JP2886586B2 - Novel guanidinobenzoic acid derivatives and their acid addition salts - Google Patents

Description

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

[Prior art and problems to be solved]

Conventionally, various guanidinobenzoic acid derivatives have the action of inhibiting the proteases trypsin, plasmin, thrombin and the like, and have been used as pharmaceuticals. (Special Publication 49-
No. 2107, JP-A-52-89640, JP-B-61-1063
However, the effect of a conventionally known guanidinobenzoic acid derivative is not necessarily sufficient, and the development of a novel compound having a more excellent action has been desired.

[Means for solving the problem]

During the research and development of a novel protease inhibitor, the present inventors have found that a series of guanidinobenzoic acid derivatives represented by the general formula (I) have excellent effects, and completed the present invention. Was.

That is, the present invention relates to the general formula [In the formula, R represents a 4- (imidazol-1-yl) phenyl group, a 4-indolyl group, a 5-indolyl group, a 2-carbazolyl group, a 1,4-benzodioxan-2-yl-methyl group, a 2-dibenzo group. A guanidinobenzoic acid derivative represented by the formula: or a pharmacologically acceptable acid addition salt thereof.

The compound (I) of the present invention has the following formula (II) By reacting 4-guanidinobenzoic acid or a reactive derivative thereof with the compound (III) or a reactive derivative thereof.

[The compound (III) is 4- (imidazol-1-yl) phenol, 4-hydroxyindole, 5-hydroxyindole, 2-hydroxycarbazole,
Represents a compound selected from the group consisting of hydroxymethyl-1,4-benzodioxane and 2-hydroxydibenzofuran.] Also, 4-guanidinobenzoic acid (II) and a compound (II
For the reaction with I), a general dehydration reaction can be applied. For example, (a) free p in the presence of a catalyst, a condensing agent, etc.
-A method of reacting guanidinobenzoic acid (II) or an acid addition salt thereof with a compound (III) or an acid addition salt thereof. (B)
a method of reacting a reactive derivative of p-guanidinobenzoic acid (II) with a compound (III) and a method of reacting (c) free p-guanidinobenzoic acid (II) with a reactive derivative of compound (III) Etc. 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'-disuccinimide dicarbamate, 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 used. For example, when dicyclohexylcarbodiimide, which is a condensing agent, is used, 4-guanidinobenzoic acid (II) is reacted with dicyclohexylcarbodiimide in a solvent, and the compound (III) The reaction is completed by adding the solution of (1) and 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 general organic solvent,
Examples include pyridine, dimethylformamide, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide, and water. Further, as the base, pyridine, triethylamine, diisopropylethylamine, di-t-butylamine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine,
8-diazabicyclo [5,4,0] -7-undecene and the like.

Examples of the reactive derivative of 4-guanidinobenzoic acid (II) in the method (b) include acid halides such as acid chloride and acid bromide; acid anhydrides such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and isobutoxygi. Mixed acid anhydrides with acids and the like; 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 and NO-succinimide ester;

The reaction conditions vary depending on the reactive derivative to be used. For example, when acid chloride is used, the acid chloride and compound (III) are mixed in a solvent in the presence or absence of a base under ice-cooling or heating for several hours to several hours. The reaction is completed by stirring for several days.

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

The reactive derivative of the compound (III) in the method (c) includes, for example, its trifluoroacetate ester or the compound of the formula (IV) (Wherein III ′ represents a hydroxyl residue of the compound represented by the above (III)).

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.

The inhibitory effect of the guanidinobenzoic acid derivative of the general formula (I) on trypsin in vitro can be determined by the method of Muramatsu et al. [The Journal of Biochemistry (Th.
e Journal of Biochemistry), 58 , 214 (1965)]
It was as follows when performed according to.

1.5 μg of trypsin hydrolyzes p-tosylarginine methyl ester (TAME) in a reaction at 37 ° C. for 10 minutes.
The concentration of the compound represented by the general formula (I) and the concentration of the compound represented by the general formula (I) which suppresses the action of hydrolyzing casein by 20 μg of trypsin in a reaction at 37 ° C. for 10 minutes are 50%. As shown in Table 1.

The structural formulas of the test compound number and the control drug FOY (gabexate mesylate) are as follows.

As described above, 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.

When the compound (I) of the present invention is used as a medicine,
Using appropriate excipients, carriers, diluents and the like, it can be orally or parenterally administered in the form of tablets, capsules, granules, powders or injections.

Next, the present invention will be described with reference to Examples, which are for the purpose of making the present invention easier to understand by specific examples, and the production of the compound of the present invention is not limited thereto.

Example 1 4- (Imidazol-1-yl) phenyl 4-guanidinobenzoate dimethanesulfonate (Compound No. 1) To 1.10 g of 4- (guanidinobenzoic acid / hydrochloride) was added 5 ml of thionyl chloride to give about 1 The reaction mixture was refluxed under heating, and n-hexane was added to the reaction solution to obtain a precipitate of 4-guanidinobenzoic acid chloride / hydrochloride.
-Yl) phenol (0.80 g) was dissolved in pyridine (15 ml), and the above-mentioned 4-guanidinobenzoic acid chloride / hydrochloride was added.
Stirred overnight at room temperature.

A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture under ice cooling, and the precipitated crystals were collected by filtration and washed with water and acetone.
The crystals were suspended in a small amount of ethanol, and methanesulfonic acid was added thereto with stirring to make the crystals acidic and completely dissolved. Ether was added to this solution until it became slightly cloudy,
The crystals were deposited by allowing to stand in the cold. This was recrystallized from methanol to obtain 1.13 g (yield 43.1%) of the title compound.

Melting point 214-216 ° C FAB-MS 322 (M + H) ⁺ IR ν ^KBr cm ^-1 : 3310,3110,1735,1670,1600,1565,1205,1
055,780,560,535 Elemental _{analysis: C 17 H 15 N 5 O} 2 · 2CH 3 SO 3 H as calculated C (%) H (%) N (%) S (%) Theoretical values 44.44 4.51 13.64 12.49 Found 44.19 4.68 13.65 12.45 exemplary Example 2 4-Indolyl 4-guanidinobenzoate methanesulfonate (Compound No. 2) 3.23 g of 4-guanidinobenzoic acid / hydrochloride was converted to pyridine 60m.
Then, 3.91 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under ice cooling. 4-hydroxyindole 2.
20 g of pyridine was dissolved in 20 ml of pyridine, added dropwise to the above solution over 20 minutes, and stirred for 1 hour under ice cooling and for 44 hours at room temperature.

The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the generated crystals were collected by filtration and washed with water and acetone to obtain 3.23 g of a carbonate of the title compound.

The carbonate was suspended in 18 ml of dimethylformamide, and when methanol in which 2.12 g of methanesulfonic acid was dissolved was added, the mixture was dissolved while foaming. Ether was added and the resulting precipitate was collected by filtration to obtain a crude methanesulfonate.

The crude methanesulfonate was purified by silica gel column chromatography (CHCl ₃ : CH ₃ OH: CH ₃ COOH = 10: 1: 1 → 10: 2: 1) and recrystallized from ethanol to give the title compound 2.
41 g (41.2% yield) were obtained.

237-239 ° C FAB-MS 295 (M + H) ⁺ 386 (M + GIy + H) ⁺ IRν ^KBr cm ^-1 : 3380,3200,1710,1690,1610,1565,1285,120
5,1180,1100,1040,755,540 Elemental analysis: Calculated as C ₁₆ H ₁₄ N ₄ O ₂ .CH ₃ SO ₃ H C (%) H (%) N (%) S (%) Theoretical 52.30 4.65 14.35 8.21 Found 52.16 4.67 14.20 7.92 Example 3 5-Indolyl 4-guanidinobenzoate methanesulfonate (Compound No. 3) 3.23 g of 4-guanidinobenzoic acid / hydrochloride was converted to pyridine 60m
Then, 3.91 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under ice cooling. 4-hydroxyindole 2.
20 g of pyridine was dissolved in 20 ml of pyridine and added dropwise to the above solution over 20 minutes, followed by stirring for 1 hour under ice cooling and 22 hours at room temperature.

The reaction solution was filtered, and the filtrate was poured into 200 ml of a saturated aqueous solution of sodium hydrogencarbonate. The resulting crystals were collected by filtration, washed with water and acetone to obtain 3.93 g of the carbonate of the title compound.

The carbonate was suspended in a 0.1N aqueous sodium hydroxide solution and extracted with methyl ethyl ketone. The solvent was distilled off from the extract under reduced pressure to obtain 2.65 g of the free base of the title compound.

This free base was dissolved in dimethylformamide (20 ml), methanesulfonic acid (2.08 g) was added, ether (100 ml) was added, and the resulting crystals were collected by filtration. This was recrystallized from methanol to give the title compound (2.37 g, yield 40.5%).

Melting point 255-256 ° C (decomposition) FAB-MS 295 (M + H) ⁺ IRν ^KBr cm ^-1 : 3380,3280,3200,1715,1695,1630,1610,157
0,1285,1215,1165,1140,1045,765,540 Elemental _{analysis: C 16 H 14 N 4 O} 2 · CH 3 SO 3 H as calculated C (%) H (%) N (%) C (%) Theoretical Value 52.30 4.65 14.35 8.21 found 52.07 4.79 14.25 8.36 Example 4 2-carbazolyl 4-guanidinobenzoate methanesulfonate hemihydrate (Compound No. 5) 4-guanidinobenzoic acid hydrochloride 3.51 g Pyridine 60m
Then, 4.04 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under ice cooling. 2-hydroxycarbazole
3.02 g was dissolved in 20 ml of pyridine and added dropwise to the above solution over 15 minutes, and the mixture was stirred for 1 hour under ice cooling and for 72 hours at room temperature.

The reaction solution was filtered, 200 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the filtrate, and the formed crystals were collected by filtration and washed with water and acetone to give 3.74 g of 2-carbazolyl 4-guanidinobenzoate carbonate.

The carbonate was suspended in 100 ml of a 0.1N aqueous sodium hydroxide solution and extracted three times with 100 ml of methyl ethyl ketone. After the extract was washed with saturated saline, the solvent was distilled off under reduced pressure to obtain 2.22 g of the free base of the title compound.

This was suspended in 20 ml of ethanol, and methanesulfonic acid 1.
The addition of 48 g resulted in a clear solution. Here, ether 80m
l was added and the resulting crystals were collected by filtration.

This was recrystallized from methanol to give 2.36 g of the title compound.
(34.1% yield).

Melting point 257.5-259.5 ° C (decomposition) FAB-MS 322 (M + H) ⁺ IR ν ^KBr cm ^-1 : 3390,3190,1720,1695,1615,1575,1465,1
275,1140,1045,730,540 Elemental _{analysis: C 20 H 16 N 4 O} 2 · CH 3 SO 3 H · 1 / 2H 2 O Calculated C (%) H (%) N (%) S (%) Theoretical Value 56.12 4.71 12.46 7.13 found 56.19 4.64 12.61 7.12 Example 5 1,4-benzodioxan-2-yl-methyl 4-guanidinobenzoate acetate.1 / 2 hydrate (Compound No. 6) 4-guanidinobenzoic 3.23 g of acid / hydrochloride in 60 m of pyridine
Then, 3.91 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under ice cooling. 2-hydroxymethyl-1,4
-2.62 g of benzodioxane was dissolved in 20 ml of pyridine and added dropwise to the above solution over 15 minutes, followed by stirring for 1 hour under ice cooling and 25 hours at room temperature.

The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent.
73 g was obtained.

The residue was subjected to silica gel column chromatography (CH ₃ COO
Purification with C ₂ H ₅ : CH ₃ COOH: H ₂ O = 3: 1: 1) and recrystallization from ethanol to give 1.78 g (yield 30.0%) of the title compound
I got

154-155 ° C FAB-MS 328 (M + H) ⁺ IRν ^KBr cm ^-1 : 3430,3010,1705,1645,1620,1570,1500,141
0,1290,1255,1190,1120,1055,1020,855,765 Elemental _{analysis: C 17 H 17 N 3 O} 4 · CH 3 CO 2 H · 1 / 2H 2 O Calculated C (%) H (%) N (%) Theory 57.57 5.59 10.60 Found 57.54 5.75 10.57 Example 6 2-Dibenzofuryl 4-guanidinobenzoate p
-Toluenesulfonate / monohydrate (compound No. 8) 4-guanidinobenzoic acid / hydrochloride (3.51 g) in pyridine (60 m)
Then, 4.04 g of dicyclohexylcarbodiimide was added, and the mixture was stirred for 1 hour under ice cooling. 2.15 g of 2-hydroxydibenzofuran was dissolved in 20 ml of pyridine, added dropwise to the above solution over 15 minutes, and stirred for 1 hour under ice cooling and 21 hours at room temperature.

The reaction solution was filtered, 200 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the filtrate, and the resulting crystals were collected by filtration and washed with water and acetone to give 4.10 g of the carbonate of the title compound.

The carbonate is suspended in 50 ml of a 0.2N aqueous sodium hydroxide solution,
The mixture was extracted three times with 50 ml of methyl ethyl ketone. After the extract was washed with saturated saline, the solvent was distilled off under reduced pressure to obtain 3.55 g of the free base of the title compound.

This was subjected to silica gel column chromatography (CHCl ₃
-CH ₃ OH-CH ₃ COOH 10: 1: 1), purified into p-toluenesulfonate according to a conventional method, and recrystallized from dimethylformamide-ether to give 3.45 g of the title compound.
(39.5% yield).

Melting point 241-243 ° C FAB-MS 346 (M + H) ⁺ IR ν ^KBr cm ^-1 : 3410,3190,1730,1680,1610,1585,1475,1
450,1260,1205,1160,1035,1010,820,745,555 Elemental _{analysis: C 20 H 15 N 3 O} 3 · CH 3 C 6 H 4 SO 3 H · H 2 O Calculated C (%) H (%) N (%) S (%) Theoretical value 60.55 4.70 7.85 5.99 Actual value 60.91 4.61 8.04 5.83

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // A61K 31/335 A61K 31/335 31/34 31/34 31/40 AED 31/40 AED 31/415 31/415 (72) Inventor Shinichi Shimada 1-1-10 Hyogozuka, Utsunomiya City, Tochigi Prefectural Housing 211 (72) Inventor Tadayoshi Koyama 773-3 Ishibashi-cho, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 2-A (72) Inventor Motohide Seya Tochigi 773-3 SK Mansion 3-A, Ishibashi, Ishibashi-cho, Shimotsuga-gun (72) Inventor Noriko Abe 2-4-4 Mitsumine, Oyama-shi, Tochigi Prefecture JP-A-57-53454 (JP, A) JP-A-52-89640 (JP, A) Med. Chem. , (1986), 29 (4), p. 514-9 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 209/08 C07D 209/88 C07D 233/56 C07D 307/91 C07D 319/20 CA, REGISTRY (STN)

Claims (7)

(57) [Claims] 1. The compound of the general formula (I) [In the formula, R represents a 4- (imidazol-1-yl) phenyl group, a 4-indolyl group, a 5-indolyl group, a 2-carbazolyl group, a 1,4-benzodioxan-2-yl-methyl group, a 2-dibenzo group. A guanidinobenzoic acid derivative or a pharmacologically acceptable acid addition salt thereof. 2. The guanidinobenzoic acid derivative according to claim 1, which is 4- (imidazol-1-yl) phenyl, 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof, or the pharmacology thereof. Chemically acceptable acid addition salts. 3. The guanidinobenzoic acid derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1, which is 4-indolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. 4. The guanidinobenzoic acid derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1, which is 5-indolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. 5. The guanidinobenzoic acid derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1, which is 2-carbazolyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. 6. The guanidinobenzoic acid derivative or the drug thereof according to claim 1, which is 1,4-benzodioxan-2-yl-methyl 4-guanidinobenzoate or a pharmacologically acceptable acid addition salt thereof. Physically acceptable acid addition salts. 7. A guanidinobenzoic acid derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, which is 2-dibenzofuryl 4-guanidinobenzoate or a pharmaceutically acceptable acid addition salt thereof. .