JPH06157311A - Medicine for improvement of vessel anomaly - Google Patents

Abstract

PURPOSE:To provide a medicine for prevention and improvement of vessel anomaly, containing a compound such as 2-cyclopropyl-7-methyl-3-[(2'- carboxybiphenyl-4-yl) methyl]-3H-imidazo [4, 5-b]pyridine as the active component. CONSTITUTION:A medicine for improvement of vessel anomaly, containing a compound of the formula (R<1> is a cycloalkyl, a lower alkyl, a lower alkoxy, a lower thnoalkoxy or an alkynyl; R<2> is carboxy, 1H-tetrazol-5-yl or an alkoxycarbonyl; R<3> is H or methyl) as the active component and useful especially for prevention of angiosretenosis after a percutaneous transluminal coronary anigioplasty. This medicine is useful for prevention and improvement of diseases, e.g. arteriosclerosis, peripheral arterial obstruction or angitis such as periarteritis nodosa or pleocytosis angitis observed in a transplanted organ. The effect of the compound of the formula comes from angiotensin II receptor antagonism. The dosage is 1 to 500mg/day per an adult, especially preferably 5 to 100mg by oral or intravenous administration.

Description

Detailed Description of the Invention

[0001]

The present invention relates to angiotensin II receptor antagonism based on angiotensin II receptor antagonism in vascular restenosis, arteriosclerosis, peripheral arterial occlusion, periarteritis nodosa and transplant organs after percutaneous coronary angioplasty. The present invention relates to a preventive / therapeutic / ameliorating agent for vascular lesions such as vasculitis such as cell proliferative vasculitis.

[0002]

BACKGROUND OF THE INVENTION Angiotensin (hereinafter referred to as Ang) is a physiologically active peptide existing in blood. The proteolytic enzyme renin acts on blood angiotensinogen to produce angiotensin I, which is a decapeptide, and angiotensin-converting enzyme (ACE) acts on angiotensin I to produce a bioactive form of octapeptide. Angiotensin II (hereinafter referred to as Ang II) is produced. It is widely known that Ang II has a strong blood pressure increasing (pressurizing) action, and ACE inhibitors such as captopril, setapril, and cilazapril that suppress the production of Ang II have already been clinically selected as the first treatment for hypertension. It is often used as a medicine.

On the other hand, Powell et al.
It was reported that pre-administration of an inhibitor suppresses the intimal thickening after peeling and injuring the endothelium of the common carotid artery by ballooning [Science, 245 , 186-1].
88, 1989.]. Furthermore, Naftilan et al. Have shown that Ang II plays an important role in the proliferation of vascular smooth muscle using cultured rat vascular smooth muscle cells [Hypertension, 13 , 706-711, 198].
9. and Journal of Clinical Investigation (J. Clin. Invest.), 83 , 1419-1424, 1989.].
From these facts, it has been considered that Ang II is involved in the cell proliferative changes of the blood vessel wall after arterial injury, in addition to the conventionally known blood pressure increasing effect.

In actual clinical practice, percutaneous coronary angioplasty (hereinafter referred to as PTCA) is a typical example of cell proliferative vascular lesions that occur after physical damage to blood vessels as described above.
Examples include vascular restenosis (including occlusion, the same applies hereinafter) after the procedure. PTCA is one of the treatment methods for ischemic heart diseases such as angina and myocardial infarction. Percutaneous insertion of a balloon / catheter into a blood vessel to expand the coronary artery stenosis site without performing thoracotomy. Are treated. Since its clinical introduction by Gruentzig in 1977,
PTCA has been widely used as a typical treatment for ischemic heart disease, replacing the conventional surgical vascular bypass surgery.
Due to the progress in PTCA implementation technology and the accumulation of experience, the ischemic symptom improvement rate immediately after PTCA implementation exceeded 90%, and there were very few side effects such as death cases and myocardial infarction attacks, which was excellent. It is evaluated as a cure.

However, among the cases in which PTCA was successfully performed, there are about 30 cases where restenosis of the blood vessel occurs at the same site thereafter.
Approximately -40%, and in that case PTCA must be performed again or vascular bypass surgery must be performed, which is the biggest clinical problem. An autopsy result of a patient who died after reocclusion after PTCA revealed that the site where the blood vessel was enlarged by PTCA was reoccluded by cell proliferative intimal thickening [British Heart・ Journal (Br. Heart J.), 58 , 635-643, 1987., Human Pathol., 20 , 477-485, 1989., etc.].

[0006] Therefore, the efficacy of such drugs, which are expected to prevent the cell proliferative vascular lesions from the mechanism of action, has been examined preclinically and clinically [American Heart Journal (Am. Heart J.), 122 (1 part
1), 171-187, 1991.]. The target was blood anticoagulants such as heparin, aspirin, dipyridamole, ticlopidine, platelet aggregation inhibitors such as prostacyclin and its derivatives, thromboxane A ₂ inhibitors such as trapidil, cell growth inhibitors such as ketanserin, Calcium antagonists such as diltiazem and nifedipine, lipid-lowering agents such as fish oil, eicosapentaenoic acid and lovastatin, and anti-inflammatory agents such as steroids, etc. No clear utility for vascular restenosis was observed, and no drug could reliably prevent, treat, or improve vascular restenosis after PTCA.

However, the pathological findings and lesion formation process of the vascular stenosis site in the untreated group in the experiment using the rat of Powell et al. Described above are the same as those in the vascular restenosis after PTCA in clinical practice and ACE inhibition. Since the administration of the agent was effective for prevention, it was expected that the ACE inhibitor would be effective as an agent for preventing vascular restenosis after PTCA.

[0008] From this, using cilatapril, which is a typical ACE inhibitor, for 595 patients who underwent PTCA, the efficacy of ACE inhibitor against vascular restenosis after PTCA is effective A placebo-controlled, randomized, multicenter study was conducted in Europe for sex studies [Circulation, 86 (1), 100
-110,1992.]. However, the result is a placebo and A
There was no statistically significant difference in mean vessel lumen diameter and frequency of ischemic symptoms between the CE inhibitor groups,
ACE inhibitors were also not effective in preventing restenosis after PTCA.

As described above, in the present situation, there is no drug capable of effectively preventing, treating and improving cell proliferative vascular lesions such as restenosis of blood vessels after PTCA in humans. This situation also applies to vasculitis such as arteriosclerosis, peripheral arterial occlusion, nodular periarteritis, and cell proliferative vasculitis found in transplanted organs, which show the same pathological features and clinical symptoms.

The cell proliferative vasculitis observed in transplanted organs is cell proliferation characterized by thickening of the intima of the blood vessels that appears in the chronic stage after transplant surgery for various failed organs such as heart, liver and kidney. It is a vascular lesion and occurs due to activation of immune and inflammatory mechanisms due to vascular damage and rejection during transplant surgery. Coronary arteriosclerosis, which often occurs early after heart transplantation, is accelerated coronary arterioscleros
It is called is and is an important factor that determines the prognosis or survival years of organ transplantation, and it is effective for prevention and treatment.
The lack of improvers is a serious problem in implementation and dissemination. As described above, cell proliferative vascular lesions are serious and life-threatening diseases, but there has been no effective drug until now.

[0011]

2. Description of the Related Art As described above, a drug which is expected to have a cell growth inhibitory action due to its mechanism of action has been disclosed for use in cell proliferative vascular lesions such as vascular restenosis after PTCA. For example, in JP-A-2-289515, 6- (1-imidazolylmethyl) -5,6,7,8-tetrahydronaphthalene-
A thromboxane A ₂ inhibitor that is an imidazole derivative such as 2-carboxylic acid hydrochloride, a vascular restenosis-suppressing effect after PTCA is disclosed, and DE 4031821 also discloses a similar thromboxane A ₂ inhibitor. There is disclosure.

[0012] WO 91/18639 discloses that adhesion between cells
It has been disclosed that postoperative restenosis can be suppressed by co-administering fibronectin, which is a glycoprotein that plays an extension function, at the time of performing PTCA.

