JPH0558433B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to novel naphthalene sulfonamide derivatives useful as therapeutic agents for cardiovascular diseases, and pharmacologically acceptable acid addition salts thereof.

Structure of the invention That is, the present invention is based on the general formula () (In the formula, n represents an integer of 2 or 3, and X represents a hydrogen atom or a halogen atom.) The present invention relates to a naphthalene sulfonamide derivative represented by the following formula, and a pharmacologically acceptable acid addition salt thereof.

In the general formula () of the present invention, the halogen atom represented by X is, for example, chlorine, fluorine,
Examples include bromine and iodine atoms.

The compound represented by the general formula () of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or a base can be liberated from the generated acid addition salt.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula () of the present invention include mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. , or organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, and tartaric acid.

The novel naphthalene sulfonamide derivative represented by the general formula () of the present invention can be produced as follows.

That is, the compound represented by the general formula () according to the present invention is represented by the following general formula (). (In the formula, X has the same meaning as above, and A represents a halogen atom.) A sulfonic acid halide derivative represented by the following general formula () (In the formula, n represents the same meaning as defined above.) It can be produced by reacting the following amine derivatives in a solvent.

In a particularly preferred embodiment of the method of the present invention, 3 to 5 equivalents of the amine derivative represented by the general formula () are used in an organic solvent for 1 equivalent of the sulfonic acid halide derivative represented by the general formula (). It's about getting them to react.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, and examples thereof include chloroform, benzene, toluene, dioxane, hexane, and the like.

Further, the reaction is carried out in a range from 0° to the heating reflux temperature of the solvent used.

Effect of the invention A novel naphthalene sulfonamide derivative represented by the general formula () produced in this manner,
and its pharmacologically acceptable acid addition salts have excellent smooth muscle relaxing effects and blood flow increasing effects, and are effective as vasodilators, antihypertensive agents, cerebral circulation improving agents, antianginal agents, and cerebral cardiac agents. It is extremely useful as a preventive and therapeutic agent for thrombosis in the vascular system.

As an example of the pharmacological action of the compound of the present invention, the excellent action of the compound shown in Example 1 will be described below.

a. Effect on myosin light chain kinase Using chicken gizzard smooth muscle myosin light chain as a substrate, oxygen activity was measured by measuring the amount of radioactive phosphate incorporated into the substrate protein from [γ- ³² P]ATP. The total volume of the reaction solution was 200 μl.
Its composition is 25mM Tris-HCl (PH7.0), 10mM
M MgCl ₂ , 40μg myosin light chain (myosin was prepared from chicken gizzard smooth muscle and further denatured with guanidine), 200μM CaCl ₂ , 80n
g Calmodeulin (prepared from bovine brain),
Myosin light chain kinase (prepared from chicken gizzard smooth muscle) and various concentrations of drug.
The reaction was carried out at 30°, 100 μM [γ- ³² P]
It was started by adding 20 μl of ATP and stopped by adding 0.5 ml of 20% TCA. After stopping the reaction, add 3 ml of 5% TCA and 0.1 ml of 1 mg/ml albumin solution and centrifuge.
Acid-insoluble proteins were immobilized on the bottom of the test tube. Furthermore, remove the supernatant, add 3 ml of 5% TCA, and centrifuge. 2 operations
Repeated ~3 times. Precipitate protein with 1N-NaOH
Dissolve in 2 ml and put into a vial containing approx. 10 ml.
Measurement is performed using a liquid scintillation counter using the Cherenkov effect. The activity in the presence of calcium was set as 100, and the activity in the absence of calcium was set as 0. From the activity when the drug is added to the reaction solution
The concentration of drug that gave 50% inhibition was defined as _IC50 .

(Results) Compound of the present invention Example 1 IC ₅₀ =6.8 μM b Ca ²⁺ PDE/basal PDE (Ca ²⁺ −dependent
Ca ²⁺ -dependent PDE is an enzyme that catalyzes the reaction from cAMP (or cGMP) to 5′-AMP (or 5′-GMP), and its activity can be measured using the reaction product 5′- We used a method to quantify AMP (5'-GMP). Ca ²⁺ -dependent PDEs can degrade both cAMP and cGMP;
Since the Km is lower, using cGMP as a substrate allows the maximum reaction rate to be obtained at a lower concentration.

The composition of the oxygen activity measurement reaction solution was 0.4M Tris.
HCl (PH8.0) 50μl, 50mM MgCl ₂ 50μl, 1m
50μl of M _CaCl2 (or 10mM EGTA), 1
mg/ml bovine serum albumin 50μl, Ca ²⁺ PDE (prepared from rat brain), calmodyulin 200n
g (prepared from bovine brain) and the drug.
The volume was 450 μl. There 4 μM [ ^3H ]-cGMP
The reaction was started by adding 50 μl of (2.5 μCi/ml).
The reaction was typically incubated at 30° for 15 minutes, heated in boiling water for 3-5 minutes, and cooled in ice water. The [ ³ H]− generated here
Start the operation to decompose GMP into [ ³ H]-guanosine. 5-nucleotidase (Snake venum) was added to the reaction solution and incubated again at 30° for 10 minutes. This completes all enzymatic reactions and transfers the reaction solution to a cation exchange resin (BioRad Co., Ltd.).
AG50x4, 200 to 400 mesh) column to adsorb the generated [ ³ H]-guanosine. Add about 2 ml of water to the reaction solution (550 μl) and pour it directly into the column. Wash the test tube with a small amount of water and pour the washing solution into the column as well. After washing the column with about 20 ml of water, [ ^3H ]-guanosine adsorbed on the resin is eluted with 1.5 ml of 3N- _NH4OH , and the eluate is directly received in a vial. Next, emulsified scintillation solution was added to the eluate received in a vial, and radioactivity was measured. Enzyme activity in the presence of Ca ²⁺ was defined as 100, and enzyme activity in the presence of EGTA was defined as 0. IC ₅₀ is the concentration of drug that gives 50% inhibition
And so.

(Results) Compound of the present invention Example 1 IC ₅₀ =66 μM When measuring the activity of basal PDE, the enzyme activity of the same enzyme as above in the presence of EGTA is measured.
In this case, the enzyme activity in the presence of EGTA is taken as 100,
The activity in the absence of enzyme is set to 0. The percent inhibition was determined from the activity when the drug was added to the reaction solution. Normally, enzyme activity in the presence of EGTA is low;
Measure with approximately 5 times the amount of enzyme as in the case of Ca ²⁺ PDE measurement.

(Results) Compound of the present invention Example 1 = 9.1% (9.1% (100 μM) c cAMP/cGMP-PDE (cyclic AMP/cyclic
Effect on GMP2phos phodiesterase) 0.4μM [ ^8-3H ]cAMP or cGMP
(100000cpm), 5mM MgCl ₂ , 0.1mg/ml bovine serum albumin, 1mMEGTA, 50mM
Tris-HCl (PH8.0), cAMP or cGMP-PDE
(prepared from human platelets) and a tissue containing the drug in a total volume of 0.5 ml. After incubating at 30° for 15 minutes, the reaction was stopped by heating in a boiling water bath for 3-5 minutes. Here, the substrate [8
− ³ H]cAMP or cGMP by PDE
5′−[8− ³ H]−AMP or 5′−[8− ³ H]−
Hydrolyzed to GMP. Additionally, 1 mg/ml 5'-nucleotidase (Crotalus atrox, Sigma,
Add 50 μl of Snake venum) to the reaction mixture and incubate at 30°.
After incubating for 10 minutes, finally [8-
^3H ] Adenosine or guanosine can be obtained. These nucleosides and unreacted substrates were removed using a cation exchange resin (Bio Rad AG
50x4, 200−400 mesh) column,
Only the generated [8- ³ H]adenosine or guanosine was adsorbed. Reaction solution (0.55ml)
Approximately 2 ml of water was added to the solution and poured directly into the column.The test tube was then washed with a small amount of water, and the washing solution was also poured into the column. After washing the column with about 20 ml of water, [8- ³ H]-adenosine or guanosine adsorbed on the resin was eluted with 1.5 ml of 3 N-NH ₄ OH, and the eluate was collected in a vial. 8 ml of emulsified scintillation liquid was added to this, and radioactivity was measured. Inhibition of the drug reduces the activity in the presence of the enzyme by 100
The % inhibition was determined from the activity in the presence of the drug, with the activity in the absence of the enzyme being set to 0. Also,
The concentration of drug that gave 50% inhibition was defined as _IC50 .

(Results) Compound of the present invention Example 1 cAMP inhibition % = 36.6% (100 μM) cGMP IC ₅₀ = 90 μM d Effect on C kinase Incorporation of radioactive phosphate of [γ- ³² P]ATP into the substrate (Histones) was measured. Enzyme activity was measured. Its composition is 25mM Tris−
HCl (PH7.0), 10mM _MgCl2 , 1mM
CaCl ₂ , 40 μg Histone s, 50 μg phosphatidylserine, 10 μM 2-mercaptoethanol, C kinase (prepared from rabbit brain),
and drugs. Reactions were performed at 30°, 100 μM
Start by adding 20μl of [γ- ^32P ]ATP, 20%
It was stopped by adding 0.5ml TCA. After stopping the reaction, add 3ml of 5% TCA and 0.1ml of 1mg/ml albumin solution.
ml and centrifuged to fix the acid-insoluble protein on the bottom of the test tube. The supernatant was removed, 3 ml of 5% TCA was added, and the mixture was centrifuged. After repeating this operation two to three times, the precipitated protein was dissolved in 2 ml of 1N-NaOH, placed in a vial containing approximately 10 ml, and measured using a liquid scintillation counter using the Cherenkov effect. The activity in the presence of phosphatidylserine was defined as 100, and the activity in the absence of phosphatidylserine was defined as 0.
The percent inhibition was measured from the activity when the drug was added to the reaction solution.

(Results) Compound of the present invention Example 1 Inhibition % = 45.3% (100 μM) e Effect on A kinase Using Histone H2B as a substrate, [γ- ³² P]ATP
Enzyme activity was measured by measuring the amount of radioactive phosphate incorporated into the substrate protein. The total volume of the reaction solution was 200ml, and its composition was 25mM.
Tris-HCl (PH7.0), 10mM Mg acetate, 2
mM EGTA, 40 μg Histone H2B, A kinase (prepared from rabbit skeletal muscle), 1 μM cyclic
AMP and drugs. The reaction was carried out at 30°.
Start by adding 20 μl of 100 μM [γ- ³² P]ATP,
It was stopped by adding 0.5 ml of 20% TCA. After stopping the reaction, add 3ml of 5% TCA and 1mg/ml albumin solution.
0.1 ml was added and centrifuged to fix the acid-insoluble protein at the bottom of the test tube. The supernatant was removed, 3 ml of 5% TCA was added, and the mixture was centrifuged. After repeating this operation 2-3 times,
The precipitated protein was dissolved in 2 ml of 1N NaOH, placed in a vial containing about 10 ml, and measured using a liquid scintillation counter using the Cherenkov effect. The activity in the presence of cAMP was set as 100, and the activity in the absence of cAMP was set as 0. From the activity when the drug is added to the reaction solution, calculate the concentration of the drug that causes 50% inhibition.
It was set as IC ₅₀ .

(Results) Compound of the present invention Example 1 IC ₅₀ = 85 μM f Effect on vascular smooth muscle Rabbits weighing 1.9 to 2.8 kg were sacrificed by exsanguination and laparotomy was performed to remove the superior mesenteric artery (outer diameter 2.0 to 3.0 mm). The extracted blood vessels were incised in a spiral shape according to a conventional method, and specimens were prepared with a width of 1.5 to 2.5 mm and a length of 20 to 30 mm. The helical strip specimen was placed in 20 ml Krebs-Henseleit solution kept at 37 ± 0.5°.
g - 0.5 g of tension was applied and suspended. These nutrient solutions are always kept warm at 37±5° with 95% oxygen and 5% oxygen.
It was aerated with carbon dioxide mixed gas. The lower end of the specimen was fixed, and the upper end was connected to a Nihon Kohden FD transducer (SB-1T) to record isometric tension changes. The specimen should be prepared at least before starting the experiment.
Suspend in the nutrient solution for 60 minutes, during which time the nutrient solution
It was replaced every 15 minutes and used for experiments.

