CN102241673A - Acrylamide compounds and medicinal uses thereof - Google Patents
Acrylamide compounds and medicinal uses thereof Download PDFInfo
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- CN102241673A CN102241673A CN2010101724816A CN201010172481A CN102241673A CN 102241673 A CN102241673 A CN 102241673A CN 2010101724816 A CN2010101724816 A CN 2010101724816A CN 201010172481 A CN201010172481 A CN 201010172481A CN 102241673 A CN102241673 A CN 102241673A
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Abstract
The invention relates to compounds of the general formula I, or their isomers, medicinal salts and solvates. The invention also relates to compositions containing the compounds shown of the general formula I, or their isomers, medicinal salts and solvates, and pharmaceutically acceptable carriers, excipients or diluents. The invention further relates to uses of the compounds shown of the general formula I, or their isomers, medicinal salts and solvates in resisting cell apoptosis and preventing or treating of diseases or symptoms related to cell apoptosis, and especially in protecting cardiac muscle cells and preventing or treating diseases or symptoms related to cardiac muscle cell apoptosis.
Description
Technical field
The present invention relates to the medical chemistry field; particularly; the present invention relates to acrylamides and pharmaceutical composition thereof; the invention still further relates to described compound and pharmaceutical composition thereof and be used for anti-apoptotic; prevention or treatment and apoptosis-related disease or the purposes of symptom, and the purposes that is used for protecting myocardial cell and prevention or treatment and apoptosis of cardiac muscle diseases associated or symptom.
Background technology
Apoptosis generally is meant body cell in growth course or under some factor effect, a kind of apoptosis that the regulation and control by gene in the cell and product thereof take place.Apoptosis is prevalent in organic sphere, has both betided under the physiological status, also betides under the pathological state.To fetal development and form take place, defence and immune response, the disease of stable, the body of normal cell populations or cell injury, the generation progress aging, tumour that causes when poisoning play an important role in the tissue, are the focuses of biomedical research always.
Studies show that have the generation of a lot of major diseases all relevant with the cell transition apoptosis, for example in the evolution of acquired immune deficiency syndrome (AIDS), CD4
+The minimizing of T cell number; In the graft-rejection, the necrocytosis of cytotoxic T cell mediation; Ischemic and reperfusion injury, the apoptosis of myocardial cell and neurocyte; Neural system degenerative disorders (as Alzheimer time disease, Parkinson's disease etc.); Be exposed to multiple histocyte apoptosis that ionizing rays causes etc.
Evidence suggests that the generation of apoptosis of cardiac muscle and many heart diseases, development and prognosis have confidential relation.Find that by the research apoptosis of cardiac muscle the myocardium death of infarct is not equal to myocardial necrosis, apoptosis is one of mechanism of myocardial infarction, and be the main mode of the cardiac muscle death due to early stage myocardium death of infarct and the ischemia/reperfusion, a large amount of apoptosis that this moment is myocardium have increased the weight of myocardium destruction.1989, find during observation hunger property myocardial atrophy ultrastructures such as Nepomniashchikh that myocardial cell's structural protein are synthetic to be reduced, cell count reduces, but the companion cell nuclear phase should not reduce pro rata, and tentatively proposing the myocardial atrophy of hunger property thus is by due to the apoptosis.1994, employing Electronic Speculum such as Gottlieb and Kawano obtained the direct evidence of apoptosis of cardiac muscle in conjunction with the dna gel electrophoresis method, and the former discloses reperfusion injury and brings out the rabbit apoptosis of cardiac muscle, 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 proved the existence of apoptosis.Because methodological progress and Study of apoptosis are deeply, in multiple heart trouble, found the pathological effect of apoptosis of cardiac muscle.Studies show that spontaneously hypertensive mouse (SHR) heart damage is relevant with apoptosis; Turn to heart failure by plump heart late period is due to the apoptosis of cardiac muscle; Acute myocardial infarction is except that necrosis, and the early stage and reperfusion injury of infraction is inducing apoptosis also; Apoptosis of cardiac muscle sees heart and right ventricle's 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 the ischemia/reperfusion has its characteristics and rule, utilizes its characteristics can prevent and reduce apoptosis, for the clinical prevention ischemia/reperfusion injury provides enlightenment; In refilling process, the apoptosis that produces contraction bands zone (around the infarct kitchen range) is induced generation by some inducements, can utilize the inhibition factor of apoptosis such as medicine to wait and prevent apoptosis, the corresponding disease that the treatment apoptosis causes.
But at present can be for clinical application be used for anti-apoptotic and the protection medicament categories of cell and quantity also seldom; selectivity and target are not high; therefore constantly research and develop the medicine of new anti-apoptotic safely and effectively and protection cell, the medicine that especially has brand-new mechanism of action has crucial meaning.
Summary of the invention
In order to develop the medicine of new anti-apoptotic safely and effectively and protection cell; the contriver is through long-term, a large amount of experimental studies; found a class acrylamides; it has anti-apoptotic; protection myocardial cell's effect can be used in prevention or treatment and apoptosis of cardiac muscle diseases associated or symptom.Particularly,
A first aspect of the present invention relates to the acrylamides shown in the general formula I, or its isomer, pharmacologically acceptable salt and solvate.
Wherein
A representative=S or-SR
4
X represents F, Cl, Br or I;
R
1Represent thienyl or substituted thiophene base, wherein said thienyl, thiazolyl is not substituted or by (for example 1-2 of 1-3,1,2, or 3) be independently selected from following substituting group and replace: halogen, nitro, hydroxyl, amino, cyano group, the C1-C6 alkyl, the C1-C6 alkoxyl group, with the C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be chosen wantonly by hydroxyl,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-and alkyl] 2 replacements, perhaps described alkyl, alkoxyl group and haloalkyl are chosen quilt-O-wantonly,-S-,-NH-,-COO-replaces;
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, the single replacement 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;
R
4Represent the C1-C6 alkyl.
The general formula that is preferably as follows (I) compound, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=S or-SR
4
R
1Represent thienyl or substituted thiophene base;
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, the single replacement 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;
R
4Represent methylidene, ethyl, propyl group, sec.-propyl, butyl, amyl group.
The general formula that is preferably as follows especially (I) compound, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=S or-SR
4
R
1Represent 2-thienyl or 3-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;
R
4Represent methylidene.
General formula (I) compound, or its isomer, pharmacologically acceptable salt and solvate, preferred especially following compound:
(1) (2E)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(2) (2E)-and 3-(3-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(3) (2E)-and 3-(2-thienyl)-N-[1-(4-tolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(4) (2E)-and 3-(2-thienyl)-N-[1-(2-anisole amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(5) (2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-benzyl, 2-three chloroethyls)-2-acrylamide;
(6) (2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-hexamethylene, 2-three chloroethyls)-2-acrylamide;
(7) (2E)-and 3-(2-thienyl)-N-[1-isopropylamino sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(8) (2E)-and 3-(2-thienyl)-N-[1-(2-fluoroanilino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(9) (2E)-and 3-(2-thienyl)-N-[1-(3-isopropoxy third amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(10) (2E)-and 3-(2-thienyl)-N-[1-(2-methoxycarbonyl base phenylamino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(11) (2E)-3-(2-thienyl)-N-(1-ring amino sulfo-formamido group-2,2 in heptan, 2-three chloroethyls)-2-acrylamide;
(12) (2E)-and 3-(2-thienyl)-N-[1-(1-morpholinyl) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(13) (2E)-and 3-(2-thienyl)-N-[1-(4-methylpiperazine base) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(14) (2E)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) first sulfo-methylene amino-2,2,2-three chloroethyls]-the 2-acrylamide;
(15) (2E)-3-phenyl-[1-(1-morpholinyl) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide;
(16) (2E)-3-phenyl-[1-(piperidino) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide;
(17) (2E)-3-phenyl-[1-(3-methoxy-benzyl) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide.
General formula of the present invention (I) compound can prepare by following method:
The example that synthesizes with compound 6, The compounds of this invention is starting raw material with the 2 thiophene carboxaldehyde, with propanedioic acid be reacting generating compound 2 under the catalytic condition of solvent piperidines at pyridine, prepare acyl chlorides through sulfur oxychloride again, splash into and obtain compound 3 in the strong aqua, make compound 4 with the trichoro-aldehyde hydrate in reflux in toluene with 3, make lsothiocyanates 5 with the potassium sulfocyanate reaction again through superchlorination then, last and 8-quinolylamine refluxes and obtains compound 6.
Another aspect of the present invention relates to pharmaceutical composition, and it comprises compound shown in the general formula (I) or its isomer, their salt or solvate, and pharmaceutically acceptable carrier, vehicle or thinner.
The invention still further relates to the described general formula of first aspect (I) compound or its isomer, pharmacologically acceptable salt and solvate, be used to prepare anti-apoptotic, the purposes of the medicine of prevention or treatment and apoptosis-related disease or symptom.
The invention still further relates to the described general formula of first aspect (I) compound or its isomer, pharmacologically acceptable salt and solvate, be used to prepare the purposes of the medicine of protecting myocardial cell and prevention or treatment and apoptosis of cardiac muscle diseases associated 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 the described general formula of first aspect present invention (I) compound or its isomer, pharmacologically acceptable salt and the solvate for the treatment of significant quantity to the experimenter that these needs are arranged.
The invention still further relates to the method for a kind of myocardial cell of protection, prevention or treatment and apoptosis of cardiac muscle diseases associated or symptom; described method comprises the described general formula of first aspect present invention (I) compound or its isomer, pharmacologically acceptable salt and the solvate for the treatment of significant quantity to the experimenter that these needs are arranged.
Of the present invention and apoptosis-related disease or symptom comprise: cardiovascular disorder, nerve degenerative diseases, multiple sclerosis, viral infection etc.
Of the present invention and apoptosis of cardiac muscle diseases associated or symptom include but not limited to the myocardial atrophy of (i) hunger property, (ii) myocarditis, (iii) in heart failure, the (iv) myocardial damage that causes of essential hypertension, (the v) myocardial damage that causes in early days of acute myocardial infarction, (vi) acute myocardial infarction pours into the myocardial damage that causes again, (vii) myocardial cell's pathology of causing of heart transplantation, (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 there is chiral centre in compound of Formula I.When the needs compound of Formula I is single enantiomorph, can use the reactant that in all possible step, all is in single enantiomeric forms to prepare, perhaps in the presence of the reagent of single enantiomeric forms or catalyzer, react and prepare, perhaps split stereoisomer mixture and prepare by ordinary method.Some preferable methods comprise uses microorganism to split, the salt of the diastereomer that any spendable acid such as fractionation and chiral acid such as amygdalic acid, camphorsulfonic acid, tartrate, lactic acid forms, the perhaps salt of the diastereomer of formation such as fractionation and chiral base such as brucine (bracine), Peruvian bark alkaloid and derivative thereof.Method commonly used is seen " Enantiomers, Racemates andResolution " (Wiley Interscience, 1981) that people such as Jaques edits.
