CN107759616B

CN107759616B - Compound and preparation method and application thereof

Info

Publication number: CN107759616B
Application number: CN201610707991.6A
Authority: CN
Inventors: 陈陆; 李俊菲; 周奇; 胡燕
Original assignee: Shanghai Microport Medical Group Co Ltd
Current assignee: Shanghai Microport Medical Group Co Ltd
Priority date: 2016-08-23
Filing date: 2016-08-23
Publication date: 2020-11-17
Anticipated expiration: 2036-08-23
Also published as: CN107759616A

Abstract

The invention discloses a compound with a structure shown in a formula I or pharmaceutically acceptable salt or halide thereof, and a preparation method and application thereof:

wherein A represents a bond, -O-, -R_X‑、‑N(R_X)‑、‑C(O)‑、‑N(R_X)C(O)‑、‑N(R_X)C(O)O‑、‑C(O)N(R_X)‑、‑N(R_X)C(O)N(R_X)‑、‑OC(O)‑、‑C(O)O‑、‑OC(O)O‑、‑OC(O)N(R_X)‑、‑S(O)₂‑、‑S(O)₂N(R_X)‑、‑OS(O)₂N(R_X)‑、‑N(R_X)S(O)₂-, or-OS (O)₂O‑；R_XIs C1-C8 alkyl optionally substituted with C1-C4 alkoxycarbonyl.

Description

Compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a compound for a medicine stent and a preparation method and application thereof.

Background

Rapamycin is a macrolide immunosuppressant that blocks signal transduction through various cytokine receptors, blocks the progression of T lymphocytes and other cells from G1 phase to S phase, and thus exerts immunosuppressive effects. Meanwhile, rapamycin is also researched and shown to be used for Alzheimer's disease.

In recent years, rapamycin has also been widely used in the field of coronary stents, which inhibits proliferation and clonal expansion of cells by acting on mTOR in vivo, blocking activation of cytokines and growth factors, and retards activation of the cell cycle at G1, thereby counteracting the occurrence of restenosis after stent implantation.

Rapamycin has the structure shown in formula VIII, wherein the left-hand site-labeled moiety (i.e., the C9-C21 moiety) binds to FKBP12 in vivo, and the right-hand site-labeled moiety (i.e., the C1-C7 plus the C29-C34 moiety) binds to mTOR, and is the main effective site for inhibition of smooth muscle proliferation:

。

with the development of pharmaceutical technology, a series of rapamycin derivatives are developed and applied to drug stents, and the structural modification of the rapamycin derivatives is located at the 43-carbon of rapamycin, such as: the compounds are applied to drug stents, and have remarkable clinical effect on the restenosis of a patient with an anti-stent implanted lesion, but the restenosis rate of the diabetic patient is always greatly higher than that of a non-diabetic patient in the diabetic patient group.

There is a pressing need in the art to provide a class of compounds that are effective against restenosis in diabetic patients following stent implantation at the lesion.

Disclosure of Invention

The invention aims to provide a compound which can effectively resist restenosis of a lesion part of a diabetic patient implanted with a stent, and a preparation method and application thereof.

In a first aspect of the invention, there is provided a class of compounds having the structure of formula i:

wherein A represents a bond or one of the following groups: -O-, -R_X-、-N(R_X)-、-C(O)-、-N(R_X)C(O)-、-N(R_X)C(O)O-、-C(O)N(R_X)-、-N(R_X)C(O)N(R_X)-、-OC(O)-、-C(O)O-、-OC(O)O-、-OC(O)N(R_X)-、-S(O)₂-、-S(O)₂N(R_X)-、-OS(O)₂N(R_X)-、-N(R_X)S(O)₂-, or-OS (O)₂O-；

R_XIs C1-C8 alkyl optionally substituted with C1-C4 alkoxycarbonyl.

In another preferred embodiment, the compound has the structure shown in formula II:

in another preferred embodiment, the structure of A in the above compound is selected from the group consisting of-O-, -CO-, -CONCH₃-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-, or-OS (O)₂O-。

In another preferred embodiment, the halide is selected from fluoride, chloride or bromide; more preferably the halide is chloride.

In a second aspect of the present invention, there is provided a process for the preparation of a compound provided by the present invention as described above, said process comprising the steps of:

(1) dissolving a mixture of methyl iodide and/or benzyl chloride and a compound with a structure shown in a formula III in an organic solvent to obtain a solution 1;

(2) mixing the solution 1 with a compound with a structure shown as a formula IV to obtain a solution 2;

wherein B represents-CH₃、-OH、-R_X、-N(R_X)、-CHO、-N(R_X)CHO、-N(R_X)COOH、-C(O)N(R_X)、-N(R_X)C(O)N(R_X)、-OCOH、-COOH、-OCOOH、-OC(O)N(R_X)、-S(O)₂H、-S(O)₂N(R_X)、-OS(O)₂N(R_X)、-N(R_X)S(O)₂H. or-OS (O)₂OH；

R_XIs C1-C8 alkyl optionally substituted with C1-C4 alkoxycarbonyl;

(3) heating the solution 2 at 25-95 ℃ for 1 hour-2 weeks to obtain a reaction mixture; the heating temperature is preferably 30-65 ℃; more preferably 35-55 ℃; the heating time is preferably 2 to 7 days; more preferably 3-5 days;

(4) and separating the reaction mixture to obtain the compound with the structure shown in the formula I.

In another preferred embodiment, B is selected from-OH, -COH, -CONCH₃、-OCH₂CH₂OH、-OCH₂CH₂OCH₃or-OS (O)₂OH。

In another preferred embodiment, the organic solvent is selected from: acetone, acetonitrile, ethyl acetate, chloroform, dichloromethane, carbon tetrachloride, methanol, diethyl ether or petroleum ether.

In a third aspect of the invention, there is provided a composition comprising an excipient and a therapeutically effective amount of a compound provided by the invention, or a pharmaceutically acceptable salt or halide thereof, as described above.

In a fourth aspect of the present invention, there is provided a use of a compound provided by the present invention as described above, or a pharmaceutically acceptable salt or halide thereof, in the manufacture of a medicament for inhibiting cell proliferation and clonal expansion.

In a fifth aspect of the invention, there is provided the use of a compound provided by the invention as described above, or a pharmaceutically acceptable salt or halide thereof, in the manufacture of an interventional medical device; the interventional medical device is selected from coronary artery stent, intracranial stent, peripheral stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic stent, urethral stent or tracheal stent.

In a sixth aspect of the present invention there is provided an interventional medical device comprising a drug delivery structure comprising a compound provided by the present invention as described above, or a pharmaceutically acceptable salt or halide thereof; the interventional medical device is selected from coronary artery stent, intracranial stent, peripheral stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic stent, urethral stent or tracheal stent.

In a seventh aspect of the invention, there is provided a use of a compound provided by the invention as described above, or a pharmaceutically acceptable salt or halide thereof, in the manufacture of a medicament for inhibiting vascular restenosis in a diabetic patient.

Accordingly, the present invention provides a class of compounds effective against restenosis in diabetic patients following stent implantation.

Detailed Description

As to the structural modification of the 43-carbon of rapamycin, the inventors have conducted extensive and intensive studies and have unexpectedly found that a compound having the structure represented by formula I, which is obtained by introducing a new structure, has a significant effect on the diabetic population against restenosis caused by stent implantation at the lesion thereof.

Compound (I)

The compounds, as described herein, inhibit cell proliferation and clonal expansion. In one aspect, the compounds described herein are derivatives of rapamycin. More specifically, described herein are derivatives of rapamycin having a modified structure at the 43-carbon.

