WO2011140681A1 - 丙烯酰胺类化合物及其抑制细胞凋亡的用途 - Google Patents
丙烯酰胺类化合物及其抑制细胞凋亡的用途 Download PDFInfo
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- WO2011140681A1 WO2011140681A1 PCT/CN2010/000687 CN2010000687W WO2011140681A1 WO 2011140681 A1 WO2011140681 A1 WO 2011140681A1 CN 2010000687 W CN2010000687 W CN 2010000687W WO 2011140681 A1 WO2011140681 A1 WO 2011140681A1
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- Prior art keywords
- thienyl
- alkyl
- trichloroethyl
- acrylamide
- group
- Prior art date
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- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000001587 sorbitan monostearate Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- IXFPJGBNCFXKPI-FSIHEZPISA-N thapsigargin Chemical compound CCCC(=O)O[C@H]1C[C@](C)(OC(C)=O)[C@H]2[C@H](OC(=O)CCCCCCC)[C@@H](OC(=O)C(\C)=C/C)C(C)=C2[C@@H]2OC(=O)[C@@](C)(O)[C@]21O IXFPJGBNCFXKPI-FSIHEZPISA-N 0.000 description 1
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Classifications
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A61K31/33—Heterocyclic compounds
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- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/194—Radicals derived from thio- or thiono carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/21—Radicals derived from sulfur analogues of carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to the acrylamide compound and pharmaceutical composition thereof, and to the use of the compound and the pharmaceutical composition thereof for anti-apoptosis, prevention or treatment of apoptosis Use of the disease or condition, and for use in protecting cardiomyocytes and preventing or treating diseases or conditions associated with cardiomyocyte apoptosis. Background technique
- Apoptosis generally refers to a programmed cell death that occurs through the regulation of intracellular genes and their products during the development of the body's cells or under certain factors. Apoptosis is prevalent in the biological world, both in physiological conditions and in pathological conditions. It plays an important role in embryonic development and morphogenesis, the stability of normal cell populations in the tissues, the defense and immune response of the body, cell damage, aging and tumors caused by diseases or poisoning, and has always been a hot spot in biomedical research. .
- cardiomyocyte apoptosis is closely related to the development, progression and prognosis of many heart diseases.
- myocardial death is not equal to myocardial necrosis. Death is one of the mechanisms of myocardial infarction, and it is the main way of myocardial death and myocardial death caused by ischemia/reperfusion in early infarction. A large amount of apoptosis of the myocardium aggravates the destruction of the myocardium.
- apoptosis was also demonstrated in the cultured neonatal rat cardiomyocytes such as Tanaka. Due to advances in methodologies and advances in apoptosis, pathological effects of cardiomyocyte apoptosis have been found in a variety of heart diseases. Studies have shown that cardiac damage in spontaneously hypertensive mice (SHR) is associated with apoptosis; late from hypertrophic heart to heart failure caused by cardiomyocyte apoptosis; acute myocardial infarction in addition to necrosis, early infarction and reperfusion injury Death; Cardiomyocyte apoptosis is also seen in transplanted heart and right ventricular dysplasia cardiomyopathy, hypoxia also induces cardiomyocyte apoptosis.
- SHR spontaneously hypertensive mice
- Apoptosis is reversible to some extent.
- Apoptosis in myocardial infarction and ischemia/reperfusion has its characteristics and regularity. It can prevent and reduce apoptosis by using its characteristics, and prevent ischemia/reperfusion for clinical prevention.
- Injury provides inspiration; during reperfusion, apoptosis in the region of the contractile zone (around the infarct) is induced by a number of inducements that can be used to prevent apoptosis, such as drugs, to treat apoptosis. The corresponding disease.
- the inventors discovered a class of acrylamide compounds through long-term, large-scale real-world studies. It has anti-apoptosis and protects cardiomyocytes and can be used to prevent or treat diseases or symptoms associated with cardiomyocyte apoptosis. specifically,
- a first aspect of the invention relates to an acrylamide compound of the formula I, or an isomer, a pharmaceutically acceptable salt thereof and a solvate thereof.
- X represents F, Cl, Br or I
- thienyl group wherein the thienyl group or the thiazolyl group is unsubstituted or is independently selected from the group consisting of 1-3 (for example, 1-2, 1, 2, or 3) Substituent substitution: halogen, nitro, hydroxy, amino, cyano, CI-C6 alkyl, C1-C6 alkoxy, and (1 6 3 ⁇ 4 alkyl, and wherein alkyl, decyl and Haloalkyl can be optionally hydroxy, -0-(Cl-C4)-alkyl, oxo, amino,
- R 2 , R 3 represent hydrogen, CI-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, amino C1-C6 alkyl, monosubstituted Or a disubstituted amino C1-C6 alkyl group, a phenyl C1-C6 alkyl group, a substituted phenyl C1-C6 alkyl group, a heterocyclic group C1-C6 alkyl group, a phenyl group, a substituted phenyl group, a heterocyclic group or a substituted heterocyclic ring.
- a group, wherein R 2 and R 3 may be cyclized to a saturated cycloalkane, a nitrogen-containing or an oxygen-containing heterocycle;
- R 4 represents a C1-C6 alkyl group.
- R 2 , R 3 represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, amino CI-C6 alkyl, monosubstituted Or disubstituted amino C1-C6 alkyl, phenyl C1-C6 alkyl, substituted phenyl C1-C6 alkyl, heterocyclyl C1-C6 alkyl, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic a group, wherein R 2 and R 3 may be cyclized to a saturated cycloalkane, a nitrogen-containing or an oxygen-containing heterocycle;
- ⁇ represents fluorenyl, ethyl, propyl, isopropyl, butyl, pentyl.
- A stands for -S or -SR 4 ;
- R 2 and R 3 represent hydrogen, methyl, isopropyl, 2-methoxyethyl, 3-isopropoxypropyl, 2-N,N-didecylethyl, cyclohexyl, cycloheptyl , o-nonyloxyphenyl, o-fluorophenyl, o-chlorophenyl, p-chlorophenyl, benzyl or 8-quinolinyl, wherein R 2 and R 3 may be cyclized to a piperidine ring, a morpholine ring or N-mercaptopiperazine ring;
- R 4 represents a methyl group.
- the compound of the present invention is prepared by reacting 2-thiophenecarboxaldehyde with malonic acid under the catalysis of pyridine as a solvent piperidine to form compound 2, and then preparing acid chloride by thionyl chloride.
- pyridine as a solvent piperidine
- acid chloride by thionyl chloride.
- compound 3 Into concentrated ammonia to obtain compound 3, 3 and trichloroacetaldehyde hydrate in toluene to obtain compound 4, and then chlorination and then react with potassium thiocyanate to obtain isothiocyanate 5, and finally with 8- Aminoquinoline refluxed to give compound 6.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I) or an isomer thereof, a salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
- the present invention also relates to the compound of the above formula (I), or an isomer, a pharmaceutically acceptable salt thereof and a solvate thereof, for use in the preparation of anti-apoptosis, prevention or treatment of diseases or symptoms associated with apoptosis.
- the use of the drug is a compound of the above formula (I), or an isomer, a pharmaceutically acceptable salt thereof and a solvate thereof.
- the present invention also relates to the compound of the above formula (I), or an isomer, a pharmaceutically acceptable salt thereof and a solvate thereof, for use in the preparation of a protective cardiomyocyte and for preventing or treating a disease or a symptom associated with cardiomyocyte apoptosis.
- the use of the drug also relates to a method of anti-apoptosis, prevention or treatment of a disease or condition associated with apoptosis, the method comprising administering to a subject in need thereof a therapeutically effective amount of the first aspect of the invention
- a compound of the formula (I) or an isomer thereof, a pharmaceutically acceptable salt and a solvate are examples of the first aspect of the invention.
- the invention also relates to a method of protecting cardiomyocytes, preventing or treating a disease or condition associated with cardiomyocyte apoptosis, the method comprising administering to a subject in need thereof a therapeutically effective amount of the first aspect of the invention A compound of the formula (I) or an isomer thereof, a pharmaceutically acceptable salt and a solvate.
- the diseases or symptoms associated with apoptosis according to the present invention include cardiovascular diseases, neurodegenerative diseases, multiple sclerosis, viral infections and the like.
- the diseases or symptoms associated with cardiomyocyte apoptosis according to the invention include, but are not limited to
- heterocycle includes but is not limited to: pyridine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, oxazole, isoxazole, hydrazine, benzofuran, benzimidazole, oxazole, pyridazine , pyrimidine, pyrazine, quinoline, isoquinoline, anthracene, phenothiazine, phenazine.
- a compound of formula I has a chiral center.
- a compound of formula I can be prepared using a reactant in the form of a single enantiomer in all possible steps, or in a single enantiomer form of the reagent or catalyst. It is prepared by carrying out the reaction in the presence of a solution, or by dissolving a mixture of stereoisomers by a conventional method.
- Some preferred methods include the use of microorganisms for resolution, resolution and chiral acids such as mandelic acid, camphorsulfonic acid, tartar a salt of a diastereomer formed by any acid which can be used, such as an acid or a lactic acid, or a non-formation with a chiral base such as a brac ine, a cinchona alkaloid, or a derivative thereof. a salt of an enantiomer.
- a commonly used method is found in "Enant iomers, Racemates and Reso lium ion” (Wi ley Intersc ience, 1981) edited by Jaques et al.
- Physiologically acceptable salts of the compounds of formula I include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts.
- Suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonate Salts of acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid and the like.
- acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of a salt for use as an intermediate to obtain a compound of the invention and a pharmaceutically acceptable salt thereof.
- suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts.
- the compound of the formula I and pharmaceutically acceptable salts and solvates thereof are included.
- the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
- prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I).
- Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985.
- the invention also includes active metabolites of the compounds of the invention.
- compositions comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
- the pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration.
- the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
- compositions of the present invention comprise an effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt or hydrate thereof and one or more suitable pharmaceutically acceptable carriers.
- Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulose, Polyethylene Glycol, Sodium Carboxymethyl Cellulose, Polyacrylate, Beeswax, Lanolin.
- composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Internal, intraventricular, intrasternal and intracranial injection or input, or with an explant reservoir.
- oral, intraperitoneal or intravenous administration is preferred.
- the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, gels, aqueous solutions or aqueous suspensions.
- the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
- the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
- Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
- the compounds of the invention When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the invention may be formulated into different topical preparations according to different affected faces or organs.
- the form is specifically described as follows:
- the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH of sterile saline, which may or may not be added.
- Preservatives such as benzyl chloride alkoxide.
- the compound can also be formulated into a bone form such as a vaseline cream.
- the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
- Carriers for ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used, including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
- a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
- carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
- sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
- the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
- the present invention provides an acrylamide compound and proves that it has anti-apoptotic and cell-protecting effects, and is a disease or symptom caused by apoptosis. It is a new method and approach to treat diseases or symptoms caused by apoptosis of cardiomyocytes. detailed description
- Example 1 The method of Example 1 was carried out, and the 8-aminoquinoline was changed to 2-fluoroaniline to give a yellow solid (0.33 g).
- 'H-NMR 400MHz, DMSO- ⁇
- ⁇ 6. 52-6. 56 (d, IH); ⁇ 7. 12-7. 29 (m, 4H); ⁇ 7. 39-7. 45 (m, 2 ⁇ ); ⁇ 7. 66-7. 73 (m, 2H); ⁇ 7. 86-7. 90 (t, IH); ⁇ 8. 52-8. 54 (d, 1 ⁇ ); ⁇ 904-9. 06 (d, IH).
- the white solid was 0.18 g, which was obtained by the method of Example 1, and the 8-aminoquinoline was changed to cycloheptylamine.
- ⁇ -NMR 400MHz, DMSO-i/e
- ⁇ 1. 43-1. 53 (m, 11H); ⁇ 1. 87-1. 90 (m, 2H) ; ⁇ 4. 19 (s, 1 ⁇ ); ⁇ 6. 51-6. 55 (d, 1 ⁇ ); ⁇
- Example 1 (2 ⁇ )-3-(2-thienyl)-N-[1-(8-quinolinylamino)thiodecanoylamino-2, 2, 2-tri Chloroethyl] -2 - acrylamide 2. 0g added to 5ml of water to form a suspension, added 0. 5ml 50% NaOH aqueous solution, stirred for 10min, added 0.
- Isolation and culture of cardiomyocytes are based on differential adherence separation methods (Kreider, A. Messing, H. Doan, SU Kim, RP Lisak and DE Pleasure, Enrichment of Schwann cell cultures from neonatal rat sciatic nerve by differential adhesion, Brain Res 2 (1981), pp. 433 444. ), take the newborn Wistar suckling rat within 24 hours, disinfect the chest and abdomen skin with iodine alcohol, use scissors to open the chest slightly to the left in the midline of the xiphoid process, remove the chest and remove the heart.
- the culture solution was aspirated. After counting under a microscope, the cell density was adjusted with DMEM containing 10% FBS, and inoculated into a 96-well plate according to 1 ⁇ 10 4 and placed in a 37 ⁇ 5% CO 2 incubator. After 24 hours, the medium was changed, and the medium containing 0.1% Brdu was added. After that, the medium was changed once every 48 hours, and the primary cardiomyocytes were obtained after 4 days of culture.
- MTT Cell inhibition rate
- the isolated primary cultured cardiomyocytes were seeded into 96-well plates at a volume of 10 4 cells per well at a volume of 100 ul per well (the marginal wells were filled with sterile PBS). At 5% CO 2, 37 . After incubating for 4 days in C incubator, different concentrations of the compound of formula I (0.3 ⁇ M, 1 ⁇ , 3 ⁇ , 10 ⁇ , 30 ⁇ , 100 ⁇ ) were added, and 3 duplicate wells were set for each concentration, and zero-adjusted wells were set at the same time ( Culture medium, MTT, DMS0), control well (culture medium, DMS0).
- TG thapsigargin, TG
- the cells were randomly divided into 5 groups: (1) solvent control group (DMSO); (2) TG intervention group (0.4 uM); (3) TG (0.4 uM) + compound intervention group (0.3 uM); (4) TG (0.4) uM) + compound intervention group (luM); (5) TG (0.4uM) + compound intervention group (3uM).
- TG was prepared in DMSO, the mother liquor was 4 mM, and the compound of the present invention was prepared in DMSO, and the mother liquor was 150 mM.
- the cell viability was determined according to the above MTT method, thereby determining the protection of the compound of the present invention against TG-induced cardiomyocyte apoptosis. Function, the results are shown in Table 2.
- 1, 1 X Wash Buffer Add 20 mL of 10 ⁇ Wash Buffer to 180 mL of ultrapure water and store in 4 environments for 7 days.
- Fixative solution Add 7.3 mL of 37% furfural solution to 14.7 mL of 1 x Wash Buffer and preheat to 37 ⁇ before use. This solution is ready for use.
- Mi totracker/Hoechs t solution (-20 storage): Dissolve Mi totracker CMXR0S with 94 uL of water-free DMS0 to make an ImM solution. This solution can be stored in -20 dry and dark conditions for 6 months. In order to avoid multiple freeze-thaw cycles, a single-use dispensing is performed. Add 5. 5uLlmM of Mi totracker Red Solutine and lluL of Hoechs t dye to the cell culture medium to obtain a final volume of 5. 5mL of application solution. This application liquid is now available.
- Alexa Fluor 488 Phal loidin solution The Alexa Fluor 488 Phal loidin was dissolved in 140 methanol to make a mother liquor which was stored in the dark at -20 Torr for 12 months.
- the application solution was prepared by adding 27. 5 ⁇ L of Alexa Fluor 488 Phal loidin mother liquor to 1.5 mL of 1 ⁇ Wash Buffer. This application liquid is now available.
- the sputum method Primary cultured cardiomyocytes according to the method described in Example 18, cell density 10 4 /mL, 100 ul of this cell suspension was added to each well. Incubate the cells for 96 hours in a 37, 5% C0 2 environment (change the solution every 48 hours).
- Aspirate each well solution can be spliced) and wash once with l x Wash Buffer ( l OOuL/well). Care must be taken during handling and washing to maintain cell attachment and integrity. Slow suction and discharge of liquids will produce good results.
- Aspirate Wash Buffer add 1 ⁇ permeabilizing solution (100 uL/well) and incubate for 15 min at room temperature. Aspirate the permeate and wash once with 100 ⁇ L/ ⁇ L of 1 X Wash Buffer. Aspirate Wash Buffer and add 50 uL of Alexa Fluor 488 Phal loidin Solut ion solution to each L. Incubate for 30 min at room temperature in the dark.
- This analytical method is a high content screening analysis method. It is a new method of apoptosis detection in recent years, and simultaneous multivariate analysis of apoptosis by specific fluorescent staining.
- Three parameters related to the apoptotic process were analyzed: nuclear morphology changes, mitochondrial swelling and or mitochondrial membrane potential, F-actin content.
- HCS Reader can observe the morphology of the nucleus by Hoechs t staining, and quantitatively compare the nuclear area and nuclear intensity. Decreased mitochondrial membrane potential and increased mitochondrial volume have been recognized as early markers of apoptosis and can be quantified by the mitochondrial tracer Mi toTracker® Red.
