CN113801004A - Phenyl bisphenol derivative, preparation method and medical application thereof - Google Patents

Phenyl bisphenol derivative, preparation method and medical application thereof Download PDF

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CN113801004A
CN113801004A CN202111220267.8A CN202111220267A CN113801004A CN 113801004 A CN113801004 A CN 113801004A CN 202111220267 A CN202111220267 A CN 202111220267A CN 113801004 A CN113801004 A CN 113801004A
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cyclopropylethyl
pharmaceutically acceptable
prodrug
compound
stereoisomer
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秦琳琳
魏用刚
万松林
罗新峰
王伟
刘国亮
任磊
宣兆利
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Tibet Haisike Pharmaceutical Co ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/08—Quinones with polycyclic non-condensed quinoid structure

Abstract

The invention relates to a phenyl bisphenol derivative, a preparation method and application thereof in medicine. The phenyl bisphenol derivative can promote sedation hypnosis, brain protection, and treat and/or prevent diseases related to the central nervous system.

Description

Phenyl bisphenol derivative, preparation method and medical application thereof
Technical Field
The invention relates to a phenyl bisphenol derivative shown in a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method and a pharmaceutical composition thereof, and application of the compound in the field of central nerves.
Background
GABAAReceptors are the major inhibitory neurotransmitter receptors in the central nervous system. GABAAThe receptor is composed of a pentamer of transmembrane polypeptide subunits, with 19 different subunits constituting a variety of different GABA' sAThe receptor subtype. GABAAThe receptor is involved in the pathogenesis and diagnostic treatment of a plurality of diseases such as anesthesia, sedation, depression, anxiety, epilepsy, dysmnesia, drug dependence and the like. Thus, GABAAReceptors are pharmacologically and clinically important targets for drug action. Propofol and its derivatives are important GABAAA compound that is a target.
Propofol is useful for inducing and maintaining general anesthesia, and also for enhancing sedation and the like in monitored patients undergoing mechanical ventilation. Propofol has been successfully used as a sedative in conscious patients with concomitant local or regional anesthesia, and also as a sedative in diagnostics, such as colonoscopy or fluoroscopy imaging, which causes discomfort in conscious patients. Also as diagnostic imaging or radiotherapy for children. And propofol has a similar or better sedative effect than midazolam or other sedatives (CN 200680025438; drugs 50, 1995, 636), with faster recovery and similar or lower amnesic effects, especially short-term sedation.
Propofol is also used clinically in the treatment of refractory status epilepticus. The drugs commonly used for treating refractory status epilepticus comprise midazolam, propofol, high-dose thiopentan and the like, but clinical studies prove that intravenous continuous infusion of propofol is the better method for treating refractory status epilepticus at present. Shen Yun Zhen Jun et al (Chinese and foreign medical research, 2015, (13)34, 30-31) reported that in the observation of the curative effect of propofol on epilepsy persistence, propofol has a significant effect on epilepsy persistence, shorter average control time, rapid curative effect and low tracheal intubation rate compared with midazolam, and is worthy of clinical popularization and application. bear-Weiming et al (third military medical science, 2013, 15) research shows that small-dose static-pushing propofol has an exciting effect on epilepsy waves of peripheral cortex around focus of on-screen tumor patients with epileptic seizure, can assist in positioning an epileptogenic focus, guides effective treatment of the epileptogenic focus in operation, and is beneficial to improving the control rate of late-stage epilepsy.
The propofol in vivo has few metabolites, has obvious functions of reducing intracranial pressure, cerebral metabolism, antioxidation and the like, can obviously improve neurological deficit, and has better effect on cerebral protection. The literature reports that propofol target-controlled infusion is safe and effective for use in cardiac surgery patients, can maintain hemodynamics of patients stably, has more and more proved brain protection effect, and has advanced the research on the action mechanism (Journal of Ningxia Medical University,34(7) -2012-750). The curative effect result of Wangning and the like (journal of clinical neurology, 2002, No. 06) on the postoperative treatment of patients with senile cerebral hemorrhage by propofol indicates that the grade of the clinical neurological deficit degree of the propofol group at the 7 th postoperative day is obviously lower than that of a control group, and the propofol contributes to the cerebral protection of the postoperative patients with senile cerebral hemorrhage. Chenyu et al (J.Anaesthetics, (22) 10-2002-.
Therefore, the method has clinical significance for further research on propofol and analogues thereof.
