JPH08113594A - Aspartic acid derivative and medicinal preparation containing the same - Google Patents

Abstract

PURPOSE: To obtain a specific aspartic acid derivative having antagonistic action on the GPIIb/IIIa receptor on blood platelet surface, having blood platelet coagulation-inhibitory action and anti-thrombogenic action, thus useful as a blood platelet coagulation inhibitor or anti-thrombogenic agent. CONSTITUTION: This new aspartic acid derivative having the above-mentioned actions is expressed by formula I [B is a (substituted) 0-10C alkylene; E is a (substituted) o-, m- or p-phenylene, or a (substituted) 0-10C alkylene; G is OH, a 0-10C alkylamino, a 1-10C alkoxyl, etc.; L is OH, a 0-10C alkylamino, a 1-10C alkoxyl, (substituted) amino acid, etc.; A is a group of formula II (M is H, a 1-10C alkyl, a 1-10C alkoxycarbonyl, etc.; Q is H, a 1-10C alkyl, an aryl-0-8C alkyl, an acylamino, a 1-10C alkoxyl, etc.)], e.g. N- N-[3-(piperidin-4- yloxyacetylamino)-benzoyl]-L-aspartyl}-L-phenylalanine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel aspartic acid derivative, and a pharmaceutical preparation containing the derivative, which has an inhibitory action on platelet aggregation and an antithrombotic action.

[0002]

2. Description of the Related Art Platelet aggregation plays an important role in thrombus formation and blood coagulation. The final step in the platelet aggregation process is the activation of the GPIIb / IIIa receptor on the platelet surface, which in turn binds fibrinogen. Therefore, GPIIb / IIIa
Inhibitors that prevent binding to adhesion proteins such as and fibrinogen are believed to be useful in preventing thrombus formation and blood coagulation. When fibrinogen binds to GPIIb / IIIa, A on fibrinogen
rg-Gly-Asp-Ser (RGDS) is said to be its active site (Phillips).
Blood, 1988, 71, 831-843). Therefore, RGDS analogs have been developed as GPIIb / IIIa receptor antagonists (Patent Publication; EP512831, EP).
445796, EP372486, EP513675)
However, more active antagonists are desired.

[0003]

SUMMARY OF THE INVENTION The object of the present invention is G
It is intended to provide a novel aspartic acid derivative having a PIIb / IIIa receptor antagonistic action, a platelet aggregation inhibitory action and an antithrombotic action, and a pharmaceutical preparation containing the same.

[0004]

As a result of intensive studies, the present inventors have found a new aspartic acid derivative having the structure shown in Formula 1, and have completed the present invention in accordance with the above object.

[0005]

Embedded image

(In the formula 1, B represents (C; 0-10) alkylene which may be substituted with a substituent (the substituent is (C; 1-10) alkyl, aryl (C; 0-). 8)
Alkyl, (C; 0-10) alkylamino, acylamino, (C; 1-10) alkoxy, aryl (C; 0
~ 8) alkoxy, (representing aryl (C; 0-8) alkyl) amino, hydroxy, or halogeno), E
Is ortho-, meta-, which may be substituted with a substituent,
Alternatively, it represents a para-phenylene group or (C; 0-10) alkylene which may be substituted with a substituent (the substituent is (C; 1-10) alkyl, aryl (C; 0).
To 8) alkyl, (C; 0-10) alkylamino, acylamino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, (aryl (C; 0-8)
Alkyl) amino, hydroxy, or halogeno), G is hydroxy, (C; 0-10) alkylamino, di (C; 0-10) alkylamino, (aryl (C; 1-10) alkyl) Amino, (C; 1-10)
Alkoxy, aryl (C; 0-8) alkoxy,
(C; 1-10) alkylcarbonyloxy (C; 1-
10) Alkoxy or aryl (C; 1-10) alkylcarbonyloxy (C; 1-10) alkoxy is shown, and L is hydroxy, (C; 0-10) alkylamino, di (C; 0-10) alkyl. Amino, (aryl (C; 1-10) alkyl) amino, (C; 1-10)
Alkoxy, aryl (C; 0-8) alkoxy,
(C; 1-10) alkylcarbonyloxy (C; 1-
10) Alkoxy, aryl (C; 1-10) alkylcarbonyloxy (C; 1-10) alkoxy, or an amino acid which is bonded with a substituent and which is optionally substituted with a substituent and an ester thereof, or an amino group Represents an α-aminocarboxylic acid which may be substituted with a substituent and an ester thereof, which are bonded with each other (the substituent is (C;
-10) alkyl, aryl (C; 0-8) alkyl,
Or A represents a halogeno), and A represents a substituent represented by Formula 2. C represents carbon. )

[0007]

[Chemical 4]

(In the formula 2, M represents hydrogen, (C; 1-10) alkyl, (C; 1-10) alkoxycarbonyl, or aryl (C; 0-8) alkoxycarbonyl, and Q represents hydrogen. (C; 1-10) alkyl, aryl (C; 0-8) alkyl, (C; 0-10) alkylamino, acylamino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, Hydroxy or halogeno is shown, and C is carbon.)