- Table 3 Nuclear area test results:
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Description
丙烯酰胺类化合物及其抑制细胞凋亡的用途
技术领域
本发明涉及医药化学领域, 具体地, 本发明涉及丙烯酰胺类化 合物及其药物组合物, 本发明还涉及所述化合物及其药物组合物用 于抗细胞凋亡,预防或治疗与细胞凋亡有关的疾病或症状的用途, 以及用于保护心肌细胞和预防或治疗与心肌细胞凋亡有关的疾病 或症状中的用途。 背景技术
细胞凋亡一般是指机体细胞在发育过程中或在某些因素作用 下, 通过细胞内基因及其产物的调控而发生的一种程序性细胞死 亡。 细胞凋亡普遍存在于生物界, 既发生于生理状态下, 也发生于 病理状态下。 对胚胎发育及形态发生、 组织内正常细胞群的稳定、 机体的防御和免疫反应、 疾病或中毒时引起的细胞损伤、 老化、 肿 瘤的发生进^^着重要作用, 一直是生物医学研究的热点。
研究表明, 有很多重大疾病的发生都与细胞过度凋亡有关, 例 如在艾滋病的发展过程中, CD4+ T细胞数目的减少; 移植排斥反应 中, 细胞毒性 T细胞介导的细胞死亡; 缺血及再濯注损伤, 心肌细 胞和神经细胞的凋亡; 神经系统退化性疾病(如阿尔海默次病、 帕 金森氏症等) ; 暴露于电离辐射引起的多种组织细胞凋亡等。
有证据表明, 心肌细胞凋亡与许多心脏疾病的发生、 发展和 预后有着密切的关系。 通过研究心肌细胞凋亡发现^^死的心肌死 亡不等于心肌坏死, ^亡是心肌梗死的机制之一, 而且是梗死早 期心肌死亡及缺血 /再灌注所致的心肌死亡的主要方式,此时心肌 的大量凋亡, 加重了心肌的破坏。 1989年, Nepomniashchikh等
观察饥饿性心肌萎缩超微结构时发现, 心肌细胞结构蛋白合成降 低, 细胞数减少, 但不伴细胞核相应成比例地减少, 由此初步提 出饥俄性心肌萎缩是由细胞凋亡所致。 1994 年, Got t l ieb 和 Kawano等釆用电镜结合 DNA凝胶电泳方法取得了心肌细胞凋亡的 直接证据, 前者揭示再灌注损伤诱发兔心肌细胞凋亡, 后者证实 心肌炎患者伴发心肌细胞凋亡。 Tanaka 等培养的乳鼠心肌细胞 中,也证明了凋亡的存在。 由于方法学的进步和凋亡的研究深入, 已在多种心脏病中发现心肌细胞凋亡的病理作用。 研究表明, 自 发性高血压小鼠(SHR)心脏损害与凋亡有关;晚期由肥厚心脏转向 心力衰竭为心肌细胞凋亡所致; 急性心梗除坏死外, 梗塞早期和 再灌注损伤也诱发凋亡; 心肌细胞凋亡同样见于移植的心脏和右 室发育不良性心肌病, 缺氧同样诱导心肌细胞凋亡。
凋亡在某种程度上具有可复性,心肌梗死和缺血 /再灌注中的 细胞凋亡有其特点和规律,利用其特点可以预防和减少细胞凋亡, 为临床预防缺血 /再灌注损伤提供启示; 在再灌注过程中, 产生收 缩带区域(梗死灶周围) 的细胞凋亡是由一些诱因诱导产生的, 可以利用凋亡的抑制因素如药物等来预防凋亡, 治疗凋亡引起的 相应疾病。
但目前可供临床应用的用于抗细胞凋亡和保护细胞的药物种 类和数量还很少, 选择性和靶向性都不高, 因此不断研究开发新的 安全有效的抗细胞凋亡和保护细胞的药物,尤其是具有全新作用机 制的药物具有十分重要的意义。 发明内容
为了开发新的安全有效的抗细胞凋亡和保护细胞的药物,发明 人经过长期、 大量的实脸研究, 发现了一类丙烯酰胺类化合物, 其
具有抗细胞凋亡,保护心肌细胞的作用, 能够用于预防或治疗与心 肌细胞凋亡有关的疾病或症状。 具体地,
本发明的第一方面涉及通式 I所示的丙烯酰胺类化合物, 或 其异构体、 可药用盐及溶剂化物。
A代表 =S或- SR4 ;
X代表 F、 Cl、 Br或 I;
代表噻哈基或取代噻吩基, 其中所述的噻吩基、 噻唑基未被 取代或被 1-3个(例如 1-2个、 1个、 2个、 或 3个)独立地选自下 列的取代基取代: 卤素、 硝基、 羟基、 氨基、 氰基、 CI- C6烷基、 C1-C6烷氧基、 和(1 6 ¾代烷基, 并且其中所述的烷基、 垸氧基 和卤代烷基可以任选被羟基、 - 0- (Cl- C4) -烷基、 氧代、 氨基、
-NH- (C1-C4) -烷基、 或- N- [ (C1-C6) -烷基] 2所取代, 或者所述的 烷基、 烷氧基和 代烷基任选被- 0-、 -S -、 - NH -、 - C00-取代;
R2、 R3代表氢、 CI- C6烷基、 C3-C6环烷基、 取代 C3- C6环烷 基、 C1-C6烷氧基 C1-C6烷基、 氨基 C1-C6烷基、 单取代或二取代 氨基 C1-C6烷基、 苯基 C1-C6烷基、 取代苯基 C1-C6烷基、 杂环基 C1-C6烷基、 苯基、 取代苯基、 杂环基或取代杂环基, 其中 R2和 R3 可以合环成饱和环烷烃、 含氮或含氧杂环;
R4代表 C1-C6烷基。
优选如下的通式(I )化合物, 或其异构体、 可药用盐及溶剂 化物, 其中:
A代表 -S或- SR4 ;
代表噻哈基或取代噻吩基;
R2、 R3代表氢、 C1-C6烷基、 C3- C6环烷基、取代 C3-C6环烷基、 C1-C6烷氧基 C1-C6烷基、 氨基 CI- C6烷基、 单取代或二取代氨基 C1-C6烷基、苯基 C1-C6烷基、取代苯基 C1-C6烷基、杂环基 C1-C6 烷基、 苯基、取代苯基、 杂环基或取代杂环基, 其中 R2和 R3可以合 环成饱和环烷烃、 含氮或含氧杂环;
^代表曱基、 乙基、 丙基、 异丙基、 丁基、 戊基。
特别优选如下的通式(I )化合物, 或其异构体、 可药用盐及 溶剂化物, 其中:
A代表 -S或- SR4 ;
代表 2-噻吩基或 3-噻吩基;
R2、 R3代表氢、 甲基、 异丙基、 2-曱氧基乙基、 3-异丙氧基丙 基、 2- N,N-二曱基乙基、 环己基、 环庚基、 邻曱氧基苯基、 邻氟苯 基、 邻氯苯基、 对氯苯基、 苄基或 8-喹啉基, 其中 R2和 R3可以合 环成哌啶环、 吗啉环或 N-曱基哌嗪环;
R4代表甲基。
通式(I )化合物, 或其异构体、 可药用盐及溶剂化物, 特别 优选以下的化合物:
( 1 ) (2E) -3- (2-噻吩基) - N- [l- (8-喹啉基氨基)硫代曱酰氨基 -2, 2, 2 -三氯乙基] -2-丙烯酰胺;
( 2 ) (2E) -3- (3-噻吩基) -N- [1- (8-喹啉基氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 3 ) (2E) - 3- (2-噻吩基) - N- [l- (4-甲苯基氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 4 ) (2E) -3- (2-噻吩基) -N- [1- (2-甲氧基苯氨基)硫代甲酰氨
基- 2, 2, 2-三氯乙基] -2-丙烯酰胺;
(5) (2£)-3-(2-噻吩基) -(1-苄氨基硫代曱酰氨基-2,2,2- 三氯乙基) -2-丙烯酰胺;
(6 ) (2E) -3- (2-噻吩基) -N- (1-环己氨基硫代甲酰氨基
-2, 2, 2-三氯乙基) -2-丙烯酰胺;
( 7 ) (2E) -3- (2-噻吩基) -N- [1-异丙氨基硫代甲酰氨基
-2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 8 ) (2E) -3- (2-噻吩基) -N- [1- (2-氟苯氨基)硫代甲酰氨基 - 2, 2, 2-三氯乙基]- 2-丙烯酰胺;
( 9 ) (2E) -3- (2-噻吩基) -N- [1- (3-异丙氧基丙氨基)硫代甲酰 氨基- 2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 10) (2E)-3-(2-噻哈基) -N-[l-(2-曱氧曱酰基苯氨基)硫代 曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
(11) (2E) -3- (2-噻吩基) -N- (1-环庚氨基硫代甲酰氨基
- 2, 2, 2-三氯乙基) -2-丙烯酰胺;
( 12 ) (2E)-3-(2-噻吩基) [1-(1 -吗啉基)硫代曱酰氨基 -2, 2, 2 -三氯乙基] -2-丙烯酰胺;
( 13) (2E)-3-(2-噻哈基) -N-[l-(4-甲基哌嗪基)硫代甲酰氨 基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
(14) (2E) -3- (2-噻吩基) -N- [1- (8-喹啉基氨基)甲硫代亚甲 氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 15 ) (2E)-3-苯基 -[1-(1-吗啉基)硫代甲酰氨基 - 2, 2, 2-三氯 乙基] -2-丙烯酰胺;
( 16 ) (2E)- 3-苯基 -[1-(1-哌啶基)硫代曱酰氨基 -2, 2, 2-三氯 乙基] -2-丙烯酰胺;