In one aspect of the invention, there is provided a compound of formula i or a pharmaceutically acceptable salt or halide thereof:

wherein A is a bond, -O-, -R_X-、-N(R_X)-、-C(O)-、-N(R_X)C(O)-、-N(R_X)C(O)O-、-C(O)N(R_X)-、-N(R_X)C(O)N(R_X)-、-OC(O)-、-C(O)O-、-OC(O)O-、-OC(O)N(R_X)-、-S(O)₂-、-S(O)₂N(R_X)-、-OS(O)₂N(R_X)-、-N(R_X)S(O)₂-, or-OS (O)₂O-；

R_XIs C1-C8 alkyl optionally substituted with C1-C4 alkoxycarbonyl.

Cis-trans isomers may be formed as shown by "+" in formula I.

Preferably, the compound of formula I has the following structure according to formula II:

。

in some preferred embodiments of the present invention, wherein a has the structure: -O-, -CO-, -CONCH₃-、-OCH₂CH₂O-、-OCH₂CH₂OCH₂-or-OS (O)₂O-。

In a particular embodiment, the compounds of the present invention are prepared according to a pharmaceutically acceptable acid addition salt (a pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and adipic acid.

The terms "compound of the invention", "compound of the invention" or "compound provided by the invention" are used interchangeably and refer to compounds having the structure shown in formula I.

"pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not diminish the biological activity or properties of the compound and which is relatively non-toxic, e.g., by being administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of the components it contains.

The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain particular aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the invention with an acid, such as sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

References to pharmaceutically acceptable salts are understood to include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of the invention are conveniently prepared or formed according to the methods described herein.

The term "pharmaceutically acceptable halide" refers to a compound in the form of its presence, which is formed by reacting a compound of the present invention with hydrogen fluoride, hydrochloric acid, hydrobromic acid, and the like, to form its fluoride, chloride, and bromide, respectively, for example, its chloride, which has the structure shown in formula v:

。

in other embodiments, the compounds of the present invention are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-sized forms. In addition, the compounds of the present invention include crystalline forms, as well as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.

Synthesis of Compounds

The invention also provides a preparation method of the compound with the structure shown in the formula I. In particular, the amount of the solvent to be used,

dissolving methyl iodide and/or benzyl chloride and a compound with a structure shown in a formula III in an organic solvent to obtain a solution 1;

secondly, mixing a compound with a structure shown in a formula IV with the solution 1 to obtain a solution 2;

step three, heating the solution 2 for a period of time to obtain a reaction mixture;

and fourthly, separating the reaction mixture to obtain the compound with the structure shown in the formula I.

In the first step, the organic solvent is selected from acetone, acetonitrile, ethyl acetate, chloroform, dichloromethane, carbon tetrachloride, methanol, diethyl ether or petroleum ether.

Methyl iodide and/or benzyl chloride affect the rate of reaction, and in general it is preferred that the ratio of methyl iodide and/or benzyl chloride to the compound of formula III is 1: 1-1:30, most preferably 1: 5-1: 10.

in general, the ratio of the mixture of methyl iodide and/or benzyl chloride and the compound having the structure shown in formula III to the solvent is as follows: every 1g of the mixture is dissolved in 25-100ml of solvent to obtain a higher dissolution efficiency.

In the second step, B represents-CH in the compound with the structure shown as formula IV₃、-OH、-R_X、-N(R_X)、-CHO、-N(R_X)CHO、-N(R_X)COOH、-C(O)N(R_X)、-N(R_X)C(O)N(R_X)、-OCOH、-COOH、-OCOOH、-OC(O)N(R_X)、-S(O)₂H、-S(O)₂N(R_X)、-OS(O)₂N(R_X)、-N(R_X)S(O)₂H. or-OS (O)₂OH；

R_XIs optionally substituted by C1-C4 alkoxycarbonylSubstituted C1-C8 alkyl;

in some preferred embodiments of the invention, B is selected from-OH, -COH, -CONCH₃、-OCH₂CH₂OH、-OCH₂CH₂OCH₃or-OS (O)₂OH。

The heating temperature and the heating time in the third step are linked, and generally, the time required for heating to be high is short, and vice versa.

