CN108069833B - Benzocyclo-ring derivatives, preparation method and medical application thereof - Google Patents

Benzocyclo-ring derivatives, preparation method and medical application thereof Download PDF

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CN108069833B
CN108069833B CN201711040543.6A CN201711040543A CN108069833B CN 108069833 B CN108069833 B CN 108069833B CN 201711040543 A CN201711040543 A CN 201711040543A CN 108069833 B CN108069833 B CN 108069833B
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pharmaceutically acceptable
trien
methylbicyclo
octa
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CN108069833A (en
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范江
江伟
陈清平
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Tibet Haisike Pharmaceutical Co ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • 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
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Abstract

The invention relates to a benzotetracyclic derivative, a preparation method and application thereof in medicine, in particular to a benzotetracyclic derivative shown as a formula (I), or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the same and application of the compound or the composition in the field of central nerve,

Description

Benzocyclo-ring derivatives, preparation method and medical application thereof
Technical Field
The invention relates to a benzotetracyclic derivative shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the same, and application of the compound and the composition 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 diagnosis and treatment of various diseases such as anesthesia, 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 activates multiple GABAAThe receptor subtype, a clinically mature intravenous anesthetic, is widely used for induction and maintenance of general anesthesia. The remarkable pharmacokinetic and pharmacodynamic properties of propofol are fast onset, short maintenance time and fast reversibility. However, propofol also has obvious limitations and disadvantages. Some degree of pain or discomfort was reported in about 70% of patients injected with propofol (Pascale Picard (2000)&Analgesia,90, 963-969). Clinically, hypotension is caused. At the same time, respiratory depression, apnea, hypoxemia, etc. are also considerable risks when propofol is used. These adverse effects largely hamper the use of propofol in some clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.
Fospropofol is a water-soluble prodrug of propofol, alleviating pain at the site of intravenous injection of propofol, but because it is still acting as a prodrug of propofol, there is still a risk of respiratory depression and adverse hemodynamic effects (CohenLB (2008). At the same time, fospropofol can also cause paresthesia and itching.
In view of the limitations and disadvantages of propofol and fospropofol, there is a need to develop new GABA with better pharmacokinetic and pharmacodynamic properties and fewer side effectsAA receptor agonist.
CN1228414 describes benzo-four-membered ring derivatives and their addition salts with a pharmaceutically acceptable acid for the treatment of depression, anxiety, phobias, which compounds have the general formula:
Figure BDA0001453388130000011
wherein Z1、Z2、Z3And Z4Each independently selected from H, F, Cl, Br, I, C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl and X represents O. The structure of the invention is greatly different from that of the invention.
CN1323794 describes benzo-four-membered ring derivatives and their addition salts with pharmaceutically acceptable acids or bases, which have the following general formula:
Figure BDA0001453388130000021
wherein:
Figure BDA0001453388130000022
represents a single or double bond; n is an integer of 1 to 6; r1And R2Each independently selected from H, C1-6Alkyl, cycloalkyl, aryl; x is selected from-CH ═ CH-, O, S (═ O)mM is an integer of 0 to 2 or NR3Wherein R is3Selected from H, C1-6Alkyl, aryl. Y represents-CH or-CH2(ii) a T represents a monocyclic or polycyclic ring C3-12Cycloalkyl, wherein one of the carbon atoms of the cycloalkyl group is optionally substituted by a group selected from O, Se or S (═ O)pWherein p is an integer of 0 to 2, NR3This invention differs greatly from the structure of the present invention and is not considered to be part of the present invention as specifically described in this patent.
WO9615099 describes compounds for use in the treatment of central nervous system disorders, of the general formula:
Figure BDA0001453388130000023
wherein N is an integer of 0 to 2, X is selected from O, S, -N (R)5) Or methylene, R1Selected from H, -NH2、-NHR5Or a hydroxyl group; r2、R3Each independently selected from H, -COOH, -COOR5、-CONH2、-CONHR5、-CON(R5)2、CONHSO2R5Or tetrazole, R4Selected from H, hydroxy, amino, -NHR5、CF3、C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-6Cycloalkyl, phenyl or C1-4Alkoxy radical, R5Can be H, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-6Cycloalkyl, ring a may be a partially or fully saturated aromatic ring or a pharmaceutically acceptable salt, which is a structure that is quite different from the present invention.
Disclosure of Invention
The invention aims to provide GABA with novel structure, better drug effect and higher safetyAReceptor agonists, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, processes for their preparation, pharmaceutical compositions and their use in the central nervous field to provide a more optimal route of drug selection for inducing or maintaining general anesthesia, promoting sedation hypnosis, treating and/or preventing anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases and central nervous system related diseases in animals or humans.
The invention provides a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0001453388130000031
in a preferred embodiment of the invention, a compound of formula (I) according to claim 1, wherein the compound is selected from one of the following structures:
Figure BDA0001453388130000032
the present invention also provides a pharmaceutical composition comprising: the compound of the present invention or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides a pharmaceutical composition comprising: the compounds of the present invention, and one or more therapeutic agents selected from opioid analgesics, sedative hypnotics and/or cardiovascular agents. The pharmaceutical composition provided by the invention is any pharmaceutically acceptable dosage form, preferably lipid emulsion, injection, tablet, aerosol, powder spray, membrane, granule, dispersible tablet, freeze-dried powder injection, capsule, ointment, suppository, cream, implant, syrup, oral solution, oral suspension, oral emulsion, powder or gel, more preferably freeze-dried powder injection, injection or lipid emulsion.
The compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt, the eutectic crystal or the prodrug thereof or the pharmaceutical composition can be used as GABAAReceptor agonists for the preparation of CNS-related medicaments for the induction or maintenance of general anaesthesia, sedation hypnosis, treatment and/or prevention of anxiety, nausea, vomiting, migraine, convulsions, epilepsy, neurodegenerative diseases and CNS-related diseases in animals or humans. Novel GABA of the present inventionAReceptor agonists, which are safer and have a shorter duration of action, and more particularly, which are present in solid form and have better water solubility than propofol, can be administered in a non-fat emulsion, thereby reducing the likelihood of injection pain, while avoiding emulsifier-induced allergic reactions and reducing the chance of bacterial infection of the formulation. The compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt, the eutectic crystal or the prodrug thereof is used for preparing related medicaments or treating related diseases, and has better medicinal effect and higher safety.
Therefore, the invention also provides the application of the compound shown in the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs or a pharmaceutical composition comprising the compound in the preparation of medicines in the central nervous field.
In a preferred embodiment of the present invention, there is provided a use of a compound represented by general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament in the central nervous field, wherein the medicament in the central nervous field comprises: a drug for inducing and maintaining anesthesia in animals including mammals such as companion animals, zoo animals and livestock, preferably horses or dogs, a drug for promoting sedation and hypnosis in animals or humans, or a drug for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy.
In a preferred embodiment of the present invention, there is provided a use of a compound represented by general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof, or a pharmaceutical composition comprising the same, for preparing a medicament in the central nervous field, including a medicament for inducing and maintaining anesthesia in an animal or human.
The present invention also provides a method for inducing and maintaining anesthesia in an animal or human, which comprises administering to the animal or human an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or a pharmaceutical composition comprising the same.
The present invention also provides a method for promoting sedative-hypnotic activity in animals or humans, which comprises administering an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or pharmaceutical compositions comprising the same to animals or humans.
The present invention also provides a method for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion or epilepsy in an animal or human, which comprises administering to the animal or human an effective amount of a compound represented by the general formula (I) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, prodrugs thereof or a pharmaceutical composition comprising the same.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where 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。
by "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base 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.
By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. 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 yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, 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.
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 () at 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 sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetonitrile (CD)3CN), internal standard Tetramethylsilane (TMS).
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.
Example 1
(S) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 1)
(S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000061
Figure BDA0001453388130000071
The first step is as follows: 1-benzyloxy-2-bromobenzene (1B)
1-(benzyloxy)-2-bromobenzene
Figure BDA0001453388130000072
2-bromophenol (200.00g, 1.156mol), benzyl bromide (217.48g, 1.272mol), potassium carbonate (319.54g, 2.312mol), potassium iodide (9.60g, 58mmol) were dissolved in acetone (1200ml) in a 2L three-necked flask, stirred mechanically until homogeneous, and heated to reflux for 10 hours. After cooling to room temperature, filtration was carried out and the filter cake was rinsed with petroleum ether. The filtrate was dried by spinning, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether 0/100-1/50) using a plug, and concentrated to dryness to give 1-benzyloxy-2-bromobenzene (1B) as a yellow oil (300g, 98.64% yield).
