JPH07304744A - New isoquinoline derivative and acid addition thereof salt - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a medicine, having inhibitory action on a proteolytic enzyme. CONSTITUTION:A 6-substituted isoquinoline derivative of formula I (R is H or COOR<1>; R<1> is H, a 1-4C alkyl, phenyl or benzyl) or its acid addition salt such as 6-(4-guanidinobenzoyl)oxyisoquinoline. The compound of formula I is obtained by dehydrating a 4guanidinobenzoic acid of formula II or its reactive derivative with a 6-hydroxyisoquinoline compound of formula III or its reactive derivative in the presence of a catalyst (e.g. sulfuric acid), a condensation agent (e.g. dicyclohexylcarbodiimide), etc., in a solvent (e.g. pyridine) at -30 to 100 deg.C. The compound of formula I has excellent anti-trypsin action and is useful as a therapeutic agent for a disease such as pancreatitis caused by activation of a proteolytic enzyme or a complement.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 6-substituted isoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof. The compounds of the present invention are useful as pharmaceuticals.

[0002]

2. Description of the Related Art Conventionally, various guanidinobenzoic acid derivatives have been used as pharmaceuticals because they have the activity of inhibiting the activities of proteolytic enzymes trypsin, plasmin, thrombin and the like (Japanese Examined Patent Publication No. 49-2107). Japanese Laid-Open Publication No. 52-89640,
Japanese Patent Publication No. 61-1063, etc.). However, the effect is not always sufficient, and further development of a highly safe protease inhibitor has been desired.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a substance having a proteolytic enzyme inhibitory activity which is superior to that of conventional proteolytic enzyme inhibitors.

[0004]

Means for Solving the Problems In the process of studying a novel protease inhibitor, the present inventors have found that a novel 6-substituted isoquinoline derivative represented by the following general formula (I) is an excellent protein. The inventors have found that they have a degrading enzyme inhibitory activity and have completed the present invention.

That is, the present invention relates to a 6-substituted isoquinoline derivative represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof.

[0006]

[Chemical 2] [In the formula, R represents hydrogen or a COOR ¹ group. However, R ¹
Is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms,
A group selected from the group consisting of a phenyl group and a benzyl group is shown. ]

The compound (I) of the present invention comprises 4-guanidinobenzoic acid represented by the formula (II) or a reactive derivative thereof,

[Chemical 3] It can be obtained by reacting with a 6-hydroxyisoquinoline compound represented by the following formula (III) or a reactive derivative thereof.

[Chemical 4] [In the formula, R and R ¹ shown in R are used in the same meaning as above]

For the reaction of 4-guanidinobenzoic acid (II) or its reactive derivative with 6-hydroxyisoquinoline compound (III) or its reactive derivative, a general dehydration reaction can be applied. For example, (a) catalyst,
In the presence of a condensing agent, etc., free 4-guanidinobenzoic acid (I
I) or an acid addition salt thereof and a method for reacting a 6-hydroxyisoquinoline compound (III) or an acid addition salt thereof,
(B) a method of reacting a reactive derivative of 4-guanidinobenzoic acid (II) with a 6-hydroxyisoquinoline compound (III), (c) free 4-guanidinobenzoic acid (II) and a 6-hydroxyisoquinoline compound (II) A method of reacting with the reactive derivative of 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, dimethylformamide diethyl acetal, N, N'-dimethylphosphorylamidic Dichloride, phenyl dichlorophosphate, etc. can be used. At this time, a base catalyst such as dimethylaminopyridine or pyrrolidinopyridine may be used in combination.

The reaction conditions differ depending on the catalyst or condensing agent used. For example, when dicondensing agent dicyclohexylcarbodiimide is used, 4-guanidinobenzoic acid (II) is reacted with dicyclohexylcarbodiimide in a solvent, The reaction is terminated by adding a solution of 6-hydroxyisoquinoline compound (III) to the above and stirring at -30 to 100 ° C for several hours to several days in the presence or absence of a base.

The solvent used at this time is a common organic solvent such as pyridine, dimethylformamide,
In addition to chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide, water and the like can be mentioned. Further, as the base, pyridine, triethylamine, diisopropylethylamine, di-t-butylamine, dimethylaminopyridine, pyrrolidinopyridine, N
-Methylmorpholine, 1,8-diazabicyclo [5,5
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 such as 2-bromo-1-pyridinium iodide, 2-
Chloro-3,5-dinitropyridine, 2-chloro-1-
Methylpyridinium iodide; active esters such as p-nitrophenyl ester, N-O-succinimide ester and the like can be mentioned.

The reaction conditions vary depending on the reactive derivative used. For example, when an acid chloride is used, the acid chloride and the 6-hydroxyisoquinoline compound are used in a solvent.
(III) in the presence or absence of a base -30 to 100
The reaction is completed by stirring at 0 ° C for several hours to several days.

The solvent used at this time is a general organic solvent such as pyridine, chloroform, dichloromethane, benzene, toluene, xylene, dioxane,
Tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide, dimethylsulfoxide and the like can be mentioned. As the base, triethylamine, diisopropylethylamine, di-t-butylamine, pyridine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, etc. Available.

The reactive derivative of the 6-hydroxyisoquinoline compound (III) in the method (c) is, for example, its trifluoroacetic acid ester or the formula (IV).

[Chemical 5] A compound represented by the formula [III 'represents a hydroxyl residue of the 6-hydroxyisoquinoline compound represented by the formula (III)] 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 into 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 inhibition of trypsin of the 6-substituted isoquinoline derivative of the formula (I) is described by Muramatsu et al. [The Journal of Biochemistry, 58. , 214 (1
965)], the results are shown in Table 1 below. Trypsin 1.5 μg was added to the p-
Table 1 shows the concentration of the compound represented by the formula (I) which suppresses the action of hydrolyzing tosylarginine methyl ester (TAME) by 50%. The test compound number of the compound of the present invention and the structural formula of the control drug Foypan (registered trademark, manufactured by Ono Yakuhin) are as follows.

[0019]

[Chemical 6]

[0020]

[Table 1] ───────────────────── Number 50% inhibitory concentration (M) ────────────────── ──── 1) 8.4 × 10 ^-8 2) 7.2 × 10 ^-8 3) 7.8 × 10 ^-8 4) 1.9 × 10 ^-7 5) 1.8 × 10 ^-7 ─────────── ────────── FOIPAN 6.5 × 10 ^-8 ─────────────────────

Thus, the compound (I) of the present invention has an excellent antitrypsin action, and is useful as a therapeutic agent for diseases caused by activation of proteolytic enzymes or complements, such as pancreatitis.

When the compound (I) of the present invention is used as a medicine, it is made into a dosage form such as tablets, capsules, granules, powders or injections using an appropriate excipient, carrier, diluent or the like. It can be administered parenterally.

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

Reference Example 1 6-Hydroxyisoquinoline 6-Methoxyisoquinoline 510 mg to 48% hydrobromic acid 34 ml
Was added and refluxed under heating for 2 hours, and then the reaction solution was concentrated under reduced pressure. The obtained solid was dissolved in 10 ml of water, and sodium hydrogen carbonate was added to neutralize it. The precipitated crystals were collected by filtration and recrystallized from 2-propanol to obtain 20 mg (yield 4.3%) of the title compound having the following physical properties.

Melting point: 224-225 ° C.

[0025]

Reference Example 2 Methyl 6-hydroxy-1-isoquinolinecarboxylate 10.00 g of 6-hydroxy-1-isoquinolinecarboxylic acid was suspended in 50 ml of methanol, 50 ml of saturated hydrogen chloride methanol 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 30 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate (200 ml × 3) .The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The crystals were dried and concentrated under reduced pressure to give crude crystals. The obtained crude crystals were recrystallized from ethanol-water to obtain 5.32 g (yield 49.5%) of the title compound having the following physical properties.

Melting point: 180 to 182 ° C. IR: ν ^KBr cm ⁻¹ : 3420, 3000, 1730, 1720, 1640, 15
90. Elemental analysis value: Calculated as C ₁₁ H ₉ NO ₃

[0027]

Reference Example 3 Ethyl 6-hydroxy-1-isoquinolinecarboxylic acid 5.10 g of 6-hydroxy-1-isoquinolinecarboxylic acid,
Using 25 ml of ethanol and 25 ml of saturated hydrogen chloride methanol solution, the reaction and post-treatment were carried out according to the method described in Reference Example 2, and 1.83 g of the title compound having the following physical properties (yield 3
1.2%).

Melting point: 194 to 195.5 ° C. IR: ν ^KBr cm ⁻¹ : 3420, 3000, 1720, 1640, 1600. Elemental analysis value: calculated as C ₁₂ H ₁₁ NO _3.

[0029]

Reference Example 4 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 hydrogencarbonate 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a red oil. The obtained oil was crystallized from ethanol-water,
The title compound (6.97 g, yield 47.2%) having the following physical properties was obtained.

Melting point: 143-144 ° C. IR: ν ^KBr cm ⁻¹ : 3420, 3020, 1720, 1640, 1590. Elemental analysis value: calculated as C ₁₇ H ₁₃ NO _3.

[0031]

Example 1 6- (4-guanidinobenzoyl) oxyisoquinoline dimethanesulfonate 4.50 g of 4-guanidinobenzoic acid hydrochloride was dissolved in 90 ml of pyridine, and 4.10 g of dicyclohexylcarbodiimide was cooled with ice.
Was added and stirred for 1 hour. Then, a solution of 3.00 g of 6-hydroxyisoquinoline in 50 ml of pyridine was added dropwise,
The mixture was stirred under ice cooling for 1 hour and further at room temperature for 16 hours. The precipitated reaction product was collected by filtration, and the obtained solid was 20 ml of methanol.
Was added and the mixture was stirred for 2.5 hours, and then the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, 20 ml of methanol was added to the resulting residue to suspend it, and methanesulfonic acid was added dropwise until the liquid property became acidic under ice cooling, and then the insoluble matter was filtered off. Ether was added to the filtrate for crystallization, and 2.10 g of the title compound having the following physical properties was obtained.
(Yield 20.4%) was obtained.

Melting point: 195 to 206 ° C. IR: ν ^KBr cm ⁻¹ : 3400 to 2800, 1730, 1700, 1660, 16
40, 1570. Elemental analysis: Calculated as C ₁₇ H ₁₄ N ₄ O ₂・ 2CH ₃ SO ₃ H C (%) H (%) N (%) S (%) Theoretical value 45.78 4.45 11.24 12.86 Measured value 45.82 4.60 11.22 12.59

[0033]

Example 2 Methyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid hydrochloride To 1.35 g of 4-guanidinobenzoic acid was added 12.5 ml of thionyl chloride, and the mixture was heated under reflux for 45 minutes. N-Hexane was added to the reaction mixture for crystallization, and the precipitated crystals were collected by filtration to obtain 4-guanidinobenzoic acid chloride hydrochloride. This compound was added to a solution of 1.02 g of methyl 6-hydroxy-1-isoquinolinecarboxylate in 12.5 ml of pyridine at -5 ° C, the reaction temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Acetone 12.5 ml was added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to give 1.33 g (yield 66.4%) of the title compound having the following physical properties.

Melting point: 192-194 ° C. IR: ν ^KBr cm ⁻¹ : 3300, 3100, 1720, 1680, 1630, 16
00, 1570. Elemental analysis: Calculated as C ₁₉ H ₁₆ N ₄ O ₄ · HCl

[0035]

Example 3 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid ethyl hydrochloride 4-guanidinobenzoic acid 0.99 g, thionyl chloride 10.0 ml,
Methyl 6-hydroxy-1-isoquinolinecarboxylate
Using 0.80 g and 10.0 ml of pyridine, the reaction and post-treatment were carried out according to the method described in Example 2 to obtain 1.11 g (yield 72.6%) of the title compound having the following physical properties.

Melting point: 210 to 211.5 ° C. IR: ν ^KBr cm ⁻¹ : 3300, 3100, 1720, 1710, 1680, 16
50, 1630, 1600. Elemental analysis value: calculated as C ₂₀ H ₁₈ N ₄ O ₄ · HCl

[0037]

Example 4 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid benzyl hydrochloride 1/4 hydrate 4-guanidinobenzoic acid 2.70 g, thionyl chloride 20.0 ml,
Benzyl 6-hydroxy-1-isoquinolinecarboxylate
When 2.80 g and 20.0 ml of pyridine were used and the reaction and post-treatment were carried out according to the method described in Example 2, 1.68 g (yield 35.1%) of the title compound having the following physical properties was obtained.

Melting point: 193.5 to 194 ° C. IR: ν ^KBr cm ⁻¹ : 3300, 3100, 1730, 1680, 1630, 16
00, 1570. Elemental analysis: Calculated as C ₂₅ H ₂₀ N ₄ O ₄ · HCl · 1/4 H ₂ O

[0039]

Example 5 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid hydrochloride 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid benzyl hydrochloride prepared according to the method described in Example 4 1 Tetrahydrate (1.00 g) was dissolved in 30% hydrogen bromide-acetic acid solution (8 ml), and the mixture was stirred at room temperature for 7 days. Acetone 50 ml was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in 4.3 ml of dimethyl sulfoxide, diluted with 16 ml of water, neutralized with saturated sodium hydrogen carbonate under ice cooling, 16 ml of water was added, and the precipitated solid was collected by filtration. The obtained solid was suspended in 6 ml of methanol, adjusted to pH 2 with 2N hydrochloric acid, and allowed to stand at 4 ° C for 15 hours for crystallization to give 0.09 g of the title compound having the following physical properties.
(Yield 10.5%) was obtained.

Melting point: 175 to 181 ° C. IR: ν ^KBr cm ⁻¹ : 3500 to 2750, 1740, 1680, 1630, 16
00, 1570, 1520. Elemental analysis value: Calculated as C ₁₈ H ₁₄ N ₄ O ₄ · HCl

[0041]

INDUSTRIAL APPLICABILITY The novel isoquinoline derivative of the present invention or an acid addition salt thereof has an excellent protease inhibitory action,
It is effective in treating diseases caused by the action of proteolytic enzymes.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Shinichi Shimada 1-10-2 Hyogozuka, Utsunomiya City, Tochigi Prefecture 211 (72) Inventor Motohide Seya 773-3 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 3-A (72) Innovator Nomoto Nobu 325-4 Yakushiji, Minamikawachi-cho, Kawachi-gun, Tochigi Green Town 112-1-5-102 (72) Inventor Masayuki Okue Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi 405 (72) Invention Person Hidetsuka Totsuka 1-12-27 Chuo, Kazo City, Saitama Prefecture

Claims (6)

[Claims] 1. A 6-substituted isoquinoline derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [In the formula, R represents hydrogen or a COOR ¹ group. However, R ¹
Is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms,
It represents a group selected from the group consisting of a phenyl group and a benzyl group. ] 2. The compound according to claim 1, which is 6- (4-guanidinobenzoyl) oxyisoquinoline or a pharmaceutically acceptable acid addition salt thereof. 3. The compound according to claim 1, which is 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid or a pharmaceutically acceptable acid addition salt thereof. 4. The compound according to claim 1, which is methyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 5. The compound according to claim 1, which is ethyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 6. The compound according to claim 1, which is benzyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof.