3.37 (s, MI), 1.85 (m, 2H), 1.22 (t, J=7.2 Hz, 3H). 0.90 (t, J=7.5 Hz, 3H); m...

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Abstract

The present invention relates to compounds useful as inhibitors of one or more histone demethylses. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

Description

PRIORITY OF INVENTION[0001]This application claims priority from U.S. Provisional Application No. 61 / 778,759, filed 13 Mar. 2013. The entire content of this provisional application is hereby incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to compounds useful as inhibitors of histone demethylases.BACKGROUND OF THE INVENTION[0003]Packaging the 3 billion nucleotides of the human genome into the nucleus of a cell requires tremendous compaction. To accomplish this feat, DNA in our chromosomes is wrapped around spools of proteins called histones to form dense repeating protein / DNA polymers known as chromatin: the defining template for gene regulation. Far from serving as mere packaging modules, chromatin templates form the basis of a newly appreciated and fundamentally important set of gene control mechanisms termed epigenetic regulation. By conferring a wide range of specific chemical modifications to histones and DNA, epigenetic regul...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D498/04
CPCC07D498/04C07D487/04C07D487/14A61K31/337A61K31/437A61K31/517A61K31/519A61K31/5377A61K45/06C12N9/99A61P35/00A61P35/04A61P43/00
Inventor ALBRECHT, BRIAN K.BELLON, STEVEN F.GEHLING, VICTOR S.HARMANGE, JEAN-CHRISTOPHE
Owner CONSTELLATION PHARMA INC
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