Ms m/z(ESI):262.9[M+H+]。
The second step is that: 5- (benzyloxy) bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (1C)
5-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
Figure BDA0001453388130000073
1-benzyloxy-2-bromobenzene (1B) (50g, 190mmol),1, 1-diethoxyethylene (44g, 380mmol), sodium amide (30g, 760mmol) were dissolved in tetrahydrofuran (450mL) in a single vial, and the mixture was heated to reflux for 2 hours, filtered with celite, the cake was rinsed with THF, the filtrate was added to a 3N hydrogen chloride ice-water solution, the pH was maintained in the acidic range, extraction was performed with ethyl acetate (150 mL. times.1), the organic phase was washed with water (100 mL. times.2), saturated brine (100 mL. times.1), dried, filtered and concentrated, the crude product was purified by column chromatography (ethyl acetate: petroleum ether 1/50-1/5) and concentrated to dryness to give 5- (benzyloxy) bicyclo [4.2.0] oct-1, 3, 5-trien-7-one (1C) (29.5g, yield 69.2%).
Ms m/z(ESI):225.2[M+H+]。
The third step: 5- (benzyloxy) -7-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-ol (1D)
5-(benzyloxy)-7-methylbicyclo[4.2.0]octa-1,3,5-trien-7-ol
Figure BDA0001453388130000081
5- (benzyloxy) bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (1C) (118g, 526mmol) was dissolved in tetrahydrofuran (800ml) in a three-necked flask, the temperature was lowered to-40 ℃, methyl magnesium bromide (263ml, 789mmol) was added dropwise to the reaction mixture, the temperature was maintained at-30 ℃ to-40 ℃, and after completion of addition, the reaction was allowed to proceed for 1 hour with incubation. Keeping the temperature below 0 ℃, dropwise adding saturated ammonium chloride aqueous solution to quench the reaction, separating the liquid, extracting the aqueous phase with ethyl acetate (400ml × 1), combining the organic phases, adding anhydrous sodium sulfate, drying, filtering and concentrating. The crude product was purified by column chromatography (ethyl acetate: petroleum ether: 1/30-1/5) using a plug, and concentrated to dryness to give 5- (benzyloxy) -7-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-ol (1D) (78.7g, 62.2% yield).
1H NMR(400MHz,CDCl3)7.42-7.37(m,5H),7.20-7.18(dd,1H),6.78-6.75(m,2H),5.28-5.15(q,2H),4.13-4.08(dd,1H),3.32-3.16(m,2H),2.24(s,6H),1.75(s,3H).
The fourth step: 2- (benzyloxy) -8-methylbicyclo [4.2.0] octa-1, 3, 5-triene (1E)
2-(benzyloxy)-8-methylbicyclo[4.2.0]octa-1,3,5-triene
Figure BDA0001453388130000082
5- (benzyloxy) -7-methylbicyclo [4.2.0] octa-1, 3, 5-trien-7-ol (1D) (74g, 308mmol) was dissolved in a single-neck flask with dichloromethane (700ml), the temperature was reduced with an ice bath, and triethylsilane (72g, 616mmol) and trifluoroacetic acid (140g, 1232mmol) were added dropwise to the reaction mixture, and the mixture was allowed to naturally warm to room temperature and reacted for 2 hours. The reaction solution was washed with water (500ml × 1), saturated aqueous sodium bicarbonate (500ml × 1), saturated brine (500ml × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1/50-1/30) to give 2- (benzyloxy) -8-methylbicyclo [4.2.0] oct-1, 3, 5-triene (1E) (45.7g, yield 66.26%) as a colorless oil.
Ms m/z(ESI):225.2[M+H+]。
The fifth step: 8-Methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (1F)
8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000091
2- (benzyloxy) -8-methyl-bicyclo [4.2.0] octa-1, 3, 5-triene (1E) (24g, 107mmol), palladium on carbon (2.4g, 10%) was dissolved in a single-neck flask with methanol (240ml), and ammonium formate (34g, 535mmol) was added and reacted at room temperature for 2 hours. After filtration through Celite, the filtrate was concentrated, and ethyl acetate (100ml) was added thereto to dissolve the filtrate, and the solution was washed with water (100 ml. times.2), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated to give 8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (1F) (14.4g, yield 100%) as a pale yellow oil.
1H NMR(400MHz,CDCl3)7.10-7.07(q,1H),6.69-6.67(d,1H),6.62-6.60(d,1H),4.78(s,1H),3.61-3.57(m,1H),3.35-3.30(dd,1H),2.66-2.62(dd,1H),1.45-1.43(d,3H).
And a sixth step: (S) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1G)
(S)-3-bromo-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000092
8-methyl bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1F) (23.7g, 177mmol), diisopropylamine (1.8g, 17.7mmol) were dissolved in dichloromethane (200ml) in a three-necked flask, the temperature was reduced to about-70 ℃, bromosuccinimide (29.9g, 168mmol) was dissolved in dichloromethane (1300ml), and then the solution was slowly added dropwise to the reaction mixture, and after completion of the addition, the reaction was carried out for 2 hours. After the reaction was completed, the organic phase was washed with water (500ml × 1), dilute hydrochloric acid (500ml × 1), and water (500ml × 1), the organic phase was dried, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1/100-1/30) and concentrated to dryness to give 3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (22g, 58.5%) as a white solid. Chiral preparation to obtain (S) -3-bromo-8-methyl bicyclo [4.2.0] octa-1, 3, 5-triene-2-ol (1G).
The chiral preparation method comprises the following steps:
3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (15g) is taken for resolution,
the preparation conditions are as follows:
apparatus, Thar 200preparative SFC (SFC-7);
column ChiralCel OD,300 × 50mm i.d.,10 μm.;
mobile phase A: CO 22And B: ethanol;
gradient B15%;
the flow rate is 180 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is about 2 min;
sample preparation, dissolving the sample in methanol to obtain 62.5 mg/ml; injection, 3ml per needle.
Two optical isomers, compound 1G (retention time: 1.905min, 6.12G, white solid, ee% ═ 98.5%,) and compound 2B (retention time: 2.324min, 6.32G, white solid, ee% ═ 99.1%) were obtained after separation.
Ms m/z(ESI):212.9[M+H+]。
1H NMR(400MHz,CDCl3)7.32-7.30(d,1H),6.57-6.55(d,1H),5.38(s,1H),3.61-3.57(m,1H),3.29-3.24(dd,1H),2.62-2.58(dd,1H),1.44-1.42(d,3H).
The seventh step: (S) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1H)
(S)-3-bromo-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-yl 4-nitrobenzenesulfonate
Figure BDA0001453388130000101
(S) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1G) (5G, 23.5mmol), 4-nitrobenzenesulfonyl chloride (5.2G, 23.5mmol) and dichloromethane (35ml) were dissolved in a single-necked flask, and triethylamine (2.4G, 23.5mmol) was added dropwise to the reaction mixture to react at room temperature for 20 minutes. The dichloromethane was concentrated off, dissolved in ethyl acetate (50mL), and the organic phase was washed with water (50 mL. times.1), saturated sodium bicarbonate (50 mL. times.1), dried with anhydrous sodium sulfate, filtered and concentrated to a solid, slurried with 50mL petroleum ether, filtered, rinsed with a small amount of petroleum ether, and dried to give (S) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1H) (8.32g, 89% yield) as an off-white solid.
1H NMR(400MHz,CDCl3)8.39-8.37(m,2H),8.16-8.14(m,2H),7.37-7.35(d,1H),6.90-6.88(d,1H),3.80-3.76(m,1H),3.33-3.32(dd,1H),2.68-2.64(dd,1H),1.46-1.44(d,3H).
Eighth step: (S) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1I)
(S)-3-(1-cyclopropylvinyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-yl 4-nitrobenzenesulfonate
Figure BDA0001453388130000111
(S) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1H) (8.32g, 20.9mmol),2- (1-cyclopropylvinyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (6.08g, 31.3mmol), potassium phosphate heptahydrate (12.7g, 37.6mmol) were dissolved in a single vial with toluene (64ml) and water (24ml), replaced with nitrogen three times, and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (0.832g, 10%) was added and replaced with nitrogen three times, followed by heating to 90 ℃ under nitrogen protection for 6 hours and standing at room temperature overnight. Cooled to room temperature, filtered through celite, the filtrate was rinsed with ethyl acetate (50mL), water (50mL), allowed to stand for separation, the organic phase was washed with saturated brine (80mL × 1), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1/1000-1/100) to give (S) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1I) (6.27g, 77.9% yield) as a yellow solid.
1H NMR(400MHz,CDCl3)8.33-8.31(d,2H),8.07-8.04(d,2H),7.06-7.04(d,1H),6.97-6.95(d,1H),4.63-4.56(dd,2H),3.72-3.70(m,1H),3.39-3.34(dd,1H),2.70-2.66(dd,1H),1.47-1.45(d,3H),1.30-1.25(m,1H),0.71-0.66(m,1H),0.58-0.53(m,1H),0.33-0.31(m,2H).
The ninth step: (S) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1J)
(S)-3-(1-cyclopropylvinyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000112
(S) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (1I) (6.17g, 16mmol) and sodium hydroxide (1.92g, 48mmol) were dissolved in t-butanol (60ml) and heated to 80 ℃ for 2 hours. Cool to room temperature, adjust pH to 5 with 1M dilute hydrochloric acid, and adjust with EA: PE ═ 1: 1 (25 ml. times.2), combined, washed with saturated brine (25 ml. times.2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative (acetonitrile/0.1% ammonium acetate) to give (S) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1J) (0.8g, 20% yield).
1H NMR(400MHz,CDCl3)7.01-6.99(d,1H),6.64-6.62(d,1H),5.50(s,1H),5.24(dd,1H),4.99(dd,1H),3.60-3.57(m,1H),3.32-3.27(dd,1H),2.65-2.61(dd,1H),1.64-1.60(m,1H),1.45-1.43(d,3H),0.80-0.75(m,2H),0.56-0.52(m,2H).
The tenth step: (S) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 1)
(S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000121
(S) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1J) (0.8g, 3.99mmol) and triethylsilane (0.7g, 5.99mmol) were dissolved in a single-neck flask with dichloromethane (10ml), the temperature was lowered to-30 ℃ or lower, trifluoroacetic acid (0.7g, 5.99mmol) was diluted with dichloromethane (1ml), the mixture was added dropwise to the reaction mixture, the mixture was allowed to react at-30 ℃ or lower for 2 hours, and the mixture was allowed to warm to room temperature for 1 hour. The solvent was evaporated to dryness, ethyl acetate (20ml) was added, washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated to afford (S) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-ol (compound 1) (151.76mg, yield 18.8%) as a chiral preparation.
The chiral preparation method comprises the following steps:
(8S) -3- (1-Cyclopropylethyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (0.8g) was used for resolution,
the preparation conditions are as follows:
MG II preparatory SFC (SFC-1);
column ChiralCel OJ,250 × 30mm i.d.,5 μm.;
mobile phase A: CO 22And B: isopropyl alcohol;
gradient B10%;
the flow rate is 50 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is 5 min;
sample preparation, dissolving the sample in methanol to prepare 4 mg/ml; injection 1 ml/needle.
Two optical isomers, compound 1 (retention time: 4.94min, 151.76mg, yellow oil, ee% ═ 99.3%), compound 3 (retention time: 5.06min, 168.44mg, yellow oil, ee%: 97.6%) were obtained after separation.
Ms m/z(ESI):201.2[M-H+]。
1H NMR(400MHz,CDCl3)7.14-7.12(d,1H),6.68-6.66(d,1H),4.56(s,1H),3.56(m,1H),3.31-3.26(m,1H),2.63-2.59(dd,1H),2.41-2.37(m,1H),1.45-1.44(d,3H),1.29-1.27(d,3H),1.06-1.04(m,1H),0.54-0.42(m,2H),0.21-0.17(m,2H).
Example 2
(R) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 2)
(R)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000131
The first step is as follows: (R) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2B)
(R)-3-bromo-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000132
8-methyl bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1F) (23.7g, 177mmol), diisopropylamine (1.8g, 17.7mmol) were dissolved in dichloromethane (200ml) in a three-necked flask, the temperature was reduced to about-70 ℃, bromosuccinimide (29.9g, 168mmol) was dissolved in dichloromethane (1300ml), and then the solution was slowly added dropwise to the reaction mixture, and after completion of the addition, the reaction was carried out for 2 hours. After the reaction was completed, the organic phase was washed with water (500ml × 1), dilute hydrochloric acid (500ml × 1), and water (500ml × 1), the organic phase was dried, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1/100-1/30) and concentrated to dryness to give 3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (22g, 58.5%) as a white solid. Chiral preparation of (R) -3-bromo-8-methyl bicyclo [4.2.0] octa-1, 3, 5-triene-2-ol (2B).
The chiral preparation method comprises the following steps:
3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (15g) is taken for resolution,
the preparation conditions are as follows:
apparatus, Thar 200preparative SFC (SFC-7);
column ChiralCel OD,300 × 50mm i.d.,10 μm.;
mobile phase A: CO 22And B: ethanol;
gradient B15%;
the flow rate is 180 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is about 2 min;
sample preparation, dissolving the sample in methanol to obtain 62.5 mg/ml; injection, 3ml per needle.
Two optical isomers, compound 1G (retention time: 1.905, 6.12G, white solid, ee% ═ 99%), and compound 2B (retention time: 2.324s, 6.32G, white solid, ee%: 99%) were obtained after separation.
Ms m/z(ESI):212.9[M+H+]。
1H NMR(400MHz,CDCl3)7.32-7.30(d,1H),6.57-6.55(d,1H),3.61-3.57(m,1H),3.29-3.24(dd,1H),2.62-2.58(dd,1H),1.44-1.42(d,3H).
The second step is that: (R) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2C)
(R)-3-bromo-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-yl 4-nitrobenzenesulfonate
Figure BDA0001453388130000141
(R) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2B) (5g, 23.5mmol), 4-nitrobenzenesulfonyl chloride (5.2g, 23.5mmol) and dichloromethane (35ml) were dissolved in a single-necked flask, and triethylamine (2.4g, 23.5mmol) was added dropwise to the reaction mixture to react at room temperature for 20 minutes. The methylene chloride was concentrated off, dissolved in ethyl acetate (50mL), and the organic phase was washed with water (50 mL. times.1), saturated sodium bicarbonate (50 mL. times.1), dried with anhydrous sodium sulfate, filtered and concentrated to a solid, slurried with 50mL of petroleum ether, filtered, rinsed with a small amount of petroleum ether, and dried to give (R) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2C) (8.52g, 91.2% yield) as an off-white solid.
1H NMR(400MHz,CDCl3)8.39-8.37(m,2H),8.16-8.14(m,2H),7.37-7.35(d,1H),6.90-6.88(d,1H),3.80-3.76(m,1H),3.33-3.32(dd,1H),2.68-2.64(dd,1H),1.46-1.44(d,3H).
The third step: (R) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2D)
(R)-3-(1-cyclopropylvinyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-yl 4-nitrobenzenesulfonate
Figure BDA0001453388130000151
(R) -3-bromo-8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2C) (8.52g, 20.9mmol),2- (1-cyclopropylvinyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (6.23g, 32.1mmol), potassium phosphate heptahydrate (13.0g, 38.5mmol) were dissolved in toluene (64ml) and water (24ml) in a single vial, replaced with nitrogen three times, and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (0.852g, 10%) was added and replaced with nitrogen three times, followed by heating to 90 ℃ under nitrogen protection for 6 hours and standing at room temperature overnight. Cooled to room temperature, filtered through celite, the filtrate was rinsed with ethyl acetate (50mL), water (50mL), allowed to stand for separation, the organic phase was washed with saturated brine (80mL × 1), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1/1000-1/100) to give (R) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2D) (6.32g, 76.6% yield) as a yellow solid.
1H NMR(400MHz,CDCl3)8.33-8.31(d,2H),8.07-8.04(d,2H),7.06-7.04(d,1H),6.97-6.95(d,1H),4.63-4.56(dd,2H),3.72-3.70(m,1H),3.39-3.34(dd,1H),2.70-2.66(dd,1H),1.47-1.45(d,3H),1.30-1.25(m,1H),0.71-0.66(m,1H),0.58-0.53(m,1H),0.33-0.31(m,2H).
The fourth step: (R) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2E)
(R)-3-(1-cyclopropylvinyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000161
(R) -3- (1-Cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl 4-nitrobenzenesulfonate (2D) (6.32g, 16.4mmol), sodium hydroxide (1.97g, 49.2mmol) was dissolved in t-butanol (60ml), and the mixture was heated to 80 ℃ for 2 hours. Cool to room temperature, adjust pH to 5 with 1M dilute hydrochloric acid, and adjust with EA: PE ═ 1: 1 (25 ml. times.2), combined, washed with saturated brine (25 ml. times.2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative (acetonitrile/0.1% ammonium acetate) to give (R) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2E) (1.1g, yield 33%).
1H NMR(400MHz,CDCl3)7.01-6.99(d,1H),6.64-6.62(d,1H),5.50(s,1H),5.24(dd,1H),4.99(dd,1H),3.60-3.57(m,1H),3.32-3.27(dd,1H),2.65-2.61(dd,1H),1.64-1.60(m,1H),1.45-1.43(d,3H),0.80-0.75(m,2H),0.56-0.52(m,2H).
The fifth step: (R) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 2)
(R)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000162
(R) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2E) (1.1g, 5.5mmol), triethylsilane (0.96g, 8.2mmol) and dichloromethane (10ml) were dissolved in a single-neck flask, the temperature was lowered to-30 ℃ or lower, trifluoroacetic acid (0.94g, 8.2mmol) was diluted with dichloromethane (1ml) and added dropwise to the reaction mixture, the mixture was reacted at-30 ℃ or lower for 2 hours, and the mixture was allowed to warm to room temperature for 1 hour. The solvent was evaporated to dryness, ethyl acetate (20ml) was added, washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated to afford (R) -3- ((R) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-ol (compound 2) (289.65mg, yield 26%) as a chiral preparation.