It will be appreciated by those skilled in the art that The compounds of this invention also can use with its pharmacologically acceptable salt or solvate forms.Acceptable salt comprises the salt of the routine that is formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium on the physiology of compound of Formula I.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, pounces on 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, though itself be not pharmaceutically acceptable, can be used to prepare 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-methylglucosamine and procaine salt.When after this 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 promptly carries out chemical conversion by metabolic process once administration, becomes afterwards to have active medicine.Usually, this class prodrug is the functional derivatives of The compounds of this invention, and it changes into the compound of required formula (I) in vivo easily.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described in 1985 and has selected and the ordinary method of the suitable prodrug derivant of preparation.
The present invention also comprises the active metabolite of The compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, and it contains raceme or the optically active isomer and at least a pharmaceutically acceptable carrier of The compounds of this invention, 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 such as human serum albumin, buffer substance such 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 following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, the cheek medication, local application, non-enterally administer, as in subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the 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.
When medicine for oral use, 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 lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When local medication, 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 different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste.
When 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, the 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 sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, the using dosage of The compounds of this invention and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.
The beneficial effect of the invention
The invention provides a kind of acrylamides; and prove that it has the effect of anti-apoptotic and protection cell; be disease or symptom that the treatment apoptosis causes, particularly treat 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 only is used to illustrate the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the 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 fusing point instrument, 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)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
1.12g 2 thiophene carboxaldehyde and 3.12g propanedioic acid are dissolved in the 15ml pyridine, add the catalytic amount piperidines, 80 ℃ were reacted 6 hours down, reaction solution is poured in the 20ml water, the 10%NaOH aqueous solution is regulated PH12, ethyl acetate extraction, and the water intaking layer is adjusted to PH3 with 2N hydrochloric acid, separate out a large amount of yellow solids (2E)-3-(2-thienyl) vinylformic acid, filter wash 1.12g.(2E)-3-(2-thienyl) vinylformic acid is dissolved in the 10ml anhydrous methylene chloride, add catalytic amount DMF, splash into the 1.5ml oxalyl chloride under the ice-water bath, drip to finish and be warming up to stirring at room 2 hours, reaction solution splashes in 0 ℃ of 10ml strong aqua, stir 30min, separatory get dichloromethane layer steam desolventize white needle-like crystals (2E)-3-(2-thienyl) acrylamide 0.7g.Itself and 1.20g trichoro-aldehyde hydrate are added in the 30ml toluene 110 ℃ refluxed 8 hours, be cooled to room temperature and separate out a large amount of yellow tabular crystals (2E)-3-(2-thienyl)-N-(1-hydroxyl-2,2,2-three chloroethyls) acrylamide 1.20g.It is dissolved among the anhydrous THF of 20ml, adds DMF catalysis, splash into SOCl under the room temperature
21.2ml, be heated to 60 ℃ of reactions 2 hours. dissolve with anhydrous propanone after the solvent evaporated, add 0.3gKSCN, 40 ℃ were stirred 2 hours, diatomite filtration, filtrate is sherwood oil with the developping agent system: ethyl acetate=20:1 wash-out obtains yellow needle-like crystal (2E)-3-(2-thienyl)-N-(1-isothiocyanic acid base-2,2,2-three chloroethyls) acrylamide 0.81g.It is dissolved among the 10ml THF, add 0.30g 8-quinolylamine and be heated to 60 ℃ of reactions 2 hours, be cooled to room temperature and separate out the cotton-shaped solid of a large amount of whites (2E)-3-(2-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide, get pure product 0.92g with the THF recrystallization.
1H-NMR(400MHz，DMSO-d
6)δ6.63-6.67(d，1H)；δ7.12-7.14(q，1H)；δ7.42-7.43(d，1H)；δ7.53-7.73(m，6H)；δ8.42-8.44(dd，1H)；δ8.95-9.03(m，3H)；δ9.54-9.56(d，1H)；δ11.03(s，1H)。MS(TOF)487.0(M+)。
Embodiment 2(2E)-and 3-(3-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 2 thiophene carboxaldehyde into the 3-thiophenecarboxaldehyde, yellow solid 0.60g.
1H-NMR(400MHz，DMSO-d
6)δ6.67-6.71(d，1H)；δ7.35-7.36(d，1H)；δ7.54-7.72(m，6H)；δ7.87-7.88(d，1H)；δ8.42-8.44(dd，1H)；δ8.96-9.03(m，3H)；δ9.54-9.56(d，1H)；δ11.05(s，1H)。MS(TOF)487.0(M+)。
Embodiment 3(2E)-and 3-(2-thienyl)-N-[1-(4-tolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into the 4-monomethylaniline, yellow solid 60mg.
1H-NMR(400MHz，DMSO-d
6)δ2.28(s，3H)；δ6.47-6.51(d，1H)；δ7.13-7.18(m，3H)；δ7.36-7.45(m，4H)；δ7.66-7.72(m，2H)；δ8.03(，1H)；δ8.96-8.98(d，1H)；δ10.21(s，1H)。MS(TOF)450.0(M+)。
Embodiment 4(2E)-and 3-(2-thienyl)-N-[1-(2-anisole amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into the 2-anisidine, yellow solid 0.23g.
1H-NMR(400MHz，DMSO-d
6)δ3.83(s，3H)；δ6.52-6.56(d，1H)；δ6.90-7.14(m，4H)；δ7.41-7.45(m，2H)；δ7.65-7.72(m，2H)；δ7.90-7.92(d，1H)；δ8.48(s，1H)；δ9.00-9.02(d，1H)；δ9.80(s，1H)。MS(TOF)464.0(M+)。
Embodiment 5(2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-benzyl, 2-three chloroethyls)-2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into benzylamine, yellow solid 0.12g.
1H-NMR(400MHz，DMSO-d
6)δ4.68-4.69(d，2H)；δ6.52-6.56(d，1H)；δ6.52-6.56(d，1H)；δ7.11-7.14(dd，1H)；δ7.31-7.43(m，7H)；δ7.64-7.71(m，2H)；δ8.00-8.03(d，1H)；δ8.61-8.63(t，1H)；δ8.94-8.96(d，1H)。MS(TOF)447.9(M+)。
Embodiment 6(2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-hexamethylene, 2-three chloroethyls)-2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into cyclo-hexylamine, yellow solid 0.22g.
1H-NMR(400MHz，DMSO-d
6)δ1.14-1.31(m，5H)；δ1.51-1.64(m，3H)；δ1.88(n，2H)；δ3.97-3.99(，1H)；δ6.51-6.55(d，1H)；δ7.12-7.14(dd，1H)；δ7.30-7.43(m，2H)；δ7.65-7.83(m，3H)；δ8.17-8.19(d，1H)；δ8.91-8.93(d，1H)。MS(TOF)440.0(M+)。
Embodiment 7(2E)-and 3-(2-thienyl)-N-[1-isopropylamino sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into Isopropylamine, yellow solid 0.29g.
1H-NMR(400MHz，DMSO-d
6)δ1.11-1.13(m，6H)；δ4.21-4.24(dd，1H)；δ6.51-6.55(d，1H)；δ7.12-7.14(dd，1H)；δ7.30-7.43(m，2H)；δ7.65-7.76(m，3H)；δ8.15-8.17(d，1H)；δ8.91-8.93(d，1H)。MS(TOF)401.9(M+)。
Embodiment 8(2E)-and 3-(2-thienyl)-N-[1-(2-fluoroanilino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into the 2-fluoroaniline, yellow solid 0.30g.
1H-NMR(400MHz，DMSO-d
6)δ6.52-6.56(d，1H)；δ7.12-7.29(m，4H)；δ7.39-7.45(m，2H)；δ7.66-7.73(m，2H)；δ7.86-7.90(t，1H)；δ8.52-8.54(d，1H)；δ904-9.06(d，1H)。MS(TOF)453.0(M+)。
Embodiment 9(2E)-and 3-(2-thienyl)-N-[1-(3-isopropoxy third amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into 3-isopropoxy Tri N-Propyl Amine, yellow solid 0.20g.
1H-NMR(400MHz，DMSO-d
6)δ1.06-1.08(d，6H)；δ1.68-1.71(t，2H)；δ3.31-3.51(m，4H)；δ6.52-6.55(d，1H)；δ7.11-7.13(dd，1H)；δ7.31-7.43(m，2H)；δ7.64-7.70(m，2H)；δ7.86-7.88(d，1H)；δ8.20-8.22(t，1H)；δ8.88-8.90(d，1H)。MS(TOF)458.0(M+)。
Embodiment 10(2E)-and 3-(2-thienyl)-N-[1-(2-methoxycarbonyl base phenylamino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into 2-methoxycarbonyl base aniline, purple white solid 0.36g.
1H-NMR(400MHz，DMSO-d
6)δ3.79-3.80(s，3H)；δ6.59-6.62(d，1H)；δ7.12-7.14(dd，1H)；δ7.28-7.32(m，1H)；δ7.42-7.46(m，2H)；δ7.55-7.59(m，1H)；δ7.65-7.72(m，2H)；δ7.77-7.79(d，1H)δ7.84-7.86(dd，1H)；δ8.88-9.01(m，2H)。MS(TOF)492.0(M+)。
Embodiment 11(2E)-3-(2-thienyl)-N-(1-ring amino sulfo-formamido group-2,2 in heptan, 2-three chloroethyls)-2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into cycloheptylamino, white solid 0.18g.
1H-NMR(400MHz，DMSO-d
6)δ1.43-1.53(m，11H)；δ1.87-1.90(m，2H)；δ4.19(s，1H)；δ6.51-6.55(d，1H)；δ7.11-7.13(dd，1H)；δ7.30-7.35(t，1H)；δ7.42(d，1H)；δ7.64-7.78(m，3H)；δ8.20-8.22(d，1H)；δ8.87-8.90(d，2H)。MS(TOF)453.0(M+)。
Embodiment 12(2E)-and 3-(2-thienyl)-N-[1-(1-morpholinyl) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into morpholine, white solid 0.15g.
1H-NMR(400MHz，DMSO-d
6)δ3.61-3.64(m，4H)；δ3.83(m，4H)；δ6.78-6.82(d，1H)；δ7.40-7.45(m，3H)；δ7.52-7.45(m，4H)；δ7.89-7.91(d，1H)；δ8.34-8.36(d，1H)。MS(TOF)421.9(M+)。
Embodiment 13(2E)-and 3-(2-thienyl)-N-[1-(4-methylpiperazine base) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, change wherein 8-quinolylamine into N methyl piperazine, white solid 0.17g.
1H-NMR(400MHz，DMSO-d
6)δ2.18(s，3H)；δ2.31-2.40(m，4H)；δ3.78-3.83(m，4H)；δ6.76-6.80(d，1H)；δ7.41-7.45(m，3H)；δ7.52-7.60(m，2H)；δ7.65-7.67(m，2H)；δ7.83-7.85(d，1H)；δ8.32-8.35(d，1H)。MS(TOF)435.3(M+)。
Embodiment 14(2E)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) first sulfo-methylene amino-2,2,2-three chloroethyls]-the 2-acrylamide
Adopt the method for embodiment 1, with embodiment 1 (2E)-3-(2-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide 2.0g adding 5ml water, form suspension, add the 0.5ml50%NaOH aqueous solution, stir 10min, add the 0.54ml methyl iodide, room temperature reaction 2 hours, extracted with diethyl ether, the saturated common salt washing, anhydrous magnesium sulfate drying, solvent evaporate to dryness get white solid (2E)-3-(2-thienyl)-N-[1-(8-quinolyl amino) first sulfo-methylene amino-2,2,2-three chloroethyls]-2-acrylamide 1.30g.
1H-NMR(400MHz，DMSO-d
6)δ2.79(s，3H)；δ6.26-6.28(d，1H)；δ6.86-6.90(d，1H)；δ7.40-7.43(m，3H)；δ7.53-7.64(m，6H)；δ8.43-8.45(dd，1H)；δ8.92-8.97(m，3H)；δ9.59(s，1H)。MS(TOF)501.1(M+)。
Embodiment 15(2E)-3-phenyl-[1-(1-morpholinothio formamido group)-2,2,2-three chloroethyls]-2-acrylamide
Adopt the method for embodiment 1, change wherein 2 thiophene carboxaldehyde into phenyl aldehyde, the 8-quinolylamine changes morpholine into, white solid 0.19g.
1H-NMR(400MHz，DMSO-d
6)δ3.61-3.64(m，4H)；δ3.79-3.83(m，4H)；δ6.78-6.82(d，1H)；δ7.41-7.46(m，3H)；δ7.52-7.61(m，2H)；δ7.64-7.67(dd，1H)；δ7.89-7.91(d，1H)；δ8.34-8.36(d，1H)。MS(TOF)422.7(M+)。
Embodiment 16(2E)-3-phenyl-[1-(piperidino sulfo-formamido group)-2,2,2-three chloroethyls]-2-acrylamide
Adopt the method for embodiment 1, change wherein 2 thiophene carboxaldehyde into phenyl aldehyde, the 8-quinolylamine changes piperidines into, white solid 0.15g.
1H-NMR(400MHz，DMSO-d
6)δ1.53-1.62(m，6H)；δ3.81-3.82(t，4H)；δ6.74-6.78(d，1H)；δ7.41-7.46(m，3H)；δ7.52-7.71(m，5H)；δ8.36-8.38(d，1H)；δ9.59(s，1H)。MS(TOF)420.7(M+)。
Embodiment 17(2E)-3-phenyl-[1-(3-methoxy-benzyl) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide
Adopt the method for embodiment 1, change wherein 2 thiophene carboxaldehyde into phenyl aldehyde, the 8-quinolylamine changes 4-Methoxybenzylamine into, white solid 0.17g.
1H-NMR(400MHz，DMSO-d
6)δ3.72(s，3H)；δ4.58-4.60(d，2H)；δ6.77-6.81(d，1H)；6.90-6.92(d，2H)；δ7.24-7.26(d，2H)；δ7.36-7.46(m，4H)；δ7.52-7.60(m，3H)；δ7.96-7.98(d，1H)；δ8.55(t，1H)；δ8.97-8.99(d，1H)。MS(TOF)472.8(M+)。
Embodiment 18The experiment of compound protection myocardial cell activity
The myocardial cell is former be commissioned to train foster
Myocardial cell's separation and cultivation are with reference to the adherent isolating method (Kreider of differential, 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 the 24h, through tincture of iodine alcohol disinfecting skin of chest abdomen,, tiltedly open chest and take out heart and place ice precooling PBS with scissors median line under xiphoid-process chest of taking back out slightly; PBS with 0.01M blows and beats heart removal blood cell and its hetero-organization gently, and heart is cut into 0.5mm
3The fragment of size washes 2-3 time repeatedly with 0.01M PBS; Fragment is placed Erlenmeyer flask, add 4ml 0.125% pancreatin, 37 ℃ of water-bath concussions of 1ml 0.1% collagenase II (final concentration is respectively 0.1% and 0.02%) 10min abandons supernatant; Add 4ml 0.125% pancreatin once more, 1ml 0.1% collagenase II, 37 ℃ of water-bath concussion digestion 10min draw supernatant and move to centrifuge tube, supernatant is added the DMEM that contains 10%FBS stop digestion; Repeat water-bath concussion digestion step 3-4 time, till the tissue block complete digestion; With the cell suspension collected with the centrifugal 10min of 1000rpm after, remove supernatant, it is resuspended to add substratum again; In Tissue Culture Flask, place 37 ℃ of CO2 incubators to hatch behind the 1.5h resuspended cell inoculation, behind the microscopically counting, adjust cell density, by 1 * 10 with the DMEM nutrient solution that contains 10%FBS with the nutrient solution sucking-off
4Be inoculated into 96 orifice plates, place 37 ℃ of later half amounts of 5%CO2 incubator 24h to change liquid, add the substratum that contains 0.1%Brdu; Change liquid 1 time behind every afterwards 48h, cultivate and to obtain former generation myocardial cell after 4 days.
