JP2654847B2 - New isoquinoline derivatives - Google Patents

Description

The present invention relates to a novel isoquinoline derivative and an acid addition salt thereof. The compounds of the present invention are useful as pharmaceutical intermediates.

[Prior art and problems to be solved]

Conventionally, various isoquinoline derivatives have been found. However, 5-hydroxy-1-isoquinoline carboxylate is slightly ethyl ester (J. Org. Chem. 27 ,
4571, (1962)).

[Means for solving the problem]

The present inventors have discovered a series of isoquinoline derivatives represented by the general formula (I) during research and development of novel protease inhibitors. When this compound is used as a synthetic intermediate to produce a novel isoquinoline derivative, this compound can be produced efficiently, and it has been found that the obtained compound has an excellent inhibitory effect on proteases. Reached. That is, the present invention provides a compound represented by the general formula (I): [In the formula, R represents a straight or branched alkyl group having 3 or 4 carbon atoms, a phenyl group, a benzyl group, a —CH ₂ CONR ¹ R ² group (R ¹ and R ² represent hydrogen or C ¹ to C 4 A linear or branched alkyl group which may be the same or different from each other), or a pharmaceutically acceptable acid addition salt thereof.

The compound (I) of the present invention has the following formula (II) A 5-hydroxy-1-isoquinolinecarboxylic acid or a reactive derivative thereof represented by the following formula (III): ROH (III) wherein R is a straight-chain or branched-chain alkyl group having 3 or 4 carbon atoms, phenyl Group, benzyl group, —CH ₂ CONR ¹ R ² group (R ¹ and R ² are hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different) Represents a selected group], or a reactive derivative thereof.

In addition, a general dehydration reaction can be applied to the reaction between 5-hydroxy-1-isoquinolinecarboxylic acid (II) and the hydroxy compound (III). For example, (a) a method of reacting a free carboxylic acid (II) or an acid addition salt thereof with a hydroxy compound (III) or an acid addition salt thereof in the presence of a catalyst, a condensing agent, and the like; (b) a carboxylic acid (II) And a reactive derivative of the hydroxy compound (III).

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'-disuccinimidicarbamate, 1-
(3-dimethylaminopropyl) -3-ethylcarbodiimide, dimethylformamide diethyl acetal, N,
N'-dimethylphosphoramidic dichloride, phenyl dichlorophosphate and the like can be used. At this time, a base catalyst such as dimethylaminopyridine and pyrrolidinopyridine may be used in combination.

The reaction conditions vary depending on the catalyst or the condensing agent to be used. For example, when dicyclohexylcarbodiimide as a condensing agent is used, carboxylic acid (II) is reacted with dicyclohexylcarbodiimide in a solvent, and a solution of compound (III) is added thereto. The reaction is terminated by stirring at −30 to 100 ° C. for several hours to several days in the presence or absence of a base. As the solvent used at this time, a common organic solvent such as pyridine, dimethylformamide, chloroform, dichloromethane, carbon tetrachloride,
Water may be used in addition to benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide.
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. No.

As the reactive derivative of the compound (III) in the method (b), for example, (IV) RX (IV) (wherein, R represents the same group as described above, and X represents chloro, bromo, or iodo) Alkyl halide, trifluoroacetate, or (V) (Wherein, R represents the same group as described above).

The reaction conditions vary depending on the reactive derivative used. For example, when an alkyl halide is used, the alkali metal salt of carboxylic acid (II) and the alkyl halide are-
The reaction is completed by stirring at 30 to 100 ° C. for several hours to several days.

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

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,
Organic acids such as malic acid, citric acid, methanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid can be used.

Next, the present invention will be described with reference to examples, but the present invention is specifically and easily understood, and the production of the compound of the present invention is not limited thereto.

Example 1 Propyl 5-hydroxy-1-isoquinolinecarboxylate 3.00 g of 5-hydroxy-1-isoquinolinecarboxylic acid
Is suspended in 50 ml of 1-propanol saturated with hydrogen chloride gas,
The mixture was heated under reflux for 25 hours.

The solvent was distilled off under reduced pressure, 50 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted three times with 100 ml of ethyl acetate. The extract was concentrated under reduced pressure, and the residue was recrystallized from aqueous ethanol to give 1.48 g (yield 40.3%) of the title compound having the following melting point.

Mp: 148~150 ℃ FAB-MS: 232 (M + H) + IR: ν KBr cm -1: 3430,2970,1720,1585,1460,1265,1170,1120,820,740 Elemental analysis: C ₁₃ H ₁₃ NO ₃ Calculated as C (%) H (%) N (%) Theoretical 67.52 5.67 6.06 Found 67.42 5.77 6.11 Example 2 2.51 g of isopropyl 5-hydroxy-1-isoquinolinecarboxylate 5-hydroxy-1-isoquinolinecarboxylic acid
Was suspended in 20 ml of ethanol, 20 ml of an ethanol solution in which 0.88 g of potassium hydroxide was dissolved was added, and the mixture was evaporated under reduced pressure. The residue was suspended in 20 ml of dimethylformamide (DMF), 2.26 g of 2-iodopropane was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 27 hours.

The reaction solution was poured into a 5% aqueous sodium thiosulfate solution (200 ml) and extracted three times with ethyl acetate (100 ml). The extract was concentrated under reduced pressure, and the residue was recrystallized from aqueous 2-propanol to give 1.36 g (yield 44.2%) of the title compound having the following melting point.

Melting point: 182-183 ° C EI-MS: 231M ⁺ IR: ν ^KBr cm ^-1 : 3450,2980,1725,1585,1460,1370,1270,1170,1105,930,8
20,740 Elemental analysis: C ₁₃ H ₁₃ NO ₃ Calculated C (%) H (%) N (%) Theoretical values 67.52 5.67 6.06 Found 67.32 5.62 5.96 Example 3 Benzyl 5-hydroxy-1-isoquinolinecarboxylate 5- Hydroxy-1-isoquinoline carboxylic acid 3.00 g
And potassium hydroxide 1.05 g, benzyl iodide 4.16 g,
The reaction was purified according to the method described in Example 2 to obtain 1.14 g (yield 25.7%) of the title compound having the following melting point.

Melting point: 164.5-166 ° C EI-MS: 279M ⁺ IR: ν ^KBr cm ^-1 : 3430,3040,2950,1720,1580,1460,1370,1260,1170,1120,
950,820,750,695,565 Elemental analysis: C ₁₇ H ₁₃ NO ₃ Calculated C (%) H (%) N (%) Theoretical values 73.11 4.69 5.02 Found 73.00 4.78 5.07 Example 4 N, N-dimethylcarbamoylmethyl 5-hydroxy -
1-isoquinoline carboxylate 5-hydroxy-1-isoquinoline carboxylic acid 3.00 g
And 1.05 g of potassium hydroxide and 3.00 g of α-bromo-N, N-dimethylacetamide were reacted and purified according to the method described in Example 2 to give 2.20 g (yield 50.6%) of the title compound having the following melting point. Obtained.

Melting point: 205-208 ° C EI-MS: 274M ⁺ IR: ν ^KBr cm ^-1 : 3150, 1720, 1650, 1260, 1160, 1120, 815 Elemental analysis: Calculated as C ₁₄ H ₁₄ N ₂ O ₄ C (% H) (%) N (%) Theoretical 61.31 5.14 10.21 Found 61.11 5.34 10.11 Example 5 Butyl 5-hydroxy-1-isoquinolinecarboxylate 3.00 g of 5-hydroxy-1-isoquinolinecarboxylic acid
Using 1.05 g of potassium hydroxide and 11.6 g of 1-iodobutane, the reaction and purification were carried out according to the method described in Example 2 to obtain 0.54 g (yield 13.9 g) of the title compound having the following melting point.

Melting point: 148-150 ° C EI-MS: 245M ⁺ IR: ν ^KBr cm ^-1 : 2950,2570,1720,1580,1450,1255,1170,1120,825,750,57
0 Elemental analysis: Calculated as C ₁₄ H ₁₅ NO ₃ C (%) H (%) N (%) Theoretical 68.84 5.78 5.73 Found 68.79 6.19 5.68 The novel isoquinoline derivative (I) of the present invention is represented by the following formula: By reacting with 4-guanidinobenzoic acid (IV) or a reactive derivative thereof shown below, an end product, an isoquinoline derivative (VII) represented by the following formula, can be efficiently obtained.

Since this reaction is a dehydration reaction, a method similar to the above-described dehydration reaction can be applied.

As a reference example, a specific example of a method for obtaining the final product isoquinoline derivative (VII) from the novel isoquinoline derivative (I) of the present invention will be described as a reference example.

Reference Example 4-Guanidinobenzoic acid (1.08 g) was dissolved in pyridine (20 ml), dicyclohexylcarbodiimide (1.03 g) was added, and the mixture was stirred under ice cooling for 1 hour. 1.16 g of propyl 5-hydroxy-1-isoquinolinecarboxylate (produced according to the method described in Example 1) dissolved in a pyridine-DMF mixed solution was added dropwise, and the mixture was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 16 hours. After filtering the reaction solution, 50 ml of ether was added to the filtrate, and the resulting precipitate was collected by filtration. The precipitate was suspended in 20 ml of water, 30 ml of a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was filtered. The precipitate was washed with water and acetone to obtain 1.71 g of a carbonate.

The carbonate is suspended in 10 ml of methanol, and methanesulfonic acid is suspended.
When 0.87 g was added, the mixture dissolved while foaming to give a clear solution. 50 ml of ether was added to the solution, the supernatant was removed by decantation, and an oil was obtained. The oil was purified by silica gel chromatography (eluted with CHCl ₃ : CH ₃ OH: CH ₃ COOH = 10: 1: 1). The eluate was concentrated under reduced pressure, 100 ml of ether was added to the concentrate, and the mixture was decanted to remove the supernatant, thereby obtaining an oil. Oily substance 2-
Recrystallization from propanol gave 0.84 g (yield 31.3%) of 1'-propoxy-5'-isoquinolyl 4-guanidinobenzoate / 3/2 methanesulfonate having the following physical properties.

Melting point: 170-174 ° C FAB-MS 393 (M + H) ⁺ IR: ν ^KBr cm ^-1 : 3300,3250,3120,1740,1690,1610,1580,1270,1230,1170,
1040,820,775,555,535 Elemental _{analysis: C 21 H 20 N 4 O} 4 · 3 / 2CH 3 SO 3 calculated C (%) as H H (%) N (% ) S (%) Theoretical values 50.37 4.88 10.44 8.96 Found 50.32 4.99 10.36 8.84 The in vitro trypsin inhibitory activity (50% inhibitory concentration) of this compound was determined by the method of Muramatsu et al. [The Journal of Biochemistr.
y), 58 , 214 (1965)].

When the substrate is p-tosyl arginine methyl ester 5.
7 × 10 ⁻⁸ M, 1.5 × 10 ⁻⁷ M for casein.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The isoquinoline derivative of the present invention is a novel compound, and can efficiently obtain an isoquinoline derivative having a proteolytic enzyme inhibitory action for reacting this compound with 4-guanidinobenzoic acid.

Therefore, the isoquinoline derivative of the present invention is useful as a pharmaceutical intermediate.

Continued on the front page (72) Inventor Shinichi Shimada 1-1-2 Hyogozuka, Utsunomiya City, Tochigi Prefecture Prefectural Housing 211 (72) Inventor Tadayoshi Koyama 773-3 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 2-A ( 72) Inventor Motohide Seya 773-3 SK Mansion 3-A, Ishibashi-cho, Ishibashi-cho, Shimotsuga-gun, Tochigi Prefecture (72) Inventor Noriko Abe 2-4-4 Mitsumine, Oyama-shi, Tochigi Prefecture

Claims (6)

(57) [Claims] 1. The compound of the general formula (I) [In the formula, R represents a straight or branched alkyl group having 3 or 4 carbon atoms, a phenyl group, a benzyl group, a —CH ₂ CONR ¹ R ² group (R ¹ and R ² represent hydrogen or C ¹ to C 4 A straight-chain or branched alkyl group which may be the same or different), or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, which is propyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 3. The compound according to claim 1, which is isopropyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof. 4. The compound according to claim 1, which is benzyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof. 5. The compound according to claim 1, which is N, N-dimethylcarbamoylmethyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof. 6. The compound according to claim 1, which is butyl 5-hydroxy-1-isoquinolinecarboxylate or a pharmacologically acceptable acid addition salt thereof.