WO1994012503A1

WO1994012503A1 - Pulmonary hypertension remedy

Info

Publication number: WO1994012503A1
Application number: PCT/JP1993/001757
Authority: WO
Inventors: Masahiko Oka; Kiyotomo Seto
Original assignee: Nissan Chemical Industries, Ltd.
Priority date: 1992-12-03
Filing date: 1993-12-02
Publication date: 1994-06-09
Also published as: JPH06172173A

Abstract

A pulmonary hypertension remedy containing an active ingredient comprising a compound represented by general formula (I) or, if it can form a salt, a pharmaceutically acceptable salt thereof, both of which have a potent pulmonary hypertension resistance and are reduced in toxicity, thus being useful for treating pulmonary hypertension, wherein A represents OH or OC(O)CH3-nXn (wherein X represents fluorine, chlorine, bromine, methyl or methoxy; and n represents an integer of 0 to 3) or A may be combined with B to represent a bond; B represents hydrogen or may be combined with A to represent a bond; when R1 represents hydrogen, then R2 represents hydrogen, C(Z)CH¿3-n?Xn (wherein Z represents oxygen or sulfur) or C(Z)NHCH3-nXn; when R?1¿ does not represent hydrogen, then R?1 and R2¿ are combined together to represent (CH¿2?)m (wherein m represents 4 or 5), (CH2)m-1 C(Z), N(R?5)(CH¿2)2C(Z) (wherein R5 represents hydrogen or methyl), (CH¿2?)m-2NHC(Z) or (CH2)m-2OC(Z); and R?3 and R4¿, which may be the same or different from each other, each represents hydrogen or C¿1?-C4 alkyl, or alternatively R?3 and R4¿ are combined together to represent 1,4-butylene or 1,5-pentylene which may be each substituted by C¿1?-C4 alkyl.

Description

Description Lung height] fiLff ^ therapeutic agent

The present invention relates to a method for treating pulmonary hyper-JflDE, which is characterized by using a viranobenzoxadiazole derivative as an active ingredient, and to a pharmaceutical, which is characterized by containing them as an active ingredient. Background art

Patents 327127 and Amerili Patent 4900752 disclose that pyranoben zooxadiazole derivatives have a strong K-channel activating effect, and that circulatory system such as high JfilflE disease, angina pectoris, arrhythmia, etc. It discloses the possibility of being used to treat disorders, but does not mention the possibility of treating pulmonary bleeding.

On the other hand, it has been disclosed that benzopyran derivatives, which are known to activate K-channels, may be effective in treating pulmonary hypertension (Japanese Patent No. 413438 discloses a correlation between the two effects). Absent.

High pulmonary jfiLE disease is defined as a mean pulmonary artery pressure of 25 ramHg or higher and occurs when there is a sustained increase in pulmonary arterioles or pulmonary veins. The cause of the onset is not always clear, and there is no fundamental treatment method.In addition to restricting exercise in daily life, eliminating mental anxiety factors, etc., administration of diuretics and vasodilators Or oxygen inhalation is performed. Recently, surgical procedures such as simultaneous cardiopulmonary transplantation have been performed. For pharmacological treatment of pulmonary hypertension, Ca ⁺⁺ antagonists such as difudipine, ACEP and harmful drugs such as captopril, and vasodilators such as hydralazine are used. The selectivity for the pulmonary artery is low, and it often does not respond. Disclosure of the invention

The present inventors have intensively searched for a compound capable of treating pulmonary hypertension. Was completed.

The compound according to the present invention has the general formula (I)

[In the formula, A 0H or _{_{0C (0) CH 8 - n}} X n (X denotes a fluorine atom, a chlorine atom, a bromine atom, methylcarbamoyl group or a methoxy group, n represents an integer of 0-3 ) Means together with B means a bond;

B means a hydrogen atom or, together with A, means a bond;

When R ¹ is a hydrogen atom and R ² represents a hydrogen _{atom, C (Z) CH 8 -} n X n (Z means an oxygen atom or a sulfur atom.) Or C (Z) NHCH ₈ - means _n X _n ;

When R ¹ is not a hydrogen atom, R ¹ and R ² are joined together (m means 4 or 5), (CH ^^ iXZ), N (R ⁵ ) (CH ₂ ) ₂ C (Z ) (R ⁵ represents a hydrogen atom or a methyl group.) Or (CH ₂ ) _m -Z) or (CH ₂ ) _m - ₂₀ C (Z);

R ³ and R ⁴ are the same as or different from each other, and each represents a hydrogen atom or a ^ alkyl group, or R ³ and R ⁴ are taken together and are substituted with an alkyl group. 1,4-butylene or 1,5-pentylene. Or a salt capable of forming a compound represented by the formula (1), which is an acceptable salt, and details of its production method are described in Japanese Patent No. 327127 and Patent No. 4900752 ^^. It is described in.

Further, the compound used in the present invention has an asymmetric center and has optical isomers, and the present invention also includes these optical isomers. The method for producing optical isomers is disclosed in US Pat. No. 5,097,037 and EP 409165.

An object of the present invention is to provide a method for treating pulmonary hypertension, which comprises using, as an active ingredient, a compound represented by the general formula (I) or a salt thereof when a salt can be formed. And a pharmaceutical characterized by containing them as an active ingredient.

The medical products mentioned here include oral preparations such as tablets and syrups, as well as parenteral preparations such as ointments, creams, lotions, pastes, jellies, gels, mousses, and aerosols.

In the present invention, the content of the compound of the formula (I) is 0.005% to 10%, preferably 0.05% to 3%, and the application amount is 1% O.OOlmg to 100rag, preferably 0.0Lmg to: lOmg, applied once or several times a day, but may be increased or decreased taking into account the patient's symptoms, weight, age, sex, etc.

In the compound used in the present invention, when R ¹ is a hydrogen atom, R ² is preferably C0CH ₈ , C0CH ₂ CH ₈ , C0CH ₂ F, COCFs, C0CH ₂ C1, C0NHCH ₃ , and when R ¹ is other than a hydrogen atom, Is the combination of R ¹ and R ² --(CH ₂ ) ₈ C0-,-(CH ₂ ) ₄ C0-,-(CH ₂ ) ₈₀ C0-, -NH (CH ₂ ) ₂ C0-,- (CH ₂ ) ₄ -,-(CH ₂ ) _5- and the like are preferable. R ⁸ and R ⁴ are preferably an alkyl group, and particularly preferably a methyl group and an ethyl group. Particularly preferred compounds include compounds represented by the following formulas (11), (III) and (IV).

These compounds have low toxicity and can be used as pharmaceuticals, as disclosed in Japanese Patent Publication No. 327127 ^ and Amerili Patent No. 4900752. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the mean pulmonary artery pressure when a compound represented by the formula (III) (NIP-121) and a typical Ca ⁺⁺ antagonist, diphedipine (formula V), were administered. BEST MODE FOR CARRYING OUT THE INVENTION

Next, test examples and prescription examples are shown, but the present invention is not limited to these examples.

Fiber example)

Male adult Sprague-Dawley rats were bred for 3-4 weeks at a low pressure equivalent to 17,000 ft to produce chronic hypoxic pulmonary hypertension rats. Pulmonary artery pressure was measured with a Statham transducer with the catheter placed in the pulmonary artery. The drug was dissolved in a solvent (polyethylene glycol 400: ethanol: water = 2: 3: 5) and administered cumulatively at 10-minute intervals.

FIG. 1 shows the results of the compound (NIP-121) represented by the formula (III) and nifidipine (formula V), which is a typical Ca ⁺⁺ antagonist. NIP-121 showed a clear mean pulmonary artery hypotensive effect at a dose of 10 / zgAg or higher, but diphediopine did not show a decrease even at a dose of 1,000 / igkg.

From the above, it is understood that the compound of the present invention has a strong t¾0 髙 JfiLffi action.

(Prescription example)

Formulation Example 1: Tablet

10 g of the compound of formula (III)

Lactose 260 g

600 g microcrystalline cellulose

350g corn starch

Hydroxypropyl cellulose 100 g

C C-Ca 150 g

(Carboxymethylcellulose Calcium)

Magnesium stearate 30g

1,500 g After mixing the above components in a conventional manner, 10,000 tablets of sugar male containing 1 mg of the active ingredient (compound of the formula (III)) per tablet were mixed. Formulation Example 2: Capsules

10 g of the compound of formula (III)

440 g

Microcrystalline cellulose 1,000 g

Magnesium stearate 50 e

1, 500 g

After mixing the above components in a conventional manner, the mixture was filled into gelatin capsules to produce 10,000 capsules containing 1 mg of the active ingredient (compound of the formula (III)) in one capsule. Formulation Example 3: Ointment

Compound of formula (III) 1.0 g

Liquid paraffin 10.0 g

Cetanol 20.0 g

White ヮ serine 68.4 g

Etylparaben 0.1

0.5 g of 1 menthol

100.0 g

The above ^; minutes were mixed by a conventional method to obtain 1% ointment. Formulation Example 4: Liquid

5 g of the compound of formula (III)

Propylene glycol 205 g

Ethyl alcohol 790 g

1, 0 0 0 g

Above Bfi¾ component is mixed in the usual way to form a 0.5% liquid Formulation Example 5: Aerosol

Compound of formula (III) l g

Perfume 1 g

Ethyl alcohol 3 98 g

Propellant F12 / 11, 80/20 600 g

1, 0 0 0 g

The upper part was mixed by a conventional method to obtain 0.1% aerosol. Availability ^ ±

As described above, since the compound according to the present invention has a strong anti-pulmonary blood pressure effect,

You.

Claims

The scope of the claims

1. General formula (I)

Wherein A represents 0H or 0C (0) CH ₃ _-n X „(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. ) Means together with B means a bond;

B means a hydrogen atom or, together with A, means a bond;

When R ¹ is a hydrogen atom, R ² represents a hydrogen atom, C (Z) CH _3- »X„ (Z means an oxygen atom or a sulfur atom) or C (Z) NHCH _3- ;

When R ¹ is not a hydrogen atom, R ¹ and R ² are joined together (CH ₂ ) _m (m means 4 or 5.), (CH ^ a-! CKZ), N (R ⁵ ) ( _{_{. CH 2) 2 C (Z}} ) (R 6 is that a hydrogen atom or a methyl group), (CH ₂₎ _m - means _{_{2 0C (Z) - 2 HC}} (Z) or (CH ₂₎ ";

R ⁸ and R ⁴ are the same or different from each other, and represent a arsenic atom or a CC ₄ alkyl group, or are substituted with 〜C ₄ alkyl group around R ⁸ and R ⁴ May mean a 1,4-butylene group or a 1,5-benthylene group. ] A compound for treating pulmonary hypertension, comprising a compound represented by the formula (I) or a salt thereof if the salt can be formed, or an acceptable salt thereof as an active ingredient.

2. In the general formula (I), R ¹ is a hydrogen atom, and R ² is C0CH ₃ , C0CH ₂ CH ₈ , C0CH ₂ F, COCFs, C0CH ₂ C1 or C0NHCH ₈ , or R ¹ and R ² together Natsute _{_{- (CH 2) 8 C0-,}} - (CH 2) 4 C0-, - (CH 2) s 0C0-, -NH (CH 2) 2 C0-, _ (CH 2) 4 - or - (CH ₂₎ ₆ - can be Hai髙JfiLE disease treatment according to claim 1, further comprising a compound as an active ingredient.

3. Formula (II)

The therapeutic agent c for pulmonary hyper jfiiE disease according to claim 1, which comprises a compound represented by the following formula:

4. Formula (III)

2. The therapeutic agent for pulmonary! FiLE disease according to claim 1, comprising a compound represented by the following formula:

5. Equation (IV)

2. The therapeutic agent for high pulmonary JfiLEE disease according to claim 1, comprising a compound represented by the following formula: