JPH09118653A - Nitro-substituted bicyclic compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new nitro-substituted bicyclic compound having human platelet agglutination suppressing action and industrially useful as a synthetic intermediate for medicines such as antiallergic agent. SOLUTION: This new nitro-substituted bicyclic compound is represented by formula I (A is methylene or oxygen atom; R is H or a 1-6C alkyl), e.g. 5-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid. The compound of formula I is obtained by reacting a compound of formula II, e.g. 7-nitro-1- tetralone with glyoxalic acid while dividedly or continuously charging glyoxalic acid in the presence of an acid such as sulfuric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to general formula (1)

[0002]

Embedded image (In the formula, A represents a methylene group or an oxygen atom, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), an antiallergic agent, an antithrombotic agent, a platelet aggregation inhibitor (JP-B-60). -45626), or a nitro-substituted bicyclic compound that is industrially useful as a synthetic intermediate for pharmaceuticals such as fibrinogen antagonists, and a method for producing the same.

[0003]

2. Description of the Related Art General formula (3) [Chemical formula 4]

[0004]

Embedded image Bicyclic compounds represented by the formula (wherein X represents a hydrogen atom, a lower alkyl group or a lower alkoxy group) are already known (for example, JP-A-4-338358 and JP-B-60-45626). , An.Quim., Ser.C, 81, 280 (1985), J.Org.Chem., 23,
1832 (1958) etc.).

As a method for producing the compound of general formula (3), general formula (4)

[0006]

Embedded image A method of reacting a compound represented by the formula (wherein X has the same meaning as in the case of the general formula (3)) with glyoxylic acid in the presence of a base is disclosed (J.Org.Chem., 23 . , 1832 (19
58), Japanese Examined Patent Publication No. 60-45626, An.Quim., Ser.C, 81 , 280 (1
985)). Further, a method has been disclosed in which a compound represented by the general formula (4) and glyoxylic acid are collectively mixed at the start of the reaction and reacted in the presence of an acid (JP-A-4-338358).

However, a compound represented by the general formula (1) in which X in the general formula (3) is a nitro group has not been known. Further, when an attempt is made to produce a compound in which R is a hydrogen atom in the general formula (1) according to the above-mentioned known production method, the compound of the general formula (4) in which R is a nitro group has extremely low reactivity. Long reaction times and high reaction temperatures are required. As a result, unstable glyoxylic acid is decomposed before it is consumed for the production of the target product, and the target product cannot be obtained, the yield is significantly reduced, or a large excess of glyoxylic acid is required. was there.

[0008]

DISCLOSURE OF THE INVENTION The present invention provides a novel nitro-substituted bicyclic compound represented by the general formula (1) which is useful as a synthetic intermediate for pharmaceuticals and the like, and a high yield and simple industrial production thereof. It is intended to provide a method.

[0009]

Means for Solving the Problems As a result of intensive studies to solve these problems, the present inventors have found that in the presence of an acid as a catalyst, the compound of the general formula (2)

[0010]

[Chemical 6] (In the formula, A represents a methylene group or an oxygen atom) By reacting glyoxylic acid with continuous or divided insertion by means such as dropping, the decomposition of glyoxylic acid can be suppressed, and general formula ( R in 1)
A novel compound having a hydrogen atom can be produced in high yield, and further, a novel ester compound in which R is an alkyl group having 1 to 6 carbon atoms in the general formula (1) is produced by a known esterification reaction of the novel compound. They have found that they can be easily manufactured and completed the present invention. That is, the present invention

[1] General formula (1) [Chemical formula 7]

[0012]

Embedded image (Wherein A represents a methylene group or an oxygen atom, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and a nitro-substituted bicyclic compound,

[2] The compound represented by the general formula (1) is the nitro-substituted bicyclic compound according to [1], wherein the nitro group is in the para position with respect to A.

[3] General formula (2) [Chemical formula 8]

[0015]

Embedded image (Wherein A represents a methylene group or an oxygen atom) is reacted in the presence of an acid while splitting or continuously inserting glyoxylic acid, and in the general formula (1), R is A method for producing a nitro-substituted bicyclic compound which is a hydrogen atom.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compounds included in the general formula (1) of the present invention are specifically exemplified, but the present invention is not limited thereto. (1) 5-Nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (2) 6-Nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (3) 7-Nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (4) 8-Nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (5) 5-Nitro-4-oxo-3-chromanilidene acetic acid (6) 6-Nitro-4-oxo-3-chromanilidene acetic acid (7) 7-Nitro-4-oxo-3-chromanilidene acetic acid (8) 8- Nitro-4-oxo-3-chromanilideneacetic acid and an alkyl ester having 1 to 6 carbon atoms of the compound of (1) to (8), wherein the alkyl group having 1 to 6 carbon atoms includes a methyl group, an ethyl group, Propi Group, isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, a hexyl group, a cyclopentyl group,
And cyclohexyl group.

Next, a method for producing the compound of the present invention will be described. The compound in which R is a hydrogen atom in the general formula (1) is produced by reacting the compound represented by the general formula (2) with glyoxylic acid. The solvent used in the reaction may be any as long as it is inert to the reaction, for example, water, dimethylformamide, dimethylsulfoxide,
Tetrahydrofuran, dioxane, etc. are mentioned, Preferably water, dioxane, tetrahydrofuran, or these mixed solvents are used. Glyoxylic acid can be used in the form of an aqueous solution, a solid hydrate, or a form dissolved in a solvent used for the reaction.

Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid and perchloric acid, organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, toluenesulfonic acid and camphorsulfonic acid, and strongly acidic ions. Solid acids such as exchange resins are mentioned, preferably sulfuric acid, hydrochloric acid and trifluoroacetic acid are used, and more preferably sulfuric acid is used.
The amount of acid used in the reaction is in the range of 0.05 to 5 molar equivalents, preferably 0.1 to 2 molar equivalents, relative to the compound represented by the general formula (2).

The reaction can be carried out in the range of room temperature to the boiling point of the solvent, preferably in the range of 50 to 100 ° C. The total amount of glyoxylic acid to be inserted is not particularly limited as long as it is 1 molar equivalent or more with respect to the compound represented by the general formula (2), but preferably 1.1 to 2.5 molar equivalents. Used. The insertion operation of glyoxylic acid is 2 to 5
It is inserted 0 times, preferably 3 to 10 times in a divided manner, or is inserted continuously by a means such as dropping. The time required for the insertion operation is in the range of 10 to 90% of the total reaction time. The reaction is completed in the range of 5 to 48 hours, and the compound of the general formula (2)
Most of the compound represented by the formula (1) disappears, and a compound in which R is a hydrogen atom in the general formula (1) is obtained.

This compound can be isolated by a usual operation such as filtration or extraction, and if necessary, recrystallization,
It can be purified by an operation such as chromatography. In the general formula (1), R is an alkyl group having 1 to 6 carbon atoms,
Generally known ester such as reacting a carboxylic acid compound in which is a hydrogen atom with a corresponding alkyl alcohol having 1 to 6 carbon atoms using an inorganic acid or organic acid such as sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, etc. as a catalyst It can be easily produced by a chemical conversion method or a transesterification method.

[0021]

The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited thereto. Example 1 Synthesis of 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid 7-Nitro-1-tetralone (30 g), 80% sulfuric acid (10 m
A solution of l) in dioxane (60 ml) was heated to 90 ° C. with stirring. Four
A 0% aqueous solution of glyoxylic acid was added in 10 ml portions at 1 hour intervals in 3 divided portions, and the mixture was heated under reflux for 3 hours. After allowing to cool, the precipitated solid was collected by filtration, washed with cold water, and dried under reduced pressure to give the title compound (33.3 g) as a pale-yellow solid. 86% yield. Melting point: Decomposition NMR above 200 ° C (270MHz, DMSO-d6): δppm = 8.60 (1H, d, J = 2.2Hz), 8.41
(1H, dd, J = 2.2,8.8Hz), 7.72 (1H, d, J = 8.8Hz), 6.72 (1H, t,
J = 1.5Hz), 3.32-3.38 (2H, m), 3.14 (2H, t, J = 6.0Hz) .IR (KBr): 1698,1675,1608,1522,1419,1347,1276,925,74
. 3,715cm ^-1 Elemental analysis: (C ₁₂ H ₉ NO as ₅₎ Calculated: C, 58.30; H, 3.67 ; N, 5.67% Analysis values: C, 58.42; H, 3.73 ; N, 5.44%

