JPH06172173A - Agent for treatment of pulmonary hypertension - Google Patents

Abstract

PURPOSE:To obtain the subject treating agent having low toxicity and excellent therapeutic effect by using a specific compound (salt) as an active component. CONSTITUTION:The objective agent contains, as an active component, a compound of formula I [A is OH, OC(O)CH3-nXn (X is F, Cl, Br, methyl, etc.; n is 0-3), etc.; B is H or together with A form a bond; when R<1> is H, R<2> is H, C(Z)CH3-nXn (Z is O or S) or C(Z)NHCH3-nXn and, when R<1> is not H, R<1> and R<2> together form (CH2)m (m is 4 or 5); R<3> and R<4> are H, 1-4C alkyl, etc.], a compound of formula II, etc., or its pharmaceutically permissible salt when the above compound can form a salt. The active component is preferably administered at a daily dose of 0.01-10mg in one or several divided doses.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for treating pulmonary hypertension characterized by using a pyranobenzoxadiazole derivative as an active ingredient and a pharmaceutical composition containing the same as an active ingredient. Regarding things.

[0002]

2. Description of the Related Art European Patent No. 327127 and American Patent No. 4900752 disclose that a pyranobenzoxadiazole derivative has a strong K-channel activating effect, and has a circulatory system such as hypertension, angina, and arrhythmia. It discloses possible uses for the treatment of disorders, but does not mention possible treatment of pulmonary hypertension.

On the other hand, it has been disclosed that a benzopyran derivative known to activate K-channel may be effective for treating pulmonary hypertension (European Patent 41343).
No. 8) is not clear about the correlation between both actions.

[0004]

[Problems to be Solved by the Invention] Pulmonary hypertension is defined as a mean pulmonary arterial pressure of 25 mmHg or more and develops when there is a continuous increase in pressure in the pulmonary small arteries or pulmonary veins.
The cause of the onset is not always clear, and there is no fundamental cure, and exercise restrictions in daily life, elimination of psychological anxiety factors, etc., drug administration of diuretics and vasodilators, or oxygen Inhalation is performed. Recently, surgical treatment such as simultaneous cardiopulmonary transplantation may be performed.

[0006] For drug therapy of pulmonary hypertension, Ca ⁺⁺ antagonists such as nifedipine, ACE inhibitors such as captopril, and vasodilators such as hydralazine are used, but these drugs are generally selective for the pulmonary artery. Is low and there are many cases where it does not react.

The present inventors have conducted extensive research into compounds capable of treating pulmonary hypertension and found that the pyranobenzoxadiazole derivative represented by the general formula (I) has a strong antipulmonary hypertensive effect. Was completed.

[0007]

[Means for Solving the Problems]

 The compounds according to the present invention have the general formula (I)

[0008]

[Chemical 5]

[Wherein A represents OH or OC (O) CH _3-n X _n (X represents a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, and n represents an integer of 0 to 3) Or together with B means a bond; B means a hydrogen atom or together with A means a bond; and when R ¹ is a hydrogen atom, R ² is Hydrogen atom, C (Z) CH _3-n X _n (Z means an oxygen atom or a sulfur atom) or C (Z) NHCH _3-n X _n ; R ¹ when R ¹ is not a hydrogen atom And R ² together (C
H ₂ ) _m (m means 4 or 5), (CH ₂ ) _m-1 C (Z), N
(R ⁵ ) (CH ₂ ) ₂ C (Z) (R ⁵ represents a hydrogen atom or a methyl group.), (CH ₂ ) _m-2 NHC (Z) or (CH ₂ ) _m-2 OC (Z ) Means; R
³ and R ⁴ are the same or different from each other, a hydrogen atom or C ₁
You mean -C ₄ alkyl group, R ³ and R ⁴ together may be substituted by C ₁ -C ₄ alkyl group 1,
It means 4-butylene group or 1,5-pentylene group. ]
Or a pharmaceutically acceptable salt of the compound which can form a salt thereof, and the production method thereof is described in detail in EP 327127 and US Pat.

The compound used in the present invention has an asymmetric center and has optical isomers, but the present invention also includes these optical isomers. For the production method of optical isomers, see
3-141286, U.S. Pat. No. 5097037, and European Patent 409165. An object of the present invention is to use a compound represented by the general formula (I), or a pharmaceutically acceptable salt when it can form a salt, as an active ingredient, a method for treating pulmonary hypertension, And a pharmaceutical composition containing them as an active ingredient.

The pharmaceutical composition referred to herein includes oral agents such as tablets and syrups, as well as parenteral agents such as ointments, creams, lotions, pastes, jellies, gels, mousses and aerosols. In the present invention, the content of the compound of general formula (I) is 0.005% to 10%, preferably 0.05% to 3%, and the applied amount is 0.001 mg to 100 mg per day, preferably 0.01%.
The dosage is in the range of 10 mg to 10 mg, and it is applied once or several times a day, but it can be increased or decreased in consideration of the patient's symptoms, body weight, age, sex and the like.

The compound used in the present invention is R¹Is hydrogen
As a child, R²Is COCH₃, COCH₂CH₃, COCH₂F, COCF₃, COCH₂
Cl, CONHCH₃Is preferred, R¹Is a hydrogen atom, R¹
And R²Together- (CH₂)₃CO-,-(CH₂)_FourCO-,-(CH₂)₃O
CO-, -NH (CH₂)₂CO-,-(CH₂) _Four-,-(CH₂)_Five-I like
Yes. R³And R^FourIs C₁~ C_FourAlkyl group is preferred, methyl
Radicals and ethyl radicals are particularly preferred. With particularly preferred compounds
And compounds represented by formulas (II), (III) and (IV)
Can be mentioned.