There is a need in the art to further develop GABA having novel structure, good drug effect and safetyAReceptor agonists, provide more and more optimal drug selection routes, so as to better promote sedation hypnosis, brain protection, and treat and/or prevent central nervous system related diseases such as anxiety, nausea, vomiting, migraine, convulsion, epilepsy, neurodegenerative diseases and the like.
Disclosure of Invention
The invention relates to a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0003312344710000021
wherein
B is selected from
Figure BDA0003312344710000022
R1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
R3、R4、R5and R6Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
n is selected from 1 or 2.
Preferably, in the compound of the general formula (I) of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
R1is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl or ethyl; r2Is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl, ethyl or cyclopropyl;
R3、R4、R5and R6Each independently selected from methyl, ethyl or cyclopropyl.
Preferably, in the compound of the general formula (I) of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
R1is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl or ethyl; r2Is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl, ethyl or cyclopropyl;
b is selected from one of the following structures:
Figure BDA0003312344710000031
preferably, in the compound of the general formula (I) of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
R1is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl or ethyl; r2Is selected from C1-4Alkyl or C3-4Cycloalkyl, preferably methyl, ethyl or cyclopropyl;
b is selected from one of the following structures:
Figure BDA0003312344710000041
preferably, in the compound of general formula (I) of the present invention or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, the compound is selected from one of the following structures:
Figure BDA0003312344710000042
the invention also relates to a compound of the general formula (II) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0003312344710000051
wherein
R7And R8Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
R9、R10、R11and R12Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
m is selected from 1 or 2.
Preferably, in the compound of the general formula (II) of the present invention or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
R7selected from methyl or ethyl; r8Selected from methyl, ethyl or cyclopropyl;
R9、R10、R11and R12Each independently selected from methyl, ethyl or cyclopropyl.
The invention also relates to a pharmaceutical composition, which comprises the compound shown in the general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
The invention also relates to the application of the compound of the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof or the pharmaceutical composition in the preparation of the medicine for promoting sedation and hypnosis, brain protection, and treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion or epilepsy of animals or human beings.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I referred to in the groups and compounds of the invention each include their isotopes, wherein carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further substituted by one or more of their pairsSubstituted by corresponding isotopes, wherein isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F include17F and19isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt which maintains the biological effectiveness and properties of the free acid or free base of the compound of the present invention, and the free acid is obtained by reaction with a non-toxic inorganic or organic base, and the free base is obtained by reaction with a non-toxic inorganic or organic acid.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" refers to a compound that can be metabolized in vivo to a biologically active compound of the invention. Prodrugs of the invention are prepared by modifying the phenolic groups in compounds of the invention, which modifications may be removed by routine manipulation or in vivo, to provide compounds of the invention which are biologically active. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group.
By "animal" is meant mammals, such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.
ED50(effective half amount): the dose required to cause 50% of mice to lose orthotropic reflex was tested.
ED95(95% effective amount): the dose required to cause loss of the orthotropic reflex in 95% of mice was tested.
LD50(median lethal dose): the dose required to cause death in 50% of mice was tested.
LD5(5% lethal dose): the dose required to cause 5% of mice to die was tested.
solutol HS-15: polyethylene glycol (PEG) lithium dodecahydroxystearate.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl etherSulfoxide base (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetonitrile (CD)3CN), internal standard Tetramethylsilane (TMS).
The MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
The ratio shown by the silica gel column chromatography is volume ratio.
Brief description:
Pd(dppf)Cl2: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride.
Example 1
2- [ (1R) -1-Cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -4-hydroxy-5-isopropyl-phenyl ] -6-isopropyl-phenol (1)
2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-6-isopropyl-phenol(1)
Figure BDA0003312344710000071
Figure BDA0003312344710000081
The first step is as follows: (4E) -2- [ (1R) -1-cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -5-isopropyl-4-oxo-cyclohexa-2, 5-dien-1-enyl ] -6-isopropyl-cyclohexa-2, 5-dien-1-one (1b)
(4E)-2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl]-5-isopropyl-4-oxo-cyclohexa-2,5-dien-1-ylidene]-6-isopropyl-cyclohexa-2,5-dien-1-one(1b)
Figure BDA0003312344710000082
Adding 2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol (1a) (5.0g,24.47mmol) and 50mL of diethyl ether into a 250mL three-necked flask, stirring uniformly, cooling to 0 ℃, adding silver oxide (6.81g,29.37mmol) in portions, naturally returning to room temperature for 5 hours, directly filtering the reaction solution after the reaction is finished, washing a filter cake with diethyl ether (20mL multiplied by 3), combining filtrates, and concentrating to obtain a yellow solid product (4E) -2- [ (1R) -1-cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -5-isopropyl-4-oxo-cyclohexa-2, 5-dien-1-enyl ] -6-isopropyl-cyclohexa-2, 5-dien-1-one (1b) (4.2g crude) was used directly in the next step.
