CN108017681B - O-aryl glycoside derivative, pharmaceutical composition and application thereof - Google Patents
O-aryl glycoside derivative, pharmaceutical composition and application thereof Download PDFInfo
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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Abstract
The invention relates to an O-aryl glucoside derivative, a preparation method thereof, a medicine or a medicine composition prepared from the O-aryl glucoside derivative and application of the O-aryl glucoside derivative and the medicine composition. The O-aryl glycoside derivative (I), isomer, prodrug, solvate or pharmaceutically acceptable salt thereof of the present invention has the following structure. The O-aryl glucoside derivative has good effect of treating ischemic nerve injury, particularly has no strict time window limitation in treating ischemic nerve injury after stroke molding, and can be continuously administered for multiple times within 7 days to generate better curative effect.
Description
Technical Field
The invention relates to an O-aryl glucoside derivative, an isomer, a prodrug, a solvate and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition and application thereof.
Background
Stroke (stroke) is a disease in which the rupture or blockage of cerebral blood vessels causes nerve damage, and is one of the three major causes of death in humans. There are about 1500 million new strokes per year, of which about 80% are ischemic strokes and more silent strokes or luminal peduncles without significant clinical symptoms. Diabetes, hypertension, coronary heart disease, middle-aged and elderly people and the like are people with high stroke. Stroke survivors present with a variety of physical disabilities, commonly associated with post-stroke depression and cognitive dysfunction, have created a heavy social and economic burden.
Current pharmacotherapy against stroke is focused mainly on improving cerebral blood circulation and protection from nerve damage. Measures to improve cerebral blood circulation are mainly thrombolytic drug such as tPA therapy, and antiplatelet aggregation drug and anticoagulant drug therapy to avoid the second stroke. The time window for thrombolytic therapy has long been severely limited, only 3-4.5 hours after stroke, and only about 5% of stroke patients benefit, since thrombolytic drug treatment beyond this time window can exacerbate nerve damage. In contrast, clinical trials with over 120 neuroprotective agents failed inefficiently, while most of the neuroprotective agents approved for marketing were not effective in clinical applications.
In conclusion, there is an urgent need in the medical field to discover and develop innovative drugs that can be used to treat stroke, break through the time window limitation of treatment, and have low side effects and high efficacy.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel O-aryl glucoside derivative, a preparation method thereof, a pharmaceutical composition and application thereof. The O-aryl glycoside derivative has good effect of treating ischemic nerve injury, and has no strict limitation of treatment time window.
The invention provides an O-aryl glycoside derivative (I), an isomer, a prodrug, a solvate or a pharmaceutically acceptable salt thereof;
wherein X is-OR1、-NR2R2aor-SR3；
Y is cyano, -OR1、-NR2R2a、-SR3、-NR2S(O)2R4、-S(O)2NR2R2a、-S(O)2R4、-CR5R5a-Z, or Z;
r is C1-4Alkyl, halogen, or C1-3A haloalkyl group;
Ra、Rband RcAre each independently H, C1-4An alkyl or acyl group;
R1is H, C1-4Alkyl, acyl, -P (O) (OR)6)2、-S(O)1-2(OR7)、-P(O)(OR6)-Z、-S(O)1-2-Z, or Z;
R2and R3Are each independently H, C1-4Alkyl, acyl, or Z;
R2ais H, C1-4Alkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl;
R4is H, hydroxy, amino, alkylamino, C1-4Alkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-Z, or Z;
R5and R5aEach independently is H, halogen, or C1-4An alkyl group;
R6and R7Are each independently H, C1-6Alkyl, or Z;
z is
R8Is C1-4An alkyl group;
R9is H, C1-4Alkyl, or acyl; or, R8And R9Are linked to each other to form a 5-8 membered heterocycloalkyl group, said heterocycloalkyl group further comprising 1-2 heteroatoms or groups as follows: n, O, S, S (O)1-2Or C (O);
and, the compounds of formula I do not include the following:
3-hydroxy-5-methylphenyl- β -D-glucopyranoside;
3-hydroxy-5-n-propylphenyl- β -D-glucopyranoside;
orcinol ferulate-beta-D-glucopyranoside.
Wherein, in R, the C1-4The alkyl group is preferably methyl; halogen is preferably F or Cl; c1-3The haloalkyl group is preferably CF3。
Ra、Rb、Rc、R1、R2、R2a、R3、R4Or R9The acyl group is preferably an alkylacyl group or an arylacyl group; more preferably acetyl.
In a preferred embodiment of the present invention, the O-aryl glycoside derivative (I), an isomer, a prodrug, a solvate or a pharmaceutically acceptable salt thereof, has a general formula preferably as follows:
wherein, X is OR1、NR2R2a、SR3；
V is a connecting bond, -O-, -S-, -NR2a-、-NR2S(O)2-、-S(O)2-、-CR5R5a-、-OP(O)(OR6)-、-OP(O)(OR6)O-、-S(O)2O-、-OS(O)1-2-、-OS(O)1-2O-, or-S (O)2NR2a-；
R is C1-4Alkyl, halogen, or C1-3A haloalkyl group;
Ra、Rband RcAre each independently H, C1-4An alkyl or acyl group;
R1is H, C1-4Alkyl, acyl, -P (O) (OR)6)2or-S (O)1-2(OR7)；
R2And R3Are each independently H, C1-4Alkyl, acyl;
R2ais H, C1-4Alkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R5and R5aEach independently is H, halogen, or C1-4An alkyl group;
R6and R7Each independently is H, or C1-8An alkyl group;
R8is C1-4An alkyl group;
R9is H, C1-4Alkyl, or acyl; or, R8And R9Are linked to each other to form a 5-8 membered heterocycloalkyl group, said heterocycloalkyl group further comprising 1-2 heteroatoms or groups as follows: n, O, S, S (O) 1-2Or C (O);
and, the compounds of formula IA do not include the following:
orcinol ferulate-beta-D-glucopyranoside.
Included in the definition of structural formula (IA) are each:
in one preferred embodiment, X is OR1；
In one preferred embodiment, R8Is methyl;
in one of the preferred embodiments, R9Is H or acetyl;
in one of the preferred embodiments, the first and second,Ra、Rband RcEach independently is H or acetyl.
In a preferred embodiment of the present invention, the O-aryl glycoside derivative (I), an isomer, a prodrug, a solvate or a pharmaceutically acceptable salt thereof, has a general formula more preferably as follows:
wherein Y is cyano, -OR1、-NR2R2a、-SR3、-NR2S(O)2R4、-S(O)2R4or-S (O)2NR2R2a；
W is-O-, -S-, or-NR2a-；
R is C1-4Alkyl, halogen, or C1-3A haloalkyl group;
Ra、Rband RcAre each independently H, C1-4An alkyl or acyl group;
R1is H, C1-4Alkyl, acyl, -P (O) (OR)6)2or-S (O)1-2(OR7)；
R2And R3Are each independently H, C1-4Alkyl, acyl;
R2ais H, C1-4Alkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R4is H, hydroxy, amino, alkylamino, C1-4Alkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R6And R7Each independently is H, or C1-8An alkyl group;
R8is C1-4An alkyl group;
R9is H, C1-4Alkyl, or acyl; or, R8And R9Are linked to each other to form a 5-to 8-membered heterocycloalkyl group, said heterocycloalkyl group further comprising 1-2 heteroatoms or groups as follows: n, O, S, S (O)1-2Or C (O).
Included in the definition of structural formula (IB) are each:
in one preferred embodiment, Y is OR1；
In one of the preferred embodiments, R8Is methyl;
in one of the preferred embodiments, R9Is hydrogen or acetyl;
in one of the preferred embodiments, Ra、RbAnd RcEach independently is H or acetyl.
The O-aryl glycoside derivative (I), isomer, prodrug, solvate or pharmaceutically acceptable salt thereof is optimally any of the following structures:
the pharmaceutically acceptable salts of the O-aryl glycoside derivatives (I) can be synthesized by a general chemical method.
In general, salts can be prepared by reacting the free base or acid with equal chemical equivalents or an excess of acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.
The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of active components and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of O-aryl glucoside derivatives (I), isomers, prodrugs and pharmaceutically acceptable salts thereof.
The medicament or pharmaceutical composition may further comprise other therapeutic agents for treating nerve damage.
In the medicament or the pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include a pharmaceutically acceptable carrier, diluent and/or excipient.
The pharmaceutical composition can be formulated into various types of administration unit dosage forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably liquids, suspensions, emulsions, suppositories, injections (solutions and suspensions), and the like.
For shaping the pharmaceutical composition in the form of tablets, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. Optionally, conventional coating materials can be selected to make into sugar-coated tablet, gelatin film-coated tablet, enteric coated tablet, film-coated tablet, double-layer film tablet and multilayer tablet.
For shaping the pharmaceutical composition in the form of pellets, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.
For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.
For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added.
In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, wherein the O-aryl glycoside derivative (I), the isomer, prodrug, solvate, or pharmaceutically acceptable salt thereof can be selected from a wide range, and the safe and effective dose thereof is determined according to the age, body weight, disease condition, disease course, administration route, etc. of the subject to be treated, and usually may be 5 to 95% by mass, preferably 30 to 80% by mass.
In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; the injection can be administered alone or mixed with infusion solution (such as glucose solution and amino acid solution) for intravenous injection; the suppository is administered to the rectum.
The invention also provides the application of the O-aryl glucoside derivative (I), the isomer, the prodrug, the solvate or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing a medicament for treating nerve injury. Wherein the nerve damage includes, but is not limited to: nerve damage caused by ischemic stroke, hemorrhagic stroke and other types of nerve damage such as vascular dementia and neurodegenerative diseases, and direct or indirect nerve damage caused by chronic inflammation, diabetes, hypertension, coronary heart disease or brain trauma.
The invention also provides the O-aryl glycoside derivative (I), the isomer, the prodrug, the solvate or the pharmaceutically acceptable salt thereof and one or more other therapeutic agents for treating nerve injury diseases.
The invention also provides the application of the O-aryl glycoside derivative (I), the isomer, the prodrug, the solvate or the pharmaceutically acceptable salt thereof and one or more other therapeutic agents in combination for preparing the medicament for treating nerve injury.
The other therapeutic agents may be administered in a single therapeutic dosage form or in separate therapeutic dosage forms sequentially with the O-aryl glycoside derivative (I), isomer, prodrug, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
Unless otherwise indicated, the following terms appearing in the specification and claims of the present invention have the following meanings:
the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8, 1 to 6, 1 to 4, 1 to 3 carbon atoms, representative examples of alkyl groups including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4-dimethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3 to 20 carbon atoms. Preferably 3-12 membered cycloalkyl. "monocyclic cycloalkyl" is preferably 3-10 membered monocyclic cycloalkyl, more preferably 3-8 membered monocyclic cycloalkyl, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "polycyclic cycloalkyl" includes "bridged cyclic groups", "fused cycloalkyl" and "spirocycloalkyl", representative examples of "bridged cyclic groups" include, but are not limited to: bornyl, bicyclo [2.2.1] heptenyl, bicyclo [3.1.1] heptenyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.2] nonanyl, bicyclo [3.3.1] nonanyl, bicyclo [4.2.1] nonanyl, adamantyl, and the like. "fused cycloalkyl" includes cycloalkyl rings fused to phenyl, cycloalkyl, or heteroaryl groups, and fused cycloalkyl groups include, but are not limited to: benzocyclobutene, 2, 3-dihydro-1-H-indene, 2, 3-cyclopentenopyridine, 5, 6-dihydro-4H-cyclopentyl [ B ] thiophene, decahydronaphthalene and the like. Representative examples of "spirocycloalkyl" include, but are not limited to: spiro [2,4] heptanyl, spiro [4,5] decanyl, and the like. The monocyclic cycloalkyl or polycyclic cycloalkyl groups can be linked to the parent molecule through any carbon atom in the ring.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur, which cyclic group may be a monocyclic or polycyclic group, in the present invention the number of heteroatoms in the heterocycloalkyl is preferably 1,2,3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl may optionally be oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts. "monocyclic heterocycloalkyl" is preferably 3-10 membered monocyclic heterocycloalkyl, more preferably 3-8 membered monocyclic heterocycloalkyl. For example: aziridinyl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl, and the like. "polycyclic heterocycloalkyl" includes "fused heterocycloalkyl", "spiroheterocyclyl", and "bridged heterocycloalkyl". "fused heterocycloalkyl" includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl or heteroaryl group, including but not limited to: 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, indolinyl, 2, 3-dihydrobenzo [ b ] thienyl, dihydrobenzopyranyl, 1,2,3, 4-tetrahydroquinolyl, and the like. Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl can be linked to the parent molecule through any ring atom in the ring. The above ring atoms particularly denote carbon atoms and/or nitrogen atoms constituting the ring skeleton.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent core structure through an alkyl group. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl above.
The term "heterocycloalkylalkyl" refers to a linkage between a heterocycloalkyi and the parent core structure through an alkyl group. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl described above.
The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group, for example: phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, or the like.
The term "heteroaryl" refers to an aromatic ring group formed by replacement of at least 1 ring carbon atom with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic ring structure or a 7-12 membered bicyclic ring structure, preferably a 5-6 membered heteroaryl. In the present invention, the number of hetero atoms is preferably 1,2 or 3, and includes pyridyl, pyrimidyl, pyridazin-3 (2H) -onyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, tetrazolyl, indazolyl, isoindolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzo [ d ] [1,3] dioxolanyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.
The term "arylalkyl" refers to an alkyl linkage between an aryl group and the parent nucleus structure. Thus, "arylalkyl" encompasses the above definitions of alkyl and aryl groups.
The term "heteroarylalkyl" refers to a heterocycloalkyl group attached to the parent nucleus structure through an alkyl group. Thus, "heteroarylalkyl" embraces the definitions of alkyl and heteroaryl as described above.
The term "halogen" denotes fluorine, chlorine, bromine or iodine.
The term "acyl" refers to the group-C (O) -R 'including alkanoyl, cycloalkylacyl or arylacyl, wherein R' is independently selected from alkyl, cycloalkyl or aryl, said alkyl or aryl being unsubstituted or independently selected from C by 1 to 31-4Alkyl, halogen, nitro, trihalomethyl, C1-3One or more groups in the alkoxy group are substituted at any position. The acyl group includes, but is not limited to: acetyl, benzoyl, trifluoroacetyl, and the like.
The term "amino" refers to the group-NH2The term "alkylamino" refers to an amino group wherein at least one hydrogen atom is replaced by an alkyl groupIncluding but not limited to: -NHCH2、-NHCH2CH3. Thus, "alkylamino" encompasses the above definitions of alkyl and amino.
The "room temperature" of the invention means 15-30 ℃.
By "prodrug" is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.
The "solvate" as referred to herein refers to a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar proportion of solvent molecules in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a "hydrate", and if the solvent is ethanol, the solvate formed is an ethanolate. The hydrate is formed by combining one or more water molecules with the substance, wherein the state of the water molecules is H2O, such combination being capable of forming a hydrate comprising one or more water molecules.
The "Pharmaceutically acceptable salts" described herein are discussed in Berge, et al, "pharmaceutical acceptable salts", j.pharm.sci.,66,1-19(1977), and are apparent to the pharmaceutical chemist that they are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, excretion, etc. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with an acid, for example: hydrochloride, hydrobromide, sulphate, pyrosulphate, hydrogen sulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, benzoate, methylbenzoate, phthalate, maleate, methanesulphonate, p-toluenesulphonate, (D, L) -tartaric acid, citric acid, maleic acid, (D, L) -malic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulphonate, naphthalene-1-sulphonate, mandelate, pyruvate, stearate, ascorbate, salicylate. When the compound of the present invention contains an acidic group, pharmaceutically acceptable salts thereof may further include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; examples of the organic base salt include salts with ammonia, alkylamines, hydroxyalkylamines, amino acids (lysine and arginine), and N-methylglucamine.
The term "isomers" as used herein means that the compounds of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, and all such isomers, including stereoisomers and geometric isomers, are encompassed by the present invention. Among them, the "isomer" in the present invention is preferably a "stereoisomer". In the present invention, when the compound of formula (I) or a salt thereof exists in stereoisomeric forms (e.g., which contain one or more asymmetric carbon atoms), individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The invention also includes individual isomers of the compounds or salts represented by formula (I), as well as mixtures of isomers in which one or more chiral centers are inverted. The scope of the invention includes: mixtures of stereoisomers, and purified enantiomerically or enantiomerically/diastereomerically enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all the specific groups defined above. The invention also includes geometric isomers, including cis-trans isomers, of the compounds of formula (I) or salts thereof.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The structures of all compounds of the invention can be determined by nuclear magnetic resonance1H NMR) and/or mass spectrometric detection (MS).
1H NMR chemical shifts (. delta.) are recorded by PPM (10)-6). NMR was performed on a Bruker AVANCE-400 spectrometer. A suitable solvent is deuterated chloroform (CDCl)3) Deuterated methanol (MeOD-d)4) Deuterated dimethyl sulfoxide (DMSO-d)6) Tetramethylsilane as internal standard (TMS).
Liquid chromatography-mass spectrometry (LCMS) was determined by Agilent 1200HPLC/6120 mass spectrometer using Xbridge C18, 4.6X 50mm, 3.5 μm, gradient elution conditions one: 80-5% of solvent A1And 20-95% of solvent B1(1.8 min) and then 95% solvent B1And 5% solvent A1(over 3 minutes) as a volume percent of a solvent based on the total solvent volume. Solvent A 1: 0.01% trifluoroacetic acid (TFA) in water; solvent B1: 0.01% trifluoroacetic acid in acetonitrile; the percentages are the volume percent of solute in solution. Gradient elution conditions two: 80-5% of solvent A2And 20-95% of solvent B2(1.5 min) and then 95% solvent B2And 5% of solvent A2(over 2 minutes) as a volume percent of a solvent based on the volume of the total solvent. Solvent A2: 10mM ammonium bicarbonate in water; solvent B2: and (3) acetonitrile.
The compound of the invention can be separated and purified by using a conventional column chromatography, a flash separator or a high performance liquid chromatography, and an elution system can be an ethyl acetate/petroleum ether system or a dichloromethane/methanol system.
Flash system/Cheetah flash column chromatographyTM) Agela Technologies MP200 is used, and F is used as a matched separation columnlash columm Silica-CS(80g)，Cat No.CS140080-0。
High performance liquid chromatograph (prep-HPLC) using shimadzu LC-20 for liquid chromatography, column: waters xbridge Pre C18, 10um, 19mm 250 mm. Mobile phase A: 0.05% aqueous trifluoroacetic acid (percentage is volume percent), mobile phase B: acetonitrile; detection wavelength: 214nm &254 nm; flow rate: 15.0 mL/min.
The column chromatography generally uses 200-mesh and 300-mesh silica gel of the yellow sea of the tobacco station as a carrier. The thin-layer silica gel plate (TLC) is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate.
Example 1: synthesis of Compound 1-1
Step 1: synthesis of Compound 1.1
Orcinol (10g, 82.6mmol) and imidazole (6.03g, 80.6mmol) were dissolved in dichloromethane (250mL) under ice-bath, and tert-butyldimethylchlorosilane (12.1g, 80.6mmol) was added dropwise. The reaction was then stirred at room temperature overnight. After TLC monitoring indicated that the starting material was reacted completely, the reaction solution was washed with water (50mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound 1.1(8.8g, 46% yield) as a colorless oil.
Step 2: synthesis of Compound 1.2
Ferulic acid (3g, 15.5mmol) was dissolved in pyridine (5mL) under ice-bath, and acetic anhydride (4.5mL) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid (3M), and then extracted with ethyl acetate (10mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dichloromethane (40mL) and oxalyl chloride (5.5g, 43.4mmol) and a catalytic amount of N, N-dimethylformamide were added under ice bath. After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction system was concentrated to give compound 1.2(2.95g) as a pale yellow solid.
And step 3: synthesis of Compound 1.3
To compound 1.1(6.7g, 28.1mmol) and D-glucose pentaacetate (11g, 28.1mmol) in dichloromethane (100mL) under ice bath was added dropwise boron trifluoride ether (3.99g, 28.1mmol) and after completion of addition, the reaction was stirred at room temperature overnight. The reaction solution was adjusted to pH 8 with an aqueous solution of sodium hydroxide (1M), and the solution was separated. The organic phase was dried over anhydrous sodium sulfate and spin dried. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate ═ 4:1) to give compound 1.3(3.4g, 21% yield) as a white solid.
And 4, step 4: synthesis of Compound 1.4
Compound 1.3(4.0g, 7mmol) and tetrabutylammonium fluoride (1.83g,7mmol) were dissolved in tetrahydrofuran (120mL), followed by stirring at room temperature for 30 minutes. The reaction was diluted with water (120mL) and extracted with ethyl acetate. The organic phase was spin dried to give compound 1.5(4.1g) as a wine red solid.
And 5: synthesis of Compound 1-1
To a solution of compound 1.4(4.1g, 7mmol) and triethylamine (1.96mL, 14mmol) in dichloromethane (67mL) was slowly added dropwise a solution of compound 1.2 in dichloromethane (2.4g, 8.4mmol, 67 mL). After the addition, the reaction was stirred at room temperature for 2 hours. The reaction was then concentrated and the crude product was purified by flash column chromatography (petroleum ether: ethyl acetate 5:2) to give compound 1-1(3.5g, 73%) as a white solid.
1H NMR(400MHz,CD3OD):δ7.87(d,J＝16.0Hz,1H),7.42(d,J＝1.8Hz,1H),7.29(dd,J＝8.2,1.8Hz,1H),7.12(d,J＝8.2Hz,1H),6.83–6.59(m,4H),5.48–5.29(m,2H),5.25–5.06(m,2H),4.30(dd,J＝12.0,5.6Hz,1H),4.22–4.05(m,2H),3.89(d,J＝6.4Hz,3H),2.37(s,3H),2.30(d,J＝4.4Hz,3H),2.05(dd,J＝9.8,4.4Hz,8H),2.02(s,3H)。
m/z:[M+H2O]+689.8
Example 2: synthesis of Compound 1-2
Step 1: synthesis of Compound 2.1
Compound 1.3(1g,1.76mmol) and sodium methoxide (95mg,1.76mmol) were dissolved in methanol (50mL), and the reaction was stirred at room temperature for 2 hours. The reaction was acidified with acetic acid at pH 6 and spun dry. The crude product was purified by flash column chromatography (dichloromethane: methanol ═ 15:1) to give compound 2.1(600mg, 89% yield) as a white solid.
Step 2: synthesis of Compound 2.2
To a solution of compound 1.2(440mg, 1.0mmol) in pyridine (10mL) was added dropwise a toluene solution of compound 2.1 (256mg, 1.0mmol, 30 mL). The reaction was stirred at room temperature overnight and concentrated directly, and the residue was purified by flash column chromatography (dichloromethane: methanol ═ 15:1) to give compound 2.2(230mg, yield 37%) as a white solid.
And step 3: synthesis of Compound 1-2
To a solution of compound 2.2(230mg,0.4mmol) in dichloromethane (3mL) was added 3-pyrroline (0.25mL) dropwise. The reaction system was stirred at room temperature for 5 minutes and then concentrated, and the residue was purified by flash column chromatography (dichloromethane: methanol ═ 10:1), and the purified product was dissolved in tetrahydrofuran (3mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.4mL, 0.4mmol) was added dropwise. Stirred at room temperature for 30 minutes. The reaction was concentrated and the crude product was purified by prep-HPLC to give compound 1-2(42mg, 26% yield) as a white solid.
1H NMR(400MHz,CD3OD)δ7.63(d,J＝15.6Hz,1H),7.19(s,1H),7.08(d,J＝8.0Hz,1H),6.82(d,J＝8.4Hz,1H),6.48-6.30(m,3H),6.27(s,1H),4.80-4.88(m,1H,overlapped with water signal),4.56(d,J＝12.4Hz,1H),4.33-4.25(m,1H),3.90(s,3H),3.72-3.68(m,1H),3.50-3.40(m,3H),2.17(s,3H)。
m/z:[M+H]+463.1
Example 3: synthesis of Compounds 1-3
Step 1: synthesis of Compound 3.1
To a solution of orcinol (10g, 0.08mol) in acetonitrile (250mL) was added potassium carbonate (33g, 0.24mol) and benzyl bromide (15.4g, 0.09mol), and the reaction was stirred at 80 ℃ overnight. The reaction system is filtered, and the filtrate is dried by spinning. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate ═ 4:1) to give compound 3.1(6.5g, yield: 38%) as a yellow oil.
Step 2: synthesis of Compound 3.2
To a solution of D-glucose pentaacetate (11.7g, 0.03mmol) and compound 3.1(6.5g, 0.03mol) in dichloromethane (50mL) was added dropwise boron trifluoride diethyl etherate (4.3g, 0.03 mol). The reaction was stirred at room temperature overnight. The reaction solution was adjusted to pH 6 with an aqueous sodium hydroxide solution (1M), and concentrated. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give compound 3.2(5.7g, yield: 36%) as a yellow oil.
And 3, step 3: synthesis of Compound 3.3
To a solution of compound 3.2(4.7g, 8.63mmol) in methanol (80mL) was added sodium methoxide (932mg, 17.3mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 6 with acetic acid and concentrated. The crude product was purified by flash column chromatography (methanol: dichloromethane ═ 1:10) to give compound 3.3(2.7g, yield: 84%) as a white solid.
And 4, step 4: synthesis of Compound 3.4
To a solution of compound 3.3(1.7g, 4.52mmol) in pyridine (20mL) was added p-toluenesulfonyl chloride (1.3g, 6.78mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100mL), washed with hydrochloric acid (1.0M), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash column chromatography (methanol: dichloromethane ═ 1:11) to give compound 3.4(1.1g, yield: 46%) as a white foamy solid.
And 5: synthesis of Compound 3.5
Compound 3.4(1.1g, 2.1mmol) and sodium azide (682mg, 10.5mmol) were dissolved in N, N-dimethylformamide (10mL), and the reaction was stirred at 80 ℃ overnight. The reaction solution was diluted with ethyl acetate (30mL), washed with water (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give compound 3.5(1.1g) as a yellow oil.
Step 6: synthesis of Compound 3.6
Compound 3.5(1.1g, 2.74mmol) was dissolved in methanol (30mL), followed by addition of palladium on carbon (100mg), and the suspension was stirred overnight at 40 ℃ under hydrogen atmosphere. LCMS detection reaction was complete. The reaction solution was concentrated by filtration to give compound 3.6(600mg, yield: 77%) as a yellow solid.
And 7: synthesis of Compound 3.7
To a solution of compound 3.6(200mg, 0.70mmol) and compound 1.2(165mg, 0.70mmol) in N, N-dimethylformamide (3mL) were added N, N-diisopropylethylamine (181mg, 1.4mmol) and HATU (293mg, 0.77mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (20mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry. The crude product was purified by flash column chromatography (dichloromethane: methanol ═ 11:1) to give compound 3.7(180mg, yield: 40%) as a yellow solid.
And step 8: synthesis of Compounds 1-3
Compound 3.7(130mg, 0.26mmol) and sodium methoxide (28.1mg, 0.52mmol) were dissolved in methanol (3mL), and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (10mL), and the organic phase was washed with water (10mL) and saturated sodium chloride (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and spin dried. The crude product was purified by prep-HPLC to give compounds 1-3(60mg, yield: 50%) as white solids.
1H NMR(400MHz,CD3OD):δ7.49(d,J＝15.2Hz,1H),7.15(d,J＝1.8Hz,1H),7.05(dd,J＝8.2,1.6Hz,1H),6.82(d,J＝8.2Hz,1H),6.50(d,J＝15.6Hz,1H),6.39(s,1H),6.34(t,J＝2.0Hz,1H),6.28(s,1H),4.85(t,J＝5.6Hz,2H),3.91(s,3H),3.85–3.72(m,1H),3.63–3.40(m,4H),3.26(t,J＝8.8Hz,1H),2.18(d,J＝8.2Hz,3H)。
m/z:[M+H]+462.2
Biological examples:
example 1: dose-effect relationship for compound 1-1 to treat ischemic nerve injury
(1) Laboratory animal
The experimental animal is purchased from SPF Kunming strain mice of university of Kunming medical science, male, and has a weight of 20-25g and a qualification number of SCXK (Yunnan) K2015-0002. The room temperature is controlled at 20-25 ℃, the humidity is 40-70%, the lighting time is 12 hours, the darkness is 12 hours, and the lamp-on time is as follows: 7: 00am, light-off time: 19: 00 pm. The rat box and padding were changed twice a week. The breeding mode is group breeding, and each cage has 10 animals. Feeding sterilized feed of Jiangsu cooperative medical bioengineering Limited company, feed qualification No.: (2014)01008. Feed was supplied once per cage per day with free access. Tap water is supplied by the drinking water box and is freely drunk by animals.
(2) Experimental method
Grouping:
a: compound 1-1 was administered intraperitoneally (i.p.) at different dose groups (1.0mg/kg, 2.5mg/kg, 5.0mg/kg, 10.0mg/kg, 20.0mg/kg) and vehicle control group (saline control);
b: compound 1-1 was gavaged (i.g.) to different dose groups (3.5mg/kg, 9.0mg/kg, 18.0mg/kg, 35.0mg/kg) and vehicle control (saline control).
The administration mode comprises the following steps: test compound 1-1 or normal saline was administered by intraperitoneal injection/intragastric administration according to the experimental design.
The administration time is as follows: the administration was immediately after the ischemia of the thrombus.
Detection indexes are as follows: maximum area of ischemic focus and total volume of ischemic focus
(3) Experimental procedure
A photochemical induction model of mouse hippocampal brain ischemic injury is adopted. Injecting Rose Bengal (Rose Bengal, Sigma, 100mg/kg) into abdominal cavity of mouse, placing back into breeding cage, injecting sodium pentobarbital (80mg/kg) into abdominal cavity, removing hair at top of head after animal is deeply anesthetized, sterilizing skin at top of head with iodophor, cutting off skin at top of head longitudinally at sagittal center, exposing skull, stripping skull surface connective tissue membrane, and trimming with scalpel. After the operation is finished, the animal is fixed on a brain stereotaxic apparatus, the bregma point of the bregma is taken as a reference origin, and a hole is punched corresponding to the surface of the skull (2.5 mm behind the bregma and 2.0mm beside the central suture). One end of the optical fiber (with the core diameter of 200 μm, FC/TC interface, single mode) is connected with the laser, and the other end is ground flat (with compact and uniform light spot) and then goes deep into the upper part of the hippocampus and descends 1.4mm from the surface of the skull. Blue laser (wavelength 473nm) was irradiated for 20 minutes at a light intensity of 30 mW. Sewing scalp after molding, placing on an operating table, keeping warm, and returning to the breeding cage after the animal is awake.
Immediately administering the medicine to mice of different experimental groups after the light embolism lacks blood, namely after the laser light is turned off, cutting off the head of the mouse after 24h, removing olfactory bulb, cerebellum and brainstem, and slicing the mouse by using a vibrating microtome under the environment of artificial hydrocephalus with the thickness of 350 mu m. Sections were soaked in 2.5% TTC solution and incubated for staining at 37 ℃ for 15min and then fixed in 4% PFA for 15 min. The normal brain tissue is stained red, and the white part is the ischemic brain area. Compared with a control group, the influence and the degree of the medicine on the ischemic nerve injury are evaluated according to evaluation parameters such as the maximum area and the volume of an ischemic focus.
(4) Data statistics
ImageJ counts the area of the ischemic spot; data were tested for One-Way analysis of variance using SPSS 11.0 software (One Way-ANOVA) with mean ± SEM, with significant differences set at P < 0.05. And (4) drawing a result graph by using Origin 8.0.
(5) Results of the experiment
After modeling of ischemic stroke, mice were given varying doses of compound 1-1 immediately by intraperitoneal injection. The results show that: the maximal area and volume of ischemic focus of each dose group (1.0mg/kg, 2.5mg/kg, 5.0mg/kg, 10.0mg/kg) of the compounds 1-1 were lower than those of the control group. The maximal area and volume of the ischemic focus of the 2.5mg/kg dose group differed significantly from those of the saline group (P <0.001), indicating that compound 1-1 significantly reduced the maximal area and total volume of nerve damage and had a significant dose-effect relationship. The detailed results are shown in Table 1.
Table 1:
note: p < 0.05; p < 0.01; p <0.001(vs. saline), One Way-ANOVA followed by LSD.
After modeling of the ischemic stroke model, different doses of compound 1-1 were administered to the animals by gavage. The results show that: the maximal area and volume of ischemic foci in the compound 1-1 dose groups (9.0mg/kg, 18.0mg/kg, 35.0mg/kg) differed significantly from those in the saline group (P <0.001), indicating that compound 1-1 significantly reduced the maximal area and total volume of nerve damage and had a significant dose-effect relationship. The detailed results are shown in Table 2.
Table 2:
note: p <0.001(vs. salene), One Way-ANOVA closed by LSD.
Example 1 shows that: the compound 1-1 can treat ischemic nerve injury through common administration routes such as injection, oral administration and the like, has obvious dose-effect relationship, and the optimal effect can achieve the effect of reducing the volume of nerve injury by about 30-40%.
Example 2: time-Effect relationship of Compound 1-1 for treatment of ischemic nerve injury
(1) Laboratory animal
The experimental animal is purchased from SPF Kunming strain mice of university of Kunming medical science, male, and has a weight of 20-25g and a qualification number of SCXK (Dian) K2015-0002. The room temperature is controlled to be 20-25 ℃, the humidity is 40-70%, the lighting time is 12 hours, the darkness is 12 hours, and the lamp-on time is as follows: 7: 00am, light-off time: 19: 00 pm. The rat box and padding were changed twice a week. The breeding mode is group breeding, and each cage has 10 animals. Feeding sterilized feed of Jiangsu cooperative medical bioengineering limited company, feed qualification number: (2014)01008. Feed was supplied once per cage per day with free access. Tap water is supplied by the drinking water box and is freely drunk by animals.
(2) Experimental method
Grouping:
a: compound 1-1(2.5mg/kg) administered group in 0h, 3h, 5h abdominal cavity (i.p.), normal saline control group;
compound B1-1 (35.0mg/kg) group administered by intragastric administration (i.g.) for 0h, 3h and 5h, and normal saline control group;
the administration mode comprises the following steps: test compound 1-1 or normal saline was administered intraperitoneally/gavage according to the experimental design.
The administration time is as follows: the drug is administered 0h, 3h and 5h after the optical embolism ischemia.
Detection indexes are as follows: the maximum area of the ischemic focus and the total volume of the ischemic focus.
(3) Experimental procedure
A photochemical induction model of mouse hippocampal brain ischemic injury is adopted. Injecting Rose Bengal (Rose Bengal, Sigma, 100mg/kg) into abdominal cavity of mouse, placing back into rearing cage, after the Rose Bengal is fully absorbed and distributed for 1 hr, injecting pentobarbital sodium (80mg/kg) into abdominal cavity, after the animal is deeply anesthetized, removing hair on top of head, disinfecting skin on top of head with iodophor, cutting off skin on top of head longitudinally in sagittal center, exposing skull, stripping connective tissue membrane on surface of skull, and trimming with scalpel. After the operation is finished, the animal is fixed on a brain stereotaxic apparatus, the bregma point of the bregma is taken as a reference origin, and a hole is punched corresponding to the surface of the skull (2.5 mm behind the bregma and 2.0mm beside the central suture). One end of the optical fiber (core diameter 200 μm, FC/TC interface, single mode) is connected with the laser, and the other end is ground flat (compact and uniform in light spot) and then goes deep into the upper part of the hippocampus and goes down 1.4mm from the surface of the skull. Blue laser (wavelength 473nm) was irradiated for 20 minutes at a light intensity of 30 mW. After the model is made, the scalp is sutured, the scalp is placed on an operating table and kept warm, and the animal is placed back into the rearing cage after being awake.
Immediately administering the medicine to mice of different experimental groups after the light embolism ischemia is finished, cutting off the head of the mouse after 24h, removing olfactory bulb, cerebellum and brainstem, and slicing in an artificial hydrocephalus environment to obtain the section with the thickness of 350 mu m. Sections were soaked in 2.5% TTC solution and incubated for staining at 37 ℃ for 15min and then fixed in 4% PFA for 15 min. The normal brain tissue is stained red, and the white part is the ischemic brain area. Compared with a control group, the influence and degree of the drug on the ischemic injury are evaluated according to evaluation parameters such as the maximum area and the volume of an ischemic focus.
(4) Data statistics
ImageJ counts the area of the ischemic spot; data were tested for One-Way analysis of variance using SPSS 11.0 software (One Way-ANOVA) with mean ± SEM, with significant differences set at P < 0.05. And (4) drawing a result graph by using Origin 8.0.
(5) Results of the experiment
Compounds 1-1(2.5mg/kg) were administered to mice by intraperitoneal injection 0h, 3h, 5h after ischemic stroke molding. The results show that: the maximal area and volume of the ischemic focus of the mice in the compound 1-1(2.5mg/kg)0h and 3h administration groups are respectively significantly different from those in the normal saline group (P <0.001 and P <0.01), and the maximal area and volume of the ischemic focus of the mice in the 5h administration groups are not significantly different from those in the normal saline group (P >0.05), which indicates that the intraperitoneal injection of the compound 1-1(2.5mg/kg) has a significant time-effect relationship on the treatment of ischemic injury. The detailed results are shown in Table 3.
Table 3:
note: p < 0.01; p <0.001(vs. salene), One Way-ANOVA closed by LSD.
Compounds 1-1(35.0mg/kg) were administered to mice by gavage 0h, 3h, 5h after ischemic stroke molding. The results show that: the maximal area and volume of the ischemic focus of the mice in the 0h administration group are significantly different from those of the normal saline group (P is less than 0.001); the groups administered 3h and 5h after ischemia have the tendency of reducing the maximum area and volume of an ischemic focus, but have no significant difference compared with the group of normal saline (P >0.05), and the fact that the compound 1-1(35.0mg/kg) is administered by intragastric administration has a significant time-effect relationship on the treatment of ischemic nerve injury is suggested. The detailed results are shown in Table 4.
Table 4:
note: p <0.001(vs. saline), One Way-ANOVA followed by LSD.
Example 2 shows that: acute evaluation (24 hours) of compound 1-1 for treatment of nerve injury has a significant time window limitation, but since the evaluation method is TTC staining, which is an indirect evaluation, there may be some false negative or false positive. It is also possible that this time window limit disappears as the effect of the drug continues.
Example 3: drug effect of compound 1-1 for treating ischemic nerve injury by multiple administration
(1) Laboratory animal
The experimental animal is purchased from SPF Kunming strain mice of university of Kunming medical science, male, and has a weight of 20-25g and a qualification number of SCXK (Dian) K2015-0002. The room temperature is controlled to be 20-25 ℃, the humidity is 40-70%, the lighting time is 12 hours, the darkness is 12 hours, and the lamp-on time is as follows: 7: 00am, light-off time: 19: 00 pm. The rat box and padding were changed twice a week. The breeding mode is group breeding, and each cage has 10 animals. Feeding sterilized feed of Jiangsu cooperative medical bioengineering limited company, feed qualification number: (2014)01008. Feed was supplied once a day per cage for free feeding. Tap water is supplied by the drinking water box and is freely drunk by animals.
(2) Experimental methods
Grouping: compound 1-1(2.5mg/kg) intraperitoneal (i.p.) single-dose group, compound 1-1(2.5mg/kg) intraperitoneal (multi-dose) group, and saline group;
the administration mode comprises the following steps: test compound 1-1 or normal saline is administered by intraperitoneal injection/gastric lavage according to experimental design.
The administration time is as follows: the administration was immediately after ischemia in the single-dose group; the continuous administration group was administered immediately after ischemia, and then administered in the same manner at the same time point every day for 7 days.
Detection indexes are as follows: neuronal injury area, neuronal injury volume.
(4) Experimental procedure
A photochemical induction model of mouse hippocampal brain ischemic injury is adopted. Injecting Rose Bengal (Rose Bengal, Sigma, 100mg/kg) into abdominal cavity of mouse, placing back into rearing cage, after the Rose Bengal is fully absorbed and distributed for 1 hr, injecting pentobarbital sodium (80mg/kg) into abdominal cavity, after the animal is deeply anesthetized, removing hair on top of head, disinfecting skin on top of head with iodophor, cutting off skin on top of head longitudinally in sagittal center, exposing skull, stripping connective tissue membrane on surface of skull, and trimming with scalpel. After the operation is finished, the animal is fixed on a brain stereotaxic apparatus, the bregma point of the bregma is taken as a reference origin, and a hole is punched corresponding to the surface of the skull (2.5 mm behind the bregma and 2.0mm beside the central suture). One end of the optical fiber (core diameter 200 μm, FC/TC interface, single mode) is connected with the laser, and the other end is ground flat (compact and uniform in light spot) and then goes deep into the upper part of the hippocampus and goes down 1.4mm from the surface of the skull. Blue laser (wavelength 473nm) was irradiated for 20 minutes at a light intensity of 30 mW. After the model is made, the scalp is sutured, the scalp is placed on an operating table and kept warm, and the animal is placed back into the rearing cage after being awake.
On day 7 after ischemia, mice were perfused with PBS and 4% PFA, respectively, and brain tissue was taken out and immersed in 4% PFA for post-fixation. Subjecting brain tissue to gradient dehydration with 15% and 30% sucrose solution, removing olfactory bulb, cerebellum and brain stem from the dehydrated brain tissue, and treating with phosphate buffer (8.000g NaCl, 0.200g KCl, 0.272g KH) with a vibrating microtome2PO4+2.866g Na2HPO4Dissolving with pure water and fixing the volume to 1L, pH: 7.2-7.4) and the thickness is 40 mu m, and the section is pasted on an anti-falling glass slide and dried at room temperature. And (3) dyeing the dried slices in a thionine staining solution for 5min, washing the slices with distilled water for 2 times, respectively decoloring the slices in 70%, 75%, 95%, 100% (I) and 100% (II) of ethanol for 2min respectively, carrying out xylene transparency twice, sealing the slices with neutral gum for 5min each time, and carrying out image acquisition by adopting an Olympus microscope.
(4) Data analysis
ImageJ counts the area of the ischemic spot; data were tested for One-Way analysis of variance using SPSS 11.0 software (One Way-ANOVA) with mean ± SEM, with significant differences set at P < 0.05. And (4) drawing a result graph by using Origin 8.0.
(5) Results of the experiment
Compound 1-1(2.5mg/kg) was administered intraperitoneally once and many times after ischemic stroke molding, and the results of nissl staining after 7 days showed: the maximal area of ischemia focus neuron damage in the single dose group was statistically different from that in the normal saline group (P < 0.05). When compound 1-1(2.5mg/kg) was administered intraperitoneally for 7 consecutive days, the maximal area and volume of ischemic focal neuronal damage was also statistically different in mice compared to saline group (P <0.05 or P < 0.01). Importantly, intraperitoneal administration of compound 1-1(2.5mg/kg) for 7 consecutive days also showed a significant reduction in total lesion volume, which was significantly better than the single dose group, suggesting that compound 1-1 treatment may not have strict post-stroke time window limitations. The detailed results are shown in Table 5.
Table 5:
note: p < 0.05; p <0.01(vs. saline), One way ANOVA followby LSD.
Example 3 shows that: TTC assessment 24 hours after stroke modeling only indirectly reflected the acute phase of the nerve injury. Therefore, by using the nissl staining on day 7, not only can false negative or false positive possibly brought by TTC staining be eliminated, but also the treatment efficacy of the drug on nerve injury can be reflected more objectively and directly, so we find that multiple administrations in 7 consecutive days after stroke modeling can produce better drug effect compared with single administration, suggesting that compound 1-1 may not have strict treatment time window limitation in the process of treating ischemic nerve injury.
Example 4: time-Effect of Single administration of Compound 1-1 for treatment of ischemic nerve injury
(1) Laboratory animal
The experimental animal is purchased from SPF Kunming strain mice of university of Kunming medical science, male, and has a weight of 20-25g and a qualification number of SCXK (Dian) K2015-0002. The room temperature is controlled to be 20-25 ℃, the humidity is 40-70%, the lighting time is 12 hours, the darkness is 12 hours, and the lamp-on time is as follows: 7: 00am, light-off time: 19: 00 pm. The rat box and padding were changed twice a week. The breeding mode is group breeding, and each cage has 10 animals. Feeding sterilized feed of Jiangsu cooperative medical bioengineering Limited company, feed qualification No.: (2014)01008. Feed was supplied once per cage per day with free access. Tap water is supplied by the drinking water box and is freely drunk by animals.
(2) Experimental methods
Grouping: compound 1-1(2.5mg/kg) administered group (i.p.) and normal saline group (i.p.) for 0h, 3h and 5 h;
the administration mode comprises the following steps: test compound 1-1 or normal saline was administered by intraperitoneal injection according to the experimental design.
The administration time is as follows: the drug is administered 0h, 3h and 5h after the optical embolism ischemia.
Detection indexes are as follows: neuronal injury area, neuronal injury volume.
(3) Experimental procedure
A photochemical induction model of mouse hippocampal brain ischemic injury is adopted. Injecting Rose Bengal (Rose Bengal, Sigma, 100mg/kg) into abdominal cavity of mouse, placing back into rearing cage, after the Rose Bengal is fully absorbed and distributed for 1 hr, injecting pentobarbital sodium (80mg/kg) into abdominal cavity, after the animal is deeply anesthetized, removing hair on top of head, disinfecting skin on top of head with iodophor, cutting off skin on top of head longitudinally in sagittal center, exposing skull, stripping connective tissue membrane on surface of skull, and trimming with scalpel. After the operation is finished, the animal is fixed on a brain stereotaxic apparatus, the bregma point of the bregma is taken as a reference origin, and a hole is punched corresponding to the surface of the skull (2.5 mm behind the bregma and 2.0mm beside the central suture). One end of the optical fiber (with the core diameter of 200 μm, FC/TC interface, single mode) is connected with the laser, and the other end is ground flat (with compact and uniform light spot) and then goes deep into the upper part of the hippocampus and descends 1.4mm from the surface of the skull. Blue laser (wavelength 473nm) was irradiated for 20 minutes at a light intensity of 30 mW. After the model is made, the scalp is sutured, the scalp is placed on an operating table and kept warm, and the animal is placed back into the rearing cage after being awake.
On day 7 after ischemia, mice were perfused with PBS and 4% PFA, respectively, and brain tissue was taken out and immersed in 4% PFA for post-fixation. The brain tissue is dehydrated by gradient with 15% and 30% sucrose solution, removing olfactory bulb, cerebellum and brainstem from the dehydrated brain tissue, and treating with phosphate buffer (8.000g NaCl, 0.200g KCl, 0.272g KH) by use of a vibrating microtome2PO4+2.866g Na2HPO4Dissolving with pure water and fixing the volume to 1L, pH: 7.2-7.4) and the thickness is 40 mu m, and the section is pasted on an anti-falling glass slide and dried at room temperature. And (3) dyeing the dried slices in a thionine staining solution for 5min, washing the slices with distilled water for 2 times, respectively decoloring the slices in 70%, 75%, 95%, 100% (I) and 100% (II) of ethanol for 2min respectively, carrying out xylene transparency twice, sealing the slices with neutral gum for 5min each time, and carrying out image acquisition by adopting an Olympus microscope.
(4) Data analysis
ImageJ counts the area of the ischemic spot; data were subjected to One-Way analysis of variance test (One Way-ANOVA) using SPSS 11.0 software, showing mean ± SEM with significant difference set as P < 0.05. And (4) drawing a result graph by using Origin 8.0.
(5) Results of the experiment
After ischemic stroke modeling, the mouse is singly administrated with compound 1-1(2.5mg/kg) in the abdominal cavity, the administration time is 0h, 3h and 5h, and the Niger staining result shows that after 7 d: the maximal area and volume of ischemia focus neuron damage are obviously reduced by single administration of the compound 1-1(0h, 3h and 5h groups), and compared with a normal saline group, the statistical significant difference (P <0.001) is achieved, which indicates that the compound 1-1 can activate a series of nerve repair mechanisms such as proliferation and transdifferentiation related to microglia and astrocyte within 7 days, so that nerve damage is well relieved, and the optimal drug effect of relieving the nerve damage is more than 40%. The detailed results are shown in Table 6.
Table 6:
note: p <0.01(vs. salene), One way ANOVA closed by LSD.
Example 4 shows that: by utilizing Niger's staining, after stroke molding, a single injection of 2.5mg/kg of compound 1-1 can produce a sustained drug effect of alleviating the degree of nerve injury for more than 7 days, has the typical characteristics of a neuroprotective agent, and also prompts that the compound 1-1 has no strict time window limitation in treating ischemic nerve injury, but is administered once within 3-5 hours after stroke molding, and the 7 th day shows better curative effect than the immediate administration after stroke molding. This pharmacodynamic feature is significantly different from thrombolytic drugs such as tPA treatment in the acute phase of stroke. Can provide a brand new treatment approach for ischemic stroke patients with more than tPA thrombolysis treatment time window. Due to this unique feature of compound 1-1, it is speculated that it may also have a therapeutic effect on hemorrhagic stroke.
Claims (15)
1. A compound of formula IA and pharmaceutically acceptable salts thereof,
wherein X is OR1；
V is-O-, -S-;
r is C1-4Alkyl, halogen, or C1-3A haloalkyl group;
Ra、Rband RcEach independently is acyl;
R1is acyl;
R8is C1-4An alkyl group;
R9is an acyl group;
the acyl group is a group-C (O) -R ', wherein R' is selected from C1-4An alkyl group.
2. The compound and pharmaceutically acceptable salts according to claim 1, characterized by:
R1Is acetyl;
and/or, R8Is methyl;
and/or, Ra、RbAnd RcEach independently is acetyl;
and/or, R9Is acetyl.
3. The compound according to claim 1 or 2, which is a 1-1 compound,
4. a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active component is a compound as claimed in any one of claims 1 to 3 and pharmaceutically acceptable salts thereof.
5. The pharmaceutical composition of claim 4, wherein: the active ingredient may also include other therapeutic agents for treating nerve damage.
6. The pharmaceutical composition of claim 4, wherein: the pharmaceutically acceptable auxiliary material is excipient.
7. The pharmaceutical composition of claim 6, wherein: the excipient is a diluent.
8. The pharmaceutical composition of claim 4, in various types of administration unit dosage forms selected from the group consisting of tablets, pills, powders, liquids, granules, capsules, suppositories, and injections.
9. The pharmaceutical composition of claim 4, in various forms of administration unit dosage form selected from the group consisting of suspensions and emulsions.
10. Use of a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 4 to 9 for the manufacture of a medicament for the treatment or alleviation of nerve damage.
11. The use as claimed in claim 10, wherein the medicament is administered by common dosage forms and routes of injection, oral capsule and tablet.
12. The use of claim 10, wherein the nerve damage comprises: ischemic stroke, hemorrhagic stroke, and other types of nerve damage.
13. The use of claim 10, wherein the nerve damage comprises: vascular dementia and neurodegenerative diseases.
14. The use of claim 10, wherein the nerve damage comprises: direct or indirect nerve damage caused by chronic inflammation, diabetes, hypertension, coronary heart disease or brain trauma.
15. A method for synthesizing the compound 1-1,
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| CN110204589B (en) * | 2019-06-28 | 2021-04-09 | 河南大学 | Effective component of feather cockscomb seed, extraction method and application thereof in preparing neuroprotective medicament |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417556A (en) * | 2012-05-17 | 2013-12-04 | 昆明制药集团股份有限公司 | Applications of stilbene compounds |
| CN104804051A (en) * | 2014-01-25 | 2015-07-29 | 昆明制药集团股份有限公司 | Acetagastrodin derivative, preparation method, preparation, and applications thereof |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103417556A (en) * | 2012-05-17 | 2013-12-04 | 昆明制药集团股份有限公司 | Applications of stilbene compounds |
| CN104804051A (en) * | 2014-01-25 | 2015-07-29 | 昆明制药集团股份有限公司 | Acetagastrodin derivative, preparation method, preparation, and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| "Evaluation of Anti-oxidant and Acetylcholinesterase Activity and Identification of Polyphenolics of the Invasive Weed Dittrichia viscosa";Imen Trimech et al.;《Phytochemical Anallysis》;20140414;第25卷;第421-428页 * |
| "Isolation and characterization of phenolic compounds from Rhodiola imbricata, a Trans-Himalayan food crop having antioxidant and anticancer potential";Alka Choudhary et al.;《Journal of Functional Foods》;20150514;第16卷;第183-193页 * |
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