The aspartic acid derivative of the present invention is optionally used as its salt. The present invention is also a pharmaceutical preparation containing an aspartic acid derivative having the structure of Formula 1. Further, the present invention is a fibrinogen receptor antagonist comprising an aspartic acid derivative having the structure shown in formula 1.

Further, the present invention is a platelet aggregation inhibitor containing an aspartic acid derivative having the structure shown in formula 1. The present invention is also an antithrombotic agent containing an aspartic acid derivative having the structure of Formula 1.

The aspartic acid derivative represented by the formula 1 of the present invention can be produced by the following method.
That is, after the compound represented by the following formula 3 and the compound represented by the formula 4 are condensed using a condensing agent, or the compound represented by the formula 3 is converted into a carboxylic acid derivative such as an acid halide or an active ester. , After condensing with a base or the like,
If necessary, the aspartic acid derivative of the present invention can be produced by removing the protecting group.

[0012]

Embedded image

(In formula 3, A and B have the same meaning as in formula 1.)

[0014]

[Chemical 6]

(In the formula 4, E, G and L have the same meanings as in the formula 1.)

Here, the compound represented by the formula 3 is represented by the following formula 5
The compound represented by the formula (6) and the compound represented by the formula (6) are condensed with a base to obtain a compound represented by the following formula (7), and then hydrolyzed with an acid or a base, if necessary, or hydrogen, etc. Can be produced by reductively desorbing. An example of the production of the compound represented by the formula 5 is 1- (benzyloxycarbonyl) -4-hydroxypiperidine (HC Brown et al., Journal of Organic Chemistry, 50, 1582-9, 1985). Further, as an example of condensation of the compound represented by Formula 5 and the compound represented by Formula 6, when T of the compound represented by Formula 6 is bromine, the method of HH Friedman et al. (Tetrahedron Letters No. 38 , 3251 (1975)).

[0017]

[Chemical 7]

(In the formula 5, A is a substituent represented by the formula 2.)

[0019]

Embedded image

(In formula 6, B has the same meaning as in formula 1, T represents halogeno, alkyl sulfonate, or aryl sulfonate, and U is hydroxy, (C; 0-10) alkylamino, (C; 1 10 to 10) alkoxy or aryl (C; 0 to 8) alkoxy, and C represents carbon.)

[0021]

[Chemical 9]

(In formula 7, A, B, and U have the same meanings as in formula 1.)

The compound represented by the formula 4 is obtained by condensing the compound represented by the following formula 8 with the compound represented by the formula 9 by using a condensing agent, or by reacting the compound represented by the formula 8 with an acid. By condensation with a halide or a carboxylic acid derivative such as an active ester using a base or the like, an amino protected compound of the formula 4 can be obtained, and then V of the compound of the formula 8 is nitro. In the case of, it can be produced by reduction, and in other cases, it can be produced by removing the amino protecting group.

[0024]

[Chemical 10]

(Wherein E has the same meaning as in formula 1, V is nitro, ((C; 1-10) alkoxycarbonyl) amino, (aryl (C; 0-8) alkoxycarbonyl))
It represents a protected amino group such as amino, (C; 1-10) alkylamide, succinylimide, or phthaloylimide. C represents carbon. )

[0026]

[Chemical 11]

(In formula 9, G and L have the same meanings as in formula 1.)

The aspartic acid derivative of the present invention is GPII
It is used as a b / IIIa receptor antagonist and a drug that inhibits thrombus formation caused by the binding of GPIIb / IIIa and an adhesion protein such as fibrinogen, that is, a platelet aggregation inhibitor and an antithrombotic agent. The compound of the present invention is used for treating and preventing recurrence of diseases caused by thrombus formation such as myocardial infarction, unstable angina, transient cerebral ischemic attack, and peripheral arterial occlusion. Furthermore, the compounds of the present invention are useful in preventing platelet activation due to interaction with an artificial surface during extracorporeal circulation such as use of heart-lung machine or hemodialysis. It can also be used for coronary artery bypass surgery, revascularization of peripheral arterial occlusion, and prevention of graft occlusion during dialysis patient shunt placement.

Although the dose varies depending on the symptom, it is generally from 0.10 to 600 mg, preferably from 1 to 200 mg per day for adults, and if necessary, it may be divided into 1 to 3 doses. The administration method can be any form suitable for administration, and oral administration is particularly preferable, but intravenous administration is also possible. The compound of the present invention is used as an active ingredient or one of the active ingredients, alone or in combination with a pharmaceutical carrier, according to known formulation techniques, such as tablets, powders, capsules, granules, syrups, solutions, suspensions, injections, eye drops, Alternatively, it may have any formulation suitable for administration of suppositories and the like.

Specific pharmaceutical carriers include starches,
Excipients such as sucrose, lactose, methyl cellulose, carboxymethyl cellulose, crystalline cellulose, sodium alginate, calcium hydrogen phosphate, magnesium aluminometasilicate, silicic acid anhydride, and synthetic aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Binders such as gelatin and polyvinylpyrrolidone, carboxymethylcellulose calcium, disintegrating agents such as crosslinked sodium carboxymethylcellulose and crosslinked polyvinylpyrrolidone, lubricants such as magnesium stearate and talc, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, meta Coating agents such as acrylic acid and methyl methacrylate copolymers, polyethylene glycol, etc. Desolvation aid, sodium lauryl sulfate, lecithin, sorbitan monooleate, polyoxyethylene cetyl ether, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil and emulsifiers such as glyceryl monostearate, chelating agents such as EDTA, buffering agents, Moisturizers, preservatives, cocoa butter and witebsol W
Examples include bases such as 35.

[0031]

EXAMPLES The present invention will now be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these.

Example 1 (1-1) Under ice cooling, N- [N- (tert-butoxycarbonyl) -O (4) -benzyl-L-aspartyl]-
L-phenylalanine benzyl ester 2.01 g
10 ml of a 4N hydrogen chloride dioxane solution was added to and stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.63 g of N- (tert-butoxycarbonyl) glycine and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.
To 58 g of N, N-dimethylformamide (DMF) solution (15 ml) was added triethylamine (1.09 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-
{N-[(tert-butoxycarbonylamino) acetyl] -O (4) -benzyl-L-aspartyl} -L-
1.57 g of phenylalanine benzyl ester was obtained (yield 100%, oily substance).

(1-2) Under ice cooling, N- {N-[(tert
-Butoxycarbonylamino) acetyl] -O (4)-
Benzyl-L-aspartyl} -L-phenylalanine benzyl ester (1.54 g) was added with 10 ml of 4N hydrochloric acid dioxane solution, stirred for 1 hour, and concentrated under reduced pressure. Dissolve the residue in methylene chloride, wash with saturated aqueous sodium hydrogen carbonate,
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give an oily substance. 1- (benzyloxycarbonyl) -4-
To 1.03 g of (carboxymethoxy) piperidine, the above oil, and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (1.56 g) in DMF solution (40 ml) under ice cooling,
Triethylamine (1.07 g) was added, and the mixture was stirred at room temperature for 3 hours. Water was added and extracted with ethyl acetate, and the organic layers were sequentially
The extract was washed with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N- (N-{[1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] acetyl} -O (4)- Benzyl-L-aspartyl) -L-phenylalanine benzyl ester 1.
49 g was obtained (53% yield, oily substance).

(1-3) Under a hydrogen atmosphere, N- (N-
{[1- (benzyloxycarbonyl) piperidine-4
-Yloxyacetylamino] acetyl} -O (4)-
Benzyl-L-aspartyl) -L-phenylalanine benzyl ester 1.49 g, a methanol suspension (60 ml) of 10% palladium on carbon 0.75 g was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure, and N-
0.69 g of {N-[(piperidin-4-yloxyacetylamino) acetyl] -L-aspartyl} -L-phenylalanine was obtained (yield 77%, amorphous).
. Instrumental analysis data for this one supports the structural formula of Equation 10 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.27-7.13 (m, 5H), 4.59-4.55
(M, 1H), 4.39 (t, 1H, J = 6.3Hz),
4.08 (s, 2H), 3.85 (dd, 2H, J = 3.
6, 16.2 Hz), 3.77-3.71 (m, 1H), 3.
32-3.26 (m, 2H), 3.09 (dd, 2H, J
= 3.6, 16.2 Hz), 3.06-3.00 (m, 1
H), 2.88 (dd, 2H, J = 8.9, 16.2Hz),
2.64 (dd, 2H, J = 3.6, 16.2Hz), 2.5
0 (dd, 2H, J = 8.9, 16.2Hz), 2.03-
1.98 (m, 2H), 1.83-1.77 (m, 2H) IR (1 / cm): 3600-3200, 1650, 1
540

[0036]

[Chemical 12]

(Example 2) (2-1) N- (tert-butoxycarbonyl) -β-
DMF solution of alanine 480 mg, N- (O (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester 1.17 g and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.18 g (13 ml)
To the above, 0.78 g of triethylamine was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N- (N- (3
-(Tert-butoxycarbonylamino) propionyl)
1.60 g of -O (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester was obtained.
(Yield 100%, oily substance).

(2-2) Under ice cooling, N- {N- [3-
(Tert-Butoxycarbonylamino) propionyl]-
6 ml of trifluoroacetic acid was added to 1.60 g of O (4) -benzyl-L-aspartyl} -L-phenylalanine benzyl ester, and the mixture was stirred for 1.5 hours and then concentrated under reduced pressure. Dissolve the residue in ethyl acetate, wash with saturated aqueous sodium hydrogen carbonate,
After drying over anhydrous sodium sulfate, concentration under reduced pressure, N-
1.34 g of [N- (3-aminopropionyl) -O (4) -benzyl-L-aspartyl] -L-phenylalanine benzyl ester was obtained (yield 100%, oily substance).

(2-3) 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine 0.77
g, N- [N- (3-aminopropionyl) -O (4)
-Benzyl-L-aspartyl] -L-phenylalanine benzyl ester 1.34 g and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.21 g DM
To solution F (13 ml) under ice cooling, triethylamine 0.7
8 g was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate.The organic layer was sequentially diluted with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate,
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- (N
-{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] propionyl}-
O (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester (1.39 g) was obtained (yield 66%, oily substance).

