CN109666055A - Adjust the compound and application thereof of nervous centralis treatment depression - Google Patents

Abstract

The present invention provides formula (I) compound, and stereoisomer, tautomer or pharmaceutically acceptable salt, as central nervous system is adjusted, treatment has depression, is with a wide range of applications.

Description

Adjust the compound and application thereof of nervous centralis treatment depression

Technical field

The present invention relates to novel structure formula (I) compound or pharmaceutically acceptable salt thereof, tautomer or in vivo it is hydrolyzable Precursor, their compositions and their application method.These novel compounds and its purposes medically.

Background technique

Post-natal depression is type most commonly seen in women phrenoblabia, is after women produces, due to sex hormone, society Can role and psychology change brought by a series of variations such as body, mood, psychology, symptom include significant functional disorder, Depressed and, appetite stimulator cold and detached to newborn, have difficulty in going to sleep, be absent minded, is out of strength, it is handicapped and lose from Numerous depression related symptoms such as letter.Typical post-natal depression was occurred in 6 weeks postpartum, in sustainable entire puerperium, was had Even continue to child before going to school.The disease incidence of post-natal depression is 15%~30%.Post-natal depression is usually sent out within 6 weeks Disease can voluntarily be restored at 3~6 months, but serious also sustainable 1~2 year, and gestation then has 20%~30% recurrence again Rate.

Some women post-natal depression is in a bad way, or even deteriorates into and can't take care of oneself or emotional flooding, needs to be hospitalized Treatment realizes rehabilitation in the environment of safety and stability.In modern society, suicide is one of the first cause of maternal death after childbirth.

The features such as selective serotonin reuptake inhibits, has toxic side effect small, take simplicity can be selected.For now very The fiest-tire medication of more developed country's treatment depressions.Representing drug has Prozac, Paxil, Sertraline, Fluvoxamine, western phthalein general It is blue.Or the novel antidepressant of other mediator mechanism is taken in selection: Trazodone: being weak antidepressants, to major depression effect phase Difference.Light modest depression to antianxiety, insomnia is optimal adaptation card.Duloxetine, Venlafaxine: it is suitable for various depressed shapes State, rapid-action, without special contraindication, but liver kidney patient is used with caution.Mirtazapine: the tolerance of this medicine is good, few side effects, is a kind of new Type antidepressant.Moclobemide: it can treat various types of depressions, also preferable to anxiety-depression admixture effect.

It is counted according to U.S.'s Disease Control and Prevention Center (CDC), the U.S. about 4,000,000 newborns in 2014, In 10%~15% puerpera meet with post-natal depression puzzlement, some patientss, which seriously arrive, needs hospitalization.It there is no at present specially Door is granted for the drug of post-natal depression, and the therapeutic choice of severe patients with postpartum depression is very limited, for treating the disease The pharmaceutical requirements of disease are very urgent.

γ-aminobutyric acid (abbreviation GABA) is a kind of naturally occurring nonprotein amino acid, is mammalian central mind Substance is conveyed through inhibiting nerve important in system, about 30% nervous centralis synapses are using GABA as mediator.In human body It plays an important role in cerebral cortex, hippocampus, thalamus, basal ganglion and cerebellum, and has to adjust to the multiple functions of body and make With.Research finds (Neuron.2008；59 (2): 207-13), the source P nerve steroidal being significantly increased during gestation and in point The rapid decline in puerperium can produce bigger effect intracerebral GABA (A) R so as to cause depressive symptom generation.

The A receptor of GABA, also referred to as γ-aminobutyric acid A receptor are a kind of ionotropic receptors, and are a kind of ligands Door-control type ion channel.The endogenic ligand in this channel is a kind of neurotransmitter for being referred to as GABA.GABA is central nervous system A kind of main mediator in system, although that GABA generates during the release of neurotransmitter is inhibition effect, GABA Itself is not a kind of inhibition but a kind of irritation mediator, because of the opening of GABA activation GABA receptor.In GABAA receptor quilt After activation, the property of can choose allows Cl- to pass through, and causes the hyperpolarization of neuron.

Drug causes GABAA receptor patient can be made to eliminate Anxiety the moderate inhibition of neuron activity, and (antianxiety is made With), and stronger inhibiting effect can then generate general anesthesia.The serious excess of drug rarely has appearance, and the reaction generated is to prolong Long anesthesia duration, or even occur dead.[1] benzodiazepine and benzodiazepine receptors combine, can be enhanced GABA with The affinity of GABA receptor increases stream in cl ion, thus can increase the depression effect that GABA can be neural.

At present the A receptor modulators of the GABA for postpartum depression of clinical stage only there are two, SAGE The SAGE-547 and SAGE-217 of Therapeutics, is respectively at Ph3 the and Ph2 stage.SAGE-547 in postpartum depression two Phase clinic shows significant therapy, but its bioavilability is low, can only Parenteral administration.SAGE-217 treats postpartum depression Clinical data is open not yet.

It is badly in need of the A receptor modulators of safe and effective, convenient drug administration the novel GABA of exploitation.

Summary of the invention

The present invention provides a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,

Wherein, R¹For C1~C6 carbonic acyl radical；

R²Selected from alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group.

Formula (I) compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt, In include following compounds,

Compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt, as drug or Pharmaceutical composition, the application in treating depression.

Specific embodiment:

The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.

Embodiment 1:

The present invention provides similar testing program according to document WO2016134301, is prepared into compound 4, ESI-MS:m/z: 359.6[M+H]⁺。

Biological test result: the biological test scheme provided according to document WO2016134301, TBPS combination experimental test The result shows that the activity of compound 4 is 0.1nM (IC50 value).

Claims (3)

1. a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,

Wherein, R¹For C1~C6 carbonic acyl radical；

R²Selected from alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group.

2. formula (I) compound as described in claim 1, stereoisomer, tautomer or pharmaceutically acceptable salt, Including following compounds,

3. the compound as described in any one of claims 1 to 2, stereoisomer, tautomer or pharmaceutically acceptable Salt, the application as drug or pharmaceutical composition, in treating depression.