CN113750085A

CN113750085A - Application of natural compound and derivative thereof in treating arterial lesion

Info

Publication number: CN113750085A
Application number: CN202110610054.XA
Authority: CN
Inventors: 姜宝红; 李谦
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2020-06-02
Filing date: 2021-06-01
Publication date: 2021-12-07
Anticipated expiration: 2041-06-01
Also published as: WO2021244547A1; CN113750085B; CN116870046A

Abstract

The invention provides application of natural compounds and derivatives thereof in treating arterial lesions. In particular, the present invention for the first time has found that the compounds of formula I have the ability to prevent and/or treat (I) aneurysms; (ii) arterial intercalary hematoma; and/or (iii) effects of arterial dissection. Wherein the dotted line, Ra, Rb, Rc, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉And R₁₀As defined in the description.

Description

Application of natural compound and derivative thereof in treating arterial lesion

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of flavonoid compounds and derivatives thereof in treating arterial lesions.

Background

Arterial lesions include aneurysms, mural hematomas, and arterial dissections, all due to arterial dilation, which may lead to later stage vascular rupture, severely endangering patient life. Arterial lesions can occur in all arteries of the body, the etiology of which is very complex, diabetes, hypertension, smoking and atherosclerosis, among the most common causative factors, and the symptoms are manifested by degradation of the extracellular matrix of the media and adventitia, thinning of the arterial wall and invasion of inflammatory cells, and finally vascular rupture, leading to death of the patient.

Clinically, no preventive and therapeutic drugs for aneurysm, interwall hematoma and arterial dissection exist, and except for surgical treatment, patients are in a state of no medicine and no medicine, so that drugs capable of preventing and/or treating aneurysm, interwall hematoma and/or arterial dissection are urgently needed in the field, and more treatment options are provided for patients.

Disclosure of Invention

The invention aims to provide the application of the compound shown in the formula I in preventing and/or treating aneurysm, intermural hematoma and/or arterial dissection.

In a first aspect, the present invention provides a use of a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a crystal form thereof, a hydrate thereof or a solvate thereof, for preparing a pharmaceutical composition or a formulation; the pharmaceutical composition or formulation is for use in the prevention and/or treatment of arterial lesions selected from the group consisting of: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection;

wherein X is selected from the group consisting of: o, substituted or unsubstituted-CH₂-；

The dotted line represents a bond or is absent;

R₁、R₂、R₃and R₄Independently selectFrom the group: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₁And R₂、R₂And R₃Or R₃And R₄Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

one of Ra and Rb is

And R is₆、R₇、R₈、R₉And R₁₀Independently selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₆And R₇、R₇And R₈、R₈And R₉Or R₉And R₁₀Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

the other of Ra and Rb is a group selected from: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted orUnsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl;

rc is selected from the group consisting of: H. oxo (═ O), OR₁₁；

Each R₁₁Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted C₁-C₆Alkyl), - (C ═ O) - (substituted or unsubstituted phenyl), substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl; and

by "substituted" is meant that one or more (e.g., 2, 3, or 4) hydrogen atoms on the group are independently substituted with a group selected from: H. halogen, -SH, -OH, -COOH, -CN, -NH₂、-(C＝O)-C₁-C₆Alkyl, -C₁-C₆Alkyl, -C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₈Cycloalkyl, phenyl or benzyl.

In another preferred embodiment, X is O; and Rc is oxo.

In another preferred embodiment, the compound has the structure of formula Ia or formula Ib:

wherein each dashed line independently represents a bond or is absent;

each R₅Independently selected from the group consisting of: H. OR (OR)₁₁(ii) a And

each R₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉、R₁₀And R₁₁Independently as defined above.

In another preferred embodiment, the compound has the structure of formula Ic:

wherein R is_b、R_c、R₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉And R₁₀Independently as defined above.

In another preferred embodiment, the compound has the structure of formula Ia:

wherein the content of the first and second substances,

represents a single bond or a double bond;

R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉and R₁₀Independently selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₁And R₂、R₂And R₃Or R₃And R₄Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

R₅selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl;

R₆、R₇、R₈、R₉and R₁₀Independently selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₆And R₇、R₇And R₈、R₈And R₉Or R₉And R₁₀Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

each R₁₁Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted C₁-C₆Alkyl), substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstitutedA substituted benzyl group; and

by "substituted" is meant that one or more (e.g., 2, 3, or 4) hydrogen atoms on the group are independently substituted with a group selected from: H. halogen, -SH, -OH, -COOH, -CN, -NH₂、-(C＝O)-C₁-C₆Alkyl radical, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₈Cycloalkyl, phenyl or benzyl.

In another preferred embodiment, R₁、R₂、R₃、R₄Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR₁₁；

Each R₁₁Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted C₁-C₆Alkyl groups).

In another preferred embodiment, R₆、R₇And R₈Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR₁₁；

In another preferred embodiment, R₉And R₁₀Wherein 1 or 2 are selected from the group consisting of: halogen, OR₁₁；

In another preferred embodiment, R₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉And R₁₀At least 1, preferably 2, 3, 4 or 5 of them are-OH or C₁-C₆An alkoxy group.

In another preferred embodimentIn (1), the R is₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉And R₁₀The remaining radicals in (A) are H or C₁-C₆An alkyl group.

In another preferred embodiment, R₁、R₃、R₆、R₇、R₉And R₁₀Is H.

In another preferred embodiment, R₂Is OR₁₁Preferably, hydroxyl or methoxy.

In another preferred embodiment, R₄Is OR₁₁Preferably, hydroxyl or methoxy.

In another preferred embodiment, R₅Is H OR OR₁₁，

R₁₁Selected from the group consisting of: H. glycosyl, substituted or unsubstituted C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted C₁-C₆Alkyl groups).

In another preferred embodiment, R₈Is OR₁₁Preferably, hydroxyl or methoxy.

In another preferred embodiment, R₂、R₄And R₈Is a hydroxyl group.

In another preferred embodiment, R₂、R₄、R₈And R₅Is a hydroxyl group.

In another preferred embodiment, the glycosyl is monosaccharide, disaccharide or trisaccharide.

In another preferred embodiment, said glycosyl groups are each independently selected from the group consisting of: glucosyl, fructosyl, mannosyl, arabinosyl, rhamnosyl, galactosyl, xylosyl, apiose, or a combination thereof.

In another preferred embodiment, the glycosyl is selected from the group consisting of: mono-glucosyl or di-glucosyl.

In another preferred embodiment, R is₁Selected from the group consisting of: H. c₁-C₆Alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In another preferred embodiment, the compound of formula I is selected from the group consisting of:

in another preferred embodiment, the compound is kaempferol.

In another preferred embodiment, the compound is not naringin.

In another preferred embodiment, the dotted line, Ra, Rb, Rc, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉And R₁₀Independently, a substituent corresponding to the specific compound as described above.

In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In another preferred embodiment, the artery is selected from the group consisting of: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, retinal artery, inferior mesenteric artery, intracranial artery, carotid artery, or a combination thereof.

In another preferred embodiment, the aneurysm includes an early stage aneurysm, a mid-stage aneurysm, and/or a late stage aneurysm.

In another preferred embodiment, the pharmaceutical composition or formulation is for one or more uses selected from the group consisting of:

(a) inhibiting the formation and/or growth of an aneurysm;

(b) reducing the thickness of the vessel wall;

(c) inhibiting elastin degradation;

(d) the integrity of the vascular structure is protected and,

(e) inhibiting the occurrence of an intercalary hematoma; and/or

(f) Protecting adventitial collagen of blood vessel.

In another preferred embodiment, the pharmaceutical composition or formulation is in a dosage form selected from the group consisting of: liquid formulations (e.g., solutions, emulsions, suspensions), solid formulations (e.g., lyophilized formulations).

In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: injection (such as injection or powder injection), and oral preparation (such as capsule, tablet, pill, powder, granule, syrup, oral liquid or tincture), preferably, the dosage form is oral preparation.

In a second aspect, the present invention provides the use of a medicinal material comprising a compound of formula I according to the first aspect of the invention and/or an extract comprising a compound of formula I for the preparation of a composition; the composition is used for preventing and/or treating arterial lesions selected from the group consisting of: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection.

In another preferred embodiment, the compound has the structure of formula Ia:

wherein R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And

as defined in the first aspect of the invention.

In another preferred embodiment, the medicinal materials are selected from: kaempferia galanga (kaempferol galanga L.), blueberry (Vaccinium Spp), sinopodophyllum japonicum (diphyleliasinessisli), pteris alba (Thesium chinensis Turcz.), eupatorium odoratum (euphorbia lunulata bge.), sophora japonica fruit, ginkgo biloba, or combinations thereof.

In another preferred embodiment, the extract is an extract of a substance selected from the group consisting of: kaempferia galanga (kaempferol galanga L.), blueberry (Vaccinium Spp.), rhizoma et radix piperis (Diphylleiensis li.), daphne giraldii (Thesium chinense Turcz.), radix euphorbiae lathyris (euphorbia chinense bge.), radix euphorbiae lunulatae (euphorbia lunulata bge.), pagodatree fruit, tea, broccoli, witch hazel, grapefruit, or a combination thereof.

In another preferred embodiment, the compound of formula I in the extract is kaempferol.

In another preferred embodiment, the solvent for extraction is selected from the group consisting of: water, an organic solvent, or a combination thereof.

In another preferred embodiment, the organic solvent is selected from the group consisting of: c₁-C₄An alcohol, acetonitrile, or a combination thereof.

In another preferred embodiment, the composition is selected from the group consisting of: a pharmaceutical composition, a food composition, a dietary supplement, or a nutraceutical composition.

In another preferred example, the extract is a blueberry extract, preferably a blueberry anthocyanin extract.

In another preferred embodiment, the pharmaceutical composition is for one or more uses selected from the group consisting of:

(a) inhibiting the formation and/or growth of an aneurysm;

(b) reducing the thickness of the vessel wall;

(c) inhibiting elastin degradation;

(d) the integrity of the vascular structure is protected and,

(e) inhibiting the occurrence of an intercalary hematoma; and/or

(f) Protecting adventitial collagen of blood vessel.

In a third aspect of the invention, there is provided a method of preventing and/or treating (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) arterial dissection, administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, an isomer, crystal form, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the invention.

In another preferred embodiment, the subject is a mammal.

In another preferred embodiment, the subject is a human, a rat, or a mouse.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 is a schematic representation of the process of forming an aneurysm, interwall hematoma and dissection model.

Figure 2 shows the results of kaempferol inhibition of aneurysms, intermural hematomas and or arterial dissections. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

Fig. 3 is a quantitative result of the maximum diameters of abdominal aortic aneurysms of naringenin and kaempferol. A is a representative diagram of each group of arteries; b is the maximum diameter quantitative graph of each group of abdominal aorta.

Figure 4 shows the results of experiments with catechins to inhibit aneurysms, intermural hematomas and or arterial dissections. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

Fig. 5 shows experimental results of biochanin a inhibiting aneurysm, intermural hematoma and or arterial dissection. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

Figure 6 shows the results of experiments with daidzein inhibiting aneurysms, intermural hematomas and or arterial dissections. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

FIG. 7 shows the results of experiments in which epigallocatechin gallate (EGCG) inhibited aneurysms, intermural hematomas and or arterial dissections. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

FIG. 8 shows the results of a cornflower-3-glucoside inhibition of aneurysms, intermural hematomas, and or aneurysms. A is a representative diagram of each group of arteries; b is the aorta tissue staining analysis picture.

Figure 9 shows the results of experiments with blueberry anthocyanin extract to inhibit aneurysms, intermural hematomas and or arterial dissections. A is a representative diagram of each group of arteries; b is the quantitative result of the maximum diameter of the abdominal aortic aneurysm.

Figure 10 shows the results of experiments with blueberry anthocyanin extract to inhibit aneurysms, intermural hematomas and or arterial dissections. A is an aorta tissue H & E staining result graph, B is an aorta tissue ground-red staining result graph, and C is an abdominal aorta wall thickness quantitative result; d is the quantitative result of the degradation fraction of the arterial elastin.

Detailed Description

The present inventors have conducted extensive and intensive studies to provide the effects of the compound of formula I in the prevention or treatment of arterial lesions through a number of screens and tests. The invention discovers for the first time that the compound of formula I (typically, kaempferol) can effectively reduce the thickness of the vascular wall, reduce the volume of aneurysm, protect the integrity of the vascular structure, inhibit inflammatory cell infiltration and radically treat arterial lesions. The present invention has been completed based on this finding.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

The term "room temperature" as used herein means a temperature of 4-40 ℃, preferably 25 ± 5 ℃.

As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical (i.e., C) having the indicated number of carbon atoms₁-C₆Representing 1-6 carbons), alkyl includes alkyl of 1, 2, 3, 4, 5, or 6 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C₂-C₆Alkenyl refers to straight or branched chain alkenyl groups having 2 to 6 carbon atoms, including alkenyl groups of 1, 2, 3, 4, 5, or 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C₂-C₆Alkynyl refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, including alkynyl groups of 1, 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "C₃-C₈Cycloalkyl "includes monocyclic or bicyclic alkyl. E.g. C₃-C₈Cycloalkyl refers to a saturated or no more than one double bond hydrocarbon ring containing from 3 to 8 ring carbon atoms. Cycloalkyl includes cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, or the like.

As used herein, unless otherwise indicated, the term "heterocycloalkyl" refers to a cycloalkyl group containing the indicated number of heteroatoms selected from O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocycloalkyl group can be a monocyclic, bicyclic, or polycyclic ring system. The heterocyclic atom is preferably 3 to 8-membered, more preferably 4 to 6-membered. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. The heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom.

Unless otherwise indicated, the term "aryl" denotes polyunsaturated (usually aromatic) hydrocarbon groups which may be monocyclic or polycyclic (up to three rings) fused together or linked covalently, non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl.

The term "heteroaryl" refers to an aryl (or ring) containing the indicated number of heteroatoms selected from O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl (benzotriazinyl), purinyl, benzimidazolyl, benzpyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.

As used herein, the term "glycosyl" refers to a monovalent substituent formed by removing the hemiacetal hydroxyl group from the cyclic form of a monosaccharide (or disaccharide, trisaccharide), such as an-O-glycosyl group formed by substituting one or more OH groups on a compound of formula I with a glycosyl group. Representative monosaccharides include pentoses and hexoses, the preferred sugar group being a monoglucosyl group (β -D glucopyranosyl, -glu) or a diglucosyl group.

In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") are intended to include both substituted and unsubstituted forms of the indicated group, with the number of substituents being oneThe number may be 1, 2, 3 or 4. Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are replaced with a group selected from the group consisting of: one or more (e.g. 2, 3 or 4) hydrogen atoms on the group are substituted by a group selected from: H. halogen, -SH, -OH, -COOH, -CN, -NH₂、-(C＝O)-C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted phenyl), C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, alkyl C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₈Cycloalkyl, phenyl or benzyl.

As used herein, the term "isomer" is intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to fall within the scope of the present disclosure.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (A), (B), (C), (D), (C), (D) and (D) a³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) In that respect All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. For example, the compounds may be prepared such that any number of hydrogen atoms are deuterated (C)²H) Isotopic substitution. The compounds of the invention may also constitute thisSome compounds contain unnatural proportions of atomic isotopes at one or more atoms. Unnatural proportions of isotopes can be defined as from amounts found in nature to amounts consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as tritium (A), (B), (C) and C)³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) Or a non-radioactive isotope, e.g. deuterium (A), (B), (C) and C)²H) Or carbon-13 (¹³C)。

As used herein, the terms "prevention" or "treatment" include disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., to prevent, delay or lessen the severity of a symptom prior to the onset of the symptom)) or therapeutic (i.e., to lessen the severity and/or duration of a symptom after the onset of the symptom). "prevention" and "treatment" as used herein include delaying and stopping the progression of the disease, and do not require 100% inhibition, eradication, or reversal. In some embodiments, the reduction, prevention, inhibition, and/or reversal is, e.g., at least about 1%, 10%, at least about 30%, at least about 50%, or at least about 80% as compared to the absence of a compound of formula I of the present invention, a drug substance or extract comprising a compound of formula I, or a pharmaceutical composition of the present invention.

Active ingredient

The active ingredients of the invention include compounds of formula I, pharmaceutically acceptable salts thereof, isomers thereof, crystalline forms thereof, hydrates thereof, or solvates thereof;

wherein the dotted line, Ra, Rb, Rc, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉And R₁₀As defined above.

As used herein, "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts is that formed by reacting a compound of the present invention with a base. Suitable bases for salt formation include, but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine and piperazine.

The compounds of the present invention may be amorphous, crystalline or mixtures thereof.

The compounds of formula I of the present invention can be obtained by extraction from plants such as kaempferia galanga through alcohol extraction, chromatography, etc., and can also be purchased commercially or synthesized by prior art synthetic methods using commercially available starting materials. The compounds of the present invention can be extracted or synthesized by one of ordinary skill in the art according to the prior art. The extract or synthesized compound can be further purified by column chromatography, high performance liquid chromatography or crystallization.

Synthetic chemistry modifications, methods of protecting functional groups are very helpful for the synthesis of compounds for use and are well known in the art, see for example r.larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, protective groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); l.fieser and m.fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.Patquette, ed.encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

Traditional Chinese medicine, food material and extract containing compound of formula I

In another aspect of the invention, the medicinal material and/or food material containing the compound of formula I, and the use of the extract containing the compound of formula I are provided, which are used for treating arterial lesions or for preparing compositions and/or preparations for treating arterial lesions. Typically, the arterial lesions include (but are not limited to): (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection.

Preferably, kaempferol-containing herbs include (but are not limited to): kaempferia galanga (kaempferol galanga L) (e.g., rhizome), Erythrophorum chinense Li (rhizome), Thymus chinensis (Thesium chinense Turcz.), Euphorbia lunulata (euphorbia lunulata Bge.), Sophora japonica fruit, Ginkgo biloba (Ginko biloba L.) (e.g., leaf, fruit), or combinations thereof.

Kaempferol is also widely present in food materials, and people have extracted pure kaempferol from tea leaves, broccoli, witch hazel and grapefruit. In the present invention, the extraction method of the extract is not particularly limited, and an extraction method commonly used in the art may be used. Such as: water extraction, alcohol extraction, supercritical extraction (CO)₂) And the like.

Preferably, the extract contains an enriched active ingredient of the invention. The active ingredient accounts for more than or equal to 1 wt%, more than or equal to 2 wt%, and more than or equal to 5 wt%, such as 1-30 wt% or 2-20 wt% of the dry weight of the extract.

In another preferred example, the extract is blueberry (fruit) anthocyanin extract. The extraction method of the blueberry anthocyanin extract has no special requirements, and the extract rich in the blueberry anthocyanin extract can be obtained by using a commercially available blueberry anthocyanin extract or by using the common method disclosed by the invention.

In another preferable example, the mass content of the total anthocyanin in the blueberry anthocyanin extract is more than or equal to 1%, more than or equal to 2%, more than or equal to 5%, more than or equal to 10%, more than or equal to 15%, more than or equal to 20%, more than or equal to 50%, more than or equal to 60%, more than or equal to 70%, more than or equal to 80%, more than or equal to 90%, and more than or equal to 100%, based on the dry weight of the extract.

Preferably, the preparation method of the blueberry anthocyanin extract comprises the following steps: mixing blueberry pulp with acidified ethanol (HCl acidified, pH3.0 + -0.2, ethanol final volume fraction of 70-80%) at a ratio of 1: 8-12, leaching at 45-55 deg.C for 2-4 hr to obtain leaching solution, and centrifuging the leaching solution to obtain supernatant. And adsorbing the supernatant with low-polarity macroporous resin (such as AB-8 resin and D101 resin), eluting with 55-65% ethanol, and evaporating the solvent to obtain the blueberry anthocyanin extract.

Pharmaceutical compositions, methods of administration and uses

The active ingredients of the invention have the function of treating and/or preventing diseases related to arterial lesions, so the active ingredients can be used for preparing pharmaceutical compositions for preventing and/or treating diseases related to arterial lesions; preferably, the arterial lesion is selected from the group consisting of: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection.

In another preferred embodiment, the aneurysm is selected from the group consisting of: an early stage aneurysm, a mid stage aneurysm, a late stage aneurysm, or a combination thereof.

The active ingredients of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, including (but not limited to): a blood pressure lowering agent (e.g., an angiotensin converting enzyme inhibitor and/or an angiotensin receptor blocker (e.g., valsartan, losartan, alisartan medoxomil, etc.)), a blood lipid lowering agent (e.g., statins, fibrates, nicotinic acids, cholesterol absorption inhibitors), a blood glucose lowering agent (e.g., sulfonylurea secretagogues, insulin sensitizers, biguanides), a polymeric salvianolic acid, or a combination thereof.

The pharmaceutical composition of the invention can be used for preparing a medicament for treating and/or preventing diseases related to arterial lesions, preferably, the arterial lesions are selected from the following group: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection.

In the pharmaceutical composition of the present invention, the first active ingredient and the second active ingredient may be formulated separately or mixed together to make a formulation.

As used herein, "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-500mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with the compound of formula I without significantly diminishing the pharmaceutical efficacy of the compound. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

In the present invention, the general range of therapeutically effective dosages for compounds of formula I will be: about 1 to 2000 mg/day, about 10 to about 1000 mg/day, about 10 to about 500 mg/day, about 10 to about 250 mg/day, or about 10 to 100 mg/day. A therapeutically effective dose will be administered in one or more doses. It will be understood, however, that the specific dose of the active ingredients of the invention for any particular patient will depend upon a variety of factors such as the age, sex, body weight, general health, diet, individual response, time of administration, severity of the condition to be treated, the activity of the particular compound administered, the dosage form, mode of application and concomitant drugs. A therapeutically effective amount for a given situation can be determined using routine experimentation and is within the ability and judgment of the clinician or physician. In any event, the active ingredient will be administered in multiple doses based on the individual condition of the patient and in a manner that allows for the delivery of a therapeutically effective amount.

The main advantages of the invention include:

1. the invention discovers for the first time that the compound shown in the formula I has the effects of slowing the expansion speed of aneurysm, reducing hematoma between arterial walls, inhibiting arterial dissection and further reducing arterial rupture, and is suitable for treating arterial related diseases.

2. The compounds and pharmaceutical compositions of the present invention provide therapeutic options beyond surgical treatment for patients with aneurysms, arterial mural hematomas, and/or arterial dissections.

3. The compound is mostly known, safe and small in toxic and side effects, and can provide a convenient choice for quickly developing a medicine for effectively treating arterial lesions.

The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Reagent

Laboratory apparatus

Model preparation and sample detection method

Preparation of aneurysm, intermural hematoma and/or arterial dissection model

Anesthesia was performed by intraperitoneal injection of 5% sutai at a dose of 20mg/kg of mouse body weight. After the mouse enters an anesthesia state, the shaver shaves the abdominal hairs, the depilatory cream is used for further and thoroughly depilating the abdominal hairs, the mouse is fixed on an operating table after the abdominal hairs are wiped off, and the body temperature is kept by a heating pad under the mouse. Wiping abdominal skin with iodine, deiodinating with 75% ethanol, cutting 1.5cm incision at the center of abdomen, carefully pushing away viscera with forceps, dividing the intestinal tract into left and right sides with gauze wetted with 3% penicillin-streptomycin, and carefully separating connective tissue and muscle tissue on the surface of aorta with forceps to fully expose abdominal aorta. The exposed abdominal aorta is about 0.5cm in length, the proximal end does not exceed the bilateral renal arteries, and the distal end does not exceed the femoral artery.

The sterilized absorbent paper (0.3cm x 0.3cm) was soaked in Porcine Pancreatic Elastase (PPE) thoroughly and then applied to the exposed abdominal aorta for 50 min, and a piece of gauze moistened with 3% normal saline penicillin-streptomycin was placed over the abdominal incision to prevent excessive loss of abdominal water. After 50 minutes, the absorbent paper on the aorta was carefully removed and the abdominal cavity was flushed with 3% penicillin-streptomycin in saline, and the peritoneum and skin were sutured with 3/8 suture needles and 5/0 suture threads. After suturing, the wound was wiped with iodine tincture, and 1 minute was followed by deiodination with 75% ethanol. Mice were placed in clean cages, fed with 1% beta-aminopropionitrile (BAPN) feed, water ad libitum, and the feed was changed every other day.

Taking materials

The whole aorta from the heart to the lower limb was immediately taken out and placed in a container containing physiological saline, and the container was placed on ice. Under a stereomicroscope, muscle and adipose tissues around the aorta were carefully removed.

Gross morphological observations

The trimmed aorta was placed on a black plate and photographed with a stereo microscope (SZX7, OLYMPUS). The maximum diameter of the AAA is measured using Cell Sens standard software (OLYMPUS, version 1.18). According to V ═ AAA max diameter x AAA length²) The formula/2 calculates the volume of AAA.

Sample fixing, dehydrating, paraffin embedding and slicing

100mL of formaldehyde, 4g of sodium dihydrogen phosphate and 6.5g of disodium hydrogen phosphate are dissolved in 900mL of distilled water to prepare paraformaldehyde fixing liquid with the volume ratio of 10%. After the aorta tissue is fixed in paraformaldehyde fixing solution for 72h, the aorta tissue is washed by tap water for 4-6h, placed in a dehydrator for automatic dehydration according to a set program, and sequentially subjected to 75% ethanol for 1.5h, 95% ethanol for 1.5h, 100% ethanol for 1.5h, xylene for 1.5h and paraffin for 1.5 h. The paraffin embedding machine is opened 2 hours in advance to melt paraffin, and the temperature is controlled at 60 ℃. After paraffin is melted, paraffin embedding is carried out on the dehydrated aorta tissue, the aorta tissue is poured into an embedding box, the tissue block which is soaked in the paraffin is placed into an embedding frame by using heated tweezers, the tissue block is gently moved to a cold platform, and after the paraffin is solidified, the paraffin block is taken down to prepare for slicing. Before slicing, the wax block is put into a refrigerator for precooling, and after cooling, the paraffin with the thickness of 5 mu m is sliced continuously by a slicer. The sections were spread on a spreader at 38 ℃ warm water, scooped up with an APES-coated slide, and air dried naturally for subsequent histopathological staining.

Hematoxylin-eosin (HE) staining

Tissue was fixed embedded and cut into 4 μm paraffin sections, which were first sliced (65 ℃, 60 minutes) and then dewaxed to the aqueous phase (xylene 15 minutes → absolute ethanol 5 minutes → 95% ethanol 5 minutes → 75% ethanol 5 minutes → running water 1 minute); placing the mixture into hematoxylin staining solution for staining for 15 minutes, and then washing the mixture for 4 minutes by running water; differentiating with 1% hydrochloric acid ethanol for 5 s (differentiation time is adjusted according to the preparation time of differentiation solution), and flushing with running water for 5 min; placing the eosin staining solution in water for 1 minute after staining for 1 minute; dehydrated and then xylene permeabilized (75% ethanol 5 min → 95% ethanol 5 min → absolute ethanol 5 min → xylene 15 min), neutral gum seal, picture taken by BX51 microscope.

Lichen red dyeing

Dewaxing was carried out in the conventional dewaxing manner as described above. Staining with orcein staining solution for 1 hr, differentiating with 1% hydrochloric acid ethanol solution for 5 min, permeabilizing with xylene, and sealing with neutral gum. And quantifying the degradation of the elastin by using pathological scoring, wherein the degradation is not degraded for 0 min, the degradation is 1 min when the degradation is less than 25%, the degradation range is 2 min when the degradation range is 25% -50%, the degradation range is 3 min when the degradation range is 50% -75%, and the degradation is 4 min when the degradation range is more than 75%. The procedure was evaluated double blindly and expressed as the average of two investigators.

Data statistics

Data are expressed as mean ± SE. Statistical analysis was performed using GraphPad Prism 6. Statistical significance of differences between groups was compared multiple times using one-way anova. After the normal distribution and homogeneity of variance are determined, Tukey's test is performed. P <0.05 is statistically significant.

Example 1

Therapeutic effect of kaempferol on aneurysm, intermural hematoma and/or arterial dissection

Animal dosing and grouping conditions: 8-week-old C57BL/6 mice were housed in animal houses for one week and then randomly divided into a normal control group, a model control group, and kaempferol 25mg/kg (gavage) group, 10 animals per group, were molded with porcine trypsin and fed with a feed containing 1% beta-aminopropionitrile starting on the day of molding to induce aneurysm, intercalary hematoma, and arterial dissection (the model corresponds to the advanced stage of aneurysm, and intercalary hematoma and arterial dissection), the day of surgery was day 0, the animals were administered CMCNa or kaempferol separately by gavage from day 5, for 10 days and strictly observing the activity of the animals, and the animals were subjected to arterial tissue evaluation on day 15 after euthanasia to evaluate the conditions of aneurysm, intercalary hematoma, and arterial dissection.

The pig pancreatic elastase and 1% beta-aminopropionitrile feed are adopted to feed and induce the models of aneurysm, intercalary hematoma and arterial dissection, so that the influence of the drugs on the growth of the aneurysm and the intercalary hematoma and the rupture of the arterial dissection can be inspected.

Using a method similar to example 1, the following compounds were tested for their preventive therapeutic effect on intercalary hematomas and or arterial dissections, and the results of the maximum diameter of abdominal aortic aneurysms compared to the model group are summarized in table 1 below.

Wherein P < 0.05; p < 0.01; p < 0.001; p < 0.0001%

TABLE 1

Note: for compounds 1-2, n-10, and for compounds 3-7, n-5.

As can be seen from Table 1 and FIGS. 1-8, the infrarenal artery portion of the model control group had significantly bulged and expanded compared to the normal control group mice, whereas the compound of the present invention was able to significantly reduce the formation, size and expansion rate of the mouse aneurysm. From histological analysis, the compound of the invention can reduce the thickness of the blood vessel wall, protect the integrity of the blood vessel structure, inhibit the degradation of an elastic layer, inhibit the generation of the hematoma between walls and protect the form of the collagen of the adventitia of the blood vessel.

Example 2

Blueberry anthocyanin extract

Washing fresh blueberry fruits with distilled water, airing the surface water, freezing at the temperature of minus 20 ℃, and mashing until the blueberry fruits are in a homogenized state. Mixing blueberry pulp with acidified ethanol (pH3.0, 75% ethanol) at a ratio of 1: 10, leaching at 50 deg.C for 3 hr to obtain leaching solution, and centrifuging the leaching solution at 4000 r/min for 1 hr to obtain supernatant. And then adsorbing the supernatant by AB-8 macroporous resin, eluting by 60% ethanol, and rotationally evaporating the solvent to obtain the blueberry anthocyanin extract.

Through high performance liquid chromatography analysis, the blueberry anthocyanin extract mainly comprises the following components: delphinidin-3-galactoside chloride, delphinidin-3-glucoside chloride, cyanidin-3-galactoside chloride, delphinidin-3-arabinoside chloride, chlorinated cyanidin-3-glucoside, petunia-3-galactoside chloride, cyanidin-3-arabinoside chloride, petunia-3-glucoside chloride, delphinidin chloride, peoniflorin-3-galactoside chloride, petunia-3-arabinoside chloride, peoniflorin-3-glucoside chloride, malvidin-3-galactoside chloride, peoniflorin-3-arabinoside chloride, malvidin-3-glucoside chloride, delphin-3-glucoside chloride, delphinidin-3-L-D chloride, and combinations thereof, Cyanidin chloride, malvidin-3-arabinoside chloride, petuniaside chloride, peoniflorin, and malvidin chloride.

The blueberry anthocyanin extract was tested for preventive treatment of intercalary hematomas and or arterial dissections using a method similar to that of example 1, with n being 10 by dry weight of blueberry anthocyanin extract.

As shown in fig. 9 to 10, the blueberry anthocyanin extract has significant effects of inhibiting the formation and expansion rate of aneurysm, inhibiting the thickening of arterial wall, and degrading elastin, which suggests that the blueberry anthocyanin extract has significant effects of inhibiting aneurysm, interwall hematoma and or arterial dissection.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. Use of a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a crystal form thereof, a hydrate thereof or a solvate thereof, for the preparation of a pharmaceutical composition or formulation; the pharmaceutical composition or formulation is for use in the prevention and/or treatment of arterial lesions selected from the group consisting of: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection;

The dotted line represents a bond or is absent;

R₁、R₂、R₃and R₄Independently selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₁And R₂、R₂And R₃Or R₃And R₄Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

one of Ra and Rb is

And R is₆、R₇、R₈、R₉And R₁₀Independently selected from the group consisting of: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted orUnsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R₆And R₇、R₇And R₈、R₈And R₉Or R₉And R₁₀Together with the attached ring carbon atoms form a 5 or 6 membered heterocyclic ring containing 1 or 2O or S heteroatoms;

the other of Ra and Rb is a group selected from: H. halogen, OR₁₁、-COOH、-CN、-NH₂Sugar radical, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl having 1-3 members selected from the group consisting of O, N and S, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5-to 10-membered aromatic heterocycle having 1 to 3 members selected from O, N and S, or substituted or unsubstituted benzyl;

rc is selected from the group consisting of: H. oxo (═ O) OR₁₁；

2. The use of claim 1, wherein said compound has the structure of formula Ia or formula Ib:

wherein each dashed line independently represents a bond or is absent;

3. The use of claim 1, wherein the compound has the structure of formula Ic:

wherein, Rb, Rc and R₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉And R₁₀Independently as defined in claim 1.

4. The use according to claim 1, wherein R is₁、R₂、R₃、R₄Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR₁₁；

Each R₁₁Independent of each otherIs selected from the group consisting of: H. glycosyl, substituted or unsubstituted C₁-C₆Alkyl, - (C ═ O) - (substituted or unsubstituted C₁-C₆Alkyl groups).

5. The use according to claim 1, wherein R is₆、R₇And R₈Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR₁₁；

6. The use according to claim 2, wherein R is₅Is H OR OR₁₁，

7. The use according to claim 1, wherein R is₂、R₄And R₈Is a hydroxyl group.

8. The use according to claim 1, wherein the glycosyl groups are each independently selected from the group consisting of: glucosyl, fructosyl, mannosyl, arabinosyl, rhamnosyl, galactosyl, xylosyl, apiose, or a combination thereof.

9. The use according to claim 1, wherein the compound of formula I is selected from the group consisting of:

10. the use according to claim 1, wherein the compound of formula I is:

11. the use of claim 1, wherein the artery is selected from the group consisting of: thoracic aorta, abdominal aorta, splenic artery, hepatic artery, superior mesenteric artery, celiac trunk artery, renal artery, retinal artery, inferior mesenteric artery, intracranial artery, carotid artery, or a combination thereof.

12. The use of claim 1, wherein the pharmaceutical composition or formulation is for one or more uses selected from the group consisting of:

(a) inhibiting the formation and/or growth of an aneurysm;

(b) reducing the thickness of the vessel wall;

(c) inhibiting elastin degradation;

(d) the integrity of the vascular structure is protected and,

(e) inhibiting the occurrence of an intercalary hematoma; and/or

(f) Protecting adventitial collagen of blood vessel.

13. The use of claim 1, wherein the pharmaceutical composition or formulation is in a dosage form selected from the group consisting of: injection (such as injection or powder injection), and oral preparation (such as capsule, tablet, pill, powder, granule, syrup, oral liquid or tincture), preferably, the dosage form is oral preparation.

14. Use of a medicinal material comprising a compound of formula I according to claim 1 and/or an extract comprising a compound of formula I for the preparation of a composition; the composition is used for preventing and/or treating arterial lesions selected from the group consisting of: (i) an aneurysm; (ii) arterial intercalary hematoma; and/or (iii) an arterial dissection;

wherein the dotted line, Ra, Rb, Rc, R₁、R₂、R₃、R₄、R₆、R₇、R₈、R₉And R₁₀And as defined in claim 1.

15. The use of claim 14, wherein the medicinal material is selected from the group consisting of: kaempferia galanga (kaempferol galanga L.), blueberry (blueberry), sinoseneci (Vaccinium Spp.), sinopodophyllum (diphyleiasinessisli), pteris alba (Thesium Turcz.), euglena ternata (euphorbia lunulata bge.), sophora japonica fruit, ginkgo biloba, or a combination thereof.