CN107652194B - Compounds for treating nervous system diseases - Google Patents
Compounds for treating nervous system diseases Download PDFInfo
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- CN107652194B CN107652194B CN201710671494.XA CN201710671494A CN107652194B CN 107652194 B CN107652194 B CN 107652194B CN 201710671494 A CN201710671494 A CN 201710671494A CN 107652194 B CN107652194 B CN 107652194B
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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Abstract
The invention belongs to the technical field of medicine, and relates to a compound with a structure shown in a formula I and pharmaceutically acceptable salts thereof,
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to compounds with a neuron injury protection effect, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds as medicines for nervous system diseases.
Background
Cerebral apoplexy (also called stroke) and cerebrovascular accident (CVA) is an acute cerebrovascular disease, and a group of diseases of brain tissue damage caused by sudden rupture of cerebral vessels or blood failure to flow into the brain due to vessel occlusion, including ischemic and hemorrhagic stroke. Cerebral apoplexy is one of the main causes of death in China, and ischemic cerebral apoplexy accounts for 60-80% of cerebral apoplexy. Has the characteristics of high disability and high lethality. Therefore, the treatment of stroke is an important research topic for nervous system diseases at present. Besides acute phase thrombolysis, neuroprotective agents are of great significance to the rehabilitation of stroke patients.
At present, the medicines for neuroprotection mainly comprise glutamate receptor antagonists, free radical scavengers, calcium channel antagonists, gamma-aminobutyric acid (GABA) agonists, citicoline, inflammation reaction inhibitors, estrogen, Erythropoietin (EPO) and the like, partial experiments prove that the medicines have certain neuroprotective effect, the clinical effect needs to be further researched, and new medicines which are used as neuroprotective agents for treating cerebral apoplexy are urgently developed in clinic.
Disclosure of Invention
The invention aims to solve the technical problem of developing a novel compound with neuroprotective effect for preparing a medicament for treating cerebral apoplexy and other nervous system diseases.
To solve the above problems, the present invention provides compounds having the structure of formula I:
wherein:
r1 and R2 are: hydrogen, halogen;
r3 is: hydrogen, alkyl, benzyl, phenethyl.
The invention relates to compounds with a structure shown in formula I and pharmaceutically acceptable salts thereof, and preferably compounds with the structure shown in formula I are:
the invention relates to a compound with a structure shown in a formula I and a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt refers to: the compound is salified with inorganic acid and organic acid.
In particular the pharmaceutically acceptable salts according to the invention refer to: hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, phosphate, acetate, propionate, butyrate, lactate, methanesulphonate, p-toluenesulphonate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate, gluconate.
The invention relates to a preparation method of a compound shown in a formula I, wherein an intermediate II reacts at room temperature in the presence of liquid bromine and trichloromethane to generate an intermediate III, the intermediate III and the intermediate IV react at room temperature in the presence of acetonitrile and sodium bicarbonate, water is added for quenching reaction, and the compound I is finally prepared by extraction, washing and purification,
The other preparation method of the compound of the formula I of the invention is that an intermediate II reacts in the presence of ethyl acetate and copper bromide to generate an intermediate III, the intermediate III and the intermediate IV react at room temperature in the presence of N, N-dimethylformamide and sodium bicarbonate, water is added to quench the reaction, and the compound I is finally prepared by extraction, washing and purification,
wherein R1, R2, R3 are as described in claim 1.
The invention also relates to a pharmaceutical composition for treating nervous system diseases, which comprises a therapeutically effective amount of any compound with the structure of the formula I or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers. Wherein the neurological disease is stroke.
The invention also relates to application of the compound with the structure shown in the formula I and pharmaceutically acceptable salts thereof in preparing medicines for treating nervous system diseases. Wherein the neurological disease is stroke.
Although the compounds of the present invention may be administered directly without any formulation, the various compounds described are preferably used in the form of pharmaceutical preparations, the route of administration may be parenteral (e.g., intravenous, intramuscular) as well as oral.
Pharmaceutical compositions of the compounds of the invention are prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. Solid dosage forms include tablets, dispersible granules, capsules, sustained release tablets, sustained release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, powdered sugar, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methyl cellulose, microcrystalline cellulose, low melting paraffin, polyethylene glycol, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.
The amount of active ingredient (compound of the invention) contained in the pharmaceutical composition and unit dosage form may be specifically adapted to the condition of the patient, the condition diagnosed by the physician, and the amount or concentration of the compound used may be adjusted over a wide range.
The compound with the structure of the formula I or the pharmaceutically acceptable salt thereof has obvious neuroprotective effect and has important significance for cerebral apoplexy and other nervous system diseases.
The neuroprotective effect of the compounds of the present invention is further illustrated by pharmacodynamic experiments below.
1, materials and methods:
1.1 Experimental materials
1.1.1 Experimental animals the experimental rats were SPF grade Sprague Dawley rats purchased from Tokyo Wintolite laboratory animal technology, Inc. Wherein 16-18 days pregnant rats are used for neuronal culture.
1.1.2 major reagents and instruments DMEM medium, Neurobasal medium, fetal bovine serum, 0.25% trypsin from Invitrogen. Cell culture plates, cell culture flasks and centrifuge tubes were purchased from Corning. 2, 2-Azobis (2-methylpropylamidine) dihydrochloride (2, 2' -Azobis (2-methylpropionidine) dihydrochloride, AAPH), CCK-8 cell viability kit was purchased from Donren corporation.
1.2 Experimental methods
1.2.1 Primary neuronal culture
After anesthetizing a 16-18 day gestational age rat with 10% chloral hydrate, placing the rat in a super clean workbench, separating out an embryo under a sterile condition, and transferring the embryo to a Neuralbasal culture medium. Taking a cortex, removing meninges and blood vessels, washing for 2 times by using a culture medium, shearing, blowing and beating dispersed cells, digesting for 10 minutes by using 0.25% pancreatin, filtering to remove all tissue blocks, suspending the cells in a DMEM culture medium containing 10% fetal calf serum, inoculating the cells in a 24-hole culture plate, removing the culture medium in the culture plate the next day, and replacing the culture medium with a neuron culture medium: neuronabasal medium with 2% B-27 supplement, followed by fluid changes every other day. After 7 days, the test was carried out.
1.2.2 AAPH-induced cell injury and cell viability assays:
2, 2-Azobis (2-methylpropylamidine) dihydrochloride (2, 2' -Azobis (2-methylpropionidine) dihydrochloride, AAPH) was dissolved in DMEM at 1 mM; 5 mM; 10 mM; 20mM and 40mM solutions were added to neurons and CCK-8 solution, respectively, and after 4 hours of the reaction, the cell viability was analyzed by measuring the absorbance at a wavelength of 495nm using a spectrophotometer and the effect of AAPH on the cell viability was observed.
1.2.3 protective action of the novel compounds on neurons.
Neurons were primary cultured and first injured by 40mM AAPH for 4 h. The medium was changed and different concentrations of the novel compounds D6, D14, D21, D22 were added, wherein the low concentration was 1. mu.M, the medium concentration was 10. mu.M and the high concentration was 100. mu.M for each compound. And (3) protecting for 24 hours, adding a CCK-8 solution, and measuring the absorbance of 495nm wavelength by using a spectrophotometer after acting for 4 hours, so as to analyze the cell activity and judge the protective effect on neurons.
