JPH04154768A - New isoquinoline derivative or its acid addition salt - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is OH or NH2) or its acid addition salt. EXAMPLE:1'-Carboxy-5'-isoquinolyl 4-guanidinobenzoate. USE:Having excellent antitrypsin action and useful as a medicine for diseases such as pancreatitis, hemorrhagic diseases or thrombosis caused by activation with proteolytic enzymes. PREPARATION:A 4-guanidinobenzoic acid expressed by formula II or its reactive derivative is made to react with a 5-hydroxyisoquinoline compound expressed by formula III (R is COOH or CONH2) to afford the objective compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel isoquinoline derivatives and acid addition salts thereof. Compounds of the invention are useful as pharmaceuticals.

Various guanidinobenzoic acid derivatives have been used as pharmaceuticals to inhibit proteolytic enzymes such as trypsin, plasmin, and thrombin (Japanese Patent Publication No. 49-2
107, JP-A-52-89640, JP-A-61-1063, etc.).

However, the effects of the conventionally known guanidinobenzoic acid derivatives are not necessarily sufficient, and there has been a desire to develop new compounds that have even better effects.

The present inventor is currently researching and developing a new protease inhibitor.
The present inventors discovered that the isoquinoline derivative represented by formula (1) has this excellent effect and completed the present invention.

That is, the present invention provides 1'-substituted-
The present invention relates to 5'-isoquinolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof.

However, in the formula, R represents a hydroxyl group or an amino group.

Specific examples of the novel compounds of the present invention include the following compounds.

1'-Ruboxy-51-isoquinolyl 4-guanidinobenzoate (Formula (1)-1)%Formula%Guanidinobenzoate (Formula N)-2) Compound of the present invention (
r) is 4-guanidinobenzoic acid represented by the following formula (II) or a reactive derivative thereof and 5-hydroxy represented by the following formula (III) H (wherein R represents a carboxyl group or a carbamoyl group) It can be obtained by reacting isoquinoline compounds.

Alternatively, the carboxyl group of compound (III) is protected with an appropriate protecting group, and the protecting group is removed after reaction with 4-guanidinobenzoic acid (11) or a reactive derivative thereof to obtain the compound (I) of the present invention. You can also do it.

A conventional reaction can be applied to the reaction between 4-guanidinobenzoic acid (II) and compound (I[l).

For example, (a) a method of reacting free 4-guanidinobenzoic acid (II) or an acid addition salt thereof with compound (III) or a carboxyl protected derivative thereof in the presence of a catalyst, a condensing agent, etc.; A method of reacting a reactive derivative of benzoic acid (If) with compound (III) or its carboxyl-protected derivative can be applied.

Examples of the catalyst in method (a) include sulfuric acid, hydrochloric acid,
Examples include acid catalysts such as p-) luenesulfonic acid, phosphorus oxychloride, polyphosphoric acid, and boron trifluoride. Examples of the condensing agent include dicyclohexylcarbodiimide, diphenylphosphoryl azide, and N.

N'-carbodiimidazole, N, N''-disuccinimidicarbamate, dimethylformamide diethyl acecool, 1-(3-dimethylaminopropyl)-3-
Ethylcarbodiimide, N,N'-dimethylphosphoramisic dichloride, phenyl dichlorophosphate, etc. can be used. At 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 for example, when using the condensing agent dicyclohexylcarbodiimide, 4-guanidinobenzoic acid (
II) and dicyclohexylcarbodiimide are reacted, and a solution of compound (I [I) or its carboxyl protected derivative is added thereto, and -
The reaction is completed by stirring at 30-100'C for several hours to several days.

Solvents used at this time include common organic solvents such as pyridine, dimethylformamide, chloroform,
Examples include dichloromethane, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide, and water. Examples of the base include pyridine, triethylamine, diisopropylethylamine, sheet butylamine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo(5,4,0)-7-undecene, and the like.

Reactive derivatives of carboxylic acids (IT) in process (b) include acid halides, such as acid chlorides, acid bromides, etc.; mixtures with acid anhydrides, such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, isobutoxyformic acid, etc. Acid anhydride nionium salts, such as 2-promo 1-
Pyridinium iodide, 2-chloro-3+5-dinitropyridine, 210-1-methylpyridinium iodide; active esters such as p-nitrophenyl ester, N-0-succinimide ester and the like.

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

As the solvent used at this time, there are some common solvents. 8 medium,
Examples include pyridine, chloroform, dichloromethane, benzene, toluene, xylene, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide, dimethylsulfoxide and the like. Also,
As the base, triethylamine, diisopropylethylamine, di-t-butylamine, pyridine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo(5,4,0)-7-
Undesen etc. can be used.

Further, examples of the carboxyl protecting group of compound (III) include common protecting groups such as esters such as benzyl group, t-butyl group, trimethylsilyl group, and tetrahydropyranyl group.

Reaction conditions vary depending on the protecting group used, but for example, when introducing a benzyl group, 5-hydroxy-
A benzyl halide such as benzyl chloride or bromide is added to 1-isoquinolinecarboxylic acid or its salt such as potassium, sodium, or tetramethylammonium, and the mixture is heated for 30 minutes in the presence or absence of a base such as potassium carbonate, sodium carbonate, or triethylamine. ~100°C
The reaction is completed by stirring for several hours to several days.

Examples of the solvent used at this time include common organic solvents such as dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, and hexamethylphosphoric triamide.

These carboxyl-protected derivatives of compound (II[) are reacted with 4-guanidinobenzoic acid (II) or a reactive derivative thereof using the method (a) or (b) described above to obtain the compound (1) of the present invention. ) can be prepared.

In order to obtain the present compound (1) from the carboxyl-protected derivative of the present compound (1), a conventional method for removing a protecting group can be applied. For example, (a) treatment with an acid such as hydrofluoric acid, trifluoroacetic acid, hydrobromic acid, or boron trifluoride;
Examples include methods such as b) catalytic reduction, and (C) treatment with metallic sodium or metallic lithium in liquid ammonia.

Reaction conditions vary depending on the method used, but for example, in the case of catalytic reduction, the carboxyl-protected derivative alcohol,
The reaction is completed by adding hydrogen peroxide to a solution of acetic acid or the like and stirring under a hydrogen gas atmosphere until no more hydrogen is absorbed.

In addition, in order to isolate and purify the compound N) 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 chromatography, are applied. be able to.

The compound (1) of the present invention obtained as described above can be converted into an acid addition salt by a conventional method, if necessary. Examples of acids include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, and carbonic acid, as well as acetic acid, lactic acid, succinic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, and benzene. Organic acids such as sulfonic acid can be used.

The in vitro trypsin inhibitory effect of compound (1) was determined by the method of Muramatsu et al. [The Journal op Biochemistry].
Of Biochemistry), 58 214 (
(1965)], the result was as follows.

In a reaction at 37°C for 310 minutes, 1.5 g of trypsin was
~Tosylarginine methyl ester (TAME) The concentration of compound (1) that inhibits the hydrolysis of casein by 50%, and the concentration of compound (1) that inhibits the hydrolysis of casein by 20 ug of trypsin in a reaction at 37°C for 210 minutes. The concentrations are as shown in Table 1.

Table 1 As described above, the compound of the present invention (Natsu) has excellent antitrypsin action and is useful as a therapeutic agent for diseases caused by activation of proteolytic enzymes, such as pancreatic diseases, bleeding disorders, and thrombosis. It is.

When using the compound (1) of the present invention as a medicine, it can be prepared into tablets, capsules, granules, powders, injections, etc. using appropriate excipients, carriers, diluents, etc., and can be administered orally or parenterally. It can be administered to

Next, the present invention will be explained with reference to Examples, but these are intended to make the present invention easier to understand by way of specific examples, and the compounds of the present invention and their production are not limited thereto.

Example 1 1'-carboxy-5'-isoquinol 4-guar 4-
3.88g of guanidinobenzoic acid hydrochloride and 60g of pyridine
4.30 g of dicyclohexycarbodiimide dissolved in d.
was added and stirred for 1 hour under water cooling. 5.03 g of benzyl 5-hydroxy-1-isoquinolinecarboxylade dissolved in 20 ml of pyridine was added dropwise, and the mixture was stirred for 1 hour under water cooling and further stirred at room temperature for 17 hours.

The reaction solution was filtered, and 400 mQ of ether was added to the filtrate to form a precipitate. The precipitate was collected by filtration and recrystallized from 150% ethanol to give 1'-benzyloxycarbonyl-5'-
Isoquinolyl 4-guanidinobenzoate hydrochloride
-3.65g of hydrate (melting point: 112-213'C)
I got it.

Dissolve 3.50 g of the above compound in 50 ml of methanol,
5% palladium-carbon 300μ was added, under hydrogen atmosphere,
Stirred at room temperature for 20 hours.

The resulting precipitate was dissolved in 100% acetic acid and filtered.

Furthermore, the precipitate was washed with 50% vinegar M 100zf. The filtrates were combined and concentrated under reduced pressure. The residue was recrystallized from 50% methyl cellosolve 300- to obtain 1.03 g (yield I6.8%) of the title compound having the following physical properties.

Melting point: 225-235°C (decomposition) FAB-MS: 351 (M+H) "I Rv"
'cm-': 3450, 3150.1?30.1700.1610.
1555.1405.1270.1240°1230,
1070.820.760 Elemental analysis value: Calculated as C+sH+aNa04・8+-+, 0 C(χ) H(χ) N(χ) Theoretical value 60.93 4.12 15.79 Actual value 60
．． 79 3.97 15.62 Example 2 Dissolve 0.55 g of 4-guanidinobenzoic acid hydrochloride in 20 d of pyridine, and dissolve 0.5 g of dicyclohexycarbodiimide.
3 g was added and stirred for 1 hour under water cooling. 0.48 g of 5-hydroxy-1-isoquinolinecarboxamide dissolved in 15-pyridine was added dropwise, and the mixture was stirred for 1 hour under water cooling and further stirred at room temperature for 17 hours.

The reaction solution was filtered, ether 400 was added to the filtrate, and the mixture was allowed to stand still. The supernatant was removed by decanting to obtain an oil.

The oil was subjected to silica gel chromatography (CHC1+:
It was purified by elution with CH30H:CHaCOOH・10:3:l). The eluate was concentrated under reduced pressure, the residue was dissolved in methanol, a saturated aqueous sodium bicarbonate solution was added, and the precipitated carbonate was collected by filtration.

The carbonate was suspended in a small amount of methanol, and methanesulfonic acid was added dropwise while cooling with water to make it acidic. After filtering off insoluble matter, the filtrate was allowed to stand, and the precipitated crystals were collected by filtration to obtain 0.18 g (yield: 20.0%) of the title compound having the following physical properties.

Melting point: 264-268"C (decomposition) FAB- and S: 350 (M+H) "I Rv"'
cm-': 3420.3170.1730.16B0.1575.
1520.1410.1275.1240°1225.
1165. lO40,765,620 elemental analysis value: C
tal(+5NsO+・CH35O,H・V28zO Calculated as C(χ) l((χ) N(χ) S(χ
) Ritomi Mikoi Nao 50.22 4.44
15.41 7.06 Actual value 50.65 4
．． 49 15.32 6.88 1'-Substituted-5'-isoquinolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof of the present invention is a novel compound and has excellent anti-inflammatory properties. Since it has trypsin action, it can be usefully used as a new therapeutic agent for diseases caused by activation of proteolytic enzymes, such as pancreatic diseases, hemorrhagic diseases, and thrombosis.

Claims (3)

[Claims] (1) 1'-Substituted-5'-isoquinolyl 4-guanidinobenzoate or its pharmacologically acceptable acid addition salt represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I). However, in the formula, R represents a hydroxyl group (-OH) or an amino group (-NH_2). (2) 1' according to claim (1), wherein the compound represented by formula (I) is 1'-carboxy-5'-isoquinolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof; -Substituted-5'-isoquinolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. (3) The 1'- according to claim (1), wherein the compound represented by formula (I) is 1'-carbamoyl-5'-isoquinolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. Substituted-5'-isoquinolyl 4-guanidinobenzoates or pharmacologically acceptable acid addition salts.