To determine the vascular smooth muscle relaxing effect, a spiral strip preparation was contracted in advance with 20 mM KCl and a constant tension was maintained, and then the drug of interest was cumulatively administered. The relaxation effect is expressed as the contraction tension due to KCl as 100%,
ED ₅₀ is expressed as the concentration of drug that causes 50% relaxation.

(Results) Compound of the present invention Example 1 ED ₅₀ = 6.1 μM g Effect on platelet aggregation Blood was collected from a healthy person, 1/10 Vol of 0.38% sodium citrate was added, and immediately mixed at 700 x g
Platelet rich blood (PRP) was obtained by centrifugation for 10 minutes and transferred to another plastic tube.
Add 1/6Vol ACD solution (prepared before use) to PRP,
Centrifugation was performed at 1500xg for 10 minutes, and the resulting platelet pellet was mixed with a modified HEPES Tyrode solution (145mM NaCl, 5mM KCl, 0.5mM
MgSO ₄ , 1mM NaH ₂ PO ₄ , 5mM
Glucose, 10mM HEPES, PH7.4). Furthermore, the platelet pellet obtained by centrifugation at 1500xg for 5 minutes was modified in the same way.
They were suspended in HEPES Tyrode solution and used as a washed platelet suspension for experiments.

To measure platelet aggregation, add an aggregation inducer to PRP or platelet suspension and stir.
Changes in turbidity caused by aggregation are detected using photocells and recorded over time. 270μl
Drugs of each concentration dissolved in saline to washed platelets of
30 μl was added and prewarmed at 37° for 1 minute. Thereafter, 3 to 6 μl of Horm (derived from horse Achilles tendon) collagen solution containing 100 μg/mM was added to induce an agglutination reaction, and changes in absorbance over time were recorded.
As a control, use a solvent in which the drug is dissolved and measure the absorbance that gives maximum aggregation by collagen.
100, and the absorbance before adding collagen is 0. Then, the drug was added, and the percent inhibition was determined from the absorbance that gave maximum aggregation by collagen at that time.

(Results) Invention compound Example 1 Inhibition % = 41.2% (100μM) Hereinafter, the present invention will be explained with reference to Examples.

Example 1 1-(5-chlornaphthalene-1-sulfonyl)
-1H-hexahydro-1,4-diazepine
A solution of 1.00 g of 5-chloro-1-naphthalenesulfonyl chloride in 10 ml of chloroform was added dropwise to a solution of 1.92 g of homopiperazine in 20 ml of chloroform while stirring, and the mixture was stirred at room temperature for 24 hours. Add water to the reaction mixture and separate the chloroform layer. Chloroform was distilled off, aqueous hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer is washed with water and then dehydrated. Evaporation of the solvent gives 1.37 g of a brown oil. Prepare the hydrochloride according to conventional methods.
Recrystallize from methanol to obtain 1.00 g of colorless prism crystals with a melting point of 198-200°.

Elemental analysis value C ₁₅ H ₁₇ ClN ₂ O ₂ S・HCl・1/2H ₂ O Theoretical value C 48.65; H 5.17; N 7.57 Experimental value C 48.49; H 5.42; N 7.55 Example 2 1-(5-Chlornaphthalene -1-sulfonyl)
Piperazine Hydrochloride Piperazine Hexahydrate 2.10g Chloroform 50
2.10 g of 5-chloro-1-naphthalenesulfonyl chloride in 20 ml of chloroform under ice cooling.
After dropping the solution, stir at room temperature for 30 minutes. The reaction solution was concentrated, the resulting residue was dissolved in an aqueous hydrochloric acid solution,
Wash with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and then extracted with ethyl acetate. After the ethyl acetate layer is dehydrated, the solvent is distilled off. The obtained residue was dissolved in chloroform, ethanolic hydrochloric acid was added, and the precipitated crystals were collected by filtration to give 2.00 g of pale yellow crystals.
get. Recrystallized from methanol, melting point 216 ~
Obtain pale yellow crystals of 218°.

Elemental analysis value C ₁₄ H ₁₅ ClN ₂ O ₂ S・HCl Theoretical value C 48.42; H 4.64; N 8.07 Experimental value C 48.12; H 4.95; N 7.81 Example 3 1-(5-bromonaphthalene-1-sulfonyl)
-1H-hexahydro-1,4-diazepine・
Hydrochloride A solution of 2.50 g of 5-bromo-1-naphthalenesulfonyl chloride in 20 ml of chloroform was added dropwise to a solution of 3.30 g of homopiperazine in 10 ml of chloroform while stirring on ice, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the same treatment as in Example 2 was carried out to obtain 2.60 g of pale yellow crystals. Recrystallized from methanol, melting point 196-200°
Obtain pale yellow crystals.

Elemental analysis value C ₁₅ H ₁₇ BrN ₂ O ₂ S・HCl Theoretical value C 44.40; H 4.47; N 6.90 Experimental value C 44.10; H 4.71; N 6.56 Example 4 1-(5-iodonaphthalene-1-sulfonyl)
-1H-hexahydro-1,4-diazepine・
Hydrochloride 5.00 g of potassium salt of 5-iodo-1-naphthalenesulfonic acid and 10.00 g of phosphorus pentachloride are heated and stirred at 50° for 1 hour. Pour the reaction solution into ice water and extract with benzene. After drying the benzene layer, the solvent was distilled off,
3.00 g of 5-iodo-1-naphthalenesulfonyl chloride was obtained as pale yellow crystals. Next, a solution of 3.00 g of the obtained sulfonyl chloride in 20 ml of chloroform was added dropwise to a solution of 3.40 g of homopiperazine in 10 ml of chloroform while stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the same treatment as in Example 2 is carried out to obtain 2.60 g of light brown crystals. Recrystallization from a mixture of methanol, water and ether gives brown needles with a melting point of 246-248°6.

Elemental analysis value C ₁₅ H ₁₇ IN ₂ O ₂ S・HCl Theoretical value C 39.79; H 4.01; N 6.19 Experimental value C 39.74; H 4.28; N 5.96 Example 5 1-(6-Chlornaphthalene-1-sulfonyl)
-1H-Hexahydro-1,4-diazepine A solution of 1.40 g of 6-chloro-1-naphthalenesulfonyl chloride in 20 ml of chloroform was added dropwise to a solution of 2.00 g of homopiperazine in 10 ml of chloroform while stirring on ice, and the mixture was stirred at room temperature for 30 minutes. do. The following treatment was carried out in the same manner as in Example 2, and the resulting residue was subjected to column chromatography (carrier: silica gel; distillation solvent:
Chloroform → Chloroform: Methanol = 9:
Purify in step 1) to obtain 0.90 g of colorless crystals. Construct hydrochloride using conventional methods. Recrystallized from methanol,
Colorless needles with a melting point of 234-235° are obtained.

Elemental analysis value C ₁₅ H ₁₇ ClN ₂ O ₂ S・HCl Theoretical value C 49.87; H 5.02; N 7.75 Experimental value C 49.81; H 5.25; N 7.45 Reference example 1 6-bromo-1-naphthalenesulfonic acid potassium salt 6 -Amino-1-naphthalenesulfonic acid 5.00g
Sodium carbonate was added to a 30 ml suspension of water at room temperature under stirring.
Add 1.30g to dissolve all the sulfonic acid. Subsequently, 7 ml of 47% hydrobromic acid was added to the reaction solution, cooled on ice, and 1.70 g of sodium nitrite was added to water at an internal temperature of 0 to 5°.
Gradually add 12 ml of solution dropwise. After the addition, the reaction solution is stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, and 3.54 g of cuprous bromide was cooled to below 0° in advance.
% hydrobromic acid solution (43 ml) under stirring. After addition, the reaction was incubated at room temperature for 30 min and then at 80°.
After stirring for 30 minutes, cool on ice. Filter the precipitated crystals and add water
Dissolve in 50ml. A 50% aqueous potassium hydroxide solution is added, and the precipitated crystals are collected by filtration to obtain 2.39 g of light brown crystals. Recrystallize from water to obtain pale brown crystals with a melting point of over 300°.