The chiral preparation method comprises the following steps:
(8R) -3- (1-Cyclopropylethyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1.1g) was used for resolution,
the preparation conditions are as follows:
apparatus, Thar 350 preparatory SFC (SFC-6);
column chiralPak AD,300 × 50mm I.D.,10 μm.;
mobile phase A: CO 22And B: isopropyl alcohol;
gradient B20%;
the flow rate is 200 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is about 2.6 min;
sample preparation, dissolving the sample in methanol to prepare 3.7 mg/ml; injection, 3ml per needle.
Two optical isomers, compound 2 (retention time: 4.24min, 289.65mg, yellow oil, ee% ═ 100%), compound 4 (retention time: 4.39min, 208.75mg, yellow oil, ee% ═ 98.9%) were obtained after separation. Ms M/z (ESI) 201.2[ M-H+]。
1H NMR(400MHz,CDCl3)7.14-7.12(d,1H),6.68-6.66(d,1H),4.56(s,1H),3.56(m,1H),3.31-3.26(m,1H),2.63-2.59(dd,1H),2.41-2.37(m,1H),1.45-1.44(d,3H),1.29-1.27(d,3H),1.06-1.04(m,1H),0.54-0.42(m,2H),0.21-0.17(m,2H).
Example 3
(S) -3- ((S) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 3)
(S)-3-((S)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000171
(S) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1J) (0.8g, 3.99mmol) and triethylsilane (0.7g, 5.99mmol) were dissolved in a single-neck flask with dichloromethane (10ml), the temperature was lowered to-30 ℃ or lower, trifluoroacetic acid (0.7g, 5.99mmol) was diluted with dichloromethane (1ml), the mixture was added dropwise to the reaction mixture, the mixture was allowed to react at-30 ℃ or lower for 2 hours, and the mixture was allowed to warm to room temperature for 1 hour. The solvent was evaporated to dryness, ethyl acetate (20ml) was added, washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated to afford (S) -3- ((S) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-ol (compound 3) (168.44mg, yield 20.8%) as a chiral preparation.
The chiral preparation method comprises the following steps:
(8S) -3- (1-Cyclopropylethyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (0.8g) was used for resolution,
the preparation conditions are as follows:
MG II preparatory SFC (SFC-1);
column ChiralCel OJ,250 × 30mm i.d.,5 μm.;
mobile phase A: CO 22And B: isopropyl alcohol;
gradient B10%;
the flow rate is 50 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is 5 min;
sample preparation, dissolving the sample in methanol to prepare 4 mg/ml; injection 1 ml/needle.
Two optical isomers, compound 1 (retention time: 4.94min, 151.76mg, yellow oil, ee% ═ 99.3%), compound 3 (retention time: 5.06min, 168.44mg, yellow oil, ee% ═ 97.6%) were obtained after separation.
Ms m/z(ESI):201.2[M-H+]。
1H NMR(400MHz,CDCl3)7.14-7.12(d,1H),6.68-6.66(d,1H),4.56(s,1H),3.56(m,1H),3.31-3.26(m,1H),2.63-2.59(dd,1H),2.41-2.37(m,1H),1.45-1.44(d,3H),1.29-1.27(d,3H),1.06-1.04(m,1H),0.54-0.42(m,2H),0.21-0.17(m,2H).
Example 4
(R) -3- ((S) -1-Cyclopropylethyl) -8-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-ol (Compound 4)
(R)-3-((S)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-2-ol
Figure BDA0001453388130000181
(R) -3- (1-cyclopropylvinyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (2E) (1.1g, 5.5mmol), triethylsilane (0.96g, 8.2mmol) and dichloromethane (10ml) were dissolved in a single-neck flask, the temperature was lowered to-30 ℃ or lower, trifluoroacetic acid (0.94g, 8.2mmol) was diluted with dichloromethane (1ml) and added dropwise to the reaction mixture, the mixture was reacted at-30 ℃ or lower for 2 hours, and the mixture was allowed to warm to room temperature for 1 hour. The solvent was evaporated to dryness, ethyl acetate (20ml) was added, washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated to afford (R) -3- ((S) -1-cyclopropylethyl) -8-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-ol (compound 4) (208.75mg, yield 19%) as a chiral preparation.
The chiral preparation method comprises the following steps:
(8R) -3- (1-Cyclopropylethyl) -8-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (1.1g) was used for resolution,
the preparation conditions are as follows:
apparatus, Thar 350 preparatory SFC (SFC-6);
column chiralPak AD,300 × 50mm I.D.,10 μm.;
mobile phase A: CO 22And B: isopropyl alcohol;
gradient B20%;
the flow rate is 200 mL/min;
back pressure is 100 bar;
the column temperature is 38 ℃; the wavelength is 220 nm;
the period is about 2.6 min;
sample preparation, dissolving the sample in methanol to prepare 3.7 mg/ml; injection, 3ml per needle.
Two optical isomers, compound 2 (retention time: 4.24min, 289.65mg, yellow oil, ee% ═ 100%), compound 4 (retention time: 4.39min, 208.75mg, yellow oil, ee% ═ 98.9%) were obtained after separation.
Ms m/z(ESI):201.2[M-H+]。
1H NMR(400MHz,CDCl3)7.14-7.12(d,1H),6.68-6.66(d,1H),4.56(s,1H),3.56(m,1H),3.31-3.26(m,1H),2.63-2.59(dd,1H),2.41-2.37(m,1H),1.45-1.44(d,3H),1.29-1.27(d,3H),1.06-1.04(m,1H),0.54-0.42(m,2H),0.21-0.17(m,2H).
Biological assay
1. Mouse righting reflex experiment
Test animals: ICR mice, half of each male and female, 240 mice, 18-22g of body weight, 6-8 weeks old, composed of
The production license number is scxk 2015-030 provided by the animal experimental company Limited.
Compound and configuration: accurately weighing a certain amount of tested compound, dissolving the compound in DMSO, adding solutol HS-15 for solubilization, adding physiological saline, and mixing by vortex. The final concentration of DMSO was 10%, and the final concentration of solutol HS-15 was 10%. It is prepared fresh before use.
The test method comprises the following steps: the day before the experiment, animals were fasted for 12 hours without water deprivation. On the day of the test, animals were randomly grouped into males and females, each group consisting of 8 animals. The test compound solutions were administered intravenously in a volume of 10ml/kg at a dose ranging from 1 to 60mg/kg, adjusted to the disappearance of the righting reflex in the animals after administration. And recording the righting reflection disappearance time, the righting reflection recovery time and the walking time. The time from disappearance of righting reflex to recovery of righting reflex after administration is anesthesia induction time, the time from disappearance of righting reflex to recovery of righting reflex is anesthesia duration time, the time from recovery of righting reflex to walking is anesthesia recovery time, and anesthesia effect is evaluated by indexes such as anesthesia induction time, anesthesia maintenance time, and righting reflex disappearance rate.
Righting reflection disappearance time: the righting reflex disappeared, so that the patient was in the supine position and could last for a period of 60 s;
righting reflection recovery time: the righting reflecting capacity is recovered, so that the righting time in the supine position is less than 2 s.
Walking time: the righting reflex capacity is recovered to the time when the autonomous forward movement and the muscle tension of the limbs are recovered.
Data processing and analysis:
calculating the righting and reflecting disappearance rate, anesthesia induction time, anesthesia duration, anesthesia recovery time and mortality of each group of animals by using microsoft excel software.
Graphpad Prism 6.0 was used to fit the dose-righting reflex disappearance curve, dose-mortality curve and calculate the righting reflex median Effective Dose (ED)50)。
The experimental results are shown in table 1 and table 2.
TABLE 1 mouse righting reflex test data
Figure BDA0001453388130000201
Figure BDA0001453388130000202
And (4) conclusion: the compound of the invention has better activity, quick response time and long anesthesia time.

Claims (7)

1. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt thereof,
Figure FDA0002652695900000011
2. a compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
Figure FDA0002652695900000012
3. a pharmaceutical composition comprising: a compound according to any one of claims 1-2, or a stereoisomer, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
4. A pharmaceutical composition comprising: a compound as claimed in any one of claims 1-2, or a stereoisomer, pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from opioid analgesics, sedative hypnotics or cardiovascular agents.
5. The pharmaceutical composition according to claim 3 or 4, which is in any pharmaceutically acceptable dosage form.
6. The pharmaceutical composition according to claim 5, wherein the dosage form is selected from lipid emulsion, injection, tablet, aerosol, powder spray, film, granule, capsule, ointment, suppository, cream, implant, syrup, oral solution, oral suspension, oral emulsion, dispersion tablet, lyophilized powder for injection, powder or gel.
7. Use of a compound according to any one of claims 1-2 or a stereoisomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 3-6, for the manufacture of a medicament for the central nervous field selected from the group consisting of a medicament for inducing and maintaining anesthesia in an animal or human, a medicament for promoting sedative-hypnosis in an animal or human, or a medicament for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, epilepsy.
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WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101151234A (en) * 2005-03-31 2008-03-26 三共农业株式会社 Process for producing cyclopropylphenol derivative
WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof
WO2014180327A1 (en) * 2013-05-10 2014-11-13 四川海思科制药有限公司 Phenol derivative, method of preparing same, and pharmaceutical application of same
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