Example 2 Synthesis of 6-nitro-4-oxo-3-chromanilideneacetic acid 6-nitro-4-chromanone (30 g), 80% sulfuric acid (15 m
A solution of l) in dioxane (60 ml) was heated to 90 ° C. with stirring. Four
A 0% aqueous glyoxylic acid solution (30 ml) was added dropwise over 2 hours. After heating and refluxing for another 2 hours, the mixture was allowed to cool, and the precipitated solid was collected by filtration. The obtained product was washed with cold water and dried under reduced pressure to give the title compound (34.0 g) as an orange solid. 88% yield. Melting point: 180-182 ° C NMR (270MHz, DMSO-d6): δppm = 8.57 (1H, d, J = 2.9Hz), 8.42
(1H, dd, J = 2.9,9.0Hz), 7.3 (1H, d, J = 9.0Hz), 6.75 (1H, t, J =
2.2Hz), 5.76 (2H, d, J = 2.2Hz) .IR (KBr): 3450,3102,1701,1673,1615,1524,1341,1280,10
. 87,1032,853,750cm ^-1 elemental analysis (C ₁₁ as H ₇ NO ₆₎ Calculated: C, 53.02; H, 2.83 ; N, 5.62% Analysis values: C, 53.25; H, 2.78 ; N, 5.39%

Example 3 Synthesis of 7-nitro-4-oxo-3-chromanilideneacetic acid Using 7-nitro-4-chromanone as a starting material, the title compound (33 g) was obtained as a light brown solid in the same manner as in Example 2. . 85% yield. Melting point: 163-165 ° C NMR (270MHz, DMSO-d6): δppm = 8.09 (1H, d, 9.5Hz), 7.90 (1
H, dd, J = 2.2,9.5Hz), 7.88 (1H, d, J = 2.2Hz), 6.75 (1H, t, J =
2.2Hz), 5.71 (2H, d, J = 2.2Hz).

Example 4 Synthesis of methyl 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetate 7-Nitro-1-oxo-1,2,3,4-tetrahydro-2 -Naptylidene acetic acid (100 g) was added to methanol (1,000 m
l), suspended in concentrated sulfuric acid (5 ml), and stirred under reflux for 5 hours. Cool to room temperature, collect the precipitated crystals by filtration, and use methanol (150 ml).
After being washed twice with 50 ° C. and dried under reduced pressure at 50 ° C./10 mmHg for 5 hours, the title compound (97 g) was obtained. Yield 92%. Melting point: 125-126 ° C NMR (270MHz, CDCl3): δppm = 8.61 (1H, d, J = 2.9Hz,), 8.42 (1
H, dd, J = 2.9,8.8Hz), 7.72 (1H, d, J = 8.8Hz), 6.74 (1H, s), 3.
76 (3H, s), 3.32-3.38 (2H, m), 3.15 (2H, t, J = 6.6Hz).

Example 5 Synthesis of ethyl 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetate 7-Nitro-1-oxo-1,2,3,4-tetrahydro-2 -Naphthylidene acetic acid (100 g) was added to ethanol (1,000 m
l), suspended in concentrated sulfuric acid (5 ml), and stirred under reflux for 5 hours. Cool to room temperature, collect the precipitated crystals by filtration, and use ethanol (150 ml).
After being washed twice with, the mixture was dried under reduced pressure at 50 ° C./10 mmHg for 5 hours to obtain the title compound (100 g). Yield 90%. Melting point: 111-112 ° C NMR (270MHz, CDCl3): δppm = 8.92 (1H, d, J = 2.9Hz), 8.35 (1
H, dd, J = 2.9,8.8Hz), 7.50 (1H, d, J = 8.8Hz), 6.95 (1H, t, J =
2.2Hz), 4.28 (2H, q, J = 7.3Hz), 3.47-3.52 (2H, m), 3.16 (2H,
t, J = 5.9Hz), 1.35 (3H, t, J = 7.3Hz).

Example 6 Synthesis of methyl 6-nitro-4-oxo-3-chromanilidene acetate 6-nitro-4-oxo-3-chromanilidenaacetic acid (100
g) in methanol (1,000 ml) and add concentrated sulfuric acid (5 ml).
The mixture was stirred under reflux for 6 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed twice with methanol (150 ml), 50 ° C / 10 mmH
The title compound (94 g) was obtained as pale yellow crystals by drying under reduced pressure at g for 5 hours. 89% yield. Melting point: 163-165 ° C NMR (270MHz, DMSO-d6): δppm = 8.57 (1H, d, J = 2.9Hz), 8.43
(1H, dd, J = 9.5,2.9Hz), 7.34 (1H, d, J = 9.5Hz), 6.78 (1H, t, J
= 2.2Hz), 5.78 (2H, d, J = 2.2Hz), 3.78 (3H, s).

Example 7 Synthesis of ethyl 6-nitro-4-oxo-3-chromanilidene acetate 6-Nitro-4-oxo-3-chromanilidene acetic acid (100
g) was suspended in ethanol (1,000 ml), concentrated sulfuric acid (5 ml) was added, and the mixture was stirred under reflux for 6 hr. After cooling to room temperature, the precipitated crystals were collected by filtration and washed twice with ethanol (150 ml), 50 ° C / 10 m
The title compound (95 g) was obtained as pale yellow crystals by drying under reduced pressure at mHg for 5 hours. 85% yield. Melting point: 119-121 ° C NMR (270MHz, CDCl3): δppm = 8.87 (1H, d, J = 2.9Hz), 8.37 (1
H, dd, J = 2.9,8.8Hz), 7.15 (1H, d, J = 8.8Hz), 6.98 (1H, t, J =
2.2Hz), 5.77 (2H, d, J = 2.2Hz), 4.29 (2H, q, J = 7.3Hz), 1.36
(3H, t, J = 7.3Hz).

Example 8 Synthesis of methyl 7-nitro-4-oxo-3-chromanilidene acetate 7-Nitro-4-oxo-3-chromanilidene acetic acid (100
g) was suspended in methanol (1,000 ml), concentrated sulfuric acid (5 ml) was added, and the mixture was stirred under reflux for 6 hours. After cooling to room temperature, the precipitated crystals were collected by filtration and washed twice with 150 ml of methanol, 50 ° C / 10 mmH
The title compound (97 g) was obtained as pale yellow crystals by drying under reduced pressure at 5 g for 5 hours. 87% yield. Melting point: 146-148 ° C NMR (270 MHz, CDCl3): δppm = 8.14 (1H, d, 9.5 Hz), 7.90 (1H,
d, J = 2.2Hz), 7.88 (1H, dd, J = 2.2,9.5Hz), 6.98 (1H, t, J = 2.2
Hz), 5.73 (2H, d, J = 2.2Hz), 3.85 (3H, s).

Comparative Example 1 Synthesis of 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid by the batch mixing method According to the production method of JP-A-4-338358, under acidic conditions. The reaction of 7-nitro-1-tetralone with glyoxylic acid was performed by a method of mixing the raw materials all together. Dioxane (60 ml) was added to 40% aqueous glyoxylic acid solution (30 ml), and 7-nitro-1-tetralone (30 g) and 8
0% sulfuric acid (10 ml) was mixed all together and heated under reflux for 24 hours.
After allowing to cool, the precipitated solid was collected by filtration and washed with cold water. The obtained compound was a mixture of substrate and product, and was purified by silica gel column chromatography (methanol: chloroform = 1: 20) to give the title compound (10.9 g). The yield was 28%, which was lower than that in Example 1.

[0030] Synthetic base-catalyzed method of Comparative Example 2 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylidene acetate J.Org.Chem., According to the method of 23.1832 (1958) , 7-nitro-1-tetralone was reacted with glyoxylic acid under basic conditions. 7-Nitro-1-tetralone (30
g), 40% glyoxylic acid aqueous solution (30 ml), 6N aqueous sodium hydroxide solution (30 ml) in tetrahydrofuran (50 m
l) The solution was stirred at room temperature for 2 days. After the reaction was completed, concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 20) to give the title compound (7.4g). The yield was 19%, which was lower than that in Example 1.

The usefulness of the compound of the present invention as a pharmaceutical intermediate will be described below with reference to Reference Examples by the synthesis and evaluation of fibrinogen antagonists, but the usefulness of the compound of the present invention is not limited thereto. is not.

Reference Example 1 7- (4-amidinobenzoyl) amino-1,2,3,3
Synthesis of 4-tetrahydronaphthalene-2-acetic acid hydrochloride (Step 1) Synthesis of 7-amino-1,2,3,4-tetrahydronaphthalene-2-ethyl acetate The compound obtained in Example 1 (2.48 g), concentrated Sulfuric acid (1.2g), 10
% Pd / C (0.6 g) was suspended in ethanol (40 ml), and the mixture was stirred at 50 ° C. for 3 hours under a pressurized hydrogen atmosphere (10 Kg / cm ² ). The reaction solution was filtered to separate the catalyst, and the obtained reaction solution was concentrated under reduced pressure. The obtained oily substance was dissolved in ethanol (60 ml), and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure,
It was again dissolved in ethanol (60 ml) and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, the crude product was dissolved in chloroform and washed with an aqueous potassium carbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 18) to give the title compound (1.6 g).

(Step 2) 7- (4-cyanobenzoyl)
Amino-1,2,3,4-tetrahydronaphthalene-2
-Synthesis of ethyl acetate 4-cyanobenzoyl chloride (1.1 g) and step 1
7-Amino-1,2,3,4-tetrahydronaphthalene-2-ethyl acetate (1.3 g) obtained in 1. was added to chloroform (30 m
l), and triethylamine (1.8 ml) was added under ice cooling. After stirring at room temperature for 1 hour, the chloroform layer was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (ethanol: chloroform = 1: 50) to give the title compound (0.89 g).

(Step 3) Synthesis of 7- (4-amidinobenzoyl) amino-1,2,3,4-tetrahydronaphthalene-2-ethyl acetate hydrochloride 7- (4-cyanobenzoyl) obtained in Step 2 Hydrogen chloride gas was passed through an ethanol (15 ml) solution of amino-1,2,3,4-tetrahydronaphthalene-2-ethyl acetate (0.85 g) under ice cooling for 30 minutes. After standing at room temperature overnight, ethanol was distilled off under reduced pressure. The obtained residue was dissolved in methanol (20 ml), ammonium acetate (1.0 g) was added, and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure,
The title compound (0.83g) was obtained. Melting point: 207 to 210 ° C NMR (270 MHz, DMSO-d6): δppm = 8.30 (4H, s), 8.08 (2H, d), 7.
92 (2H, d), 7.48-7.50 (2H, m), 7.05 (1H, d), 4.10 (2H, q), 2.7
4-2.85 (3H, m), 2.14-2.47 (4H, m), 1.87-1.91 (1H, m), 1.34-
1.49 (1H, m), 1.21 (3H, t).

(Step 4) Synthesis of 7- (4-amidinobenzoyl) amino-1,2,3,4-tetrahydronaphthalene-2-acetic acid hydrochloride 7- (4-amidinobenzoyl) amino-obtained in Step 3
Ethyl 1,2,3,4-tetrahydronaphthalene-2-ethyl acetate hydrochloride (0.1 g) was dissolved in methanol (2 ml), 2N aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solution was acidified with 3N hydrochloric acid to obtain the title compound (0.07g). Melting point: 236-238 ° C NMR (270MHz, TFA-d): δppm = 8.20 (2H, d), 8.03 (2H, d), 2.96
-3.07 (3H, m), 2.41-2.69 (4H, m), 2.11-2.15 (1H, m), 1.56-
1.71 (1H, m).

Reference Example 2 6-[(4-amidinobenzoyl) amino] chroman-
Synthesis of 2-acetic acid hydrochloride By subjecting the compound obtained in Example 2 to the same reaction as in Reference Example 1, the title compound was obtained as an amorphous solid. NMR (270MHz, DMSO-d6): δppm = 10.32 (1H, s), 9.50 (2H, br
s), 9.23 (2H, brs), 8.14 (2H, d), 7.94 (2H, d), 7.50 (1H, s),
7.46 (1H, dd), 6.76 (1H, d), 4.18 (1H, d), 3.81-3.85 (1H, m),
2.84-2.93 (1H, m), 2.25-2.58 (4H, m).

Reference Example 3 7-amino-1,2,3, synthesized in Step 1 of Reference Example 1
Separate Synthesis of 4-Tetrahydronaphthalene-2-ethyl acetate 7-Nitro-1-oxo-synthesized by the method of Example 5
Ethyl 1,2,3,4-tetrahydro-2-naphthylidene acetate (100 g) was suspended in ethanol (1,000 ml) and concentrated in sulfuric acid.
(24 ml) and 10% -Pd / C (10 g) were added at 50-60 ° C, hydrogen pressure 8-
It was reduced at 10 kg / cm ² for 20 hours. After cooling to room temperature and purging with nitrogen, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 18) to give the title compound (75 g).

Example of Pharmacological Test Human Platelet Aggregation Inhibitory Action Test Method Blood was collected from a healthy person using an injection syringe, and 3.8% sodium citrate was used as an anticoagulant (a ratio of 1 to 9 blood).
Was added. Then, it is centrifuged at 120xG at room temperature for 15 minutes to obtain platelet rich plasma (PRP: platelet rich pl
asma). The remaining plasma from which PRP was separated
Centrifuge at 200xG for 20 minutes to obtain platelet-poor plasma (PPP: pla
telet poor plasma). Platelet count is based on an automatic platelet counter (Toa Medical Electronics Co., Ltd., Sysmex PL-10
P) so that the PRP becomes about 250,000 / μl.
Diluted with PP. The platelet aggregation ability was measured as follows using a 6-channel aggregometer (NKK, HEMA TRACER 1). After heating PRP at 37 ° C for 2 minutes, the test drug solvent (control) or various concentrations of test drug (30 µl) were added, and after 2 minutes, 30 µl of adenosine diphosphate (final concentration: 5 µM) was added. In addition, platelet aggregation was induced. The inhibition rate was determined by comparing the maximum aggregation rates of the control and test drug groups. The concentration of the test drug at 50% inhibition (IC ₅₀ ) was determined from the inhibition rate and the concentration of the test drug, and used as an index of the platelet aggregation inhibitory action. Each of the compounds obtained in Reference Examples 1 and 2 has an IC _{50 of} inhibiting platelet aggregation.
= 57 nM and 49 nM. This activity was extremely strong as compared with typical antiplatelet drugs aspirin (IC ₅₀ = 1,000 μM or more) and cilostazol (IC ₅₀ = 12.8 μM).

[0039]

INDUSTRIAL APPLICABILITY The present invention provides a novel nitro-substituted bicyclic compound useful as an intermediate for pharmaceuticals and the like as shown in the examples of fibrinogen antagonists. Moreover, these compounds can be easily produced in high yield by the production method of the present invention.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, A represents a methylene group or an oxygen atom, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). 2. The nitro-substituted bicyclic compound according to claim 1, wherein in the compound represented by the general formula (1), the nitro group is in the para position with respect to A. 3. General formula (2) [Chemical formula 2] The compound represented by the formula (wherein A represents a methylene group or an oxygen atom) is reacted in the presence of an acid while splitting or continuously inserting glyoxylic acid. The method for producing a nitro-substituted bicyclic compound according to claim 1 or 2, wherein R in 1) is a hydrogen atom.