( 17 ) (2E)- 3-苯基- [1- (3-曱氧基苄基)硫代甲酰氨基 -2, 2, 2-
三氯乙基] -2-丙烯酰胺。
以化合物 6的合成为例,本发明化合物以 2-噻吩甲醛为起始原 料, 与丙二酸在吡啶为溶剂哌啶催化的条件下反应生成化合物 2, 再经过氯化亚砜制备酰氯, 滴入浓氨水中得到化合物 3, 将 3与三 氯乙醛水合物在甲苯中回流制得化合物 4, 然后经过氯化再与硫氰 酸钾反应制得异硫氰酸酯 5,最后与 8-氨基喹啉回流得到化合物 6。
本发明的另一方面涉及药物组合物, 其包含通式( I ) 所示 化合物或其异构体、 它们的盐或溶剂化物, 以及药学上可接受的载 体、 赋形剂或稀释剂。
本发明还涉及第一方面所述通式( I )化合物或其异构体、 可 药用盐及溶剂化物,用于制备抗细胞凋亡,预防或治疗与细胞凋亡 有关的疾病或症状的药物的用途。
本发明还涉及第一方面所述通式( I )化合物或其异构体、 可 药用盐及溶剂化物,用于制备保护心肌细胞和预防或治疗与心肌细 胞凋亡有关的疾病或症状的药物的用途。
本发明还涉及一种抗细胞凋亡、 预防或治疗与细胞凋亡有关 的疾病或症状的方法, 所述方法包括向有此需要的受试者给予治 疗有效量的本发明第一方面所述通式 ( I )化合物或其异构体, 可药用盐及溶剂化物。
本发明还涉及一种保护心肌细胞、 预防或治疗与心肌细胞凋 亡有关的疾病或症状的方法, 所述方法包括向有此需要的受试者 给予治疗有效量的本发明第一方面所述通式 ( I )化合物或其异 构体, 可药用盐及溶剂化物。
本发明所述与细胞凋亡有关的疾病或症状包括:心血管疾病, 神经退行性疾病, 多发性硬化症, 病毒性感染等。
本发明所述与心肌细胞凋亡有关的疾病或症状包括但不限于
( i )饥饿性心肌萎缩, ( i i )心肌炎, ( i i i )心力衰竭, ( iv ) 原发性高血压引起的心肌损伤, (V)急性心梗早期引起的心肌损 伤, (vi )急性心梗再灌注引起的心肌损伤, (vi i)心脏移植引起 的心肌细胞病变, (vi i i)发育不良性心肌病; 或缺氧引起的心肌 细胞凋亡, 或心血管系统硬化。
根据本发明, 术语 "杂环" 包括但不限于: 吡啶、 吡咯、 呋 喃、 噻吩、 吡唑、 咪唑、 噻唑、 唑、 异唑、 吲哚、 苯并呋喃、 苯 并咪唑、 咔唑、 哒嗪、 嘧啶、 吡嗪、 喹啉、 异喹啉、 嘌呤、 吩噻 、 吩嗪。
本领域技术人员应该认识到通式 I化合物存在手性中心。 当 需要通式 I化合物为单一的对映体时, 可以使用在所有可能的步 骤中均处于单一对映异构体形式的反应物来制备, 或者在单一对 映异构体形式的试剂或催化剂的存在下进行反应来制备, 或者通 过常规方法拆分立体异构体混合物来制备。 一些优选的方法包括 使用微生物进行拆分, 拆分与手性酸如扁桃酸、 樟脑磺酸、 酒石
酸、 乳酸等任何可使用的酸形成的非对映异构体的盐, 或者拆分 与手性碱如番木鳖碱(brac ine)、金鸡纳树生物碱及其衍生物等形 成的非对映异构体的盐。 常用的方法见 Jaques 等人编辑的 "Enant iomers , Racemates and Reso lut ion" (Wi ley Intersc ience, 1981)。
本领域技术人员应该意识到, 本发明化合物也可以以其可药 用盐或溶剂化物的形式使用。 通式 I化合物的生理学上可接受的 盐包括由药学上可接受的无机酸或有机酸或者无机碱或有机碱形 成的常规的盐以及季铵的酸加成盐。 合适的酸盐的更具体的例子 包括盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸、 高氯酸、 富马酸、 乙酸、 丙酸、 琥珀酸、 羟基乙酸、 曱酸、 乳酸、 马来酸、 酒石酸、 柠檬 酸、 朴酸、 丙二酸、 羟基马来酸、 苯乙酸、 谷氨酸、 苯曱酸、 水 杨酸、 富马酸、 曱苯磺酸、 甲磺酸、 萘 -2-磺酸、 苯磺酸、 羟基萘 曱酸、 氢碘酸、 苹果酸、 s teroic、 鞣酸等的盐。 其它的酸, 如草 酸, 虽然其本身并非药学上可接受的, 但可以用于制备用作中间 体的盐, 以获得本发明化合物及其可药用盐。 合适的碱盐的更具 体的例子包括钠、 锂、 钾、 镁、 铝、 钙、 锌、 N,N,-二苄基乙二胺、 氯代普鲁卡因、 胆碱、 二乙醇胺、 乙二胺、 N-甲基葡糖胺和普鲁 卡因盐。 此后涉及到本发明的化合物时, 包括通式 I化合物及其 可药用盐和溶剂化物。
本发明还包括本发明化合物的前药, 该前药一经给药, 即通 过代谢过程进行化学转化, 之后变成具有活性的药物。 通常, 这 类前药是本发明化合物的功能性衍生物, 其在体内容易转化成所 需的式(I)的化合物。 例如, 在" Des ign Of Prodrugs", H Bund Saard, El sevier编辑, 1985中描述了选择和制备适宜前药衍生 物的常规方法。
本发明也包括本发明化合物的活性代谢物。
本发明的另一个方面涉及药物组合物, 其含有本发明化合物 的消旋体或旋光异构体和至少一种药学上可接受的载体, 其可用 于体内治疗并具有生物相容性。 所述药物组合物可以根据不同给 药途径而制备成各种形式。 本发明所提及的化合物也可以被制备 成各种药学可接受的盐。
本发明的药物组合物包括有效剂量的本发明通式 I化合物或 其可药用盐或水合物和一种或多种适宜的可药用载体。 这里的药 用载体包括但不限于: 离子交换剂, 氧化铝, 硬脂酸铝, 卵磷脂, 血清蛋白如人血白蛋白, 緩冲物质如磷酸盐, 甘油, 山梨酸, 山 梨酸钾, 饱和植物脂肪酸的部分甘油酯混合物, 水, 盐或电解质, 如硫酸鱼精蛋白, 磷酸氢二钠, 磷酸氢钾, 氯化钠, 锌盐, 胶态 二氧化硅, 三硅酸镁, 聚乙烯吡咯烷酮, 纤维素物质, 聚乙二醇, 羧甲基纤维素钠, 聚丙烯酸酯, 蜂蜡, 羊毛脂。
本发明化合物的药物组合物可以以下面的任意方式施用: 口 服, 喷雾吸入, 直肠用药, 鼻腔用药, 颊部用药, 局部用药, 非 肠道用药, 如皮下、 静脉、 肌内、 腹膜内、 鞘内、 心室内、 胸骨 内和颅内注射或输入, 或借助一种外植储器用药。其中优选口服、 腹膜内或静脉内给药方式。
当口服用药时,本发明化合物可制成任意口服可接受的制剂 形式,包括但不限于片剂、 胶袭、 水溶液或水悬浮液。 其中, 片剂 使用的载体一般包括乳糖和玉米淀粉, 另外也可加入润滑剂如硬 脂酸镁。 胶嚢制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。 水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合 使用。 如果需要, 以上口服制剂形式中还可加入一些甜味剂、 芳 香剂或着色剂。
当局部用药时,特别是治疗局部外敷容易达到的患面或器官, 如眼睛、 皮肤或下肠道神经性疾病时, 可根据不同的患面或器官 将本发明化合物制成不同的局部用药制剂形式, 具体说明如下: 当眼部局部施用时, 本发明化合物可配制成一种微粉化悬浮 液或溶液的制剂形式, 所使用载体为等渗的一定 pH的无菌盐水, 其中可加入也可不加防腐剂如氯化苄基烷醇盐。 对于眼用, 也可 将化合物制成骨剂形式如凡士林膏。
当皮肤局部施用时, 本发明化合物可制成适当的软膏、 洗剂 或霜剂制剂形式, 其中将活性成分悬浮或溶解于一种或多种载体 中。 软膏制剂可使用的载体包括但不限于: 矿物油, 液体凡士林, 白凡士林, 丙二醇, 聚氧化乙烯, 聚氧化丙烯, 乳化蜡和水; 洗 剂或霜剂可使用的载体包括但不限于: 矿物油, 脱水山梨糖醇单 硬脂酸酯, 吐温 60, 十六烷酯蜡, 十六碳烯芳醇, 2-辛基十二烷 醇, 苄醇和水。
本发明化合物还可以无菌注射制剂形式用药, 包括无菌注射 水或油悬浮液或无菌注射溶液。 其中, 可使用的载体和溶剂包括 水、 林格氏溶液和等渗氯化钠溶液。 另外, 灭菌的非挥发油也可 用作溶剂或悬浮介质, 如单甘油酯或二甘油酯。
另外需要指出, 本发明化合物的使用剂量和使用方法取决于 诸多因素, 包括患者的年龄、 体重、 性别、 自然健康状况、 营养 状况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程 度以及诊治医师的主观判断。 发明的有益效果
本发明提供了一种丙烯酰胺类化合物, 并证明其具有抗细胞 凋亡和保护细胞的作用, 为治疗细胞凋亡引起的疾病或症状, 特
别是治疗心肌细胞凋亡引起的疾病或症状提供了新的方法和途 径。 具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述, 但是 本领域技术人员将会理解, 下列实施例仅用于说明本发明, 而不 应视为限定本发明的范围。 实施例中未注明具体条件者, 按照常 规条件或制造商建议的条件进行。 所用试剂或仪器未注明生产厂 商者, 均为可以通过市购获得的常规产品。
化合物的熔点由 RY-1 熔点仪测定, 温度计未较正。 质谱由 Micromas s ZabSpec 高分辨率质谱仪 (分辨率 1000 )测定。 ^ NMR 由 JNM-ECA-400超导 NMR仪测定,工作频率 !H NMR 400MHz , 13C NMR 100MHz。 实 施 例 1 (2E) -3- (2-噻吩基) - N- [1- (8-喹啉基氨基)硫代 甲酰氨基 -2, 2, 2-三氯
将 1. 12g 2-噻吩曱醛和 3. 12g丙二酸溶于 15ml吡啶, 加入催 化量哌啶, 80 下反应 6小时, 反应液倒入 20ml水中, 10%NaOH 水溶液调节 PH12 , 乙酸乙酯萃取, 取水层用 2N盐酸调节至 PH3,析 出大量黄色固体(2E) - 3- (2-噻吩基)丙烯酸,过滤水洗得 1. 12g。将 (2E) -3- (2-噻吩基)丙烯酸溶于 10ml无水二氯甲烷中,加入催化量 DMF, 冰水浴下滴入 1. 5ml草酰氯, 滴毕升温至室温搅拌 2小时, 反应液滴入 O Oml浓氨水中, 搅拌 30min, 分液取二氯甲烷层蒸 除溶剂得白色针状晶体(2E) -3- (2-噻吩基)丙烯酰胺 0. 7g。 将其与
1. 20g三氯乙醛水合物加入 30ml曱苯中 110 回流 8小时,冷却至 室温析出大量黄色片状晶体 (2E) -3- (2-噻哈基) -N- (1-羟基-2, 2 , 2-三氯乙基)丙烯酰胺 1. 20g。将其溶于 20ml无水 THF中,加入 DMF 催化, 室温下滴入 S0Cl21. 2ml, 加热至 60 反应 2小时.蒸千溶剂 后用无水丙酮溶解,加入 0. 3gKSCN, 40Ό搅拌 2小时,硅藻土过滤, 滤液用展开剂系统为石油醚: 乙酸乙酯 =20: 1洗脱, 得到黄色针状 晶体(2E) -3- (2-噻吩基) -N- (l-异硫氰酸基 -2, 2, 2-三氯乙基)丙 烯酰胺 0. 81g。 将其溶于 lOmlTHF中, 加入 0. 30g 8-氨基喹啉加热 至 60 反应 2小时,冷却至室温析出大量白色絮状固体(2E) -3- (2- 噻吩基) -N- [l- (8-喹啉基氨基)硫代 -2, 2, 2-三氯乙 基] -2-丙烯酰胺, 用 0. 92g。
'H-NMR (400MHz, DMSO- ) δ 6. 63-6. 67 (d, 1Η δ 7. 12-7. 14 (q, 1Η); δ 7. 42-7. 43 (d, 1Η); δ 7. 53-7. 73 (m, 6Η); δ 8. 42-8. 44 (dd, 1H); δ 8. 95-9. 03 (m, 3H); δ 9. 54-9. 56 (d, 1Η); δ 11. 03 (s, 1Η)。 MS (TOF) 487. 0 (M+)。 实 施 例 2 (2E) -3- (3—噻吩基)— N- [1- (8-喹啉基氨基)硫代曱 酰氨基 -2, 2, 2 -三氯乙基] - 2-丙烯酰胺
采用实施例 1 的方法,将其中的 2-噻吩甲醛改为 3-噻吩甲醛, 得黄色固体 0. 60g。 'H-NMR (400MHz, DMSO-i6) δ 6. 67-6. 71 (d, 1H); δ 7. 35-7. 36 (d, 1Η); δ 7. 54-7. 72 (m, 6Η); δ 7. 87-7. 88 (d, 1H); δ 8. 42-8. 44 (dd, 1H); δ 8. 96-9. 03 (m, 3H); δ 9. 54-9. 56 (d, 1Η); δ 11. 05 (s,lH)。 MS (TOF) 487. 0 (M+)。
实 施 例 3 (2E)-3-(2-噻吩基) -N-[l-(4-曱苯基氨基)硫代曱 酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺 '
釆用实施例 1 的方法,将其中的 8-氨基喹啉改为 4-曱基苯胺, 得黄色固体 60mg。 ^-NMR (400MHz, DMS0-i¾) 62.28 (s,3H); δ
6.47-6.51(d, 1H); δ 7.13-7.18 (m, 3H) ; 57.36-7.45 (m, 4H); δ
7.66-7.72 (m, 2H); δ 8.03 (, 1H); δ 8.96-8.98 (d, 1Η); δ
采用实施例 1 的方法, 将其中的 8-氨基喹淋改为 2-甲氧基苯 胺, 得黄色固体 0.23g。 'H-NMR (400MHz,DMSO-i6) δ 3.83 (s, 3Η); δ 6.52-6.56 (d, 1H); δ 6.90-7.14 (m, 4H); δ 7.41-7.45 (m, 2Η); δ 7.65-7.72 (m, 2H); δ 7.90-7.92 (d, 1Η); 68.48 (s, 1H); δ
9.00-9.02 (d,lH); δ9.80(s,lH)。 MS (TOF) 464.0 (M+)。 实 施 例 5 (2E)-3-(2-噻吩基) -N-(l-苄氨基硫代甲酰氨基 -2, 2, 2-三氯乙基) -2-
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为苄胺, 得黄
色固体 0. 12g。 !H-NMR (400MHz, DMS0-i 6) δ 4. 68-4. 69 (d,.2H) ; δ
6. 52-6. 56 (d, IH); δ 6. 52-6. 56 (d, IH); δ 7. 11-7. 14 (dd, IH); δ
7. 31-7. 43 (m, 7H); δ 7. 64-7. 71 (m, 2H); δ 8, 00-8. 03 (d, 1Η); δ
8. 61-8. 63 (t,lH) ; 5 8. 94-8. 96 (d,lH)。 MS (TOF) 447. 9 (M+)。 实 施 例 6 (2E) -3- (2-噻吩基) - N- (1-环己氨基硫代曱酰氨基 -2, 2, 2-三氯乙基) -2-
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为环己基胺, 得黄色固体 0. 22g。 ^-NMR (400MHz, DMSO-cO δ 1. 14-1. 31 (m, 5H); δ 1. 51-1. 64 (m, 3Η); δ 1. 88 (η, 2Η); δ 3. 97-3. 99 (, 1Η); δ
6. 51-6. 55 (d, 1Η); δ 7. 12-7. 14 (dd, 1Η); δ 7. 30-7. 43 (m, 2Η); δ
7. 65-7. 83 (m, 3H); δ 8. 17-8. 19 (d, 1Η); δ 8. 91-8. 93 (d, IH)。
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为异丙胺, 得 黄色固体 0. 29g。 ^-NMR (400MHz, DMSO-^) δ 1. 11-1. 13 (m, 6H) ; δ 4. 21-4. 24 (dd, 1Η); δ 6. 51-6. 55 (d, 1Η); δ 7. 12-7. 14 (dd, 1Η); δ 7. 30-7. 43 (m, 2H) ; δ 7. 65-7. 76 (m, 3Η) ; δ 8. 15-8. 17 (d, 1H) ; δ 8. 91-8. 93 (d,lH)。 MS (TOF) 401. 9 (M+)。
实 施 例 8 (2E) -3- (2 -噻吩基) -N- [1- (2-氟苯氨基)硫代甲酰 氨基 -2, 2, 2-三氯乙基] -2
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为 2-氟苯胺, 得黄色固体 0. 30g。 'H-NMR (400MHz, DMSO-^) δ 6. 52-6. 56 (d, IH); δ 7. 12-7. 29 (m, 4H); δ 7. 39-7. 45 (m, 2Η); δ 7. 66-7. 73 (m, 2H); δ 7. 86-7. 90 (t, IH); δ 8. 52-8. 54 (d, 1Η); δ 904-9. 06 (d, IH)。
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为 3-异丙氧基 正丙胺, 得黄色固体 0. 20g。 'H-NMR (400MHz, DMSO-^) δ
1. 06-1. 08 (d, 6H); δ 1. 68-1. 71 (t, 2Η); δ 3. 31-3. 51 (m, 4H); δ
6. 52-6. 55 (d, 1H) ; δ 7. 11-7. 13 (dd, IH) ; δ 7. 31-7. 43 (m, 2H) ; δ
7. 64-7. 70 (m, 2H); δ 7. 86-7. 88 (d, 1Η); δ 8. 20-8. 22 (t, 1Η); δ
8. 88-8. 90 (d,lH)。 MS (TOF) 458. 0 (M+)。 实 施 例 10 (2E) -3- (2-噻吩基) -N- [1- (2-曱氧曱酰基苯氨基) 硫代曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为 2-甲氧甲酰 基苯胺, 得紫白色固体 0. 36g。 'H-NMR (400MHz, DMSO-cTj δ
3. 79-3. 80 (s, 3H); δ 6. 59-6. 62 (d, 1Η); δ 7. 12-7. 14 (dd, 1Η); δ 7. 28-7. 32 (m, 1Η); δ 7. 42-7. 46 (m, 2Η); δ 7. 55-7. 59 (m, IH); δ
7. 65-7. 72 (m, 2H); δ 7. 77—7. 79 (d, 1Η) δ 7. 84-7. 86 (dd, IH); δ
8. 88—9. 01 (m, 2H)。 MS (TOF) 492. 0 (M+)。 实 施 例 11 (2E) -3- (2-噻吩基) - N- (l-环庚氨基硫代曱酰氨 基- 2, 2, 2-三氯乙基) -2-丙烯酰胺
采用实施例 1 的方法, 将其中的 8-氨基喹啉改为环庚基胺, 得白色固体 0. 18g。 ^-NMR (400MHz, DMSO-i/e) δ 1. 43-1. 53 (m, 11H); δ 1. 87-1. 90 (m, 2H) ; δ 4. 19 (s, 1Η); δ 6. 51-6. 55 (d, 1Η); δ
7. 11-7. 13 (dd, 1Η); δ 7. 30-7. 35 (t, 1Η); δ 7. 42 (d, 1Η); δ
7. 64-7. 78 (m, 3Η); δ 8. 20-8. 22 (d, IH); δ 8. 87-8. 90 (d, 2H)。
釆用实施例 1 的方法, 将其中的 8-氨基喹淋改为吗啉, 得白
色固体 0. 15g 0 ^-NMR (400MHz, DMS0-i 6) δ 3. 61-3. 64 (m, 4H) ; δ
3. 83 (m, 4H) ; δ 6. 78-6. 82 (d, 1H) ; δ 7. 40-7. 45 (m, 3H) ; δ
7. 52-7. 45 (m, 4H) ; δ 7. 89-7. 91 (d, 1H) ; δ 8. 34-8. 36 (d, 1H) 。 MS (TOF) 421. 9 (M+)。 实 施 例 13 (2E) -3- (2-噻吩基) -N- [1- (4-甲基哌嗪基)硫代 甲酰氨基 -2, 2, 2-三氯乙 ] -2-丙烯酰胺
采用实施例 1 的方法,将其中的 8-氨基喹啉改为 N-甲基哌嗪, 得白色固体 0. 17g。 ^-NMR (400MHz, DMS0-i 6) δ 2. 18 (s, 3H) ; δ 2. 31-2. 40 (m, 4H) ; δ 3. 78-3. 83 (m, 4Η) ; δ 6. 76-6. 80 (d, 1Η); δ 7. 41-7. 45 (m, 3H) ; δ 7. 52-7. 60 (m, 2Η) ; δ 7. 65-7. 67 (m, 2Η); δ 7. 83-7. 85 (d,lH) ; δ 8. 32-8. 35 (d,lH)。 MS (TOF) 435. 3 (M+)。 实 施 例 14 (2E) -3- (2—噻吩基) -N- [1- (8-喹啉基氨基)甲硫 代亚甲氨基 -2, 2, 2-三氯乙 -2-丙烯酰胺
采用 实施例 1 的方法, 将实施例 1 (2Ε) -3- (2-噻吩 基) -N- [1- (8-喹啉基氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] -2 -丙 烯酰胺 2. 0g加入 5ml水,形成混悬液,加入 0. 5ml50%NaOH水溶液, 搅拌 10min, 加入 0. 54ml礁甲烷, 室温反应 2小时, 乙醚萃取, 饱 和食盐水洗, 无水硫酸锬干燥, 溶剂蒸干得白色固体(2E) -3- (2-噻
吩基) -N-[l-(8-喹啉基氨基)曱硫代亚甲氨基 -2, 2, 2-三氯乙 基] -2-丙烯酰胺 1.30g。 ^-NMR (400MHz, DMS0-c 62.79(s, 3H); δ
6.26-6.28 (d, IH); δ 6.86-6.90 (d, IH); δ 7.40-7.43 (m, 3H) ; δ
7.53-7.64 (m, 6H); δ 8.43-8.45 (dd, IH); δ 8.92-8.97 (m, 3H); δ 9.59(s,lH)。 MS(TOF) 501.1 (M+)。 实 施 例 15 (2E)- 3-苯基- [1-(1-吗啉基硫代甲酰氨 基) -2, 2, 2 -三氯乙基] -2 -丙烯酰胺
釆用实施例 1 的方法, 将其中的 2-噻吩曱醛改为苯曱醛, 8- 氨基喹啉改为吗啉, 得白色固体 0.19g0 ^-NMR (400MHz, DMSO-^) δ 3.61-3.64 (m, 4H); δ 3.79-3.83 (m, 4Η); δ 6.78-6.82 (d, IH); δ 7.41-7.46 (m, 3H) ; δ 7.52-7.61(m,2H); δ 7.64-7.67 (dd, 1H); δ 7.89-7.91(d,lH); δ 8.34-8.36 (d, lH)。 MS (TOF) 422.7 (M+)。 实 施 例 16 (2E)-3-苯基- [1- (1-哌啶基硫代曱酰氨 基) -2, 2, 2-三氯乙基]- 2-丙烯酰胺
釆用实施例 1 的方法, 将其中的 2-噻吩甲醛改为苯曱醛, 8- 氨基喹啉改为哌啶, 得白色固体 0.15g。 -NMR (400MHz, DMSO- ) δ 1.53-1.62 (m, 6H); δ 3.81-3.82 (t, 4Η); δ 6.74-6.78 (d, IH); δ 7.41-7.46 (m, 3H); δ 7.52-7.71 (m, 5Η); δ 8.36-8.38 (d, IH); δ
9.59(s,lH)。 MS(TOF) 420.7 (M+) 实 施 例 17 i2E)- 3-苯基- [l-(3-甲氧基苄基)硫代甲酰氨 -2, 2, 2-三氯乙基] -2-丙烯酰胺
采用实施例 1 的方法, 将其中的 2-噻吩甲醛改为苯曱醛, 8- 氨基喹啉改为对 甲氧基苄胺, 得 白 色 固体 0.17g 。 ^-NMR (400MHz, DMS0-if6) δ 3.72 (s, 3H) ; δ 4.58-4.60 (d, 2H); δ
6.77-6.81 (d, 1Η); 6.90-6.92 (d, 2H); δ 7.24-7.26 (d, 2Η); δ
7.36-7.46 (m, 4H); δ 7.52-7.60 (m, 3H) ; δ 7.96-7.98 (d, 1H); δ
8.55 (t, 1H); δ 8.97-8.99 (d, 1H)。 MS (TOF) 472.8 (M+)。 实 施 例 18 化合物保护心肌细胞活性实验
心肌细胞原代培养
心肌细胞的分离和培养参照差速贴壁分离的方法(Kreider, A. Messing, H. Doan, S. U. Kim, R. P. Lisak and D. E. Pleasure, Enrichment of Schwann cell cultures from neonatal rat sciatic nerve by differential adhesion, Brain Res 2 (1981) , pp. 433 444. ) , 取 24h内新生的 Wistar乳鼠, 经碘酒酒精消毒胸腹部 皮肤, 用剪刀在剑突下正中线稍偏左开胸, 斜开胸取出心脏置于冰 预冷 PBS中;用 0.01M 的 PBS轻轻吹打心脏去除血液细胞和其他组 织,将心脏剪成 0.5mm3大小的碎块,用 0.01M PBS反复冲洗 2-3次; 将碎块置于雉形瓶中,加入 4ml 0.125%胰酶, lml 0.1%胶原酶 Π (终 浓度分别为 0.1%和 0.02%) 37Ό水浴震荡 10min, 弃上清; 再次加
入 4ml 0.125%胰酶, lml 0.1%胶原酶 Π, 37 水浴震荡消化 lOmin, 吸取上清移至离心管, 将上清加入含 10°/D FBS的 DMEM终止消化; 重复水浴震荡消化步骤 3-4次, 直至组织块完全消化为止; 将收集 的细胞悬液以 lOOOrpm离心 lOmin后, 去上清, 再加培养基重悬; 将重悬的细胞接种到细胞培养瓶中, 置于 37 C02孵箱中孵育 1.5h后将培养液吸出,在显微镜下计数后,用含 10% FBS的 DMEM培 养液调整细胞密度,按 1 X 104接种到 96孔板, 置于 37Ό 5%C02孵 箱中 24h后半量换液, 补加含 0.1% Brdu的培养基; 之后每 48h后 换液 1次, 培养 4天后即可获得原代心肌细胞。 细胞抑制率 (MTT )测定
将分离的原代培养心肌细胞按照每孔 104个细胞接种到 96孔 板, 每孔体积 lOOul (边缘孔用无菌 PBS填充) 。 在 5%C02, 37 。C孵箱培养 4d后,分别加入不同浓度的通式 I化合物( 0.3 μ M、 1 μΜ、 3μΜ、 10μΜ、 30μΜ、 100 μ Μ ) , 每个浓度设置 3个复孔, 同时设置调零孔(培养液、 MTT、 DMS0 ),对照孔(培养液、 DMS0 )。 继续孵育处理 48 h后, 每孔加入 20ulMTT溶液(5mg/ml, 用 PBS ( pH=7.4 ) 配即 0· 5%ΜΤΤ) , 继续培养 4h。 终止培养, 小心吸去 孔内培养液。 每孔加入 150ulDMSO, 置摇床上低速振荡 lOmin, 使 结晶物充分溶解。 在酶联免疫检测仪于波长 550nm处测定各孔吸 光度(0D)值, 每孔重复 5次并记录结果。 结果见表 1。
MTT法检测不同浓度化合物对心肌细胞抑制率的影响
结果表明: 实施例中所述化合物在 300 μΜ浓度内对正常心肌 细胞的存活率没有影响。 保护心肌细胞活性测定 -保护由 TG诱导的心肌细胞凋亡活性 心肌细胞按照上述方法原代培养 4天开始加毒胡萝卜内酯
( thapsigargin, TG)诱导细胞凋亡, 在诱导细胞凋亡前 30min加 本发明化合物进行预处理。 细胞随机分成 5组: (1)溶剂对照组 ( DMSO ) ; (2) TG干预组( 0.4uM) ; ( 3 ) TG ( 0.4uM) +化合物 干预组( 0.3uM ); ( 4 ) TG ( 0.4uM ) +化合物干预组( luM ); (5) TG ( 0.4uM ) +化合物干预组( 3uM )。 TG用 DMSO配制, 母液为 4mM, 本发明化合物用 DMSO配制,母液为 150mM。按照上述 MTT法测定细 胞存活率, 从而测定本发明化合物对 TG诱导心肌细胞凋亡的保护
作用, 结果见表 2。
表 2 MTT法检测不同浓度化合物对 TG i秀导的心肌细胞存活率的 影响
注: 细胞存活率 =1-细胞抑制率
实验结果: 与单加入 TG组相比, 在同时加入 TG和实施例化合
物时, 心肌细胞存活率有明显提高, 表明表 2中所述实施例化合物 能够明显改善 TG引起的细胞凋亡作用,对心肌细胞具有保护作用。 实施例 19 式 I化合物对缺氧诱导心肌细胞凋亡的保护作用 溶液准备 (下述试剂可购于 Invi trogen公司)
1、 1 X Wash Buffer: 把 20mL的 10 χ Wash Buffer加到 180mL 超纯水中, 4 环境保存 7天。
2、 固定液: 把 7. 3mL37%的曱醛溶液加到 14. 7 mL的 1 x Wash Buffer中, 使用前预热到 37Ό。 此溶液现用现配。
3、 1 X透膜液: 把 ¼L的 10 X透膜液加到 36mL的超纯水中, 把此应用液在 4。C保存 7天。
4、 Mi totracker/Hoechs t溶液(-20 保存) : 用 94uL的无 水 DMS0溶解 Mi totracker CMXR0S制成 ImM的溶液,此溶液能在 -20 干燥避光的条件下保存 6个月。 为避免多次冻融循环, 进行单次 使用量的分装。把 5. 5uLlmM的 Mi totracker Red Solut ion 和 lluL 的 Hoechs t染料加到细胞培养基中,得到最终体积为 5. 5mL的应用 液。 此应用液现用现配。
5、 Alexa Fluor 488 Phal loidin溶液:用 140 甲醇把 Alexa Fluor 488 Phal loidin溶解制成母液, 此溶液能在 -20 Ό干燥避光 的条件下保存 12个月。把 27. 5 μ L的 Alexa Fluor 488 Phal loidin 母液加到 5. 5mL的 1 χ Wash Buffer中制成应用液。 此应用液现用 现配。 实猃方法: 按照实施例 18所述方法原代培养的心肌细胞, 细 胞密度 104个 /mL, 每孔加入 l OOuL此细胞悬液。 在 37 、 5%C02环 境孵育细胞 96小时 (每 48h换一次液) 。 原代培养 4天后放到缺
氧孵箱诱导细胞凋亡,在诱导细胞凋亡前 30min加入不同浓度的本 发明化合物进行预处理, 放入 37 、 5%C02- 95%N2孵箱培养 15. 5h。 在完成化合物孵育前 30分钟, 加入 50uL的培养基, 50uL的
Mi totracker/Hoechs t溶液, 37 ;、 5% C02-95%N2继续孵育细胞
30mino
每孔直接加入 lOOuL的固定液, 而不吸去培养基, 通风橱室温 孵育 10min。 预热的固定液对于保持细胞完整性特别重要。
吸去每孔溶液(可以扣板) , 用 l x Wash Buffer ( l OOuL/孔) 洗一次。操作和洗涤过程中要特别小心,以保持细胞贴附和完整性。 慢速的吸放液体会产生很好的结果。 吸去 Wash Buffer, 加入 1 χ 透膜液(l OOuL/孔) 室温孵育 15min。 吸去透膜液, 每孔用 100 μ L/孑 L的 1 X Wash Buffer洗一次。 吸去 Wash Buffer, 每孑 L加人 50uL Alexa Fluor 488 Phal loidin Solut ion溶液,室温避光孵育 30min。 吸去 Alexa Fluor 488 Phal loidin溶液, 用 l x Wash Buffer洗三 次, 把最后一次的溶液留在孔中。 用封口膜把板子边缘包上(防止 干燥) , 用 HCS Reader检测。 环境保存板子。 最后用荧光染色 检测心肌细胞凋亡程度, 结果见表 3、 表 4和表 5。
此分析方法为高内涵筛选分析法。它是近年来新出现的一种凋 亡检测方法, 通过特定的荧光染色对凋亡同时进行多因素分析。 主要分析与凋亡过程相关的三个参数: 包括核形态学改变, 线粒 体肿胀和或线粒体膜电位, F-肌动蛋白含量。 HCS Reader能通过 Hoechs t染色对细胞核的形态学进行观测, 并对细胞核面积和核 强度进行定量比较。 线粒体膜电位的下降和线粒体体积的增加, 已经被公认为是细胞凋亡早期的标志物, 可通过线粒体示踪剂 Mi toTracker® Red来进行定量。
表 3 核面积检测结果:
Claims
A i^=S ^S ;
X代表 F、 Cl、 Br或 I;
代表噻吩基或取代噻吩基, 其中所述的噻吩基、 噻唑基未被 取代或被 1-3个(例如 1-2个、 1个、 2个、 或 3个)独立地选自下 列的取代基取代: 卤素、 硝基、 羟基、 氨基、 氰基、 C1-C6烷基、 C1-C6烷氧基、 和 C1-C6面代烷基, 并且其中所述的烷基、 烷氧基 和卤代烷基可以任选被羟基、 -0- (C1-C4) -烷基、 氧代、 氨基、 -NH- (C1-C4) -烷基、 或 -N- [ (C1-C6) -烷基] 2所取代, 或者所述的 烷基、 烷氧基和 代烷基任选被 -0-、 -S -、 -NH -、 -C00-取代;
R2、 R3代表氢、 C1-C6烷基、 C3- C6环烷基、 取代 C3-C6环烷 基、 C1-C6烷氧基 C1-C6烷基、 氨基 C1-C6烷基、 单取代或二取代 氨基 C1-C6烷基、 苯基 C1-C6烷基、 取代苯基 C1-C6烷基、 杂环基 C1-C6烷基、 苯基、 取代苯基、 杂环基或取代杂环基, 其中 R2和 R3 可以合环成饱和环烷烃、 含氮或含氧杂环;
R4代表 C1-C6烷基。
2. 通式 I化合物, 或其异构体、 可药用盐及溶剂化物, 其中: A代表 =S或和- SR4 ;
X代表 F、 Cl、 Br或 I; Ri代表噻吩基或取代噻吩基;
R2、 R3代表氢、 C1-C6烷基、 C3-C6环烷基、取代 C3-C6环烷基、 C1-C6烷氧基 CI- C6烷基、 氨基 C1-C6烷基、 单取代或二取代氨基 C1-C6烷基、苯基 C1-C6烷基、取代苯基 C1-C6烷基、杂环基 C1-C6 烷基、 苯基、取代苯基、 杂环基或取代杂环基, 其中 112和113可以合 环成饱和环烷烃、 含氮或含氧杂环;
R4代表甲基、 乙基、 丙基、 异丙基、 丁基、 戊基。
3. 通式 I化合物, 或其异构体、 可药用盐及溶剂化物, 其中: A代表 =S或- SR4 ;
X代表 C1;
代表 2-噻吩基或 3-噻吩基;
R2、 R3代表氢、 曱基、 异丙基、 2-甲氧基乙基、 3-异丙氧基丙基、 2-N, N-二甲基乙基、 环己基、 环庚基、 邻甲氧基苯基、 邻氟苯基、 邻氯苯基、 对氯苯基、 苄基或 8-喹啉基, 其中 R2和 R3可以合环成 哌啶环、 吗啉环、 N-甲基哌臻环;
R4代表曱基、 乙基。
4. 具有下述结构的权利要求 1的化合物, 或其异构体、可药用 盐及溶剂化物, :
( 1 ) (2E) -3- (2-噻吩基) -N- [l- (8-喹啉基氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] - 2-雨烯酰胺;
( 2 ) (2E) -3- (3-噻吩基) -N- [1- (8-喹啉基氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 3 ) (2E) -3- (2-噻吩基) -N- [l- (4-甲苯氨基)硫代甲酰氨基 -2, 2, 2-三氯乙基] - 2-丙烯酰胺; ( 4 ) (2E) -3- (2-噻吩基) -N- [1- (2-曱氧基苯氨基)硫代甲酰氨 基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 5 ) (2E)-3-(2-噻吩基) -N-(l-苄氨基硫代曱酰氨基 - 2, 2, 2- 三氯乙基) -2-丙烯酰胺;
( 6 ) (2E) -3- (2-噻吩基) -N- (1-环己氨基硫代甲酰氨基
-2, 2, 2-三氯乙基)- 2-丙烯酰胺;
( 7 ) (2E)— 3-(2-噻吩基) -[1-异丙氨基硫代甲酰氨基
-2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 8 ) (2E)-3-(2-噻吩基) -N-[l-(2-氟苯氨基)硫代曱酰氨基 -2, 2, 2-三氯乙基] -2 -丙烯酰胺;
( ) (2E) -3- (2-噻吩基) -N- [1- (3-异丙氧基丙氨基)硫代曱酰 氨基- 2, 2, 2-三氯乙基]- 2-丙烯酰胺;
(10) (2E) -3- (2-噻哈基) -N- [1- (2-甲氧甲酰基苯氨基)硫代 曱酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
(11) (2E) -3- (2 -噻吩基) -N- (1-环庚氨基硫代曱酰氨基
-2, 2, 2 -三氯乙基) -2-丙烯酰胺;
(12) (2E) -3- (2-噻吩基) -N- [1- (1-吗啉基)硫代甲酰氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
(13) (2E)-3-(2-噻吩基) -N-[l-(4-甲基哌嗪基)硫代甲酰氨 基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
(14) (2E) -3- (2-噻吩基) -N- [1- (8-喹啉基氨基)曱硫代亚曱 氨基 -2, 2, 2-三氯乙基] -2-丙烯酰胺;
( 15 ) (2E)-3-苯基 -[1-(1 -吗啉基)硫代曱酰氨基 - 2, 2, 2-三氯 乙基] -2-丙烯酰胺;
( 16 ) (2E)-3-苯基 -[1-(1-哌啶基)硫代曱酰氨基 -2, 2, 2-三氯 乙基] -2-丙烯酰胺; 或 ( 17 ) (2E) -3-苯基 - [1- (3-曱氧基苄基)硫代甲酰氨基 -2, 2, 2- 三氯乙基] - 2-丙烯酰胺。
5. 药物组合物,其包含权利要求 1 - 4任一项所述化合物或其 异构体、 可药用盐及溶剂化物, 以及药学上可接受的载体、 赋形剂 或稀释剂。
6. 权利要求 1-4任一项所述化合物或其异构体, 可药用盐及 溶剂化物, 用于制备抗细胞凋亡、 预防或治疗与细胞凋亡有关的 疾病或症状的药物的用途。
7. 权利要求 1-4 任一项所述化合物或其异构体, 可药用盐及 溶剂化物, 用于制备保护心肌细胞、 预防或治疗与心肌细胞凋亡 有关的疾病或症状的药物的用途。
8. 一种抗细胞凋亡、 预防或治疗与细胞凋亡有关的疾病或症 状的方法, 所述方法包括向有此需要的受试者给予治疗有效量的 权利要求 1-4 任一项所述化合物或其异构体, 可药用盐及溶剂化 物。
9. 一种保护心肌细胞、 预防或治疗与心肌细胞凋亡有关的疾 病或症状的方法, 所述方法包括向有此需要的受试者给予治疗有 效量的权利要求 1-4任一项所述化合物或其异构体, 可药用盐及 溶剂化物。
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EP10851188.2A EP2573078B1 (en) | 2010-05-14 | 2010-05-14 | Acrylamide compounds and use thereof for inhibiting apoptosis |
US13/697,810 US9199978B2 (en) | 2010-05-14 | 2010-05-14 | Acrylamide compounds and use thereof for inhibiting apoptosis |
US14/922,963 US9439881B2 (en) | 2010-05-14 | 2015-10-26 | Acrylamide compounds and use thereof for inhibiting apoptosis |
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WO2002022581A1 (en) * | 2000-09-14 | 2002-03-21 | Gliatech, Inc. | Nitrogen-containing compounds and their use as glycine transport inhibitors |
WO2007101710A1 (en) * | 2006-03-09 | 2007-09-13 | Cenix Bioscience Gmbh | Use of inhibitors of scavenger receptor class proteins for the treatment of infectious diseases |
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WO2010011898A1 (en) * | 2008-07-25 | 2010-01-28 | Indiana University Research Technology Corporation | Method for treatment of bone diseases and fractures |
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WO2002022581A1 (en) * | 2000-09-14 | 2002-03-21 | Gliatech, Inc. | Nitrogen-containing compounds and their use as glycine transport inhibitors |
WO2007101710A1 (en) * | 2006-03-09 | 2007-09-13 | Cenix Bioscience Gmbh | Use of inhibitors of scavenger receptor class proteins for the treatment of infectious diseases |
Non-Patent Citations (5)
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"Design Of Prodrugs", 1985, ELSEVIER |
"Enantiomers, Racemates and Resolution", 1981, WILEY INTERSCIENCE |
KAI LONG ET AL.: "Structure - activity relationship studies of salubrinal lead to its active biotinylated derivative", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 3849 - 3852, XP027801504 * |
KREIDER, A. MESSING; H. DOAN; S.U. KIM; R.P. LISAK; D.E. PLEASURE: "Enrichment of Schwann cell cultures from neonatal rat sciatic nerve by differential adhesion", BRAIN RES, vol. 2, 1981, pages 433 - 444 |
See also references of EP2573078A4 * |
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EP2573078A1 (en) | 2013-03-27 |
US20160038445A1 (en) | 2016-02-11 |
EP2573078B1 (en) | 2016-11-02 |
US9199978B2 (en) | 2015-12-01 |
US20130158022A1 (en) | 2013-06-20 |
US9439881B2 (en) | 2016-09-13 |
EP2573078A4 (en) | 2013-11-20 |
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