JP2798005B2 - Agent for treating / preventing diseases caused by smooth muscle cell proliferation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic / prophylactic agent for diseases caused by smooth muscle cell proliferation, and more particularly to diseases caused by smooth muscle cell proliferation containing a specific aminopyridazine derivative or a salt thereof as an active ingredient. A therapeutic or prophylactic agent.

[0002]

2. Description of the Related Art In recent years, as a method for surgically treating a narrowed blood vessel, percutaneous coronary dilatation (Percutaneous Tra) has been proposed.
nsluminal Coronary Angiop
lasty: PTCA), percutaneous arterial dilatation (Perc)
utaneous Transluminal Ang
ioplasty (PTA) is becoming widespread. In these methods, a balloon catheter is remotely inserted from a femoral artery or the like, the balloon is inflated at the stenosis, and the blood vessel is physically expanded. However, with this treatment, stenosis may occur again 3 to 6 months after the treatment. In this restenosis, no cholesterol deposition is observed, but rather so-called fibrous intimal hyperplasia composed mostly of smooth muscle cells and the intercellular matrix produced by these cells (Journal of American).
an College of Cordiology
vol. 23, (6), 1278-1288, 199
4, May). In addition, vascular stenosis after transplantation of organs such as heart, liver, kidney, and blood vessels is also caused by proliferation of smooth muscle cells (FASEB Journalvol 7, 1055).
-1060, 1993, August).

[0003] Therefore, as a method for treating and preventing restenosis after PTCA operation and PTA operation and vascular stenosis after organ transplantation, it is effective to suppress the migration and proliferation of smooth muscle cells generated in the blood vessel lumen. it was thought. In order to solve such a problem, a search for a drug has been carried out.
-38715, JP-A-2-121922, JP-A-3
-83923, JP-A-3-83957, JP-A-3-3-957
118383, JP-A-4-99775, JP-A-4-99775
154720 publications, etc.), which have not yet been developed.

[0004] On the other hand, various pharmacological actions have been reported for various phthalazine derivatives. For example, JP-A-56-
No. 53659, JP-A-56-53660 and JP-A-57-48972 disclose 1-anilino-4.
-Phenylphthalazine derivatives are disclosed in JP-A-60-21.
JP-A-8377 and JP-A-60-243074 disclose that the following two compounds have potent platelet aggregation inhibitory activity in vitro.

[0005]

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[0006]

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[0007] British Patent No. 1303016, Journal of Medicinal Chemistry (J. Med. C)
hem. ), 12,555 (1969), etc., only describe the anti-inflammatory and anti-lithium effects of the 1-amino-4-phenylphthalazine derivative.

Further, European Patent Publication No. 449203
(JP-A-4-21666) discloses a 1-α-substituted benzylamino-4-phenylphthalazine derivative, and EP-A-534443 discloses a 3,6-disubstituted pyridazine derivative. . Both have strong platelet aggregation inhibitory effects, and are effective against cerebrovascular disorders such as cerebral thrombosis and cerebral embolism, ischemic heart diseases such as myocardial infarction, and circulatory disorders such as peripheral circulatory disorders. It is disclosed that can be expected. However, it has not been known that these phthalazine derivatives have a smooth muscle cell proliferation inhibitory action.

[0009]

Means for Solving the Problems The inventors of the present invention have been studying for the purpose of solving the above-mentioned problems, and as a result, it has been found that aminopyridazine derivatives which are known to have platelet aggregation inhibitory action are produced in the lumen of blood vessels. The present inventors have found for the first time that they have an action of suppressing the proliferation of smooth muscle cells, and have completed the present invention. That is, the gist of the present invention is represented by the following general formula (I)

[0010]

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In the above formula, R¹Is a cyclohexyl group; C
₁~ C_FourAn alkyl group of C₁~ C_FourAlkoxy group and
And one or more substituents selected from
A phenyl group; C₁~ C_FourAn alkyl group of C₁~
C_Four1 selected from an alkoxy group and a halogen atom
A thienyl group optionally having the above substituents; or C
₁~ C_FourAn alkyl group of C₁~ C_FourAlkoxy group and
And one or more substituents selected from
Represents a furyl group which may be^TwoIs -CHR^ThreeR^Four(R^Three
Is a hydrogen atom or C₁~ C_FourRepresents an alkyl group of^Four
Is C₁~ C_FourAlkyl group; cyclohexyl group; thienyl
Or a C group₁~ C_FourAn alkyl group of C ₁~ C_FourNo
One or more positions selected from alkoxy groups and halogen atoms
Represents a phenyl group which may have a substituent. ) Or C
₁~ C_FourAn alkyl group of C₁~ C_FourAlkoxy group and
And C₁~ C₆One or more substituents selected from alkylene groups of
Represents a cyclohexyl group which may have a group, and ring A is
Represents a benzene ring, a thiophene ring or a furan ring. }so
An aminopyridazine derivative represented by the formula
For treatment and prevention of diseases caused by smooth muscle cell proliferation
Exists.

