WO2009015560A1 - Utilisation d'allylcystéine ou de ses analogues et composition pharmaceutique - Google Patents
Utilisation d'allylcystéine ou de ses analogues et composition pharmaceutique Download PDFInfo
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- WO2009015560A1 WO2009015560A1 PCT/CN2008/001408 CN2008001408W WO2009015560A1 WO 2009015560 A1 WO2009015560 A1 WO 2009015560A1 CN 2008001408 W CN2008001408 W CN 2008001408W WO 2009015560 A1 WO2009015560 A1 WO 2009015560A1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Definitions
- the invention belongs to the field of medical technology.
- the present invention relates to a novel medical use of an allylcysteine compound or an analogue thereof for the preparation of a medicament for preventing and/or treating myocardial damage; allylcysteine or an analogue thereof has improved cells in preparation Survival rate, production of endogenous H 2 S, reduction of LDH leakage rate (LDH leakage, LDH release) of cardiomyocytes damaged by hypoxia and hypoglycemia, increase of SOD and/or Catalase activity, and enhancement of tissue inhibition of hydroxyl radical production Use of a drug for inhibiting lipid peroxidation and/or inhibiting cardiomyocyte apoptosis; propargylcysteine, a pharmaceutically acceptable salt thereof or a solvate thereof have been prepared by reducing myocardial infarct size and reducing Use of lactate dehydrogenase and creatine muscle enzyme release, activity of increasing superoxide dismutase, reduction of malondialdehyde levels,
- Allylcysteine is a natural organic sulfur compound in garlic and is the main active ingredient in Aged garlic extract. It has been reported in the literature that SAC has anti-oxidation, neuroprotective effects and inhibition of excess oxygen free radical-induced lipid shield peroxidation.
- allyl structure of SAC has a certain structure-activity relationship with its neuroprotective effect.
- SAC analogs ethylcysteine (SEC;), propylcysteine (SPC), allylmercaptocysteine (SAMC) are also natural organic sulfur compounds in garlic, The report also has certain antioxidant properties; butylcysteine (SBC) and pentylcysteine (SPEC) are one and two carbons longer than the former two, which are supposed to have similar antioxidant activity;
- SBC butylcysteine
- SPEC pentylcysteine
- SPRC propylcysteine
- propargylglycine is similar, and it is speculated that it has better selectivity for CSE enzyme.
- allylcysteine as used herein has the following formula and structure: 2
- R is selected from a linear or branched alkyl group of C r C 5 , an alkenyl group of d- and an alkynyl group, preferably a terminal alkene and a terminal alkyne. Due to its common core structure with allylcysteine, it is similar in nature to allylcysteine.
- preferred allyl cysteine analogs include: ethylcysteine (SEC), propylcysteine (SPC), allylmercaptocysteine (SAMC), butyl half Cystine (SBC), pentylcysteine (SPEC), and propargylcysteine (SPRC), each having a molecular formula and structure
- SAMC its molecular formula is: C 6 H u 0 2 NS 2 , its structural formula is: ⁇ S s ⁇ COOH
- SPRC which has the formula: C 6 H 9 0 2 NS, has the structural formula: ⁇ cooH
- SOD superoxide dismutase
- Catalase refers to catalase.
- LDH lactate dehydrogenase
- CK creatine kinase
- MDA refers to the lipid peroxide malondialdehyde.
- the amount of active ingredient used refers to the weight of allylcysteine or a pharmaceutically acceptable salt thereof or a solvate thereof.
- pharmaceutically acceptable salt as used herein, unless otherwise indicated, is understood to mean a salt which is physiologically acceptable, especially when applied as a medicament to humans and/or mammals.
- pharmaceutically acceptable carrier refers to those materials which are well known in the art for use as fillers or carrier materials in pills, tablets, capsules and the like. These substances are generally approved by health care professionals for this purpose and as an inactive ingredient of the agent. Compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients, ⁇ 2 version, Edited by A. Wade and P. J. Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994).
- Another object of the present invention is to provide an allylcysteine or an analog thereof for preparing a leaching rate of LDH having improved cell survival rate, generating endogenous H 2 S, and reducing hypoxia-glucose-damaged cardiomyocytes.
- a further object of the present invention is to provide a propargyl C to enhance the activity of SOD and/or Catalase, to increase the ability of tissues to inhibit the production of hydroxyl radicals, to inhibit lipid peroxidation and/or to inhibit the apoptosis of cardiomyocytes.
- Cysteine a pharmaceutically acceptable salt thereof or a solvate thereof have been prepared by reducing the myocardial infarct size, reducing the dry release of lactate dehydrogenase and creatine muscle enzyme, increasing the activity of superoxide dismutase, and reducing Use of small malondialdehyde in ice-flat, endogenous hydrogen sulfide production and/or anti-apoptotic drugs. It is still another object of the present invention to provide a pharmaceutical composition for preventing and/or treating myocardial damage.
- the present invention provides the following technical solutions:
- the invention provides the use of a compound of formula I below for the manufacture of a medicament for the prevention and/or treatment of myocardial damage:
- R is selected from a linear or branched alkyl group of Ci-C 5 , an alkenyl group and an alkynyl group of CC 5 , preferably an terminal alkene and a terminal alkyne; and wherein the compound of the formula I is a compound itself, A pharmaceutically acceptable salt or solvate thereof is present.
- the myocardial injury heart disease is a heart disease of ischemia-anoxia myocardial injury.
- the present invention provides a compound of the formula I for producing a leaching rate of LDH, an increase in SOD and/or a Catalase activity in a cardiomyocyte having improved cell viability, endogenous H 2 S, low hypoxia and hypoglycemia.
- R is selected from a linear or branched alkyl group of CVC 5 , an alkenyl group and an alkynyl group of dC 5 , preferably a terminal alkene and a terminal alkyne; and wherein the compound of the formula I is a compound itself, a pharmaceutically acceptable form thereof An acceptable salt or solvate is present.
- the present invention provides a compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, which has the effect of reducing the myocardial infarct size, reducing the release of lactate dehydrogenase and creatine muscle enzyme, and increasing superoxide dismutase
- R is selected from a linear or branched alkyl group of d-Cs, a chain fluorenyl group of -Cs and an alkynyl group, preferably an terminal olefin and a terminal alkyne.
- the compound of formula I is selected from the group consisting of: allylcysteine, ethylcysteine, propylcysteine, allylmercaptocysteine , butylcysteine, pentylcysteine and propargylcysteine, preferably allylcysteine and propargylcysteine, most preferably allylcysteine acid.
- the pharmaceutical dosage form is selected from the group consisting of: an oral preparation, a parenteral preparation, a topical preparation, an inhalation preparation, and a transdermal preparation.
- the present invention provides a pharmaceutical composition for preventing and/or treating myocardial damage, the pharmaceutical composition comprising:
- R is selected from linear or branched dC 5 alkyl group, an alkenyl group having 5 dC and alkynyl groups, preferably terminal end Hay and alkynyl;
- the solvate of the compound of formula I is a hydrate.
- the compound of formula I is selected from the group consisting of: allylcysteine, ethylcysteine, propylcysteine, allylmercaptocysteine Acid, butylcysteine, pentylcysteine and propargylcysteine, preferably propylpropylcysteine and propargylcysteine, most preferably allylcysteine Amino acid.
- the pharmaceutical composition is: an oral preparation, a parenteral preparation such as an injection, a topical preparation, an inhalation preparation or a transdermal preparation.
- the pharmaceutical composition is an oral preparation selected from the group consisting of a tablet, a capsule, a granule, a pill, a drop, a juice or a syrup; preferably,
- the pharmaceutically acceptable carrier is selected from the group consisting of: disintegrants, lubricants, binders, fillers, solvents, perfumes, sweeteners, antioxidants, surfactants, preservatives, flavoring agents, and coloring agents.
- the invention provides a process for the preparation of a compound of formula I:
- R is selected from the group consisting of a linear or branched alkyl group of dC 5 , an alkenyl group of d- and an alkynyl group, preferably a terminal alkene and a terminal alkyne;
- the method includes the following steps:
- the L-cysteine hydrochloride is dissolved in the pre-cooled NH OH solution, stirred by Br-R, and the substituent R is defined as before; the mixed solution is stirred at 0 -5 ° C for 1-5 hours and then filtered. The filtrate is distilled under reduced pressure, concentrated, and then filtered. The precipitated solid is washed repeatedly with ethanol, then evaporated to dryness in vacuo, and then recrystallized from water/ethanol in a volume ratio of 1:3 to 3:1.
- allylcysteine or an analogue thereof for the preparation of a medicament for preventing and/or treating myocardial damage, wherein said allylcysteine Or an analog thereof is present as the compound itself, a pharmaceutically acceptable salt or solvate thereof.
- the myocardial injury heart disease is a heart disease of ischemia-anoxia myocardial injury.
- the allylcysteine or an analog thereof is the compound itself, a pharmaceutically acceptable salt or solvate thereof.
- the allyl cysteine analogue is selected from the group consisting of: ethylcysteine, propylcysteine, allylmercaptocysteine, butyl Cysteine, pentylcysteine and propargylcysteine.
- propargylcysteine a pharmaceutically acceptable salt thereof or a solvate thereof thereof, is provided in the preparation having reduced myocardial infarct size, reduced lactate dehydrogenase and creatine muscle enzyme release
- a drug for increasing the activity of superoxide dismutase, reducing the level of malondialdehyde, endogenously producing hydrogen, and/or inhibiting apoptosis is provided.
- the pharmaceutical dosage form is selected from the group consisting of: an oral preparation, a parenteral preparation, a topical preparation, an inhaled preparation, and a transdermal preparation.
- a pharmaceutical composition for preventing and/or treating myocardial damage comprising: allylcysteine as an active ingredient or the like And one or more pharmaceutically acceptable carriers, wherein the allylcysteine or analog thereof is present as the compound itself, a pharmaceutically acceptable salt or solvate thereof.
- the solvate of the allylcysteine or the like is a hydrate.
- the allyl cysteine analog is selected from the group consisting of: ethylcysteine, propylcysteine, allylmercaptocysteine, Butylcysteine, pentylcysteine and propargylcysteine.
- the pharmaceutical composition is: an oral preparation, a parenteral preparation such as an injection, a topically administered preparation, an inhaled administration preparation or a transdermal preparation.
- the pharmaceutical composition is an oral preparation selected from the group consisting of a tablet, a capsule, a granule, a pill, a drop, a juice or a syrup; preferably,
- the pharmaceutically acceptable carrier is selected from the group consisting of: disintegrants, lubricants, binders, fillers, solvents, perfumes, sweeteners, antioxidants, surfactants, preservatives, flavoring agents, and coloring agents.
- the present invention provides a method for producing an allyl cysteine analog: propargylcysteine, characterized in that the method comprises the following steps:
- the L-cysteine hydrochloride was dissolved in a pre-cooled N3 ⁇ 4OH solution, stirred with 3-bromopropyne, and the mixture was stirred at 0 ° C for 2 hours, then filtered, and the filtrate was evaporated under reduced pressure, and then filtered. The precipitated solid was repeatedly washed with ethanol, evaporated to dryness in vacuo, and then recrystallized from 2:3 by volume of water/ethanol to obtain white needle crystals.
- SPRC propargylcysteine
- the present inventors conducted the following in vivo and in vitro experiments on the above allylcysteine compound, thereby fully demonstrating the feasibility of the medical use of the present invention:
- the present invention detects the supernatant of hypoxia-deficient cardiomyocytes treated with SAC and its analogs by hypoxia-deficient cardiomyocyte experiments, and the results show that the concentration of H 2 S is significantly increased, indicating that SAC and its analogs are in vivo. Generate endogenous 3 ⁇ 4S.
- the invention adopts in vitro cardiomyocyte culture experiment, and the result proves that SAC and its analogs can improve cell survival rate, can generate endogenous H 2 S, can reduce the leakage rate of LDH of myocardial cells damaged by hypoxia and hypoglycemia; can improve SOD, Catalase activity, enhances the ability of tissues to inhibit the production of hydroxyl free radicals; inhibits lipid peroxidation and inhibits cardiomyocyte apoptosis, indicating that the allylcysteine and its analogues can be used as therapeutic drugs For the treatment of myocardial injury, especially ischemia and hypoxia, myocardial damage and heart disease.
- compositions of the invention may be prepared by methods well known in the art, preferably in the form of a formulation. Such methods include the step of mixing the active component with a carrier which comprises one or more accessory ingredients.
- auxiliary components include those commonly used in the art, such as fillers, binders, Thinners, disintegrants, lubricants, colorants, flavoring agents, and wetting agents.
- Formulations suitable for oral administration may be prepared as dispersion units, pellets or granules, as solutions or suspensions, such as pills, tablets or capsules containing a predetermined amount of active ingredient. It is also possible to formulate a formulation for rectal administration as a suppository or enemas.
- suitable formulations include aqueous and non-aqueous sterile injectables (purity of the active compound > 90%).
- Such formulations may be presented in unit dosage form or in the form of multi-dose containers such as sealed vials and ampoules, and such formulations may be lyophilized (lyophilized) in a sterile liquid carrier such as water, such as water, before use. Store under.
- Formulations suitable for nasal inhalation administration include fine dust or mist which can be produced by metered doses of pressurized aerosols, nebulizers or inhalers.
- Suitable additives and/or carriers in the context of the present invention are all materials known to the skilled person from the prior art for obtaining herbal preparations.
- the choice of these carriers and their amount depends on whether the drug is administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, orally or locally.
- Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration, while solutions, suspensions, reconstituted dry preparations and sprays are suitable for the gastrointestinal tract External and topical preparations, inhaled administration. It may also be a test for rectal use.
- the carrier film or patch optionally in storage form with other agents that promote skin penetration, is an example of a dosage form suitable for transdermal administration.
- Examples of carriers and additives in oral administration dosage forms are disintegrants, lubricants, binders, fillers, and optionally used include solvents, perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
- solvents perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
- waxes and fatty acid esters can be used, and for parenterally administered components, carrier materials, preservatives, suspending agents and the like can be used.
- the amount of active substance administered to a patient will vary as a function of patient weight, mode of administration, and severity of disease.
- the compound according to the invention can be released from the formulation in a delayed manner, for the mouth Take, rectal or transdermal administration.
- a corresponding sustained release formulation especially a "once a day" dosage form which is only taken once a day, is particularly suitable for the indication according to the invention.
- the carrier of the oral administration form of the present invention may be, for example, water, ethanol, dimethylmethanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose.
- the pharmaceutical and pharmaceutical components according to the present invention can be prepared with the aid of known pharmaceutical preparation techniques, such as advanced means, equipment, methods and procedures.
- a solid preparation such as a tablet
- the active ingredient of the drug that is, allylcysteine or a pharmaceutically acceptable salt thereof or a solvate thereof
- the drug carrier for example, a conventional tablet ingredient such as corn flour, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or a pharmaceutically acceptable gel shield to form a uniform distribution of allyl half
- a solid component of cystine or a pharmaceutically acceptable salt thereof or a solvate thereof for example, a conventional tablet ingredient such as corn flour, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or a pharmaceutically acceptable gel shield to form a uniform distribution of allyl half
- cystine or a pharmaceutically acceptable salt thereof or a solvate thereof for example, a
- Uniform distribution is understood herein to mean that the active ingredient allylcysteine or a pharmaceutically acceptable salt thereof or a solvate thereof is uniformly distributed throughout the composition so that it can be easily divided into unit dosage forms having the same activity. , such as pills, pills or capsules.
- the solid components are then divided into unit dosage forms.
- Tablets or pills of a pharmaceutical or pharmaceutical ingredient according to the invention may also be coated or mixed in another component to provide a sustained release dosage form.
- suitable coating components are a mixture of a polymeric acid and a polymeric acid with a material such as shellac, cetyl alcohol and/or cellulose acetate.
- the pharmaceutical composition of the present invention can be formulated into a clinically acceptable dosage form such as a tablet, a capsule, Granules, oral liquid preparations, subcutaneous preparations, suppositories, and the like.
- Oral preparations such as tablets, granules or capsules can be prepared by adding an appropriate amount of the carrier.
- These dosage forms are prepared according to methods well known to those skilled in the art.
- the carrier used for the molding process of tablets, granules, capsules, etc. is a commonly used auxiliary agent, such as starch, gelatin, gum arabic, polyethylene glycol, etc., in addition to surfactants, lubricants, disintegrants. , preservatives, flavoring agents, pigments, etc.
- the barrel of the drawing is to be explained
- Figure 1 is a bar graph showing the effect of SAC and its analogs on the survival rate of cardiomyocytes damaged by hypoxia/glycoxia for 6 hours/reoxygenated glycoside for 3 hours;
- Control was the normal control group; Vehicle was the model group; a: Compared with the normal control group, the model group was /? ⁇ 0.05; *: The administration group of SAC and its analogs was _p ⁇ 0.05 compared with the model group.
- Figure 2 is a bar graph showing the effect of SAC and its analogs on the amount of H 2 S released from cardiomyocytes damaged by hypoxia and hypoglycemia for 6 hours/reoxygenated glycoside for 3 hours;
- Control was the normal control group; Vehicle was the model group; a: Compared with the normal control group, the model group was _p ⁇ 0.05; *: The administration group of SAC and its analogs was ⁇ 0.05 compared with the model group.
- Figure 3 is a bar graph showing the effect of SAC and its analogues on the LDH leakage rate of myocardial cells in the absence of hypoxia/glycogen for 6 hours/reoxygenated glycoside for 3 hours;
- Control is the normal control group;
- Vehicle is the model group;
- a Compared with the normal control group, the model group is ⁇ 0.05;
- * The SAC and its analog administration groups are compared with the model group, / 0.05;
- the SAC and analogue groups were compared with those treated with PAG (propargyl glycine, supplied by Shanghai Yongzheng Chemical Co., Ltd.), ⁇ 0.05.
- Figure 4 is a bar graph showing the effect of SAC and its analogues on the total SOD activity of cardiomyocytes in the absence of hypoxia and hypoglycemia for 6 hours/reoxygenated glycoside for 3 hours;
- Control is the normal control group;
- Vehicle is the model group;
- a Compared with the normal control group, the model group is ⁇ 0.05;
- * The SAC and its analog administration groups are compared with the model group, ?0.05; # ⁇ ⁇
- Each SAC and analogue group was compared with the intervention group of PAG (propargylglycine, Shanghai Yongzheng Chemical Co., Ltd.), ⁇ 0.05.
- Figure 5 is a bar graph showing the effect of SAC and its analogs on the activity of heart-to-day Cu-Zn SOD for 6 hours of hypoxia/deficient hypoxia/reoxygenated glycoside;
- Control is the normal control group;
- Vehicle is the model group;
- a Compared with the normal control group, the model group is /? ⁇ 0.05;
- * The SAC and its analog administration groups are compared with the model group, ? ⁇ 0.05 #:
- Each SAC and analogue group was compared with the intervention group of PAG (propargyl glycine, Shanghai Yongzheng Chemical Co., Ltd.), _p ⁇ 0.05.
- Figure 6 is a bar graph showing the effect of SAC and its analogues on the Mn SOD activity of the heart-and-moon cells of the 6-hour hypoxia/glycans/reoxygenated glycoside for 3 hours of injury;
- Control is the normal control group
- Vehicle is the model group: a: Compared with the normal control group, the model group is ⁇ 0.05; *: The SAC and its analog administration groups are compared with the model group, ⁇ 0.05; #: Each SAC and analogue group was compared with the intervention group by PAG (propargyl glycine, supplied by Shanghai Yongzheng Chemical Co., Ltd.), ⁇ 0.05.
- Figure 7 is a bar graph showing the effect of SAC and its analogues on catalase activity of cardiomyocytes damaged by hypoxia and hypoglycemia for 6 hours/reoxygenated glycoside for 3 hours;
- Control was the normal control group; Vehicle was the model group; a: Compared with the normal control group, the model group was 0.05; *: The SAC and its analog administration groups were compared with the model group, ? ⁇ 0.05.
- Figure 8 is a bar graph showing the effect of SAC and its analogues on the rate of inhibition of hydroxyl radicals in cardiomyocytes induced by hypoxia and hypoglycemia for 6 hours/reoxygenated glycosidation for 3 hours;
- Control is the normal control group
- Vehicle is the model group
- a Compared with the normal control group, the model group is ⁇ 0.05
- * The SAC and its analog administration groups are compared with the model group, /? ⁇ 0.05;
- Figure 9 shows the effect of SAC and its analogues on MDA of myocardial cells damaged by hypoxia and hypoglycemia for 6 hours/reoxygenated glycoside for 3 hours.
- Control was the normal control group;
- Vehicle was the model group;
- a Compared with the normal control group, the model group was /? ⁇ 0.05;
- * The SAC and its analog administration groups were 7 ⁇ 0.05 compared with the model group;
- Fig. 10 is a photomicrograph showing the effect of SAC and its analogues on cardiomyocyte apoptosis induced by hypoxia and hypoglycemia, wherein the arrow points to the nucleus of the latent condensed and deep-stained cells.
- Vehicle is the Ml model group; *: Compared with the Ml model group, /? ⁇ 0.01.
- Figure 13 shows the effects of SPRC and SAC on electrocardiogram in rats with myocardial infarction
- Sham was sham operation group
- Sham+SPRC was sham operation + SPRC 50mg/kg group
- Sham+SAC was sham operation + SAC 50mg/kg group
- Ml was myocardial infarction model group
- MI+SPRC was model + SPRC 50mg/ Kg group
- MI+SAC is model + SAC 50mg/kg.
- Figure 14 shows the effects of SPRC and SAC on plasma LDH, CK, MDA and SOD in rats with myocardial infarction
- Sham is sham operation group
- Sham+SPRC is sham operation + SPRC 50mg/kg group
- Sham+SAC is sham operation + SAC 50mg/kg group
- Ml is myocardial infarction model group
- MI+SPRC is model + SPRC 50mg/ In the kg group
- MI+SAC was model + SAC 50 mg/kg; *: compared with MI group, /? ⁇ 0.01; #: MI group compared with Sham group, ? ⁇ 0.01.
- Figure 15 is a bar graph showing the effects of SPRC and SAC on serum 3 ⁇ 4S concentration and CSE activity in myocardial tissue in rats with myocardial infarction;
- Sham is ⁇ > surgery group; Sham + SPRC is sham operation + SPRC 50mg / kg group; Sham + SAC is sham operation + SAC 50mg / kg group; Ml is myocardial infarction model group; M + SPRC is model + SPRC 50mg /kg group; MI+SAC was model +SAC 50mg/kg; *: SPRC and SAC were compared with the model group, /? ⁇ 0.01; #:Ml group compared with Sham group, ⁇ 0.01.
- Figure 16 is a diagram showing the effect of SPRC and SAC on the expression of Bcl-2, Bax and CSE protein in the left ventricle of rats with myocardial infarction;
- Sham was sham operation group; Sham+SPRC was sham operation + SPRC 50mg/kg group; Sham+SAC was sham operation + SAC 50mg/kg group; Ml was myocardial infarction model group; M+SPRC was model + SPRC 50mg/ Kg group; MI+SAC is model + SAC 50mg/kg.
- Figure 17 is a protein electropherogram showing the effects of SPRC and SAC on Bcl-2, Bax and CSE gene expression in the left ventricle of rats with myocardial infarction; Among them, Sham was ⁇ surgery group; Sham + SPRC was sham operation + SPRC 50mg/kg group; Sham + SAC was sham operation + SAC 50mg/kg group; Ml was myocardial infarction model group; MI+SPRC was model + SPRC 50mg/ Kg group; MI+SAC is model + SAC 50mg/kg.
- Figure 18 is a bar graph showing the effect of SPRC dose groups on the survival rate and degree of damage of 3 ⁇ 40 2 injured H9c2 cardiomyocytes;
- Control is a normal control group;
- Model is a model group;
- PAG propargyl glycine, supplied by Shanghai Yongzheng Chemical Co., Ltd.
- SPRC 1E-7 SPRC 10" 7 mol/L;
- SPRC 1E-6 SPRC 1 (T 6 mol L;
- SPRC 1E-5 SPRC 10 -5 mol/L;
- SPRC+PAG SPRC 10 -5 mol/L + PAG 10 -4 mol/L;
- # model group and Compared with the normal control group, j? ⁇ 0.01;
- * SPRC each dose group compared with the model group, ⁇ 0.05;&: SPRC+PAG group compared with SPRC high dose group.
- Figure 19 is a bar graph showing the effect of SPRC dose groups on H 2 O 2 damaged H9c2 myocardial Mn-SOD activity and MDA content;
- Control is the normal control group;
- Model is the model group;
- P AG (propargyl glycine, supplied by Shanghai Yongzheng Chemical Co., Ltd.): PAG 10-4 mol/L;
- SPRC 1E-7 SPRC 10" 7 mol/L
- SPRC 1E-6 SPRC 10" 6 mol/L;
- SPRC 1E-5 SPRC 10 -5 mol/L;
- SPRC+PAG SPRC 10 -5 mol/L+ PAG 10 -4 mol/L;
- Figure 20 is an electron micrograph showing the effect of SPRC on H 2 0 2 damage H9c2 cardiomyocyte apoptosis;
- Control is the normal control group;
- Model is the model group; PAG: PAG 10 mol L; SPRC: SPRC 10" 5 mol / L; SPRC + PAG: SPRC l (T 5 mol L + PAG 10 4 mol L. Best way
- Example 1 Validation of SAC and its analogues to improve cell viability and to generate endogenous H 2 S
- the 3 day old SD suckling mice were cultured in the original method.
- the heart samples were taken and washed in PBS under the aseptic conditions, and transferred to an Erlenmeyer flask containing 0.08% trypsin for 3 minutes at 37 ° C, and continuously digested under magnetic stirring. 8 times.
- the supernatant was collected after each digestion, the suspension was digested serum, centrifuged at 2000 rpm for 5 minutes and the cell pellet was collected adjusted to a cell density of 10-6, were cultured in DMEM containing 10% calf serum, for the third day of the experiment.
- the previously cultured cells were randomly divided into the following groups:
- Normal control group no drug intervention, no hypoxia and hypoglycemia;
- Model group no drug intervention, hypoxia and hypoglycemia for 6 hours / reoxygenated complex sugar
- SAC and its analogue group 10 _5 mol/L, hypoxia/deficiency/reoxygenated saccharide, respectively.
- the cell survival rate was measured by MTT assay. The results were as shown in Fig. 1.
- the survival rate of the model group was 54.35%, which was significantly lower than that of the normal control group. SAC and its analogues could significantly improve the cell survival rate, and the one-way analysis of variance was ⁇ 0.05.
- the primary cultured neonatal rat cardiomyocytes were hypoxic and hypoglycemic for 6 hours/reoxygenated complex sugar, and were divided into normal control group, model group, SAC and its analogue group. The grouping was the same as in Example 1.
- the primary cultured neonatal rat cardiomyocytes were hypoxic and hypoglycemic for 6 hours/reoxygenated complex sugar, which were divided into normal control group, model group, SAC and its analogue group. The grouping was the same as in Example 1.
- the SOD was detected by hydroxylamine method, and the amount of SOD corresponding to the SOD inhibition rate of each gram of tissue protein in 50 ml of 1 ml reaction solution was a SOD activity unit (U).
- the results showed that (Fig. 4), SAC and its analogues could significantly increase the activity of total SOD, which was significantly higher than that of the model group ( ⁇ 0.05).
- the classification test found that saturated chain SPC, SBC, SPEC mainly increased Cu in cytoplasm.
- the activity of -Zn SOD (Fig. 5) and can be blocked by PAG; while the new compounds SPRC and SEC mainly increase the activity of Mn SOD in mitochondria (Fig. 6), which can also be blocked by PAG, indicating that SAC and its analogues can Significantly improve the vitality of SOD, and its role is partly related to H 2 S production.
- Catalase catalyzes the remaining hydrogen peroxide to oxidize the chromogenic substrate under the catalysis of peroxidase, producing a red product (N-(4-antipyryl)-3 - chloro-5- sulfonate-p-benzpquinonemonoimine )
- the maximum absorption wavelength is 520 nm.
- One enzyme activity unit (U) can catalyze the decomposition of 1 micromole of hydrogen peroxide in 1 minute at 25 ° C and pH 7.0. The results showed (Fig. 7) that the activity of catalase in the model group was significantly lower than that in the normal control group ( ⁇ 0.05). Both SAC and its analogs could increase the activity of catalase (j!? ⁇ 0.05). .
- the primary cultured neonatal rat cardiomyocytes were hypoxic and hypoglycemic for 6 hours/reoxygenated complex sugar, which were divided into normal control group, model group, SAC and its analogue group. The grouping was the same as in Example 1.
- the primary cultured neonatal rat cardiomyocytes were hypoxic and hypoglycemic for 6 hours/reoxygenated complex sugar, which were divided into normal control group, model group, SAC and its analogue group. The grouping was the same as in Example 1.
- the SPRC was dissolved in physiological saline.
- the sham operation group had the same operation except that the coronary artery was not ligated.
- the drug was administered for 2 days.
- the electrocardiogram was measured 48 hours after the operation.
- the abdominal aorta was taken for blood. After the sacrifice, the heart was quickly taken, placed in 0.1% TTC solution of pH 7.4, and incubated at 37 °C for 15 min to observe the infarct size.
- Table 1 shows the effect of SPRC on myocardial infarct size.
- Table 2 shows the effects of SPRC on plasma LDH, C activity, MDA content and SOD activity.
- the concentration of H 2 S in the SPRC group was significantly higher than that in the model group (Fig. 15A), suggesting endogenous H 2 S production.
- the activity of CSE in myocardial tissue was the same as the change of H 2 S concentration in plasma.
- the CSE activity in SPRC group was significantly higher than that in model group ( ⁇ 0.01), and it was higher than that in SAC group, there was significant difference ( ⁇ 0.05). See Figure B).
- H 2 S has the effect of scavenging reactive oxygen species. Therefore, it is speculated that the myocardial protection of SPRC and SAC after myocardial infarction is mediated by endogenous 3 ⁇ 4S.
- Table 3 shows the effect of SPRC on H 2 S in plasma and CSE enzymes in myocardial tissue.
- H9c2 is cultured at 10 °/.
- the calf serum was cultured in DMEM, placed in a 37 ⁇ , 5% C0 2 incubator, and the cells were grown to 90% monolayer passage.
- the cell density was adjusted to 5 ⁇ 10 4 /well and seeded in 96-well plates. Divided into:
- Model group no drug intervention, 20 ( ⁇ mol/LH 2 O 2 for 2 hours); PAG group (PAG): PAG l (T 4 mol/L;
- SPRC dose groups SPRC 1 ⁇ -7, SPRC 1 ⁇ -6, SPRC 1E-5, respectively, SPRC
- the cell survival rate was measured by MTT assay. The results showed that (Fig. 18A), the survival rate of the model group was significantly lower than that of the normal control group, and the SPRC medium dose group and the high dose group could significantly improve the cell survival rate (p ⁇ 0.05). PAG blocks the protective effect of SPRC on cells.
- Each group (n 4) took 10 6 cells per sample, fully lysed, and detected the intracellular LDH content by pyruvate method. The results are shown in Fig. 18B.
- the LDH leakage rate of SPRC groups was significantly higher than that of the model group. Decreased, while PAG can significantly block the protective effect of SPRC, indicating that the cardiovascular protection of SPRC is at least partially related to endogenous H 2 S production.
- Table 4 shows the results of SPRC increase H LDH leakage of myocardial cell injury in H9c2 202 cell line H9c2 myocardial viability, the low P contention 3 ⁇ 40 2.
- the 3 ⁇ 40 2 damaged cardiomyocyte cell line H9c2 was randomly divided into normal control group (Control), model group (Model), PAG group (PAG), SPRC low, medium and high dose groups, and the grouping was the same as in Example 12.
- the MDA content of the model group was significantly higher than that of the normal control group (Fig. 19B) (? ⁇ 0.05).
- the SPRC low, medium and high dose groups were significantly lower than the model group, confirming that SPRC can inhibit reactive oxygen species-induced lipid peroxidation, and PAG can block its effects.
- Table 5 shows the results of SPRC to increase the activity of SOD' and inhibit the lipid peroxidation product MDA.
- H 2 0 2 damaged cardiomyocyte cell line H9c2 was randomly divided into normal control group (Control), model group (Model), PAG group (PAG), SPRC low, medium and high dose groups, and the grouping was the same as in Example 12.
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Description
烯丙基半胱氨酸或其类似物的用途及药物耝合物 技术领域
本发明属于医药技术领域。 本发明涉及烯丙基半胱氨酸化合物或其类 似物在制备用于预防和 /或治疗心肌损伤的药物方面的新医药用途;烯丙基 半胱氨酸或其类似物在制备具有提高细胞存活率、 生成内源性 H2S、 降低 缺氧缺糖损伤心肌细胞的 LDH的漏出率 (LDH leakage、 LDH release)、 提 高 SOD和 /或 Catalase的活性、 提高组织抑制羟自由基产生的能力、 抑制 脂质过氧化和 /或抑制心肌细胞凋亡作用的药物中的应用; 炔丙基半胱氨 酸、其药学上可接受的盐或其溶剂化物在制备具有通过减少心肌梗死面积、 减轻乳酸脱氢酶和肌酸肌酶的释放、 提高超氧化物歧化酶的活性、 减小丙 二醛的水平、 内源性生成硫化氢和 /或抑制凋亡作用的药物中的应用; 以及 一种用于预防和 /或治疗心肌损伤的药物组合物。 背景技术
烯丙基半胱氨酸(SAC )是大蒜中的天然有机硫化合物, 是陈年大蒜 提取物 ( Aged garlic extract ) 中的主要有效成分。 文献报道 SAC具有抗氧 化、 神经保护作用及抑制过量氧自由基诱导的脂盾过氧化等活性。
据文献报道, SAC的烯丙基结构与其神经保护作用具有一定的构效关 系。 已知的 SAC类似物: 乙基半胱氨酸( SEC;)、 丙基半胱氨酸( SPC ) 、 烯丙基巯基半胱氨酸(SAMC )也是大蒜中的天然有机硫化合物, 具文献 报道也具有一定的抗氧化性;丁基半胱氨酸( SBC )及戊基半胱氨酸( SPEC ) 较前两者结构分别延长一个和两个碳, 推测具有类似抗氧化活性; 化合物 块丙基半胱氨酸( SPRC )与炔丙基甘氨酸的结构有相似性,推测其对 CSE 酶有较好选择性。
迄今为止,未见有关 SAC对缺氧缺糖损伤心肌细胞以及心肌损伤的作 用的报道。
发明内容
为有助于理解本发明, 下面定义了一些术语。 本文定义的术语具有本 发明相关领域的普通技术人员通常理解的含义。
除非另外说明 , 本文所用的术语 "烯丙基半胱氨酸"具有如下的分子式 和结构: 2
简称 SAC, 其分子式为: C6H„02NS, 其结构式为: ^^& ^COOH。 除非另外说明, 本文所用的术语 "烯丙基半胱氨酸及其类似物"是指结 构如下式所示的化合物:
其中, R选自 CrC5的直链或支链烷基、 d- 的链烯基和链炔基, 优 选端烯和端炔。 由于其与烯丙基半胱氨酸具有共同的核心结构, 在性质上 与烯丙基半胱氨酸相类似。 其中, 优选的烯丙基半胱氨酸类似物包括: 乙 基半胱氨酸( SEC )、丙基半胱氨酸( SPC )、烯丙基巯基半胱氨酸( SAMC )、 丁基半胱氨酸( SBC )、戊基半胱氨酸( SPEC )以及炔丙基半胱氨酸( SPRC ), 其分子式和结构分别具
SEC, 其分子式为:
SBC, 其分子式为: C7H1502NS, 其结构式为:
H2
SAMC, 其分子式为: C6Hu02NS2, 其结构式为: ^^ S s ^ COOH
NH,
SPRC, 其分子式为: C6H902NS, 其结构式为: ^ cooH 除非另外说明, 本文所用的术语 "SOD"是指超氧化物歧化酶。
除非另外说明, 本文所用的术语 "Catalase"是指过氧化氢酶。
除非另外说明, 本文所用的术语 "LDH"是指乳酸脱氢酶。
除非另外说明, 本文所用的术语 "CK"是指肌酸肌酶。
除非另外说明 , 本文所用的术语 "MDA"是指脂质过氧化物丙二醛。 除非另外说明, 活性成分的用量指的是烯丙基半胱氨酸或其药学上可 接受的盐或其溶剂化物的重量。
除非另外说明, 本文所用的术语"药学上可接受的盐"可被理解成由具 有生理学上-尤其在作为药物施加至人类和 /或哺乳动物时可接受的盐。
除非另外说明, 本文所用的术语 "可药用载体 "指的是那些本领域中公 知用作丸剂、 片剂、 胶嚢剂等中的填充剂或载体物质的物质。 这些物质通 常被保健专家认可用于这一目的且作为药剂的非活性成分. 有关可药用载 体和赋形剂的汇编可以在《药物赋形剂手册》 ( Handbook of Pharmaceutical excipients , 笫 2 版, 由 A . Wade 和 P . J . Weller 编辑; American Pharmaceutical Association 出版, Washington and The Pharmaceutical Press, London , 1994 )等工具书中找到。
本发明的一个目的在于, 提供烯丙基半胱氨酸化合物或其类似物在制 备用于预防和 /或治疗心肌损伤的药物方面的新医药用途。本发明的另一个 目的在于, 提供烯丙基半胱氨酸或其类似物在制备具有提高细胞存活率、 生成内源性 H2S、降低缺氧缺糖损伤心肌细胞的 LDH的漏出率、提高 SOD 和 /或 Catalase的活性、 提高组织抑制羟自由基产生的能力、 抑制脂质过氧 化和 /或抑制心肌细胞凋亡作用的药物中的应用, 本发明的又一个目的在 于, 提供炔丙基半胱氨酸、 其药学上可接受的盐或其溶剂化物在制备具有 通过减少心肌梗死面积、 減轻乳酸脱氢酶和肌酸肌酶的幹放、 提高超氧化 物歧化酶的活性、 减小丙二醛的氷平、 内源性生成硫化氢和 /或抑制凋亡作 用的药物中的应用。 本发明的再一个目的在于, 提供一种用于预防和 /或治 疗心肌损伤的药物组合物。
针对上述发明目的, 本发明提供以下技术方案:
式 I
其中, R选自 Ci-C5的直链或支链烷基、 C C5的链烯基和链炔基, 优 选端烯和端炔; 并且, 所述的式 I化合物是以其化合物本身、 其药学上可 接受的盐或溶剂化物存在的。
优选地, 在本发明的用途中, 所述心肌损伤性心脏病是缺血缺氧心肌 损伤心脏病。
另一方面, 本发明提供下式 I化合物在制备具有提高细胞存活率、 生 成内源性 H2S、 条低缺氧缺糖损伤心肌细胞的 LDH的漏出率、 提高 SOD 和 /或 Catalase的活性、 提高组织抑制羟自由基产生的能力、 抑制脂质过氧 化和 /或抑制心肌细胞凋亡作用的药物中的应用:
式 I
其中, R选自 CVC5的直链或支链烷基、 d-C5的链烯基和链炔基, 优 选端烯和端炔; 并且, 所述的式 I化合物是以其化合物本身、 其药学上可 接受的盐或溶剂化物存在的。
另一方面, 本发明提供以下式 I化合物、 其药学上可接受的盐或其溶 剂化物在制备具有通过減少心肌梗死面积、 减轻乳酸脱氢酶和肌酸肌酶的 释放、 提高超氧化物歧化酶的活性、 减小丙二醛的水平、 内源性生成^ [匕 氢和 /或抑制凋亡作用的药物中的应用:
式 I
其中, R选自 d-Cs的直链或支链烷基、 -Cs的链浠基和链炔基, 优 选端烯和端炔。
优选地, 在本发明的上述用途中, 所述的式 I化合物选自: 烯丙基半 胱氨酸、 乙基半胱氨酸、 丙基半胱氨酸、 烯丙基巯基半胱氨酸、 丁基半胱 氨酸、 戊基半胱氨酸和炔丙基半胱氨酸, 优选为烯丙基半胱氨酸和炔丙基 半胱氨酸, 最优选为烯丙基半胱氨酸。
优选地, 在本发明的上述用途中, 所述药物的剂型选自: 口服制 剂、 肠胃外给药制剂、 局部给药制剂、 吸入式给药制剂和透皮制剂。
又一方面, 本发明提供一种用于预防和 /或治疗心肌损伤的药 物组合物, 所述药物组合物包含:
作为活性组分的式 I化合物、 其药学上可接受的盐或其溶剂 化物:
式 I
其中, R选自 d-C5的直链或支链烷基、 d-C5的链烯基和链 炔基, 优选端浠和端炔;
以及一种或多种药学上可接受的载体。
优选地, 在本发明的药物组合物中, 所述式 I化合物的溶剂化物 是水合物。
优选地, 在本发明的药物组合物中, 所述的式 I化合物选自: 烯丙基 半胱氨酸、 乙基半胱氨酸、 丙基半胱氨酸、 烯丙基巯基半胱氨酸、 丁基半 胱氨酸、 戊基半胱氨酸和炔丙基半胱氨酸, 优选为浠丙基半胱氨酸和炔丙 基半胱氨酸, 最优选为烯丙基半胱氨酸。
优选地,在本发明的药物组合物中,所述药物组合物为: 口服制剂、 肠胃外给药制剂如注射剂、 局部给药制剂、 吸入式给药制剂或透皮制剂。
优选地, 在本发明的药物组合物中, 所述药物组合物为选自如下的 口服制剂: 片剂、 胶嚢剂、 颗粒剂、 丸剂、 滴剂、 果汁或糖浆剂; 优选地, 所述药学上可接受的载体选自: 崩解剂、 润滑剂、 粘合剂、 填充剂、 溶剂、 香料、 甜味剂、 抗氧化剂、 表面活性剂、 防腐剂、 矫味剂和色素。
再一方面, 本发明提供一种以下式 I化合物的制备方法:
其中, R选自 d-C5的直链或支链烷基、 d- 的链烯基和链 炔基, 优选端烯和端炔;
所述方法包括以下步骤:
将 L-半胱氨酸盐酸盐溶解在预冷的 NH OH溶液中, 加入 Br-R搅拌, 取代基 R的定义如前; 混合溶液在 0 -5°C下搅拌 1-5小时后过滤, 滤液减 压蒸馏、 浓缩后再过滤, 析出固体用乙醇反复洗涤后, 真空蒸干, 经 1 : 3-3: 1体积比的水 /乙醇重结晶即得。
下面, 本发明将结合本发明涉及的若干优选的实施方案, 具体描述本 发明的技术方案。
根据本发明的一个优选的实施方案, 烯丙基半胱氨酸或其类似物在制 备用于预防和 /或治疗心肌损伤的药物中的应用, 其中, 所述的烯丙基半胱 氨酸或其类似物是以其化合物本身、其药学上可接受的盐或溶剂化物存在。
优选地, 在本发明的用途中, 所述心肌损伤性心脏病是缺血缺氧心肌 损伤心脏病。
根据本发明的一个优选的实施方案, 提供烯丙基半胱氨酸或其类似物 在制备具有提高细胞存活早、 生成内源性 ¾S、 降低缺氧缺糖损伤心肌细 胞的 LDH的漏出率、 提高 SOD和 /或 Catalase的活性、 提高组织抑制羟自 由基产生的能力、抑制脂质过氧化和 /或抑制心肌细胞凋亡作用的药物中的
应用, 其中, 所述的烯丙基半胱氨酸或其类似物是以其化合物本身、 其药 学上可接受的盐或溶剂化物。
优选地, 在本发明的用途中, 所述的烯丙基半胱氨酸类似物选自: 乙 基半胱氨酸、 丙基半胱氨酸、 烯丙基巯基半胱氨酸、 丁基半胱氨酸、 戊基 半胱氨酸和炔丙基半胱氨酸。
根据本发明的一个优选的实施方案, 提供炔丙基半胱氨酸、 其药学上 可接受的盐或其溶剂化物在制备具有通过减少心肌梗死面积、 减轻乳酸脱 氢酶和肌酸肌酶的释放、提高超氧化物歧化酶的活性、减小丙二醛的水平、 内源性生成^ 氢和 /或抑制凋亡作用的药物中的应用。
优选地, 在本发明的用途中, 所述药物的剂型选自: 口服制剂、 肠胃外给药制剂、 局部给药制剂、 吸入式给药制剂和透皮制剂。
根据本发明的一个优选的实施方案, 提供一种用于预防和 /或 治疗心肌损伤的药物组合物, 所述药物组合物包含: 作为活性组 分的烯丙基半胱氨酸或其类似物, 以及一种或多种药学上可接受 的载体, 其中, 所述的烯丙基半胱氨酸或其类似物是以其化合物 本身、 其药学上可接受的盐或溶剂化物存在。
