CN106977500A - It is a kind of to be used to treat medicine of cerebral infarction and preparation method thereof - Google Patents

It is a kind of to be used to treat medicine of cerebral infarction and preparation method thereof Download PDF

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CN106977500A
CN106977500A CN201710247959.9A CN201710247959A CN106977500A CN 106977500 A CN106977500 A CN 106977500A CN 201710247959 A CN201710247959 A CN 201710247959A CN 106977500 A CN106977500 A CN 106977500A
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compound
alkyl
cerebral infarction
formula
haloalkyl
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肖韩艳
李海燕
刘鹤
赵东旭
董嘉楠
刘颖
张岩
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Mudanjiang Medical University
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Mudanjiang Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

Be used to treat the new compound of cerebral infarction the present invention relates to a kind of, with and preparation method thereof and Pharmaceutical composition comprising it.The compound has the common structure shown in Formulas I：

Description

Medicine for treating cerebral infarction and preparation method thereof
Technical Field
The present invention relates to a novel compound for treating cerebral infarction, a preparation method thereof and a pharmaceutical composition comprising the same.
Background
Cerebral infarction is a common disease caused by aging, poor body resistance, high working and living pressure, hypofunction and aging of human bodies of middle-aged and old people, is influenced by wind-cold-dampness and fatigue, cerebral vascular atrophy and sclerosis occur, blood fat and harmful components in blood accumulate, blood vessels are blocked, dizziness and headache appear, intermittent angina is sometimes shown on the head, the mind is not good, serious patients possibly have stroke dementia in the later period, and the patients are difficult to cure. The common clinical types of cerebral infarction include cerebral thrombosis, lacunar infarction, cerebral embolism and the like, and the cerebral infarction accounts for 80% of all cerebral apoplexy. Several diseases with greater relevance are: diabetes, obesity, hypertension, rheumatic heart disease, arrhythmia, dehydration due to various reasons, arteritis, shock, and excessive blood pressure drop.
The pathology of cerebral infarction is divided into an extremely acute stage (about 3 hours from onset) and an acute stage (about 2 weeks from onset). Cerebral infarction neuronal death is known to be associated with excitatory amino acid toxicity and free radicals. In excitatory amino acid toxicity, calcium influx, associated with the release of glutamate by energy disorders and the binding of acids to their receptors, leads to the development of intracellular disorders in the extreme acute phase, in which inflammatory reactions occur. In the case of free radicals, its increased or hypoxic condition induces the expression of inflammatory genes by producing transcription factors such as nuclear factor kappa B transcription (NF-. kappa.B), hypoxia-induced transcription factor 1(HIF-1), signal transducers of transcription, and activator protein 3(STAT3), among others. By these mechanisms, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and the like are produced. These cytokines are thought to promote symptoms such as brain edema and inflammatory cell infiltration, and contribute to neurological deficit.
For the inhibition of inflammatory cytokines, which have been reported to have a neurotoxic effect in the pathology of cerebral infarction, cerebral ischemic conditions can be alleviated by intracerebroventricular administration of TNF- α antibodies. In addition, it has been reported that DPH-067517, an inhibitor of TNF-. alpha.converting enzyme, inhibits the expression of TNF-. alpha.on the cerebral infarction side and reduces neurological deficit and cerebral infarction volume in a rat cerebral infarction model. It has also been reported that injection of recombinant IL-1 beta in the ventricles of rats increases cerebral infarction, and that cerebral ischemic disorders are relieved by administration of IL-1 beta receptor antagonists. However, no drug having a direct effect on the IL-1. beta. molecule itself in cerebral infarction is available on the market, and DPH-067517 cannot inhibit the expression of IL-1. beta. on the cerebral infarction side.
Although there have been many reports concerning a single inflammatory cytokine and cerebral infarction, the effects thereof are insufficient, and it is necessary to develop more drugs that can be used for treating cerebral infarction.
Disclosure of Invention
In its many embodiments, the present invention provides: novel compounds for the treatment of cerebral infarction, processes for the preparation of the compounds, pharmaceutical compositions comprising at least one of the compounds, processes for the preparation of pharmaceutical compositions comprising at least one of the compounds, and the use and methods of using the compounds or pharmaceutical compositions for the treatment of cerebral infarction.
In one aspect, the present application discloses compounds having a common structure of formula I or pharmaceutically acceptable salts, esters, amides thereof:
wherein,
R1、R2each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, nitro, -CHO, -OR11、-COOR12、-SO2R13Or- (CH)2)r-N(R14)(R15) Wherein R is11、R12、R13Each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl; r14、R15Each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or R14、R15May form, together with the nitrogen atom to which it is attached, a 5-7 membered heterocycloalkyl group; r is 0, 1, 2, 3 or 4;
R3is H, C1-4 alkyl, C1-4 haloalkyl, nitro, cyano, -OR21、-COOR22、-SO2R23、-N(R24)(R25) C6-10 aryl or 5-7 membered heteroaryl, wherein R21、R22、R24、R25Each independently is H or C1-4 alkyl, R23Is H, C1-4 alkyl or amino, said C6-10 aryl or 5-7 membered heteroaryl being optionally substituted with 1-3 groups selected from halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl;
n is 0, 1, 2, 3, 4 or 5.
The invention also features pharmaceutical compositions including a pharmaceutically acceptable carrier and any of the compounds of formula I described above, and pharmaceutical compositions prepared by mixing at least one compound of formula I with a pharmaceutically acceptable carrier.
The invention also features a process for preparing a pharmaceutical composition, the process comprising admixing any of the above compounds with a pharmaceutically acceptable carrier.
The invention also provides uses and methods of using the compounds or compositions of the invention. For example, one embodiment of the present invention is the use and method for treating cerebral infarction in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of any compound of formula I or a pharmaceutical composition thereof.
Another embodiment of the present invention is the use of a compound or composition of the present invention for the manufacture of a medicament for the treatment of cerebral infarction.
Term(s) for
The following terms are defined below and by their use in this disclosure.
"alkyl" includes aliphatic hydrocarbons, which may be straight or branched chain, and contain from 1 to 20 carbon atoms in the chain. Preferred alkyl groups contain 1 to 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to 4 carbon atoms in the chain. Branched means that more than 1 lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, sec-pentyl, hexyl, heptyl, nonyl, decyl, octyl. For example, C4 alkyl groups include, but are not limited to, n-butyl, isobutyl, and tert-butyl. In some embodiments, alkyl is independently substituted with 1-5, preferably 1-3 groups including, but not limited to, oxo, amino, alkoxy, carboxyl, cycloalkyl, nitro, hydroxy, and halo (fluoro, chloro, bromo, or iodo).
"cycloalkyl" includes non-aromatic monocyclic ring systems containing 3 to 7 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In some embodiments, cycloalkyl is independently substituted with 1-5, preferably 1-3 groups including, but not limited to, oxo, amino, alkoxy, carboxyl, cycloalkyl, nitro, hydroxy, and halo (fluoro, chloro, bromo, or iodo).
"halogen" includes fluorine, chlorine, bromine and iodine.
"aryl" includes aromatic groups such as phenyl and naphthyl. When substituted, the aryl group may have 1 to 3 substituents independently selected from halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl.
"heteroaryl" includes stable aromatic monocyclic ring systems having 5-7 ring atoms, wherein at least one of the ring atoms is an element other than carbon, such as nitrogen, oxygen, or sulfur, alone or in combination. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, tetrazolyl, triazolyl. When substituted, the heteroaryl group may have 1 to 3 substituents independently selected from halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl.
"Heterocycloalkyl" includes saturated cyclic groups having 5 to 7 ring atoms, the system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl. When substituted, the heterocycloalkyl group can have 1-3 substituents independently selected from halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, ester, aldehyde, sulfonyl.
"pharmaceutically acceptable salts, esters, and amides" include carboxylic acid salts, amino acid addition salts, esters, and amides that, within a reasonable benefit/risk ratio, are pharmacologically effective in proper contact with the patient's tissues without undue toxicity, irritation, or allergic response. These salts, esters and amides may be, for example, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl salts, esters and amides. Representative pharmaceutically acceptable esters of the invention include C1-4 alkyl esters, C3-7 cycloalkyl esters, phenyl esters, and phenyl (C1-4) alkyl esters. Preferred esters include methyl and ethyl esters.