Example 6 1-(6-bromonaphthalene-1-sulfonyl)
-1H-hexahydro-1,4-diazepine 2.00 g of potassium salt of 6-bromo-1-naphthalenesulfonic acid and 4.00 g of phosphorus pentachloride are heated and stirred at 60° for 1 hour. Pour the reaction solution into ice water and extract with benzene. After drying the benzene layer, the solvent was distilled off, and 1.80 g of the sulfonyl chloride was obtained as a brown oily substance.
obtain. Next, 2.50 g of homopiperazine in chloroform
After dropping a solution of 1.80 g of the obtained sulfonyl chloride in 20 ml of chloroform into the 10 ml solution while stirring on ice,
Stir for 30 minutes at room temperature. Thereafter, the same procedure as in Example 5 was carried out to obtain 1.30 g of a yellow oily substance. Construct hydrochloride using conventional methods. Recrystallization from methanol gives colorless needles with a melting point of 239-241° (decomposition).

Elemental analysis value C ₁₅ H ₁₇ BrN ₂ O ₂ S・HCl Theoretical value C 44.40; H 4.47; N 6.90 Experimental value C 44.16; H 4.69; N 6.61 Reference example 2 6-iodo-1-naphthalenesulfonic acid potassium salt 6 -Amino-1-naphthalenesulfonic acid 5.00g
Sodium carbonate was added to a 30 ml suspension of water at room temperature under stirring.
Add 1.30g to dissolve all the sulfonic acid. Subsequently, 7 ml of concentrated hydrochloric acid is added to the reaction solution, and a solution of 1.70 g of sodium nitrite in 12 ml of water is gradually added dropwise at an internal temperature of 0 to 5°. After the addition, the reaction solution is stirred at room temperature for 30 minutes. Then, under ice cooling, 4.12 g of potassium iodide was added to 6
ml solution and at room temperature for 30 minutes, then bring the internal temperature to 80°.
Stir for 30 minutes. Add 4.27 g of sodium hydrogen sulfite to the reaction mixture under ice-cooling, stir at room temperature for 10 minutes, and collect the precipitated crystals by filtration. Dissolve the precipitated crystals in water, add 50% aqueous potassium hydroxide solution, and filter the precipitated crystals to obtain 1.30 g of pale red crystals. Recrystallize from water to obtain pale red crystals with a melting point of over 300°.

Example 7 1-(6-iodonaphthalene-1-sulfonyl)
-1H-hexahydro-1,4-diazepine 6-iodo-1-naphthalenesulfonic acid potassium salt 1.10 g, phosphorus pentachloride 3.00 g and homopiperazine 1.60 g were treated in the same manner as in Example 6 to produce a colorless Obtain 0.60 g of crystals. Recrystallize from ethanol to obtain pale yellow crystals with a melting point of 129-130°.

Elemental analysis value C ₁₅ H ₁₇ IN ₂ O ₂ S Theoretical value C 43.28; H 4.12; N 6.73 Experimental value C 43.43; H 4.29; N 6.12 Example 8 1-(Naphthalene-1-sulfonyl)-1H-hexahydro-1 , 4-Diazepine hydrochloride To a solution of 5.50 g of homopiperazine in 10 ml of chloroform, a solution of 2.50 g of α-naphthalene sulfonium chloride in 20 ml of chloroform was added dropwise under ice-cooling and stirring.
Stir for 30 minutes at room temperature. Thereafter, treatment was carried out in the same manner as in Example 2 to obtain 3.10 g of colorless crystals. Recrystallization from ethanol gives colorless needles with a melting point of 203-205°.

Elemental analysis value C ₁₅ H ₁₈ N ₂ O ₂ S・HCl Theoretical value C 55.12; H 5.86; N 8.57 Experimental value C 55.21; H 5.86; N 8.37

Claims (1)

[Claims] 1. General formula (In the formula, n represents an integer of 2 or 3, and X represents a hydrogen atom or a halogen atom.) A naphthalene sulfonamide derivative represented by the following formula, and a pharmacologically acceptable acid addition salt thereof.