In one embodiment of the present invention, the third step is to put the solution 2 in a reaction flask and heat it at 25-95 ℃ for 1 hour-2 weeks to obtain a reaction mixture.

In a preferred embodiment of the present invention, the heating temperature may be 30 to 65 ℃, more preferably 35 to 55 ℃; the heating time may be 2 to 7 days, more preferably 3 to 5 days.

In one embodiment of the present invention, the fourth step is to cool the obtained reaction mixture to precipitate the compound represented by the formula i.

In a preferred embodiment of the present invention, the temperature may be lowered to room temperature, and then the mixture may be washed with saturated saline and dried under reduced pressure.

In another preferred embodiment of the invention, the compound with the structure shown in the formula I can be precipitated by cooling to room temperature and then carrying out ice bath.

Term(s) for

The compounds and their structures according to the invention are shown in the following table:

unless otherwise defined, terms used in this application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, sugar chemistry, biochemistry and pharmacology are used if not otherwise stated. In this application, "or" and "means" and/or "are used unless otherwise stated.

"alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be saturated (meaning not containing any unsaturated units such as carbon-carbon double bonds or carbon-carbon triple bonds) or the alkyl moiety may be unsaturated (meaning containing at least one unsaturated unit). The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain.

An "alkyl" moiety (moity) may have from 1 to 8 carbon atoms (as long as appearing herein, a numerical range such as "1 to 8" refers to each integer in the given range, e.g., "1 to 8 carbon atoms" refers to an alkyl group that may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 8 carbon atoms, although the present definition also encompasses the occurrence of the term "alkyl" in the absence of a given numerical range). The alkyl group of the compounds described herein may be designated as "C₁-C₈Alkyl "or the like. By way of example "C₁-C₈Alkyl "means one, two, three, four, five, six, seven or eight carbon atoms in the alkyl chain. Typical alkyl groups include, but are not limited to, methyl, ethyl, propylisopropyl, butylisobutyl, tert-butyl, pentyl, hexyl, heptane, octane, and the like.

The term "alkoxycarbonyl" refers to a compound having the general formula alkyl-O-C ═ O, where alkyl is as defined herein.

The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties when the atoms connected by the bond are considered part of a larger structure. In one aspect, when a group described herein is a bond, the absence of a reference group allows for the formation of a bond between the remaining defined groups.

In certain embodiments, the compounds have one or more stereocenters, and each center independently exists in R or S form. Reference herein to compounds includes all diastereomeric, enantiomeric, epimeric and appropriate mixtures thereof. Stereoisomers can be obtained by methods such as separation of stereoisomers by chiral chromatography columns.

The terms "treat," "treatment process," or "therapy" as used herein include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom.

The term "an effective amount" is intended to be used for the purpose of treating disease.

The terms "compound", "composition", "agent", "drug" or "medicine" are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), induces a desired pharmacological and/or physiological response through local and/or systemic action.

The term "administered" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug (produg), derivative (derivative), or analog (analog) of the active compound, which results in an equivalent amount of the active compound in the individual to whom it is administered.

The terms "subject" or "patient" are used interchangeably herein to refer to an animal (including a human) that can be treated with the compounds and/or methods. "individual" or "patient" herein encompasses both the male and female sex unless specifically stated otherwise. Thus, a "subject" or "patient" includes any mammal, including, but not limited to, humans, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cows, etc., which would benefit from treatment with the compounds. Preferably, the animal suitable for treatment with the compounds and/or methods of the invention is a human. In general, the terms "patient" and "individual" are used interchangeably herein.

Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as is commonly understood and used by one of ordinary skill in the art. Furthermore, as used herein, the singular tense of a noun, unless otherwise conflicting with context, encompasses the plural form of that noun; the use of plural nouns also covers the singular form of such nouns.