Cell inhibitory rate (MTT) is measured
Isolating former being commissioned to train nourished heart the myocyte according to every hole 10
4Individual cell inoculation is to 96 orifice plates, every pore volume 100ul (marginal pore is filled with aseptic PBS).At 5%CO2, after 37 ℃ of incubators are cultivated 4d, add 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 respectively, each concentration is provided with 3 multiple holes, zeroing hole (nutrient solution, MTT, DMSO) is set simultaneously, control wells (nutrient solution, DMSO).After continuing to hatch processing 48h, every hole adds 20ulMTT solution (5mg/ml, joining with PBS (pH=7.4) is 0.5%MTT), continues to cultivate 4h.Stop cultivating, the careful suction removed nutrient solution in the hole.Every hole adds 150ulDMSO, puts low-speed oscillation 10min on the 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 write down the result.The results are shown in Table 1.
Table 1MTT method detects the influence of different concns compound to myocardial cell's inhibiting rate
| Group | Myocardial cell's inhibiting rate (%) |
| Control group | 100 |
| Embodiment 4 compounds 300 μ M | 5.55±2.29 |
| Embodiment 5 compounds 300 μ M | 0.76±4.04 |
| Embodiment 6 compounds 300 μ M | 5.54±3.61 |
| Embodiment 7 compounds 300 μ M | 1.32±3.42 |
| Embodiment 8 compounds 300 μ M | 6.82±1.21 |
| Embodiment 9 compounds 300 μ M | 5.30±0.95 |
| Embodiment 10 compounds 300 μ M | 3.24±1.70 |
| Embodiment 11 compounds 300 μ M | 7.62±5.77 |
| Embodiment 12 compounds 300 μ M | 10.44±5.66 |
| Embodiment 13 compounds 300 μ M | 1.66±2.70 |
| Embodiment 14 compounds 300 μ M | 8.34±5.78 |
The result shows: the survival rate to normal myocardial cell in 300 μ M concentration of compound described in the embodiment does not influence.
Protection myocardial cell activity mensuration-Protection is by TG inductive apoptosis of cardiac muscle activity
The myocardial cell is former according to the method described above to be commissioned to train to support and to begin to add thapsigargin in 4 days (30min adds The compounds of this invention and carries out pre-treatment before cell death inducing for thapsigargin, TG) cell death inducing.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 compounds of this invention, the results are shown in Table 2 the provide protection that TG induces apoptosis of cardiac muscle.
Table 2MTT method detects the influence of different concns compound to TG inductive myocardial cell survival rate
| Group | Myocardial cell's survival rate (%) |
| The solvent control group | 100 |
| The TG intervention group | 59±1.1 |
| Embodiment 5 compounds | |
| 0.3 μ M group | 82±4 |
| 1 μ M group | 76±8 |
| 3 μ M group | 74±9 |
| Embodiment 6 compounds | |
| 1 μ M group | 76±7 |
| 3 μ M group | 70±6 |
| 10 μ M group | 78±9 |
| Embodiment 7 compounds | |
| 1 μ M group | 69±5 |
| 3 μ M group | 70±8 |
| 10 μ M group | 77±11 |
| Embodiment 12 compounds | |
| 0.3 μ M group | 79±7 |
| 1 μ M group | 80±9 |
| 3 μ M group | 83±11 |
| Embodiment 13 compounds | |
| 0.3 μ M group | 72±3 |
| 1 μ M group | 71±3 |
| 3 μ M group | 67±3 |
Annotate: cell survival rate=1-cell inhibitory rate
Experimental result: compare with single TG group that adds; when adding TG and embodiment compound at the same time; myocardial cell's survival rate is significantly improved, and shows that the compound of embodiment described in the table 2 can obviously improve the apoptosis effect that TG causes, has provide protection to the myocardial cell.
Embodiment 19Formula I compound is to the provide protection of hypoxia inducible apoptosis of cardiac muscle
Solution is prepared(following reagent can be purchased the company in Invitrogen)
1,1 * Wash Buffer: 10 * Wash Buffer of 20mL is added in the 180mL ultrapure water, and 4 ℃ of environment were preserved 7 days.
2, stationary liquid: the formaldehyde solution of 7.3mL37% is added among 1 * Wash Buffer of 14.7mL, is preheating to 37 ℃ before the use.This solution matching while using.
3,1 * saturating film liquid: 10 of 4mL * saturating film liquid is added in the ultrapure water of 36mL, this is used liquid preserved 7 days at 4 ℃.
4, Mitotracker/Hoechst solution (20 ℃ of preservations): the anhydrous DMSO with 94uL dissolves the solution that Mitotracker CMXROS makes 1mM, and this solution can be preserved 6 months under the condition of-20 ℃ of dry lucifuges.For avoiding repeatedly freeze-thaw cycle, carry out the packing of single usage quantity.The Hoechst dyestuff of the Mitotracker Red Solution of 5.5uL1mM and 11uL is added in the cell culture medium, and obtaining final volume is the application liquid of 5.5mL.This uses the liquid matching while using.
5, Alexa Fluor 488Phalloidin solution: with 140 μ L methyl alcohol mother liquor is made in AlexaFluor 488Phalloidin dissolving, this solution can be preserved 12 months under the condition of-20 ℃ of dry lucifuges.The Alexa Fluor 488Phalloidin mother liquor of 27.5 μ L is added among 1 * Wash Buffer of 5.5mL and makes application liquid.This uses the liquid matching while using.
Experimental technique:According to embodiment 18 described methods cardiac muscle cells of former generation, cell density 10
4Individual/mL, every hole adds this cell suspension of 100uL.At 37 ℃, 5%CO
2Environment incubated cell 96 hours (every 48h changes a not good liquor).Former be commissioned to train to support be put into anoxic incubator cell death inducing after 4 days, the The compounds of this invention that 30min adds different concns before cell death inducing carries out pre-treatment, puts into 37 ℃, 5%CO
2-95%N
2Incubator is cultivated 15.5h.Hatched preceding 30 minutes finishing compound, add the substratum of 50uL, the Mitotracker/Hoechst solution of 50uL, 37 ℃, 5%CO
2-95%N
2Continue incubated cell 30min.
Every hole directly adds the stationary liquid of 100uL, and does not inhale substratum, stink cupboard incubated at room 10min.The stationary liquid of preheating is for keeping cell integrity particularly important.
Every hole solution (can buckle) is removed in suction, washes once with 1 * Wash Buffer (100uL/ hole).Want SC in operation and the washing process, attach and integrity to keep cell.The good result of generation is known from experience in suction tapping at a slow speed.Wash Buffer is removed in suction, adds 1 * saturating film liquid (100uL/ hole) incubated at room 15min.Film liquid is removed in suction, and every hole is washed once with 1 * Wash Buffer in 100 μ L/ holes.Wash Buffer is removed in suction, and every hole adds 50uL Alexa Fluor488Phalloidin Solution solution, and the room temperature lucifuge is hatched 30min.AlexaFluor 488Phalloidin solution is removed in suction, and it is inferior to give a baby a bath on the third day after its birth with 1 * Wash Buffer, and last solution is stayed in the hole.Board edge is wrapped (preventing drying) with sealing film, detected with HCSReader.4 ℃ of environment are preserved plank.Detect the apoptosis of cardiac muscle degree with fluorescent dye at last, the results are shown in Table 3, table 4 and table 5.
This analytical procedure is high intension screening analytical method.It is emerging in recent years a kind of apoptosis detection method, by specific fluorescent dye apoptosis is carried out multiplicity simultaneously.Main analyze three parameters relevant with apoptotic process: comprise the karyomorphology change, mitochondrial swelling with or mitochondrial membrane potential, F-Actin muscle content.HCS Reader can observe by the dye morphology of pair cell nuclear of Hoechst, and pair cell nuclear area and nuclear intensity are carried out quantitative comparison.The increase of the decline of mitochondrial membrane potential and plastosome volume has been acknowledged as the early stage mark of apoptosis, can pass through the plastosome tracer agent
Red carries out quantitatively.
Table 3 nuclear area detected result:
| Group | Nuclear area (%) |
| Control group | 113.86±3.06 |
| The anoxic group | 98.26±1.00 |
| Embodiment 1 compound 10 μ M group | 112.61±7.78 |
| Embodiment 5 compounds 0.3 μ M group | 120.23±5.49 |
| Embodiment 6 compounds 1 μ M group | 100.00±4.63 |
| Embodiment 12 compounds 10 μ M group | 102.93±5.12 |
Table 4 mitochondrial membrane potential detected result:
| Group | Mitochondrial membrane potential |
| Control group | 100±1 |
| The anoxic group | 96.04±3.61 |
| Embodiment 1 compound 10 μ M group | 112.68±1.46 |
| Embodiment 5 compounds 0.3 μ M group | 117.76±1.87 |
| Embodiment 6 compounds 1 μ M group | 112.92±0.82 |
| Embodiment 12 compounds 10 μ M group | 133.11±6.30 |
| Embodiment 13 compounds 3 μ M group | 116.41±0.64 |
Table 5 light flux (optical throughput) detected result:
| Group | light?flux |
| Control group | 1247.52±48.059 |
| The anoxic group | 1044.91±16.53 |
| Embodiment 1 compound 10 μ M group | 1201.92±29.95 |
| Embodiment 5 compounds 0.3 μ M group | 1331.12±53.30 |
| Embodiment 6 compounds 1 μ M group | 1077.08±55.63 |
Experimental result: compare with the anoxic group; after adding the embodiment compound; myocardial cell's nuclear area, mitochondrial membrane potential and light flux have remarkable increase, show that the embodiment compound has the obvious apoptosis effect that anoxic causes that improves, and can protect the 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 modifications 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 (9)
1. compound of Formula I, or its isomer, pharmacologically acceptable salt and solvate,
Wherein:
A representative=S or-SR
4
X represents F, Cl, Br or I;
R
1Represent thienyl or substituted thiophene base, wherein said thienyl, thiazolyl is not substituted or by (for example 1-2 of 1-3,1,2, or 3) be independently selected from following substituting group and replace: halogen, nitro, hydroxyl, amino, cyano group, the C1-C6 alkyl, the C1-C6 alkoxyl group, with the C1-C6 haloalkyl, and wherein said alkyl, alkoxyl group and haloalkyl can be chosen wantonly by hydroxyl,-O-(C1-C4)-alkyl, oxo, amino,-NH-(C1-C4)-alkyl, or-N-[(C1-C6)-and alkyl] 2 replacements, perhaps described alkyl, alkoxyl group and haloalkyl are chosen quilt-O-wantonly,-S-,-NH-,-COO-replaces;
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, the single replacement 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;
R
4Represent the C1-C6 alkyl.
2. compound of Formula I, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=S or and-SR
4
X represents F, Cl, Br or I;
R
1Represent thienyl or substituted thiophene base;
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, the single replacement 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;
R
4Represent methylidene, ethyl, propyl group, sec.-propyl, butyl, amyl group.
3. compound of Formula I, or its isomer, pharmacologically acceptable salt and solvate, wherein:
A representative=S or-SR
4
X represents Cl;
R
1Represent 2-thienyl or 3-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, N methyl piperazine ring;
R
4Represent methylidene, ethyl.
4. the compound that has the claim 1 of following structure, or its isomer, pharmacologically acceptable salt and solvate:
(1) (2E)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(2) (2E)-and 3-(3-thienyl)-N-[1-(8-quinolyl amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(3) (2E)-and 3-(2-thienyl)-N-[1-(4-toluino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(4) (2E)-and 3-(2-thienyl)-N-[1-(2-anisole amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(5) (2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-benzyl, 2-three chloroethyls)-2-acrylamide;
(6) (2E)-3-(2-thienyl)-N-(the amino sulfo-formamido group-2,2 of 1-hexamethylene, 2-three chloroethyls)-2-acrylamide;
(7) (2E)-and 3-(2-thienyl)-N-[1-isopropylamino sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(8) (2E)-and 3-(2-thienyl)-N-[1-(2-fluoroanilino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(9) (2E)-and 3-(2-thienyl)-N-[1-(3-isopropoxy third amino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(10) (2E)-and 3-(2-thienyl)-N-[1-(2-methoxycarbonyl base phenylamino) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(11) (2E)-3-(2-thienyl)-N-(1-ring amino sulfo-formamido group-2,2 in heptan, 2-three chloroethyls)-2-acrylamide;
(12) (2E)-and 3-(2-thienyl)-N-[1-(1-morpholinyl) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(13) (2E)-and 3-(2-thienyl)-N-[1-(4-methylpiperazine base) sulfo-formamido group-2,2,2-three chloroethyls]-the 2-acrylamide;
(14) (2E)-and 3-(2-thienyl)-N-[1-(8-quinolyl amino) first sulfo-methylene amino-2,2,2-three chloroethyls]-the 2-acrylamide;
(15) (2E)-3-phenyl-[1-(1-morpholinyl) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide;
(16) (2E)-3-phenyl-[1-(piperidino) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide; Or
(17) (2E)-3-phenyl-[1-(3-methoxy-benzyl) sulfo-formamido group-2,2,2-three chloroethyls]-2-acrylamide.
5. pharmaceutical composition, it comprises each described compound of claim 1-4 or its isomer, pharmacologically acceptable salt and solvate, and pharmaceutically acceptable carrier, vehicle or thinner.
6. each described compound of claim 1-4 or its isomer, pharmacologically acceptable salt and solvate are used to prepare the purposes of the medicine of anti-apoptotic, prevention or treatment and apoptosis-related disease or symptom.
7. each described compound of claim 1-4 or its isomer, pharmacologically acceptable salt and solvate are used to prepare the purposes of the medicine of protecting myocardial cell, prevention or treatment and apoptosis of cardiac muscle diseases associated or symptom.
8. an anti-apoptotic, prevention or treatment and apoptosis-related disease or the method for symptom, described method comprises each described compound of claim 1-4 or its isomer, pharmacologically acceptable salt and the solvate for the treatment of significant quantity to the experimenter that these needs are arranged.
9. method of protecting myocardial cell, prevention or treatment and apoptosis of cardiac muscle diseases associated or symptom; described method comprises each described compound of claim 1-4 or its isomer, pharmacologically acceptable salt and the solvate for the treatment of significant quantity to the experimenter that these needs are arranged.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN103387551A (en) * | 2012-05-11 | 2013-11-13 | 中国人民解放军军事医学科学院毒物药物研究所 | Thiazole compounds and uses thereof |
| WO2015090209A1 (en) * | 2013-12-20 | 2015-06-25 | 中国人民解放军军事医学科学院毒物药物研究所 | New urea compound, manufacturing method and application thereof |
| CN109232341A (en) * | 2018-10-08 | 2019-01-18 | 中国人民解放军总医院 | A kind of compound or its pharmaceutically acceptable salt and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387551A (en) * | 2012-05-11 | 2013-11-13 | 中国人民解放军军事医学科学院毒物药物研究所 | Thiazole compounds and uses thereof |
| WO2013166989A1 (en) * | 2012-05-11 | 2013-11-14 | 中国人民解放军军事医学科学院毒物药物研究所 | Thiazole compound and use thereof |
| CN103387551B (en) * | 2012-05-11 | 2015-05-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Thiazole compounds and uses thereof |
| US9139543B2 (en) | 2012-05-11 | 2015-09-22 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Thiazole compounds and uses thereof |
| WO2015090209A1 (en) * | 2013-12-20 | 2015-06-25 | 中国人民解放军军事医学科学院毒物药物研究所 | New urea compound, manufacturing method and application thereof |
| CN105814018A (en) * | 2013-12-20 | 2016-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | New urea compound, manufacturing method and application thereof |
| US9718770B2 (en) | 2013-12-20 | 2017-08-01 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Substituted thioureas as heat shock protein 70 inhibitors |
| CN109232341A (en) * | 2018-10-08 | 2019-01-18 | 中国人民解放军总医院 | A kind of compound or its pharmaceutically acceptable salt and application thereof |
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