[0013]

[Chemical 6]

These compounds are described in European patent 327127.
As disclosed in U.S. Pat. No. 4,962,849 and U.S. Pat. No. 4,900,752, it has low toxicity and can be used as a medicine. Next, test examples and formulation examples will be shown, but the present invention is not limited to these examples.

[0015]

【Example】

(Test Example) Male mature Sprague-Dawley rats were bred under a low pressure equivalent to 17,000 ft for 3 to 4 weeks to prepare chronic hypoxic pulmonary hypertensive rats. Pulmonary artery pressure was measured with a Statham transducer with a catheter placed in the pulmonary artery.

The drug is a solvent (polyethylene glycol 40
It was dissolved in 0: ethanol: water = 2: 3: 5) and was cumulatively administered at 10-minute intervals. Compound represented by formula (III) (NIP
-121) and the representative Ca ⁺⁺ antagonist nifedipine (formula V) are shown in Fig. 1. NIP-121 showed a clear mean pulmonary arterial pressure-lowering effect at doses of 10 μg / kg or higher, but no decrease was observed even after administration of 1,000 μg / kg of nifedipine.

From the above, it can be seen that the compound of the present invention has a strong anti-pulmonary hypertensive effect.

[0018]

[Chemical 7]

(Formulation Example) Formulation Example 1 Tablets Compound represented by Formula (III) 10 g Lactose 260 g Microcrystalline cellulose 600 g Corn starch 350 g Hydroxypropyl cellulose 100 g CMC-Ca 150 g (Carboxymethylcellulose Calcium) Magnesium stearate 30 g ───── ───────────────── Total amount 1,500 g After mixing the above ingredients by a conventional method, 10,000 sugar-coated tablets each containing 1 mg of the active ingredient were produced.

Formulation Example 2 Capsules Compound represented by the formula (III) 10 g Lactose 440 g Microcrystalline cellulose 1,000 g Magnesium stearate 50 g ─────────────────────── -Total amount 1,500 g The above ingredients were mixed by a conventional method, and then filled into gelatin capsules to prepare 10,000 capsules containing 1 mg of the active ingredient in each capsule.

Formulation Example 3 Ointment Compound represented by formula (III) 1.0 g Liquid paraffin 10.0 g Cetanol 20.0 g White petrolatum 68.4 g Ethyl paraben 0.1 g l-Menthol 0.5 g ──────── ──────────────── Total amount 100.0 g The above ingredients were mixed by a conventional method to prepare a 1% ointment.

Formulation Example 4 Liquid formulation Compound of formula (III) 5 g Propylene glycol 205 g Ethyl alcohol 790 g ─────────────────────── Total amount 1,000 g Above The ingredients were mixed by a conventional method to give a 0.5% liquid preparation.

Formulation Example 5 Aerosol Compound represented by formula (III) 1 g Perfume 1 g Ethyl alcohol 398 g Propellant F12 / 11, 80/20 600 g ────────────────────── --- Total amount 1,000 g The above components were mixed by a conventional method to give a 0.1% aerosol.

[0024]

[Brief description of drawings]

FIG. 1 shows the mean pulmonary arterial pressure when a compound represented by formula (III) (NIP-121) and a representative Ca ⁺⁺ antagonist nifedipine (formula V) were administered.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): [In the formula, A represents OH or OC (O) CH _3-n X _n (X represents a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group,
n means an integer of 0 to 3. ), Or together with B means a bond; B means a hydrogen atom,
Means a bond together with A; R ² when R ¹ is a hydrogen atom
Means a hydrogen atom, C (Z) CH _3-n X _n (Z means an oxygen atom or a sulfur atom) or C (Z) NHCH _3-n X _n ; R ¹ when R ¹ is not a hydrogen atom ¹ and R ² are taken together to form (CH ₂ ) _m (m means 4 or 5), (CH ₂ ) _m-1 C (Z), N (R ⁵ ) (CH ₂ ) ₂ C ( Z)
(R ⁵ represents a hydrogen atom or a methyl group.), (CH ₂ ) _m-2
NHC (Z) or (CH ₂ ) _m-2 OC (Z); R ³ and R ⁴ are the same or different from each other, and each represent a hydrogen atom or a C ₁ -C ₄ alkyl group, or R ³ And R ⁴ together represent a 1,4-butylene group or a 1,5-pentylene group optionally substituted by a C ₁ -C ₄ alkyl group. ] The pulmonary hypertension therapeutic agent which uses the compound represented by these, or its salt which can form a pharmaceutically acceptable salt as an active ingredient. 2. R in the general formula (I)¹Is a hydrogen atom, R²
Is COCH₃, COCH₂CH₃, COCH₂F, COCF₃, COCH₂Cl or
CONHCH₃Is a compound, or R¹And R²Together- (C
H₂)₃CO-,-(CH₂)_FourCO-,-(CH₂)₃OCO-, -NH (CH₂)₂CO-,-
(CH₂)_Four-,-(CH ₂)_Five-A claim that the compound is the active ingredient
Item 2. A therapeutic agent for pulmonary hypertension according to item 1. 3. In the general formula (I), R ¹ is a hydrogen atom, R ²
The therapeutic agent for pulmonary hypertension according to claim 1, which comprises a compound represented by the formula (II) in which is CH ₃ CO as an active ingredient. [Chemical 2] 4. The compound represented by the formula (III), wherein R ¹ and R ² in the general formula (I) are — (CH ₂ ) ₄ CO— together as an active ingredient. Remedy for pulmonary hypertension. [Chemical 3] 5. The compound represented by the formula (IV), wherein R ¹ and R ² in the general formula (I) are taken together to be — (CH ₂ ) ₃ CO—, as an active ingredient. Remedy for pulmonary hypertension. [Chemical 4]