Therapeutic uses

The compounds of the invention inhibit cell proliferation and clonal expansion. In another embodiment, the compounds described are capable of preventing or reducing the occurrence of restenosis when using an interventional medical device, such as, but not limited to, a stent. In another embodiment, the compounds described are capable of preventing or reducing restenosis problems in diabetics when using stents.

The compound of the invention is used for preparing a pharmaceutical preparation for inhibiting cell proliferation and clonal expansion, and comprises the following components: using the compound directly or using any one of the ingredients obtained during the preparation process; used in vitro screening experiments to screen and verify components for inhibiting cell proliferation and clonal expansion. In another embodiment, the use of a compound of the invention is for the preparation of a medicament for inhibiting vascular restenosis in a diabetic patient.

In some embodiments, the method is for the interventional medical device to include a drug release structure comprising a compound of the present invention.

The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The main advantages of the invention are:

1. the structure of the novel structural compound provided by the invention is shown as a formula I or a formula II;

2. compared with rapamycin, the compound provided by the invention has higher selectivity on the effect of inhibiting intimal hyperplasia in a diabetes animal model. This suggests that the use of this compound in clinical diabetics may reduce the rate of restenosis following stent implantation.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.

The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution.

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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

LY294002 used in the examples described below is a compound having the structure shown in formula III.

Example 1

Preparation of Compound 1

(1) 2g of LY294002 and 0.1g of methyl iodide were mixed and dissolved in n-propyl acetate;

(2) to the above solution was added 10g of rapamycin;

(3) putting the solution obtained in the step (2) into a reaction bottle, and heating for 4d at 75 ℃;

(4) after the reaction was completed, the reaction mixture was left to stand at room temperature without heating, washed with a saturated saline solution, and dried under reduced pressure to obtain compound 1 as a powdery substance.

The product (compound 1) was confirmed by LCMS with new peaks Rf 4.708 and M + 1220.

Example 2

Preparation of Compound 2

(1) 2g of LY294002 and 0.15g of benzyl chloride were dissolved in acetonitrile;

(2) adding 12g of a compound with a structure shown in a formula VI into the solution;

；

(3) putting the solution obtained in the step (2) into a reaction bottle, and heating for 12d at 35 ℃;

(4) after the reaction was completed, heating was stopped, the reaction mixture was left to stand at room temperature and subjected to ice-bath to obtain a precipitate as compound 2. The product (compound 2) was confirmed by LCMS with new peaks Rf 4.992 and M + 1232.

Example 3

Preparation of Compound 3

(1) 5g of LY294002 and 0.1g of benzyl chloride were dissolved in acetonitrile;

(2) adding 10g of a compound with a structure shown in a formula VII into the solution;

(3) putting the solution obtained in the step (2) into a reaction bottle, and heating for 24 hours at 90 ℃;

(4) after the reaction was completed, heating was stopped, the reaction mixture was left to stand at room temperature and subjected to ice bath to obtain a precipitate as compound 3.

The product (compound 3) was confirmed by LCMS with new peaks Rf 4.554 and M + 1261.

Example 4

Effect test

Animal experiments:

A. study subjects: the breeding method comprises selecting Bama miniature pig, male, and 1-2 months old, and feeding with inducing feed formula for 5 months. The formula of the induction feed comprises: 30% of cane sugar, 15% of beef tallow, 3% of cholesterol, 17% of soybean cake, 5% of fish meal, 20% of corn, 5% of wheat middling and 5% of rice bran. Pigs showing hyperglycemia, hyperinsulinemia, and early diabetic nephropathy such as microalbuminuria, urinary glucose, and nephritis were selected as subjects.

B. Experimental sample preparation and experimental grouping

Rapamycin and the compounds 1 to 3 obtained in examples 1 to 3 are respectively loaded on the surface of a naked stent to prepare drug-loaded stents containing different drugs, wherein the drug-loaded doses are all 140ug/cm². Different stents were implanted into different groups of animals to form 4 groups as follows:

1. rapamycin scaffolds group: implantation of rapamycin containing stents in animals

2. Compound 1 scaffold group: animal Implantation of scaffolds containing Compound 1

3. Compound 2 scaffold group: animal Implantation of scaffolds containing Compound 2

4. Compound 3 scaffold group: animal Implantation of scaffolds containing Compound 3

C. Stent implantation

Aspirin and clopidogrel were administered daily starting 3 days before surgery. The animals were anesthetized before surgery and fixed on the operating table in supine position to establish venous access, tracheal intubation and ventilator assisted breathing. After the coronary angiography is locally sterilized, the right femoral artery is punctured, the right femoral artery is fed into a guide wire through a puncture needle, a 6F femoral artery sheath is fed along the guide wire, and heparin 150Ukg is fed through a sheath tube. Sent into a 6F right coronary guide catheter through a sheath tube for left and right coronary angiography respectively. The target vessel is selected to avoid as large a branch of the vessel as possible. The pressure pump is used for filling the saccule to release the stent in vitro, and the saccule is withdrawn after the stent is completely attached to the wall and causes injury. And (5) performing postoperative review radiography. The catheter is withdrawn, the femoral artery sheath is pulled out, and the local pressure of the operation area is used for hemostasis. After the pig is awake, the pig is returned to the cage for continuous feeding.

D. Results of the experiment

After the stent is implanted, the breeding is continued for 45 d. After 45d, the vascular intimal hyperplasia condition of the injury part is examined, the ratio (I/M ratio) of the implantation of the stent into the vascular intima (intima) and the thickness (media) of the medium vessel is measured, and the result is shown in the table below.

Numbering	Experimental group	I/M
			1	Rapamycin stent set	0.472±0.231
2	Compound 1 scaffold group	0.295±0.115
			3	Compound 2 scaffold group	0.340±0.127
4	Compound 3 scaffold group	0.360±0.145

The results show that the compounds 1-3 obtained in the embodiments 1-3 of the invention have stronger capacities of inhibiting cell proliferation and clonal expansion than rapamycin, and bring better effect of inhibiting intimal hyperplasia; and has higher selectivity for inhibition of the inner membrane relative to the middle membrane.

The above subjects used pigs inducing early diabetic nephropathy manifestation, and as can be seen from the experimental results, the compounds of the present invention may have more excellent effects on the prevention of restenosis at the lesion in the stent-implanted diabetic patients.

The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.

Claims

1. A compound having the structure of formula I:

wherein A represents-O-, -C (O) -, or-C (O) N (CH)₃)-。

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula ii:

3. the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a halide selected from fluoride, chloride or bromide.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the halide is chloride;

5. a process for the preparation of a compound according to claim 1, comprising the steps of:

wherein B represents-OH, -COOH, or-C (O) NH (CH)₃)；

(3) Heating the solution 2 at 25-95 ℃ for 1 hour-2 weeks to obtain a reaction mixture;

6. The method of claim 5, wherein the heating temperature is 30-65 ℃.

7. The method of claim 5, wherein the heating temperature is 35-55 ℃.

8. The method of claim 5, wherein the heating time is 2 to 7 days.

9. The method of claim 5, wherein the heating time is 3 to 5 days.

10. The method of claim 5, wherein the organic solvent is selected from the group consisting of: acetone, acetonitrile, ethyl acetate, chloroform, dichloromethane, carbon tetrachloride, methanol, diethyl ether or petroleum ether.

11. A composition comprising an excipient and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting cell proliferation and clonal expansion.

13. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of an interventional medical device; the interventional medical device is selected from coronary artery stent, intracranial stent, peripheral stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic stent, urethral stent or tracheal stent.

14. An interventional medical device comprising a drug delivery structure comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; the interventional medical device is selected from coronary artery stent, intracranial stent, peripheral stent, intraoperative stent, heart valve stent, biliary stent, esophageal stent, intestinal stent, pancreatic stent, urethral stent or tracheal stent.

15. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting vascular restenosis in a diabetic patient.