JP3048698B2 - Amidino-substituted aromatic compounds and salts thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel orally administrable amidino-substituted aromatic compound showing a potent anticoagulant effect by reversibly inhibiting activated blood coagulation factor X (hereinafter abbreviated as FXa). Or a salt thereof, and a blood coagulation inhibitor containing them as an active ingredient, or an agent for preventing or treating thrombus or embolus.

[0002]

2. Description of the Related Art Hitherto, antithrombin agents have been widely developed as thrombus formation inhibitors. However, these antithrombin agents suppress the thrombin agglutination of platelets by thrombin as well as the anticoagulant effect. It was known to cause a trend. Therefore, the development of anticoagulants based on actions other than the thrombin inhibitory action has been promoted, and F
1,2-bis (5-amidino-2-benzofuranyl) ethane (hereinafter abbreviated as DABE) represented by the following formula (3) as an anticoagulant based on Xa inhibitory action [THROMBOSIS RESEARCH 19]
Vol., Pp. 339-349, 1980].

[0003]

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[0004]

However, this compound (3) has not only an FXa inhibitory effect but also a thrombin inhibitory effect, and the separation of these effects is insufficient, the water solubility is extremely low, and the compound is orally administered. However, they have drawbacks such as no anticoagulant action. Therefore, clinical development of a drug which is specific to FXa, has high activity, has good solubility, and is effective even in oral administration has been desired.

[0005]

In view of the above circumstances, the present inventors have synthesized various amidino group-substituted aromatic compounds, and have conducted intensive studies on their pharmacological actions. Salt has good water-solubility, shows strong anticoagulant effect by inhibiting FXa specifically and reversibly even in oral administration, and is useful as a preventive and therapeutic agent for various diseases based on thrombus and embolus And completed the present invention.

That is, the present invention provides the following general formula (1)

[0007]

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[Wherein, R ¹ represents a carboxyl group, an alkoxycarbonyl group, a carboxymethyl group or an alkoxycarbonylmethyl group, and R ² and R ³ each independently represent a hydrogen atom, or a carboxyl group or an alkoxycarbonyl group. It represents an optionally substituted alkyl group having 1 to 6 carbon atoms, and m and n each independently represent an integer of 0 to 3. X and Y are each independently an oxygen atom, a sulfur atom, an ethenyl group (-CH = CH-) or the following formula (2)

[0009]

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(Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted by a carboxyl group or an alkoxycarbonyl group). The present invention relates to an amidino group-substituted aromatic compound or a salt thereof, and a blood coagulation inhibitor or an agent for preventing or treating thrombus or embolus containing the compound or its salt as an active ingredient.

In the compound represented by the general formula (1) of the present invention, the alkyl group having 1 to 6 carbon atoms may be linear or branched. Include methyl, ethyl, propyl, isopropyl, butyl, secondary or tertiary butyl, pentyl and hexyl groups. Examples of the alkoxy group in the alkoxycarbonyl group or the alkoxycarbonylmethyl group include those having 1 to 6 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary or secondary. Examples include tertiary butoxy, pentyloxy, and hexyloxy groups.

[0012] the carbon to which R ¹ is attached to the present invention compounds (1), and further there are optical isomers or stereoisomers from sometimes alkyl group be selected as a substituent R ² or R ³ However, any of these optical isomers, stereoisomers, and mixtures thereof are included in the present invention.

The salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include hydrochloride, hydrobromide, hydroiodide and phosphoric acid salt,
Minerates such as nitrates and sulfates; methanesulfonates, 2
-Organic sulfonates such as hydroxyethane sulfonate, p-toluene sulfonate; acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate And organic carboxylate salts such as maleate, malate, mandelate and the like.

The compound (1) of the present invention can be produced, for example, according to the following reaction formula.

[0015]

Embedded image

Wherein X, Y, m, n, R ¹ , R ² and R
³ is the same as described above, p represents an integer of 0 to 1, and R ⁵
Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms)

That is, the nitrile compound represented by the formula (4) is reacted with an alcohol (R ⁶ OH) in the presence of hydrogen halide, and the resulting imino ether compound (5) is reacted with ammonia, whereby the amidino group is substituted. An aromatic compound (1a) is produced. Furthermore, the carboxylic acid derivative (1b) can be produced by hydrolyzing the compound (1a).