Representative salts include hydrobromide, hydrochloride, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, mesylate, salicylate, and laurylsulfonate. These salts may contain alkali and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, zinc; and non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine, and ethylamine.
Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-4 alkyl amines, and secondary di (C1-4 alkyl) amines. Dialkylamides have 2 independently selectable alkyl groups (e.g., methylpropylamides). Secondary amines include 5-or 6-membered heterocycloalkyl or heteroaryl moieties such as morpholinyl, said moieties containing at least one nitrogen atom and optionally 1-2 additional heteroatoms. Preferred amides are derived from ammonia, C1-4 alkyl primary amines and di (C1-4 alkyl) amines.
"composition" includes a product comprising the specified ingredients in the specified amounts, as well as any product obtained by combining the specified ingredients in the specified amounts.
With respect to the number of moieties (non-limiting example(s) include substituents, groups, or rings) in a compound, unless otherwise defined, the phrase "at least one" means that as many moieties as chemically allowed can be present, and the determination of the maximum number of such moieties is well known to those skilled in the art. Preferably 1 to 3 substituents, or more preferably 1 to 2 substituents are present, wherein at least 1 substituent is in the para position.
Prodrugs and solvates of the compounds of the present invention are also included herein. The term "prodrug" as used herein denotes a compound that is a drug precursor that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. If the compounds of the invention have at least one chiral center, they may accordingly exist as enantiomers. If the compounds have more than two chiral centers, they may also exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention.
In one embodiment of the compounds of the invention, R1Is OH, C1-4 alkoxy or- (CH)2)r-N(R14)(R15)。
In one embodiment of the compounds of the invention, R2Is OH or C1-4 alkoxy.
In one embodiment of the compounds of the invention, R3Is C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -SO2R23Or 5-7 membered heteroaryl.
In one embodiment of the compounds of the invention, R3Is a pyridyl group.
In one embodiment of the compounds of the present invention, the compound is selected from:
synthesis method
The present invention provides methods for preparing the disclosed compounds according to conventional organic synthesis methods, as well as matrix synthesis methods or combinatorial synthesis methods. Scheme 1 depicts the proposed synthetic route. Using these schemes, the following guidelines and examples, one of skill in the art may develop similar or analogous methods for preparing compounds within the scope of the present invention.
It will be appreciated by those skilled in the art that the synthesis of the compounds of the invention can be accelerated by purchasing the intermediates or protected intermediate compounds described in any of the schemes disclosed herein. It will also be appreciated by those skilled in the art that during the preparation of any of the compounds of the present invention, any protection is required and/or desiredSensitive or reactive groups on the molecule of interest. This can be achieved by means of conventional protecting groups, such as those described in "protective groups in Organic Synthesis", John Wiley&Sons press, 1999. These protecting groups may be removed at a suitable stage using methods known in the art. Examples of the synthetic routes described include scheme 1 and synthetic examples 1-6. In the schemes and examples, R1、R2、R3And n is as described and defined hereinabove, X represents halogen, preferably chlorine or bromine. Compounds analogous to the target compounds of these examples can be, and in many cases have been, prepared according to analogous routes.
Scheme 1
The compounds of the present invention can be prepared by the chemical methods shown in scheme 1. Reacting a compound shown as a formula II with a Grignard reagent shown as a formula III in the presence of a Ni complex to obtain a compound shown as a formula I, wherein the Ni complex comprises NiCl2、Ni(OAc)2Complexes with ligands including triphenylphosphine (PPh), trimethylphosphine, 1, 3-bisdiphenylphosphinopropane (dppp), e.g. NiCl2(dppp)。
Preparation
The invention also provides pharmaceutical compositions comprising at least one compound of the invention and a pharmaceutically acceptable carrier.
To prepare the pharmaceutical compositions of the present invention, at least one compound of formula I, or a salt thereof, for example, as an active ingredient is intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical techniques. The form of the carrier depends on the type of mode of administration, for example oral administration, or parenteral administration such as intramuscular administration. In preparing the compositions for oral dosage form, any of the conventional pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations such as powders, capsules, caplets, soft capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most convenient oral dosage unit form in which case solid pharmaceutical carriers are generally employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier will typically comprise sterile water, but may also contain other ingredients, for example, for purposes such as solubilization, or for preservation. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein may contain, per dosage unit, the amount of active ingredient required to deliver the effective dose described above. The pharmaceutical compositions herein may contain from about 0.1mg to about 1g of active agent per unit dosage unit. However, the dosage may vary depending on the requirements of the patient, the severity of the disease to be treated and the compound used. Either daily or periodic administration may be employed.
Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, injections, autoinjection devices or suppositories; the compositions are for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented as a form suitable for once weekly or once monthly administration; for example, insoluble salts of the active compounds may be suitable to provide long acting formulations for intramuscular injection.
The novel compositions of the present invention may be incorporated into liquid forms for oral administration or for administration by injection, including aqueous solutions, suitably flavoured syrups, aqueous or oily suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil or peanut oil, and similar pharmaceutically acceptable carriers. Dispersing or suspending agents suitable for use in aqueous suspensions include synthetic and natural gums such as acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
The compounds of the invention may be administered in a single daily dose, or the total dose may be administered in divided doses 2, 3 or 4 times per day, 1 time per week, 1 time per two weeks, 1 time per month.
The desired dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the specification of the formulation, the mode of administration and the advancement of the disease condition. In addition, factors related to the particular patient being treated may lead to the need to adjust the dosage, including patient age, weight, diet and time of administration.
Advantageous effects
The compound shown in the formula I can obviously reduce the cerebral infarction volume of a cerebral infarction model rat, can obviously inhibit the production of intracerebral inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and chemotactic factor MCP-1 of the cerebral infarction model rat, and reduces the increase of the concentration of the compounds, so that the compound has an obvious therapeutic effect on cerebral infarction and can be used as a novel therapeutic medicine for cerebral infarction.
Detailed Description
The following examples are intended to illustrate the invention without limiting it.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned in this application are herein incorporated by reference.
Synthesis example 1: 4- (5, 7-dihydroxy-4-oxo-2- ((3,5, 6-trimethylpyrazin-2-yl) methyl) -4H-chromen-3-yl) benzenesulfonamide (compound 1)
A three-necked flask was charged with Mg (0.29g, 12mmol), diethyl ether 10ml and a small amount of iodine under nitrogen protection, and then a solution of 2-bromomethyl-3, 5, 6-trimethylpyrazine (2.14g, 10mmol) in diethyl ether (100ml) was slowly added dropwise and stirred at 40 ℃ for 12h to obtain a diethyl ether solution of ((3,5, 6-trimethylpyrazin-2-yl) methyl) magnesium bromide.
In a further three-necked flask, under nitrogen, was charged 4- (2-chloro-5, 7-dihydroxy-4-oxo-4H-chromen-3-yl) benzenesulfonamide (0.73g, 2mmol), NiCl2(dppp) (0.37g, 2mmol) and diethyl ether 50ml, the diethyl ether solution obtained in the previous step was added dropwise, followed by stirring at room temperature for 32 hours. The reaction mixture was treated with 1M aqueous hydrochloric acid and then extracted 3 times with ether, the combined organic layers were filtered through celite, concentrated under reduced pressure and separated by silica gel column chromatography eluting with a gradient of cyclohexane-ethyl acetate (10:1-1:10), and the solvent was removed under reduced pressure and dried to give the title compound as a white solid in 0.48g, yield 51.3%.
ESI-MS：468.12[M+H]+
Elemental analysis: theoretical/measured values, C (59.09/59.17), H (4.53/4.62), N (8.99/8.84), O (20.53/20.47), S (6.86/6.84)
1H NMR(400MHz,CDCl3)11.74(s,1H),10.24(s,1H),7.64-7.71(m,4H),7.32(s,2H),6.16(s,1H),5.97(s,1H),3.24(s,2H),2.73(s,6H),2.70(s,3H)。
Synthesis example 2: 3- (3-ethylphenyl) -5, 7-dimethoxy-2- ((3,5, 6-trimethylpyrazin-2-yl) methyl) -4H-chromen-4-one (Compound 2)
Following the procedure of example 1, substituting 2-chloro-3- (3-ethylphenyl) -5, 7-dimethoxy-4H-chromen-4-one for 4- (2-chloro-5, 7-dihydroxy-4-oxo-4H-chromen-3-yl) benzenesulfonamide, the title compound was obtained as a light yellow solid in 47.6% yield.
ESI-MS：445.20[M+H]+
Elemental analysis: theoretical/measured values, C (72.95/72.84), H (6.35/6.43), N (6.30/6.38), O (14.40/14.35)
1H NMR(400MHz,CDCl3)7.14-7.21(m,3H),6.98(d,1H),6.78(s,1H),6.36(s,1H),3.84(s,6H),3.24(s,2H),2.73(s,6H),2.70(s,3H),2.61(q,2H),1.20(t,3H)。
Synthetic example 3: 3- (4-Difluoromethylphenyl-5-methoxy-7- (pyrrolidin-1-ylmethyl) -2- ((3,5, 6-trimethylpyrazin-2-yl) methyl) -4H-chromen-4-one (Compound 3)
The title compound was obtained as a white solid in 39.7% yield by the method of example 1 substituting 2-bromo-3- (4-difluoromethylphenyl-5-methoxy-7- (pyrrolidin-1-ylmethyl) -4H-chromen-4-one for 4- (2-chloro-5, 7-dihydroxy-4-oxo-4H-chromen-3-yl) benzenesulfonamide.
ESI-MS：520.23[M+H]+
Elemental analysis: theoretical/measured values, C (69.35/69.47), H (6.01/6.12), F (7.31/7.14), N (8.09/8.11), O (9.24/9.16)
1H NMR(400MHz,CDCl3)7.17-7.29(m,4H),6.78(s,1H),6.72(s,1H),6.46(s,1H),3.85(s,3H),3.64(s,2H),3.24(s,2H),2.73(s,6H),2.70(s,3H),2.51(t,4H),1.71(m,4H)。
Following a similar procedure, the following compounds were synthesized:
next, the effect of the representative compound on the cerebral infarction model is specifically explained by experimental examples.
Test example 1: test Compounds for their Effect on intracerebral production of TNF-alpha, IL-1 beta, IL-6 and MCP-1 in the rat Central cerebral artery occlusion-reperfusion model
1. Animal(s) production
Wistar rats, male, weight 180-220 g. 2 per group, 8 groups in total, and a sham operation group: giving physiological saline equal to the drug test group for false operation; model group: the physiological saline with the same amount as that of the drug experiment group is given for cerebral ischemia reperfusion operation; compounds 1-6 groups were tested and compounds 1-6 were administered at a dose of 10mg/kg, respectively.
2. Method of producing a composite material
The middle cerebral artery of male Wistar rats was occluded using suture (silicon-coated nylon wire), and 10mg/kg of the test compound dissolved in saline was intravenously administered 30 minutes after the occlusion, and the middle cerebral artery was reperfused 60 minutes after the administration.
10 rats were taken from each group and the brains were isolated 12 hours after occlusion (see Koizumi, J. et al, Jpn. J. Stroke, 8, 1-8, 1986). Brain tissue was homogenized and centrifuged supernatants were collected for measurement of cytokines and chemokines by ELISA. Intracerebral TNF- α, IL-1 β and IL-6 were measured using an immunoassay kit according to the manufacturer's protocol; MCP-1 was measured using MCP-1 immediate ELISA kit according to the manufacturer's protocol.
3. Results
The effect of the test compound was evaluated by calculating the inhibition rate of each of the brain cytokines according to the following formula:
the results are set forth in table 1 below:
table 1: test Compound inhibition rates (%) for TNF-. alpha.IL-1. beta., IL-6 and MCP-1
Group of TNF-α IL-1β IL-6 MCP-1
Compound group 1 79.2±8.4 83.3±9.2 55.9±4.6 47.2±3.7
Compound 2 group 76.3±5.1 79.4±6.4 48.7±3.1 44.1±2.9
Compound 3 group 77.4±7.2 76.4±8.6 50.1±4.5 45.7±4.3
Compound 4 group 81.5±8.9 84.9±10.3 59.3±3.2 55.6±6.1
Compound 5 group 70.1±6.3 75.8±8.5 43.1±3.8 46.9±3.0
Compound 6 group 74.6±8.1 76.4±10.2 47.4±5.6 45.8±4.4
The above test results show that: the concentrations of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and chemotactic factor MCP-1 in the brain of the rats in the model group are obviously increased, which indicates that the cerebral infarction rats have intracerebral inflammation. The compounds 1-6 of the invention can obviously inhibit the production of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and chemotactic factor MCP-1 in the brain of the cerebral infarction model rat, and reduce the increase of the concentration of the inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and chemotactic factor MCP-1.
Test example 2: test of the Effect of Compounds on cerebral infarct volume in the rat Central cerebral artery occlusion-reperfusion model
The rats in test example 1 were taken 10 mice per group, sacrificed to take brains, and coronal brain slices approximately 2mm thick were excised and immediately placed in 2% TTC solution and incubated at 37 ℃ for 30 minutes. Infarcted areas appeared white and non-infarcted areas appeared red. The digital camera takes the record, measures the area of each area by computer image processing, and calculates the percentage (%) of the infarct area in the whole brain tissue. The results are shown in table 2 below:
table 2: cerebral infarct volume after occlusion-reperfusion in middle cerebral artery of experimental group rats
Note: p <0.01 in comparison to model group
The above test results show that: the brain tissue of the mouse in the pseudo-operation group has no infarction, and the brain tissue of the rat in the model group has obvious infarction phenomenon, which shows that the modeling of the rat with cerebral infarction is successful. The compounds 1-6 of the invention can obviously reduce the volume of cerebral infarction, and prove that the compounds have good therapeutic effect on cerebral infarction.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (9)

1. A compound of formula I or a pharmaceutically acceptable salt, ester, amide thereof:
wherein,
R1、R2each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, nitro, -CHO, -OR11、-COOR12、-SO2R13Or- (CH)2)r-N(R14)(R15) Wherein R is11、R12、R13Each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl; r14、R15Each independently H, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, or R14、R15May form, together with the nitrogen atom to which it is attached, a 5-7 membered heterocycloalkyl group; r is 0, 1, 2, 3 or 4;
R3is H, C1-4 alkyl, C1-4 haloalkyl, nitro, cyano, -OR21、-COOR22、-SO2R23、-N(R24)(R25) C6-10 aryl or 5-7 membered heteroaryl, wherein R21、R22、R24、R25Each independently is H or C1-4 alkyl, R23Is H, C1-4 alkyl or amino, said C6-10 aryl or 5-7 membered heteroaryl being optionally substituted with 1-3 groups selected from halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl;
n is 0, 1, 2, 3, 4 or 5.
2. A compound of claim 1, wherein R is1Is OH, C1-4 alkoxy or- (CH)2)r-N(R14)(R15)。
3. A compound of claim 1, wherein R is2Is OH or C1-4 alkoxy.
4. A compound of claim 1, wherein R is3Is C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -SO2R23Or 5-7 membered heteroaryl.
5. A compound of claim 1, wherein R is3Is a pyridyl group.
6. The compound of claim 1, wherein the compound is selected from the group consisting of:
7. a process for the preparation of a compound of formula I according to claim 1, which comprises the following scheme:
scheme 1
R1、R2、R3And n is as defined in claim 1, X represents halogen, preferably chlorine or bromine;
wherein, the compound shown in the formula II and the Grignard reagent shown in the formula III react in the presence of a Ni complex to obtain the compound shown in the formula I, and the Ni complex comprises NiCl2、Ni(OAc)2Complexes with ligands including triphenylphosphine, trimethylphosphine, 1, 3-bisdiphenylphosphinopropane (dppp), e.g. NiCl2(dppp)。
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of formula I as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, amide thereof.
9. The use of a compound of formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, amide thereof or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of cerebral infarction.
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