CN113402543B - Butylphthalide ring-opening derivative and preparation method and application thereof - Google Patents

Butylphthalide ring-opening derivative and preparation method and application thereof Download PDF

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CN113402543B
CN113402543B CN202010184045.4A CN202010184045A CN113402543B CN 113402543 B CN113402543 B CN 113402543B CN 202010184045 A CN202010184045 A CN 202010184045A CN 113402543 B CN113402543 B CN 113402543B
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CN113402543A (en
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程增江
满艳哲
程思奇
赵京华
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Kebei Yuanyuan (Suzhou) Pharmaceutical Technology Co.,Ltd.
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Corbeille Park Beijing Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous 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
    • 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
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/094—Esters of phosphoric acids with arylalkanols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a butylphthalide open-loop derivative, a preparation method and application thereof. The butylphthalide open-loop derivative can obviously improve the ischemic symptoms of rats in cerebral ischemia reperfusion models, and the compound has wide application prospects in preparation of medicaments for preventing and treating heart and cerebral ischemic diseases, improving heart and cerebral circulatory disturbance, resisting thrombus and the like.

Description

Butylphthalide ring-opening derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a butylphthalide open-loop derivative, and a preparation method and application thereof.
Background
Acute ischemic stroke, coronary heart disease and myocardial infarction are ischemic injury diseases caused by thrombosis induced by various factors, and bring great pain and even life risk to patients. Currently, the research on the medicines is always a hot spot and a leading edge of the research and development of the medicines. Acute ischemic stroke is an impairment of brain function caused by an impaired blood supply to the brain due to ischemia. With the rapid aging of population, the incidence of cerebral ischemia is on a continuously increasing trend, and has become the first leading disability and the second leading death of the world, and the burden of society and family is also increased.
The pathogenesis of cerebral ischemia is very complex and is a malignant cascade process with multiple factors, multiple mechanisms and multiple links. Over the years, the mechanisms surrounding cerebral ischemia and reperfusion injury have been studied including excitotoxicity, ionic imbalance, oxidative stress, cortical diffusive depolarization, and inflammatory responses. At present, the anti-cerebral ischemia drugs commonly used in clinic mainly comprise platelet aggregation resistant drugs, thrombolytics, neuroprotective agents, free radical scavengers and the like. Although these drugs can exert a certain therapeutic effect by different mechanisms, it is difficult to achieve a very satisfactory therapeutic effect by a single use. Although experts and scholars at home and abroad carry out extensive research on the pathogenesis and prevention and treatment of cerebral ischemia and make great progress, practical and effective clinical prevention and treatment measures are still lacked up to now.
Among the existing therapeutic drugs, Butylphthalide, also known as 3-butyl-1 (3H) -isobenzocerapyranone (NBP), is one of the more widely used therapeutic drugs. It is noteworthy that although NBP acts on many pathological events of cerebral ischemia, its overall efficacy is not high and is often used in combination with other drugs to achieve the therapeutic effect. In addition, butylphthalide has poor water solubility, which limits its wide use in treating acute cerebral ischemia to some extent.
Therefore, how to adopt a new strategy to research and develop a novel high-efficiency medicine with multiple functions for preventing and treating cerebral ischemia is an important subject which is generally concerned by medical scientists all over the world currently.
Disclosure of Invention
In order to improve the problems, the invention provides a compound shown as a formula (I), a racemate, a stereoisomer, a nitrogen oxide, an isotope substitute, a pharmaceutically acceptable salt or a solvate thereof:
Figure BDA0002413529070000021
wherein:
each R1Identical or different, independently of one another, from halogen, CN, OH, NO2Unsubstituted or optionally substituted by one, two or more RaSubstituted of the following groups: c1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、-NR6R7、-C(O)R8、-OC(O)R9、-S(O)2R10、-OS(O)2R11；
n is selected from 0, 1,2, 3 or 4;
R2selected from halogen, CN, OH, NO2Unsubstituted or optionally substituted by one, two or more RbSubstituted of the following groups: c1-40Alkyl radical, C3-40Cycloalkyl, -OR4、-SR5、-NR6R7、-C(O)R8、-OC(O)R9、-S(O)2R10、-OS(O)2R11；
R3Selected from- (O) P (OR)12)(OR13) or-C (O) R14；
Each R4Identical or different, independently of one another, from C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;
each R5Identical or different, independently of one another, from C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;
each R6Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -C (O) R8、-S(O)2R10；
Each R7Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -C (O) R8、-S(O)2R10；
Or, R6And R7Together with the N atom to which they are attached form a 5-20 membered heteroaryl or 3-20 membered heterocyclyl group;
each R8Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、NR6R7；
Each R9Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;
each R10Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、NR6R7；
Each R11Same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;
R12、R13same or different, independently from each other selected from H, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;
R14selected from unsubstituted or optionally substituted by one, two or more Rcsubstituted-C1-40alkylene-NR6R7；
Each Ra、RbIdentical or different, independently of one another, from halogen, CN, OH, SH, oxo (═ O), NO2、C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、-NR6R7、-C(O)R8、-OC(O)R9、-S(O)2R10、-OS(O)2R11；
Each RcIdentical or different, independently of one another, from halogen, CN, OH, SH, oxo (═ O), NO2、C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、-NR6R7、-C(O)R8、-OC(O)R9、-S(O)2R10、-OS(O)2R11Side chain groups of natural or unnatural amino acids;
X1and X2Identical or different, independently of one another, from O, S, -O [ (CHR)15)pO]q-；
R15Selected from H, halogen, CN, OH, C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-40Cycloalkyl radical, C3-40Cycloalkenyl radical, C3-40Cycloalkynyl group, C6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -OR4、-SR5、NR6R7；
p and q are the same or different and are independently selected from 1,2 or 3.
According to an embodiment of the invention, H in the compound of formula (I) may optionally be replaced by an isotope thereof, such as D.
According to an embodiment of the present invention, the compound of formula (I) may comprise chiral centers, each of which may be the same or different in configuration, selected independently from the R configuration, S configuration or racemate.
According to an exemplary embodiment of the present invention, the compound of formula (I) has a structure represented by the following formula (I-1) or formula (I-2):
Figure BDA0002413529070000031
wherein:
each R1Identical or different, independently of one another, from halogen, CN, OH, unsubstituted or optionally substituted by one, two or more RaSubstituted of the following groups: c1-6Alkyl, -OR4、-NR6R7；
n is selected from 0, 1 or 2;
R2selected from unsubstituted or optionally substituted by one, two or more RbSubstituted C1-6An alkyl group;
each R4Identical or different, independently of one another, from C1-6An alkyl group;
R6、R7same or different, independently from each other selected from H, C1-6An alkyl group;
each Ra、RbIdentical or different, independently of one another, from halogen, CN, OH, SH, oxo (═ O), NO2、C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, -OR4、-NR6R7；
RcSelected from halogen, CN, OH, C1-6An alkyl group;
each X1Identical or different, independently of one another, from O, -O [ (CHR)15)pO]q-；
Each X2Identical or different, independently of one another, from O, -O [ (CHR)15)pO]q-；
R15Selected from H, halogen, OH, C1-6Alkyl, -OR4、NR6R7；
p and q are the same or different and are independently selected from 1 or 2.
According to an embodiment of the invention, the compound of formula (I) is selected from the following compounds:
Figure BDA0002413529070000041
the invention also provides a preparation method of the compound shown in the formula (I), which comprises the step of carrying out reaction by using the compound M1 as a starting material to obtain the compound shown in the formula (I):
Figure BDA0002413529070000042
wherein:
PG is a protecting group;
R1、R2、X1、X2n has the definitions described above;
r is selected from 0, R31Is selected from H; or
R is selected from 1 or 2, R31Is selected from R3Groups after removal of 1 or 2H.
According to embodiments of the present invention, PG may be selected from a phosphate protecting group or an amino protecting group. Wherein suitable PG may be selected from C1-40Alkyl radical, C6-20Aryl radical C1-40Alkyl-, such as tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl.
According to an embodiment of the invention, when R is 0, the compound M1 is capable of providing R3Reacting the compound of the group to obtain the compound of the formula (I).
According to embodiments of the present invention, R can be provided3The compound of the group may be selected from phosphorus oxychloride, natural or unnatural amino acids.
According to embodiments of the present invention, R can be provided3The compound of the group can be selected fromFrom R3-L1Wherein L is1Selected from leaving groups such as halogen, halo C1-40An alkyl group.
According to an embodiment of the invention, when r is 1 or 2, compound M1 is reacted under conditions to deprotect the protecting group PG to give the compound of formula (I). The conditions for the deprotection of the protecting group PG are known to those skilled in the art.
The present invention also provides a process for the preparation of compound M1, comprising reacting compound M2 with compound M3, followed by compound M4, or with compound M4, followed by compound M3, to give compound M1:
Figure BDA0002413529070000051
wherein L is2、L3Identical or different, independently of one another, from the leaving groups described above;
R1、R2、R3、X1、X2、R31PG, n, r independently have the definitions described above.
According to an embodiment of the present invention, the preparation method may be performed in the presence of a solvent such as an organic solvent. For example, the organic solvent may be selected from at least one of the following: ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and/or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and possibly substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, and xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.
According to an embodiment of the invention, the preparation process may be carried out, for example, in the presence of an acid or a base, or under hydrogenation conditions.
The acid may be an organic acid or an inorganic acid, for example, at least one selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, HCl, sulfuric acid.
The base may be an organic base or an inorganic base. For example, the inorganic base may be selected from at least one of the following: hydrides, hydroxides, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals. Preferred bases are sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate; the organic base may be selected from at least one of the following: tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted triethylamine, trimethylamine, N, N-diisopropylethylamine, tri-N-propylamine, tri-N-butylamine, tri-N-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N, N-dimethylaniline, N-methylmorpholine, pyridine, 2, 3-or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2, 6-dimethylpyridine, 2,4, 6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, methylquinoline, N, N, N-tetramethylethylenediamine, N, N-dimethyl-1, 4-diazacyclohexane, N, N-diethyl-1, 4-diazabicyclocyclohexane, 1, 8-bis (dimethylamino) naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), butylimidazole and methylimidazole.
The hydrogenation may be carried out in the presence of a catalyst and hydrogen. The catalyst may be selected from palladium on carbon or palladium hydroxide.
The present invention also provides a compound M1, M2, M3 or M4 as a raw material or an intermediate.
The invention also provides application of the compound M1, M2, M3 or M4 in preparing the compound shown in the formula (I).
The invention also provides a pharmaceutical composition, which comprises at least one of a therapeutically effective amount of a compound shown in the formula (I), a racemate, a stereoisomer, a nitrogen oxide, an isotope substitute, a pharmaceutically acceptable salt or a solvate thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to an embodiment of the invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
The invention also provides a method for preventing or treating ischemic cardiovascular and cerebrovascular diseases, cardiovascular and cerebrovascular circulatory disorders and cerebral thrombosis, which comprises the step of administering a patient with a prevention or treatment effective amount of at least one of a compound shown as a formula (I), a racemate, a stereoisomer, a nitrogen oxide, an isotope substitute, a pharmaceutically acceptable salt or a solvate thereof.
The invention also provides a method for improving cerebral infarction volume or neurological deficit after cerebral ischemia-reperfusion, which comprises administering to a patient a prophylactically or therapeutically effective amount of at least one compound represented by formula (I), racemate, stereoisomer, nitric oxide, isotope substitute, pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the patient is a human.
The invention also provides at least one of a compound shown in the formula (I), a racemate, a stereoisomer, a nitrogen oxide, an isotope substitute, a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition thereof, which is used for preventing or treating heart and brain ischemic diseases, heart and brain circulatory disorders and cerebral thrombosis.
The invention also provides at least one of a compound shown in formula (I), a racemate, a stereoisomer, a nitrogen oxide, an isotope substitute, a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition thereof, which is used for improving the cerebral infarction volume or the neurological deficit after cerebral ischemia-reperfusion.
The invention also provides application of at least one of the compound shown in the formula (I), racemate, stereoisomer, nitrogen oxide, isotope substitute, pharmaceutically acceptable salt or solvate thereof in preparing a medicament.
The medicine can be used for preventing or treating heart and brain ischemic diseases, heart and brain circulatory disturbance and cerebral thrombosis, or improving cerebral infarction volume or nerve defect after cerebral ischemia reperfusion.
As a medicament, the compounds of the present invention may be administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Can be administered topically (e.g., transdermal, dermal, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. The administration may be parenteral in a single bolus form, or may be by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or desirable.
In preparing the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of active compound.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may also contain: lubricants such as talc, magnesium stearate and mineral oil; a humectant; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweetening agents and flavoring agents. The compositions of the present invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
The compositions may be formulated in unit dosage forms, each dosage containing from about 5 to about 1000mg, more usually from about 100 to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete single dosage units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in admixture with suitable pharmaceutical excipients.
The effective dose of the active compound can vary widely and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered; age, weight and response of the individual patient; severity of patient symptoms, etc.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is generally uniformly distributed throughout the composition such that the composition may be readily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid pre-formulations are then divided into unit dosage forms of the type described above containing, for example, from about 0.1 to 1000mg of the active ingredient of the invention.
The tablets or pills of the present invention may be coated or compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill contains an inner dose and an outer dose component, the latter being in the form of a capsule of the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach, leaving the inner component intact through the duodenum or delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions; and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by the oral or nasal respiratory route to achieve a local or systemic effect. The composition may be atomized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a mask or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally by means of a device that delivers the formulation in a suitable manner.
The amount of compound or composition administered to a patient is not fixed and depends on the drug administered, the purpose of the administration such as prevention or treatment; the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the disease state being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the age, weight and general condition of the patient.
The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterilized by filtration. The aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is usually 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers may result in the formation of a pharmaceutical salt.
Therapeutic dosages of the compounds of the invention may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the invention in the pharmaceutical composition may not be fixed and will depend on a variety of factors including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present invention can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
Advantageous effects
The butylphthalide open-loop derivative provided by the invention has a good protection effect on cerebral ischemia reperfusion injury, and can be used for preparing medicaments for treating cardiovascular and cerebrovascular ischemic diseases, improving cardiovascular and cerebrovascular circulatory disturbance, resisting thrombus and the like.
The preparation method of the compound is convenient and fast, and is easy for large-scale production.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
Unless otherwise indicated, the numerical ranges set forth in the specification and claims are equivalent to at least each and every specific integer numerical value set forth therein. For example, a numerical range of "1-40" is equivalent to reciting each of the integer values in the numerical range of "1-10," i.e., 1,2, 3,4, 5,6, 7, 8, 9, 10, and each of the integer values in the numerical range of "11-40," i.e., 11, 12, 13, 14, 15, 35, 36, 37, 38, 39, 40. It is understood that "more" of one, two, or more as used herein in describing substituents shall mean an integer ≧ 3, such as 3,4, 5,6, 7, 8, 9, or 10. Further, when certain numerical ranges are defined as "numbers," it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to not only recite each integer of 0, 1,2, 3,4, 5,6, 7, 8, 9, and 10, but also to recite at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
The term "halogen" denotes fluorine, chlorine, bromine and iodine.
The term "C1-40Alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms. For example, "C1-10Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms," C1-6Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3,4, 5 or 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a1, 2-dimethylpropyl group, a neopentyl group, a1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a1, 3-dimethylbutyl group or a1, 2-dimethylbutyl group, or the like, or isomers thereof.
The term "C2-40Alkenyl "is understood as preferably meaning straight or branchedA chain monovalent hydrocarbon radical comprising one or more double bonds and having 2 to 40 carbon atoms, preferably "C2-10Alkenyl ". "C2-10Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2,3, 4,5 or 6 carbon atoms (i.e. C)2-6Alkenyl) having 2 or 3 carbon atoms (i.e., C)2-3Alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-enyl, m-n-enyl, m-E-4-enyl, m-2-enyl, m-pent-1-enyl, m-2-methyl-enyl, m-2-methylvinyl, m-2-methyl-2-methylvinyl, m-but-2-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.
The term "C2-40Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C2-10Alkynyl ". The term "C2-10Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2,3, 4,5 or 6 carbon atoms (i.e. having 2,3, 4,5 or 6 carbon atoms)，“C2-6Alkynyl ") having 2 or 3 carbon atoms (" C)2-3Alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, and so-1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-2-ynyl, 4-methylpent-alkynyl, 4-ynyl, 2-methylpent-3-ynyl, 3-methylpent-ynyl, 3-1-methylpent-1-ynyl, 3-1-methylpent-ynyl, 3-ynyl, 2-methylpent-1-ynyl, 3-1-methylpent-1-ynyl, methyl-1-methylpent-1-ynyl, 2-1-methylpent-1-ynyl, 2-1-methylpent-1-ynyl, 2-1-methylpent-1-methylpent-1-ynyl, 2-1-ynyl, 2-1-2-1-2-ynyl, 2-alkynyl, 2-butynyl, 2-butynyl, 2, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-40Cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 40 carbon atoms, preferably "C3-10Cycloalkyl groups ". The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains from 1 to 5 heteroatoms independently selected from N, O and S as a total ring member having from 3 to 20 (e.g., having 3,4, 5,6, 7, 8, 9, 10, etc.) non-aromatic cyclic groups, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a5, 5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a5, 6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolyl. According to the invention, the heterocyclic radical is non-aromatic. When the 3-20 membered heterocyclic group is linked to another group to form the compound of the present invention, the carbon atom of the 3-20 membered heterocyclic group may be linked to another group, or the heterocyclic atom of the 3-20 membered heterocyclic ring may be linked to another group. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, it may be such that the nitrogen atom on the piperazinyl group is attached to another group. Or when the 3-20 membered heterocyclyl group is selected from piperidinyl, it may be that the nitrogen atom on the piperidinyl ring and the carbon atom in the para position are attached to other groups.
The term "C6-20Aryl "is understood to preferably mean a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6 to 20 carbon atoms, preferably" C6-14Aryl ". The term "C6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C)10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl. When said C is6-20When the aryl group is substituted, it may be mono-or polysubstituted. And, the substitution site thereof is not limited, and may be, for example, ortho-, para-or meta-substitution.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like. When the 5-20 membered heteroaryl group is linked to another group to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked to another group, or the heteroatom on the 5-20 membered heteroaryl ring may be linked to another group. When the 5-20 membered heteroaryl group is substituted, it may be mono-or poly-substituted. And, there is no limitation on the substitution site thereof, and for example, hydrogen bonded to a carbon atom on a heteroaryl ring may be substituted, or hydrogen bonded to a heteroatom on a heteroaryl ring may be substituted.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative non-limiting examples, forms may be included that are substituted at one, two or more of their 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonded to other groups, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
The term "oxo" refers to an oxy substitution (═ O) formed by oxidation of a carbon atom, a nitrogen atom or a sulfur atom in a substituent.
The term "side chain group of an amino acid" refers to a group other than amino and carboxyl groups directly linked to an alpha carbon or beta carbon in an amino acid molecule. Wherein, the amino acid can be natural amino acid and unnatural amino acid. For example, the natural amino acid may be selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, or histidine.
Unless otherwise indicated, the definitions of terms herein apply equally to groups comprising the term, e.g. C1-6The definition of alkyl also applies to C1-6Alkyloxy, -N (C)1-6Alkyl radical)2、-NHC1-6Alkyl or-S (O)2-C1-6Alkyl groups, and the like.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be in the form of various pharmaceutically acceptable saltsThe formula (I) exists. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; these compounds may also form inner salts if they contain both an acidic centre (e.g. carboxyl) and a basic centre (e.g. amino). Acid addition salts include, but are not limited to: hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetic acid, pyruvic acid, lauric acid ester, cinnamate, benzoate, acetate, glyoxylate, trifluoroacetate, pivalate, propionate, butyrate, hexanoate, heptanoate, undecanoate, stearate, ascorbate, camphorate, camphorsulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, salicylate, succinate, gluconate, quinic acid, pamoate, glycolate, tartrate, lactate, 2- (4-hydroxybenzoyl) benzoate, Cyclopentanepropionate, digluconate, 3-hydroxy-2-naphthoate, nicotinate, embonate, pectinate, 3-phenylpropionate, picrate, pivalate, itaconate, triflate, dodecylsulfate, p-toluenesulfonate, napadisylate, malonate, adipate, alginate, mandelate, glucoheptonate, glycerophosphate, sulfosalicylate, hemisulfate or thiocyanate, aspartate, and the like; base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts and the like, specifically include but are not limited to: sodium salt, lithium salt, potassium salt, ammonium salt, aluminum salt, magnesium salt, calcium salt, barium salt, ferric salt, ferrous salt, manganese salt, manganous salt, zinc salt and ammonium salt (including NH)3Salts with organic amines (NH)4Salts), methylammonium salts, trimethylammonium salts, diethylammonium salts, triethylammonium salts, propylamine salts, tripropylammonium salts, isopropylammonium salts, tert-butylammonium salts, N' -dibenzylethylenediamine diammonium salts, dicyclohexylammonium salts, 1, 6-hexanediammonium salts, benzylammonium salts, ethanolamine salts, N-dimethylethanolamine ammonium salts, N-diethylethanolamine ammonium saltsTriethanolammonium salt, tromethamine salt, lysine salt, arginine salt, histidine salt, glucammonium salt, N-methylglucammonium salt, dimethylglucammonium salt, ethylglucammonium salt, meglumine salt, betaine salt, caffeine salt, chloroprocaine salt, procaine salt, lidocaine salt, pyridine salt, picoline salt, piperidine salt, morpholine salt, piperazine salt, purine salt, theobromine salt, choline salt) and the like.
The compounds of the invention may be present in the form of solvates, such as hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulphonic acids. The chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.
The term "leaving group"refers to an atom or group of atoms that is replaced in a chemical reaction by a stable species that carries a bound electron away. Preferably, the leaving group is selected from: halogen (e.g. chlorine, bromine or iodine), hydroxy, halogeno C1-40Alkyl, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromobenzene) sulfonyloxy, (4-nitrobenzene) sulfonyloxy, (2-nitrobenzene) sulfonyloxy, (4-isopropylbenzene) sulfonyloxy, (2,4, 6-triisopropylbenzene) sulfonyloxy, (2,4, 6-trimethylbenzene) sulfonyloxy, (4-tert-butylbenzene) sulfonyloxy, benzenesulfonyloxy and (4-methoxybenzene) sulfonyloxy.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual, or human, which includes one or more of the following: (1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology. (2) Inhibiting the disease: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition. (3) And (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1: synthesis of Compound S1
The synthetic route is as follows:
Figure BDA0002413529070000151
the synthesis process comprises the following steps:
intermediate (a 1): butylphthalide (NBP, 5.0g, 26.3mmol) was weighed out and dissolved in 20mL of methanol, 2M aqueous sodium hydroxide solution was added thereto in 20mL, stirred at 50 ℃ for 1h, methanol was distilled off, diluted with water, acidified to pH 2-3 to precipitate a solid, and the crude solid was dissolved in dichloromethane and used directly in the next step.
Intermediate a 2: to a dichloromethane solution of crude product A1, triethylamine (3.03g, 30mmol) is added, acetyl chloride (2.05g, 26.3mmol) is added thereto under ice bath, stirring is carried out at room temperature, after TLC detection reaction is completed, 10mL of water is added, dichloromethane is added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and the crude product is directly subjected to next reaction.
Intermediate a 3: dissolving the crude product of the previous step in 50mL of dichloromethane, adding 2-camphanol (8.0g, 52mmol), dicyclohexylcarbodiimide (DCC, 10.7g, 52mmol) and dimethylaminopyridine (DMAP, 3.2g, 26.3mmol), stirring overnight at room temperature, after TLC monitoring until the reaction is complete, adding 40mL of water, extracting with dichloromethane for 3 times, combining the organic phases, washing with saturated aqueous sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting the crude product to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain 5.75g of intermediate A3 as a pale yellow solid with a yield of 56% in the three steps. ESI-MS 387.2[ M + H ]]+。
Intermediate a 4: intermediate A3(5.0g, 12.9mmol) was weighed and dissolved in 20mL of methanol, potassium carbonate (3.6g, 25.8mmol) was added thereto, stirring was performed at room temperature, TLC was performed until the reaction was completed, the methanol was distilled off, 20mL of water and 30mL of ethyl acetate were added, ethyl acetate was extracted 3 times, the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure,the crude product was crystallized from ethyl acetate n-heptane and filtered to give 3.77g of intermediate a4 as an off-white solid in 85% yield. ESI-MS 345.2[ M + H ]]+。
Synthesis of compound S1: weighing the intermediate A4(1.0g, 2.9mmol), dissolving with 10mL of dichloromethane, adding triethylamine (585mg, 5.8mmol), cooling to 0 ℃, stirring, adding phosphorus oxychloride (444mg, 2.9mmol), reacting at 0-5 ℃ for 1h, monitoring by TLC until the reaction is complete, adding 10mL of water, stirring for 1h, adjusting the pH to 2-3 with dilute hydrochloric acid, extracting with dichloromethane for 3 times, combining organic phases, washing with saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, crystallizing the crude product with ethyl acetate n-heptane, and filtering to obtain 960mg of the target S1 as an off-white solid with the yield of 78%.
ESI-MS:425.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.79(1H,m),7.57(1H,m),7.46(1H,m),7.21(1H,m),6.38(1H,m),5.51(2H,br s),4.97(1H,d,J＝7.4),2.35(1H,m),2.05(3H,m),1.74(2H,m),1.59(2H,m),1.47(2H,m),1.37(1H,m),1.27(1H,m),1.04(1H,dd,J＝10.9,J＝2.7),0.91(3H,s),0.87(3H,s),0.86(3H,m),0.84(3H,s).
Example 2: synthesis of Compound S2
The synthetic route is as follows:
Figure BDA0002413529070000161
wherein Boc represents a tert-butoxycarbonyl group.
Synthesis of compound S2: intermediate A4(344mg, 1mmol), dicyclohexylcarbodiimide (DCC, 412mg, 2mmol), 4-dimethylaminopyridine (DMAP, 122mg, 1mmol) were weighed into a 50mL reaction flask, dissolved in 10mL dichloromethane, to which Boc-L-alanine (189mg, 1mmol) was added, stirred at room temperature overnight, TLC monitored for reaction completion, 10mL water was added, dichloromethane was extracted 3 times, the organic phases were combined, concentrated under reduced pressure, and the crude product was chromatographed over silica gel column (petroleum ether/ethyl acetate 10:1) to give 463.5mg intermediate A5 as a pale yellow solid in 90% yield.
A5(463mg, 0.9mmol) was weighed out and placed in a reaction flask, 10mL of dichloromethane was added at room temperature to dissolve it, 4mL of trifluoroacetic acid was added thereto, stirring was carried out at room temperature, TLC was used to detect completion of the reaction, the pH was adjusted to 7-8 with ammonia water, dichloromethane was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was crystallized from ethyl acetate n-heptane system to give 329mg of the target S2 as an off-white solid in 88% yield.
ESI-MS:416.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.82(1H,m),7.41(1H,m),7.37(1H,m),7.30(1H,m),6.61(1H,m),4.98(1H,d,J＝7.4),3.55(1H,m),2.72(2H,m),2.36(1H,m),2.07(1H,m),1.92(2H,m),1.74(2H,m),1.51(2H,m),1.37(3H,m),1.27(1H,m),1.16(3H,m),1.05(1H,dd,J＝10.9,J＝2.7),0.93(3H,m),0.91(3H,s),0.88(3H,s),0.85(3H,s).
Example 3: synthesis of Compound S3
The synthetic route is as follows:
Figure BDA0002413529070000171
synthesis of intermediate a 6: intermediate A4(307mg, 0.89mmol) was dissolved in 5mL of DMF and triethylamine (182mg, 1.8mmol), di-tert-butyl chloromethyl phosphate (258mg, 1mmol) were added sequentially thereto at room temperature, stirred at 60 ℃ for 4h, monitored by TLC until the reaction was complete, poured into 20mL of ice water, stirred for 0.5h, a large amount of solid precipitated, filtered and dried under vacuum to give 380mg of intermediate A6 as an off-white solid in 75% yield.
Synthesis of compound S3: a6(380mg, 0.67mmol) was weighed and placed in a reaction flask, dichloromethane (10 mL) was added at room temperature to dissolve it, trifluoroacetic acid (4 mL) was added thereto, stirring was carried out at room temperature, TLC detection of reaction completion was carried out, water washing was carried out 3 times, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentration under reduced pressure, and the crude product was separated and purified by preparative liquid phase separation (C18 column) from 10mM ammonium acetate in acetonitrile (20% -80%) to give 250mg of the objective S3 as an off-white solid in 82% yield.
ESI-MS:455.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.81(1H,m),7.51(1H,m),7.35(1H,m),7.29(1H,m),5.45(2H,m),5.09(1H,d,J＝7.4),4.91(1H,m),2.35(1H,m),2.05(1H,m),1.81(4H,m),1.47(5H,m),1.27(1H,m),1.08(1H,dd,J＝10.8,J＝2.7),0.95(3H,m),0.90(3H,s),0.86(3H,s),0.84(3H,s).
Example 4: synthesis of Compound S4
The synthetic route is as follows:
Figure BDA0002413529070000181
intermediate a 7: intermediate A4(822mg, 2.38mmol), potassium carbonate (550mg, 4mmol) were weighed into a 50mL reaction flask, 10mL DMF was added, chloromethyl methyl sulfide (230mg, 2.4mmol), potassium iodide (38mg, 0.23mmol) were added sequentially thereto with stirring at room temperature overnight with stirring at room temperature, TLC monitored for reaction completion, poured into water 30mL, a solid precipitated, and the solid crystallized from ethyl acetate and n-heptane to give 693mg of intermediate A7 as a pale yellow solid in 72% yield. ESI-MS 405.2[ M + H ]]+。
Synthesis of intermediate A8: a7(693mg, 1.72mmol) was weighed out and placed in a reaction flask, 10mL of dichloromethane was added at room temperature to dissolve it, 2mL of sulfonyl chloride was added thereto, stirring was performed at room temperature, TLC was performed to detect completion of the reaction, concentration was performed under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 10:1) to obtain 546mg of the target compound with a yield of 81%.
Synthesis of compound S4: intermediate A8(546mg, 1.39mmol) and potassium carbonate (550mg, 4mmol) were weighed into a reaction flask, 10mL of DMF was added, L-alanine (120mg, 1.4mmol) and potassium iodide (16mg, 0.13mmol) were added thereto in sequence with stirring at room temperature, stirring was carried out overnight at room temperature, TLC was used to monitor completion of the reaction, poured into water 30mL, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was recrystallized from ethanol water to give 310mg of the title S4 as an off-white solid in 50% yield.
ESI-MS:446.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.89(1H,m),7.43(1H,m),7.37(2H,m),5.41(1H,m),5.31(2H,m),4.99(1H,d,J＝7.3),3.59(1H,m),2.92(2H,m),2.33(1H,m),2.05(1H,m),1.92(2H,m),1.74(2H,m),1.41(5H,m),1.31(1H,m),1.16(3H,m),1.04(1H,dd,J＝10.9,J＝2.7),0.93(3H,m),0.91(3H,s),0.88(3H,s),0.85(3H,s).
Example 5: synthesis of Compound S5
The synthetic route is as follows:
Figure BDA0002413529070000191
wherein Fmoc is fluorenylmethyloxycarbonyl.
Synthesis of intermediate a 9: weighing borneol (422mg, 2.74mmol), placing the borneol in a 50mL reaction bottle, adding 10mL of DMF for dissolving, adding sodium hydride (110mg, 2.74mmol) at room temperature, stirring for 1h at room temperature, adding a mixed solution of chloromethyl methyl sulfide (260mg, 2.74mmol) and potassium iodide 40mg in 3mL of DMF, stirring overnight at room temperature, monitoring the reaction completion by TLC, pouring the mixture into 30mL of water, separating out a solid, directly carrying out the next reaction on the solid, placing the solid in the reaction bottle, adding dichloromethane 10mL for dissolving at room temperature, adding sulfonyl chloride 2mL, stirring at room temperature, detecting the reaction completion by TLC, concentrating under reduced pressure, crystallizing the crude product by ethanol and water to obtain 282mg of target A9 as an off-white solid with the yield of 51%.
Intermediate a 10: to a solution of A1(452mg, 2.17mmol) in dichloromethane was added triethylamine (404mg, 4mmol), Fmoc-L-alanyl chloride (716mg, 2.17mmol) was added thereto under ice-bath, stirring was carried out at room temperature, after completion of TLC detection reaction, 10mL of water was added, dichloromethane was extracted 3 times, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 3:1) to give 763mg of intermediate A10 as a pale yellow solid in 70% yield. ESI-MS 502.2[ M + H ]]+。
Synthesis of compound S5: intermediate A10(763mg, 1.52mmol) and potassium carbonate (550mg, 4mmol) were weighed into a reaction flask, 10mL of DMF was added, to which A9(282mg, 1.4mmol) and potassium iodide (16mg, 0.13mmol) were added in sequence with stirring at room temperature, overnight stirring at room temperature, TLC monitored for reaction completion, poured into 30mL of water, extracted with ethyl acetate 3 times, the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was chromatographed over silica gel column (petroleum ether/ethyl acetate volume ratio 9:1) to give 304mg of target S5 as a off-white solid in 45% yield.
ESI-MS:446.3[M+H]+；
1H NMR(400MHz,CDCl3):δ7.89(1H,m),7.42(1H,m),7.38(1H,m),7.30(1H,m),6.63(1H,m),5.45(2H,m),3.97(1H,m),3.55(1H,m),2.70(2H,m),2.28(1H,m),1.91(3H,m),1.54(4H,m),1.37(2H,m),1.23(2H,m),1.16(3H,m),0.95(1H,dd,J＝10.8,J＝2.7),0.90(3H,m),0.87(3H,s),0.86(3H,s),0.85(3H,s).
Example 6: synthesis of Compound S6
The synthetic route is as follows:
Figure BDA0002413529070000201
wherein Bn represents a benzyl group.
Synthesis of intermediate a 11: to a solution of A1(542mg, 2.6mmol) in dichloromethane was added triethylamine (404mg, 4mmol), to which was added dibenzylphosphoryl chloride (770mg, 2.6mmol) under ice-bath, stirred at room temperature, after TLC detection reaction was completed, 10mL of water was added, dichloromethane was extracted 3 times, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 4:1) to give 892mg of intermediate A11 as a pale yellow solid in 73% yield. ESI-MS:467.2[ M-H ]]-。
Synthesis of intermediate a 12: weighing intermediate A11(891mg, 1.9mmol) and potassium carbonate (550mg, 4mmol), placing in a reaction flask, adding 10mL DMF, stirring at room temperature, adding A9(382mg, 1.9mmol), potassium iodide (32mg, 0.2mmol) in sequence, stirring at room temperature overnight, TLC to monitor reaction completion, pouring into 30mL water, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure, subjecting the crude product to chromatographySilica gel column chromatography (petroleum ether/ethyl acetate volume ratio 9:1) afforded 629mg of target a12 as an off-white solid in 52% yield. ESI-MS 635.3[ M + H ]]+。
Synthesis of compound S6: weighing the intermediate A12(629mg, 0.99mmol), placing 10mL of methanol into a reaction bottle, stirring at room temperature, adding 100mg of 10% palladium carbon, introducing hydrogen, reacting at room temperature under normal pressure, monitoring the reaction by TLC to be complete, pouring into 30mL of water, separating out a solid, filtering, crystallizing the crude product by using ethanol and water to obtain 410mg of a target S6 which is a white-like solid with the yield of 91%.
ESI-MS:455.2[M+H]+；
1H NMR(400MHz,CDCl3):δ7.85(1H,m),7.57(1H,m),7.47(1H,m),7.27(1H,m),6.41(1H,m),5.45(2H,m),4.00(1H,m),2.27(1H,m),2.01(2H,m),1.92(1H,m),1.61(2H,m),1.54(2H,m),1.47(2H,m),1.22(2H,m),0.96(1H,dd,J＝10.7,J＝2.7),0.89(3H,m),0.87(3H,s),0.86(3H,s),0.85(3H,s).
EXAMPLE 7 Effect of Compounds S1, S2, S4, S5 on focal cerebral ischemia reperfusion injury
1. Materials and methods
1.1 Experimental animals
Sprague-dawley (sd) rat, male, body weight: 250-
1.2 Experimental methods
1.2.1 preparation of focal cerebral ischemia reperfusion model. The method mainly comprises the following steps: 10% chloral hydrate (350mg/kg) was intraperitoneally injected to anesthetize rats, the right external carotid artery was isolated, ligated and severed, and a nylon plug thread, which was swollen at the tip of the human head, was slowly inserted from the stump of the external carotid artery along the sum of the carotid arteries, approximately 18mm, to block the entrance of the middle cerebral artery, resulting in ischemia. Removing the thrombus line after 2h of ischemia and performing 24h of reperfusion; after the animal is awakened, Homer and dyskinesia of the contralateral body appear, namely the model preparation is successful.
1.2.2 animal groups and administration of Experimental animals were randomly divided into 6 groups, i.e., model group, positive control butylphthalide group (10mg/kg), S1 group (10mg/kg), S2 group (10mg/kg), S4 group (10mg/kg), S5 group (10mg/kg), each group containing 10-12 animals. Each group of the test substances and the positive control group were administered 1 time by tail vein injection immediately after reperfusion, and 1 time in total.
Each group was administered at a volume of 0.5mL/100 g.
1.3.3 determination of neurological Defect score and cerebral infarct volume
The symptom of neurological deficit was assessed using a modified Bederson 5-score.
And (4) measuring the volume of the cerebral infarction, and taking the brain of the animal after scoring the last neurological deficit. Removing olfactory brain, lower brainstem and cerebellum, weighing the rest part, cutting the brain into 5 pieces with substantially the same thickness along coronal plane, warm-bathing in 37 deg.C red tetrazolium dye for 30min to obtain deep red brain tissue and pale dead area. Then, the brain slices are fixed in 10% formaldehyde, white tissues are carefully dug down and weighed, and the percentage of the weight of the infarcted tissues to the total weight of the brain is used as an infarct volume judgment index.
2. Results
2.1 Effect on post-ischemic reperfusion cerebral infarct volume and neurological deficit score
Compared with the model group, the medicine group can obviously reduce the infarct volume of the cerebral ischemia-reperfusion rat (P is less than 0.05); the influence on the nerve defect symptoms can improve the nerve defect symptoms of rats. The results are shown in Table 1.
TABLE 1 Effect on cerebral infarct volume and neurological deficit score after cerebral ischemia-reperfusion
Figure BDA0002413529070000211
Figure BDA0002413529070000212
Figure BDA0002413529070000221
P <0.05, P <0.01, compared to model groups.
From the above experimental results, it can be seen that the compounds of the examples are superior to the butylphthalide group in terms of improvement of cerebral infarction volume and neurological deficit after cerebral ischemia-reperfusion.
The foregoing description is illustrative of embodiments of the present invention. However, the scope of the present invention should not be limited to the above-described embodiments. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (11)

1. A compound shown as a formula (I), a racemate, a stereoisomer and a pharmaceutically acceptable salt thereof:
Figure FDA0003629613260000011
wherein:
each R1Identical or different, independently of one another, from the group consisting of unsubstituted or optionally substituted by one, two or more RaSubstituted of the following groups: c1-6Alkyl, -OR4；R4Is selected from C1-6An alkyl group;
n is selected from 0, 1,2, 3 or 4;
R2selected from unsubstituted or optionally substituted by one, two or more RbSubstituted C1-6An alkyl group;
R3selected from- (O) P (OR)12)(OR13) or-C (O) R14；
R12、R13Same or different, independently from each other selected from H, C1-6An alkyl group;
R14selected from unsubstituted or optionally substituted by one, two or more Rcsubstituted-C1-3alkylene-NR6R7；R6Selected from H, C1-6An alkyl group; r7Selected from H, C1-6An alkyl group;
each Ra、Rb、RcIdentical or different, independently of one another, from C1-6An alkyl group;
X1and X2Identical or different, independently of one another, from O, -O [ (CHR)15)pO]q-；
R15Selected from H, C1-6An alkyl group;
p and q are selected from 1;
h in the compound of formula (I) is optionally replaced by D.
2. The compound of claim 1, wherein the compound of formula (I) has a structure represented by formula (I-1) or formula (I-2) below:
Figure FDA0003629613260000012
wherein:
each R1Identical or different, independently of one another, from the group consisting of unsubstituted or optionally substituted by one, two or more RaSubstituted of the following groups: c1-6Alkyl, -OR4；R4Is selected from C1-6An alkyl group;
n is selected from 0, 1 or 2;
R2selected from unsubstituted or optionally substituted by one, two or more RbSubstituted C1-6An alkyl group;
each Ra、RbIdentical or different, independently of one another, from C1-6An alkyl group;
Rcis selected from C1-6An alkyl group;
X1selected from O and O [ (CHR)15)pO]q-；
X2Selected from O and O [ (CHR)15)pO]q-；
R15Selected from H, C1-6An alkyl group;
p and q are selected from 1;
h in the compound of formula (I) is optionally replaced by D.
3. The compound of claim 1 or 2, wherein the configuration of each chiral center of the compound of formula (I) is the same or different and is independently selected from the group consisting of R configuration, S configuration, and racemate.
4. The compound of claim 3, wherein the compound is selected from the group consisting of:
Figure FDA0003629613260000021
5. a process for the preparation of a compound according to any one of claims 1 to 4, which comprises reacting compound M1 as starting material to give a compound of formula (I):
Figure FDA0003629613260000031
wherein:
PG is a protecting group;
R1、R2、X1、X2n has the definition as defined in any one of claims 1 to 4;
r is selected from 0, R31Is selected from H; or
R is selected from 1 or 2, R31Is selected from R3Groups after removal of 1 or 2H.
6. A process for the preparation of compound M1, comprising reacting compound M2 with compound M3, followed by compound M4, or with compound M4, followed by compound M3, to give compound M1:
Figure FDA0003629613260000032
wherein L is2、L3Identical or different, independently of one another, from a leaving group;
R1、R2、R3、X1、X2、R31PG, n, r independently have the definitions as defined in claim 5.
7. A compound selected from M1 of claim 6.
8. Use of a compound according to claim 7 for the preparation of a compound of formula (I) according to any one of claims 1 to 4.
9. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4.
10. Use of at least one compound of formula (I), its racemate, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the preparation of a medicament.
11. The use according to claim 10, wherein the medicament is a medicament for preventing or treating ischemic cardiovascular and cerebrovascular diseases, cardiovascular and cerebrovascular circulatory disorders, cerebral thrombosis, or for improving cerebral infarction volume or neurological deficit after cerebral ischemia-reperfusion.
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