The nitrile compound (4) and alcohol (R ⁶ O)
The reaction with H) is carried out, for example, in the presence of a hydrogen halide such as hydrogen chloride or hydrogen bromide in an equivalent to a large excess of an alcohol having 1 to 6 carbon atoms such as methanol, ethanol or propanol (R
⁶ OH). If necessary, the solvent may be an aliphatic ether such as diethyl ether, a halogenated hydrocarbon such as chloroform or dichloromethane, an aprotic solvent such as benzene, or a mixed solvent thereof. The reaction is usually carried out at a temperature of 10 ° C to 60 ° C below zero for 3 to 120 hours. Preferably, the reaction is carried out at 0 to 30 ° C. for 10 to 70 hours using a halogenated hydrocarbon such as chloroform or dichloromethane as a solvent in the presence of a large excess of methanol or ethanol.

The reaction between the obtained imino ether compound (5) and ammonia is carried out, for example, by reacting the imino ether compound (5) with an alcohol having 1 to 6 carbon atoms such as ethanol and propanol, an aliphatic ether such as diethyl ether, The reaction is carried out by reacting ammonia in a halogenated hydrocarbon such as chloroform, an aprotic solvent such as benzene, a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. The reaction is usually carried out at a temperature of 10 ° C to 140 ° C below 0.5 to 20 ° C.
Performed for 0 hours. Preferably 10 to 10 degrees Celsius in ethanol
Performed at 30 ° C. for 10 to 40 hours.

Further, the hydrolysis reaction of the obtained amidino derivative (1a) is carried out by treating it in an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as tosylic acid at 0 ° C. to heating under reflux. .

The thus obtained amidino-substituted aromatic compound (1) and a salt thereof have a specific and excellent FXa inhibitory action, and are useful as a blood coagulation inhibitor, and as a preventive and therapeutic agent for thrombus and embolus. Since compound (1) exerts its effect even orally, it can be administered either orally or parenterally. The dose of the compound of the present invention may be appropriately increased or decreased depending on the condition, age, body weight, etc. of the patient. Generally, in the case of oral administration, 10 to 600 mg / day, more preferably 50 to 300 mg / day per adult is appropriate. Dosage forms include tablets, capsules, powders, granules and the like. These can be produced by known formulation techniques together with usual excipients, lubricants, binders and other additives. In the case of parenteral administration, 0.1 to 100 mg / day, preferably 1 to 3 per adult.
It is appropriate to inject 0 mg / day subcutaneously, intravenously or intravenously.

[0022]

The compound of the present invention exhibits an excellent anticoagulant action based on a specific FXa inhibitory action. Therefore, the compound of the present invention does not act on platelets at all, and various diseases caused by thrombus and embolism such as cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger's disease, deep vein thrombosis, and generalized It can treat or prevent intravascular coagulation syndrome, thrombus formation after artificial valve replacement, reocclusion after revascularization, and thrombus formation during extracorporeal blood circulation.

[0023]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

Reference Example 1 2- (5-cyano-2-benzofuranyl) -2-oxoacetic acid methyl ester a) Method such as dan [Liebig Annalen der.
Chemie, 1982, pp. 1836-1869], and a solution of 21.0 g of 2-acetyl-5-benzofurancarbonitrile dissolved in 300 ml of dichloromethane is added dropwise with stirring at 10 ° C. under reduced temperature at 10 ° C. with a solution of 18.2 g of bromine in 30 ml of dichloromethane. did. The temperature was raised to ice-cooling, and the reaction solution to which chloroform was added was washed with a 10% aqueous sodium thiosulfate solution. The organic layer was dried and concentrated to dryness. The crude crystals obtained were recrystallized from a mixture of benzene and n-hexane to give colorless crystals of 2- (2-bromo-1-oxoethyl) -5.
-21.0 g of benzofurancarbonitrile were obtained. mp 156-158 ° C ¹ H-NMR (CDCl ₃ ) δ: 4.44 (2H, s), 7.60-7.90 (3H, m), 8.11 (1
H, s) FD MS (m / z): 263 (M ⁺ ), 265 (M ⁺ ) b) 244 mg of selenium dioxide was dissolved in 10 ml of dry methanol while heating, and the 2- (2- Brom-1-
(Oxoethyl) -5-benzofurancarbonitrile
056 g was added, and the mixture was heated under reflux for 12 hours. After cooling, the insolubles were removed by filtration, and the residue obtained by concentrating to dryness was subjected to silica gel column chromatography and eluted with a mixed solvent of toluene and ethyl acetate to give the title compound 129 as colorless needles.
mg was obtained. mp 196-199 ° C ¹ H-NMR (CDCl ₃ ) δ: 4.03 (3H, s), 7.66-7.96 (2H, m), 8.17 (2
H, s) FD MS (m / z): 229 (M ⁺ )

Reference Example 2 [(7-cyano-2-naphthyl) methyl] triphenylphosphonium bromide

Embedded image a) Adcock's method [Australian Journal of Chemical Society, 1965, 18
Volume, 1351-1364].
11.0 g of naphthalene carboxylic acid was converted to thionyl chloride (70 m).
and heated to reflux for 4 hours. To the residue obtained by concentrating and drying the reaction solution was added 300 ml of concentrated aqueous ammonia under cooling to dissolve and stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated saline, dried, and the solvent was distilled off to obtain colorless needles of 7-methyl-2 represented by the following formula.
8.5 g of naphthalenecarboxamide were obtained.

Embedded image mp 210-212 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H,
b) 8.04 g of 7-methyl-2-naphthalenecarboxamide obtained in a) was suspended in 100 ml of tetrahydrofuran, and triphenylphosphine was added at room temperature. 66g
Was added in 100 ml of carbon tetrachloride. After stirring at room temperature for 30 minutes, the mixture was stirred at a bath temperature of 60 ° C for 40 hours. After cooling to room temperature, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. 28.35 g of the obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane and ethyl acetate to obtain 5.73 g of colorless scaly 7-methyl-2-naphthalenecarbonitrile. Was. mp 134-136 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H,
s), 7.40-8.20 (6H, m) c) N-bromosuccinimide was added to a suspension of 5.7 g of 7-methyl-2-naphthalenecarbonitrile obtained in b) in 100 ml of carbon tetrachloride. 6.37 g and 2,2-azodi-iso-butyronitrile (30 mg) were added, and the mixture was heated under reflux for 2 hours. A reaction solution diluted with dichloromethane was washed with water and saturated saline and dried. The solvent was distilled off to obtain 8.34 g of 7- (bromomethyl) -2-naphthalenecarbonitrile represented by the following formula as pale yellow needles.

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 4.65 (2H,
s), 7.55-8.28 (6H, m) d) 11.6 g of triphenylphosphine in a solution of 8.34 g of 7- (bromomethyl) -2-naphthalenecarbonitrile obtained in section c in 200 ml of xylene. And add
The mixture was heated under reflux for 16 hours. Diethyl ether was added, and the precipitated crystals were collected by filtration and dried to obtain 12.10 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 5.96 (2H, d,
J = 15.3 Hz), 7.10-8.00 (21H,
m)

Reference Example 3 (6-Cyano-1-methyl-2-indolyl) methyltriphenylphosphonium bromide a) Method of dan and the like [Liebig-Annalene der.
Chemie, 1986, pp. 438-455] and dissolving 1.5 g of 6-cyano-2-indolecarboxylic acid methyl ester in 20 ml of N, N-dimethylformamide, and adding 60% sodium hydride under ice-cooling and stirring. 3
20 mg was added, and the mixture was stirred at room temperature for 10 minutes. Then, 0.47 ml of methyl iodide was added and the mixture was stirred at room temperature for 2 hours.
A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with methanol. The obtained crystals were recrystallized from a mixture of dichloromethane and methanol to obtain 1.4 g of 6-cyano-1-methyl-2-indolecarboxylic acid methyl ester. ^{1 H-NMR (DMSO-d} 6) δ: 3.92 (3H, s), 4.10 (3H, s), 7.42 (1H,
s), 7.52 (1H, dd), 7.98 (1H, d), 8.38 (1H, br) b) 5.7 g of methyl 6-cyano-1-methyl-2-indolecarboxylate obtained in item a) was added to tetrahydrofuran. To the solution dissolved in 120 ml, a catalytic amount of sodium hydrogen carbonate, 5.6 g of calcium iodide and 1.8 g of sodium borohydride were added under ice-cooling and stirring, followed by stirring for 5 hours.
Ice water and acetic acid were added to the reaction solution, and the residue obtained by distilling off tetrahydrofuran under reduced pressure was extracted with ethyl acetate and dried. The residue obtained by distilling off the solvent was diluted with dichloromethane 5
To the solution dissolved in 0 ml, a solution of 1 ml of phosphorus tribromide in 10 ml of dichloromethane was added dropwise with stirring under ice-cooling, followed by stirring at the same temperature for 2 hours and further at room temperature for 2 hours. Ice water was added to the reaction solution, which was washed with an aqueous sodium carbonate solution and then dried.
After the organic layer was concentrated under reduced pressure to about half, 15 g of triphenylphosphine was added, and the mixture was heated under reflux for 12 hours. The precipitate was collected by filtration to obtain 10.5 g of the title compound. ^{1 H-NMR (DMSO-d} 6) δ: 3.33 (3H, s), 5.55 (2H, d), 6.26 (1H,
s), 7.20-8.10 (18H, m)

Reference Example 4 2- (5-cyano-2-benzofuranyl) -3- (6-
Cyano-2-benzofuranyl) propanoic acid methyl ester a) (6-cyano-2-benzofuranyl) methyltriphenylphosphonium chloride 1.91 g and 2- (5-
0.91 g of (cyano-2-benzofuranyl) -2-oxoacetic acid methyl ester was suspended in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol and stirred, and stirred at room temperature for 1,8-diazabicyclo (5.4.0) -7-. 740 mg of undecene was added. After stirring for 2 hours, the precipitated crystals are collected by filtration to give 2- (5-cyano-2-benzofuranyl) -3- (6-cyano-2-benzofuranyl) as a yellow powder.
1.45 g of propenoic acid methyl ester was obtained as a mixture of E and Z forms. mp 254-256 ° C. ¹ H-NMR (CDCl ₃ ) δ: 4.08 (3H, s), 6.96-7.96 (9H, m) b) The 2- (5-) mixture of the E-form and Z-form obtained in section a) In a suspension of 1.3 g of methyl cyano-2-benzofuranyl) -3- (6-cyano-2-benzofuranyl) propenoate in 100 ml of N, N-dimethylformamide, the method of Haas et al. [Angebandet Chemie] , 19
1975, Vol. 67, p. 785], and 1.2 g of barium sulfate obtained by adding palladium oxide / monohydrate / barium sulfate were subjected to catalytic reduction under normal pressure for 3 hours. The catalyst was removed by filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 1.09 g of the title compound as a colorless powder. mp 163-166 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.60 (2H, t), 3.76 (3H, s), 4.44 (1H, t),
6.52 (1H, s), 6.72 (1H, s), 6.52-6.92 (6H, m)

According to the same method as in Reference Example 4, Reference Examples 5 to
Eight compounds were synthesized. Reference Example 5 2- (5-cyano-2-benzofuranyl) -3- (6-
Cyano-1-methyl-2-indolyl) propanoic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ: 3.42-3.80 (2H, m), 3.70 (3H, s), 3.72 (3
H, s), 4.35 (1H, t), 6.30 (1H, s), 6.70 (1H, s), 7.16-7.90 (6
H, m) Reference Example 6 2,3-bis (5-cyano-2-benzofuranyl) propanoic acid methyl ester colorless powder mp 145-147 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.52 (2H, t), 3.76 (3H, s), 4.40 (1H, t),
6.52 (1H, s), 6.72 (1H, s), 7.52-7.92 (6H, m) Reference Example 7 2- (5-cyano-2-benzofuranyl) -3- (7-
Cyano-2-naphthyl) propanoic acid methyl ester ¹ H-NMR (DMSO-d ₆ ) δ: 3.60-3.80 (2H, m), 3.70 (3H, s), 4.00-
4.20 (1H, m), 6.83 (1H, s), 7.50-8.20 (8H, m) Reference Example 8 2- (5-cyano-2-benzofuranyl) -3- (6-
Cyano-2-indolyl) propanoic acid methyl ester ¹ H-NMR (CDCl ₃ ) δ: 3.45 to 3.85 (2H, m), 3.77 (3H, s), 4.40 (1
H, t), 6.37 (1H, s), 6.70 (1H, s), 7.20-7.85 (6H, m), 9.45 (1
H, s)

Example 1 2- (5-amidino-2-benzofuranyl) -3- (7
-Amidino-2-naphthyl) propanoic acid dihydrochloride 2- (5-cyano-2-benzofuranyl) -3- (7-
Cyano-2-naphthyl) propanoic acid methyl ester 5
Hydrochloric acid gas was blown into a solution of 70 mg dissolved in 50 ml of ethanol under ice cooling and stirring, and the mixture was allowed to warm to room temperature and left standing for 24 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 50 ml of an ethanol solution containing 13% (w / v) of ammonia and allowed to stand for 24 hours. The solvent was distilled off and 2- (5-
Amidino-2-benzofuranyl) -3- (7-amidino-2-naphthyl) propanoic acid ethyl ester dihydrochloride was obtained. This was dissolved in 100 ml of 2N hydrochloric acid, heated under reflux for 30 minutes, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using a high-porous polymer-type synthetic adsorbent (divinylbenzene polymer: Diaion HP-20), and then eluted with a mixed solvent of water and acetonitrile. The residue obtained by concentrating the portion containing the target substance is subjected to reversed-phase high performance liquid chromatography using octadecyl group chemically bonded silica gel as a packing material, and is eluted with a mixed solvent of water and acetonitrile, and the fraction of the target substance is obtained. The title compound 3 was obtained as a pale yellow solid by adding dilute hydrochloric acid to the residue.
52 mg were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 4.30-4.60 (1H, m), 6.95 (1H, s), 7.60-
8.20 (7H, m), 8.40 (1H, br), 9.20-9.60 (8H, m) FAB MS (m / z): 401 (M + 1)

According to the same method as in Example 1, Examples 2 to
Compound 5 was synthesized. Example 2 2- (5-amidino-2-benzofuranyl) -3- (6
Amidino-1-methyl-2-indolyl) propanoic acid dihydrochloride solid ¹ H-NMR (DMSO-d ₆ ) δ: 3.82 (3H, s), 4.40-4.70 (1H, m), 6.40
(1H, s), 7.10 (1H, s), 7.40-8.40 (6H, m), 8.80-9.70 (8H, m) Example 3 2,3-bis (5-amidino-2-benzofuranyl) propanoic acid Hydrochloride solid ¹ H-NMR (DMSO-d ₆ ) δ: 3.60 (2 H, m), 4.56 (1 H, t), 6.84 (1 H,
s), 7.08 (1H, s), 7.72-8.16 (6H, m), 9.36 (8H) Example 4 2- (5-amidino-2-benzofuranyl) -3- (6
-Amidino-2-benzofuranyl) propanoic acid dihydrochloride solid ¹ H-NMR (DMSO-d ₆ ) δ: 3.60 (2H, m), 4.56 (1H, t), 6.84 (1H,
s), 7.08 (1H, s), 7.82-8.16 (6H, m), 9.28 (8H) Example 5 2- (5-amidino-2-benzofuranyl) -3- (6
-Amidino-2-indolyl) propanoic acid dihydrochloride solid FAB MS (m / z): 390 (M + 1) ¹ H-NMR (DMSO-d ₆ ) δ: 4.60 (1H, t), 6.36 (1H, s), 7.01 (1H,
s), 7.36-8.00 (5H, m), 8.15 (1H, s), 8.90-9.60 (8H, m), 11.9
5 (1H, s)

Example 6 2- (5-amidino-2-benzofuranyl) -3- (5
-Amidino-2-indolyl) propanoic acid dihydrochloride (5-cyano-2-indolyl) methyltriphenylphosphonium bromide 4 g and 2- (5-cyano-2-benzofuranyl) -2-oxoacetic acid methyl ester 2 g
Was dissolved in a mixture of 30 ml of tetrahydrofuran and 100 ml of methanol, and 1.6 ml of 1,8-diazabicyclo (5.4.0) -7-undecene was added under ice-cooling and stirring. After returning to room temperature and stirring for 2 hours, the solvent was distilled off. Chloroform was added to the resulting residue, and the precipitated crystals were collected by filtration. Furthermore,
The residue obtained by concentrating the filtrate was subjected to silica gel column chromatography, eluted with a mixed solvent of chloroform and acetone, and the portion containing the desired product was concentrated to dryness. 5-cyano-2-benzofuranyl)
2.7 g of methyl 3- (5-cyano-2-indolyl) propenoate was obtained as a mixture of E and Z forms. IR (KBr) cm ^-1 : 3300,2224,1713 2- (5-cyano-2-benzofuranyl) -3- (5-
A mixture of the E, Z form of cyano-2-indolyl) propenoic acid methyl ester was treated with N, N-dimethylformamide 10
3 g of palladium oxide / monohydrate / barium sulfate was added to a solution dissolved in a mixture of 100 ml of methanol and 100 ml of methanol, and the mixture was subjected to normal pressure catalytic reduction for 3 hours. The catalyst was removed by filtration, and the residue obtained by evaporating the solvent from the filtrate was purified by silica gel column chromatography to give 2- (5-cyano-2-benzofuranyl)-
3- (5-Cyano-2-indolyl) propanoic acid methyl ester was obtained. Then, a solution of this in a mixture of 100 ml of ethanol and 50 ml of dichloromethane was blown with hydrochloric acid gas under ice-cooling and stirring to saturate the mixture, and the mixture was allowed to stand at 5 ° C. for 2 days. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 50 ml of an ethanol solution containing 13% (w / v) of ammonia and left for 24 hours. The solvent was distilled off to give 2- (5-amidino-2-benzofuranyl) -3- (5-amidino-2).
-Indolyl) propanoic acid ethyl ester dihydrochloride was obtained. This was dissolved in 100 ml of 2N hydrochloric acid,
The mixture was heated under reflux for 30 minutes and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography with a high-porous polymer-type synthetic adsorbent (divinylbenzene polymer: Diaion HP-20), and was eluted with a mixed solvent of water and acetonitrile. The residue was dried to give 1.2 g of the title compound as a solid. ¹ H-NMR (DMSO-d ₆ ) δ: 4.40-4.70 (1 H, m), 6.35 (1 H, s), 7.02
(1H, s), 7.52 (2H, s), 7.81 (2H, s), 8.10 (3H, d), 8.80-9.60
(8H, m)

Test Example 1 A fixed amount of water was added to a fixed amount of a sample for measurement of solubility in water, and the mixture was shaken at 25 ° C. for 10 minutes. Table 1 shows the results.

[0033]

[Table 1]

Test Example 2 Measurement of Anticoagulant Effect Plasma was separated from human blood using a centrifuge. To 100 μl of the plasma was added 100 μl of a physiological saline solution or 100 μl of a physiological saline solution, and the mixture was allowed to stand at 37 ° C. for 2 minutes. To this was added 100 μl of a 0.02 molar solution of calcium chloride which had been kept at 37 ° C. in advance, and the coagulation time was measured using Crotech (manufactured by Sanko Junyaku). The coagulation time when only physiological saline was added was used as a control, and the concentration of the sample (CT2
This was used as an index of the anticoagulant effect. Table 2 shows the anticoagulant activity of representative compounds.

Test Example 3 Measurement of Activated Blood Coagulation Factor X (FXa) Inhibiting Effect Tris-pH 180 of physiological saline solution, pH 8.4
A mixture of 200 μl of hydrochloric acid buffer and an aqueous solution of 1 mmol S-2222 (manufactured by Daiichi Kagaku Co., Ltd.) was incubated at 37 ° C., and the pH of human activated blood coagulation factor X (0.6 unit / ml) was adjusted to pH7. 20 μl of 45 Tris-HCl buffer
And leave for 15 minutes. After adding 100 μl of 60% acetic acid, the absorbance was measured. A blank to which only physiological saline was added instead of the sample was used as a blank, and a blank to which 60% acetic acid was added prior to activated blood coagulation factor X was used as a control.
Determine the analyte concentration (abbreviated as IC ₅₀₎ at which 50% inhibition,
It was used as an index of the activated blood coagulation factor X inhibitory action. Table 2 shows the anti-activating blood coagulation factor X action of representative compounds.

Test Example 4 Measurement of Thrombin Inhibitory Action Fibrinogen (Type 1: manufactured by Daiichi Pure Chemicals Co., Ltd.)
mg / ml pH 7.45 Tris-HCl buffer solution 100μ
l and 100 μl of physiological saline at 37 ° C., 100 μl of a pH 7.45 Tris-HCl buffer solution of various concentrations of thrombin (for thrombin topical: Sankyo) was added, and the coagulation time was measured using Crotech (manufactured by Sanko Junyaku). And a calibration curve was prepared. Physiological saline solution 100 of the specimen instead of physiological saline
μl was added and the clotting time was measured to determine% inhibition. % Inhibition
In addition, the sample concentration when inhibiting 50% from the sample concentration (IC
₅₀ ) and used as an index of thrombin inhibitory action.
Table 2 shows the thrombin inhibitory effects of representative compounds.

[0037]

[Table 2]

As shown in Table 2, the conventionally known DA
Compared with BE, the compound of the present invention specifically inhibited FXa and showed a strong anticoagulant effect.

Test Example 5 Measurement of anticoagulant action by oral administration A male rat under anesthesia was administered with a sample dissolved in 10 ml of water per 1 kg of body weight, blood was collected over time to separate plasma, and activated partial thromboplastin time was measured. (APTT) was measured. Similarly, the APTT when only water was administered was measured and used as a control. The ratio of the APTT at the time of administration of the sample to that of the control was used as an index of the anticoagulant effect. Table 3 shows the anticoagulant activity of representative compounds by oral administration.

[0040]

[Table 3]

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 307/84 C07D 307/84 333/60 333/60 333/68 333/68 405/06 405/06 409/06 409/06 (72) Inventor Naoaki Kanaya 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd.Tokyo R & D Center (72) Inventor Yukio Yokoyama 1-1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Co., Ltd. Tokyo Research and Development Center (56) References Thromb. Res. , 19 (3), p. 339-349 (1980) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 307/79 A61K 31/343 A61K 31/405 C07D 209/18 C07D 307/84 C07D 333/60 C07D 333/68 C07D 405/06 C07D 409/06 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a carboxyl group, an alkoxycarbonyl group, a carboxymethyl group or an alkoxycarbonylmethyl group, and R ² and R ³ each independently represent a hydrogen atom, or a carboxyl group or an alkoxycarbonyl group. Means an alkyl group having 1 to 6 carbon atoms which may be
m and n each independently represent an integer of 0 to 3. X and Y each independently represent an oxygen atom, a sulfur atom, an ethenyl group (—CH ＝ CH—) or the following formula (2): (In the formula, R ⁴ represents a hydrogen atom or a carbon atom which may be substituted by a carboxyl group or an alkoxycarbonyl group.
Amidino group-substituted aromatic compound or a salt thereof. 2. A blood coagulation inhibitor comprising the compound according to claim 1 or a salt thereof as an active ingredient, or an agent for preventing or treating thrombus or embolus. 3. A compound of the general formula (4) [Wherein, R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted by a carboxyl group or an alkoxycarbonyl group, and R ⁵ represents a hydrogen atom, or Means an alkyl group having 1 to 6 carbon atoms, m
And n each independently represent an integer of 0 to 3;
Means an integer of 1. X and Y each independently represent an oxygen atom, a sulfur atom, an ethenyl group (—CH ＝ CH—) or the following formula (2): (In the formula, R ⁴ represents a hydrogen atom or a carbon atom which may be substituted by a carboxyl group or an alkoxycarbonyl group.
Which means a group represented by the following formulas: 4. A compound of the general formula (5) Wherein means R ² and R ³ are each independently hydrogen atom, or a carboxyl group or alkoxycarbonyl group is an alkyl group having 1 to 6 carbon atoms which may be substituted, R ⁶ is 1 to carbon atoms 6 represents an alkyl group, m and n each independently represent an integer of 0 to 3, and p represents an integer of 0 to 1. X and Y each independently represent an oxygen atom, a sulfur atom,
An ethenyl group (—CH ＝ CH—) or the following formula (2): (In the formula, R ⁴ represents a hydrogen atom or a carbon atom which may be substituted by a carboxyl group or an alkoxycarbonyl group.
Which means a group represented by the following formulas: