CN113750085B - Use of natural compounds and derivatives thereof for the treatment of arterial lesions - Google Patents

Use of natural compounds and derivatives thereof for the treatment of arterial lesions Download PDF

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CN113750085B
CN113750085B CN202110610054.XA CN202110610054A CN113750085B CN 113750085 B CN113750085 B CN 113750085B CN 202110610054 A CN202110610054 A CN 202110610054A CN 113750085 B CN113750085 B CN 113750085B
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substituted
arterial
unsubstituted
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CN113750085A (en
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姜宝红
李谦
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The invention provides the use of natural compounds and derivatives thereof in the treatment of arterial lesions. In particular, the present invention for the first time finds that the compounds of formula I have the effect of preventing and/or treating (I) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) the effect of arterial dissection. Wherein the dotted line, ra, rb, rc, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 As defined by the description.

Description

Use of natural compounds and derivatives thereof for the treatment of arterial lesions
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, wall hematomas, arterial dissection, etc., all of which are caused by arterial dilation, and the development to a later stage will lead to vascular rupture, serious patient life threatening. Arterial lesions can appear on all arteries throughout the body, and their etiology is very complex, diabetes, hypertension, smoking, atherosclerosis, etc. are the most common causative factors, and symptoms are represented by degradation of extracellular matrix of the middle and adventitia, thinning of arterial walls and invasion of inflammatory cells, and eventually vascular rupture, leading to death of the patient.
Clinically, there is no preventive and therapeutic drug for aneurysms, wall hematomas and arterial dissection, and patients are in a non-medically acceptable state except for surgical treatment, so that there is an urgent need in the art for drugs capable of preventing and/or treating aneurysms, wall hematomas and/or arterial dissection, providing patients with more therapeutic options.
Disclosure of Invention
The invention aims to provide the application of a compound shown as the formula I in preventing and/or treating aneurysms, wall hematomas and/or arterial interlayers.
In a first aspect, the present invention provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a crystal form thereof, a hydrate 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) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) arterial dissection;
wherein X is selected from the group consisting of: o, substituted or unsubstituted-CH 2 -；
The dashed line indicates a bond or absence;
R 1 、R 2 、R 3 and R is 4 Independently selected from the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R is 1 And R is 2 、R 2 And R is 3 Or R 3 And R is 4 Together with the linking ring carbon atoms, form a 5-or 6-membered heterocyclic ring containing 1 or 2O or S heteroatoms;
among Ra and RbOne isAnd R is 6 、R 7 、R 8 、R 9 And R is 10 Independently selected from the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R is 6 And R is 7 、R 7 And R is 8 、R 8 And R is 9 Or R 9 And R is 10 Together with the linking 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 the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl;
rc is selected from the group consisting of: H. oxo (=o), OR 11 ；
Each R is 11 Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl), - (c=o) - (substituted or unsubstituted phenyl), substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, 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 the group consisting of: H. halogen, -SH, -OH, -COOH, -CN, -NH 2 、-(C＝O)-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 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:
In the formulae, each dotted line independently represents a bond or absence;
each R is 5 Independently selected from the group consisting of: H. OR (OR) 11 The method comprises the steps of carrying out a first treatment on the surface of the And
each R is 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 、R 10 And R is 11 Independently as defined above.
In another preferred embodiment, the compound has the structure of formula Ic:
wherein R is b 、R c 、R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 And R is 10 Independently as defined above.
In another preferred embodiment, the compound has the structure of formula Ia:
wherein, the liquid crystal display device comprises a liquid crystal display device,represents a single bond or a double bond;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R is 10 Independently selected from the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R is 1 And R is 2 、R 2 And R is 3 Or R 3 And R is 4 Together with the linking ring carbon atoms, form a 5-or 6-membered heterocyclic ring containing 1 or 2O or S heteroatoms;
R 5 selected from the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl;
R 6 、R 7 、R 8 、R 9 and R is 10 Independently selected from the group consisting of: H. halogen, OR 11 、-COOH、-CN、-NH 2 Glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl having 1 to 3 members selected from O, N and S, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle having 1-3 members selected from O, N and S, or substituted or unsubstituted benzyl; or R is 6 And R is 7 、R 7 And R is 8 、R 8 And R is 9 Or R 9 And R is 10 Together with the linking ring carbon atoms, form a 5-or 6-membered heterocyclic ring containing 1 or 2O or S heteroatoms;
each R is 11 Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl), substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, 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 the group consisting of: H. halogen, -SH, -OH, -COOH, -CN, -NH 2 、-(C＝O)-C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, phenyl or benzyl.
In another preferred embodiment, R 1 、R 2 、R 3 、R 4 Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR 11 ；
Each R is 11 Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl).
In another preferred embodiment, R 6 、R 7 And R is 8 Wherein 1, 2 or 3 are selected from the group consisting of: halogen, OR 11 ；
Each R is 11 Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl).
In another preferred embodiment, R 9 And R is 10 1 or 2 of which are selected from the group consisting of: halogen, OR 11 ；
Each R is 11 Independently selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl).
In another preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 And R is 10 At least 1, preferably 2, 3, 4 or 5, of them being-OH or C 1 -C 6 An alkoxy group.
In another preferred embodiment, R is 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 And R is 10 The remaining groups in (a) are H or C 1 -C 6 An alkyl group.
In another preferred embodiment, R 1 、R 3 、R 6 、R 7 、R 9 And R is 10 H.
In another preferred embodiment, R 2 Is OR (OR) 11 Preferably, hydroxy or methoxy.
In another preferred embodiment, R 4 Is OR (OR) 11 Preferably, hydroxy or methoxy.
In another preferred embodiment, R 5 Is H OR OR 11 ，
R 11 Selected from the group consisting of: H. glycosyl, substituted or unsubstituted C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted C 1 -C 6 Alkyl).
In another preferred embodiment, R 8 Is OR (OR) 11 Preferably, hydroxy or methoxy.
In another preferred embodiment, R 2 、R 4 And R is 8 Is hydroxyl.
In another preferred embodiment, R 2 、R 4 、R 8 And R is 5 Is hydroxyl.
In another preferred embodiment, the glycosyl is a monosaccharide, disaccharide or trisaccharide.
In another preferred embodiment, the 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-or di-glucosyl.
In another preferred embodiment, said R 1 Selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, 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 dashed lines, ra, rb, rc, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 Independently are substituents corresponding to the specific compounds 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, trunk abdominal artery, renal artery, omentum artery, inferior mesenteric artery, intracranial artery, carotid artery, or a combination thereof.
In another preferred embodiment, the aneurysm includes an early aneurysm, a mid-term aneurysm, and/or a late aneurysm.
In another preferred embodiment, the pharmaceutical composition or formulation is for use in one or more of the following selected from the group consisting of:
(a) Inhibiting the formation and/or growth of aneurysms;
(b) Reducing the thickness of the vessel wall;
(c) Inhibiting elastin degradation;
(d) The integrity of the vascular structure is protected,
(e) Inhibiting the occurrence of wall hematoma; and/or
(f) Protecting adventitia collagen.
In another preferred embodiment, the dosage form of the pharmaceutical composition or formulation is 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), oral preparation (such as capsule, tablet, pill, powder, granule, syrup, oral liquid or tincture), and more 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) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) arterial dissection.
In another preferred embodiment, the compound has the structure of formula Ia:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Andas defined in the first aspect of the invention.
In another preferred embodiment, the medicinal material is selected from: kaempferia galanga (kaempferol galanga l.), blueberry (vaccine Spp), sedge (diphylleinasensis li), bai Ruicao (Thesium chinense turcz.), euphorbia lathyris (euphormbianulata bge.), pagoda tree fruit, ginkgo, 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 (vaccine Spp), sedum aizoon (diphyleianensis li), bai Ruicao (Thesium chinense turcz.), euphorbia lathyris (euphormbianulata bge.), pagodatree fruit, tea, broccoli, wu Zhenzi, grapefruit, or combinations thereof.
In another preferred embodiment, the compound of formula I in the extract is kaempferol.
In another preferred embodiment, the extracted solvent is selected from the group consisting of: water, organic solvents, or combinations thereof.
In another preferred embodiment, the organic solvent is selected from the group consisting of: c (C) 1 -C 4 Alcohols, acetonitrile, or combinations 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 embodiment, 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 aneurysms;
(b) Reducing the thickness of the vessel wall;
(c) Inhibiting elastin degradation;
(d) The integrity of the vascular structure is protected,
(e) Inhibiting the occurrence of wall hematoma; and/or
(f) Protecting adventitia collagen.
In a third aspect of the invention, there is provided a method of preventing and/or treating (i) an aneurysm; (ii) an inter-arterial wall 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, a crystal form, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention.
In another preferred embodiment, the subject is a mammal.
In another preferred embodiment, the subject is a human, rat, mouse.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is a schematic illustration of the process of forming an aneurysm, interwall hematoma and arterial dissection model.
Fig. 2 shows experimental results of kaempferol inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
FIG. 3 shows the results of quantification of maximum diameter of abdominal aortic aneurysm by naringenin and kaempferol. A is an artery representative graph of each group; b is a maximum diameter quantification of abdominal aorta for each group.
Fig. 4 shows the experimental results of catechin inhibiting aneurysm, wall hematoma and or arterial dissection. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
Fig. 5 shows the experimental results of the inhibition of aneurysms, interwall hematomas, and or arterial dissection by biochanin a. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
Fig. 6 shows the experimental results of daidzein inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
Fig. 7 shows experimental results of epigallocatechin gallate (EGCG) inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
FIG. 8 shows the experimental results of procyanidin-3-glucoside inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is a representative diagram of each group of arteries; and B is an aortic tissue staining analysis chart.
Fig. 9 shows experimental results of blueberry anthocyanin extract inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is a representative diagram of each group of arteries; b is the maximum diameter quantitative result of the abdominal aortic aneurysm.
Fig. 10 shows experimental results of blueberry anthocyanin extract inhibiting aneurysms, interwall hematomas, and or arterial dissection. A is an H & E staining result diagram of the aortic tissue, B is a red staining result diagram of the aortic tissue, and C is an abdominal aortic 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, through a large number of screens and tests, the role of the compounds of formula I in the prevention or treatment of arterial lesions. The invention discovers that the compound shown in the formula I (typically, kaempferol) can effectively reduce the thickness of the vascular wall, reduce the volume of the aneurysm, protect the integrity of vascular structures, inhibit inflammatory cell infiltration and radically treat arterial lesions for the first time. The present invention has been completed on the basis of this finding.
Terminology
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, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "room temperature" refers to a temperature of 4-40 ℃, preferably 25±5 ℃.
The term "alkyl" as used herein, by itself or as part of another substituent, refers to a straight or branched hydrocarbon radical having the indicated number of carbon atoms (i.e., C 1 -C 6 Represents 1-6 carbons), the alkyl group includes alkyl groups of 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example C 2 -C 6 Alkenyl refers to straight or branched alkenyl groups having 2 to 6 carbon atoms, alkenyl groups 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. For example C 2 -C 6 Alkynyl refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, alkynyl groups 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 "C 3 -C 8 Cycloalkyl "includes mono-or bicycloalkyl. For example C 3 -C 8 Cycloalkyl refers to a hydrocarbon ring comprising 3 to 8 ring carbon atoms saturated or not more than one double bond. 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 specified 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. Heterocycloalkyl groups may be monocyclic, bicyclic or polycyclic ring systems. 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, imidazolidone, 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. Heterocycloalkyl groups can be attached to the remainder of the molecule via a ring carbon or heteroatom.
Unless otherwise stated, the term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together or covalently linked, non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl.
The term "heteroaryl" refers to an aryl group (or ring) containing the specified 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. Heteroaryl groups may be attached to the remainder of the molecule through heteroatoms. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl (benzotriazinyl), purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl (isobenzofuryl), isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, 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 a hemiacetal hydroxyl group from a cyclic form of a monosaccharide (or disaccharide, trisaccharide), such as a glycosyl to replace one or more OH groups on a compound of formula I, to form an-O-glycosyl. Representative monosaccharides include pentoses and hexoses, with preferred glycosyl groups being mono-glycosyl (. Beta. -D glucopyranosyl, -glu) or di-glycosyl.
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, and the number of substituents may be 1, 2, 3 or 4. Unless otherwise indicated, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of: one or more (e.g., 2, 3 or 4) hydrogen atoms on the group are substituted with a group selected from the group consisting of: H. halogen, -SH, -OH, -COOH, -CN, -NH 2 、-(C＝O)-C 1 -C 6 Alkyl, - (c=o) - (substituted or unsubstituted phenyl), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, alkyl C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, 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 asymmetric centers, the (Z), (E) isomers of double bonds, etc. Thus, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are all within the scope of the invention.
Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, 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 a radioisotope, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite 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, compounds can be prepared such that any number of hydrogen atoms are replaced by deuterium 2 H) Isotopic substitution. 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. Isotopes in non-natural proportions can be defined as amounts found in nature to amounts consisting of 100% of the atoms in question. For example, the compounds may incorporate radioactive isotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) Or non-radioactive isotopes, e.g. deuterium @, of 2 H) Or C-13% 13 C)。
As used herein, the term "preventing" or "treatment" includes disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., prior to the onset of symptoms to prevent, delay or reduce the severity of symptoms)) or therapeutic (i.e., after the onset of symptoms to reduce the severity and/or duration of symptoms). "preventing" and "treating" as used herein includes slowing and stopping the progression of the disease, and does not require 100% inhibition, elimination, and reversal. In some embodiments, the reduction, prevention, inhibition, and/or reversal is, for example, 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 medicinal material or extract comprising a compound of formula I, or a pharmaceutical composition of the present invention.
Active ingredient
The active ingredients of the invention comprise a compound of formula I, pharmaceutically acceptable salts, isomers, crystal forms, hydrates or solvates thereof;
wherein the dotted line, ra, rb, rc, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R 10 As defined above.
As used herein, "pharmaceutically acceptable salts" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and 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, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts is the salts of the compounds of the present invention with bases. 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 water, triethylamine, diethylamine and piperazine.
The compounds of the present invention may be amorphous, crystalline or mixtures thereof.
The compound of the formula I can be extracted from kaempferia galanga and other plants by alcohol extraction, chromatography and the like, and can be purchased commercially or synthesized by using commercial raw materials by a synthesis method in the prior art. The compounds of the present invention may be extracted or synthesized by one of ordinary skill in the art in accordance with known techniques. The extract or the synthesized compound can be further purified by column chromatography, high performance liquid chromatography or crystallization.
Synthetic chemistry engineering, protective functional group methodology are helpful for the synthetic application of compounds and are well known in the art, see for example r.larock, comprehensive Organic Transformations, VCH Publishers (1989); greene and P.G.M.Wuts, protectiveGroups in Organic Synthesis,3rd Ed., john Wiley and Sons (1999); fieser and M. Fieser, fieser and Fieser's Reagents for Organic Synthesis, john Wiley and Sons (1994); and L.Paquette, ed.encyclopedia of Reagents for Organic Synthesis, john Wiley and Sons (1995), et al.
Chinese medicine, food material and extract containing compound of formula I
In a further aspect of the invention there is provided a pharmaceutical and/or food material comprising a compound of formula I, and the use of an extract comprising a compound of formula I, for the treatment of arterial lesions or for the preparation of a composition and/or formulation for the treatment of arterial lesions. Typically, the arterial lesions include (but are not limited to): (i) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) arterial dissection.
In another preferred embodiment, the compound of formula I in the extract is kaempferol.
Preferably, the kaempferol-containing medicinal materials include (but are not limited to): rhizoma Kaempferiae (kaempferol galanga L) (e.g., rhizome), radix Caulophylli (Diphylleinasensis Li.), bai Ruicao (the fruit of the tree genus Turkish (Euphormbilunulata Bge)), fructus Sophorae, semen Ginkgo (Ginkgo biloba L.), or combinations thereof.
Kaempferol is also widely present in food materials, and pure kaempferol has been extracted from tea leaves, broccoli, wu Zhenzi and grapefruit. In the invention, the pair ofThe extraction method of the extract is not particularly limited, and extraction methods commonly used in the art can be used. Such as: water extraction, alcohol extraction, supercritical extraction (CO) 2 ) Etc.
Preferably, the extract contains an enriched active ingredient of the invention. The active ingredients account for more than or equal to 1wt%, more than or equal to 2wt%, more than or equal to 5wt%, such as 1-30wt% or 2-20wt% of the dry weight of the extract.
In another preferred embodiment, the extract is a blueberry (fruit) blume extract. The extraction method of the blueberry flower extract is not particularly required, and the blueberry flower extract which is rich in blueberry flower extract and is obtained by using the commercially available blueberry flower extract or the method which is commonly used in the invention.
In another preferred example, the mass content of the total blue-and-white pigment in the blueberry blue-and-white pigment 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% by dry weight of the extract.
Preferably, the preparation method of the blueberry blue-and-white extract comprises the following steps: mixing blueberry pulp and acidified ethanol (HCl acidified, pH 3.0+ -0.2, ethanol final volume fraction of 70-80%) according to a feed liquid ratio of 1:8-12, leaching at 45-55deg.C for 2-4h to obtain leaching solution, and centrifuging the leaching solution to obtain supernatant. And then the supernatant is adsorbed by macroporous resin with weak polarity (such as AB-8 and D101 type resin) and eluted by 55-65% ethanol, and the solvent is evaporated to obtain the blueberry azulene extract.
Pharmaceutical compositions, methods of administration and uses
The active ingredient of the invention has the function of treating and/or preventing the diseases related to the arterial lesions, so the active ingredient can be used for preparing a pharmaceutical composition for preventing and/or treating the diseases related to the arterial lesions; preferably, the arterial lesions are selected from the group consisting of: (i) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) arterial dissection.
In another preferred embodiment, the aneurysm is selected from the group consisting of: early aneurysms, mid-term aneurysms, late aneurysms, or combinations 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): hypotensives (e.g., angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers (e.g., valsartan, losartan, alisartan esters, etc.), hypolipidemic agents (e.g., statins, fibrates, niacin, cholesterol absorption inhibitors), hypoglycemic agents (e.g., sulfonylurea secretagogues, insulin sensitizers, biguanides), multimeric salvianolic acids, or combinations thereof.
The pharmaceutical composition of the invention can be used for preparing a medicament for the treatment and/or prevention of diseases associated with arterial lesions, preferably selected from the group consisting of: (i) aneurysms; (ii) an inter-arterial wall hematoma; and/or (iii) arterial dissection.
In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
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 prepare 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 compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-500mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with the compound of formula I without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
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 used 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, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, 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 substances, 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration 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 doses of the 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. However, it will be appreciated that the particular dosage of the active ingredient of the present invention for any particular patient will depend on a variety of factors, for example, the age, sex, weight, general health, diet, individual response of the patient to be treated, the time of administration, the severity of the disease to be treated, the activity of the particular compound administered, the dosage form, the mode of application and concomitant medication. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability and judgment of a 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 that the compound shown in the formula I has the effects of slowing down the expansion speed of the aneurysm, reducing hematoma between arterial walls, inhibiting arterial interlayer and further reducing arterial rupture, and is suitable for treating arterial related diseases.
2. The compounds and pharmaceutical compositions of the present invention provide treatment options other than surgical treatment for patients with aneurysms, interarterial wall hematomas, and/or arterial dissection.
3. The compound is a compound which is mostly known and safe and has small toxic and side effects, and can provide convenient selection for rapidly developing drugs for effectively treating arterial lesions.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions, such as, for example, sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Reagent(s)
Experimental instrument
Model preparation and sample detection method
Preparation of models of aneurysms, wall-to-wall hematomas and/or arterial dissection
The mice were anesthetized with 5% sultai by intraperitoneal injection at a dose of 20mg/kg according to their body weight. After the mice enter an anesthetic state, the shaver shaves off the abdominal hair, the abdominal hair is further thoroughly dehaired by using the dehairing paste, the mice are fixed on an operating table after the abdomen is wiped off, and the body temperature is kept under the body by using a heating pad. After the skin of the abdomen was rubbed with iodine, the skin was deiodinated with 75% ethanol, an incision of about 1.5cm was made in the center of the abdomen, the viscera were carefully pushed away with forceps, then the intestinal tract was separated to the left and right with 3% penicillin-streptomycin-wetted gauze, and connective tissue and muscle tissue on the surface of the aorta were carefully separated with forceps, so that the abdominal aorta was fully exposed. The length of the exposed abdominal aorta is about 0.5cm, the proximal end does not exceed the bilateral renal arteries, and the distal end does not exceed the femoral arteries.
Sterilizing absorbent paper (0.3 cm×0.3 cm) was thoroughly soaked in Porcine Pancreatic Elastase (PPE), then applied to the exposed abdominal aorta for 50 min, and a piece of gauze moistened with 3% penicillin-streptomycin physiological saline 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 physiological saline containing 3% penicillin-streptomycin, and the peritoneum and skin were sutured with 3/8 suture needles and 5/0 suture lines. After suturing, the wound was rubbed with iodine, and after 1 minute, deiodinated with 75% ethanol. Mice were placed in clean rearing cages, fed with 1% beta-aminopropionitrile (BAPN) feed, were allowed to drink water ad libitum, and feed was changed every other day.
Drawing materials
According to the dosage of 4ml/kg of the body weight of the mice, 10% chloral hydrate is injected into the abdominal cavity for euthanasia, the whole aorta from the heart to the lower limb is rapidly taken out, and the whole aorta is placed in a container containing physiological saline, and the container is placed on ice. Under a stereoscopic microscope, muscles and adipose tissue surrounding the aorta were carefully removed.
General morphology observations
The trimmed aorta was placed on a black plate and photographed with a stereomicroscope (SZX 7, OLYMPUS). The maximum diameter of the AAA was measured using Cell Sens standard software (OLYMPUS, version 1.18). According to v= (AAA maximum diameter x AAA length) 2 ) The equation/2 calculates the volume of AAA.
Fixing, dehydrating, embedding and slicing the sample
100mL of formaldehyde, 4g of sodium dihydrogen phosphate, 6.5g of disodium hydrogen phosphate, and 900mL of distilled water were dissolved to prepare a paraformaldehyde fixed solution with a volume ratio of 10%. After the aortic tissue is fixed in paraformaldehyde fixing solution for 72 hours, washing with tap water for 4-6 hours, placing the aortic tissue in a dehydrator, setting a program to automatically dehydrate, and sequentially carrying out treatment on the aortic tissue by 75% ethanol for 1.5 hours, 95% ethanol for 1.5 hours, 100% ethanol for 1.5 hours, xylene for 1.5 hours and paraffin for 1.5 hours. The paraffin embedding machine is opened to melt paraffin in advance for 2 hours, and the temperature is controlled at 60 ℃. After paraffin is melted, the dehydrated aortic tissue is embedded in paraffin, the embedded tissue is poured into an embedding box, the tissue blocks after paraffin dipping are put into the embedding box by using heated forceps, the tissue blocks are slightly moved to a cooling table, and after the paraffin is solidified, the paraffin blocks are taken down for slicing. Before slicing, the wax block is placed into a refrigerator for precooling, and after cooling, a slicer continuously cuts paraffin sections with the thickness of 5 mu m. The slices are spread on warm water at 38 ℃ of a slice spreading machine, fished with a slide glass coated with APES, and naturally air-dried for subsequent pathological histologic staining.
Hematoxylin-eosin (HE) staining
The tissue is fixed and embedded, cut into paraffin sections of 4 mu m, firstly the paraffin sections are baked (65 ℃ for 60 minutes) and then dewaxed to the water phase (xylene for 15 minutes, absolute ethanol for 5 minutes, 95% ethanol for 5 minutes, 75% ethanol for 5 minutes, running water for 1 minute); placing the mixture into hematoxylin staining solution for staining for 15 minutes, and washing the mixture with running water for 4 minutes; differentiating with 1% ethanol hydrochloride for 5 seconds (differentiation time is adjusted according to the preparation time of the differentiation liquid), and flushing with running water for 5 minutes; the eosin staining solution is placed in water for 1 minute after being stained for 1 minute; the gel was dehydrated and then permeabilized with xylene (75% ethanol 5 min. Fwdarw.95% ethanol 5 min. Fwdarw.absolute ethanol 5 min. Fwdarw.15 min. Xylene) and the pictures were taken with a BX51 microscope.
Lichen red dyeing
Dewaxing was performed in the conventional dewaxing manner described above. The lichen red staining solution is stained for 1 hour, the ethanol solution of 1% hydrochloric acid is differentiated for 5 minutes, and the mixture is permeabilized by dimethylbenzene, and the neutral resin is sealed. The degradation of elastin is quantified by pathological scoring, wherein the degradation is less than 25% and 1 minute, the degradation range is 25% -50% and 2 minutes, the degradation range is 50% -75% and 3 minutes, and the degradation is more than 75% and 4 minutes. The procedure was double blind evaluated and expressed as the average of two investigators.
Data statistics
Data are expressed as mean ± SE. Statistical analysis was performed using GraphPad Prism 6. The statistical significance of the differences between the groups was compared multiple times using a one-way anova. After the normal distribution and variance alignment are determined, a Tukey test is performed. P <0.05 is statistically significant.
Example 1
Therapeutic action of kaempferol on aneurysms, wall hematomas and/or arterial dissection
Animal dosing and grouping conditions: the 8 week old C57BL/6 mice enter animal houses to adapt to feeding for one week, then are randomly divided into a normal control group, a model control group and a kaempferol 25mg/kg (lavage) group, 10 animals in each group are subjected to molding by porcine pancreatic elastase and are fed with feed containing 1% of beta-aminopropionitrile on the molding day, so that aneurysms, wall hematomas and arterial interlayers (the model corresponds to the late period of the aneurysms and the wall hematomas and the arterial interlayers) are induced, the day of operation is 0, CMCNa or kaempferol is respectively administered to the animals by a intragastric administration mode from the day 5, the animal movement condition is continuously observed for 10 days, and arterial tissues are obtained after the animals are euthanized on the day 15 to evaluate the aneurysms, the arterial wall hematomas and the arterial interlayer rupture.
The model of inducing aneurysm, wall hematoma and arterial interlayer by feeding pig pancreatic elastase and 1% beta-aminopropionitrile feed can be used for examining the influence of medicine on aneurysm growth and wall hematoma and arterial interlayer rupture.
Using a method similar to example 1, the following compounds were tested for their prophylactic and therapeutic effects on interwall hematomas and/or arterial dissection, and the maximum diameter results 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 that: for compounds 1-2, n=10, and for compounds 3-7, n=5.
As can be seen from table 1 and fig. 1-8, the model control group showed significant expansion and distension of the sub-renal artery portion, while the compounds of the present invention significantly reduced the formation, size and distension rate of the mouse aneurysm, as compared to the normal control group mice. From histological analysis, the compound of the invention can reduce the thickness of the vascular wall, protect the integrity of vascular structures, inhibit the degradation of an elastic layer, inhibit the occurrence of wall hematoma and protect the morphology of adventitia collagen.
Example 2
Blueberry anthocyanin extract
Fresh blueberry fruits are washed by distilled water, the surface water is dried in the air, frozen at the temperature of minus 20 ℃, and smashed until the fresh blueberry fruits are in a homogenate state. Mixing blueberry pulp and acidified ethanol (pH 3.0, 75% ethanol) according to a feed liquid ratio of 1:10, leaching at 50deg.C for 3h to obtain leaching solution, and centrifuging the leaching solution at 4 000r/min for 1h to obtain supernatant. And then adsorbing the supernatant by using AB-8 macroporous resin, eluting with 60% ethanol, and rotationally evaporating the solvent to obtain the blueberry azulene extract.
Through high performance liquid chromatography analysis, the main components of the blueberry azulene extract comprise: delphinidin-3-galactoside chloride, delphinidin-3-glucoside chloride, cyanidin-3-galactoside chloride, delphinidin-3-arabinoside chloride, chlorinated cyanidin-3-glucoside, petuniin-3-galactoside chloride, cyanidin-3-arabinoside chloride, petuniin-3-glucoside chloride, delphinidin-3-glucoside chloride, paeoniflorin-3-galactose glucoside chloride, petuniin-3-arabinoside chloride, paeoniflorin-3-glucoside chloride, malvidin-3-galactose glucoside chloride, paeoniflorin-3-arabinoside chloride, paeoniflorin-3-glucoside chloride, malvidin-3-glucoside chloride, paeoniflorin-3-arabinoside chloride, malvidin-3-glucoside chloride, malvidin-3-arabinoside chloride, paeoniflorin chloride, malvidin chloride.
The blueberry anthocyanin extract was tested for its prophylactic and therapeutic effect on wall hematomas and/or arterial dissection using a similar method to example 1, n=10, based on the dry weight of blueberry anthocyanin extract.
As shown in fig. 9-10, the blueberry anthocyanin extract has significant effects of inhibiting aneurysm formation and expansion speed, inhibiting arterial wall thickening, and elastin degradation, suggesting that the blueberry anthocyanin extract has significant effects of inhibiting aneurysms, wall hematomas, and or arterial dissection.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (8)

1. The use of a kaempferol compound having the structure of the formula, a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition or formulation comprising kaempferol as the sole active ingredient; the pharmaceutical composition or formulation is used for preventing and/or treating arterial lesions selected from the group consisting of:
(i) Inter-arterial wall hematoma; and/or (ii) arterial dissection;
and the pharmaceutical composition or formulation is for use in one or more selected from the group consisting of:
(a) Reducing the thickness of the vessel wall;
(b) Protecting the integrity of vascular structures; and/or
(c) Inhibiting the occurrence of wall hematoma;
wherein the artery is selected from the group consisting of: thoracic aorta, abdominal aorta, spleen artery, hepatic artery, renal artery, or a combination thereof.
2. The use according to claim 1, wherein the artery is selected from the abdominal aorta.
3. The use according to claim 1, wherein the pharmaceutical composition or formulation is for:
(d) Inhibiting the formation and/or growth of aneurysms;
(c) Inhibiting elastin degradation; and/or
(f) Protecting adventitia collagen.
4. The use according to claim 1, wherein the dosage form of the pharmaceutical composition or formulation is selected from the group consisting of: injection and oral preparation.
5. The use according to claim 4, wherein the dosage form is an oral formulation.
6. The use according to claim 4, wherein the injection is an injection or a powder injection.
7. The use according to claim 5, wherein the oral formulation is selected from the group consisting of capsules, tablets, pills, powders, granules, syrups, oral liquids and tinctures.
8. The use according to claim 1, wherein the kaempferol compound is extracted from: kaempferia galanga (kaempferol galanga l.), blueberry (saccinium spp.), sedge (diphyleianensis li), bai Ruicao (Thesium chinense turcz.), euphorbia lathyris (euphoria lunulata bge), pagoda tree fruit, or combinations thereof.
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