Hereinafter, the present invention will be described in detail. The therapeutic / prophylactic agent for a disease caused by smooth muscle cell proliferation of the present invention,
The aminopyridazine derivative of the above general formula (I) or a salt thereof is used as an active ingredient. As the C ₁ -C ₄ alkyl group in the above general formula, a methyl group, an ethyl group, an n-propyl group,
i-propyl group, n-butyl group, t-butyl group and the like. As the C ₁ -C ₄ alkoxy group, a methoxy group,
Ethoxy, n-propoxy, i-propoxy, n
-Butoxy group, t-butoxy group and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. As the C ₁ -C ₆ alkylene group, any 2
And those in which two substituents are linked to represent a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a propylene group, an ethylethylene group, a dimethylmethylene group, or the like.

R¹Is a phenyl group, a 2-thienyl group
Or a 2-furyl group is preferred, and a phenyl group is particularly preferred.
New R^TwoIs -CHR^Three'R^Four'(R^Three'Is C₁
~ C _FourRepresents an alkyl group of^Four'Is a cyclohexyl group
Represents ) Is preferred, especially

[0014]

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Is preferred. As the ring A, a compound representing a benzene ring or a thiophene ring is preferable, and a benzene ring is particularly preferable.

Salts which can be formed by the aminopyridazine derivative of the general formula (I) include, for example, hydrochloride, hydrobromide,
Salts of inorganic acids such as hydroiodide, sulfate, phosphate, or methanesulfonate, p-toluenesulfonate,
Benzenesulfonate, camphorsulfonate, acetate, benzoate, malate, lactate, glycolate, glucuronate, maleate, fumarate, oxalate, ascorbate, citric acid Salts of organic acids such as salt, salicylate, nicotinate, tartrate and the like can be mentioned. Since the compound of the general formula (I) and a salt thereof may exist in the form of a hydrate or a solvate, these hydrates and solvates are also included in the compound of the present invention.

Further, when an asymmetric carbon is present in the aminopyridazine derivative of the general formula (I), the (R) form,
Any of the (S) form and (RS) form can be used, and these are all included in the compound as the active ingredient of the present invention. Specific examples of diseases caused by smooth muscle cell proliferation include restenosis after PTCA operation, vascular stenosis after transplantation of organs such as heart, liver, kidney, and blood vessels, and restenosis after PTA operation. Table 1 below shows specific examples of the aminopyridazine derivative of the present invention.

[0018]

[Table 1]

[0019]

[Table 2]

[0020]

[Table 3]

[0021]

[Table 4]

[0022]

[Table 5]

[0023]

[Table 6]

Such an aminopyridazine derivative is a compound described in European Patent Publication Nos. 449203 and 534443, and any compound can be synthesized according to the method described in the publication. The therapeutic / prophylactic agent for diseases caused by smooth muscle cell proliferation of the present invention is effective against various diseases caused by migration and proliferation of smooth muscle cells generated in a blood vessel lumen. Specifically, it is used for prevention or treatment of restenosis after PTCA operation, restenosis after percutaneous arterial dilatation (PTA), and vascular stenosis after transplantation of organs such as heart, liver, kidney and blood vessels. .

When the aminopyridazine derivative of the present invention is used orally in the clinical application as a therapeutic / preventive agent for diseases caused by proliferation of smooth muscle cells, 1 to 200 mg once daily for adults is used. It is preferably administered three times,
In the case of intravenous injection, once per adult 0.01-10mg
Is preferably administered 1 to 5 times a day or continuous infusion of 0.01 to 50 mg a day. In the case of rectal administration,
It is preferable to administer 1 to 100 mg at a time, 1 to 3 times a day. Further, it is more preferable that the above dose is appropriately increased or decreased depending on age, disease state and symptoms.

In formulating, one or more aminopyridazine derivatives or pharmaceutically acceptable salts thereof are mixed with commonly used pharmaceutical carriers, excipients and other additives. The carrier may be solid or liquid. Examples of solid carriers include lactose, white clay (kaolin), sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, sodium chloride, etc. Is mentioned.

Examples of the liquid carrier include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like. Pharmaceutical preparations can take a variety of dosage forms, including tablets, powders, granules, hard gelatin capsules, suppositories, or troches when using solid carriers. The amount of solid carrier may vary widely but preferably will be from about 1 mg to about 1 g.
When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous suspension.

[0028]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the invention.

Synthesis Example (R) -1- (1-cyclohexylethylamino) -4
-Phenylphthalazine ｛Compound N in Table 1 above
o. Synthesis of fumarate salt of (R) -form 17 of the present invention (hereinafter abbreviated as “compound A”). 144.4 g (0.6 mol) of 1-chloro-4-phenylphthalazine was added to 400 ml of N-methylpyrrolidone,
(R)-(-)-1-cyclohexylethylamine 23
After adding 0 g (1.8 mol), the mixture was
The mixture was heated and stirred at 130 ° C. for 6 hours. After completion of the reaction, the mixture was cooled, 4.0 l of a 5% aqueous NaOH solution was added, and the mixture was extracted with chloroform. The organic layer was dried over MgSO ₄ , concentrated, purified by silica gel column chromatography (eluent, ethyl acetate: hexane: chloroform = 1: 3: 1), recrystallized from ether-chloroform,
(R) -1- (1-cyclohexylethylamino) -4
-150.2 g of phenylphthalazine was synthesized. Melting point 1
64.0-167.0 ° C

The thus obtained (R) -1- (1-cyclohexylethylamino) -4-phenylphthalazine 1
00.0 g and fumaric acid 32.0 g in methanol 1.0 l
And stirred under reflux for 16 hours. The mixture was allowed to cool to 20 ° C. while stirring, and the crystals were collected by filtration.
1 and dried at about 60 ° C. and 1-2 mmHg to obtain 121.5 g of fumaric acid. 240-250 ° C (decomposition)

Example 1 Effect on rat intimal hypertrophy model An SD rat (20 weeks old) under pentobarbital anesthesia was fixed in a dorsal position to expose the left carotid artery. A Fogarty catheter for removing thrombus (2 French) was inserted into the aortic bifurcation (about 5 cm) from the external carotid artery without inflating the balloon. The balloon was inflated and pulled to the insertion section while rotating. This operation was repeated three times to detach the endothelial cells of the carotid artery. After the operation, pull out the catheter,
The external carotid artery was ligated and the incision was closed with a medical clip. Compound A is suspended in a 0.7% tragacanth solution,
They were orally administered once daily at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg. A 0.7% tragacanth solution was similarly orally administered to the control group. On the first day,
Immediately after carotid intima detachment.

Two weeks after the intimal detachment, 3% Evans blue was intravenously administered through the femoral vein under pentobarbital anesthesia. Thirty minutes later, the abdomen was opened, the whole body was perfused from the aorta with 0.01 M phosphate buffer, and the carotid artery was extracted. The portion of the carotid artery from which endothelial cell detachment was confirmed was formed into 6 to 8 pieces of artery having a length of 2 mm, fixed with formalin, and then embedded in paraffin. A tissue section of a cross section was prepared from each block and stained with Elastica-Wangiesson. The area of the intima / media in each section was measured with a digitizer, and the degree of intimal hyperplasia was represented by the area ratio of intima / media. Table 2 shows the results. Compound A dose-dependently inhibited intimal thickening of rat carotid artery due to intimal detachment.

[0033]

[Table 7] *; P <0.05 (Test method) One-way analysis of variance Dunnett type

Example 2 Effect on Rat Intimal Hyperplasia Model An SD rat (20 weeks old) under pentobarbital anesthesia was fixed in a dorsal position to expose the left carotid artery. A Fogarty catheter for removing thrombus (2 French) was inserted into the aortic bifurcation (about 5 cm) from the external carotid artery without inflating the balloon. The balloon was inflated and pulled to the insertion section while rotating. This operation was repeated three times to detach the endothelial cells of the carotid artery. After the operation, pull out the catheter,
The external carotid artery was ligated and the incision was closed with a medical clip. Compound A is suspended in a 0.7% tragacanth solution,
A dose of 3 mg / kg was orally administered once a day, and a control group was similarly orally administered a 0.7% tragacanth solution. In group A, the first administration was performed immediately after carotid intima detachment,
In the group, the treatment started 4 days after carotid intimal detachment. Two weeks after the intimal detachment, 3% Evans blue was intravenously administered through the femoral vein under pentobarbital anesthesia. Thirty minutes later, the abdomen was opened, the whole body was perfused from the aorta with 0.01 M phosphate buffer, and the carotid artery was extracted.

The removed carotid artery where endothelial cell detachment was confirmed was formed into 6 to 8 pieces of 2 mm long artery, fixed in formalin, and embedded in paraffin. A tissue section of a cross section was prepared from each block and stained with Elastica-Wangiesson. The area of the intima / media in each section was measured with a digitizer, and the degree of intimal hyperplasia was represented by the area ratio of intima / media. Table 3 shows the results. Compound A is 3 mg / k
By oral administration of g, carotid intimal hypertrophy due to intimal detachment was suppressed in rats, and administration was significant 4 days after carotid intimal detachment.

[0036]

[Table 8] *; P <0.05 (Test method) One-way analysis of variance Dunnett type

[0037]

EFFECTS OF THE INVENTION The aminopyridazine derivative inhibits the migration and proliferation of smooth muscle cells, so that diseases caused by smooth muscle cell proliferation, such as restenosis after percutaneous coronary dilatation (PTCA), heart, liver, It is useful for prevention or treatment of vascular stenosis after transplantation of organs such as kidneys and blood vessels, and restenosis after percutaneous arterial dilatation (PTA).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 409/04 237 C07D 409/04 237 495/04 105 495/04 105Z // C07D 491/048 C07D 491/048 (C07D 405 / 04 237: 34 307: 36) (C07D 409/04 237: 34 333: 10) (72) Inventor Tokumichi Iwase 1000 Kamoshida-cho, Aoba-ku, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Research Institute Yokohama Research Laboratory (56) References JP-A-6-329540 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/50 C07D 237/34 C07D 405/04 237 C07D 409/04 237 C07D 495/04 105 C07D 491/048 C07D 405/04 C07D 409/04 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (11)

(57) [Claims] 1. A compound represented by the following general formula (I)中 で In the above formula, R¹Is a cyclohexyl group; C₁~ C_Fourof
Alkyl group, C₁~ C_FourAlkoxy groups and halogens
A group which may have one or more substituents selected from atoms
Enyl group; C₁~ C_FourAn alkyl group of C₁~ C_FourAl
At least one substitution selected from a oxy group and a halogen atom
A thienyl group optionally having a group; or C₁~ C_Fourof
Alkyl group, C₁~ C_FourAlkoxy groups and halogens
A group which may have one or more substituents selected from atoms
Represents a lyl group;^TwoIs -CHR^ThreeR ^Four(R^ThreeIs a hydrogen atom
Or C₁~ C_FourRepresents an alkyl group of^FourIs C₁~ C
_FourAn alkyl group; a cyclohexyl group; a thienyl group;
Is C₁~ C_FourAn alkyl group of C₁~ C_FourAn alkoxy group
And one or more substituents selected from halogen atoms
Represents an optionally substituted phenyl group. ) Or C₁~ C_Fourof
Alkyl group, C₁~ C _FourAn alkoxy group and C₁~ C
₆Having one or more substituents selected from alkylene groups of
Represents an optionally substituted cyclohexyl group, and ring A is benzene
Represents a ring, a thiophene ring or a furan ring. Represented by｝
Aminopyridazine derivative or salt thereof as active ingredient
An agent for treating / preventing diseases caused by smooth muscle cell proliferation. Wherein R ² is ^{-CHR 3 'R 4' (R} 3 ' is C
₁ represents an alkyl group of ~C ^_4, R ₄ 'represents a cyclohexyl group. 2. The therapeutic or preventive agent for a disease caused by smooth muscle cell proliferation according to claim 1, wherein 3. The method according to claim 1, wherein R ¹ represents a phenyl group, a 2-thienyl group or a 2-furyl group. 4. The therapeutic or prophylactic agent for a disease caused by smooth muscle cell proliferation according to claim 1, wherein R ¹ represents a phenyl group. 5. The therapeutic or preventive agent for a disease caused by smooth muscle cell proliferation according to claim 1, wherein ring A represents a benzene ring or a thiophene ring. 6. The therapeutic or preventive agent for a disease caused by smooth muscle cell proliferation according to claim 1, wherein ring A represents a benzene ring. 7. R ¹ represents a phenyl group, and R ² represents And the ring A represents a benzene ring. The therapeutic / prophylactic agent for diseases caused by smooth muscle cell proliferation according to claim 1, wherein the ring A represents a benzene ring. 8. Treatment and prevention of a disease caused by proliferation of smooth muscle cells containing (R) -1- (1-cyclohexylethylamino) -4-phenylphthalazine or a pharmaceutically acceptable salt thereof as an active ingredient. Agent. 9. The therapeutic / prophylactic agent according to claim 1, wherein the disease caused by smooth muscle cell proliferation is restenosis after percutaneous coronary dilatation. 10. The therapeutic / prophylactic agent according to claim 1, wherein the disease caused by smooth muscle cell proliferation is vascular stenosis after organ transplantation. 11. The therapeutic / prophylactic agent according to claim 1, wherein the disease caused by smooth muscle cell proliferation is restenosis after percutaneous arterial dilatation.