(2-4) Under hydrogen atmosphere, N- (N-
{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] propionyl} -O
A methanol suspension (60 ml) of (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester (1.39 g) and 10% palladium on carbon (0.50 g) was stirred overnight. The catalyst was filtered with water, the filtrate was concentrated under reduced pressure and then ethanol was added. The precipitated crystals were collected by filtration and N- {N- [3- (piperidin-4-yloxyacetylamino) propionyl] -L-aspartyl}-
0.55 g of L-phenylalanine was obtained (yield 68%,
Colorless crystals, melting point 198-200 ° C). Instrumental analysis data for this one supports the structural formula of Equation 11 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.27-7.13 (m, 5H), 4.59-4.55
(M, 1H), 4.39 (t, 1H, J = 6.3Hz),
3.95 (s, 2H), 3.68-3.63 (m, 1
H), 3.40-3.32 (m, 2H), 3.30-3.2
0 (m, 2H), 3.13 (m, 4H), 2.70-2.
35 (m, 4H), 2.00-1.93 (m, 2H),
1.80-1.75 (m, 2H) IR (1 / cm): 3600-3200, 1650, 15
40

[0042]

[Chemical 13]

Example 3 (3-1) Under ice cooling, N- [N- (tert-butoxycarbonyl) -O (4) -benzyl-L-aspartyl]-
L-phenylalanine benzyl ester 1.50 g
To the mixture was added 5 ml of trifluoroacetic acid, the mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
An oily substance was obtained. 0.54 g of 4- (tert-butoxycarbonylamino) butyric acid and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.19 g of DMF
To the solution (30 ml) under ice cooling, triethylamine 0.81
g was added, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N- {N
-[4- (tert-butoxycarbonylamino) butanoyl] -O (4) -benzyl-L-aspartyl} -L
-1.55 g of phenylalanine benzyl ester was obtained (yield 90%, oily substance).

(3-2) Under ice cooling, N- {N- [4-
(Tert-Butoxycarbonylamino) butanoyl] -O
(4) -Benzyl-L-aspartyl} -L-phenylalanine benzyl ester (1.55 g) was mixed with 5 ml of trifluoroacetic acid, stirred for 1 hour, and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.70 g of 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.0
0.73 g of triethylamine was added to 6 g of DMF solution (30 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction,
N- (N- {4- [1- (benzyloxycarbonyl)
Piperidin-4-yloxyacetylamino] butanoyl} -O (4) -benzyl-L-aspartyl) -L-
1.59 g of phenylalanine benzyl ester was obtained (yield 81%, oily substance).

(3-3) Under a hydrogen atmosphere, N- (N-
{4- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] butanoyl} -O
A suspension of (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester (1.59 g) and 10% palladium on carbon (0.7 g) in methanol (50 ml) was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure,
0.65 g of N- {N- [4- (piperidin-4-yloxyacetylamino) butanoyl] -L-aspartyl} -L-phenylalanine was obtained (yield 66%, colorless crystals, melting point 191-192 ° C). . Instrumental analysis data for this one supports the structural formula of Equation 12 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.26-7.12 (m, 5H), 4.57-4.53
(M, 1H), 4.43-4.39 (m, 1H), 3.9
9 (s, 2H), 3.71-3.69 (m, 1H), 3.
31-3.26 (m, 2H), 3.13-3.08 (m, 3)
H), 3.05-2.99 (m, 2H), 2.93-2.8.
7 (m, 1H), 2.68 (dd, 1H, J = 5.31,
16.66Hz), 2.50 (dd, 1H, J = 8.60, 1
6.66Hz), 2.15 (t, 2H, J = 7.51Hz),
2.01-1.98 (m, 2H), 1.82-1.81
(M, 2H), 1.67-1.63 (m, 2H) IR (1 / cm): 3600-3200, 1650, 15
40

[0047]

Embedded image

(Example 4) (4-1) Under ice cooling, N- [N- (tert-butoxycarbonyl) -O (4) -benzyl-L-aspartyl]-
To 1.0 g of L-phenylalanine benzyl ester was added 5 ml of trifluoroacetic acid, the mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.39 g of 5- (tert-butoxycarbonylamino) valeric acid and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 0.79 g of DM
To the F solution (20 ml) under ice cooling, triethylamine 0.5
4 g was added, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate.The organic layer was sequentially diluted with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate,
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N- {N
-[5- (tert-Butoxycarbonylamino) pentanoyl] -O (4) -benzyl-L-aspartyl} -L
0.87 g of phenylalanine benzyl ester was obtained (74% yield, oily substance).

(4-2) Under ice cooling, N- {N- [5-
(Tert-Butoxycarbonylamino) pentanoyl]
5 ml of trifluoroacetic acid was added to 0.87 g of -O (4) -benzyl-L-aspartyl} -L-phenylalanine benzyl ester, and the mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.39 g of 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
0.45 g of triethylamine was added to 0.58 g of DMF solution (20 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours.
Water was added, and the mixture was extracted with ethyl acetate.The organic layers were sequentially diluted with dilute hydrochloric acid,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with methylene chloride-methanol, N- (N- {5- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] pentanoyl} -O (4 ) -Benzyl-L-aspartyl) -L-phenylalanine benzyl ester 0.
96 g was obtained (87% yield, oily substance).

(4-3) Under a hydrogen atmosphere, N- (N-
{5- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] pentanoyl} -O
(4) -Benzyl-L-aspartyl) -L-phenylalanine benzyl ester 0.96 g, 10% palladium on carbon 0.5 g of a methanol suspension (20 ml) was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure,
N- {N- [5- (piperidin-4-yloxyacetylamino) pentanoyl] -L-aspartyl} -L-
0.30 g of phenylalanine was obtained (yield 50%, amorphous). The instrumental analysis data of this product is shown in the following equation 13
Support the structural formula of.

¹ H-NMR (D ₂ O) δ (ppm):
7.27-7.12 (m, 5H), 4.59-4.55
(M, 1H), 4.43-4.38 (m, 1H), 3.9
6 (s, 2H), 3.67-3.62 (m, 1H), 3.
28-3.23 (m, 2H), 3.13 (t, 2H, J =
6.78Hz), 3.08 (dd, 1H, J = 5.13, 1
3.92 Hz), 3.04-2.97 (m, 2H), 2.9
2-2.88 (m, 1H), 2.68 (dd, 1H, J =
5.31, 16.48Hz), 2.50 (dd, 1H, J =
8.79, 16.48 Hz), 2.14 (t, 2H, J = 6.
96Hz), 1.98-1.94 (m, 2H), 1.80-
1.75 (m, 2H), 1.46-1.38 (m, 4H) IR (1 / cm): 3600-3200, 1660, 1
540

[0052]

[Chemical 15]

(Example 5) (5-1) Under ice cooling, N- [N- (tert-butoxycarbonyl) -O (4) -benzyl-L-aspartyl]-
L-phenylalanine benzyl ester 1.18 g
To the mixture was added 5 ml of trifluoroacetic acid, the mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
An oily substance was obtained. 0.50 g of 3- (tert-butoxycarbonylamino) benzoic acid and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 0.93 g of D
To the MF solution (30 ml) under ice cooling, triethylamine (0.1 ml) was added.
64 g was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N-
{N- [3- (tert-butoxycarbonylamino) benzoyl] -O (4) -benzyl-L-aspartyl}-
1.39 g of L-phenylalanine benzyl ester was obtained (yield 97%, oily substance).

(5-2) Under ice cooling, N- {N- [3-
(Tert-Butoxycarbonylamino) benzoyl] -O
5 ml of trifluoroacetic acid was added to 1.39 g of (4) -benzyl-L-aspartyl} -L-phenylalanine benzyl ester, the mixture was stirred for 1 hour, and concentrated under reduced pressure.
The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.60 g of 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 0.90
0.62 g of triethylamine was added to a DMF solution (30 ml) of g under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and extracted with ethyl acetate-hexane to give N-
(N- {3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl}
-O (4) -benzyl-L-aspartyl) -L-phenylalanine benzyl ester (0.90 g) was obtained (yield 52%, oily substance).

(5-3) Under a hydrogen atmosphere, N- (N-
{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O
(4) -Benzyl-L-aspartyl) -L-phenylalanine benzyl ester 0.90 g, 10% palladium-carbon 0.4 g of a methanol suspension (30 ml) was stirred overnight. The catalyst was filtered with water and the filtrate was concentrated under reduced pressure to give N- {N- [3- (piperidin-4-yloxyacetylamino) benzoyl] -L-aspartyl} -L.
-0.20 g of phenylalanine was obtained (yield 35%, colorless crystals, melting point 204-205 ° C). Instrumental analysis data for this one supports the structural formula of Equation 14 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.58-7.57 (m, 1H), 7.53-7.50
(M, 1H), 7.43-7.38 (m, 2H), 7.0
6-6.96 (m, 5H), 4.80-4.76 (m, 1
H), 4.62-4.59 (m, 1H), 4.17 (s,
2H), 3.77-3.76 (m, 1H), 3.34-3.
29 (m, 2H), 3.12 (dd, 1H, J = 4.9)
4,14.10 Hz), 3.07-3.01 (m, 2H),
2.91-2.81 (m, 2H), 2.71-2.65
(M, 1H), 2.06-2.03 (m, 2H), 1.8
6-1.84 (m, 2H) IR (1 / cm): 3600-3250, 1700, 16
60,1540

[0057]

Embedded image

Example 6 (6-1) N- (tert-butoxycarbonyl)-
A methylene chloride solution (25 ml) of O (4) -benzyl-L-aspartic acid 1.00 g, 2-phenylethylamine 0.39 g, and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.44 g. 0.98 g of triethylamine was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction,
N- [N- (tert-butoxycarbonyl) -O
1.26 g of (4) -benzyl-L-aspartyl] -2-phenylethylamine was obtained (yield 93%, oily substance).

(6-2) Under ice cooling, N- [N- (ter
t-butoxycarbonyl) -O (4) -benzyl-L-
Aspartyl] -2-phenylethylamine 1.05
After adding 5 ml of trifluoroacetic acid to g, the mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.60 g of 3- (tert-butoxycarbonylamino) benzoic acid and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.
0.77 g of triethylamine was added to 12 g of DMF solution (30 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate.The organic layers were sequentially diluted with dilute hydrochloric acid,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with methylene chloride-methanol, N- {N- [3- (tert-butoxycarbonylamino) benzoyl] -O (4) -benzyl-L-aspartyl} -2 was obtained. -Phenylethylamine 1.27 g
Was obtained (yield 92%, oily substance).

(6-3) Under ice cooling, N- {N- [3-
(Tert-Butoxycarbonylamino) benzoyl]
-O (4) -benzyl-L-aspartyl} -2-phenylethylamine 1.27 g and trifluoroacetic acid 5 ml
Was added, the mixture was stirred for 1 hour, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [N- (3-aminobenzoyl) was obtained from the fraction eluted with methylene chloride-methanol.
0.70 g of -O (4) -benzyl-L-aspartyl] -2-phenylethylamine was obtained (yield 67%, oily substance).

(6-4) 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine 0.22
g and N- [N- (3-aminobenzoyl) -O (4)-
Benzyl-L-aspartyl] -2-phenylethylamine 0.37 g, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 0.33 g in DMF solution (10 ml)
To the mixture, 0.23 g of triethylamine was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- (N- {3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O (4 ) -Benzyl-L-
Aspartyl) -2-phenylethylamine 0.42
g was obtained (yield 78%, oily substance).

(6-5) Under a hydrogen atmosphere, N- (N-
{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O
(4) -Benzyl-L-aspartyl) -2-phenylethylamine 0.42 g, 10% palladium on carbon 0.2 g
A suspension of methanol in 10 ml (10 ml) was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure, and N- {N- [3-
0.23 g of (piperidin-4-yloxyacetylamino) benzoyl] -L-aspartyl} -2-phenylethylamine was obtained (80% yield, amorphous). Instrumental analysis data for this one supports the structural formula of Equation 15 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.64 (s, 1H), 7.54-7.52 (m, 1
H), 7.44-7.42 (m, 2H), 7.12-7.0
6 (m, 5H), 4.72-4.69 (m, 1H), 4.
19 (s, 2H), 3.81-3.78 (m, 1H),
3.41-3.31 (m, 4H), 3.09-3.06
(M, 2H), 2.80-2.76 (m, 2H), 2.7
2-2.68 (m, 2H), 2.13-2.05 (m, 2
H), 1.88-1.87 (m, 2H) IR (1 / cm): 3600-3200, 1640, 15
40

[0064]

[Chemical 17]

Example 7 (7-1) N- (tert-butoxycarbonyl) -O
(4) -benzyl-L-aspartic acid 1.00 g and 4
A solution of 0.49 g of phenylbutylamine, 1.44 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate in 25 ml of methylene chloride was added with 0.98 g of triethylamine under ice cooling, and the mixture was mixed at room temperature for 3 times. Stir for hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N-
1.42 g of [N- (tert-butoxycarbonyl) -O (4) -benzyl-L-aspartyl] -4-phenylbutylamine was obtained (96% yield, oily substance).

(7-2) Under ice cooling, N- [N- (tert-
Butoxycarbonyl) -O (4) -benzyl-L-aspartyl] -4-phenylbutylamine (1.42 g) was added with 10 ml of trifluoroacetic acid, stirred for 1 hour, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 0.74 g of 3- (tert-butoxycarbonylamino) benzoic acid and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.38 g of D
To the MF solution (30 ml) under ice cooling, triethylamine (0.1 ml) was added.
95 g was added, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N-
{N- [3- (tert-butoxycarbonylamino) benzoyl] -O (4) -benzyl-L-aspartyl}-
1.30 g of 4-phenylbutylamine was obtained (yield 77
%, Oily substance).

(7-3) Under ice cooling, N- {N- [3-
(Tert-Butoxycarbonylamino) benzoyl]
-O (4) -benzyl-L-aspartyl} -4-phenylbutylamine 1.30 g and trifluoroacetic acid 10 ml
Was added, the mixture was stirred for 1 hour, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily substance. 1-benzyloxycarbonyl-4- (carboxymethoxy)
0.22 g of piperidine and the above oil, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.00 g of DM
To solution F (30 ml) under ice cooling, triethylamine 0.6
9 g was added, and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- (N-
{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O
1.21 g of (4) -benzyl-L-aspartyl) -4-phenylbutylamine was obtained (yield 71%, oily substance).

(7-4) Under hydrogen atmosphere, N- (N-
{3- [1- (benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O
(4) -Benzyl-L-aspartyl) -4-phenylbutylamine 1.21 g, 10% palladium carbon 0.5 g
A methanol suspension of (20 ml) was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure, and N- {N- [3-
0.42 g of (piperidin-4-yloxyacetylamino) benzoyl] -L-aspartyl} -4-phenylbutylamine was obtained (yield 50%, colorless crystals, melting point 18).
2-183 ° C). Instrumental analysis data for this one supports the structural formula of Equation 16 below.

