JPH0859658A - New isoquinoline derivative and its acid addition salt - Google Patents

Abstract

PURPOSE: To obtain a new compound, having inhibiting activities against kallikrein and useful for treating and preventing diseases caused by the production of the kallikrein such as pancreatitis. CONSTITUTION: A compound of formula I (R<1> is H, a 1-4C alkyl, phenyl or benzyl), e.g. ethyl 5-[4-(4,5-dihydro-1H-imidazol-2yl)amino] benzoyloxy-1- isoquinolinecarboxylate hyd-rochloride hydrate. The compound of formula I is obtained by carrying out the dehydrating reaction of 4-(4,5-dihydro-1H- imidazol-2yl)aminobenzoic acid of formula II or its reactive derivative with a 5- or a 6-hydroxyisoquinoline compound of formula III (R<2> and R<3> are each H or OH) or its reactive derivative in the presence of a catalyst (e.g. sulfuric acid) and a condensing agent (e.g. diphenylphosphoryl azide) at -30 to +100 deg.C.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 5 or 6-
[4- (4,5-dihydro-1H-imidazole-2-
It relates to an yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid derivative and a pharmaceutically acceptable acid addition salt thereof. The compound of the present invention has kallikrein inhibitory activity, and is useful as a therapeutic agent for diseases caused by kallikrein.

[0002]

2. Description of the Related Art When prekallikrein contained in zymogen granules escapes into intercellular spaces due to cell disruption or the like, kallikrein is produced by being activated by Hageman (XII) factor or trypsin. The generated kallikrein is
By decomposing kininogen in extracellular fluid to release kinin, kinin has actions such as vasodilation and enhancement of capillary permeability, resulting in edema, promoting bleeding, and causing shock. Because of this, kallikrein
For example, it is considered to be involved in the onset and progression of diseases such as pancreatitis. Therefore, inhibition of kallikrein activity is considered to be effective against diseases such as pancreatitis, and its development has been desired.

[0003]

As a result of various studies on compounds having kallikrein-inhibiting activity, the present invention has completed the present invention by finding that a specific isoquinolinecarboxylic acid derivative has such an action. .
That is, an object of the present invention is to provide a novel compound having kallikrein inhibitory activity.

[0004]

Means for Solving the Problems The present inventor has made the following equation (I)
And a novel 5 or 6- [4- (4,5-dihydro-1H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid derivative represented by the formula and a pharmaceutically acceptable acid addition salt thereof Has been found to have excellent pancreatic kallikrein inhibitory activity, and completed the present invention.

That is, the present invention has the formula (I)

Embedded image 5 or 6- [4- (4,5-dihydro-1
H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid derivative and a pharmaceutically acceptable acid addition salt thereof. [In the formula, R ¹ represents a group selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a phenyl group and a benzyl group. Further, the 4- [4,5-dihydro-1H-imidazol-2-yl) aminobenzoyloxy group is
It is bonded to the 5- or 6-position of the isoquinoline ring. The compound (I) of the present invention has the following formula (II)

[Chemical 3] 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid or a reactive derivative thereof represented by the following formula (III)

[Chemical 4] [In the formula, R ² and R ³ are different and each represents a hydrogen atom or a hydroxyl group. R ¹ has the same meaning as in formula (I)] and is obtained by reacting a 5- or 6-hydroxyisoquinoline compound represented by the above or a reactive derivative thereof. Also, 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid (II) and 5 or 6
-Reaction with a hydroxyisoquinoline compound (III)
A general dehydration reaction can be applied. For example,
(A) Free 4- (4,5-) in the presence of a catalyst, a condensing agent, etc.
A method of reacting dihydro-1H-imidazol-2-yl) aminobenzoic acid (II) or an acid addition salt thereof with a compound (III) or an acid addition salt thereof, (b) 4- (4,5)
-Dihydro-1H-imidazol-2-yl) aminobenzoic acid (II) reactive derivative with compound (III), (c) free 4- (4,5-dihydro-1)
A method of reacting H-imidazol-2-yl) aminobenzoic acid (II) with a reactive derivative of compound (III) can be applied.

Examples of the catalyst in the method (a) include acid catalysts such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, phosphorus oxychloride, polyphosphoric acid and boron trifluoride. Examples of the condensing agent include diphenylphosphoryl azide, dicyclohexylcarbodiimide, N, N'-carbodiimidazole, N, N'-disuccinimidyl carbonate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and dimethyl. Formamide diethyl acetal, N, N'-dimethylphosphoramidic dichloride, phenyl dichlorophosphate can be used. This time,
A base catalyst such as dimethylaminopyridine or pyrrolidinopyridine can also be used in combination.

The reaction conditions vary depending on the catalyst or condensing agent used, but when dicyclohexylcarbodiimide as a condensing agent is used, 4- (4,5) is used in a solvent.
-Dihydro-1H-imidazol-2-yl) aminobenzoic acid (II) is reacted with dicyclohexylcarbodiimide, to which a solution of compound (III) is added, and in the presence or absence of a base, -30 to The reaction is completed by stirring at 100 ° C. for several hours to several days.

The solvent used at this time is a general organic solvent such as pyridine, dimethylformamide, chloroform, dichloromethane, carbon tetrachloride, benzene,
Toluene, xylene, diethyl ether, dioxane,
Tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide and the like and water can be mentioned. Examples of the base include pyridine, triethylamine, diisopropylethylamine, di-t-butylamine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene and the like. Can be mentioned.

Examples of the reactive derivative of carboxylic acid (II) in the method (b) include acid halides such as acid chloride and acid bromide; mixed acid anhydrides such as trifluoroacetic acid, methanesulfonic acid and benzenesulfonic acid. Mixed acid anhydrides such as isobutoxyformic acid; onium salts, eg 2
-Bromo-1-pyridinium iodide, 2-chloro-
3,5-dinitropyridine, 2-chloro-1-methylpyridinium iodide; active esters such as p-nitrophenyl ester and N-O-succinimide ester.

The reaction conditions vary depending on the reactive derivative used. For example, when an acid chloride is used, the acid chloride and compound (III) are added in a solvent in the presence or absence of a base at −30 to 100 ° C. The reaction is completed by stirring for several hours to several days.

Examples of the solvent used at this time include general organic solvents such as pyridine, chloroform, dichloromethane, benzene, toluene, xylene, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide and dimethylsulfoxide. Further, as the base, triethylamine, diisopropylethylamine, di-t-butylamine, pyridine, dimethylaminopyridine, pyrrolidinopyridine, N
-Methylmorpholine, 1,8-diazabicyclo [5,5
4,0] -7-undecene or the like can be used.

Further, the compound (III) in the method (c)
As the reactive derivative of, for example, its trifluoroacetic acid ester, or the formula (IV)

[Chemical 5] (In the formula, III ′ represents a hydroxyl residue of the compound represented by (III) above) and the like can be used.

In order to isolate and purify the compound (I) of the present invention from the reaction solution, extraction, concentration, crystallization, filtration, recrystallization,
It can be performed by applying chemical operations commonly used for isolation and purification such as various chromatography.

The compound (I) of the present invention obtained as described above can be converted to an acid addition salt by a conventional method, if necessary. Examples of the acid include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid and carbonic acid, and acetic acid, lactic acid, succinic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid,
Organic acids such as toluenesulfonic acid and benzenesulfonic acid can be used.

The in vitro inhibitory activity of the 5- or 6-substituted isoquinoline derivative of formula (I) on pancreatic kallikrein can be determined by the method of Morita et al. [The Journal
The Journal of Biochemist
ry), 82 , 1495 (1977)] and the method of Kato et al. [The Journal of Biochemistry (TheJo
urnal of Biochemistry), 87 , 1127 (198)
0)] as a basic method and a slight modification. That is, the reaction of pancreatic kallikrein at 37 ° C for 15 minutes hydrolyzes the substrate prolylphenylalanylarginyl-4-methylcoumarin-7-amide (Pro-Phe-Arg-MCA) by 50%. The inhibitory concentration was measured. Table 1 shows 50% inhibitory concentrations of typical compounds among the compounds represented by the formula (I). The test compound numbers and structural formulas of the compounds of the present invention are as follows.

[0016]

Embedded image Test compound number Structural formula 1) 5- [4- (4,5-dihydro-1H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid benzyl hydrochloride 1/2 hydrate 2) 6- [4- (4,5-Dihydro-1H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid benzyl hydrochloride

[0017]

[Table 1] ────────────────────── Test compound number 50% inhibitory concentration (μM) ─────────────── ──────── 1) 10 2) 3.0 ──────────────────────

As described above, the compound (I) of the present invention has a pancreatic kallikrein inhibitory action and is useful as a therapeutic agent for diseases caused by kallikrein, such as pancreatitis. When the compound (I) of the present invention is used as a medicine, it is orally or parenterally prepared into a dosage form such as tablets, capsules, granules, powders or injections using a suitable excipient, carrier, diluent or the like. Can be administered to.

The present invention will be described below with reference to Reference Examples and Examples, which are for the purpose of facilitating the understanding of the present invention by means of specific examples, and the production of the compound of the present invention is limited thereby. is not.

[0020]

[Reference Example 1] Ethyl 5-hydroxy-1-isoquinolinecarboxylate 4.16 g of 5-hydroxy-1-isoquinolinecarboxylic acid was suspended in 75 ml of ethanol, and hydrogen chloride was introduced to saturate the solution in the cold state, followed by heating under reflux for 17 hours. . The solvent was concentrated under reduced pressure, and the residue was recrystallized from hydrous ethanol to obtain 2.60 g of the title compound having the following melting point. Melting point: 152-153 ° C

[0021]

[Reference Example 2] 11.38 g of phenyl 5 -hydroxy-1-isoquinolinecarboxylic acid phenyl 5-benzyloxy-1-isoquinolinecarboxylic acid was dissolved in 300 ml of methanol, and 0.33 g of 10% palladium-activated carbon was added, and the mixture was allowed to stand at room temperature under a hydrogen stream. It was stirred vigorously for 52 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crystalline residue was recrystallized from ethanol-water to give 5.14 g of the title compound having the following melting point. Melting point: 190-192 ° C

[0022]

Reference Example 3 Benzyl 5-hydroxy-1-isoquinolinecarboxylate 3.00 g of 5-hydroxy-1-isoquinolinecarboxylic acid was suspended in 20 ml of ethanol, and an ethanol solution in which 1.05 g of potassium hydroxide was dissolved was added, followed by concentration under reduced pressure. did. The residue was suspended in 20 ml of dimethylformamide and benzyl iodide 4.
16 g was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 27 hours. The reaction mixture was poured into 200 ml of a 5% aqueous sodium thiosulfate solution and extracted with ethyl acetate (100 ml × 3). The organic layer was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to obtain 1.14 g of the title compound having the following melting point. Melting point: 165-166 ° C

[0023]

Reference Example 4 Ethyl 6-hydroxy-1-isoquinolinecarboxylate 5.10 g of 6-hydroxy-1-isoquinolinecarboxylic acid was suspended in 25 ml of ethanol, 25 ml of saturated hydrogen chloride-ethanol solution was added, and the mixture was heated under reflux for 70 hours. The reaction mixture was concentrated under reduced pressure to about half the amount, and the precipitated crystals were collected by filtration. The obtained crystals were suspended in water (15 ml), neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml × 3),
The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude crystals. The obtained crude crystals were recrystallized from ethanol-water to give 5.14 g of the title compound having the following melting point. Melting point: 194-195.5 ° C

[0024]

Reference Example 5 Benzyl 6-hydroxy-1-isoquinolinecarboxylate 10.00 g of 6-hydroxy-1-isoquinolinecarboxylic acid was dissolved in 100 ml of dimethylformamide, 11.1 g of sodium hydrogen carbonate was added, and 9.92 g of benzyl bromide was added for 10 minutes. It dripped over, and also stirred at 80 degreeC for 1 hour. Reaction mixture with ice water
After pouring into 100 ml and extracting with ethyl acetate (100 ml × 3), the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a red oily substance. When the obtained oily substance was crystallized from ethanol-water,
6.97 g of the title compound was obtained with the following melting point. Melting point: 143-
144 ° C

[0025]

Example 1 5- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Ethyl carboxylic acid hydrochloride monohydrate 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid 2.05 g was added with thionyl chloride 20 ml 45
Heated to reflux for minutes. 4- (4,5-Dihydro-1H-imidazol-2-yl) aminobenzoic acid chloride hydrochloride was obtained by adding n-hexane to the reaction mixture for crystallization and collecting the precipitated crystals by filtration. To a solution of 1.52 g of ethyl 1-isoquinolinecarboxylate in 20 ml of pyridine was added at -5 ° C,
The reaction temperature was raised to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel 42 g, developing solvent; chloroform-methanol-acetic acid = 9: 1: 1) to give an oil. The obtained oily substance was diluted with 14 ml of methanol and adjusted to pH 2 with 2N-hydrochloric acid, and 50 ml of ether was added for crystallization to give 1.80 g of the title compound having the following physical properties (yield 5
8.3%).

Melting point: 130 to 135 ° C. IR: ν ^KBr cm ⁻¹ : 3400,1740,1660,1600. Elemental analysis value: calculated as C ₂₂ H ₂₀ N ₄ O ₄ .HCl.H ₂ O C (%) H (%) N (%) Theoretical value 57.58 5.05 12.21 Actual value 57.71 5.05 12.33

[0027]

Example 2 5- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Phosphorus carboxylic acid hydrochloride 3/2 hydrate 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid 2.05 g, thionyl chloride 20 ml, phenyl 5-hydroxy-1-isoquinolinecarboxylic acid 1.86,
When 20 ml of pyridine was used and the reaction and post-treatment were carried out according to the method described in Example 1, 1.76 g (yield 51.4%) of the title compound having the following physical properties was obtained.

Melting point: 141 to 149 ° C. IR: ν ^KBr cm ⁻¹ : 3400,1740,1650,1600. Elemental analysis value: calculated as C ₂₆ H ₂₀ N ₄ O ₄ .HCl.3 / 2H ₂ O C (% ) H (%) N (%) Theoretical value 60.53 4.69 10.86 Measured value 60.77 4.75 10.70

[0029]

Example 3 5- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Benzylcarboxylate hydrochloride hemihydrate 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid 2.05 g, thionyl chloride 20 ml, benzyl 5-hydroxy-1-isoquinolinecarboxylate 1.87 g
Using 20 ml of pyridine, the reaction and post-treatment were carried out according to the method described in Example 1 to obtain 1.76 g (yield 51.4%) of the title compound having the following physical properties.

Melting point: 139 to 143 ° C. IR: ν ^KBr cm ⁻¹ : 3450,1735,1650,1590. Elemental analysis value: calculated as C ₂₇ H ₂₂ N ₄ O ₄ .HCl.1 / 2H ₂ O C (% ) H (%) N (%) Theoretical value 63.34 4.73 10.94 Measured value 63.60 5.03 10.94

[0031]

Example 4 5- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Carboxylic acid hydrochloride hemihydrate obtained by the method described in Example 3 5- [4- (4,5-
Dihydro-1H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid benzyl hydrochloride hemihydrate (1.00 g) in 30% hydrogen bromide-acetic acid solution (8 ml)
And was stirred at room temperature for 40 hours. Acetone 50 ml was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid obtained was dissolved in 4.2 ml of dimethylsulfoxide and dissolved in 15 ml of water.
Dilute with and add saturated aqueous sodium hydrogen carbonate solution under ice cooling.
After adjusting the pH to 8 and further diluting with 15 ml of water, the precipitated solid matter was collected by filtration. The obtained solid was suspended in 7 ml of methanol, adjusted to pH 2 with 2N hydrochloric acid, and crystallized by adding 20 ml of acetone to give 1.76 g of the title compound having the following physical properties (yield 5
1.4%).

Melting point: 156 to 160 ° C. IR: ν ^KBr cm ⁻¹ : 3500 to 2800,1745,1695,1600. Elemental analysis value: calculated as C ₂₀ H ₁₆ N ₄ O ₄ .HCl.1 / 2H ₂ O (%) H (%) N (%) Theoretical 56.95 4.30 13.28 Actual 56.96 4.33 13.21

[0033]

Example 5 6- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Ethyl carboxylic acid hydrochloride 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid 0.63 g was added with thionyl chloride 6.4 ml.
Heated to reflux for 45 minutes. The reaction mixture was crystallized by adding n-hexane, and the precipitated crystals were collected by filtration to give 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoyl chloride hydrochloride as 6-hydroxy- A solution of 0.44 g of ethyl 1-isoquinolinecarboxylate in 6.4 ml of pyridine was added at -5 ° C, and the reaction temperature was raised to room temperature and stirred for 1 hour. 30 ml of acetone was added to the reaction mixture, and the precipitated crystals were collected by filtration.
The obtained crystals were recrystallized from methanol to give 0.41 g (yield 45.4%) of the title compound having the following physical properties.

Melting point: 213.5 to 215.5 ° C. IR: ν ^KBr cm ⁻¹ : 3500 to 2700,1740,1660,1600.

[0035]

Example 6 6- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Benzyl carboxylic acid hydrochloride 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoic acid 1.45 g, thionyl chloride 15 ml, ethyl 6-hydroxy-1-isoquinolinecarboxylate 1.35 g,
The reaction and post-treatment were carried out according to the method described in Example 5 using 15 ml of pyridine to obtain 1.34 g (yield 52.6%) of the title compound having the following physical properties.

Melting point: 148 to 149.5 ° C. IR: ν ^KBr cm ⁻¹ : 3500 to 2700,1740,1660,1600.

[0037]

Example 7 6- [4- (4,5-dihydro-1H-imidazole-
2-yl) amino] benzoyloxy-1-isoquinoli
Carboxylic acid hydrochloride 4/1 hydrate 6- [4- (4,5-obtained by the method described in Example 6)
Dihydro-1H-imidazol-2-yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid benzyl hydrochloride 0.50 g was dissolved in 30% hydrogen bromide-acetic acid solution 4 ml,
Stir at room temperature for 7 days. 10 ml of acetone was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid is dissolved in 1.5 ml of dimethyl sulfoxide, diluted with 6 ml of water,
Under ice cooling, add saturated aqueous sodium hydrogen carbonate solution to adjust the pH to 8,
After further diluting with 6 ml of water, the precipitated solid matter was collected by filtration. The obtained solid was suspended in 3 ml of methanol and adjusted to pH 2 with 2N hydrochloric acid, and then 10 ml of acetone was added for crystallization to obtain 0.14 g (yield 33.0%) of the title compound having the following physical properties.

Melting point: 196 to 199 ° C. IR: ν ^KBr cm ⁻¹ : 3400 to 2700,1720,1660,1630,1600,1
520. Elemental analysis value: calculated as C ₂₀ H ₁₆ N ₄ O ₄ · HCl · 1 / 4H ₂ O C (%) H (%) N (%) theoretical value 57.70 4.23 13.46 measured value 57.61 4.42 13.55

[0039]

INDUSTRIAL APPLICABILITY The novel isoquinoline derivative of the present invention or an acid addition salt thereof has a kallikrein inhibitory action and is effective in treating diseases caused by kallikrein, such as pancreatitis.

[Chemical 6]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 233: 44) (72) Inventor Shinichi Shimada 1-10-2 Hyogozuka, Utsunomiya City, Tochigi Prefecture Home 211 (72) Inventor Motohide Seya 773-3 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 3-A (72) Inventor Shin Nomoto 4-11 Gion, Minamikochi-cho, Kawachi-gun, Tochigi 5-102 (72) ) Inventor Masayuki Okue 405 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi Prefecture (72) Inventor Eisuke Tomizuka 1-12-27 Chuo, Kazo City, Saitama Prefecture

Claims (8)

[Claims] 1. A compound represented by the following general formula (I): 5 or 6
-[4- (4,5-dihydro-1H-imidazole-2
-Yl) amino] benzoyloxy-1-isoquinolinecarboxylic acid derivative and a pharmaceutically acceptable acid addition salt thereof. Embedded image [In the formula, R ¹ represents a group selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a phenyl group and a benzyl group. Further, the 4- (4,5-dihydro-1H-imidazol-2-yl) aminobenzoyloxy group is bonded to the 5- or 6-position of the isoquinoline ring]. 2. 5- [4- (4,5-dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
Ethyl 1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 3. 5- [4- (4,5-dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
Phenyl 1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 4. 5- [4- (4,5-dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
Benzyl 1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 5. 5- [4- (4,5-dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
1-Isoquinolinecarboxylic acid or a pharmaceutically acceptable acid addition salt thereof. 6. A 6- [4- (4,5-dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
Ethyl 1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 7. 6- [4- (4,5-Dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
Benzyl 1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 8. 6- [4- (4,5-Dihydro-1H-
Imidazol-2-yl) amino] benzoyloxy-
1-Isoquinolinecarboxylic acid or a pharmaceutically acceptable acid addition salt thereof.