JP2003113084A - Drug for treating and / or preventing pulmonary hypertension - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new use of a specific phenylpyridazinone derivative having a cardiotonic effect and to provide a new preventive and / or therapeutic agent for pulmonary hypertension. SOLUTION: The following general formula (1) or (2): A therapeutic and / or prophylactic agent for pulmonary hypertension, comprising a phenylpyridazinone derivative or a salt thereof, or a hydrate or solvate thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a therapeutic and / or prophylactic agent for pulmonary hypertension, which comprises a specific phenylpyridazinone derivative or a salt thereof, or a hydrate or solvate thereof as an active ingredient. .

[0002]

BACKGROUND OF THE INVENTION Primary pulmonary hypertension is a disease of unknown cause and has been designated as an intractable disease by the Ministry of Health, Labor and Welfare. Although the number of patients in Japan is extremely small, no useful treatment has been established. Until now, drugs and antiplatelet agents that expand the pulmonary artery have been used,
In patients with advanced symptoms, cardiotonic agents are associated with the use of cardiotonic agents. These therapeutic agents were expected to improve cardiac output by improving vascular resistance in the pulmonary artery and improving cardiac function, but they are associated with excessive blood pressure drop, edema, proarrhythmia, and increased heart rate The current situation is insufficient.

On the other hand, JP-A-60-126282 and JP-A-61-289032 describe specific phenylpyridazinone derivatives, and it is described that these compounds are useful as cardiotonic agents. However, as far as the present inventors know, it has never been reported or even suggested that these compounds are effective for pulmonary hypertension.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been shown to selectively increase pulmonary arteries as a therapeutic and / or prophylactic agent effective against pulmonary hypertension, especially primary pulmonary hypertension, and also associated with heart failure. It is an object of the present invention to provide a new therapeutic and / or prophylactic drug which has no adverse effect on patients.

[0005]

Means for Solving the Problems As a result of intensive studies in view of the above-mentioned object, the present inventor found that a specific phenylpyridazinone derivative, which has been known as a cardiotonic agent, is used as a therapeutic and / or prophylactic agent for pulmonary hypertension. The present invention has been completed based on the finding that it has no adverse effect even in patients with heart failure.

That is, the gist of the present invention is the following general formula (1) or (2):

[0007]

[Chemical 5]

(In the above general formulas (1) and (2), R ₁ and
R _2's each independently represent a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group, and R _3's are a hydrogen atom or an acyl group. Alternatively, it represents an alkyl group, and R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring. ). A therapeutic and / or preventive agent for pulmonary hypertension, which comprises a phenylpyridazinone derivative represented by the formula (1) or a salt thereof, or a hydrate or solvate thereof as an active ingredient.

In a preferred embodiment of the present invention, the active ingredient is the following general formula (3)

[0010]

[Chemical 6]

(In the above formula, A represents a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, and an alkyl group, a cyano group, a hydroxyl group, an alkoxy group, an amino group is present on the ring. , An alkylamino group, a dialkylamino group, an acylamino group, a carboxyl group, an alkoxycarbonyl group, and a carbamoyl group, which may have at least one substituent.), Or a salt thereof. Or a hydrate or a solvate thereof; the active ingredient in the general formula (1) or (2) is that R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, represented by a methyl group or an ethyl group, R ₄ is 2-pyridyl, 4-pyridyl group, a compound represented by the 2-pyrimidyl or 4-quinolyl group; active ingredient, before In formula (3), A is 4-
A compound that is a pyridyl group; pulmonary hypertension is primary pulmonary hypertension; and administration to a patient further associated with heart failure.

The second gist of the present invention is the following general formula (1) or (2)

[0013]

[Chemical 7]

(In the above general formulas (1) and (2), R ₁ and
R _2's each independently represent a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group, and R _3's are a hydrogen atom or an acyl group. Alternatively, it represents an alkyl group, and R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring. ), A phenylpyridazinone derivative or a salt thereof, or a hydrate or solvate thereof as an active ingredient, which is a drug for selectively increasing the pulmonary artery. The preferred embodiment of is the same as described above.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

Examples of the active ingredient of the therapeutic and / or prophylactic agent of the present invention include the compounds represented by the above general formula (1) or (2). That is, in the general formulas (1) and (2), R ₁ and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group,
A nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group, R ₃ represents a hydrogen atom, an acyl group or an alkyl group, and R ₄ may have a substituent on its ring. Examples of the compound include a member ring or a 6-membered heterocycle. Among these, preferred compounds include a compound represented by the general formula (3), and R ₁ , R ₂ and R _{3 in the} general formula (1) or (2) each independently represent a hydrogen atom. , A methyl group or an ethyl group, and R ₄ is 2-pyridyl group, 4-pyridyl group, 2-
Examples thereof include compounds represented by a pyrimidyl group or a 4-quinolyl group. In the present invention, as a particularly preferable compound, a compound in which A is a 4-pyridyl group in the general formula (3), that is, 6- [4- (4-pyridylamino) phenyl] -4,5-dihydro-3 is used. (2H) Pyridazinone (hereinafter sometimes referred to as “MCI-154”) or a salt thereof, or a hydrate or solvate thereof.

Incidentally, these compounds are disclosed in JP-A-58-8.
015, 58-8016, 58-140076 and 60-126282, and the Journal of Medic
The compound is described in inal Chemistry, 1987, vol.30, No.7, 1157-1161, and can be produced by the methods described in these publications or in accordance with them.

By the way, these publications describe that the phenylpyridazinone derivative as an active ingredient in the present invention is used as a cardiotonic agent, but it is effective against pulmonary hypertension as shown in Examples below. about,
It is not listed at all and is not even suggested.

The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with mineral acids such as hydrochloric acid and phosphoric acid, and salts with organic acids such as lactic acid and acetic acid.

In the present invention, hydrates or solvates of the above-mentioned compounds can be used, and the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvent. .

The present invention will be described below by taking the case of using MCI-154 as an example. However, even when other compounds are used as active ingredients, they can be appropriately prepared and used with reference to the following.

When clinically applying the active ingredient of the drug of the present invention, MCI-154 or a pharmaceutically acceptable salt thereof is used as it is, or is mixed with a pharmaceutically acceptable carrier and used as a pharmaceutical composition. When used orally, 0.01 to 100 mg / kg of the above compound is used.
It is preferable to administer 1 to 3 times a day, and in the case of intravenous injection, 0.01 to 200 mg of the above compound is preferably administered 2 to 5 times a day or a continuous infusion of these doses. In the case of rectal administration, the above compound 0.01-
It is preferred to administer 100 mg / kg 1-3 times daily. The above doses are used by appropriately increasing or decreasing according to age, disease state, sex, symptoms and the like.

Upon formulation, MCI-154 or a pharmaceutically acceptable salt thereof can be used as a commonly used formulation carrier, that is, a composition containing an excipient and other additives. Such carriers may be solid or liquid.

When a solid carrier is used, it may be in the form of tablets, powders, granules, hard gelatin capsules, suppositories, lozenges and the like. The amount of the solid carrier at this time may be arbitrary, but it is preferably about 1 mg to about 1 g.

When a liquid carrier is used, it can be a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution such as an ampoule, or an aqueous or non-aqueous suspension.

The therapeutic and / or prophylactic agent of the present invention thus obtained has a remarkable relaxing action on the pulmonary artery, as shown in the following examples, and selectively acts on the pulmonary artery at a concentration at which the blood pressure is not lowered by the vasodilatory action. It is a drug that can be expanded to pulmonary hypertension, and is particularly effective against pulmonary hypertension, especially primary pulmonary hypertension.

[0027]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples unless it exceeds the gist thereof. The MC used in the following examples
As I-154, one produced according to the method described in Example 1 described in JP-A-60-126282 was used. Example 1 (Experimental method) The experimental method was Kitada (J. Cardiovasc. Pharma.
col. 1996: 27: 519-526). That is, male guinea pigs (body weight 300-350) under ether anesthesia
g) was killed by exsanguination, the aorta and pulmonary artery were extracted after incision of the chest. The isolated artery was chilled with ice-cold nutrient solution (Krebs-He
fat and connective tissue were removed while immersed in an inselet solution). Aorta 2-2.5 cm, pulmonary artery under microscope 0.5-0.9
A cm strip was prepared and endothelial cells were removed.

The prepared sample was 20 ml filled with a nutrient solution which was kept at 37 ° C. by aerated with 95% oxygen and 5% carbon dioxide mixed gas.
Suspended in the Magnus tube, connected one end to a transducer for isometric contraction, applied a resting tension of 1.5 g for the aorta and 0.5 g for the pulmonary artery, and after standing for 1 hour, the sample was stable. .

For α contraction 10 ⁻⁵ M norepinephrine or 10
^-5 M phenylephrine was used. 40mMK for high potassium contraction
Cl was used. MCI-154 used was dissolved in distilled water. The amount of the solution to be added was 100 ul, and a solution having a final concentration of MCI-154 in the Magnus tube of 10 ^-9 to 10 ^-5 M was prepared. After addition of various contractile agents, MCI-154 was added cumulatively from a low concentration. (Experimental Results) Table 1 shows the results of the inhibitory effect of MCI-154 on α contraction of the isolated pulmonary artery and aorta of the guinea pig. MCI-154 relaxed the pulmonary artery preparation in a concentration-dependent manner at 10 ^-9 to 10 ^-5 M. On the other hand, 10 ^-7 to 10 ^-5 M for the aorta
The concentration was relaxed in a dose-dependent manner. Low concentration of MCI-154 (1
The relaxation effect at 0 ^-8 and 10 ^-7 M) was significantly stronger in the pulmonary artery preparation.

Table 2 shows the results of the inhibitory effect of MCI-154 on hyperpotassium contraction of guinea pig isolated pulmonary artery and aorta. MCI-154 relaxed the pulmonary artery preparation in a concentration-dependent manner at 10 ^-7 to 10 ^-5 M. On the other hand, no significant relaxing effect was observed on the aorta. Table 1 Dilation effect of MCI-154 on α-contraction in isolated guinea pig pulmonary artery and aorta.

[0031]

[Table 1]

Table 2 Dilatory effect of MCI-154 on hyperpotassium contraction in isolated guinea pig pulmonary artery and aorta.

[0033]

[Table 2]

From the above results, it can be seen that MCI-154 has a remarkable relaxing action on the pulmonary artery and is a drug capable of selectively dilating the pulmonary artery at a concentration that does not lower the blood pressure due to the vasodilating action. From this, it is clear that MCI-154 has utility for primary pulmonary hypertension.

Abe et al. (J. Pharmacol. Exp. Ther. 1992: 26.
1: 1087-1095) demonstrated that MCI-154 could selectively improve the contractile function of the failing myocardium at a dose that did not show cardiotonic or antihypertensive effects in a canine acidosis heart failure model. The blood concentration of 154 is estimated to be 10 ⁻⁸ to 10 ⁻⁷ M or less (Et., Eur. J. Pharmacol. 1996: 29.
8: 247-256).

Taking these reports together with the above results, it can be expected that the use of low doses of MCI-154 will also ameliorate the heart failure seen in primary pulmonary hypertension. Conventional vasodilators lack pulmonary artery selectivity, leading to excessive hypotension and edema, and cardiotonics have problems such as increased heart rate and arrhythmogenic effects.

Therefore, it seems that one drug has a useful effect as compared with conventional vasodilators and cardiotonics, and it is clear that it can be a new therapy.

[0038]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a new use of the specific phenylpyridazinone derivative known to have a cardiotonic action, and more specifically, a new use for pulmonary hypertension. It is possible to provide therapeutic and / or prophylactic agents.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C063 AA01 BB09 CC29 DD12 EE01                 4C086 AA01 AA02 BC42 GA07 GA08                       MA01 MA04 MA22 MA23 MA31                       MA35 MA37 MA41 MA43 MA52                       MA60 MA66 NA14 ZA36 ZA42                       ZA59

Claims (10)

[Claims] 1. The following general formula (1) or (2): (In the general formulas (1) and (2), R ₁ and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, Represents an acylamino group or an alkoxy group, R ₃ represents a hydrogen atom, an acyl group or an alkyl group,
R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring. ) A therapeutic and / or prophylactic agent for pulmonary hypertension, comprising a phenylpyridazinone derivative represented by the formula (1) or a salt thereof, or a hydrate or solvate thereof as an active ingredient. 2. The active ingredient is represented by the following general formula (3): (In the above formula, A represents a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, an alkyl group on the ring,
It may have at least one substituent selected from a cyano group, a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, an acylamino group, a carboxyl group, an alkoxycarbonyl group and a carbamoyl group. ) A phenylpyridazinone derivative represented by the formula (1) or a salt thereof, or a hydrate or solvate thereof, and / or
Or prophylactic drug. 3. The active ingredient is represented by the general formula (1) or (2) according to claim 1, wherein R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a methyl group or an ethyl group. And R ₄ is a compound represented by a 2-pyridyl group, a 4-pyridyl group, a 2-pyrimidyl group or a 4-quinolyl group, and the therapeutic and / or prophylactic agent according to claim 1 or 2, . 4. The treatment according to any one of claims 1 to 3, wherein the active ingredient is a compound in which A is a 4-pyridyl group in the general formula (3) according to claim 2. And / or prophylactic drugs. 5. The therapeutic and / or prophylactic drug according to any one of claims 1 to 4, wherein the pulmonary hypertension is primary pulmonary hypertension. 6. The therapeutic and / or prophylactic agent according to any one of claims 1 to 5, which is further administered to a patient with heart failure. 7. The following general formula (1) or (2): (In the general formulas (1) and (2), R ₁ and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, Represents an acylamino group or an alkoxy group, R ₃ represents a hydrogen atom, an acyl group or an alkyl group,
R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring. ) A phenylpyridazinone derivative or salt thereof, or a hydrate or solvate thereof as an active ingredient, which is a drug for selectively increasing pulmonary arteries. 8. The active ingredient is represented by the following general formula (3): (In the above formula, A represents a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, an alkyl group on the ring,
It may have at least one substituent selected from a cyano group, a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, an acylamino group, a carboxyl group, an alkoxycarbonyl group and a carbamoyl group. 8. The drug according to claim 7, which is a phenylpyridazinone derivative or a salt thereof, or a hydrate or solvate thereof. 9. The active ingredient is represented by the general formula (1) or (2) according to claim 1, wherein R ₁ , R ₂ and R ₃ are each independently a hydrogen atom, a methyl group or an ethyl group. 9. The agent according to claim 7, wherein R ₄ is a compound represented by a 2-pyridyl group, a 4-pyridyl group, a 2-pyrimidyl group or a 4-quinolyl group. 10. The drug according to any one of claims 7 to 9, wherein the active ingredient is a compound in which A is a 4-pyridyl group in the general formula (3) according to claim 2. .