1.2.4 anti-apoptotic Effect of novel Compounds
Neurons were primary cultured and first injured by 40mM AAPH for 4 h. The medium was changed and different concentrations of the novel compounds D6, D14, D21, D22 were added, wherein the low concentration was 1. mu.M, the medium concentration was 10. mu.M and the high concentration was 100. mu.M for each compound. And (3) protecting for 24 hours, adding an anti-apoptosis detection reagent solution, observing the number of apoptotic cells under a fluorescence microscope, respectively recording normal cells and apoptotic cells with 10 visual fields, and calculating the percentage of the cells. Thereby judging the anti-apoptosis effect of the new compound.
1.2.5 statistics and analysis
The experimental results are statistically analyzed by SPSS15.0, the experimental data are expressed by mean + -standard deviation, and the variance analysis is used for the comparison among groups. P <0.05 was statistically significant.
TABLE 1 protective Effect of the Compounds of the present invention on AAPH induced neurons
TABLE 2 anti-apoptotic Effect of Compounds of the invention on AAPH induced neurons
2. As a result:
2.1AAPH can simulate cerebral apoplexy and prepare neuron damage model
The expression of neuron specific marker Neurofilament protein (NF) in primary culture neurons indicates that cultured cells are neurons respectively, and the administration of AAPH with different concentrations can cause damage to the neurons, and the cell activity is reduced along with the increase of the AAPH concentration. Wherein 40mM AAPH can obviously induce the damage of neurons.
2.2 novel Compounds are capable of reducing neuronal injury
After 40mM AAPH induced neuronal damage, add the brain glycoside carnosine-astrocyte conditioned medium for 24 h. Neuronal cell viability was then measured. The results show that the novel compounds (table 1) are able to reverse the neuronal damage caused by AAPH, with statistical significance.
2.3 novel Compounds capable of reducing apoptosis
The statistical percentage of apoptotic cells (Table 2) shows that the compounds of the invention have anti-apoptotic effect on cells by the anti-apoptotic effect test of the novel compounds of 1.2.4.
Detailed Description
Reference will now be made in detail to the various embodiments of the present invention, and while the invention will be described in conjunction with the exemplary embodiments, it will be understood that the description is not intended to limit the invention to these exemplary embodiments. On the contrary, the invention is intended to cover not only these exemplary embodiments, but also various alternatives, modifications, equivalents and other embodiments, which may be included within the spirit and scope of the invention as defined by the appended claims.
Example 1
Preparation of Compound D6 of the present invention
Sequentially adding 6.7g (40mmol) of D1, 16.6g (120mmol) of potassium carbonate and 30ml of DMF into a 100ml pear-shaped bottle, stirring at 40 ℃ for 10 minutes, adding 5.2ml (44mmol) of D2, reacting at 40 ℃ for 4 hours, cooling to room temperature, adding ice water into the reaction bottle, filtering, washing with water, and drying to obtain a white powdery solid product D312 g (39.1mmol), wherein the yield is 97.7%;
1H NMR(500MHz,CDCl3)δ2.55(s，3H)，3.95(s，3H)，5.23(s，2H)， 6.89(d，J＝8.0Hz，1H)，7.32，(m，1H)，7.38(t，1H)，7.43(m， 2H)，7.50(br.d.,1H),7.55(br.s.,1H)；
2048(8mmol) D3 and 50ml trichloromethane are added into a 200ml pear-shaped bottle in sequence, 0.5ml (8mmol) of liquid bromine is dissolved in 50ml trichloromethane and slowly dripped into the reaction bottle at room temperature, reaction is carried out for 2 hours after the dripping is finished, and after the reaction is finished, the product is washed by saturated sodium thiosulfate and a saturated sodium chloride solution, and the product is purified by a silica gel column to obtain 1.4g of a white powdery product D4 with the yield of 52.4%.
