TW391964B - Pharmaceutical compositions for inhibiting vascular smooth muscle cell migration - Google Patents

Description

Printed by the Ministry of Economic Affairs 4-Central Bureau Staff Consumer Cooperatives _A7 _______ '" B7_ V. Description of the invention (1) Background of the invention • Cell displacement in wound healing, inflammation response, adult respiratory distress syndrome, and invasion of malignant tumors Play an important role. (Savani et al., Journal of Clinical Diagnostics 95: 1 158-1 168; Kullmann et al., American Journal of Respiratory Cell Molecular Biology 8: 83-88, 1993; Brooks et al., Cells: 79, 115 ， -Υ 164, 1994). Vascular smooth muscle cells from the fluid to the endometrium during the formation of neointimal formation of vascular diseases such as atherosclerosis; PTCA accompanied by continuous narrowing, atherosclerosis of bypass veins (jacksOn etc., atherosclerosis 13: 1218 ^ 1226, 1993; Brown et al. Cardiovascular Research 28: 1815-1820, 1995; Bell and Madri, American Journal of Pathology 1 37: 7- 1, 2, 990) It plays a key role in principle. In animal models, the use of anti-growth factor antibodies to stimulate the displacement of smooth muscle cells after vascular injury or the sprint displacement caused by peptide blocking integrin (jlltegrin) was found to inhibit the formation of new intima (Ferns et al., Science 253: 1129 1132, 1991., Choi et al., Journal of Vascular Surgery 10, 12 5-135, 1994) The persistent narrowing of blood vessels after percutaneous transluminal coronary angioplasty (PTC A) was confirmed to be a tissue response, which can Divided into early and late. Thrombosis and / or vasoconstriction may be responsible for early reactions occurring hours or days after p T C a. The late response appears to be a significant Smc shift, hormonal and vascular remodeling. In these diseases, the accumulation of SMC number is obviously caused by the displacement of tissue fluid to the endometrium, which is the cause of the disease. Excessive proliferation and displacement of vascular smooth muscle cells may be caused by the National Standard for Coronary Artery (CNS) A4 (210x297 mm) with PTC A, arterectomy, laser angioplasty, and arterial bypass grafting I--(Please read first Note on the back page) Factory clothes ------ ΐτ ----- A7 A7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (2 Main mechanism of continuous blockage. See, Endometrium The proliferation of smooth muscle cells is responsible for the repeated narrowing of coronary arteries after percutaneous transluminal coronary angioplasty (PTC A). "Austin et al., Journal of the American College of Cardiology 8: 369-375 (August 1985). Percutaneous Surgical procedures such as transluminal coronary angioplasty (PTC A), arterectomy, laser angioplasty, and arterial bypass graft surgery to prevent obstruction of the artery, the concomitant narrowing of the blood vessels is still a major long-term side effect. In about 3 In 5% of patients undergoing PTCA, repeated occlusions occur within three to six months of these procedures. Strategies currently used to treat persistent narrowing of blood vessels include mechanical interventions such as the use of instrument stents or drugs Treatments include heparin, low molecular weight heparin 'coumarin, aspirin, fish oil, calcium antagonists, steroids, and prostaglandins. These strategies fail to suppress the incidence of repeated obstructions and are ineffective in treating and preventing narrowing of blood vessel performance Refer to "Preventing Percutaneous Transluminal Coronary Angioplasty (PTCA) Vascular Narrowing; Looking for Species", "Magic Street Bullet" & Hermans et al., American Heart Journal 122: 171_187 (July ΐ99ι) Among the reasons, the excessive cell proliferation and displacement occur because the growth of the cellular components in the blood and the walls of the injured arterial wall produces growth factors that stimulate the proliferation of smooth muscle cells and cause the blood vessels to continue to narrow. Agents that inhibit the displacement of smooth muscle cells treat and prevent continuous changes. Narrow aspect: effective. The present invention provides compounds that inhibit the displacement of smooth muscle cells. SUMMARY OF THE INVENTION The present invention provides a method for inhibiting the displacement of vascular smooth muscle cells in an animal, which comprises administering the target drug to other compounds, π double. The original ... bearing standard of formula I applies Chinese national standard (cns) Mu Yao (training X 297 public splash) (Please Read the note on the back of another page)

