MXPA06009004A - Drug for inhibiting vascular intimal hyperplasia - Google Patents

Abstract

A drug for inhibiting vascular intimal hyperplasia which is effective in the prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA) and stent placement in a blood vessel or effective in treatments for the progress thereof. The drug for inhibiting vascular intimal hyperplasia contains either a 3(2H)-pyridazinone compound represented by the formula (I):(wherein R1, R2, and R3 each independently represents hydrogen or C1-6 alkyl;X represents halogeno, cyano, or hydrogen;Y represents halogeno, trifluoromethyl, or hydrogen;and A represents optionally hydroxylated C1-8 alkylene) or a pharmacologically acceptable salt thereof.

Description

INHIBITOR OF H1PERPLAS1A INT1 TO VASCULAR TECHNICAL FIELD The present invention relates to an inhibitor of intimal vascular hyperplasia containing a pyridazinone compound or a pharmaceutically acceptable salt thereof as an active ingredient.

TECHNICAL BACKGROUND In the pathogenic mechanism of myocardial infarction and angina pectoris, coronary stenosis due to intimal atherosclerotic hyperplasia is considered as a main cause. On the other hand, in recent years, percutaneous transluminal coronary angioplasty (PTCA) has been widely performed to dilate stenotic lesions of the coronary artery with intimal hyperplasia and to dilate stenotic lesions of the coronary artery with intimal hyperpfasia and the placement of a vascular stent. it is done more and more. However, it is a major medical problem that vascular endothelial cells are exfoliated after PTCA or vascular stent placement, and reocclusion occurs due to intimal hyperplasia accompanied by proliferation of vascular smooth muscle cells. Therefore, highly safe drugs that selectively inhibit intimal vascular hyperplasia are promising as useful drugs not only for the prevention and treatment of atherosclerotic diseases but also for the prevention of restenosis after PTCA or after vascular stent placement. The pyrididazinone compounds or their salts are known to have an excellent antiplatelet action, cardiotonic action, vasodilator action, anti-SRS-A action (substance of slow anaphylaxis reaction), thromboxane A2 synthetase inhibitory action, therapeutic action in spinal canal stenosis and erectile dysfunction and dysfunction and stimulating and reinforcing action of angiogenesis and which are promising as antiplatelet agents (patent documents 1 to 6). However, no reports have been made as to what effect these pyridazinone compounds have on intimal vascular hyperplasia.

On the other hand, although among the various treatments for intimal vascular hyperplasia, pharmacotherapy is an established one, a better pharmacotherapy is demanded. Patent document 1: JP-B-7-107055 Patent document 2: JP-A-7-252237 Patent document 3: JP-A-7-285869 Patent document 4: WO99 / 11268 Patent document 5: WO00 / 12091 Patent document 6 : WO00 / 33845 BRIEF DESCRIPTION OF THE INVENTION Problems that the invention will solve The object of the present invention is to provide an excellent inhibitor of intimal vascular hyperplasia.

Means to solve the problems As a result of their extensive research, the present inventors have discovered that the pyridazinone compounds represented by the following formula (I) or their pharmacologically acceptable salts have excellent inhibitory activity in intimal vascular hyperplasia and have embodied the present invention . Namely, the present invention provides an inhibitor of intimal vascular hyperplasia containing a compound of 3 (2H) -pyridazinone represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [where each of R \ R and R? is independently a hydrogen atom or an alkyl group of C-, X is a halogen atom, cyano or a hydrogen atom, Y is a halogen atom, trifluoromethyl or a hydrogen atom, and A is an alkylene of C ? -8 which can be substituted with a hydroxyl group]. The inhibitor of intimal vascular hyperplasia of the present invention is preferably a pyridazinone compound of formula (I) wherein R 1 and R 2 are hydrogen atoms, R 3 is a hydrogen atom or an alkyl group of C 4 4, X is an halogen, Y is a halogen atom or a hydrogen atom, and A is a C? -4 al alkylene which can be substituted with a hydroxyl group, or a pharmacologically acceptable salt thereof. The pyridazinone compound represented by the formula (I) in the inhibitor of intimal vascular hyperplasia of the present invention is particularly and preferably 4-bromo-6- [3- (4-chlorophenyl) propoxy] -5- (3-pyridylmethyl). lamino) -3 (2H) -pyridazinone or 4-bromo-6- [3- (4-chlorophenyl) -3-hydroxypropoxyl] -5- (3-pipdylmethylamino) -3- (2H) -pyridazinone.

EFFECTS OF THE INVENTION The present invention provides a novel inhibitor of intimal vascular hyperplasia containing a pyridazinone compound (I) or a pharmacologically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the intimal area after oral administration of 10 mg / kg of compound A or 300 mg / kg of cilostazol in test example 1. * indicates that the difference was significant with P < 0.05 compared to the solvent group using the Dunnett test. Figure 2 shows the l / M ratio after oral administration of 10 mg / kg of compound A or 300 mg / kg of cilostazol in test example 1. * indicates that the difference was significant with P < 0.05 compared to the solvent group by the Dunnett test.

DETAILED DESCRIPTION OF THE INVENTION The pyridazinone compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof in the inhibitor of intimal vascular hyperplasia of the present invention will now be described. In the formula (I), the alkyl groups of d-6 as R1, R2 and R3 can be linear or branched and can, for example, be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, phenyl, hexyl or the like. R1 and R2 are preferably hydrogen atoms and R3 is preferably a hydrogen atom and or a C1-4 alkyl group.

The alkyl group of C-α-4 as R 3 may, for example, be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl or the like. Particularly preferred as R3 is a hydrogen atom. Halogen atoms such as X and Y are fluorine atoms, chlorine atoms, bromine atoms or iodine atoms. X is preferably a halogen atom and Y is preferably a halogen atom or a hydrogen atom. The alkylene of C? -8 which can be substituted with a hydroxyl group as A can be linear or branched and can, for example, be methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, 2,2-dimethylethylene, 2,2-diethylethylene, 2, -2-di-n-propylethylene, hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene, 3-hydroxypropylene or the like. A is preferably an alkylene of C? -5 which can be substituted with a hydroxyl group. In the formula (I), the methylene group can be linked to any position in the pyridine ring without particular restrictions, but preferably it is linked to the 3-position to the nitrogen atom in the pyridine ring. In addition, the substituent Y may be at any position on the benzene ring but preferably at the 4-position. Pyridazinone compound of the formula (I) wherein R 1 and R 2 are hydrogen atoms, R 3 is a hydrogen atom or an alkyl of C? -, X is a halogen atom, Y is a halogen atom or a hydrogen atom, and A is an alkylene of C? -5 which can be substituted with a hydroxyl group are particularly preferred. As preferred compounds, 4-bromo-6- [3- (4-chlorophenyl) propoxy] -5- (3-pyridylmethylamine) -3 (2H) -pyridazinone, 4-bromo-6- [3- ( 4-chlorophenyl) -3-hydroxypropoxy] -5- (3-pyridiomethylamino) -3- (2H) -pyridazinone and its pharmacologically acceptable salts. In the present invention pharmacologically acceptable salts of the pyridazinone compounds (I) include, for example, salts with inorganic acids (such as hydrochloride, hydrobromide, phosphates and sulfates), salts with organic acids (such as acetate, succinates, maleates, fumarates, malate and tartrates). These salts can be obtained from the pyridazinone compounds (I) by known methods. The pyridazinone compounds (I) of the present invention and their pharmacologically acceptable salts include their stereoisomers and optical isomers. The pyridazinone compounds (I) and their pharmacologically acceptable salts are also known compounds for their low toxicity. It can be obtained, for example, by the methods described in JP-B-7-107055, USP 5314883, EP-A-482208, JP-A-7-252237, USP 5750523 and EP-A-742211. The pyridazinone compounds (I) of the present invention and their pharmacologically acceptable salts have an excellent inhibitory action on intimal vascular hyperplasia in mammals such as humans, dogs, cattle, horses, rabbits, mice and rats.

The pyridazinone compounds (I) of the present invention and their pharmacologically acceptable salts are administered in appropriate doses selected depending on the age, weight and conditions of the patient and are usually administered to an adult human in an amount of from 0.001 mg to 5 g per day, preferably from 0.005 to 1000 mg per day, in one to several doses per day. The pyridazinone compounds (I) of the present invention and their pharmacologically acceptable salts can be administered parenterally in the form of injections (for subcutaneous, intravenous, intramuscular or intraperitoneal injection), ointments, suppositories, aerosols, eye drops or nasal drops, orally in form of tablets, capsules, granules, pills, powders, lozenges, chews, syrups, solutions, emulsions or suspensions, or by using drug delivery systems such as drug-impregnated stents or other devices that allow local and sustained delivery of the drug. The pyridazinone compounds (I) of the present invention and their pharmacologically acceptable salts can be formulated in various dosage forms in accordance with conventional methods commonly employed for the preparation of pharmaceuticals. For example, tablets, capsules, granules, pills, powders, lozenges or chewable for oral administration can be prepared using an excipient (such as sugar, lactose, glucose, starch or mannitol), a binder (such as syrups, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, or polyvinylpyrrolidone), a disintegrant (such as starch, carboxymethylcellulose or its calcium salts, microcrystalline cellulose or polyethylene glycol), a glidant (such as talc, magnesium stearate, calcium stearate or silica) or a lubricant (such as laurate sodium or glycerol) by known methods. In the case of formulations for oral administration, organic acids such as citric acid, succinic acid, maleic acid, fumaric acid, melic acid and tartaric acid can be added to improve dissolution and absorption character. Injections, aerosols, syrups, solutions, emulsions, suspensions, eye drops and nasal drops can be prepared by using a solvent for the active ingredient (such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1, 3-butylene glycol or polyethylene glycol), a surfactant (such as a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether hydrogenated castor oil or lecithin), a suspending agent (as a cellulose derivative as the salt of sodium carboxymethylcellulose or methylcellulose or a natural rubber such as tragacanth or gum arabic) or a preservative (such as p-hydroxybenzoate ester, benzalkonium chloride or a salt of sorbic acid), by ordinary methods. Suppositories can be prepared using for example cocoa butter, polyethylene glycol, lanolin, a fatty acid triglyceride or coconut oil by ordinary methods. Ointments to be percutaneously absorbed can be prepared using for example white petrolatum, liquid paraffin, higher alcohols, macrogol ointment, hydrophilic ointment or an aqueous gel base.

EXAMPLES The present invention will now be described in greater detail with reference to the test examples and examples. However, it should be understood that the present invention is not intended to be restricted by these specific examples. In the following test examples and example, compound A (4-bromo-6- [3- (4-chlorophenyl) propoxy] -5- (3-pyridylmethylamino) -3 (2H) -pyridazinone hydrochloride prepared by an ordinary method.

EXAMPLE OF TEST 1 Effect of compound A on intimal hyperplasia in rat femoral arteries 1. Formation of intimal hyperplasia by photosensitization Under intraperitoneal anesthesia with pentobarbital (50 mg / ml / kg), a catheter was placed in the left cervical vein of a Wistar rat. The left femoral artery was detached, and the probe of an ultrasonic pulse Doppler blood flowmeter was placed in the artery. The artery proximal to the placement site of the probe was irradiated with green light (540 nm, 800,000 1x) at a distance of 5 mm from the artery. A stable blood flow was confirmed 10 minutes after the start of irradiation and 15 mg / ml / kg of rose bengal was injected into the left cervical vein to damage the vascular endothelium. Then the incision is sutured. 2. Drug grouping and administration The rats were divided in order as a solvent group (9 rats), a group (10 rats) to which 10 mg / kg of compound A, and one group (10 rats) were administered to which administered 300 mg / kg of Cilostazol. The drugs were suspended in 0.5% methylcellulose solution, adjusted to be administered in a dose of 5 ml / kg, and were administered orally on the day of operation after confirming postoperative awakening and then orally administered once to the patient. day in the morning for the next three weeks. 3. Evaluation Three weeks after the operation, the left femoral artery was exposed under anesthesia. The blood was rinsed by physiological saline perfusion of the left ventricle at a pressure of from 75 to 90 mm Hg. The left femoral artery was perfused with physiological phosphate buffered saline solution (PBS) containing 1% paraformaldehyde and 2% glutaraldehyde for its fixation and dissected. For comparison, the right undamaged femoral artery was also dissected. The dissected femoral arteries were stored in 10% neutral regulated formalin. The femoral arteries were sectioned in series at a thickness of 0.5 mm to make pathological preparations and stained with hematoxylin-eosin (HE). The medial areas and the intimal area in cross sections of the tumoral arteries were measured as indices of intimal hyperplasia as a computer image analyzer and the relation of the intimal area / the average area (the ratio l / M) was calculated. 4. Statistical analysis The results are expressed as standard deviation ± average. The intimal areas and l / M ratios were analyzed for uniformity of distribution in each group by the Bartlett test. If the distribution was uniform, a one-way analysis of variance was performed and the averages for the solvent group and the corresponding groups treated with drug were analyzed by the Dunnett test to determine if there was a significant difference between the two. When the distribution was not uniform, the Kruskal-Wallis classification test was performed and there was a significant difference between the solvent group and a drug-treated group, the average classifications for the two groups were analyzed by the Dunnett test. The difference between two groups was considered significant if p < 0.5 (two sides).

