JPH0710875A - Selective phosphodiesterase iv inhibitor - Google Patents

Abstract

PURPOSE:To obtain a selective phosphodiesterase IV inhibitor useful as a treating agent for bronchial asthma, etc., by compounding 1,8-naphthyridine derivative as an active component. CONSTITUTION:This agent is obtained by compounding a compound of the formula (R<1> is H, an alkyl or alkenyl; R<2> is H or an alkyl; R<3>-R<5> are H or alkyl) or its salt as an active component. The compound of the formula inhibits the activation of phosphodiesterase and elevates the concentration of cAMP and cGMP which are intracellular second messengers, thus useful as an agent for propylaxis and treatment of bronchial asthma, thrombosis, depression, hypofunction of central system post-cerebrovascular obstruction, cerebrovascular dementia, dementia of Alzheimer type, various kinds of inflammations, obesity, heart failure, etc. Its daily dose is 1-200mg/kg.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a selective phosphodiesterase IV inhibitor, and more particularly to a selective phosphodiesterase IV (PDE IV) inhibitor containing a 1,8-naphthyridine derivative or a pharmaceutically acceptable salt thereof. .

[0002]

2. Description of the Related Art Intracellular second messengers, cAMP and cGMP, are degraded and inactivated by phosphodiesterase (PDE). PD
E is widely distributed in tissues in vivo, and PDE inhibitors are known to inhibit the PDEs and thereby increase intracellular cAMP and cGMP concentrations to bring about various pharmacological actions. For example, it causes a relaxation action in vascular smooth muscle and bronchial smooth muscle, and a positive inotropic and chronotropic action in the heart. In addition, in the central nervous system, it has a central function regulation associated with an increase in cAMP, that is, an antidepressant action and a memory / learning function improving action.
In addition, it has an aggregation inhibitory effect on platelets, an activation inhibitory effect on inflammatory cells, and a lipolytic effect on adipose tissue [CD Nicholson et al., Trends in Pharm
acol., 12, 19 (1991)].

Therefore, drugs that inhibit PDE are various diseases, namely, bronchial asthma, thrombosis, depression, central hypofunction after cerebrovascular obstruction, cerebrovascular dementia, Alzheimer's dementia, various inflammations, It is considered to be effective as a therapeutic drug for obesity and heart failure.

Theophylline has been used as a typical PDE inhibitor for the treatment of asthma. However, since the pDE inhibitory action of pomalidomide is non-specific, it has cardiotonic and central actions in addition to bronchial smooth muscle relaxing action, and therefore side effects are always a problem. Therefore, among PDE isozymes, there is a demand for the development of a drug having a specific inhibitory effect on type IV, which is often present in bronchial smooth muscle and inflammatory cells.

Further, PDE IV is also abundant in central tissues and adipose tissues. In the former, inhibition of PDE IV
Increases cAMP concentration, leading to antidepressant action and learning / memory improvement. Furthermore, in adipocytes, PDE IV inhibitory action promotes the decomposition of fat.

The present inventors have been keenly aware of PD based on these findings.
As a result of the search for E IV inhibitor, a series of 1
8-naphthyridine derivative has PDE inhibitory action and PDE IV
It has been found that it has a remarkable inhibitory action against the above, and has completed the present invention. In addition, these compounds have an effect of suppressing contraction of various isolated guinea pig trachea specimens by various contractile substances (histamine, leukotriene D ₄ ), an effect of suppressing rat neutrophil activation, and anesthesia presensitized with ovalbumin. In the guinea pig, an inhibitory effect on airway contraction induced by re-administration of ovalbumin was also found.

Therefore, these compounds are used as bronchial asthma, thrombosis, depression, hypocentralism after cerebrovascular obstruction,
Cerebrovascular dementia, Alzheimer's dementia, various inflammations,
It is considered to be effective in the prevention and treatment of various respiratory diseases such as obesity and heart failure, inflammatory diseases, central nervous system diseases, circulatory diseases.

These 1,8-naphthyridine derivatives are disclosed in JP-A-4-234389, JP-A-5-25171, JP-A-5-25172 and Journal of Organic Metallic Chemistry, vol. 213, 405.
, Pp. 417 (1981), it has never been known that these substances have a selective PDE IV inhibitory action and an antiasthmatic action.

[0009]

The present invention has the general formula (I)

[0010]

[Chemical 2]

(Wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group or an alkenyl group; R ² is a hydrogen atom or a substituted or unsubstituted alkyl group; R ³ , R ⁴ and R ⁵ are the same or different; The present invention provides a selective phosphodiesterase IV inhibitor containing a substance represented by a hydrogen atom or a substituted or unsubstituted alkyl group, which may be different, or a pharmaceutically acceptable salt thereof.

In the present specification, the alkyl group has 1 to 1 carbon atoms.
6 means a linear or branched alkyl group, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, hexyl group, isohexyl group,
Examples include sec-hexyl group and tert-hexyl group. Examples of the alkenyl group include a vinyl group, an allyl group, a butenyl group and a pentenyl group.

Further, these alkyl group and alkenyl group may be substituted with other substituents, and in this case, the substituents include halogen atom, cycloalkyl group, hydroxyl group,
Examples thereof include an acetoxy group, an alkoxy group, an oxo group, and an aryl group which may be substituted with a halogen atom or the like. Here, examples of the cycloalkyl group include a cyclopropyl group and a cyclobutyl group. Examples of the aryl group include a phenyl group and a naphthyl group.
The alkoxy group means an alkoxy group derived from the above-mentioned alkyl group, and among them, a methoxy group is most preferable.

Specific examples of the 1,8-naphthyridine derivative used in the present invention are shown in Table 1 (No. 1 and No. 2).
The present invention is not limited to these, and those having a selective phosphodiesterase IV inhibitory action are included in the present invention. The compound represented by the general formula (I) of the present invention is synthesized by a conventional method, for example, JP-A-4-23438.
No. 9 and No. 5-25171, No. 5-25172.
It can be manufactured by the method described in the publication. The pharmaceutically acceptable salt of the 1,8-naphthyridine derivative includes, for example, hydrochloride, acetate and fumarate.

[0015]

[Table 1]

[0016]

[Table 2]

According to the present invention, when the 1,8-naphthyridine derivative is administered for the purpose of preventing and treating the above-mentioned diseases, the dose and administration method vary depending on the type of the 1,8-naphthyridine derivative, the administration subject, the symptoms and the like. . For example, the dosage form may be a powder, capsule, syrup or the like, or may be a suppository, an injection, an external preparation, a drip, an aerosol or the like. The dose varies significantly depending on the severity of symptoms, patient age, type of disease, past history, etc., but is usually about 0.0 per day.
1 to 200 mg / kg, preferably 0.05 to 50 mg
/ Kg, more preferably 0.1 to 10 mg / kg, and administered once to several times a day in divided doses.

In the case of formulation, it can be produced according to a conventional method in the art using an ordinary formulation carrier. That is, when manufacturing an oral solid preparation, the main drug is an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent,
After adding flavoring agents, flavoring agents, etc., tablets, coated preparations, granules, powders, capsules, etc. are prepared according to a conventional method.

Examples of excipients include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide or the like is used. As the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl starch, polyvinylpyrrolidone, etc. are used. As the disintegrant, for example, starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like are used.

Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica,
Hardened vegetable oil or the like is used. As the colorant, those permitted to be added to pharmaceuticals are used. As the corrigent and flavoring agent, for example, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used.

[0021] These tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating may be applied. When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.

[0022]

EXAMPLES The present invention will be described in detail below with reference to examples. The 1,8-naphthyridine derivative of the present invention is an effective prophylactic / therapeutic drug for bronchial asthma, and its safety is also very high, which will be specifically described below with reference to Examples. In addition,
The numbers of the compounds (test substances) used in the examples are those described above
It corresponds to the one shown in the table.

Example 1 PDE Inhibitory Action of 1,8-Naphthyridine Derivatives (Method) Centrifugal supernatant of porcine ventricular muscle homogenate as an enzyme source was separated into isozymes by ortho- (diethylaminoethyl) -cellulose-chromatography. Was used. Each isozyme was confirmed by reaction with its activity regulator. Using [ ³ H] -cAMP as a substrate, the reaction was carried out in the presence of 5′-nucleotidase. The test substance was dissolved in dimethyl sulfoxide and added to the reaction solution. [ ³ H] -5'-AMP generated by PDE is 5'-
It was decomposed into [ ³ H] -adenosine by nucleotidase. Unreacted [ ³ H] -cA by adding anion exchange resin
The reaction was stopped by adsorbing MP. The radioactivity of [ ³ H] -adenosine in the supernatant was measured, and the PDE inhibitory effect was calculated.

(Experimental Results) The results are shown in Table 2. As is clear from the table, both compounds selectively inhibited PDE IV.

[0025]

[Table 3]

Example 2 Inhibitory effect on histamine- or leukotriene D ₄ -induced contraction of isolated guinea pig trachea specimens (Method) Hartley guinea pigs were syncope-bleeded by bruising their heads and killed by exsanguination, and then the trachea was excised and subjected to a standard procedure. Therefore, ring-shaped specimens were prepared. Keep the specimen warm at 37 ° C
The isotonic tension was measured by suspending the mixture in 10 ml of Krebs-Ringer solution in which 95% O ₂ -5% CO ₂ mixed gas was aerated. Histamine (3 μM) or leukotriene D ₄
The sample was contracted at (1 nM), and when the reaction was stabilized, the test substance dissolved in dimethyl sulfoxide was administered into Tyrode's solution. The relaxation rate was calculated assuming that the baseline before contraction was 100%.

(Experimental Results) The results are shown in Table 3. As is clear from the table, at a concentration of 10 μM, the test substance that suppressed histamine-induced contraction by 50% or more was 14/25 points, and the compound that suppressed the leukotriene D ₄ -induced contraction by 50% or more was 13/25 points. .

[0028]

[Table 4]

Example 3 Inhibitory effect on methacholine-induced contraction of isolated guinea pig lung specimen (Method) A Hartley guinea pig was syncope-killed by bruising the head and lethal to exsanguination, and then the lung was excised and a specimen was prepared according to a conventional method. did. 37 from the cannula inserted into the trachea
The physiological saline solution kept at 0 ° C was perfused and the flow rate was measured. In addition, methacholine (50 ng / ml) was perfused to induce a contraction reaction, and then a test substance was administered to observe the inhibitory effect.

(Experimental Results) The results are shown in Table 4. All of the test substances tested here showed a strong inhibitory effect on methacholine contraction at 30 μM, and the minimum effective concentration (MIC) was 10
μM.

[0031]

[Table 5]

Example 4 Inhibitory effect of 1,8-naphthyridine derivative on rat neutrophil activation (Method) Glycogen was intraperitoneally administered to Hartley guinea pigs, and ascites was collected 4 hours later. Neutrophils obtained by centrifugation were converted to formyl- _L- methionyl- _L- leucyl- _L- phen.
It was stimulated with ylalanine (fMLP), and the luminescence when the excited energy of the generated active oxygen returned to the ground state was amplified by lucigenin and measured. The test substance was dissolved in dimethyl sulfoxide and added at the time of fMLP stimulation.

(Experimental Results) Table 5 shows the results. As is clear from the table, the test substance that suppressed neutrophil activation by 30% or more at a concentration of 100 μM was 9/13 points.

[0034]

[Table 6]

Example 5 1 against antigen-induced airway contraction in sensitized guinea pigs
Inhibitory effect of 8-naphthyridine derivative (Method) Hartley guinea pigs were antigen-sensitized with ovalbumin and used for the experiment 14 days later. After anesthetizing the guinea pig with sodium pentobarbital, a three-way cannula was inserted into the trachea and artificial respiration was performed. Airway resistance
It was measured by the modified Konzett-Rossler method. The jugular vein was also cannulated and the antigen was administered. Each test substance was administered at a dose of 10 mg / kg, and was administered via the jugular vein 2 minutes before the antigen administration. (Experimental results) The results are shown in Table 6.

[0036]

[Table 7]

Example 6 Acute Toxicity of 1,8-Naphthyridine Derivatives in Mice (Method) A group of 3 to 7 ICR mice of 6 to 8 weeks old was fasted overnight and used in an experiment. A solvent (0.5% carboxymethylcellulose aqueous solution) or a solvent in which a test substance was dissolved or suspended was orally administered to mice at a dose of 0.1 ml / 10 g, and the live / dead of the animal was observed for 72 hours after the administration. Each test substance had a dose of 300 mg / kg.

(Experimental Results) The results are shown in Table 7. All the test substances tested here were negative in the acute toxicity test at a dose of 300 mg / kg. from this result,
50% lethal oral dose (LD ₅₀ value) is 300 mg / kg
It was judged as above.

[0039]

[Table 8]

[0040]

The compound represented by the general formula (I) of the present invention inhibits the activation of phosphodiesterase, so that the intracellular concentration of cAMP or cGMP is increased, and the anti-asthma action,
It produces various pharmacological actions such as cardiotonic action, antidepressant action, anti-dementia action, anti-inflammatory action and anti-obesity action. Therefore,
Bronchial asthma, thrombosis, depression, central hypofunction after cerebrovascular obstruction, cerebrovascular dementia, Alzheimer's dementia,
Effective as a prophylactic / therapeutic drug for various inflammations, obesity and heart failure

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/435 ACB ACD ACN AED 9454-4C (72) Inventor Yasuhiro Kumonaka Oka, Yaizu, Shizuoka No. 10 Sapporo Pharma Co., Ltd. Pharmaceutical Development Laboratory (72) Inventor Takemasa Hase Okameka, Yaizu City, Shizuoka Prefecture No. 10 Sapporo Pharma Co., Ltd. Pharmaceutical Development Laboratory

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group or an alkenyl group; R ² is a hydrogen atom or a substituted or unsubstituted alkyl group; R ³ , R ⁴ and R ⁵ are the same or different; Frequently, a hydrogen atom or a substituted or unsubstituted alkyl group is shown) or a phosphodiesterase IV inhibitor containing a pharmaceutically acceptable salt thereof. 2. A substituted or unsubstituted alkyl group and a substituent on an alkenyl group, which may be substituted with a halogen atom, a cycloalkyl group, a hydroxyl group, an acetoxy group, an alkoxy group, an oxo group or a halogen atom. A selective phosphodiesterase IV according to claim 1 which is a group
Inhibitor. 3. R ¹ is an alkyl group or an alkenyl group which may be substituted with a halogen atom, an aryl group, an acetoxy group or the like, and R ² is a hydrogen atom or a hydroxyl group,
The selective phosphodiesterase IV inhibitor according to claim 1, which is an alkyl group which may be substituted with an acetoxy group, an oxo group or the like. 4. Prevention and treatment of diseases such as bronchial asthma, thrombosis, depression, hypocentral function after cerebrovascular obstruction, cerebrovascular dementia, Alzheimer's dementia, various inflammations, obesity and heart failure. The selective phosphodiesterase IV inhibitor according to claim 1, which is useful for