CN102241627B - Carbamide compound and its medicinal usage - Google Patents
Carbamide compound and its medicinal usage Download PDFInfo
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Abstract
The invention relates to a compound as shown in the general formula I, or its isomer, medicinal salt and solvate; the invention also relates to a composition containing the compound as shown in the general formula I or its isomer, medicinal salt and solvate as well as a pharmaceutically acceptable carrier, excipient or diluent; the invention also relates to the usage of the compound as shown in the general formula I, or its isomer, medicinal salt and solvate in resisting cell apoptosis and preventing or treating diseases or symptoms related with cell apoptosis, especially to the usage in protecting cardiomyocytes and preventing or treating diseases or symptoms related with cardiomyocyte apoptosis.
Description
Technical field
The present invention relates to medical chemistry field; particularly; the present invention relates to carbamide compounds and pharmaceutical composition thereof; the invention still further relates to described compound and pharmaceutical composition thereof for anti-apoptotic; prevention or treatment and apoptosis-related disease or the purposes of symptom, especially for the purposes in protection myocardial cell and prevention or treatment disease or the symptom relevant with apoptosis of cardiac muscle.
Background technology
Apoptosis generally refers to body cell in growth course or under some factor effect, a kind of apoptosis occurring by the regulation and control of gene in cell and product thereof.Apoptosis is prevalent in organic sphere, has both betided under physiological status, also betides under pathological state.To fetal development and form occur, the defence of stable, the body of normal cell populations and immune response in tissue, disease or the cell injury, the generation progress aging, tumour that cause when poisoning play an important role, and are the focuses of biomedical research always.
Research shows have the generation of a lot of major diseases all relevant with cell transition apoptosis, for example, in the evolution of acquired immune deficiency syndrome (AIDS), and CD4
+the minimizing of T cell number; In graft-rejection, the necrocytosis of cytotoxic T cell mediation; Reperfusion iujurt, the apoptosis of myocardial cell and neurocyte; Neural system degenerative disorders (as Alzheimer time disease, Parkinson's disease etc.); Be exposed to Various Tissues apoptosis that ionizing rays causes etc.
Evidence suggests, generation, development and the prognosis of apoptosis of cardiac muscle and many heart diseases have close relationship.Find that by research apoptosis of cardiac muscle the cardiac muscle death of infarct is not equal to myocardial necrosis, apoptosis is one of mechanism of myocardial infarction, and be the major way of the cardiac muscle death due to the early stage myocardium death of infarct and ischemia/reperfusion, now a large amount of apoptosis of cardiac muscle, have increased the weight of myocardium destruction.1989, when the observation hunger property myocardial atrophy ultrastructures such as Nepomniashchikh, find, myocardial cell's structural protein are synthetic to be reduced, and cell count reduces, but companion cell nuclear phase should not reduce pro rata, tentatively proposing thus the myocardial atrophy of hunger property is by due to apoptosis.1994, the employing Electronic Speculum such as Gottlieb and Kawano obtained the direct evidence of apoptosis of cardiac muscle in conjunction with DNA gel electrophoresis method, and the former discloses reperfusion injury and brings out Rabbit cardiomyocyte apoptosis, the scorching patient of the latter's confirmed myocardial apoptosis of cardiac muscle that occurs together.In the neonatal rat myocardial cell that Tanaka etc. cultivate, also prove the existence of apoptosis.Because the research of methodological progress and apoptosis is goed deep into, in multiple heart trouble, find the pathological effect of apoptosis of cardiac muscle.Research shows, spontaneously hypertensive mouse (SHR) heart damage is relevant with apoptosis; Turn to heart failure by Hypertrophic Heart late period is due to apoptosis of cardiac muscle; Acute myocardial infarction, except necrosis, blocks early stage and also inducing apoptosis of reperfusion injury; Apoptosis of cardiac muscle sees heart and the right ventricular dysplasia myocardosis of transplanting equally, and anoxic is induced apoptosis of cardiac muscle equally.
Apoptosis has recoverability to a certain extent, and the apoptosis in myocardial infarction and ischemia/reperfusion has its feature and rule, utilizes its feature can prevent and reduce apoptosis, for clinical prevention ischemia/reperfusion injury provides enlightenment; In refilling process, the apoptosis that produces contraction bands region (around infarct) is produced by the induction of some inducements, and the inhibition factor that can utilize apoptosis is prevented apoptosis, the corresponding disease that treatment apoptosis causes as medicine etc.
But at present can be also little for the medicament categories for anti-apoptotic and Cell protection and the quantity of clinical application; selectivity and targeting are not high; therefore constantly research and develop new anti-apoptotic safely and effectively and the medicine of Cell protection, the medicine tool especially with brand-new mechanism of action is of great significance.
Summary of the invention
In order to develop new anti-apoptotic safely and effectively and the medicine of Cell protection; contriver is through long-term, a large amount of experimental studies; find a class carbamide compounds; it has anti-apoptotic; protection myocardial cell's effect, can be used in prevention or the treatment disease relevant with apoptosis of cardiac muscle or symptom.Particularly,
A first aspect of the present invention relates to the compound shown in general formula I, or its isomer, pharmacologically acceptable salt and solvate.
Wherein
A representative=O;
X represents F, Cl, Br or I;
R1 represents phenyl, phenyl-C1-C6 alkyl-, wherein said phenyl is not substituted or for example, by (1-2 of 1-4, 1, 2, 3 or 4) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be optionally by hydroxyls,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replace, or described alkyl, alkoxyl group and haloalkyl are optionally by-O-,-S-,-NH-,-COO-, or-CONH-institute interval, five yuan or hexa-member heterocycle or substituted heterocycle, wherein said heterocycle is not substituted or for example, by (1-2 of 1-3, 1, 2, or 3) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be optionally by hydroxyls,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replace, or described alkyl, alkoxyl group and haloalkyl are optionally by-O-,-S-,-NH-,-COO-, , described heterocycle can be nitrogen nitrogen heterocyclic, nitrogen oxa-ring, nitrogen thia ring,
R
2, R
3represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, replacement C3-C6 cycloalkyl, C1-C6 alkoxy C 1-C6 alkyl, amino C1-C6 alkyl, monosubstituted or disubstituted amido C1-C6 alkyl, phenyl C1-C6 alkyl, substituted-phenyl C1-C6 alkyl, heterocyclic radical C1-C6 alkyl, substituted heterocyclic radical C1-C6 alkyl, phenyl, substituted-phenyl, C1-C6 heterocyclic radical or replacement C1-C6 heterocyclic radical, wherein R
2and R
3can cyclization;
General formula (I) compound being preferably as follows, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=O;
X represents F, Cl, Br or I;
R
1represent phenyl, phenyl-C1-C6 alkyl-, wherein said phenyl is not substituted or for example, by (1-2 of 1-4, 1, 2, 3 or 4) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be optionally by hydroxyls,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replace, or described alkyl, alkoxyl group and haloalkyl are optionally by-O-,-S-,-NH-,-COO-, or-CONH-institute interval, thienyl, thiazolyl, wherein said thienyl, thiazolyl is not substituted or for example, by (1-2 of 1-3, 1, 2, or 3) replace independently selected from following substituting group: halogen, nitro, hydroxyl, amino, cyano group, C1-C6 alkyl, C1-C6 alkoxyl group, with C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be optionally by hydroxyls,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-alkyl] 2 replace, or described alkyl, alkoxyl group and haloalkyl are optionally by-O-,-S-,-NH-,-COO-,
R
2, R
3represent hydrogen, C1-C6 alkyl, C1-C6 cycloalkyl, replace C1-C6 cycloalkyl, C1-C6 alkoxy C 1-C6 alkyl, amino C1-C6 alkyl, monosubstituted or disubstituted amido C1-C6 alkyl, phenyl C1-C6 alkyl, substituted-phenyl C1-C6 alkyl, heterocyclic radical C1-C6 alkyl, phenyl, substituted-phenyl, heterocyclic radical or substituted heterocyclic radical, wherein R
2and R
3can cyclization become saturated rings alkane, nitrogenous or oxygen heterocyclic ring;
Particularly preferably following general formula (I) compound, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=O;
X represents Cl;
R
1represent phenyl or 2-thienyl;
R
2, R
3represent hydrogen, methyl, sec.-propyl, 2-methoxy ethyl, 3-isopropoxide propyl, 2-N, N-dimethyl ethyl, cyclohexyl, suberyl, o-methoxyphenyl, adjacent fluorophenyl, Chloro-O-Phenyl, rubigan, benzyl or 8-quinolyl, wherein R
2and R
3can cyclization become piperidine ring, morpholine ring or N methyl piperazine ring.
General formula (I) compound, or its isomer, pharmacologically acceptable salt and solvate, particularly preferably compound below:
(1) (2E)-3-phenyl-N-[1-(8-quinolyl amino) oxo formamido group-2,2,2-, tri-chloroethyls]-2-acrylamide
(2) (2E)-3-phenyl-N-[1-(4-tolyl amino) oxo formamido group-2,2,2-, tri-chloroethyls]-2-acrylamide
General formula of the present invention (I) compound can be prepared by following method:
Taking compound 5 as example, the compounds of this invention is taking cinnamide as starting raw material, be reacting generating compound 2 under the condition of solvent piperidines catalysis at pyridine with propanedioic acid, prepare acyl chlorides through sulfur oxychloride again, splash into and in strong aqua, obtain compound 3, meanwhile, 8-quinolylamine reacts synthetic compound 4 with trichloroethyl chloroformate, makes compound 5 by 3 and 4 under DIEA catalysis.
The present invention relates to pharmaceutical composition on the other hand, and it comprises compound or its isomer, pharmacologically acceptable salt and solvate shown in general formula (I), and pharmaceutically acceptable carrier, vehicle or thinner.
The invention still further relates to general formula (I) compound or its isomer, pharmacologically acceptable salt and solvate described in first aspect, for the preparation of anti-apoptotic, the purposes of the medicine of prevention or treatment and apoptosis-related disease or symptom.
The invention still further relates to general formula (I) compound or its isomer, pharmacologically acceptable salt and solvate described in first aspect, for the preparation of the purposes of the medicine of protection myocardial cell and prevention or the treatment disease relevant with apoptosis of cardiac muscle or symptom.
The invention still further relates to a kind of anti-apoptotic, prevention or treatment and apoptosis-related disease or the method for symptom, described method comprises to the experimenter who has these needs treats general formula (I) compound or its isomer, pharmacologically acceptable salt and solvate described in the first aspect present invention of significant quantity.
The invention still further relates to the method for a kind of myocardial cell of protection, prevention or the treatment disease relevant with apoptosis of cardiac muscle or symptom; described method comprises to the experimenter who has these needs treats general formula (I) compound or its isomer, pharmacologically acceptable salt and solvate described in the first aspect present invention of significant quantity.
Of the present invention and apoptosis-related disease or symptom comprise: cardiovascular disorder, nerve degenerative diseases, multiple sclerosis, viral infection etc.
The disease relevant with apoptosis of cardiac muscle of the present invention or symptom include but not limited to the myocardial atrophy of (i) hunger property, (ii) myocarditis, (iii) heart failure, (iv) myocardial damage that essential hypertension causes, (v) myocardial damage that acute myocardial infarction causes in early days, (vi) acute myocardial infarction pours into the myocardial damage causing again, (vii) myocardial cell's pathology that heart transplantation causes, (viii) dysplasia myocardosis; Or the apoptosis of cardiac muscle that causes of anoxic, or cardiovascular systems sclerosis.
According to the present invention, term " heterocycle " includes but not limited to: pyridine, pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, azoles, different azoles, indoles, cumarone, benzoglyoxaline, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, purine, thiodiphenylamine, azophenlyene.
Those skilled in the art will recognize that compound of Formula I exists chiral centre.In the time that to need compound of Formula I be single enantiomorph, can use in all possible step all reactants in single enantiomeric forms to prepare, or under the reagent of single enantiomeric forms or the existence of catalyzer, react to prepare, or split stereoisomer mixture by ordinary method and prepare.Some preferred methods comprise that use microorganism splits, split the salt of the diastereomer forming with chiral acid spendable acid as any in amygdalic acid, camphorsulfonic acid, tartrate, lactic acid etc., or fractionation with chiral base as the salt of the diastereomer of the formation such as brucine (bracine), Peruvian bark alkaloid and derivative thereof.Conventional method is shown in " Enantiomers, Racemates and Resolution " (Wiley Interscience, 1981) that the people such as Jaques edit.
It will be appreciated by those skilled in the art that the compounds of this invention also can use with the form of its pharmacologically acceptable salt or solvate.On the physiology of compound of Formula I, acceptable salt comprises the conventional salt that formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, steroic, tannic acid etc.Other acid, as oxalic acid, although itself is not pharmaceutically acceptable, can be for the preparation of the salt as intermediate, to obtain the compounds of this invention and pharmacologically acceptable salt thereof.The example more specifically of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.After this, while relating to compound of the present invention, comprise compound of Formula I and pharmacologically acceptable salt thereof and solvate.
The present invention also comprises the prodrug of the compounds of this invention, and this prodrug, once administration, carries out chemical conversion by metabolic process, becomes afterwards the activated medicine of tool.Conventionally, this class prodrug is the functional derivatives of the compounds of this invention, and it easily changes into the compound of required formula (I) in vivo.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described the ordinary method of selecting and prepare suitable prodrug derivant in 1985.
The present invention also comprises the active metabolite of the compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, the raceme that it contains the compounds of this invention or optically active isomer and at least one pharmaceutically acceptable carrier, and it can be used for interior therapeutic and has biocompatibility.Described pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises compound of Formula I of the present invention or its pharmacologically acceptable salt or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is as human serum albumin, and buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The pharmaceutical composition of the compounds of this invention can be used with any-mode below: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as in subcutaneous, vein, intramuscular, intraperitoneal, sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
In the time of oral medication, the compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add in addition lubricant as Magnesium Stearate.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation normally mixes use by activeconstituents with suitable emulsifying agent and suspension agent.If need, also can add some sweeting agents, perfume compound or tinting material in above oral preparations form.
In the time of local application, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can the compounds of this invention be made to different local application's dosage forms according to different trouble faces or organ, be described as follows:
In the time of eye topical application, the compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, the carrier that uses for waiting Sterile Saline of the certain pH of oozing, wherein can add also not adding preservative agent as zephiran chloride alkoxide.For eye use, also compound can be made to paste form as vaseline paste.
In the time of topical application, the compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of the compounds of this invention, comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, using dosage and the using method of the compounds of this invention depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.
The beneficial effect of the invention
The invention provides a kind of carbamide compounds, and prove that it has the effect of anti-apoptotic and Cell protection, is the disease or the symptom that cause for the treatment of apoptosis, particularly treats disease or the symptom that apoptosis of cardiac muscle causes new method and approach is provided.
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
The fusing point of compound is measured by RY-1 melting point apparatus, and thermometer is calibration not.Mass spectrum is measured by Micromass ZabSpec high resolution mass spectrometer (resolving power 1000).
1h NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency
1h NMR 400MHz,
13c NMR 100MHz.
embodiment 1(2E)-3-phenyl-N-[1-(8-quinolyl amino) oxo formamido group-2,2,2-, tri-chloroethyls]-2-acrylamide
Cinnamide 6.50g and trichoro-aldehyde hydrate 8.01g are dissolved in 300ml toluene, 110 DEG C are refluxed 8 hours, be prepared into intermediate (2E)-3-phenyl-N-[1-hydroxyl-2,2,2-tri-chloroethyls]-2-acrylamide, by (2E)-3-phenyl-N-[1-hydroxyl-2,2,2-tri-chloroethyls]-2-acrylamide 4.00g is dissolved in the anhydrous THF of 40ml, under room temperature, splashes into 4.9mlSOCl
2, drip complete 60 DEG C of backflows 3 hours that are heated to.Solvent evaporate to dryness, be dissolved in anhydrous diethyl ether 20ml, splash in 0 DEG C of strong aqua 20ml, stir 30min.Separatory, which floor evaporate to dryness has obtain intermediate (2E)-3-phenyl-N-[1-amino-2,2,2-, tri-chloroethyls]-2-acrylamide 2.93g.0.58g 8-quinolylamine is dissolved in to the anhydrous THF of 8ml, adds 1mlDIEA, be cooled to-10 DEG C, splash into 0.56ml trichloroethyl chloroformate, react 3 hours.Be warming up to room temperature, add 10ml ethyl acetate, 10ml water, vibration layering, separatory is got organic layer, saturated common salt washing, anhydrous magnesium sulfate drying, steaming desolventizes grinds and obtains gray solid 8-(2,2,2-trichlorine (ethoxymethyl) amido) quinoline 0.69g with sherwood oil afterwards.By (2E)-3-phenyl-N-[1-amino-2, 2, 2-tri-chloroethyls]-2-acrylamide 0.64g and 8-(2, 2, 2-trichlorine (ethoxymethyl) amido) quinoline 0.69g is dissolved in 20mlDMSO, add 0.4mlDIEA, 80 DEG C are reacted 14 hours, pour water into, the each 20ml of ethyl acetate, getting organic layer saturated common salt washes, anhydrous magnesium sulfate drying, solvent evaporated obtains beige powder, with developping agent system be methylene dichloride: methyl alcohol=100: 1 wash-out, obtain white solid (2E)-3-phenyl-N-[1-(8-quinolyl amino) oxo formamido group-2, 2, 2-tri-chloroethyls]-2-acrylamide 0.18g.
1H-NMR(400MHz，DMSO-d
6)δ6.76-6.78(t，1H)；δ6.91-6.95(d，1H)；δ7.40-7.44(m，3H)；δ7.53-7.61(m，6H)；δ8.37-8.39(dd，1H)；δ8.50-8.58(m，2H)；δ8.90-8.91(dd，1H)；δ9.06-9.08(d，1H)。MS(TOF)463.0(M+)。
embodiment 2(2E)-3-phenyl-N-[1-(4-tolyl amino) oxo formamido group-2,2,2-, tri-chloroethyls]-2-acrylamide
The method that adopts embodiment 1, changes 8-quinolylamine wherein to monomethylaniline into, obtains white solid 0.17g.
1H-NMR(400MHz，DMSO-d
6)δ2.22(s，3H)；δ6.62-6.67(t，1H)；δ6.91-6.95(d，1H)；δ7.04-7.06(d，2H)；δ7.30-7.33(d，2H)；δ7.40-7.61(m，7H)；δ9.18-9.20(d，1H)；δ9.59(s，1H)。MS(TOF)448.0(M+)。
embodiment 3the experiment of compound protection myocardial cell activity
cardiac myocytes
Method (the Kreider that myocardial cell's separation separates with reference to differential velocity adherent with cultivation, A.Messing, H.Doan, S.U.Kim, R.P.Lisak and D.E.Pleasure, Enrichment of Schwann cell cultures from neonatal rat sciaticnerve by differential adhesion, Brain Res 2 (1981), pp.433444.), get Wistar suckling mouse newborn in 24h, through tincture of iodine alcohol disinfecting skin of chest abdomen, with scissors median line under xiphoid-process chest of opening slightly to the left, tiltedly open chest taking-up heart and be placed in ice precooling PBS, blow and beat gently heart with the PBS of 0.01M and remove blood cell and its hetero-organization, heart is cut into 0.5mm
3the fragment of size, rinses 2-3 time repeatedly with 0.01M PBS, fragment is placed in to Erlenmeyer flask, adds 4ml 0.125% pancreatin, 37 DEG C of water-bath concussion 10min of 1ml 0.1% collagenase II (final concentration is respectively 0.1% and 0.02%), abandon supernatant, again add 4ml 0.125% pancreatin, 1ml 0.1% collagenase II, 37 DEG C of water-bath concussion digestion 10min, draw supernatant and move to centrifuge tube, and supernatant is added containing the DMEM of 10%FBS and stops digestion, repeat water-bath concussion digestion step 3-4 time, until tissue block complete digestion, by collect cell suspension with the centrifugal 10min of 1000rpm after, remove supernatant, then it is resuspended to add substratum, resuspended cell is inoculated in Tissue Culture Flask, is placed in 37 DEG C of CO2 incubators and hatches after 1.5h nutrient solution sucking-off, under the microscope after counting, adjust cell density with the DMEM nutrient solution containing 10%FBS, by 1 × 10
4be inoculated into 96 orifice plates, be placed in 37 DEG C of later half amounts of 5%CO2 incubator 24h and change liquid, add the substratum containing 0.1%Brdu, after every 48h, change liquid 1 time afterwards, cultivate and can obtain primary myocardial cell after 4 days.
cell inhibitory rate (MTT) is measured
By separate Primary cultured myocardial cells according to every hole 10
4individual cell is inoculated into 96 orifice plates, every pore volume 100ul (marginal pore is filled with aseptic PBS).At 5%CO2,37 DEG C of incubators are cultivated after 4d, add respectively the compound of Formula I (0.3 μ M, 1 μ M, 3 μ M, 10 μ M, 30 μ M, 100 μ M) of different concns, each concentration arranges 3 multiple holes, zeroing hole (nutrient solution, MTT, DMSO) is set simultaneously, control wells (nutrient solution, DMSO).Continue to hatch and process after 48h, every hole adds 20ulMTT solution (5mg/ml, joining with PBS (pH=7.4) is 0.5%MTT), continues to cultivate 4h.Stop cultivating, carefully suck nutrient solution in hole.Every hole adds 150ulDMSO, puts low-speed oscillation 10min on shaking table, and crystallisate is fully dissolved.Measure each hole absorbancy (OD) value in wavelength 550nm place at enzyme-linked immunosorbent assay instrument, every hole is repeated 5 times and is recorded result.
Table 1MTT method detects the impact of different concns compound on myocardial cell's survival rate
| Group | Myocardial cell's inhibiting rate (%) |
| Control group | 100 |
| Embodiment 1 compound | |
| 30 μ M groups | 9.57±1.62 |
| 300 μ M groups | 7.78±3.42 |
Note: cell survival rate=1-cell inhibitory rate
Result shows: embodiment 1 compound does not affect normal myocardial cell's survival rate in 300 μ M concentration.
The apoptosis of cardiac muscle activity of being induced by TG is measured-protected to protection myocardial cell activity
Myocardial cell according to the method described above former culture starts to add thapsigargin (thapsigargin, TG) cell death inducing for 4 days, and before cell death inducing, 30min adds the compounds of this invention and carries out pre-treatment.Cell is divided into 5 groups at random: (1) solvent control group (DMSO); (2) TG intervention group (0.4uM); (3) TG (0.4uM)+compound intervention group (0.3uM); (4) TG (0.4uM)+compound intervention group (1uM); (5) TG (0.4uM)+compound intervention group (3uM).TG prepares with DMSO, and mother liquor is 4mM, and the compounds of this invention is prepared with DMSO, and mother liquor is 150mM.Measure cell survival rate according to above-mentioned mtt assay, thereby measure the provide protection of the compounds of this invention to TG induction apoptosis of cardiac muscle, the results are shown in Table 2.
Table 2MTT method detects the impact of the myocardial cell survival rate of different concns compound on TG induction
| Group | Myocardial cell's survival rate (%) |
| Control group | 100 |
| TG intervention group | 59±1.1 |
| Embodiment 1 compound | |
| 0.3 μ M group | 79.3±4.6 |
| 1 μ M group | 83.8±8.3 |
| 3 μ M groups | 84.2±1.1 |
Experimental result: compared with singly adding TG group; while adding at the same time TG and embodiment compound; myocardial cell's survival rate is significantly improved, and shows that the compound of embodiment described in table 2 can obviously improve the cells apoptosis that TG causes, has provide protection to myocardial cell.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendments and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (6)
1. compound of Formula I, or its pharmacologically acceptable salt,
Wherein:
A represents O;
X represents F, Cl, Br or I;
R1 represents phenyl;
R
2represent hydrogen, C1-C6 alkyl;
R
3represent quinolyl.
2. compound of Formula I according to claim 1, or its pharmacologically acceptable salt, wherein
A represents O;
X represents Cl;
R
1represent phenyl;
R
2represent hydrogen, methyl, sec.-propyl;
R
3represent 8-quinolyl.
3. there is the compound of the claim 1 of following structure, or its pharmacologically acceptable salt:
(1) (2E)-3-phenyl-N-[1-(8-quinolyl amino) oxo formamido group-2,2,2-, tri-chloroethyls]-2-acrylamide.
4. pharmaceutical composition, it comprises compound or pharmaceutically acceptable salt thereof described in claim 1-3 any one, and pharmaceutically acceptable carrier, vehicle or thinner.
Described in claim 1-3 any one compound or pharmaceutically acceptable salt thereof for the preparation of the purposes of the medicine of anti-apoptotic, prevention or treatment and apoptosis-related disease or symptom.
Described in claim 1-3 any one compound or pharmaceutically acceptable salt thereof for the preparation of the purposes of the medicine of protection myocardial cell, prevention or the treatment disease relevant with apoptosis of cardiac muscle or symptom.
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| WO2002022611A3 (en) * | 2000-09-13 | 2002-10-31 | Vertex Pharma | Caspase inhibitors and uses thereof |
| CN101423481A (en) * | 2002-04-25 | 2009-05-06 | 小野药品工业株式会社 | Diketohydrazine derivative compound and medicine containing the compound as active ingredient |
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| PE20030701A1 (en) * | 2001-12-20 | 2003-08-21 | Schering Corp | COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
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| WO2002022611A3 (en) * | 2000-09-13 | 2002-10-31 | Vertex Pharma | Caspase inhibitors and uses thereof |
| CN101423481A (en) * | 2002-04-25 | 2009-05-06 | 小野药品工业株式会社 | Diketohydrazine derivative compound and medicine containing the compound as active ingredient |
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