Japanese Patent Application Laid-Open No. 4-235924 discloses A, such as fosinopril and ceranapril.
It is disclosed that a CE inhibitor is effective in suppressing restenosis of blood vessels after PTCA.

In WO 92/12734, an anti-growth factor monoclonal antibody is also effective against vascular smooth muscle growth factor (PDGF) that causes arteriosclerosis, and is effective in suppressing vascular restenosis after PTCA. It is disclosed to be effective.

In EP 461039, Ang II receptor antagonism which is a benzimidazole derivative such as methyl 4 '-{(2-butyl-1H-benzimidazol-1-yl) methyl} biphenyl-2-carboxylate. It is disclosed that the agent is effective for hypertension, heart failure, renal failure as well as vascular restenosis after PTCA.

Next, WO 91/18639 discloses (E) -3- [2-
Ang II receptor antagonism, which is a monocyclic imidazole derivative such as n-butyl-1- {4-carboxyphenyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid It is disclosed that the agent is effective in suppressing restenosis of blood vessels after PTCA.

Furthermore, EP 492105 discloses 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl)- It has been disclosed that an Ang II receptor antagonist, which is a monocyclic imidazole derivative such as methyl] -imidazole / potassium salt, is effective for hypertrophy or thickening of blood vessels.

[0018]

[Problems to be solved by the present invention] As described above, PT
CA is widely used for the treatment of ischemic heart disease as a safe and excellent therapeutic method. However, about 30 to 40% of the cases of postoperative revascularization at the same site postoperatively, and the drawback of having to perform PTCA again or perform vascular bypass surgery has not been solved yet, and this is clinical. It is the biggest problem above. However, at present, there is no drug that can reliably prevent, treat and improve cell proliferative vascular lesions such as vascular restenosis after PTCA.

The thromboxane A ₂ inhibitor disclosed in, for example, Japanese Patent Application Laid-Open No. 2-289515 is a drug that has just been released, and a small number of cases using trapidil for vascular restenosis after PTCA were performed. Efficacy has been reported in clinical trials [Circulation, 80 (4)
suppl.II, II-260,1989.], the effect of which is not yet established.

Regarding the efficacy of fibronectin disclosed in WO 91/18639 against cell proliferative vascular lesions, the data is not described in the said publication, and therefore the effect is not clear. is not.

A disclosed in Japanese Patent Laid-Open No. 4-329524
Regarding CE inhibitors, refer to the above-mentioned reference [circulation
(Circulation), 86 (1), 100-110, 1992.], no usefulness was found in clinical trials.

Furthermore, EP 461039 and WO 91/1863
With regard to the Ang II receptor antagonist disclosed in Publication No. 9, the effect is uncertain because there is no data specifically showing the efficacy in the publication, and the possibility of clinical application as a drug is unknown. there were.

EP 492105 discloses that an Ang II receptor antagonist, which is a monocyclic imidazole derivative, is effective for hypertrophy or thickening of blood vessels. Results of pharmacological experiments disclosed in this publication Is using a rat. However, as described below, since the rat has a different angiotensin production pathway from large animals such as humans, it is not possible to immediately predict the usefulness for vascular restenosis after PTCA in humans from the results of this pharmacological experiment. It was

As described above, there is currently no effective drug for cell proliferative vascular lesions, and there is a strong demand for a clinically useful drug.

[0025]

