CN109820840A - Application of the Bisphenol F in the drug of preparation treatment central nervous system disease - Google Patents

Abstract

The present invention provides Bisphenol F (1) shown in structure formula (I) or its pharmaceutical salts and is preparing the application in melatonin receptors agonist, and its application in the drug that preparation treats or prevents central nervous system disease relevant to melatonin receptors.Bisphenol F (1) of the present invention is extractable from plants such as Rhizoma Gastrodiae, mustard, can also be obtained by chemistry or biosynthesis means.

Description

Application of the Bisphenol F in the drug of preparation treatment central nervous system disease

Technical field:

The invention belongs to technical field of pharmaceuticals.In particular it relates to a phenolic compound Bisphenol F (1) or its pharmaceutical salts, make For melatonin receptors agonist, and its medicine in preparation treatment or prevention central nervous system disease relevant to melatonin receptors Application in object.

Background technique:

Epiphysin (melatonin, MT) is the endogenous hormone secreted by pineal body, circadian rhythm, life to organism It grows, aging etc. has important adjustment effect.Epiphysin passes through activation melatonin receptors in vivo and plays physiological function, has and changes The physiological activity such as kind sleep, anti-aging and raising immunity of organisms, while also there is adjustment effect to depression and anxiety and pain. Human body melatonin receptors include MT₁And MT₂Two kinds of hypotypes belong to g protein coupled receptor, share 7 transmembrane segments, have to epiphysin There is high-affinity, is the main function site of epiphysin in human body.MT₁And MT₂Receptor pivot nervous system and periphery group in human body Knitting has widely distributed, is distributed mainly on suprachiasmatic nucleus, hypophysis, olfactory bulb, midbrain, hypothalamus etc. in central nervous system；? Peripheral tissues are distributed mainly on cardiovascular system, spleen, thymus gland, lymph node, sexual gland, gastrointestinal tract, kidney etc..Existing research shows that swashing MT living₁Receptor can inhibit the release of the Neural spike train and prolactin of suprachiasmatic nucleus, promote sleep and blood vessel to receive with epiphysin Contracting activity is related.Melatonin receptors agonist is the research hotspot of current novel antidepression and hypnotic sedative agent, be can avoid because making For side effects such as drug dependences caused by GABA receptor and opiate receptor etc..It is taken off from 1980s successful clone Since melanocyte receptor, people have synthesized multiple melatonin receptors agonists, part of agonist be used as antidepression and Improve sleep drug listing, such as agomelatine, auspicious beauty for high, Ta Simeiqiong.

The chemical component main Types of Rhizoma Gastrodiae (Gastrodiaelata) have: phenols and its glycoside, steroidal, have polysaccharide Machine acid and its lipid, other classes.Pharmacological activity then includes anticonvulsion, anti-aging, tranquilizing soporific, protection nerve cell, improvement note Recall, is anti-inflammatory etc..Pharmacological component, which is more common in simple phenol derivatives and its glycoside, gastrodia elata polysaccharide, adenosine class compound, to be had A variety of pharmacological activity, such as anti-oxidant, neuroprotection, anti-inflammatory, hypoglycemic, antidepression, improvement learning and memory.However about the present invention The compound bisphenol F (1), it is rarely seen about anti-inflammatory, related toxicity isoreactivity report.

So far, the prior art is without Bisphenol F (1) and its pharmaceutical composition as melatonin receptors agonist, and treatment or pre- The application report of anti-central nervous system disease relevant to melatonin receptors.

Summary of the invention:

The purpose of the present invention is to provide Bisphenol F (1) or its salt shown in formula (I), as melatonin receptors agonist, and It is treating or preventing the application in central nervous system disease relevant to melatonin receptors.

In order to realize above-mentioned purpose of the invention, the present invention provides the following technical solutions:

Structure formula (I) compound represented Bisphenol F (1) or its pharmaceutical salts are preparing answering in melatonin receptors agonist With,

Compound bisphenol F (1) or its pharmaceutical salts answering in the drug that preparation treats or prevents central nervous system disease With.

Compound bisphenol F (1) or its pharmaceutical salts are in preparation treatment or prevention central nervous system relevant to melatonin receptors Application in the drug for disease of uniting.

According to the application of the compound bisphenol F (1) or its pharmaceutical salts in pharmacy, wherein the pharmaceutical salts refer to The salt formed with organic acid or inorganic acid, the organic acid be formic acid, acetic acid, ethanedioic acid, propionic acid, butyric acid, caproic acid, oneself two Acid, oxalic acid, maleic acid, succinic acid, tartaric acid, fumaric acid, citric acid, camphoric acid, camphorsulfonic acid, lactic acid, picric acid, algae Acid, aspartic acid, benzene sulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethanesulfonic acid, glucoheptonic acid, phosphoglycerol, Hemisulfic acid, 2- ethylenehydrinsulfonic acid, methanesulfonic acid, niacin, 2- naphthalene sulfonic acids, flutters acid, pectin resin acid, 3- phenyl formic acid, new penta at enanthic acid Acid, thiocyanic acid, p-methyl benzenesulfonic acid；The inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid.

Invention also provides formula (I) compound 1 containing therapeutically effective amount or its pharmaceutical salts and pharmaceutically acceptable Carrier pharmaceutical composition.

The pharmaceutical composition is preparing the application in melatonin receptors agonist.

Application of the pharmaceutical composition in the drug that preparation treats or prevents central nervous system disease.

The pharmaceutical composition treats or prevents central nervous system disease relevant to melatonin receptors in preparation Application in drug.

The present invention still further provides the preparation method of described formula (I) compound 1 of preparation, from Rhizoma Gastrodiae (G.elata) second Acetoacetic ester extracting section is isolated.Fresh gastrodia elata (45.0kg) slice, is impregnated 3 times with 90% ethyl alcohol, and filtering, residue is with 50% Ethyl alcohol impregnates 3 filterings, residue boiling 1 time, merges all filtrates, is concentrated under reduced pressure into alcohol-free.It is extracted with ethyl acetate 3 times, Ethyl acetate fraction (102g) is obtained, water phase, respectively with water, 50% ethyl alcohol and 90% elution, obtains water through macroreticular resin Position (1.6kg), 50% ethyl alcohol (71g), 90% (8g).It carries out mixing sample with 88g sample and 88g silica gel, with 880g silica gel wet process Fill column.Use EtOAc:CHCl₃System 0:100,5:95,10:90,20:80,40:60, MeOH are eluted, and 5 fractions are obtained, It is guiding with tracking activity, active site and nonactive position is isolated and purified, finally passed through from subflow part Fr 2 Me₂CO:CHCl₃System 10:90 elution, obtains target compound 1.

Bisphenol F (1) of the present invention can be extracts from plant species, and is not limited to the plant of the example above, simultaneously It can also be obtained by chemical synthesis or biosynthesis.Source or preparation method to Bisphenol F (1), this is not restricted.

The method of the preparation pharmaceutical composition, is prepared compound 1 according to above-mentioned method, then with compound 1 A certain amount of pharmaceutical acceptable carrier or excipient is added for raw material.

The method of pharmaceutical composition of the preparation containing compound 1 be raw material with compound 1, pharmaceutical acceptable carrier or tax is added Shape agent.The pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and drug system Product adjuvant.

When the compounds of this invention 1 is used as melatonin receptors agonist or drug, can directly it use, or with pharmaceutical composition The form of object uses.The pharmaceutical composition contains 0.1~99%, preferably 0.5~90% compound 1, remaining is materia medica Upper acceptable, nontoxic to humans and animals and inert pharmaceutical acceptable carrier and/or excipient.By pharmaceutical composition of the invention with The form of per weight dose uses.Drug of the invention can be injected (intravenous, intramuscular injection) and oral two kinds of forms administration.

Detailed description of the invention:

Fig. 1 is the structural formula of the compounds of this invention 1；

Fig. 2 is the melatonin receptors agonist activity (EC of the compounds of this invention 1₅₀It is 237 and 244 μM).

Specific embodiment:

To better understand the essence of the present invention, with reference to the accompanying drawing, with test example and embodiment of the invention come into One step illustrates preparation method, Structural Identification, pharmacological action and the preparation method of the invention of the compounds of this invention Bisphenol F (1) And drug composition, but the present invention is not limited with this test example and embodiment.

Embodiment 1:

The preparation of compound 1:

It is extracted from Rhizoma Gastrodiae ethyl acetate portion isolated.Fresh gastrodia elata (45.0kg) slice impregnates 3 with 90% ethyl alcohol Secondary, filtering, 50% ethyl alcohol of residue impregnates 3 filterings, residue boiling 1 time, merges all filtrates, is concentrated under reduced pressure into alcohol-free. It is extracted with ethyl acetate 3 times, obtains Ethyl acetate fraction (102g), water phase uses water, 50% ethyl alcohol through macroreticular resin respectively With 90% elution, water position (1.6kg), 50% ethyl alcohol (71g), 90% (8g) are obtained.It is mixed with 88g sample and 88g silica gel Sample, with 880g silica gel wet method dress post.Use EtOAc:CHCl₃System 0:100,5:95,10:90,20:80,40:60, MeOH progress Elution, obtains 5 fractions, is guiding with tracking activity, isolates and purifies to active site and nonactive position, finally from son Pass through Me in fraction Fr 2₂CO:CHCl₃System 10:90 elution, obtains target compound 1.

The Structural Identification of compound 1:

Optically-active is measured by 1020 polarimeter of Jascomodel (Horiba, Tokyo, Japan)；Nuclear magnetic resoance spectrum (1H and 13C NMR) it is measured with Bruker AM-400 type NMR spectrometer with superconducting magnet (Bruker, Bremerhaven, Germany), with deuterium For methanol as solvent；Thin-layer chromatography silica gel, column chromatography silica gel (200-300 mesh) are purchased from Qingdao U.S. height and Qingdao Haiyang chemical industry collection Co., Ltd, group.

Compound 1

Molecular formula: C₁₃H₁₂O₂

Molecular weight: 200.08

Character: the lobate crystallization of white

Fusing point: 160 DEG C

ESIMS(+)m/z:201([M+H]⁺)。

¹H-NMR and¹³C-NMR data are as follows:

¹H-NMR(400MHz,CD₃OD)δ_H: 6.98 (4H, d, J=8.6Hz, H-2, H-6, H-2', H-6'), 6.69 (2H, D, J=8.6Hz, H-3, H-5, H-3', H-5'), 3.77 (2H, s, H-7).¹³C-NMR(100MHz,CD3OD)δ_C:155.6(s, C-4,C-4'),132.8(s,C-1,C-1'),129.3(d,C-2,C-6,C-2',C-6'),114.6(d,C-3,C-5,C-3', C-5'),39.7(s,C-7)。

Embodiment 2:

Compound 1 is to melatonin receptors MT_1/2The agonist activity of receptor.

1 material and method

1.1 materials:

Melatonin receptors MT₁And MT₂The cell strain of agonist activity Select to use respectively corresponds human body renal epithelial cell HEK293-MT₁And HEK293-MT₂；Cell culture medium (Dulbecco's Modified Eagle containing 10% fetal calf serum Medium,DMEM)；Disposable calcium current kit.

1.2 instruments: CO₂Constant incubator Thermo Forma 3310 (U.S.)；Inverted biologic microscope XD-101 type (Nanjing)；Flexstation 3 Benchtop Multi-Mode Microplate Reader(Molecular Devices, Sunnyvale,California,USA)。

1.3 experimentation

96 hole Hei Bi are revealed the exact details into tissue culture plate using matrix BD Matrigel coating, in 37 DEG C of constant incubator 1h, suction Supernatant is taken, with 4 × 10⁴The density in/hole reveals the exact details corresponding HEK293 cell inoculation in tissue culture plate in 96 hole Hei Bi, in CO₂Concentration be 5% 37 DEG C of constant incubators in culture 16~for 24 hours；Former culture medium is discarded, 100 μ of dye liquor of fresh configuration is added The hole l/ is protected from light in 37 DEG C and is incubated for 60min.The preparation of sample to be tested: the sample to be tested of various concentration is prepared.By designated volume to Sample is added in cell, and addition sample volume is 50 holes μ l/, measures sample using 3 multi-function microplate reader of Flexstation Agonism of the product to melatonin receptors.Experimental result is analyzed using 5 software of Graphpad prism.

2. result (Fig. 2):

Compound 1 is under 0.5mM concentration, to MT_1/2The exciting rate of receptor is respectively 80.3 ± 14.4% and 103.0 ± 7.1%, EC₅₀Value is 237 and 244 μM.

3, conclusion:

Experimental result shows that compound 1 is to MT₁Receptor shows preferable agonism, under 0.5mM concentration, to MT_1/2 The exciting rate of receptor is respectively 80.3 ± 14.4% and 103.0 ± 7.1%, and quantitative dose-effect relationship shows its EC₅₀Value is 237 Hes 244μM.The above result shows that compound 1 can be as novel melatonin receptors agonist, and it can treat or improve and take off black The relevant central nervous system disease of plain receptor.

Embodiment 3:

The preparation of tablet:

Compound 1 is made as described in Example 1, and utilizes organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid Deng) or inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) made of salt, in its with excipient weight than the ratio addition for 1:5-1:10 Excipient, pelletizing press sheet.

Embodiment 4:

The preparation of oral liquid formulations:

Compound 1 is made as described in Example 1, and utilizes organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid Deng) or inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) made of salt, routinely oral solution is made in oral solution preparation method.

Embodiment 5:

The preparation of capsule, granule or electuary:

Compound 1 is made as described in Example 1, and utilizes organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid Deng) or inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) made of salt, in its with excipient weight than figuration is added for the ratio of 5:1 Capsule or granule or electuary is made in agent.

Claims (10)

1. structure formula (I) compound represented Bisphenol F (1) or its pharmaceutical salts are preparing the application in melatonin receptors agonist,

2. the application of compound bisphenol F (1) or its pharmaceutical salts in the drug that preparation treats or prevents central nervous system disease.

3. compound bisphenol F (1) or its pharmaceutical salts treat or prevent central nervous system relevant to melatonin receptors in preparation Application in the drug of disease.

4. the application of compound bisphenol F (1) according to claim 1 or 2 or 3 or its pharmaceutical salts in pharmacy, feature Be that the pharmaceutical salts refer to the salt with organic acid or inorganic acid formation, the organic acid be formic acid, acetic acid, ethanedioic acid, Propionic acid, butyric acid, caproic acid, adipic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, fumaric acid, citric acid, camphoric acid, camphor sulphur Acid, lactic acid, picric acid, alginic acid, aspartic acid, benzene sulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethanesulfonic acid, Glucoheptonic acid, hemisulfic acid, enanthic acid, 2- ethylenehydrinsulfonic acid, methanesulfonic acid, niacin, 2- naphthalene sulfonic acids, flutters acid, pectin rouge at phosphoglycerol Acid, 3- phenyl formic acid, neopentanoic acid, thiocyanic acid, p-methyl benzenesulfonic acid；The inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphur Acid, phosphoric acid, nitric acid.

5. the method for preparing formula described in claim 1 (I) compound 1 is extracted from Rhizoma Gastrodiae ethyl acetate portion and is separated, fresh day Fiber crops slice, is impregnated 3 times with 90% ethyl alcohol, filtering, and 50% ethyl alcohol of residue impregnates 3 filterings, residue boiling 1 time, is merged all Filtrate, is concentrated under reduced pressure into alcohol-free, is extracted with ethyl acetate 3 times, obtains Ethyl acetate fraction, water phase through macroreticular resin, Respectively with water, 50% ethyl alcohol and 90% elution, obtain water position, 50% ethyl alcohol position, 90% ethyl alcohol position, further with silica gel Sample is mixed, with silica gel wet method dress post, uses EtOAc:CHCl₃System 0:100,5:95,10:90,20:80,40:60, MeOH are washed It is de-, 5 fractions are obtained, is guiding with tracking activity, active site and nonactive position is isolated and purified, finally from subflow Pass through Me in part Fr 2₂CO:CHCl₃System 10:90 affords compound 1.

6. formula described in claim 1 (I) compound 1 or its pharmaceutical salts containing therapeutically effective amount and pharmaceutically acceptable The pharmaceutical composition of carrier.

7. pharmaceutical composition as claimed in claim 6 is preparing the application in melatonin receptors agonist.

8. pharmaceutical composition as claimed in claim 6 answering in the drug that preparation treats or prevents central nervous system disease With.

9. pharmaceutical composition as claimed in claim 6 treats or prevents central nervous system relevant to melatonin receptors in preparation Application in the drug of disease.

10. the method for preparing pharmaceutical composition as claimed in claim 6 is extracted from Rhizoma Gastrodiae ethyl acetate portion and is separated, fresh day Fiber crops slice, is impregnated 3 times with 90% ethyl alcohol, filtering, and 50% ethyl alcohol of residue impregnates 3 filterings, residue boiling 1 time, is merged all Filtrate, is concentrated under reduced pressure into alcohol-free, is extracted with ethyl acetate 3 times, obtains Ethyl acetate fraction, water phase through macroreticular resin, Respectively with water, 50% ethyl alcohol and 90% elution, obtain water position, 50% ethyl alcohol position, 90% ethyl alcohol position, further with silica gel Sample is mixed, with silica gel wet method dress post, uses EtOAc:CHCl₃System 0:100,5:95,10:90,20:80,40:60, MeOH are washed It is de-, 5 fractions are obtained, is guiding with tracking activity, active site and nonactive position is isolated and purified, finally from subflow Pass through Me in part Fr 2₂CO:CHCl₃System 10:90 affords compound 1, then is added one using compound 1 or its salt as raw material Pharmaceutical acceptable carrier or excipient of certainty ratio.