¹ H-NMR (D ₂ O + DCl) δ (pp
m): 7.72 (s, 1H), 7.50-7.41 (m,
2H), 7.32-7.28 (m, 2H), 7.03-6.
89 (m, 5H), 4.76-4.73 (m, 1H),
4.08 (s, 2H), 3.70-3.66 (m, 1
H), 3.32-3.24 (m, 2H), 3.08-2.9.
8 (m, 4H), 2.89-2.73 (m, 2H), 2.
32-2.28 (m, 2H), 2.01-1.98 (m,
2H), 1.82-1.79 (m, 2H), 1.32-1.
26 (m, 4H) IR (1 / cm): 3600-3200, 1650, 16
40,1540

[0070]

Embedded image

(Example 8) (8-1) 3- (tert-butoxycarbonylamino)
Benzoic acid 0.75 g and O (4) -benzyl-L-aspartic acid benzyl ester 1.50 g, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 1.40 g
0.96 g of triethylamine was added to the DMF solution of (30 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the methylene chloride-methanol elution fraction, N-
1.23 g of [3- (tert-butoxycarbonylamino) benzoyl] -O (4) -benzyl-L-aspartic acid benzyl ester was obtained (yield 73%, oily substance).

(8-2) N- [3- (tert-
Butoxycarbonylamino) benzoyl] -O (4)-
Benzyl-L-aspartic acid benzyl ester
10 ml of trifluoroacetic acid was added to 1.23 g, and the mixture was stirred for 1 hour and concentrated under reduced pressure. Dissolve the residue in ethyl acetate,
After washing with saturated aqueous sodium hydrogen carbonate and drying over anhydrous sodium sulfate,
Concentration under reduced pressure gave an oily substance. 1-benzyloxycarbonyl-4- (carboxymethoxy) piperidine 0.6
DMF solution (30 ml) of 8 g, the above oil, and 1.02 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
To the above, 0.70 g of triethylamine was added under ice cooling, and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- {3- [1-
(Benzyloxycarbonyl) piperidin-4-yloxyacetylamino] benzoyl} -O (4) -benzyl-L-aspartic acid benzyl ester 1.12 g
Was obtained (yield 69%, oily substance).

(8-3) Under a hydrogen atmosphere, N- {3-
[1- (benzyloxycarbonyl) piperidine-4-
Iloxyacetylamino] benzoyl} -O (4)-
Benzyl-L-aspartic acid benzyl ester 1.
A suspension of 12 g of 10% palladium on carbon in 0.5 g of methanol (20 ml) was stirred overnight. The catalyst was filtered using water, the filtrate was concentrated under reduced pressure, and N- [3- (piperidine-4-
0.49 g of yloxyacetylamino) benzoyl] -L-aspartic acid was obtained (yield 79%, colorless crystals, melting point 164-167 ° C.). Instrumental analysis data for this one supports the structural formula of Equation 17 below.

¹ H-NMR (D ₂ O) δ (ppm):
7.20-7.17 (m, 1H), 7.09-7.04
(M, 2H), 6.89-6.85 (m, 1H), 4.4
5-4.43 (m, 1H), 3.83 (s, 1H), 3.
42-3.35 (m, 1H), 2.89-2.82 (m,
2H), 2.68-2.64 (m, 1H), 2.55-2.
50 (m, 1H), 2.40-2.34 (m, 2H),
1.86-1.81 (m, 1H), 1.28-1.19
(M, 2H) IR (1 / cm): 3400-3200, 1650, 15
40

[0075]

[Chemical 19]

(Test Example) ADP using human washed platelets
(Adenosine diphosphate), thrombin and fibrinogen aggregation inhibitory action were measured.

(1) Platelet rich plasma, washed platelets and α
-Preparation of chymotrypsin-treated platelets Human whole blood supplemented with 3.8% sodium citrate 10% (collected from human cubital vein) at 135 xg (1100 rp)
After centrifugation at m) for 10 minutes, the supernatant is collected as platelet-rich plasma (PRP), and the lower layer is further added at 1600 × g.
After centrifugation at (3000 rpm) for 10 minutes, platelet-poor plasma (PPP) was obtained in the supernatant, and PRP and PPP were used for ADP aggregation measurement.

On the other hand, PRP was added to a Sepharose CL-2B column (manufactured by Pharmacia) equilibrated with a HEPES buffer (pH 7.4) containing 0.5% BSA and 5.5 mM glucose to give a void volume (void volume).
The fraction eluted in e) was used as a platelet suspension for thrombin aggregation measurement. Furthermore, α-chymotrypsin was added to the washed platelets at a final concentration of 10 U / ml, and the mixture was incubated at room temperature for 30
Let react for minutes. Then, a trypsin-chymotrypsin inhibitor (0.5 mg / ml) was added to stop the protease activity, and the suspension was used as an α-chymotrypsin-treated platelet suspension for fibrinogen aggregation.

(2) ADP aggregation measurement PRP was diluted with PPP to obtain a platelet count of 20-30 × 1e.
It was adjusted to 4 / μl, and the agglutination reaction by ADP was measured by an aggregometer (HEMATRACER VI manufactured by NBS). First, 0.2 ml of PRP was placed in a cuvette for an aggregometer, 25 μl of a test drug solution or physiological saline (control) was added, and the mixture was incubated at 37 ° C. for 5 minutes with stirring (1000 rpm). Then, 25 μl of ADP solution was added, and changes in transmitted light intensity caused by aggregation were recorded with time.

The maximum transmission light intensity at the time of adding the aggregation-inducing substance was defined as the maximum aggregation rate by setting the transmission light intensities of PRP and PPP to 0 and 100%, respectively. The maximum aggregation rate at the time of drug addition to the maximum aggregation rate at the addition of physiological saline was expressed as a percentage, and the 50% inhibitory concentration (IC50) of aggregation was calculated. The results are shown in Table 1.

(3) Measurement of thrombin aggregation The platelet suspension was diluted with HEPES buffer (pH 7.4) to adjust the platelet count to 20-30 × 1e4 / μl, and calcium chloride and magnesium chloride were each added to 2
It was added to be mM (final concentration). Using this platelet suspension, ADP was prepared using HEPES buffer as a control solution.
Aggregation by addition of thrombin was measured by the same method as the measurement of aggregation. The maximum aggregation rate at the time of drug addition to the maximum aggregation rate at the addition of physiological saline was expressed as a percentage, and the 50% inhibitory concentration (IC50) of aggregation was calculated. The results are shown in Table 1.

(4) Measurement of Fibrinogen Aggregation The α-chymotrypsin-treated platelet suspension was diluted with HEPES buffer (pH 7.4) to give a platelet count of 20-3.
Adjust to 0 × 1e4 / μl, add 2 mM each of calcium chloride and magnesium chloride (final concentration), and add 1 PGE1
μM (final concentration), HEPES buffer was used as a control solution, and fibrinogen (0.4 mg / m 2) was added.
The agglutination reaction according to l) was measured. The maximum aggregation rate at the time of drug addition to the maximum aggregation rate at the addition of physiological saline was expressed as a percentage, and the 50% inhibitory concentration (IC50) of aggregation was calculated. The results are shown in Table 1.

[0083]

[Table 1]

(Acute toxicity) Using an ICR male mouse (5 weeks old), an acute toxicity test by oral administration was carried out. The LD50 values of the aspartic acid derivatives of the present invention were all 300 mg or more, confirming high safety.

[0085]

As described above, the present invention provides a novel aspartic acid derivative. As shown in the test examples, the aspartic acid derivative of the present invention has a fibrinogen aggregation inhibitory action, and thus is a preventive agent for diseases associated with platelet aggregation that occurs when an adhesive protein such as fibrinogen binds to the GPIIb / IIIa receptor. And is effective as a therapeutic drug. In particular, it is effective as an antithrombotic agent.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 38/00 AED C07D 211/40 211/46 211/56 C07K 5/083 8318-4H

Claims (2)

[Claims] 1. An aspartic acid derivative represented by formula 1 shown below. Embedded image (In the formula 1, B may be substituted with a substituent (C; 0
-10) represents alkylene (the substituent is (C; 1
10) alkyl, aryl (C; 0-8) alkyl,
(C; 0-10) alkylamino, acylamino,
(C; 1-10) alkoxy, aryl (C; 0-8)
Alkoxy, (aryl (C; 0-8) alkyl) amino, hydroxy, or halogeno), E is an ortho-, meta-, or para-phenylene group optionally substituted with a substituent, or a substituent. Represents (C; 0-10) alkylene which may be substituted with (wherein the substituent is (C; 1-10) alkyl, aryl (C; 0-8) alkyl, (C; 0-10) alkyl. Amino, acylamino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, (aryl (C; 0
~ 8) alkyl) amino, hydroxy, or halogeno), G is hydroxy, (C; 0-10) alkylamino, di (C; 0-10) alkylamino, (aryl (C; 1
-10) Alkyl) amino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, (C; 1-1)
0) alkylcarbonyloxy (C; 1-10) alkoxy, or aryl (C; 1-10) alkylcarbonyloxy (C; 1-10) alkoxy, L is hydroxy, (C; 0-10) alkylamino , Di (C; 0-10) alkylamino, (aryl (C; 1
-10) Alkyl) amino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, (C; 1-1)
0) alkylcarbonyloxy (C; 1-10) alkoxy, aryl (C; 1-10) alkylcarbonyloxy (C; 1-10) alkoxy, or substituted by a substituent bonded with an amino group Is an amino acid and an ester thereof, or an α-aminocarboxylic acid which is bonded with an amino group and may be substituted with a substituent and an ester thereof (the substituent is (C; 1-10) alkyl. , Aryl (C; 0 to 8) alkyl, or halogeno), and A represents a substituent represented by Formula 2. C represents carbon. ) (In the formula 2, M is hydrogen, (C; 1-10) alkyl,
(C; 1-10) alkoxycarbonyl or aryl (C; 0-8) alkoxycarbonyl, Q represents hydrogen, (C; 1-10) alkyl, aryl (C; 0-8) alkyl, (C; 0-10) alkylamino, acylamino, (C; 1-10) alkoxy, aryl (C; 0-8) alkoxy, hydroxy, or halogeno is shown. C represents carbon. ) 2. A pharmaceutical preparation comprising the aspartic acid derivative according to claim 1.