JP2002154962A - Antidepressant/antianxiety agent comprising isoquinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new antidepressant/antianxiety agent having high inhibitory activity against phosphodiesterase IV isozyme(PDEIV). SOLUTION: This new antidepressant/antianxiety agent comprises as the active ingredient an isoquinoline derivative of the general formula (wherein, R is an ethoxy group) or a pharmaceutically acceptable salt thereof. This agent, which has a high inhibitory activity highly specific to PDEIV, is highly useful as an antidepressant/antianxiety pharmaceutical preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antidepressant or anxiolytic comprising at least one of an isoquinoline derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art The function of cAMP and cGMP as intracellular signaling substances to regulate cell functions has been elucidated, and studies have been conducted on cyclic nucleotide phosphodiesterase, which is a degrading enzyme thereof. Cyclic nucleotide phosphodiesterases are often abbreviated simply as phosphodiesterases, are classified into several isozymes, and have the molecular structure, regulatory mechanism, tissue / cellular distribution,
Specificity is being revealed. Along with this, studies on inhibitors specific to phosphodiesterase isozymes have been actively conducted, and useful inhibitors as pharmaceuticals and the like have been found.

[0003] Phosphodiesterase type IV isozyme (hereinafter abbreviated as PDEIV), which is one of the phosphodiesterase isozymes, is distributed in tissues and cells such as brain, kidney, testis, and inflammatory cells.
It has a low m value and is a specific cAMP-degrading enzyme. This P
Since inhibition of DEIV increases cAMP concentration in tissues, PDEIV inhibitors have various pharmacological effects such as antidepressant, anti-anxiety, anti-dementia effects on central nervous system, chemical mediator release inhibition and neutrophils. It is known to have an anti-inflammatory action, a bronchodilator action, a smooth muscle relaxation action, a hepatoprotective action, a diuretic action, etc., by suppressing the infiltration of spheres.

As the isoquinoline derivatives, those having pharmacological actions such as peripheral vasodilatory action and antispasmodic action are known, and drotaverine and the like are actually used as medicines. The present inventors have conducted intensive studies on new pharmacological actions of isoquinoline derivatives, and as a result, have found that the isoquinoline derivatives of the present invention have an excellent inhibitory activity with high specificity for PDEIV, and completed the present invention.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel antidepressant or anxiolytic containing an isoquinoline derivative having an excellent PDEIV inhibitory activity as an active ingredient.

[0006]

The active ingredient of the antidepressant and anxiolytic agent of the present invention is an isoquinoline derivative represented by the following general formula.

Embedded image [In the formula, R represents an ethoxy group. ]

The isoquinoline derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the above general formula, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanate Acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluene Sulfonic acid, naphthalenesulfonic acid, sulfanilic acid, acid addition salts with theophylline-acetic acid and the like can be mentioned, preferably hydrochloric acid, salts with theophylline-acetic acid and the like, and these salts are free by known methods. It can be produced from the isoquinoline derivative of the present invention or can be mutually converted.

[0008] Further, the present invention is not limited to the case where the compound of the present invention has stereoisomers such as cis-trans isomers, optical isomers and conformers, or exists in the form of hydrates. And hydrates thereof.

[0009] Among the compounds of the present invention, particularly preferred compounds are as follows. 1- (3 ′, 4′-diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline [Compound 1] 1- (3 ′, 4′-diethoxybenzyl) -6,7-diethoxy- 3,4-dihydroisoquinoline hydrochloride [Compound 2] 1- (3 ', 4'-diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline-theophylline-7-acetate [Compound 3] 1- (3 ′, 4′-Diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline-theophylline-7-acetate monohydrate [Compound 4]

The compound of the present invention is described in, for example,
No. 46818, Japanese Patent Application Laid-Open No. 62-167781,
It is described in JP-A-62-187411 and the like,
It can be manufactured by known methods. Hereinafter, the pharmacological action of the isoquinoline derivative of the present invention will be described.

[0011]

[Action] Preparation of phosphodiesterase isozyme Each phosphodiesterase isozyme was prepared according to a conventional method. That is, 5 g to 10 g of lyophilized powder of porcine aorta.
Double volume (v / w) of buffer (0.25 M sucrose, 10 mM
Tris-HCl, pH 7.8, 5 mM magnesium chloride,
0.2 mM ethylene bis (oxyethylene nitrilo) tetraacetic acid, 100 nM α-toluenesulfonyl fluoride, 100 nM leupeptin, 100 nM pepstatin) were added and homogenized. This was centrifuged at 2500 rpm for 20 minutes, and the supernatant was further centrifuged at 40,000 rpm for 1 hour. After filtering the resulting supernatant, a solution containing the same protease inhibitor as the above buffer solution (70 m
M sodium acetate, pH 6.8, 5 mM 2-mercaptoethanol).

D was equilibrated with the above dialysate and packed in a column.
The sample obtained by dialysis was added to an EAE-Sepharose-FF column (manufactured by Pharmacia), and eluted with a linear concentration gradient solution of sodium acetate from 0.07 to 1.0M. The activity of each isozyme of phosphodiesterase was measured for the eluted fraction, and fractions with concentrated activities were collected and used as an enzyme source. In this test system, type I was in fractions 20 and 21,
The isozymes were eluted and fractionated in fractions 30 and 31 for type II, fraction 29 for type III, fraction 61 for type IV and fraction 67 for type V.

2. Method for measuring phosphodiesterase activity 50 mM Tris-HCl (pH 7.5), 6 mM magnesium chloride, 1 mM ethylenebis (oxyethylenenitriro) tetraacetic acid, 2.5 mM dithiothreitol, 2.
5% dimethyl sulfoxide, 0.025 mg / ml 5 '
-A reaction system was prepared by combining nucleotides, 0.23 mg / ml bovine serum albumin and 1 to 5 µg of each enzyme (each value indicates the final concentration). This reaction mixture solution is
After pre-incubation at 5 ° C for 5-10 minutes,
[ ³ H] cAMP or [ ³ H] cGMP was added, and 30
Incubated at 10 ° C for 10-15 minutes. After adding the cation exchange resin suspended in water to the reaction solution and absorbing unreacted cAMP or cGMP to stop the reaction, 2000 g
For 5 minutes, a part of the supernatant was collected, and the radioactivity was measured with a liquid scintillation counter. A test substance dissolved in dimethyl sulfoxide or water was added to the above reaction system, and the inhibitory activity of the substance on phosphodiesterase isozymes was measured.

When measuring the inhibitory activity of a test substance on the type I isozyme, [ ³ H] cAMP was used as a substrate, and 5 μg / ml of calmodulin was allowed to coexist. In the case of measuring the inhibitory activity on type II, the substrate was [ ³ H] cAM
P was used in the presence of 10 μM cGMP. In the case of type III, using [ ³ H] cAMP as a substrate, 100 μM of Ro20-1724 (4-[(3-butoxy-4-methoxyphenyl) methyl] -2-imidazolidinone: type IV specific inhibitor ) Coexist, and in the case of type IV, [ ³
H] Using cAMP, the inhibitory activity of the test substance on each isozyme was measured in the presence of 10 μM cilostazol (a type III specific inhibitor). In the case of V-type measurement, [ ³ H] cGMP was used as a substrate.

[0015]

[Effects] As a result of measuring the inhibitory activity of phosphodiesterase on each isozyme according to the test method described above, the compound of the present invention showed a strong inhibitory activity particularly on the type IV isozyme. Table 1 shows an example of the results.

[0016]

[Table 1]

As is evident from the results shown in Table 1, the compounds of the present invention have a P value equal to or higher than that of Ro20-1724 which is known as a very specific PDEIV inhibitor.
Exhibits a DEIV inhibitory activity, and its PDEIV inhibitory activity is 10% lower than the inhibitory activity against other types of PDE isozymes.
It was specific more than twice as strong. As mentioned above, P
Inhibition of DEIV causes an increase in cAMP concentration in tissues, which is a central effect such as antidepressant action, anxiolytic action, anti-dementia action, anti-inflammatory action by suppressing chemical mediator release and neutrophil infiltration, and bronchodilation Action, smooth muscle relaxing action, hepatoprotective action, diuretic action and the like have been suggested as pharmacological effects of PDEIV inhibitors. Therefore, the substance of the present invention is extremely useful as a drug such as an antidepressant or an anxiolytic, as a medicament for preventing or treating central nervous system diseases such as depression. Further, the substance of the present invention is also useful as a hepatoprotective agent or diuretic based on PDEIV inhibitory action.

[0018]

EXAMPLES The substance of the present invention can be made into a medicine by combining it with a suitable pharmaceutical carrier or diluent, can be formulated into various formulations by a usual method, and can be solid or semi-solid for oral or parenteral administration. , Liquid or aerosol dosage forms. In the formulation, the substance of the present invention may be used alone or may be combined with other pharmaceutically active ingredients as appropriate.

As the preparation for oral administration, crystalline cellulose, cellulose derivatives, gum arabic, tragacanth, as it is or with appropriate additives such as lactose, sucrose, glucose, mannitol, corn starch, potato starch and the like, can be used. Solution, sodium alginate solution, binders such as gelatin, disintegrants such as corn starch, potato starch, potassium carboxymethylcellulose, lubricants such as talc, magnesium stearate, other bulking agents, wetting agents, buffers, preservatives , Fragrances and the like can be appropriately combined into tablets, powders, granules or capsules. Also, suppositories may be prepared by mixing with an oily base such as cocoa butter, an emulsion base, a water-soluble base such as macrogol, or a hydrophilic base.

The injection may be an aqueous solvent or a non-aqueous solvent, for example, a solution or suspension of distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol or the like. it can. Depending on the condition of the patient and the type of disease, it can be appropriately formulated into a dosage form other than the above, such as an inhalant, an aerosol, an ointment, a poultice, or an eye drop, which is optimal for the treatment.

The desired dose of the substance of the present invention varies depending on the subject of administration (age, weight, symptoms, etc. of the patient), dosage form, administration method, administration period, and the like. On the other hand, usually 10 to 2000 mg per day
It can be orally administered once or several times. In the case of parenteral administration of an injection or the like, a dose at a dose level of 3 to 1/10 of the oral dose is preferable due to the influence of absorption and the like.

[0022] Formulation examples of a pharmaceutical composition containing the substance of the present invention as an active ingredient are shown below, but the present invention is not limited thereto.

[Table 2]

[0023]

[Table 3]

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 25/22 A61P 25/22 25/24 25/24 29/00 29/00 43/00 111 43/00 111 // C07D 217/20 C07D 217/20 F term (reference) 4C034 AK03 AK15 4C086 AA01 AA02 BC30 MA01 MA04 NA14 ZA05 ZA12 ZA59 ZA75 ZA81 ZA94 ZB11 ZC20

Claims (4)

[Claims] 1. An antidepressant or anxiolytic comprising as an active ingredient at least one of an isoquinoline derivative represented by the following general formula and a pharmaceutically acceptable salt thereof. Embedded image [In the formula, R represents an ethoxy group. ] 2. The antidepressant and anxiolytic agent according to claim 1, wherein the active ingredient is 1- (3 ′, 4′-diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline hydrochloride. . 3. The antidepressant according to claim 1, wherein the active ingredient is 1- (3 ′, 4′-diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline-theophylline-7-acetate. , Anxiolytics. 4. The method according to claim 1, wherein the active ingredient is 1- (3 ′, 4′-diethoxybenzyl) -6,7-diethoxy-3,4-dihydroisoquinoline-theophylline-7-acetate monohydrate. An antidepressant and an anxiolytic according to any one of the above.