The second step is that: 2- [ (1R) -1-Cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -4-hydroxy-5-isopropyl-phenyl ] -6-isopropyl-phenol (1)
2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-6-isopropyl-phenol(1)
Figure BDA0003312344710000091
A250 mL three-necked flask was charged with (4E) -2- [ (1R) -1-cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -5-isopropyl-4-oxo-cyclohexa-2, 5-dien-1-enyl ] -6-isopropyl-cyclohexa-2, 5-dien-1-one (1b) (4.2g,10.38mmol), 25mL ethanol, 25mL tetrahydrofuran, stirred well, cooled to 0 deg.C and added solid sodium borohydride (1.18g,31.14mmol) in portions, allowed to cool to room temperature and allowed to react for 5 hours. The reaction mixture was slowly poured into 100mL of a saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate (40mL × 3), the combined organic phases were washed with a saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a volume of 30mL with silica gel and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 10) to give 2- [ (1R) -1-cyclopropylethyl ] -4- [3- [ (1R) -1-cyclopropylethyl ] -4-hydroxy-5-isopropyl-phenyl ] -6-isopropyl-phenol (1) (3.2g, yield 75.8%)
MS:405.4[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.26(d,2H),7.21(d,2H),4.93(s,2H),3.24-3.17(m,2H),3.56-3.52(m,2H),1.34-1.31(m,18H),1.13-1.09(m,2H),0.63-0.56(m.2H),0.53-0.46(m,2H),0.30-0.20(m,4H)。
Example 2
4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-hydroxy-phenyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] phenol (2)
4-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]-2,6-bis[(1R)-1-cyclopropylethyl]phenol(2)
Figure BDA0003312344710000092
Figure BDA0003312344710000101
The starting material 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (0.5g, 2.17mmol), diethyliodobenzene (PIDA) (0.175g, 0.543mmol) was dissolved in 3mL of chloroform and reacted at 40 ℃ for 1 hour to stop the reaction, which was then concentrated and subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 100:1) to give 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-hydroxy-phenyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] phenol (2) as a yellow liquid (0.43g, 40% yield).
LC-MS：457.2[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.282(4H，s)，5.098(2H，s)，2.558-2.442(4H，m)，1.346(12H，d)，1.145-1.072(4H，m)，0.617-0.556(4H，m)，0.518-0.458(4H，m)，0.273-0.194(8H，m)。
Example 3
4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3)
4-[3,5-bis[(1R)-1-cyclopropylethyl]-4-oxo-cyclohexa-2,5-dien-1-ylidene]-2,6-bis[(1R)-1-cyclopropylethyl]cyclohexa-2,5-dien-1-one(3)
Figure BDA0003312344710000102
The method comprises the following steps: 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (0.46g,2.0mmol) and 20mL of methanol were added to a 100mL three-necked flask, stirred well, 3mL of hydrogen peroxide (30%) and then a solution of iodine in methanol (0.25g of iodine in 10mL of methanol) was added dropwise, and the reaction was completed by heating to 35 ℃ for 4 hours. After the reaction, 10mL of a 2% sodium bisulfite solution was added dropwise to the reaction flask, followed by filtration, extraction with petroleum ether (20 mL. times.2), combination of organic phases, washing with water (30 mL. times.1), and drying over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate: 50:1) to give 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.09g, 9.07% yield) as a brown solid.
The second method comprises the following steps: 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (0.46g,2.0mmol) was dissolved in ethyl acetate (10mL), silver carbonate (0.55g,2.0mmol) was added, stirring was carried out at room temperature for 18h, insoluble material was filtered, the filtrate was concentrated under reduced pressure to give a tan solid, which was washed with n-hexane (20mL) to collect the brown solid product 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.21g, 45% yield).
The third method comprises the following steps: in a 50mL one-neck flask, 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (0.46g,2.0mmol) and 20mL of dichloromethane were added, followed by addition of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ, 0.91g,4.0mmol) in portions, reaction at room temperature for 1 hour after completion of the addition, and purification by column chromatography directly after drying of the reaction mixture (petroleum ether: ethyl acetate ═ 50:1) gave a brown solid product, 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.400g, yield 88%).
The method four comprises the following steps: a100 mL single-neck flask was charged with 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (0.3g,1.30mmol) and 10mL of water, charged with ferric trichloride hexahydrate (0.39g,1.43mmol), heated to 90 ℃ after completion of the charging to react for 4 hours, the reaction solution was extracted with ethyl acetate (10mL × 3), and the organic phase was combined and concentrated, followed by column chromatography purification (petroleum ether: ethyl acetate ═ 50:1) to give 34- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.1g, yield 33.3%) as a brown solid.
1HNMR(400MHz,CDCl3)：δ7.88-7.86(m,4H),δ2.42-2.34(m,4H),δ1.27(d,6H),δ1.26(d,6H),δ0.99-0.90(m,4H),δ0.64-0.58(m,4H),δ0.48-0.41(m,4H),δ0.30-0.24(m,4H),δ0.21-0.15(m,4H).
Example 4
4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-hydroxy-phenyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] phenol (2)
4-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]-2,6-bis[(1R)-1-cyclopropylethyl]phenol(2)
Figure BDA0003312344710000121
The first step is as follows: 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3)
4-[3,5-bis[(1R)-1-cyclopropylethyl]-4-oxo-cyclohexa-2,5-dien-1-ylidene]-2,6-bis[(1R)-1-cyclopropylethyl]cyclohexa-2,5-dien-1-one(3)
Figure BDA0003312344710000122
A100 mL three-necked flask was charged with 2, 6-bis ((R) -1-cyclopropylethyl) phenol (2a) (1.0g,
4.34mmol) and 10mL of tetrahydrofuran, stirring well, adding silver oxide (1.2g,5.21mmol) in portions, heating to 70 ℃ after the addition for 5 hours, after the reaction is finished, directly filtering the reaction solution, washing the filter cake with tetrahydrofuran 3 times (20mL × 3), combining the filtrates, concentrating to a small volume, mixing with silica gel, and purifying by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to obtain a yellow solid product, 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.4g, yield 40.4%).
1HNMR(400MHz,CDCl3)：δ7.88-7.86(m,4H),δ2.42-2.34(m,4H),δ1.27(d,6H),δ1.26(d,6H),δ0.99-0.90(m,4H),δ0.64-0.58(m,4H),δ0.48-0.41(m,4H),δ0.30-0.24(m,4H),δ0.21-0.15(m,4H).
The second step is that: 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-hydroxy-phenyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] phenol (2)
4-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]-2,6-bis[(1R)-1-cyclopropylethyl]phenol(2)
Figure BDA0003312344710000131
Adding 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-oxo-cyclohexa-2, 5-dien-1-enyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] cyclohexa-2, 5-dien-1-one (3) (0.4g,0.988mmol), 10mL of ethanol and 10mL of tetrahydrofuran into a 100mL three-necked flask, stirring the mixture uniformly, cooling the mixture to 0 ℃, adding solid sodium borohydride (0.112g,2.97mmol) in portions, naturally returning the mixture to room temperature after the addition is finished to react for 1h, slowly pouring the reaction solution into 100mL of saturated aqueous ammonium chloride solution to quench the mixture, extracting the mixture with ethyl acetate (40 mL. times.3), combining the organic phases, backwashing the organic phases with saturated saline (100 mL. times.2), drying the mixture with anhydrous sodium sulfate, the filtrate was filtered, concentrated under reduced pressure to a volume of 30mL, and the mixture was purified by column chromatography (ethyl acetate: petroleum ether ═ 1: 10) to give 4- [3, 5-bis [ (1R) -1-cyclopropylethyl ] -4-hydroxy-phenyl ] -2, 6-bis [ (1R) -1-cyclopropylethyl ] phenol (2) (0.26g, 64.68%)
MS:457.4[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.282(4H，s)，5.098(2H，s)，2.558-2.442(4H，m)，1.346(12H，d)，1.145-1.072(4H，m)，0.617-0.556(4H，m)，0.518-0.458(4H，m)，0.273-0.194(8H，m).