1H NMR(500MHz,DMSO-d6)δ3.82(s，3H)，4.85(s，2H)，5.21(s， 2H)，7.18(d，J＝8.0Hz，1H)，7.40(m，3H)，7.45(m,2H)，7.49(br.s.,1H),7.66(br.d., J＝8.0Hz，1H)；
334mg (1mmol) of D4, 5ml of acetonitrile, 0.1ml of para-fluoroaniline (1.1mmol) and 168mg of sodium bicarbonate are sequentially added into a 50ml pear-shaped bottle, the mixture is reacted for 12 hours at room temperature, water is added for quenching the reaction, ethyl acetate is extracted for 3 times, a saturated sodium chloride solution is washed, and the mixture is purified by a silica gel column to obtain 180mg of a light yellow powdery product D6 with the yield of 51.9 percent.
Chemical information of D6: the molecular formula is as follows: C22H20FNO3, molecular weight: 365, purity: 98%, appearance: a pale yellow powder.
Spectral data: 1H NMR (500MHz, CDCl3) Δ 3.95(s,3H),4.53(s,2H), 5.26(s,2H),6.66(m,2H),6.93(m,3H),7.33(m,1H),7.39(m,3H),7.44(m,3H), 7.56 (m, 2H); 13C NMR (500MHz, DMSO-d6) delta 50.59,56.33,70.55,111.14,113.08,113.91,115.69,115.87,123.00, 128.54,128.70,128.84,129.16,137.16,145.55,149.57,152.96,154.23,156.06,195.09
Example 2
Preparation of Compound D14 of the present invention
2656mg (16mmol) of D1, 50ml of ethyl acetate and 7.0g (28mmol) of copper bromide are sequentially added into a 100ml eggplant-shaped bottle, the mixture is stirred and refluxed for 5 hours, the reactant is cooled and then filtered by using kieselguhr, the filtrate is sequentially washed by a saturated sodium thiosulfate solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, the filtrate is evaporated to dryness under reduced pressure, and silica gel column purification is carried out, so as to obtain 2.2g of a white powdery product D11 with the yield of 56%;
370mg (1.5mmol) of D11, 5ml of N, N-dimethylformamide, 0.2ml of para-fluoroaniline (2.0mmol) and 252mg of sodium bicarbonate are sequentially added into a 50ml pear-shaped bottle, the mixture is reacted for 3 hours at room temperature, water is added for quenching reaction, ethyl acetate is extracted for 3 times, saturated sodium chloride solution is washed, and silica gel column purification is carried out to obtain 200mg of a yellow powdery product D14 with the yield of 48.5%.
Chemical information of D14: the molecular formula is C15H14FNO3, the molecular weight is 275, the purity is 98 percent, and the appearance is light yellow powder.
Spectral data: 1H NMR (500MHz, DMSO-d6) δ 3.86(s,3H),4.56(s,2H),5.73(s,1H),6.68(m,2H),6.92(m,3H),7.54 (d, J ═ 2.0Hz,1H),7.65(dd, J ═ 2.0,8.0Hz,1H),10.03(s, 1H); 13C NMR (500MHz, DMSO-d6) delta 50.4356.37,111.80,113.89,115.71, 115.86,123.42,127.55,145.60,148.25,152.70,154.14,155.97,195.28
Example 3
Preparation of Compound D21 of the present invention
Preparation of Compound D11 see example 2
370mg (1.5mmol) of D11, 5ml of N, N-dimethylformamide, 0.2ml of 2, 4-difluoroaniline (2.0mmol) and 252mg of sodium bicarbonate are added in sequence to a 50ml pear-shaped flask, the mixture is reacted for 3 hours at room temperature, the reaction is quenched by adding water, extracted 3 times with ethyl acetate, washed with saturated sodium chloride solution and purified by silica gel column to obtain 240mg of a yellow powdery product D21 with a yield of 54.6%.
Chemical information of D21: the molecular formula is C15H13F2NO3, the molecular weight is 293, the purity is 98 percent, and the appearance is yellow powder.
Spectral data: 1H NMR (500MHz, DMSO-d6) δ 3.84(s,3H),4.60(d, J ═ 5.5Hz,2H),5.34(s,1H),6.70(m,1H),6.81(m, 1H), 6.87(d, J ═ 8.0Hz,1H),7.08(m,1H),7.50(br.s.,1H),7.60(dd, J ═ 2.0,8.0Hz,1H),10.03(s, 1H); 13C NMR (500MHz, DMSO-d6) delta 49.70,56.17,103.77,111.15,113.08,115.54,123.29,127.12,133.69,148.08,150.50,152.64,153.47,194.71
Example 4
Preparation of Compound D22 of the present invention
Preparation of Compound D11 see example 2
370mg (1.5mmol) of D11, 5ml of N, N-dimethylformamide, 254mg (2mmol) of 4-chloroaniline and 252mg of sodium bicarbonate are sequentially added into a 50ml pear-shaped bottle, the mixture is reacted for 3 hours at room temperature, water is added for quenching reaction, ethyl acetate is extracted for 3 times, a saturated sodium chloride solution is washed, and the mixture is purified by a silica gel column to obtain 160mg of a light yellow powdery product D22 with the yield of 55.0 percent.
Chemical information of D22: the molecular formula is C15H14ClNO3, the molecular weight is 291, the purity is 98 percent, and the appearance is white powder.
Spectral data: 1H NMR (500MHz, DMSO-d6) δ 3.84(s,3H),4.57(s,2H),6.68(d, J ═ 8.0Hz,1H),6.89(d, J ═ 8.0Hz,1H),7.08 (d, J ═ 8.0Hz,1H),7.52(br.s.,1H),7.62(br.d.,1H), 10.03(s, 1H); 13C NMR (500MHz, DMSO-d6) delta 49.57,55.99,111.43,114.15,115.34,119.53,123.06,127.10,128.71,147.49,147.86,152.35,194.61
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. The foregoing description is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention, as well as various alternatives and modifications thereof. Indeed, the scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A compound having the structure of formula I:
wherein:
when R1 is fluoro, R2 is hydrogen, and R3 is benzyl, the following compounds are represented:
when R1 is fluorine, R2 is hydrogen, and R3 is hydrogen, the following compounds are represented:
when R1 is fluoro, R2 is fluoro, and R3 is hydrogen, the following compounds are represented:
when R1 is chloro, R2 is hydrogen, and R3 is hydrogen, the following compounds are represented:
。
2. a compound according to claim 1 having the structure of formula I and pharmaceutically acceptable salts thereof, which refer to: the compound is salified with inorganic acid and organic acid.
3. The compound according to claim 2, and pharmaceutically acceptable salts thereof, which refer to: hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, phosphate, acetate, propionate, butyrate, lactate, methanesulphonate, p-toluenesulphonate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate, gluconate.
4. A process for the preparation of a compound of formula I according to claim 1, characterized in that: reacting the intermediate II at room temperature in the presence of liquid bromine and trichloromethane to generate an intermediate III, reacting the intermediate III and the intermediate IV at room temperature in the presence of acetonitrile and sodium bicarbonate, adding water for quenching reaction, extracting, washing and purifying to finally obtain a compound I,
wherein R1, R2, R3 are as described in claim 1.
5. A process for the preparation of a compound of formula I according to claim 1, characterized in that: reacting the intermediate II in the presence of ethyl acetate and copper bromide to generate an intermediate III, reacting the intermediate III and the intermediate IV in the presence of N, N-dimethylformamide and sodium bicarbonate at room temperature, adding water to quench the reaction, extracting, washing and purifying to finally obtain a compound I,
wherein R1, R2, R3 are as described in claim 1.
6. A pharmaceutical composition for treating a neurological disease comprising a therapeutically effective amount of a compound having the structure of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
7. The pharmaceutical composition of claim 6, wherein the neurological disease is stroke.
8. Use of a compound having the structure of formula I as claimed in claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of neurological diseases.
9. The pharmaceutical aspect for use according to claim 8, wherein the neurological disease is stroke.
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