Results The results are shown in figure 1. Compound A significantly reduced the area of the intimal tunic and the ratio l / M when administered orally at a dose of 10 mg / kg and resulted to have inhibitory action of intimal hyperplasia. 300 mg / kg of Cilostazol showed no action.

EXAMPLE 1 Tablets g of compound A, 20 g of lactose, 5 g of starch, 0.1 g of magnesium stearate and 7 g of calcium carboxymethylcellulose, 42.1 g in total, were mixed by an ordinary method and made into tablets coated with sugar that each contained 50 mg of compound A.

EXAMPLE 2 Tablets Tablets containing 10.0 mg of Compound A as the active ingredient, 5.0 mg of citric acid as the organic acid, 123.0 mg of lactose as an excipient, 4.0 of hydroxypropylcellulose as a binder, 7.0 mg of croscarmellose sodium as a disintegrant and 1.0 mg were prepared. of magnesium stearate as a glidant.

EXAMPLE 3 Capsules g of Compound A, 20 g of lactose, 10 g of microcrystalline cellulose and 1 g of magnesium stearate, 41 g in total, were mixed by an ordinary method and put into gelatin capsules to obtain capsules each containing 50 g. mg of Compound A.

EXAMPLE 4 Aerosol suspension The following ingredients (A) were mixed and the resulting liquid mixture was loaded into a valve vessel. The propellant (B) was injected through the valve nozzle at 20 ° C at a calibration pressure of about 2.46 to 2.81 mg / cm2 to obtain an aerosol suspension. (A): Compound A 0.25 mass%, isopropyl myristate 0.10 mass%, ethanol 26.40 mass% (B): a mixture 60-40 (mass ratio) of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane: 73.25 mass%.

Industrial Applicability A novel intimal hyperplasia inhibitor is provided which contains a pyridazinone compound or a pharmacologically acceptable salt thereof as an active ingredient. The entire description of Japanese Patent Application No. 2004-32551 (filed February 9, 2004) including specification, claims, drawings and summary is hereby incorporated by reference in its entirety.

Claims (5)

NOVELTY OF THE INVENTION CLAIMS

1. An inhibitor of intimal vascular hyperplasia containing a compound of 3 (2H) -pyridazinone represented by the formula (I) or a pharmacologically acceptable salt thereof: wherein each of R1, R2 and R3 is independently a hydrogen atom or a C alkyl group. X is a halogen atom, cyano or a hydrogen atom, Y is a halogen atom, trifluoromethyl or a hydrogen atom, and A is an alkylene of C? -8 which can be substituted with a hydroxyl group. 2.- The inhibitor of intimate hyperplasia! Vascular according to claim 1, further characterized in that the compound represented by the formula (I) is one wherein in the formula (I), R1 and R2 are hydrogen atoms, R3 is a hydrogen atom or an alkyl group of C -? -, X is a halogen atom, Y is a halogen atom or a hydrogen atom, and A is an alkylene of C-1-5 that can be substituted with a hydroxyl group. 3. The inhibitor of vascular intimal hyperplasia according to claim 1, further characterized in that the compound represented by the formula (I) is 4-bromo-6- [3- (4-chlorophenyl) propoxy] -5- (3) -pyridylmethylamino) -3 (2H) -pyridazinone or 4-bromo-6- [3- (4-chlorophenyl) -3-hydroxypropoxyl] -5- (3-pyridylmethylamino) -3- (2H) -pyridazinone. 4. The inhibitor of intimal vascular hyperplasia according to claim 1, 2 or 3, further characterized in that the pharmacologically acceptable salt is an organic acid salt or an inorganic acid salt. 5. The inhibitor of intimal vascular hyperplasia according to claim 1, 2, or 3, further characterized in that the pharmacologically acceptable salt is a hydrochloride.