[Means for solving the problem] Okunishi et al.
What is rat and rabbit in arterial tissue of large animals such as humans and humans?
Different from ACE, there are other enzymes that produce Ang II
[Journal of Hypertension
(J. Hypertens.),2(3), 277-284, 1984.
Mical and Biophysical Research Community
Nations (Biochem.Biophys.Res.Commun.),149
(3), 1186-1192, 1987.]. This enzyme is CAGE (Chymostatin-
sensitive angiotensin II generating enzyme)
And is not suppressed by ACE inhibitors. So in humans
There are two pathways that produce Ang II, and A is an ACE inhibitor.
Even if the production pathway by CE is suppressed, the production pathway by CAGE is
Since it is still functioning, it can produce sufficient clinical effects.
It is clear that Ang II production cannot be suppressed to a high level
Became. However, drugs that simultaneously inhibit ACE and CAGE
Not yet found. On the other hand, Ang II receptor antagonism
The compounds having the activity of AngII have various physiological activities induced by AngII.
Considered to be able to block at the receptor level regardless of the production pathway of
Therefore, it is not possible to treat the above-mentioned cell proliferative vascular lesions.
It was possible to solve the clinical problems of ACE inhibitors that were sufficient,
After PTCA, vascular restenosis, arteriosclerosis, peripheral artery occlusion,
Cells found in nodular periarteritis and transplanted organs
Prevention and treatment of vascular lesions such as vasculitis such as proliferative vasculitis
・ Usefulness as an improver can be expected.

Therefore, the present inventors have a strong receptor antagonism capable of blocking the cell proliferation action of Ang II produced through any route in vascular tissue at the receptor level, and have a long duration. We have conducted intensive research into materials that have the requirement of being highly safe even when used for a certain period of time. As a result, they have found in the in vivo experiment for the first time that the compound group represented by the general formula (I) achieves the intended purpose as a prophylactic / therapeutic / ameliorating agent for cell proliferative vascular lesions, and completed the present invention.

Conventionally, based on such an idea, in vivo
None of the experiments directly demonstrated the efficacy of Ang II receptor antagonists on cell proliferative vascular lesions. For example WO 92/10
Although 185 and WO 91/18639 describe that an Ang II receptor antagonist is effective in preventing vascular restenosis after PTCA, no objective data showing the effect has been disclosed so far. There wasn't.

[0028] Therefore, an object of the present invention is to provide a therapeutic agent for vascular lesions having high clinical utility. Specifically, it contains an imidazopyridine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, and vascular restenosis after PTCA, arteriosclerosis, peripheral arterial occlusion, periarterial nodule Vasculitis such as inflammation and cell proliferative vasculitis found in transplanted organs, and cell proliferative vascular lesions, and
The present invention relates to a preventive / therapeutic / ameliorating agent for cell proliferative vascular lesions, which has an effective Ang II receptor antagonism.

The imidazopyridine derivative compound represented by the general formula (I) has already been described in JP-A-3-236377.
It is disclosed as a therapeutic agent for hypertension based on g II receptor antagonistic action, and can be produced according to the production examples and examples described in the publication. The physical properties and Ang II receptor antagonistic activity are also described in the publication. Further, a group of compounds according to the present invention is WO 91/18639.
No. disclosed in Japanese Patent Publication No. or EP 492105
The chemical structure is completely different from that of the g II receptor antagonist.

Next, the compound according to the present invention has the following general formula:
It is represented by (I).

[0031]

[Chemical 2]

In the formula, R ¹ is a cycloalkyl group, a lower alkyl group, a lower alkoxy group, a lower thioalkoxy group or an alkynyl group, R ² is a carboxy group, a 1H-tetrazol-5-yl group or an alkoxycarbonyl group, and R ³ represents a hydrogen atom or a methyl group.

More specifically, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and lower alkyl is methyl, ethyl, n-propyl, i-propyl. Base, n-
A butyl group, an i-butyl group, a t-butyl group, an amyl group, a hexyl group and other C _{1 to} C ₆ alkyl groups, and a lower alkoxy group is a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group. , A C ₁ -C ₆ alkoxy group such as butoxy group, a lower thioalkoxy group is a thiomethoxy group, a thioethoxy group,
Examples of the alkynyl group include C _{1 to} C ₆ thioalkoxy groups such as thio-n-propoxy group, thio-i-propoxy group and thiobutoxy group, and examples of the alkynyl group include 1-propynyl group and 2-propynyl group. Further, among these, compounds having a cycloalkyl group or an n-propyl group are more preferable from the viewpoint of pharmacological activity.

The alkoxycarbonyl group in R ² means an ester group, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,
Examples thereof include butoxycarbonyl group, cyclopropaneoxycarbonyl group, cyclohexyloxycarbonyl group, phenyloxycarbonyl group, benzyloxycarbonyl group and tetrahydropyranyloxycarbonyl group.

Further, as an example of a preferable compound among these compounds, 2-cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-4-) represented by the following chemical structural formula:
Iyl) methyl] -3H-imidazo [4,5-b] pyridine (II), 2-
Cyclopropyl-7-methyl-3-[{2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl} methyl] -3H-imidazo
[4,5-b] pyridine (III), 2-n-propyl-7-methyl-3-
[{2 '-(1H-tetrazol-5-yl) biphenyl-4-yl} methyl] -3H-imidazo [4,5-b] pyridine (IV) and the like can be mentioned. It goes without saying that the compound is not limited.

[0036]

[Chemical 3]

[0037]

[Chemical 4]

[0038]

[Chemical 5]

The pharmaceutically acceptable salt is not limited as long as it can form a salt with the compound of the present invention.
For example, an alkali metal addition salt such as sodium salt and potassium salt, an alkaline earth metal addition salt such as calcium salt and magnesium salt, an ammonium salt, an amine addition salt such as ethanolamine salt, hydrochloride, sulfate, nitrate, Addition of inorganic acid such as hydrobromide, hydroiodide, perchlorate, phosphate, etc., addition of sulfonic acid such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Salts, oxalates, maleates, fumarates, succinates and other organic acid addition salts can be mentioned.

The dosage form includes, for example, powders, fine granules,
Oral and injection preparations such as granules, tablets, coated tablets, capsules and the like can be mentioned. In the case of formulation, it can be produced by a conventional method using an ordinary formulation carrier.

That is, to produce an oral formulation, the compound
(I) and an excipient, and further, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc., and then a powder, a fine granule, a granule, a tablet, a coating by a conventional method. Tablets, capsules, etc.

As the excipient, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc., and as the binder,
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc. As for the flavoring agent, cocoa powder, peppermint brain, aroma powder, peppermint oil, dragon brain, cinnamon powder and the like are used as the flavoring agent. Needless to say, these tablets and granules may be sugar-coated or may be appropriately coated if necessary.

The clinical dose of the compound (I) in the present invention varies depending on the symptoms, severity, age, complications, etc. and is not limited, but it is usually 0.1 to 1000 mg per day for an adult, It is preferably 1 to 500 mg, more preferably 5 to 100 mg, which is orally or intravenously administered.

Next, as a typical example of the compound of the present invention, 2-cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-
4-yl) methyl] -3H-imidazo [4,5-b] pyridine (II) and 2-cyclopropyl-7-methyl-3-[{2 '-(1H-tetrazol-5-yl) biphenyl-4 The results of the acute toxicity test of -yl} methyl] -3H-imidazo [4,5-b] pyridine (III) are shown.

[0045]

[Acute toxicity test] (Method) A single-dose toxicity test by oral administration was conducted using 5 male and 5 female Slc: SD rats aged 7 to 8 weeks (vehicle; physiological saline).

(Results) LD ₅₀ values (mg / Kg) are summarized in the table below.

[0047]

[Table 1]

As is clear from the table, the L
D ₅₀ value is about 100 times or more the clinical dose by oral administration,
The safety is extremely high.

Next, examples will be given below for specifically explaining the present invention, but it goes without saying that the present invention is not limited thereto.

[0050]

EXAMPLES Example 1 Tablet 2-Cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-4-yl) methyl] -3H-imidazo [4,5-b] pyridine
(II) 10 g, lactose 70 g, corn starch 20 g, carboxymethylcellulose / calcium calcium 5 g and crystalline cellulose 15 g are mixed, and 30 ml of water in which 2 g of hydroxypropylcellulose is dissolved is gradually added with stirring to granulate. The granulated product was dried overnight at 40 ° C, sieved through a 42-mesh sieve, mixed with 0.5 g of calcium stearate and compressed into tablets.
A tablet containing 10 mg of compound (II) in 122.5 mg of one tablet was obtained.

Example 2 Tablet 2-Cyclopropyl-7-methyl-3-[{2 '-(1H-tetrazol-5-yl) biphenyl-4-yl} methyl] -3H-imidazo
30 g of [4,5-b] pyridine (III), 60 g of mannitol, 25 g of corn starch, 5 g of carboxymethyl cellulose calcium and 20 g of crystalline cellulose were mixed, and 2 g of hydroxypropyl cellulose was dissolved with stirring.
Granulate by gradually adding ml. After drying the granules at 40 ° C overnight, sift through a 42-mesh sieve to remove calcium stearate.
0.5g were mixed and compressed into tablets, and the compound (II
A tablet containing 10 mg of I) was obtained.

Example 3 Tablet 2-n-propyl-7-methyl-3-[{2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl} methyl] -3H-imidazo [4,5
-b] Pyridine (IV) 10g, lactose 70g, corn starch 20
g, carboxymethyl cellulose 5 g and crystalline cellulose 15 g are mixed and stirred with polyvinylpyrrolidone
Granulate by gradually adding 30 ml of ethanol containing 2 g dissolved therein. The granulated product was dried overnight at 40 ° C, sieved through a 42-mesh sieve, mixed with 0.5 g of calcium stearate and compressed into tablets.
A tablet containing 10 mg of compound (IV) in 122.5 mg of one tablet was obtained.

[0053]

EFFECT OF THE INVENTION Next, in order to show the usefulness of the present invention for vascular restenosis after PTCA, blood vessels induced by common carotid balloon injury in a dog (beagle) model having the same Ang II production pathway as humans. An example of the effect of the compound of the present invention on the proliferation and thickening of the intima will be described.

(Method) Male and female beagle adult dogs (body weight 9.0-1
3.0 kg, 13 males, 5 females) were divided into 3 groups, A, B, and C, so that their weight and sex were even. Placebo as a control in group A, 2-group as a representative example of the compound of the present invention in group B
Cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-4-yl) methyl] -3H-imidazo [4,5-b] pyridine (I
I) (10 mg / Kg / day) was used as a representative example of ACE inhibitors in group C {(2S, 3aR, 7aS) -1-[(S) -1-carboxy-3-phenylpropyl] -alanyl}. -Ethyl hexahydro-2-indolinecarboxylate (10 mg / Kg / day)
It was placed in a capsule and orally administered once every morning.

Five days after administration, pentobarbital (30 mg /
(Kg) Anesthetized by intravenous administration, and the blood pressure was measured by inserting and placing an elastane needle in the left femoral artery in the dorsal position. Then, the right common carotid artery was reached through a midline neck incision. A small incision is made in the right common carotid artery, and an embolization catheter [(Arterial embolectomy
catheter), manufactured by Vermed; size 3F x 40 cm],
The balloon was inflated with 0.2 ml of water, and balloon injury was applied to the internal carotid / external carotid artery bifurcation on the upper side and the brachiocephalic artery bifurcation on the lower side over the entire length of the common carotid artery. The small incision hole of the artery was closed with sutures using a polypropylene single thread with a needle (Ethicon, trade name; Proline thread, size 8-O), taking care not to cause stenosis, and the blood flow was confirmed. Five days after the surgery, intramuscular injection of antibiotics and disinfection of the wound site were performed.

After the operation, the administration of the drug-containing capsule was repeated every day, and at the time of 30 days after the operation, blood pressure was directly measured under anesthesia in the same manner as the operation, and then killed by exsanguination.
The common carotid arteries on both sides were excised. The left side was used as the intact control side. Equal parts of the left and right common carotid arteries were collected and the following measurements were performed.

