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Pyrazole derivative and application thereof as PDE10 inhibitor

A pyrazole and drug technology, applied in the field of pyrazole derivatives and their use as PDE10 inhibitors, to achieve good inhibitory effect, easy industrialization, and the effect of realizing industrialization

Active Publication Date: 2022-05-24
SHENZHEN CHILDRENS HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, compounds capable of selectively inhibiting different PDE families or isozymes may provide specific therapeutic effects and / or fewer side effects

Method used

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  • Pyrazole derivative and application thereof as PDE10 inhibitor
  • Pyrazole derivative and application thereof as PDE10 inhibitor
  • Pyrazole derivative and application thereof as PDE10 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Step 1): Dissolve 1,1-dimethylethyl-3-formyl-1-(1-methylethyl)-1H-pyrazole-5-carboxylate (raw material A, 2.38g) in anhydrous DCM (80 ml), nitrogen protection, and then add morpholine (1 ml) and react at room temperature for 2.5 h. Then add sodium triacetoxyborohydride (4.5g), and the reaction mixture was stirred at room temperature for 24 hours. After the reaction, sodium bicarbonate solution (150ml) and DCM (150ml) were added to collect the organic phase; the aqueous phase was extracted with DCM three times and the organic phase was combined. The solvent was removed by vacuum, and the residue was purified by silica gel rapid chromatography to give 1,1-dimethylethyl-1-(1-methylethyl)-3-(4-morpholinemethyl)-1H-pyrazole-5-carboxylate (intermediate B, 2.84g), which is a colorless oil.

[0035] 1 HNMR(400MHz，CDCl3)δ(ppm)：6.74(s,1H),3.88-3.94(m,1H),3.61-3.72(m,4H),2.55-2.70(m,4H),3.55(s,2H),1.47(s,9H),1.36(s,6H).

[0036] Elemental Analysis:C,62.11；H,8.80；N,13.58；O,1...

Embodiment 2

[0040] Example 2 Compound (I) In Vitro Compound Evaluation (Enzyme Inhibitory Activity Evaluation: Human PDE10 Inhibitory Effect)

[0041] The assay was performed using the IMAP TR-FRET Phosphodiesterase Detection Kit (Molecular Device). Add diluted 10 μL of each concentration of the experimental compound to the 384-well plate (Corning) and use 1×IMAP containing 0.1% BSA reaction buffer (prepared from 5× carried by the kit, 10 mM Tris-HCl, pH = 7.2, 10 mM MgCl 2 、0.05％NaN 3 , and 0.1% BSA) diluted to 2 ng / mL of PDE10 enzyme 5 μL and pre-warmed for 5 min at room temperature. Add 5 μL of cAMP matrix carried with a 1× IMAP containing 0.1% BSA reaction buffer diluted to 400 nM and react for 60 min at room temperature. Add the IMAP TR-FRET binding solution 60 μL of the kit and leave it for more than 3 hours, then determine the fluorescence intensity of terbium (Emission =490 nm) and TR-FRET (Emission =520 nm) with ARVO SX (PerkinElmer) at a excitation wavelength of 340 nm, and calculat...

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Abstract

The invention relates to a pyrazole derivative and application thereof as a PDE10 inhibitor. Meanwhile, the compound can be used for treating PDE10 mediated diseases; the disease is selected from schizophrenia, such as disorder, tension, unclassified or residual schizophrenia; schizophrenia-like conditions; emotional schizophrenia, such as delusional disorder or depressive type; delusional disorders; a substance-induced psychiatric disorder, such as a psychiatric disorder induced by alcohol, amphetamine, cannabis sativa, cocaine, a rosemary, an inhalant, an opium-like substance, or benxacidine; a delusional personality disorder; and schizophrenia personality disorder.

Description

Technical field [0001] The present invention relates to a pyrazole derivative and its use as a PDE10 inhibitor. Background [0002] Phosphodiesterase (PDE) is a class of intracellular enzymes that are involved in the hydrolysis of the nucleotide cyclic adenylate monophosphate (cAMP) and cyclic guanylate monophosphate (cGMP) to their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenosyl and guanylinyl cyclase, respectively, and act as secondary messengers in multiple cell channels. cAMP and cGMP act as intracellular secondary messengers that regulate numerous intracellular processes, especially in the nerve cells of the central nervous system. In nerve cells, it includes activation of cAMP and cGMP-dependent kinases, and subsequent protein phosphorylation involved in the acute regulation of synaptic transmission and in neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is manifested by the molecular...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/5377A61P25/18A61P25/24A61P25/00
CPCC07D405/12A61P25/18A61P25/24A61P25/00Y02P20/55
Inventor 谭回
Owner SHENZHEN CHILDRENS HOSPITAL
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