优选地, 在本发明的药物组合物中, 所述烯丙基半胱氨酸或 其类似物的溶剂化物是水合物。
优选地, 在本发明的药物组合物中, 所述的烯丙基半胱氨酸类似物选 自: 乙基半胱氨酸、 丙基半胱氨酸、 烯丙基巯基半胱氨酸、 丁基半胱氨酸、 戊基半胱氨酸和炔丙基半胱氨酸。
进一步优选地 , 在本发明的药物组合物中 , 所述药物组合物为: 口服制剂、 肠胃外给药制剂如注射剂、 局部给药制剂、 吸入式给药制剂或 透皮制剂。
优选地, 在本发明的药物组合物中, 所述药物组合物为选自如下 的口服制剂: 片剂、 胶嚢剂、 颗粒剂、 丸剂、 滴剂、 果汁或糖浆剂; 优选 地, 所述药学上可接受的载体选自: 崩解剂、 润滑剂、 粘合剂、 填充剂、 溶剂、 香料、 甜味剂、 抗氧化剂、 表面活性剂、 防腐剂、 矫味剂和色素。
根据本发明的一个优选的实施方案, 本发明提供一种烯丙基半胱氨酸 类似物: 炔丙基半胱氨酸的制备方法, 其特征在于, 所述方法包括以下步 骤:
将 L-半胱氨酸盐酸盐溶解在预冷的 N¾OH溶液中, 加入 3-溴丙炔搅 拌,混合溶液在 0 °C下搅拌 2 小时后过滤,滤液减压蒸馏、浓缩后再过滤, 析出固体用乙醇反复洗涤后, 真空蒸干, 经 2:3体积比的水 /乙醇重结晶得 白色针状晶体。
所述的烯丙基半胱氨酸类似物其中的炔丙基半胱氨酸( SPRC )通过下 述合成路线合成:
L-半胱氨酸盐酸盐溶解在预冷的 H4OH (2M, 240 ml)溶液中, 加入 3- 渙丙炔 (14.5 g, 0.124 mol)充分搅拌, 混合溶液在 0 °C下搅拌 2小时后过滤, 滤液减压蒸馏 (< 40 Ό)浓缩到较少容量后再过滤。 析出固体用乙醇反复洗 条后, 真空蒸干, 经 2:3体积比的水 /乙醇重结晶得到白色针状晶体, 经核 磁共 |½测氢谱结构确定。
本发明人对上述烯丙基半胱氨酸化合物进行了下述体内、 体外实验, 从而充分駘证了本发明医药用途的可实施性:
本发明通过缺氧缺糖心肌细胞实验,检测了经 SAC及其类似物处理的 缺氧缺糖心肌细胞的上清液, 结果显示 H2S 的浓度明显提高, 表明 SAC 及其类似物在体内生成内源性 ¾S。
本发明通过体外心肌细胞培养实验,结果证明 SAC及其类似物可以提 高细胞存活率,能生成内源性 H2S ;可降低缺氧缺糖损伤心肌细胞的 LDH 的漏出率; 可提高 SOD、 Catalase的活性, 提高组织抑制羟自由基产生的 能力; 可以抑制脂质过氧化以及具有抑制心肌细胞凋亡的作用, 表明所述 的烯丙基半胱氨酸及其类似物可作为治疗药物应用于治疗心肌损伤尤其是 缺血缺氧心肌损伤心脏病。
可以采用本领域所公知的方法来制备本发明的组合物, 优选为制剂形 式。 这类方法包括将活性组分与构成一种或多种辅助组分的载体混合的步 驟。 这类辅助组分包括那些本领域中常用的组分, 诸如填充剂、 粘合剂、
稀释剂、 崩解剂、 润滑剂、 着色剂、 调味剂和湿润剂。
可以将适合于口服给药的制剂制成诸知含有预定量活性组分的丸剂、 片剂或胶嚢这样的分散单位、 制成粉剂或颗粒剂、 制成溶液或混悬液。 还 可以将直肠给药用制剂制成栓剂或灌肠剂。
就非肠道给药而言, 合适的制剂包括含水和非水性无菌注射剂 (活性 化合物的纯度≥90% )。 可以将这类制剂制成单位剂量或例如密封小瓶和安 瓿这样多剂量容器的形式且可以将这类制剂在仅需要在使用前添加例如水 这样的无菌液体载体的冷冻干燥(冻干)条件下储存。
适合于经鼻部吸入给药的制剂包括可以通过计量剂量的加压气雾剂、 喷雾器或吸入器产生的细粉尘或雾。
为了制备例如片剂这样的剂量单位, 所关注的是常用添加剂的应用, 诸如填充剂、 着色剂、 聚合粘合剂等。 一般来说, 可以使用不会干扰活性 化合物的功能的任意可药用添加剂。
本发明内容中合适的添加剂和 /或载体是技术人员从以往技术中已知 的所有用来获得草本制剂的物质。 这些载体的选择和它们的用量依赖于药 物是否口服地、 静脉地、 腹腔地、 皮内地、 肌肉地、 鼻内地、 口腔地或局 部地给药。 以药片、 咀嚼片、 包衣片、 胶嚢、 颗粒、 滴剂、 果汁或糖浆形 式的制剂适合于口月艮给药, 而溶液、 悬浮液、 易复水的干燥制剂和喷剂适 合于肠胃外、 局部给药制剂、 吸入式给药。 还可能是供直肠使用的检剂。 载体膜片或贴片, 可任选地与其它促进皮肤渗透的试剂一起以溶解的形式 贮存使用, 是适合于透皮给药的剂型的范例。
口服给药剂型中的载体和添加剂的实例是崩解剂、 润滑剂、 粘合剂、 填充剂, 可选择性使用的包括溶剂、 香料、 甜味剂, 尤其是载体物质、 稀 释液、 染料、 抗氧化剂等等。 其中, 对于栓剂而言, 可使用蜡和脂肪酸酯, 对于非肠道给药的組分可使用载体物质、 防腐剂、 助悬剂等等。 给病人使 用的活性物质的量随着由病人体重, 给药方式和病重程度组成的函数关系 而变化。 按本发明的化合物能以一种迟緩的方式从制剂剂型中释放, 供口
服, 直肠或透皮给药。 相应的持续释放式制剂, 尤其是每天只需服用一次 的"一日一次"式剂型尤其适合于按本发明的适应症。
本发明的口月艮给药剂型的载体可以是, 例如: 水、 乙醇、 二甲基甲醇, 丙三醇、 乙二醇、 丙二醇、 聚乙二醇、 聚丙二醇、 葡萄糖、 果糖、 乳糖、 蔗糖、 糖浆、 淀粉、 改性淀粉、 明胶、 山梨醇、 肌醇、 甘露醇'、 微晶纤维 素、 甲基纤维素、 羧甲基纤维素、 醋酸纤维素、 虫胶、 鲸蜡醇、 聚乙烯吡 咯烷酮、 石蜡、 蜡、 天然橡胶与合成橡胶、 阿拉伯树胶、 藻酸盐、 右旋糖 苷、 饱和脂肪酸与不饱和脂肪酸、 硬脂酸、 硬脂酸镁、 硬脂酸锌、 甘油硬 脂酸酯、 月桂醇 u酸钠、 食用油、 芝麻油、 椰子油、 花生油、 大豆油、 卵 磷脂、 乳酸钠、 聚氧乙烯和丙烯脂肪酸酯、 山梨糖醇醉脂肪酸酯、 山梨酸、 苯甲酸、 柠檬酸、 抗坏血酸、 丹宁酸、 氯化钠、 氯化钾、 氯化镁、 氯化钙、 氧化镁、 氧化锌、 二氧化硅、 氧化钛、 二氧化钛、 硫酸镁、 硫酸锌、 硫酸 钙、 碳酸钾、 磷酸钙、 磷酸二钙、 澳化钾、 碘化钾、 滑石粉、 高岭土、 胶 质、 交聚维酮、 琼脂和皂土。
根据本发明的药物和药物组分可以使用已知的先进的手段、 设备、 方 法和工序等所述的药物制剂技术的帮助下制备的。 例如, 对固体制剂如片 剂而言, 可以将药物的活性成分, 也就是烯丙基半胱氨酸或其药学上可接 受的盐或其溶剂化物, 与药物载体一起颗粒化, 举例来说, 常规的药片成 分, 例如玉米面粉、 乳糖、 蔗糖、 山梨醇、 滑石粉、 硬脂酸镁、 磷酸二钙 或药物学上可接受的胶盾, 以形成一种含有均匀分布的烯丙基半胱氨酸或 其药学上可接受的盐或其溶剂化物的固体组分。
均匀分布在这里可理解成活性成分烯丙基半胱氨酸或其药学上可接受 的盐或其溶剂化物在整个组分中均一分布, 从而可以 4艮容易地被分成具有 同样活性的单位剂型, 如药片、 药丸或胶嚢。 然后固体组分被分成单位剂 型。 按本发明的药物或药物组分的片剂或丸剂也可以被包衣或混合在另一 组分中以提供一种緩释剂型。 其中, 合适的包衣组分是, 聚合酸以及聚合 酸与例如虫胶, 鲸蜡醇和 /或醋酸纤维素等材料的混合物。
可以将本发明的药物组合物制成临床可接受的剂型, 如片剂, 胶嚢,
颗粒剂, 口服液体制剂, 皮下给药制剂, 栓剂等。 加入适量的载体, 可制 成片剂、 颗粒剂或胶嚢剂等口服制剂。 这些剂型是按照本领域的技术人员 所熟知方法制备的。 用于制造片剂、 颗粒剂、 胶嚢剂等成型工艺的载体是 常用的助剂, 例如淀粉、 明胶、 阿拉伯胶、 聚乙二醇等, 此外还有表面活 性剂、 润滑剂、 崩解剂、 防腐剂、 矫味剂、 色素等。 附图的筒要说明
以下, 结合附图来详细说明本发明的实施例, 其中:
图 1是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3 小时损伤 的心肌细胞的存活率的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, /?<0.05 ; *: SAC及其类似物各给药组与模型组相比, _p<0.05。
图 2是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤 的心肌细胞的 H2S释放量的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, _p<0.05 ; *: SAC及其类似物各给药组与模型组相比, <0.05。
图 3是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤 的心肌细胞 LDH漏出率的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, <0.05; *: SAC及其类似物各给药组与模型组相比, / 0.05; # : 各 SAC及类似物組与经 PAG (炔丙基甘氨酸, 上海瀛正化工有限公 司提供)干预組比较, <0.05。
图 4是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤 的心肌细胞总 SOD活力的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, <0.05; *: SAC及其类似物各给药组与模型組相比, ;?0.05; # ·· 各 SAC及类似物组与经 PAG (炔丙基甘氨酸, 上海瀛正化工有限公 司提供)干预組比较, ?<0.05。
图 5是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤 的心月几细^ ^ Cu-Zn SOD活力的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型組与正常对 照组相比, /?<0.05; *: SAC及其类似物各给药组与模型组相比, ;?<0.05; #: 各 SAC及类似物组与经 PAG (炔丙基甘氨酸, 上海瀛正化工有限公 司提供)干预组比较, _p<0.05。
图 6是显示 SAC及其类似物对缺氧缺糖 6 小时 /复氧复糖 3小时损伤 的心月几细胞 Mn SOD活力的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组: a:模型组与正常对 照组相比, <0.05 ; *: SAC及其类似物各给药组与模型组相比, ?<0.05; # : 各 SAC及类似物组与经 PAG (炔丙基甘氨酸, 上海瀛正化工有限公 司提供)干预组比较, <0.05。
图 7是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤 的心肌细胞过氧化氢酶活力的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, 0.05 ; *: SAC及其类似物各给药组与模型组相比, ;?<0.05。
图 8是显示 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3 小时损伤 的心肌细胞羟自由基抑制率的影响的柱形图;
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, ?<0.05; *: SAC及其类似物各给药组与模型组相比, /?<0.05;
# : 各 SAC及类似物组与经 PAG (炔两基甘氨酸, 上海瀛正化工有限公 司提供)干预组比较, p<0.05。
图 9是 SAC及其类似物对缺氧缺糖 6小时 /复氧复糖 3小时损伤的心 肌细胞 MDA的影响,
其中, Control为正常对照组; Vehicle为模型组; a:模型组与正常对 照组相比, /?<0.05 ; *: SAC及其类似物各给药组与模型组相比, 7<0.05;
#: 各 SAC及类似物组与经 PAG (炔丙基甘氨酸, 上海瀛正化工有限公 司提供)干预组比较, ;?<0.05。
图 10是显示 SAC及其类似物对缺氧缺糖损伤心肌细胞凋亡的影响的 电镜染色图片, 其中, 箭头所指处为调亡固缩深染的细胞核。
图 11 SPRC合成路线图及氢谱鉴定结果。
图 12 SPRC及 SAC对心肌梗死大鼠梗死面积的影响,
其中, Vehicle为 Ml模型组; *: 与 Ml模型组相比, /?<0.01。
图 13显示 SPRC及 SAC对心肌梗死大鼠心电图的影响;
其中, Sham为假手术组; Sham+SPRC为假手术 +SPRC 50mg/kg组; Sham+SAC为假手术 +SAC 50mg/kg组; Ml为心肌梗死模型组; MI+SPRC 为模型 +SPRC 50mg/kg组; MI+SAC为模型 +SAC 50mg/kg。
图 14显示 SPRC及 SAC对心肌梗死大鼠血浆中 LDH、 CK、 MDA与 SOD的影响;
其中, Sham为假手术组; Sham+SPRC为假手术 +SPRC 50mg/kg组; Sham+SAC为假手术 +SAC 50mg/kg组, Ml为心肌梗死模型组, MI+SPRC 为模型 +SPRC 50mg/kg组, MI+SAC为模型 +SAC 50mg/kg; *: 与 MI组相 比, /?<0.01; #: MI组与 Sham组相比, ?<0.01。
图 15为显示 SPRC及 SAC对心肌梗死大鼠血清中 ¾S浓度及心肌组 织中 CSE活性的影响的柱形图;
其中, Sham为^ >手术组; Sham+SPRC为假手术 +SPRC 50mg/kg组; Sham+SAC为假手术 +SAC 50mg/kg组; Ml为心肌梗死模型组; M+SPRC 为模型 +SPRC 50mg/kg组; MI+SAC为模型 +SAC 50mg/kg; *: SPRC及 SAC 各给药组与模型组相比, /?<0.01; #: Ml组与 Sham组相比, <0.01。
图 16为显示 SPRC及 SAC对心肌梗死大鼠左心室中 Bcl-2、 Bax和 CSE蛋白表达的影响的蛋白电泳图谙;
其中, Sham为假手术组; Sham+SPRC为假手术 +SPRC 50mg/kg组; Sham+SAC为假手术 +SAC 50mg/kg组; Ml为心肌梗死模型组; M+SPRC 为模型 +SPRC 50mg/kg组; MI+SAC为模型 +SAC 50mg/kg。
图 17为显示 SPRC及 SAC对心肌梗死大鼠左心室中 Bcl-2、 Bax和 CSE 基因表达的影响的蛋白电泳图谱;
其中, Sham为^ 手术组; Sham+SPRC为假手术 +SPRC 50mg/kg组; Sham+SAC为假手术 +SAC 50mg/kg组; Ml为心肌梗死模型组; MI+SPRC 为模型 +SPRC 50mg/kg组; MI+SAC为模型 +SAC 50mg/kg。
图 18为显示 SPRC各剂量组对 ¾02损伤的 H9c2心肌细胞存活率和 损伤程度的影响的柱形图;
其中, Control为正常对照组; Model为模型组; PAG (炔丙基甘氨酸, 上海瀛正化工有限公司提供): PAG 10-4 mol/L; SPRC 1E-7: SPRC 10"7 mol/L; SPRC 1E-6: SPRC 1(T6 mol L; SPRC 1E-5: SPRC 10-5 mol/L; SPRC+PAG: SPRC 10-5 mol/L+ PAG 10-4 mol/L; #:模型组与正常对照组相 比, j?<0.01; *: SPRC各剂量组与模型组相比, <0.05; &: SPRC+PAG组 与 SPRC高剂量组相比较。
图 19为显示 SPRC各剂量组对 H202损伤的 H9c2心肌 Mn-SOD活力 和 MDA含量的影响的柱形图;
其中, Control为正常对照组; Model为模型组; P AG (炔丙基甘氨酸, 上海瀛正化工有限公司提供): PAG 10-4 mol/L; SPRC 1E-7: SPRC 10"7 mol/L; SPRC 1E-6: SPRC 10"6 mol/L; SPRC 1E-5: SPRC 10-5 mol/L; SPRC+PAG: SPRC 10-5 mol/L+ PAG 10-4 mol/L; #:模型组与正常对照组相 比, ?<0.01; *: SPRC各剂量组与模型组相比, <0.05; &: SPRC+PAG组 与 SPRC高剂量组相比较, <0.05。
图 20为显示 SPRC对 H202损伤 H9c2心肌细胞凋亡的影响的电镜图 片;
其中, Control为正常对照组; Model为模型组; PAG: PAG 10 mol L; SPRC: SPRC 10"5 mol/L; SPRC+PAG: SPRC l(T5 mol L+ PAG 104 mol L。 实施发明的最佳方式
下面结合具体实施例, 进一步阐述本发明。 但这些实施例仅限于说明 本发明而不用于限制本发明的范围。 下列实施例中未注明具体实验奈件的 实验方法, 通常按照常规条件, 或按照厂商所建议的条件。
实施例 1: 验证 SAC及其类似物提高细胞存活率, 能生成内源性 H2S 的实验
原代培养 3 日龄 SD乳鼠, 按常规方法无菌条件下取心脏样本于 PBS 中清洗、 处理, 移入含有 0.08 %胰酶的三角烧瓶中 37°C消化 10分钟, 持 续磁力搅拌下共消化 8次。 每次消化后收集上清液, 血清中止消化, 2000 转离心 5分钟, 收集细胞沉淀调细胞密度为 10— 6, 培养在含 10%小牛血清 的 DMEM中, 第三天用于实验。
将前述培养的细胞随机分为以下各组:
正常对照组: 不给予药物干预, 不缺氧缺糖;
模型组: 不给予药物干预, 缺氧缺糖 6 小时 /复氧复糖;
SAC及其类似物组: 分别给予药物 10_5mol/L, 缺氧缺糖 /复氧复糖。 以 MTT法检测细胞存活率, 结果如图 1所示, 模型组存活率 54.35% 明显低于正常对照组, SAC及其类似物均能明显提高细胞存活率, 单因素 方差分析 <0.05。
取细胞上清液 500μ1, 加入醋酸锌 250μ1, 与 Ν,Ν二甲基对苯二胺盐酸 盐 20 mM 133 μΐ和三氯高铁 30 mM 133 μΐ充分震荡后室温反应 lOmin, 10% 三氯乙酸沉淀蛋白, lOOOOg离心 lOmin, 670nm测量吸光度值。 结果如图 2 所示, 模型组较正常对照组相比 H2S 浓度明显下降, 单因素方差分析 p<0.05 , 而 SAC及其类似物均能明显提高上清液中 H2S 浓度明显升高 ( p<0.05 ) 。 实施例 2. 验证 SAC及其类似物降低缺氧缺糖损伤心肌细胞的 LDH 漏出的实验
本实施例如图 3所示。
原代培养乳鼠心肌细胞,缺氧缺糖 6 小时 /复氧复糖制模,分为正常对 照组, 模型组, SAC及其类似物组, 分组情况同实施例 1。
每组(n = 4 )每个样本取 106个细胞, 充分裂解, 丙酮酸法检测细胞
内 LDH的含量, 正常对照组细胞内 LDH为 100%, 各用药组与模型组细 胞内 LDH与正常对照组的差值为 LDH漏出率, 在反应体系中产生 1 μιηοΐ 丙酮酸为 1单位, 计算每单位 /mg蛋白。 各用药组平行给予 H2S生成阻断 剂 PAG阻断, 结果如图 3所示, 各用药组的 LDH漏出率较模型组均明显 争低, 而 PAG可以显著阻断 SAC及其类似物的保护作用,说明 SAC及其 类似物的心血管保护作用部分与内源性生成 H2S有关。 实施例 3. 验证 SAC及其类似物提高 SOD、 Catalase的活性,提高组 织抑制羟自由基产生能力的实验
本实施例如图 4-8所示。
原代培养乳鼠心肌细胞,缺氧缺糖 6 小时 /复氧复糖制模, 分为正常对 照组, 模型组, SAC及其类似物组, 分组情况同实施例 1。
羟胺法检测 SOD,每亳克组织蛋白在 1ml反应液中 SOD抑制率达 50% 时所对应的 SOD量为一个 SOD活力单位(U )。 结果显示(图 4 ) , SAC 及其类似物均能够明显提高总 SOD的活力,较模型组显著升高( <0.05 ) , 分型检测发现饱和破链 SPC、 SBC, SPEC主要提高胞浆中 Cu-Zn SOD的 活力(图 5 ) , 且可被 PAG阻断; 而新化合物 SPRC和 SEC主要提高线粒 体中 Mn SOD的活力 (图 6 ) , 同样可被 PAG阻断, 说明 SAC及其类似 物可明显提高 SOD的活力, 其作用部分与 H2S产生有关。
过氧化氢酶催化剩余的过氧化氢在过氧化物酶的催化下可以氧化生色 底 物 , 产 生 红 色 的 产 物 ( N-(4-antipyryl)-3 - chloro-5- sulfonate-p-benzpquinonemonoimine ),最大吸收波长 520 nm。 1个酶活力单 位(U )在 25°C , pH7.0条件下, 在 1分钟内可以催化分解 1微摩尔过氧 化氢。 结果显示 (图 7 ) , 模型组较正常对照组过氧化氢酶的活力显著下 降( <0.05 ) , SAC 及其类似物较模型组均能提高过氧化氢酶的活力 (j!?<0.05 ) 。
检测 Fenton反应中 OH—量, H202的量和 Fenton反应产生的 OH"量成 正比, 给予电子受体后, 用 gress试剂显色, 形成红色物盾, 550 nm波长
检测。 结果显示(图 8 ) , SAC及其类似物用药组的羟自由基抑制率明显 升高( <0.05 ) , 证实经 SAC及其类似物可以显著抑制 ΟΕΓ的产生。 PAG 不能阻断 SAC及其类似物的抑制羟自由基的能力。 实施例 4: 验证 SAC及其类似物抑制脂质过氧化的实验
本实施例如图 9所示。
原代培养乳鼠心肌细胞,缺氧缺糖 6 小时 /复氧复糖制模, 分为正常对 照組, 模型组, SAC及其类似物组, 分组情况同实施例 1。
氧自由基攻击生物膜中的多不饱和脂肪酸, 引发脂质过氧化作用, 并 因此产生脂质过氧化物丙二醛( MDA ) 。 MDA可与硫代巴比妥酸( TBA ) 缩合, 形成红色产物, 在 532 nm处有最大吸收峰。 结果显示(图 9 ) , 模 型组 MDA含量与正常对照组相比显著增高( <0.05 ) 。 SEC;、 SPC、 SPRC 给药组较模型组均明显降低, 证实 SEC、 SPC、 SPRC 能抑制抑制活性氧 诱导的脂质过氧化,且 PAG可阻断其作用。其中的化合物 SPRC '的抗脂质 过氧化作用更显著。 实施例 5: 验证 SAC及其类似物抑制心肌细胞凋亡的实验
本实施例如图 10所示。
原代培养乳鼠心肌细胞,缺氧缺糖 6 小时 /复氧复糖制模, 分为正常对 照组, 模型组, SAC及其类似物组, 分组情况同实施例 1。
Hoechst染色初步证实了 SAC及其类似物对凋亡的抑制作用(图 10 ) , 心肌细胞的凋亡对于心脏的结构和功能具有很大的损害作用, 是发生心功 能衰竭的诸多原因之一,实验结果表明 SAC及其类似物具有抑制心肌细胞 凋亡的作用, SAC及其类似物抗凋亡作用在心脏病的治疗中具有重要应用 价值。 实施例 6: SPRC的合成
本实施例如图 11所示。
L-半胱氨酸盐酸盐溶解在预冷的 M¾OH (2M, 240 ml)溶液中, 加入 3- 溴丙炔 (14.5 g, 0.124 mol)充分搅拌。混合溶液在 0 °C下搅拌 2 h后过滤,滤 液减压蒸條 (< 40 °C)浓缩到较少容量后再过滤。 析出固体用乙醇反复洗涤 后, 真空蒸干, 经 2:3体积比的水 /乙醇重结晶得到白色针状晶体。 使用核 磁共振检测氢谱结构(图 11 ) 。
实施例 7: 验证 SPRC对心肌梗死面积影响的实 4佥
本实施例如图 12和 13所示。
将 SPRC用生理盐水溶解。 体重 200-250g雄性 SD大鼠, 随机分为: 假手术组(Sham, 生理盐水, ip. n= );
假手术 +SPRC组(Sham+SPRC, 50mg/kg/day, n=4 ) ;
假手术 +SAC组(Sham+SAC, 50mg/kg/day, n=4 ) , 模型组(MI, 生 理盐水, ip. n=8 ) ;
模型 +SPRC组(MI+SPRC, 50mg kg/day, n=8 );
模型 +SAC组(MI+SAC, 50mg/kg/day, n=8 ) 。
预给药 7天(ip. ) 。 第八天, 7%水合氯醛 5ml/kg腹腔内注射麻醉后 仰卧固定, 胸部备皮。 于左侧胸腔第三肋间开胸, 用 6-0号丝线弯针在左 心耳和肺动脉圆锥之间 ,距主动 ^艮部约 2-3mm处永久性结扎左冠状动脉 前降支, 观察到供血区域心肌史白、 并以标准肢体导联 II导心电图 ST段 抬高为模型成功标准。 迅速关闭胸腔, 缝合皮肤, 保温待大鼠清醒后给予 水和标准饲料分笼饲养。 假手术组除不结扎冠状动脉外, 其余操作相同。 继续给药 2天, 术后 48小时检测心电图变化,腹主动脉取血, 处死后取迅 速心脏, 置入 pH7.4的 0.1% TTC液中, 于 37°C孵育 15 min染色观察梗死 面积。
与模型组相比, SPRC 和 SAC 能明显的减小心肌梗死面积 p<0.01 (图.12 ) , 48小时后 ST段抬高有所恢复(图 .13 ) 。 SAC与 SPRC作用 相似,;?>0.05。
表 1是 SPRC对心肌梗死面积的影响。
表 1
模型组 SPRC SAC
梗死面积 /左心室面积 (% ) 36.2±1.3 20.8±2.4 24.9±1.9 实施例 8:验证 SPRC对 LDH漏出率、血浆中 CK浓度及 MDA和 SOD 的影响的实验
本实施例如图 14所示。
左冠状动脉结扎模型, 随机分为: 假手术组, 假手术 +SPRC组, 假手 术 +SAC组,模型组,模型 +SPRC组,模型 +SAC组( MI+SAC, 50mg/kg/day, η=8 ) , 分组情况同实施例 7。
上述实验中还观察到, 模型组的血浆中 LDH、 CK活性和 MDA的含 量明显升高, SOD活性降低。 心肌梗死损伤时, 氧自由基大量产生, LDH 反应心肌细胞膜完整性破坏, LDH、 CK外漏; MDA反映心肌细胞膜脂质 过氧化,过氧化产物进入血液;对 SOD的监测可间接反映机体清除氧自由 基的能力。 结果表明, SPRC和 SAC均能明显减少心肌梗死后 LDH和 CK 漏出,抑制 MDA的升高,并有效保护 SOD活力, 显示其抗缺血引起的脂质 过氧化反应和较强的氧自由基清除能力 (图.14 ) 。
能降低 LDH漏出率, 减少血浆中 CK浓度及 MDA的产生, 提高血浆 中 SOD的水平。
表 2是 SPRC对血浆中 LDH、 C 活性, MDA的含量及 SOD活性影 响。
, ^2
LDH CK MDA SOD
(U/L) (U/ml) (nmol/ml) (U/ml)
假手术组 2573±206 0.249±0.047 3.63±0.41 156.8±3.4 假 手 术 2612±189 0.251±0.032 3.79±0.40 161.2±3.8
+SPRC组
假 手 术 2599±212 0.250±0.019 3.57±0.31 159.8±4.8
+SAC组
模型组 4641士 251# 0.502±0.055 5.78±0.61# 91.3±2.3
模 型 3096±231** 0.322±0.052 4.43士 0.51 113.8士 1.5
+SPRC组 *
模型 +SAC 3556±291* 0.322士 0.010 3.86±0.35* 107.1±5.4 组 实施例 9: ^^正 SPRC对血浆中 H2S及心肌组织中 CSE酶影响的实验 本实施例如图 15所示。
左冠状动脉结扎模型, 随机分为: 假手术组, 假手术 +SPRC组, 假手 术 +SAC组,模型組,模型 +SPRC组,模型 +SAC组( MI+SAC, 50mg/kg/day, η=8 ) , 分组情况同实施例 7。
SPRC组 H2S浓度较模型组显著升高 (图 15A ) , 提示有内源性 H2S 生成。 心肌组织中 CSE的活性与血浆中 H2S浓度变化的趋势相同, SPRC 组 CSE活性较模型组 CSE活性显著提高( <0.01 ) , 且较 SAC组 CSE活 性高, 有显著差异 ?<0.05 ) (参见图 B ) 。
根据文献报道, H2S具有清除活性氧的作用, 因此推测 SPRC、 SAC 对心肌梗死后的心肌保护作用是通过内源性生成 ¾S介导的。
表 3是 SPRC对血浆中 H2S及心肌组织中 CSE酶的影响。
^3
CSE 活 性 血浆 H2S浓度(μΜ )
(μΜ/mgprot)
假手术组 60.3±5.3 2.01士 0.14
假手术 +SPRC组 67.2士 6.4 2.41±0.12
假手术 +SAC组 65.2±4.4 2.31±0.24
模型组 34.7士 5.6# 1.58±0.15#
模型 +SPRC组 91.6±7.6* 2.58±0.07*
模型 +SAC组 61.1±3.6* 2.19±0.32* 实施例 10:验证 SPRC可提高 Bcl-2和 CSE蛋白水平的表达、 P条低 Bax 蛋白水平表达的实验
本实施例如图 16所示。
左冠状动^^结扎模型, 随机分为: £手术组, 假手术 +SPRC组, 假手 术 +SAC组,模型组,模型 +SPRC组,模型 +SAC组( MI+SAC, 50mg/kg/day, n=8 ) , 分组情况同实施例 7。
Sham组 Bax蛋白表达水平较低, Sham+SPRC组和 Sham+SAC组对 Ba 和 Bcl-2与 Sham组没有显著差异;结扎左冠状动脉使左心室 Bax蛋白 表达增加, Bcl-2表达降低,有显著差异性( p<0.05 );与 MI组比较, SPRC 组和 SAC组的 Bcl-2蛋白表达显著增加, Bax蛋白表达明显降低 ( <0.05 )。 与 MI组相比, SPRC组和 SAC组的 CSE蛋白表达显著增加, 且 SPRC对 CSE的作用明显 ?<0.01 , p< .05 ) , SPRC在蛋白水平降低了凋亡相关因 子 Bax, 提高抗凋亡因和子 Bcl-2和 CSE蛋白水平的表达(参见图.16 ) 。 实施例 11 : 证实 SPRC可降低 Bax, 提高 CSE基因水平的表达, 对 Bcl-2基因表达没有明显影响的试验。
本实施例如图 .17所示。
左冠状动脉结扎模型, 随机分为: 假手术组, 假手术 +SPRC组, 假手 术 +SAC组,模型组,模型 +SPRC組,模型 +SAC组( MI+SAC, 50mg/kg/day, η=8 ) , 分组情况同实施例 7。
SPRC和 SAC与 Sham组和 Ml组比较 Bcl-2的基因表达均无显著性差 异( /?<0.01 ); Ml组 Bax的基因表达与 Sham组比较显著增加( ;?<0.01 ); SPRC组和 SAC组与 Ml组比较 Ba 基因表达显著降低 ( p<0.05 ); 与 MI 组相比, SPRC组 CSE基因表达显著增加( O.01 ) , SAC组的 CSE基因 表达也有明显增加,但不如 SPRC对 CSE的作用明显 ( ρ<0.Ό5 ),提示 SPRC 在分子水平降低了凋亡相关基因 Bax,提高 CSE基因水平的表达(图.17 )。
实施例 12:证实 SPRC可以提高 ¾02损伤心肌细胞系 H9c2的存活率, 可降低 ¾02损伤 H9c2心肌细胞的 LDH的漏出率的实验
本实施例如图 18所示。
H9c2培养于含有 10°/。小牛血清的 DMEM中, 置 37Ό , 5%C02孵箱中 培养, 待细胞生长至 90%单层传代。 调细胞密度为 5X10-4/孔, 接种于 96 孔板。 分为:
正常对照组(Control ) :. 不给予药物干预, 不缺氧缺糖) ;
模型组(Model ) : 不给予药物干预, 20(^mol/L H2O2作用 2小时); PAG组(PAG ): PAG l(T4 mol/L;
SPRC各剂量组: SPRC 1Ε-7、 SPRC 1Ε-6、 SPRC 1E-5 ,分别给予 SPRC