1) Visual observation of patent / occluded arteries

2) After formalin fixation, hematoxylin (H
ematoxylin) -Eosin staining and Weigert elastic fiber staining were performed, and digital image analyzer (Planimete
The area surrounded by the outer elastic plate (S ₁ ), the area surrounded by the inner elastic plate (S ₂ ) and the lumen area (L) are measured using (r), and (S ₁ -S ₂ ).
Is the area of the media (M) and (S ₂ -L) is the area of the neointima (N).
Was calculated as The intimal thickening was expressed as N / S ₁ and the medial thickening was expressed as M / S ₁ .

3) Arterial tissue together with nonionic surfactant
The ACE activity in the homogenized and solubilized sample was determined by Miyazaki et al.
Method [Clinical Science (Clin.Sci.),66, 39-4
5, 1984.], the CAGE activity was also determined by the method of Okunishi et al.
Chemical and Biophysical Research Komi
Communications (Biochem.Biophys.Res.Commun.),149
(3), 1186-1192, 1987.], two types of Ang II producing fermentation
The elementary activity was measured. For protein quantification, a protein measurement kit (Pi
Made by erce Chemicals, trade name; BCA Protein AssayReag
ent) was used.

(Results) 1. Blood Pressure As shown in FIG. 1, 2-cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-), a compound of the present invention, was found 5 days after continuous administration (immediately before balloon injury). 4-yl) methyl] -3H
-Imidazo [4,5-b] pyridine (II) and the control compound {(2S, 3aR, 7aS) -1-[(S) -1-carboxy-3-phenylpropyl] -alanyl} -hexahydro-2 -Ethyl indolinecarboxylate statistically significantly lowered blood pressure, but both drugs showed a tendency to decrease 35 days after administration, but it was not significant.

[0061]

[Figure 1]

2. Patency rate of injured artery The results of examining the patency / occlusion state of the artery by visual observation are as follows:
It shows in Table 2.

[0063]

[Table 2]

As is clear from Table 2, the occlusion rate of the common carotid artery on the injured side of group A administered with placebo was as high as 83%, but the compound of the present invention, 2-cyclopropyl-7-methyl-3.
-[(2'-Carboxybiphenyl-4-yl) methyl] -3H-imidazo [4,5-b] pyridine (II) was administered to group B
It was 7%, indicating a very strong effect of preventing obstruction. On the other hand, the control substance {(2S, 3aR, 7aS) -1-[(S) -1-carboxy-
Occlusion rate in group C administered with 3-phenylpropyl] -alanyl} -hexahydro-2-indolinecarboxylate was 5
It was a moderate effect of 0%. The intact control common carotid artery was patent in all 18 patients in groups A, B, and C.

3. Evaluation of blood vessel thickening by a digital image analysis device. FIG. 2 (a) shows the intimal thickening degree (N / S ₁ ) in each of A, B, and C groups, and FIG. The degree of membrane thickening (M / S ₁ ) is shown.

[0066]

[Fig. 2]

As is apparent from FIG. 2 (a), the index (N / S ₁ ) indicating the neointimal thickening was the compound (II) of the present invention.
The value of group B was statistically significantly lower than that of group A that received placebo, demonstrating the intimal thickening inhibitory effect of the compound of the present invention. On the other hand, the numerical value of the group C to which the control compound was administered was not statistically significant although there was a slight tendency of suppression as compared with the placebo group.

In the common carotid arteries on the intact side in each of A, B, and C groups, there was almost no intimal area that could be detected by the magnification used for measurement, and no abnormal intimal thickening was observed even with strong expansion. It was

As is clear from FIG. 2 (b), there is no difference in the (M / S ₁ ) value showing the degree of media thickening among the three groups, and it is the same as the (M / S ₁ ) value on the intact side. There was no difference between them. Therefore, one month after the balloon injury, the media thickening did not occur, and there was no effect of the administered drug.

4. ACE activity and CAGE activity FIG. 3 (a) shows the ACE activity in each of A, B and C groups, and FIG.
CAGE activity of each group is shown in (b).

[0071]

[Figure 3]

As is clear from FIG. 3 (a), A on the injured side
CE activity was increased about 3 to 5 times in all three groups as compared with the intact control side. However, in the group C that received the control compound, it was statistically significantly suppressed compared to the group A that received the placebo, indicating that the ACE inhibitor is effective against vascular ACE. Was done.

On the other hand, the CAGE activity also increased remarkably in all three groups, as shown in FIG. 3 (b), and the ratio of injury side / control side was 30.
It was ~ 90 times or more.

From these experimental examples of effects, 2-cyclopropyl-7-methyl-3-[(2'-carboxybiphenyl-4-yl) methyl] -3H-imidazo [4,5-b, which is the compound of the present invention, was obtained. ] Pyridine (II) appears to strongly suppress intimal thickening caused by balloon injury. On the other hand, a typical example of the ACE inhibitor used as a control compound is {(2S, 3aR, 7aS) -1-
[(S) -1-Carboxy-3-phenylpropyl] -alanyl}-
The effect of ethyl hexahydro-2-indolinecarboxylate was weak, which is in good agreement with the above-mentioned results of clinical trials of ACE inhibitors for vascular restenosis after PTCA.

As shown in FIG. 3 (b), the reason why the compound of the present invention was obviously more effective than the ACE inhibitor was that the CAGE activity at the injury site was significantly increased and the resulting Ang II was obtained. Overproduction. That is,
As is clear from FIGS. 3 (a) and 3 (b), the CAGE activity is significantly higher than the ACE activity in the damaged site of the blood vessel, and as a result, Ang II is overproduced. Therefore, such an ACE inhibitor that inhibits only ACE activity cannot improve such an Ang II overproduction state. But An
Since the g II receptor antagonist inhibits the action at the receptor regardless of the Ang II production pathway, it can be expected to be useful clinically, and its effect is clear from the results of the above experimental examples.

[0076]

[Brief description of drawings]

FIG. 1 is a diagram comparing the mean blood pressure in each group after 5 days of continuous drug administration (immediately before balloon injury) and 35 days after administration (30 days after injury). (N = 6 for each group, shown as mean ± standard error)

[Fig. 2] Intimal thickness (N / S ₁ ) and media thickness (M / S) of each group
It is the figure which compared ₁ ). (N = 6 for each group, shown as mean ± standard error)

FIG. 3 is a diagram comparing the ACE activity and CAGE activity of the blood vessel wall of each group. (N = 6 for each group, shown as mean ± standard error)

Claims (7)

[Claims] 1. A therapeutic agent for vascular lesions comprising a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical 1] [Wherein R ¹ is a cycloalkyl group, a lower alkyl group, a lower alkoxy group, a lower thioalkoxy group or an alkynyl group, R ² is a carboxy group, a 1H-tetrazol-5-yl group or an alkoxycarbonyl group, and R ³ is It means a hydrogen atom or a methyl group. ] 2. The therapeutic agent for vascular lesion according to claim 1, which is an agent for preventing vascular restenosis after percutaneous coronary angioplasty. 3. A preventive, therapeutic or improving agent for a disease selected from the group consisting of arteriosclerosis, peripheral arterial occlusion, nodular periarteritis and vasculitis such as cell proliferative vasculitis found in transplanted organs. The therapeutic agent for vascular lesion according to claim 1. 4. A preventive / therapeutic / ameliorating agent for vascular lesions having an angiotensin II receptor antagonistic effect, which comprises the compound (I) according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 5. The compound (I) is 2-cyclopropyl-7-methyl-3-[(2′-carboxybiphenyl-4-yl) methyl] -3H.
-A therapeutic agent for vascular lesions according to claim 1, which is imidazo [4,5-b] pyridine. 6. The compound (I) is 2-cyclopropyl-7-methyl-3-[{2 ′-(1H-tetrazol-5-yl) biphenyl-4-
The therapeutic agent for vascular lesions according to claim 1, which is yl} methyl] -3H-imidazo [4,5-b] pyridine. 7. The compound (I) is 2-n-propyl-7-methyl-3.
The therapeutic agent for vascular lesions according to claim 1, which is-[{2 '-(1H-tetrazol-5-yl) biphenyl-4-yl} methyl] -3H-imidazo [4,5-b] pyridine.