V. Description of the invention (3) A7 ^ B7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 〇 〇-丨 丨 II where R > R3 is hydrogen alone, -CH3,-< 3-((ν〇6alkyl), or -C-Ar ', Wherein Ar may be substituted by phenyl, r2 is pyrrolidinyl, hexamethyleneimino, or piperidinyl; and pharmaceutically acceptable salts and solvates thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention is Regarding the discovery of a selected group of compounds, wherein the compound of formula I is effective in inhibiting the displacement of vascular smooth muscle cells. The treatment method provided by the present invention is to administer a compound of formula i or formula ^ to a human or other mammal. Or a pharmaceutically acceptable salt or solvate thereof to effectively inhibit the displacement of vascular smooth muscle cells. The word "suppression" is synonymous to include the meaning accepted by the general population, that is, the pretreatment of smooth muscle cells that occur in patients. Displacement, and continuous examination and / or treatment of smooth muscle cell displacements that are present. Therefore, if appropriate, the method includes both medical and or prophylactic treatment. Whistle '-In general, this compound is formulated as an ordinary excipient, dilute Release solution, can be compressed into tablets ’or formulated as a panacea for oral administration, or (please read the precautions on the back first and then% ^ this page) Order; Λ · —

.II-1 I -6- ____________ " B7__ V. Description of the Invention (4) Administration by intramuscular or intravenous route. The present compound can be administered transdermally, or it can be formulated in a sustained release form or a similar method. The compounds of formula I used in the method of the present invention can be prepared according to established procedures in reference materials which have been filed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635. Generally, this step starts with a 6-hydroxy and 2- (4-hydroxyphenyl) benzo-p-thiophene. The starting compounds are protected, calcined, and deprotected to form compounds of formula I. Examples of the preparation of this compound are provided in the U.S. patents mentioned above. The invention also includes the use of the following compounds:

Substitution of printed phenyl groups in the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs includes the substitution of phenyl groups by C, C6 alkyl, c, C4, oxy, hydroxy, chloro, fluoro, or tr (chloro or fluoro) methyl Substitute one or two times. The compound used in the method of the present invention comes from a pharmaceutically acceptable acid and -7- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7 V. Description of the invention (5) A variety of different organic and inorganic acids and bases are added to the test salt and include salts commonly used in medicinal chemistry and pharmaceutically acceptable. These salts are also this Part of the invention. Typical inorganic acids used to form these salts include chlorochloric acid, hydrobromic acid, hydrolytic acid, nitric acid, sulfuric acid, phosphonic acid, and diphosphonic acid, and similar salts. Derived from Salts of organic acids, such as mono- and di-acids, phenyl-substituted alkanoic acids, aryl-substituted alkanoic acids, carboxy-chain dian acids, aromatic acids, aliphatic and aromatic sulfonic acids. These are used in pharmacy Acceptable salts therefore include acetate, Acetate, trichloroacetate, propionate 'ascorbate, phenyl potassium salt, chlorophenyl potassium salt, dinitrobenzene potassium salt, hydroxyphenyl potassium salt, methoxyphenyl potassium salt' acetate phenyl potassium salt, Bromide, isobutyrate, phenyl butyrate, p-hydroxybutyrate, butyne-1,4-diacid, hexyne-1,4-diacid, caprate, caprylate, gas Compounds, cinnamate, citrate, bellate, fumarate, glycolate, heptanoate, maleate, lactate, malate, maleate, hydroxymaleate , Malonate, alginate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, benzene dibenzoate, triphthalate, phosphate, mono Hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propionate, propionate, phenyl propionate, salicylate, sebacate, succinate, suberate , Sulfate, disulfate, pyrosulfate, sulfite, sulfonate, benzenesulfonate, o-bromobenzenesulfonate, gas benzenesulfonate, europium ethanesulfonate, 2 -Isethionate, methanesulfonate, tau-2-sulfonate, toluene sulfonate, xylene sulfonate, tartrate, and other similar salts. The preferred salt is hydrogenated hydrogen gas. Salt. Typical pharmaceutically acceptable acid-added salts are made of compounds of formula I and equivalent. The paper size applies Chinese National Standard (CNS) A4 specification (210X297). (Please read the precautions on the back before this page. ) Order A7 " B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (6 mol concentration or excess acid reaction. The reactants are generally combined with a relative solvent such as ether or wood. Salts are generally at about It can be precipitated from the solution within one hour to 10 days and can be separated by filtration. The solvent can be removed by conventional methods. 'The bases commonly used to form salts include ammonia and alkali and alkaline earth metal osmium oxides, carbonates and carbonates. Hydrogen salts also include aliphatic and aromatic amines, aliphatic diamines and hydroxyalkylamines. Particularly useful bases for the preparation of additional salts include ammonium hydroxide 'potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylene'diamine, cyclohexaalkylamine, ethidium amine . Pharmaceutically acceptable salts are generally more soluble than their derivatized compounds and are therefore generally more formulated into liquid or emulsion formulations. Pharmaceutical formulations can be prepared via well-known formulations. For example, the compounds can be formulated with excipients, diluents or carriers into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents or carriers suitable for this formulation include: additives and supplements such as starch, sugar, mannose, and derivatives of silicic acid; attachment agents such as carboxymethyl cellulose and other cellulose derivatives Substances, alginate, white salt, gelatin 'and polyethylene, bilobenone; calendars such as glycerin, disintegrants such as agar gelatin' sodium carbonate, sodium bicarbonate, delaying dissolution agents such as stone soil 'absorption Action accelerators such as quaternary compounds; surfactants such as ethanol acetate, glyceryl monostearate; absorbent carriers such as china clay and pulp; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols . , Chemical. The material can also be formulated as a panacea or a solution that facilitates oral administration or is administered parenterally, such as via intramuscular, subcutaneous or intravenous routes. In addition, this compound is very suitable for the formulation of sustained release (please read the precautions on the back before ^^ this page)

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V. Description of the invention (A7 Economy, Ministry of Economy, Central Standards Bureau, Consumer Cooperatives, Printed Family Forms and Similars. This formula may be more than a period of time, and it may be only or more often that the active ingredient is released in a specific part of the intestine. For example, the encapsulating π-protective matrix can be used, for example, a polymerizable substance or ant. B. According to the present invention, the branching dose of the compound of the formula I required to inhibit smooth muscle cell displacement depends on the severity of the disease, the route of administration, and The relevant factors are determined by the lead physician.-Generally, an acceptable and effective single daily dose is from about 0.1 to about 1,000 mg / day. More typically it is from about 50 to about 2000 milliseconds / day. If it is necessary to effectively inhibit smooth muscle cell displacement, this dose will be administered to patients receiving Treatment I, from once to about three-times, or more. Topical administration of the required amount of the active compound to inhibit the smooth muscle cell displacement Or the narrowing of the blood vessels can be administered via different ridges at or near the affected site. The examples of topical application techniques here are not intended to be limited to these techniques, but are only known to 71IT. These include local catheter administration, site-specific vehicle, implantation, direct injection, or direct administration. Direct administration via a catheter allows the agent to be administered directly to the affected area-β Examples of local administration using a balloon catheter are Ep 0383 492 A2 and U.S. Patent No. 4,636,195 (Wolinsky, January 13, 1987). Topical administration via implantation is the surgical implantation of a medicated matrix into the affected area. The injected matrix releases the agent via diffusion, chemical reactions, or solvent-active agents. Lange, Science 249: 1527 1533 (September, 1990). An example of local administration via implantation methods is the use of stents. Stents are designed to Mechanically stop the coronary artery from falling out and continuously narrow β. Add the agent to the stent to directly administer the agent to the affected site. Topical administration via this technique is described in Kohn, Drug Therapy Techniques (October, 199〇) -10- This paper size applies to Chinese National Standard (CNS) Α4 specification (2.10X297 mm) Please read the note again

ί Order A7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ------______ V. Description of the Invention (S) ~~: --- Another example of the administration system is to use a polymer containing a drug in a liquid state. The form is injected into the affected area. This polymer thus forms an implant in vivo for therapeutic effects. / This technology street is described in PCTWO 90/03768 (Donn, 4 @ 19, 199〇). Another example is the delivery of a medicament via a polymerizable backfill. This technique uses a catheter to deliver a polymerized implant to a surface inside the vessel lumen. Adding a drug to a biodegradable polymer implant allows it to be released at the surgical site. In PCT WO 90/01969 (Schindler, August 23, 1989). A final example of local administration via implantation methods is the direct injection of cysts or microparticles into the affected area. These particles may consist of two substances such as proteins, lipids, carbohydrates, or synthetic polymers. These particles have agents mixed into them or form a film around the particles. The delivery system of mixed particles is

Lange, Science 249: 1527 1533 (September, 1990) and

Mathiovvitz et al. Are described in a literature published in the Journal of Applied Sciences 26: 809 (1981). Topical application from a specific site carrier is to attach the agent to a carrier that can direct the drug to the affected area. Examples of these delivery technologies include the use of carriers such as protein ligands or monoclonal antibodies. Lange published in Science 249: 1527 1 5 3 3 (September). Local administration by direct administration includes local administration. An example of a topical administration via direct administration is the direct use of this agent during an arterial bypass graft surgery. It is generally preferred to administer the compound of Formula I in the form of an acid addition salt, as is customary for the administration of a test base such as a symptom ring. It is also beneficial to administer this compound orally to older patients, such as menopausal women. Because this paper scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back before ^ Γ this page). Reprint the A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (9) The purpose is to have the following oral dosage forms. In the following formulas, the "active ingredient" represents-a compound of formula i, Formula 1: Gelatin capsules Hard gelatin capsules are prepared as follows: Ingredient amount (mg / capsule) Active ingredient 0.1-1000 starch, NF 0 -6 5 0 starch) filling powder ^ 0-6 50 silicon fluid 3 5 0 centiliter 0-15 Mix the ingredients, pass through 4 # 5 mesh US molecular sieve, and fill in hard gelatin capsules. An example of a special capsule formulation of a compound of formula I is where the compound is raloxifene, including those shown below: Formulation 2: Raloxifene Capsule Content (mg / capsule) Raloxifene 1 Starch, NF 112 Starch Flowing Powder 22 5.3 Silicon Fluid 3 50% Division 1.7 Formula 3: Raloxifene Capsule Content (mg / capsule) _ Raloxifene 5 Starch, NF 10 8 Starch Flowing Powder 22 5.3 Silicone Fluid 3 5 0 Cent Division 1.7 -12- (Please read the precautions on the back first and then ％ this page ) tr i) ly This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm>

A 5. Description of the invention (10) Formula 4 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4: Raloxifene capsules (mg / capsule) Raloxifene 10 starch, NF 103 starch flowing powder 2 2 5.3 Silicone fluid 3 5 0 centiliter 1.7 Formulation 5: Raloxifene Capsules (mg / capsule) Raloxifene-50 starch, NF 1 50, powder moving powder 397 silicon fluid 3 50 centiliter 3.0 The above specific formula can be changed within the reasonable range of variation provided. Use the following ingredients to prepare a tablet formula: Formula 6: Tablet Ingredient Amount (mg / tablet) Active Ingredient 0.0 1-1000 Cellulose, Microcrystalline 0-650 Silicon Dioxide, Baking Smoked 0-650 Stearic Acid 0- 15 Mix these ingredients and compress to form a tablet. 1. Each tablet containing 0.1-1000 mg of active ingredient can be prepared as follows: -13- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before this page)

, 1T A7. B7 V. Description of the invention (η) Tablet composition (mg / tablet) Active ingredient starch cellulose, microcrystalline polyethylene P Bihaxonone (10% solution in water) Carboxymethyl Sodium cellulose stearin-acid Talc 0.1-1000 45 3 5 4 4.5 D.5 Pass the active ingredients, starch, and cellulose through a No. 4 sieve US molecular sieve, and then mix well. The polyvinylpyrrolidone solution was mixed with the previously obtained powder and passed through a No. 14 sieve US molecular sieve. The resulting particles are at 50. Dry at -60 ° C and pass through a No. 18 mesh US molecular sieve. Carboxymethylcellulose, magnesium stearate and Talc previously passed through a No. 60 sieve US molecular sieve were added to the granules, mixed and compressed into tablets using a tablet making machine. · A suspension containing 0 · 1-1 0 0 0 mg of medicine per 5 ml dose is prepared as follows (please read the precautions on the back before $ this page) Zhang

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V. Description of the invention (A7 ^ 7 Formula 8: Suspended ingredients Active ingredient methyl sodium cellulose syrup benzoic acid solution Aromatic pigments Add pure water (mg Z5 ml) 〇 1-1 000 mg 50 mg 1.25 mg 〇.10 ml qv qv. Ml Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Pass this medicine through 45 # 1¾ 3 {~~ '~ one-one-syrup formation-seed flat m molecular sieve, and methyl nanofiber Mix and dilute the mixture and add enough water to achieve the required body time. The compounds in this hair have the ability to inhibit the displacement of vascular smooth muscle cells. The evidence is as follows: 1. The aorta of porcine aorta smooth muscle cells are from Obtained from freshly slaughtered castrated boars at a local slaughterhouse. Smooth muscle cells were prepared using procedures similar to those previously described (bcmin et al., 1989). In short, the aorta was cut vertically and the blood vessels were scraped with a scraping blade. Endothelial cells are carefully enclosed from the surface of the vascular cavity. The aorta is reused with Eagles broth modified by Dubecco, 10% fetal bovine serum, 1 glutamine (2 mM), penicillin (100 units / ml) , And streptomycin microg / ml). Then the narrow central smooth muscle is -15. (Please read the notes on the back first and then this page) The Danish bound paper prostitute is applicable to the Chinese National Standard (CNS) (Xinxin 7 Gongchu) B91964 A7 ___ '" §7 V. Description of the invention (13) The cells are peeled from the outer membrane and cut into 1-2 mm fragments & the additional implant is placed in a 24-well culture dish containing the above-mentioned medium. Observe how the fine vesicles grow from the explants within 5-7 days. After 10 to 14 days, the explants were removed, the cells were digested with trypsin, and cultured in a Ding bottle containing 15 ml of culture medium. Human smooth muscle cells Human coronary and aortic smooth muscle cells were purchased from Cl. Netic Corporation (San Diego, CA). Both cells were cultured in the medium used for porcine smooth muscle cells. Analysis of smooth k-cell displacement-channeling smooth muscle cells derived from porcine and human arteries to platelet-derived growth factor concentration gradients It was printed with a modified Boden 96-hole system and a polycarbonate filter paper (NeurOPrObe, Ine, the Central Standards Bureau Employees Cooperative of the Ministry of Economy). Smooth muscle cells were transferred to Dubacco's modified-free Eagles / F12 medium containing 2% fetal calf serum, 1-dry amine (2 mM), penicillin (100 units / ml), and streptomycin (100 μg / ml). (DMEM / F-12). After 24 hours, the cells were trypsinized with non-red pancreas / EDTA. Cells (2.5 x i 0-6 cells / ml) were suspended in 1% platelet-deficient plasma And different concentration formulas Compound I without phenol red DMEM / F-12. One hundred microliters of cell suspension was added to the upper layer of the modified Rugao Mouth plate hole. The lower layer of the hole was filled with 43 microliters of 1% platelet-deficient plasma '5ng / Milliliter of PDGI ^ DMEM / F_12 with different concentrations of compound 3 Place the plate at 37 ° C and 5% C02 for 5 hours. Remove the displacement film from the plate and remove the cells on the upper layer of the film with a cotton swab. Remove The cells to the lower layer of the film were fixed in methanol and stained with Diff-Quick staining solution (Baxter) -16- this paper 21GX297 mm) A7 fly 7 391964 5. Description of the invention (M) Microtiter plate for the situation of staining the cells Chromatographic Analyzer (Tlierm〇Max,

Molecular Dynamics, Inc) or by using an inverted microscope (Nikon,

Inc) calculated the number of cells (HpF) in the 40X high magnification field of view. This experiment involved culturing the cells with the compound first, placing the agent at the specified concentration and treating the medium first, and culturing in different bottles for 8 hours. The analytical environmental conditions of cells in these pretreatment experiments are exactly the same as those used in rapid drug effect experiments.

Table I Stimulating effects of platelet-derived growth factor (PT GF) on porcine taiji arterial smooth muscle cell displacement PDGF (ng / ml) printed by the Central Provincial Consumers Cooperative Co., Ltd. Smooth muscle cell displacement (OD 650nm) 0.04 0. .0 16 Soil 0, .008 0.80 0. .009 soil 0. .003 1.50 0, .0 13 taxi 0, .007 3.00 0, .028 soil 0. .008 6.00 0. .058 taxi 0, .0 10 12.0 0. .052 Soil 0. .0 07 25.0 0. .047 Soil 0, .009 -17- This paper size applies to Chinese National Standard (CNS) A4 (2I0X297 mm) 391964 A7 " B7 V. Description of the invention ()

Table II Compound A * and point-estradiol inhibit the hair aorta smooth muscle cell displacement by the platelet growth factor (p DGF) " S. MC displacement (OD 650 nm) Compound A 0, 〇53 ± 〇.〇15 0.03 5 ± 0.005 〇_〇3〇 ± (Γ.〇〇5 0-03 2 ± 0.007 ____ ^ * Compound A is from formula I, where r > R3 is gas and l is the above-mentioned activity of each pit group Represents the potential of the compounds of the present invention to obliquely inhibit the displacement of vascular smooth muscle cells and the effects they cause. Concentration (η Μ) 0.0 0. 1.1 0 0 point-estrous diol 〇_〇53 ± 0_〇15 0.032 0.00 0.003 〇 -〇23 ± 〇.〇〇3 0-034 Soil 0.006 (Please read the precautions on the back before f this page) Order! Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 18- This paper size applies to Chinese national standards (CNS ) M size (210X 297mm)

Claims (1)

No. 8 5 1 0 6 4 3 4 Patent Application BS Chinese Patent Application Scope Amendment (February) S Patent Application Scope Ben-391964 Amendment I i Bu You ^ 1. A pharmaceutical composition suitable for inhibiting the displacement of vascular smooth muscle cells including a compound of formula I as an active ingredient thereof (I) wherein 1 and 113 are both hydrogen; R2 is pyrrolidinyl or piperidinyl; and pharmaceutically acceptable salts and solvates thereof. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) No. 8 5 1 0 6 4 3 4 Patent Application BS Chinese Patent Application Amendment (February) S Patent Application Scope Ben-391964 Amendment I i Bu You ^ 1. A pharmaceutical composition suitable for inhibiting the displacement of vascular smooth muscle cells including a compound of formula I as an active ingredient thereof (I) wherein 1 and 113 are both hydrogen; R2 is pyrrolidinyl or piperidinyl; and pharmaceutically acceptable salts and solvates thereof. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 391964 A8 B8 T8 D8 VI. Shenli price range 丨, month 1. I compounds 〇 --------- I--: Λ / ί ί (Please read the precautions on the reverse side before filling out this page) where R > R3 is hydrogen alone, -CH3, -C- (CrC6 alkyl ), Or -C-Ar, where Ar may be substituted by phenyl if necessary; R · 2 is piohaloyl, hexamethyleneimine, or symptomatic group; and its pharmaceutically acceptable salts and The lysate is used to suppress the displacement of blood vessels and smooth muscle cells in the human body. 2. A pharmaceutical formulation suitable for inhibiting the displacement of smooth muscle cells, comprising a compound of formula I as an active ingredient, Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 〇CH2CH2R2 This paper size applies to China National Standard (CNS) A4 specification. (210X297 mm) 391964 A8 B8 T8 D8 VI. Shenli price range 丨, month 1. I compounds 〇 --------- I--: Λ / ί ί (Please read the precautions on the reverse side before filling out this page) where R > R3 is hydrogen alone, -CH3, -C- (CrC6 alkyl ), Or -C-Ar, where Ar may be substituted by phenyl if necessary; R · 2 is piohaloyl, hexamethyleneimine, or symptomatic group; and its pharmaceutically acceptable salts and The lysate is used to suppress the displacement of blood vessels and smooth muscle cells in the human body. 2. A pharmaceutical formulation suitable for inhibiting the displacement of smooth muscle cells, comprising a compound of formula I as an active ingredient, Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 〇CH2CH2R2 This paper size is applicable to China National Standard (CNS) A4. (210X297 mm)