Example 5
4- [3- [ (1R) -1-Cyclopropylethyl ] -4-hydroxy-5-isopropyl-phenyl ] -2, 6-diisopropyl-phenol (4)
4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-2,6-diisopropyl-phenol(4)
Figure BDA0003312344710000141
The first step is as follows: 4-bromo-2, 6-diisopropylphenol (4b)
4-bromo-2,6-diisopropyl-phenol(4b)
Figure BDA0003312344710000142
A250 mL three-necked flask was charged with 2, 6-diisopropylphenol (4a) (10.00g,56.09mmol) and dichloromethane (100mL), stirred well, cooled to 0 deg.C, added benzyl trimethyl ammonium tribromide (26.25g,67.31mmol) in portions, allowed to warm to room temperature naturally, and reacted for 3 hours. After completion of the reaction, the reaction mixture was washed with water (100 mL. times.1), a saturated sodium hydrogen sulfite solution (50 mL. times.1), a saturated sodium bicarbonate solution (100 mL. times.1) and a saturated sodium chloride solution (100 mL. times.1) in this order, dried over anhydrous sodium sulfate, filtered and concentrated to give 4-bromo-2, 6-diisopropylphenol (4b) (13.0g, yield 90.3%).
MS:255.0[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.14(s,2H),4.60(brs,1H),3.11(hept,2H),1.24(d,12H).
The second step is that:
2, 6-diisopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (4c)
2,6-diisopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(4c)
Figure BDA0003312344710000151
A100 mL single-neck flask was charged with 4-bromo-2, 6-diisopropylphenol (4b) (3.00g,11.67mmol) and dioxane (30mL), followed by pinacol diboron (3.85g,15.17mmol), potassium acetate (1.89g,31.50mmol), Pd (dppf) Cl2(0.85g,1.17mmol) and reacted at 100 ℃ for 6 hours under nitrogen protection. After completion of the reaction, celite was filtered, and the filtrate was extracted with water (30mL) and ethyl acetate (30mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 1), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give 2, 6-diisopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (4c) (3.0g, yield 85.0%).
MS:303.3[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.52(s,2H),5.01(s,1H),3.14(hept,2H),1.33(s,12H),1.27(d,12H).
The third step:
4-bromo-2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol (4d)
4-bromo-2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol(4d)
Figure BDA0003312344710000152
A250 mL three-necked flask was charged with 2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol (1a) (10.00g,48.95mmol) and methylene chloride (100mL), stirred well, cooled to 0 deg.C and added with benzyltrimethylammonium tribromide (22.90g,58.74mmol) in portions, allowed to warm to room temperature naturally, and reacted for 3 hours. After completion of the reaction, the reaction mixture was washed with water (100mL × 1), a saturated sodium hydrogen sulfite solution (50mL × 1), a saturated sodium hydrogen carbonate solution (100mL × 1) and a saturated sodium chloride solution (100mL × 1) in this order, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (petroleum ether: ethyl acetate: 100:1) to give 4-bromo-2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol (4d) (4.8g, yield 35.5%).
MS:281.0[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.21(d,1H),7.15(d,1H),4.88(s,1H),3.11(hept,1H),2.47-2.40(m,1H),1.27(d,3H),1.24(dd,6H),1.04-0.98(m,1H),0.61-0.55(m,1H),0.52-0.45(m,1H),0.24-0.20(m,1H),0.18-0.13(m,1H).
The fourth step:
4- [3- [ (1R) -1-Cyclopropylethyl ] -4-hydroxy-5-isopropyl-phenyl ] -2, 6-diisopropyl-phenol (4)
4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-2,6-diisopropyl-phenol(4)
Figure BDA0003312344710000161
Into a 100mL single-neck flask, 4-bromo-2- [ (1R) -1-cyclopropylethyl ] -6-isopropylphenol (4d) was added
(0.10g,0.35mmol) and dioxane (3mL) were added sequentially 2, 6-diisopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (4c) (0.14g,0.46mmol), potassium carbonate (2mol/L,1.1mL), Pd (dppf) Cl2(16mg,0.021mmol) and reacting at 100 ℃ for 6 hours under the protection of nitrogen. After the reaction, the reaction mixture was filtered through celite, water (5mL) was added to the filtrate, and the filtrate was extracted with ethyl acetate (5mL × 2), and the organic phases were combined, washed with a saturated sodium chloride solution (10mL × 1), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 50:1) to give 4- [3- [ (1R) -1-cyclopropylethyl ethyl ] ethyl]-4-hydroxy-5-isopropyl-phenyl]-2, 6-diisopropyl-phenol (4) (0.05g, yield 40.0%).
MS:379.3[M-1]-；
1HNMR：(400MHz，CDCl3)：δ7.25(d,1H),7.21-7.20(m,3H),4.96(s,1H),4.78(s,1H),3.23-3.17(m,3H),2.59-2.52(m,1H),1.28-1.23(m,21H),1.18-1.10(m,1H),0.62-0.57(m,1H),0.54-0.49(m,1H),0.30-0.22(m,2H).
Biological assay
Pentaerythrite induced acute epilepsy test for mice[1]
1. Purpose of the experiment
The antiepileptic effect of the compound is evaluated by a pentaerythrine-induced mouse acute epilepsy model.
2. Test materials
1) Test animal
ICR mice, 6-8 weeks old, 18-22g, half male and female, 40 in total, supplier achievement large laboratory animals GmbH, license number scxk (Sichuan) 2013-.
2) Reagent
Penetrapentanitrogen, purchased from Sigma-Aldrich, under batch number MKBX 1160V. The preparation is prepared into solution with required concentration by using normal saline before use.
3) Test drug
The compound 1 (example 1) was used as the test drug, and 3 dose groups of 100mg/kg, 50mg/kg and 25mg/kg were set. Accurately weighing the compound before use, sequentially adding DMSO, solutol HS-15 and normal saline as a solvent into each dose group, and uniformly mixing by vortex to prepare a solution with a required concentration. The final concentrations of DMSO and solutol HS-15 were 5% and 10%, respectively. The administration was intravenous in a volume of 10 mL/kg.
3. Test method
The day before the test, animals were fasted without water deprivation. On the day of the experiment, animals were randomized into 4 groups of 10 animals each with male and female halves, three dose groups of compound 1 (100mg/kg, 50mg/kg, 25mg/kg) and model controls with vehicle addition only. The animals in each group were first administered the test drug solution or vehicle intravenously, respectively. Pentaerythrine (85mg/kg) was administered intraperitoneally 30min after intravenous administration. The observation indexes are adopted by Racine standards (table 1) to record the seizure grade of animals, the animal seizure grade is 0-III grade, the anti-seizure effect of the compound is calculated, and the effective rate is calculated.
TABLE 1 criteria for seizure Racine
Grade of attack Performance of
Level 0 No reaction
Class I Rhythmic mouth twitching or facial twitching
Class II Nodding or drifting
Class III One limb twitching
Grade IV Multi-limb twitching or rigidity
Class V Generalized tonic-clonic seizures
4. Test results
Figure BDA0003312344710000181
And (4) conclusion: experimental results show that the compound 1 can inhibit the pentaerythrine-induced acute epileptic seizure of mice, and the antiepileptic drug effect of the compound is dose-related.
Reference to the literature
[1] Weiwei master compilation pharmacological testing methodology (fourth edition) [ M ]. people's health press 2010: 705-707.

Claims (9)

1. A compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
Figure FDA0003312344700000011
wherein
B is selected from
Figure FDA0003312344700000012
R1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
R3、R4、R5and R6Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
n is selected from 1 or 2.
2. A compound according to claim 1 or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein
R1Selected from methyl or ethyl; r2Selected from methyl, ethyl or cyclopropyl;
R3、R4、R5and R6Each independently selected from methyl, ethyl or cyclopropyl.
3. A compound according to claim 1 or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein
R1Selected from methyl or ethyl; r2Selected from methyl, ethyl or cyclopropyl;
b is selected from one of the following structures:
Figure FDA0003312344700000021
Figure FDA0003312344700000022
or
Figure FDA0003312344700000023
4. A compound according to claim 3, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein B is selected from one of the following structures:
Figure FDA0003312344700000024
5. the compound according to claim 4, or a stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound is selected from one of the following structures:
Figure FDA0003312344700000031
6. a compound of formula (II) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
Figure FDA0003312344700000032
wherein
R7And R8Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
R9、R10、R11and R12Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group;
m is selected from 1 or 2.
7. The compound according to claim 6 or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein
R7Selected from methyl or ethyl; r8Selected from methyl, ethyl or cyclopropyl;
R9、R10、R11and R12Each independently selected from methyl, ethyl or cyclopropyl.
8. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 5 or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
9. Use of a compound of general formula (I) according to any one of claims 1 to 5 or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition according to claim 8 for the preparation of a medicament for promoting sedative-hypnosis, brain protection, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans.
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