MTT法检测细胞存活率, 结果显示(图 18A ) , 模型组存活率明显低 于正常对照组, SPRC 中剂量组和高剂量组均能明显提高细胞存活率 (p<0.05 ) 。 PAG可阻断 SPRC对细胞的保护作用。
每组 ( n = 4 )每个样本取 106个细胞, 充分裂解, 丙酮酸法检测细胞 内 LDH的含量, 结果如图.18B所示, SPRC各剂量组的 LDH漏出率较模 型组均明显降低, 而 PAG可以显著阻断 SPRC的保护作用,说明 SPRC的 心血管保护作用至少部分与内源性生成 H2S有关。
表 4是 SPRC提高 H202损伤心肌细胞系 H9c2的存活率, P争低 ¾02 损伤 H9c2心肌细胞的 LDH的漏出率结果。
表 4
细胞存活率(% ) LDH露出率(% ) 正常对照组 100.0±2.4 0.0±3.6
模型组 59.4士 0.9 # 54.2±0.9 #
PAG组 58.9士 1 ,2 63.4±1.2
SPRC低剂量组 62.4±1.6 51.4±1.8
SPRC中剂量组 64.1±1.5* 50.0±2.6*
SPRC高剂量组 69.1±1.1* 43.9±3.0*
SPRC+PAG组 60·9±0.3 & 60.6±1.9 & 实施例 13:证实 SPRC可提高 SOD的活性,抑制脂质过氧化产物 MDA 产生的实验。
本实施例如图 19所示。
¾02损伤心肌细胞系 H9c2, 随机分为正常对照组(Control ) , 模型 组(Model ) , PAG组(PAG ) , SPRC低、 中、 高剂量组, 分组情况同 实施例 12。
结果显示(图.19A ) , SPRC中高剂量组均能明显提 Mn-SOD的活力, 较模型组显著升高 (/?<0.05 ) , 此作用可被 PAG阻断, 说明 SPRC显著提 高 Mn-SOD的活力, 其作用至少部分与 H2S产生有关。
模型组与正常对照组相比 MDA含量显著增高 (图.19B ) ( ?<0.05 ) 。 SPRC低、 中、 高剂量组较模型组均明显降低, 证实 SPRC可抑制活性氧 诱导的脂质过氧化, 且 PAG可阻断其作用。
表 5是 SPRC提高 SOD'的活性, 抑制脂质过氧化产物 MDA的结果。 表 5
Mn-SOD 活 力 MDA 含 量
( U/mgprot ) ( nmol/mgprot )
正常对照組 9.23±0.19 1.25±0.12
模型組 8.46±0.66 2.28±0.10 #
PAG组 7.57±0.83 2.71±0.26
SPRC低剂量组 8.75±0.68 1.89±0.09*
SPRC中剂量组 9.89±0.83* 1.70±0.08*
SPRC高剂量组 12.45±1.63* 1.42±0.04*
SPRC+PAG组 8.78±0.74 & 2.21±0,19 &
实施例 14: 证实 SPRC具有抑制心肌细胞凋亡作用的实验 本实施例如图 20所示。
H202损伤心肌细胞系 H9c2, 随机分为正常对照組(Control ) , 模型 组(Model ) , PAG组(PAG ) , SPRC低、 中、 高剂量组, 分组情况同 实施例 12。
Hoechst及 PI双染证实了所述 SPRC对凋亡的抑制作用 (图.20 ) , 心 肌细胞的凋亡对于心脏的结构和功能具有很大的损害作用, 是发生心功能 衰竭的诸多原因之一, 本实验在整体动物模型中从基因和蛋白水平证实了 SPRC的抗凋亡作用,并在细胞水平,通过 Hoechst和 PI双染法验证 SPRC 在不受其他因素干扰下对 ¾02诱导 H9c2 心肌细胞凋亡的作用。 证实了 SPRC在心脏病的治疗中具有重要应用价值。
Claims
1、 以下式 I化合物在制备用于预防和 /或治疗心肌损伤的药物中的应 用:
式 I
其中, R选自 -C5的直链或支链烷基、 d-C5的链烯基和链炔基, 优 选端烯和端炔; 并且, 所述的式 I化合物是以其化合物本身、 其药学上可 接受的盐或溶剂化物存在的。
2、 权利要求 1所述的用途, 其中所述心肌损伤性心脏病是缺血缺氧 心肌损伤心脏病。
3、 以下式 I化合物在制备具有提高细胞存活率、生成内源性 H2S、 降 低缺氧缺糖损伤心肌细胞的 LDH的漏出率、 提高 SOD和 /或 Catalase的 活性、 提高组织抑制羟自由基产生的能力、 抑制脂质过氧化和 /或抑制心 肌细胞凋亡作用的药物中的应用:
式 I
其中, R选自 d-C5的直链或支链烷基、 d-C5的链烯基和链炔基, 优 选端烯和端炔; 并且, 所述的式 I化合物是以其化合物本身、 其药学上可 接受的盐或溶剂化物存在的。
4、 以下式 I化合物、 其药学上可接受的盐或其溶剂化物在制备具有 通过减少心肌梗死面积、减轻乳酸脱氢酶和肌酸肌酶的释放、提高超氧化 物歧化酶的活性、 减小丙二醛的水平、 内源性生成^ 氢和 /或抑制凋亡
作用的药物中的应用:
其中, R选自 d-C5的直链或支链烷基、 d-C5的链烯基和链炔基,优 选端烯和端炔。
5、权利要求 1-4任一项所述的用途, 其中所述的式 I化合物选自: 烯 丙基半胱氨酸、 乙基半胱氨酸、 丙基半胱氨酸、婦丙基巯基半胱氨酸、 丁 基半胱氨酸、戊基半胱氨酸和炔丙基半胱氨酸,优选为烯丙基半胱氨酸和 炔丙基半胱氨酸, 最优选为烯丙基半胱氨酸。
6、 权利要求 1-5任一项的应用, 其中所述药物的剂型选自: 口服制 剂、 肠胃外给药制剂、 局部给药制剂、 吸入式给药制剂和透皮制剂。
7、一种用于预防和 /或治疗心肌损伤的药物组合物, 所述药物 组合物包含:
作为活性组分的式 I化合物、 其药学上可接受的盐或其溶剂 化物:
式 I
其中, R选自 d-C5的直链或支链烷基、 d-Cs的链烯基和链 炔基, 优选端烯和端炔;
以及一种或多种药学上可接受的载体。
8、权利要求 7的药物组合物,其中所述式 I化合物的溶剂^ «物是水 合物。
9、 权利要求 7或 8的药物组合物, 其中所述的式 I化合物选自: 烯
丙基半胱氨酸、 乙基半胱氨酸、 丙基半胱氨酸、 烯丙基巯基半胱氨酸、 丁 基半胱氨酸、戊基半胱氨酸和炔丙基半胱氨酸,优选为烯丙基半胱氨酸和 炔丙基半胱氨酸, 最优选为烯丙基半胱氨酸。
10、 权利要求 7-9任一项的药物组合物, 其中所述药物组合物为: 口 服制剂、肠胃外给药制剂如注射剂、局部给药制剂、吸入式给药制剂或透 皮制剂。
11、 权利要求 10的组合物, 其中所述药物组合物为选自如下的口服 制剂: 片剂、 胶嚢剂、 颗粒剂、 丸剂、 滴剂、 果汁或糖浆剂; 优选地, 所 述药学上可接受的载体选自: 崩解剂、 润滑剂、 粘合剂、 填充剂、 溶剂、 香料、 甜味剂、 抗氧化剂、 表面活性剂、 防腐剂、 矫味剂和色素。
12、 一种以下式 I化合物的制备方法:
其中, R选自 C Cs的直链或支链烷基、 CrC5的链烯基和链 炔基, 优选端烯和端炔; '
所述方法包括以下步骤 .·
将 L-半胱氨酸盐酸盐溶解在预冷的 ¾OH溶液中,加入 Br-R搅拌, 取代基 R的定义如前; 混合溶液在 0 -5Ό下搅拌 1-5小时后过滤, 滤液减 压蒸傭、 浓缩后再过滤, 析出固体用乙醇反复洗漆后, 真空蒸干, 经 1: 3-3: 1体积比的水 /乙醇重结晶即得。
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KR101188746B1 (ko) * | 2009-09-23 | 2012-10-11 | 주식회사파마킹 | 에스-알릴-엘-시스테인을 유효성분으로 포함하는 위장질환 예방 또는 치료용 조성물 |
CN102077965A (zh) * | 2010-12-14 | 2011-06-01 | 吕昌龙 | 一种制备黑大蒜及从中提取活性物质的方法 |
CN102757478B (zh) * | 2011-04-27 | 2013-11-20 | 首都医科大学 | 烯丙基半胱氨酸氨基酸衍生物及其合成方法和应用 |
CN102757477B (zh) * | 2011-04-27 | 2014-09-03 | 首都医科大学 | 烯丙基半胱氨酰氨基酸甲酯衍生物及其合成方法和应用 |
CA2847589C (en) * | 2011-09-14 | 2019-11-26 | Nuevas Alternativas Naturales, S.A.P.I. de C.V. | Preparation and compositions of highly bioavailable zerovalent sulfur and uses thereof |
CN103284987A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备防治心血管系统炎症相关疾病药物中的用途 |
CN103284988A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备治疗免疫相关炎症疾病药物中的用途 |
KR101423631B1 (ko) * | 2012-08-17 | 2014-07-25 | 주식회사파마킹 | 에스-알릴엘-시스테인을 유효성분으로 포함하는 안질환 예방 또는 치료용 조성물 및 이를 포함하는 의약제제 |
WO2014130992A1 (en) * | 2013-02-25 | 2014-08-28 | New York University | Methods and agents for preventing and treating plasma cell dyscrasias |
JP6074380B2 (ja) * | 2014-03-31 | 2017-02-01 | 株式会社ダイセル | テストステロン産生促進剤 |
JP2015196688A (ja) * | 2014-10-06 | 2015-11-09 | ユニチカ株式会社 | テストステロン産生促進剤 |
JP7163052B2 (ja) * | 2018-04-06 | 2022-10-31 | 株式会社ダイセル | S-アリルシステインの製造方法 |
KR102619728B1 (ko) * | 2023-06-09 | 2024-01-02 | 주식회사 바이오360 | 황 함유 발효흑마늘 sac를 유효성분으로 하는 열안정성 개선 구강붕해필름 및 이의 제조방법 |
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US8623919B2 (en) | 2014-01-07 |
JP2010535158A (ja) | 2010-11-18 |
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