JPH01213276A - Benzofuran derivative - Google Patents

Abstract

NEW MATERIAL:A benzofuran derivation of formula I (R<1>, R<2> are H, methyl, methoxy or they bond to each other to form -CH=CH-CH=CH-; R<3> is aromatic group which may be substituted; R<4> is H, methyl, hydroxymethyl, carboxyl which may be in the form of ester or amide; Z is -CidenticalC- or a bond; m is 0-10; n is 0-5). EXAMPLE:2-(5-Hydroxy-4,6,7-trimethyl-3-phenyl-benz[6]furan-2-yl)acetic acid. USE:Medicine, for example, antithrombotic, antivasospastic, antiallergic, proriasis- treating agent, improver for heart, brain and circulatory organs, gastritis-treating agent. PREPARATION:A compound of formula I is irradiated with light in the presence of oxygen to given the compound of formula I.

Description

[Detailed description of the invention] [Industrial application field]

The compounds of the present invention inhibit the biosynthesis of thromboxane A,
A novel drug that has two or more of the following actions: scavenging active oxygen species and inhibiting 5-lipoxygenase12, and has therapeutic and preventive actions against diseases of the heart, brain, lungs, kidneys, liver, etc. based on these actions. The invention relates to benzofuran derivatives.

[Prior art]

Thromboxane A! , leukotrienes, and reactive oxygen species are greatly involved in the underlying lesions of various diseases, and it has been shown that excessive production of any of them can become a factor that is detrimental to living organisms. For example, thromboxane A is biosynthesized from arachidonic acid mainly in platelets and leukocytes, and is known to have both a strong platelet aggregation effect and a contraction effect on blood vessels, trachea, and smooth muscle. Reactive oxygen species and various lipoxygenases oxidize polyunsaturated fatty acids and phospholipids in living bodies to produce peroxidized fatty acids and peroxidized lipids, promoting excessive production of thromboxane A, and oxidizing thromboxane A and phospholipids. This causes an imbalance in the production of stacycline. Such metabolic changes are thought to trigger thrombosis, myocardial infarction, cerebral infarction, gastrointestinal ulcer, asthma, cerebral edema, arteriosclerosis, and the like. Leukotrienes are powerful chemical mediators of allergic or inflammatory reactions, and are believed to primarily cause constriction of the peripheral airways of the lungs, and are associated with dyspnea associated with bronchial asthma. Furthermore, leukotrienes have increased capillary permeability and strong leukocyte floating ability, and are deeply related to edema and cell infiltration, which are one of the main symptoms of inflammation. The strong constrictive action of leukotriene C4 on blood vessels and myocardium is thought to be a cause of coronary artery insufficiency and angina pectoris. On the other hand, it has recently been revealed that reactive oxygen species play a major role in the development of lesions in ischemic tissues (1. Pr1dovich, Annual Review of Pharmacology).
and Toxicology. 23.239 (1983); J, M, McCo
rd and G, Ghai, American
Journal of Physiology. 246.8776 (1984)). Active oxygen species in living organisms are thought to include superoxide, oxidized radicals, -stagnant oxygen, and peroxide radicals. In particular, excessive production of superoxide is considered to be of great significance as an essential factor in the in vivo production of superoxide and subsequent cell or tissue damage caused by reactive oxygen species. Therefore, it is desired to develop a substance that inhibits thromboxane A synthase in the arachidonic acid cascade and 5-lipoxygenase, which is the initial enzyme for the biosynthesis of leukotrienes, or a substance that scavenges active oxygen species. However, no benzofuran derivatives have been found that collectively suppress the production of thromboxane A2, leukotrienes, and reactive oxygen species.

[Problems to be solved by the invention]

The present invention provides a novel benzofuran derivative that has any two or more of the following actions: inhibition of biosynthesis of thromboxane A, scavenging of reactive oxygen species, and inhibition of 5-lipoxygenase.

[Means to solve the problem]

The present invention is based on the general formula, [wherein R1%R3 are the same or different and represent a hydrogen atom, a methyl group, or a methoxy group, or R1 and R''h (combined with each other and R1 and R1 are -CH=CH-CH =CH-, R3 is an optionally substituted aromatic ring group, R' is a hydrogen atom, a methyl group, an optionally substituted hydroxymethyl group, an optionally amidated or esterified carboxyl group , Z represents a -CIC- group or a bond, Z represents an integer from 0 to IO, and n represents an integer from 0 to 5.] General formula (1) Among them, the aromatic ring group of the optionally substituted aromatic ring group represented by R3 includes phenyl, pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), thienyl (2-thienyl, 3-thienyl), etc. Substituents include, for example, alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, propyl, and isopropyl, halogen atoms such as furore, chloro, and bromine, and C, -C, such as methoxy, ethoxy, propoxy, and isopropoxy. , an alkoxy group, a hydroxyl group, a carboxyl group, a cyano group, a 1-imidazolyl group, a l-imidazolylmethyl group, a trifluoromethyl group, etc., and these substituents can be present in 1 to 3 positions on the aromatic ring group. In the general formula (1), the hydroxymethyl group represented by R' may be substituted, and in addition to the unsubstituted hydroxymethyl group, for example, methoxymethyloxymethyl, methyloxymethyl, Acetoxymethyl, nitroxymethyl, aminocarbonyloxymethyl, substituted aminocarbonyloxymethyl (e.g., methylaminocarbonyloxymethyl, ethylaminocarbonyloxymethyl, dimethylaminocarbonyloxymethyl, phenylaminocarbonyloxymethyl), cyclic aminocarbonyloxymethyl (For example, morpholinocarbonyloxymethyl, piperidinocarbonyloxymethyl, etc.) Esterified carboxyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc. having 2 to 5 carbon atoms.
Alkoxycarbonyl, for example, aryloxycarbonyl having 7 to 8 carbon atoms such as phenoxycarbonyl. The amidated carboxyl group represented by R4 may be unsubstituted aminocarbonyl, substituted aminocarbonyl in which the amino group is substituted, or cyclic aminocarbonyl. Substituents for the amino group of substituted aminocarbonyl include, for example, alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl; aryl having 6 to 10 carbon atoms such as phenyl and naphthyl (these may further be substituted at any position in the ring); For example, examples of amidated carboxyl groups include aminocarbonyl, carbon 2 to 4 mono- or di-alkylaminocarbonyl (methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl), phenylaminocarbonyl, substituted phenylaminocarbonyl (e.g. p-hydroxyphenylaminocarbonyl, p-methoxyphenylaminocarbonyl) and the like. Examples of the cyclic aminocarbonyl include morpholinocarbonyl and piperidinocarbonyl. The sum of - and n is preferably 1.2 or less. The compound (1) of the present invention improves the metabolism of polyunsaturated fatty acids (linoleic acid, γ-lylunic acid, α-lylunic acid, arachidonic acid, dihomo-γ-lylunic acid, eicosapentaenoic acid),
In particular, the effect of suppressing the production of peroxidized fatty acids (antioxidant effect) or 5-lipoxygenase metabolites (e.g., leukotrienes, 5-hydroxyeicosatetraenoic acid, 5-peroxyeicosatetraenoic acid, riboxins, etc.) Inhibitory effect on thromboxane A2 synthase, for production suppression. It has two or more of the effects of thromboxane A, receptor antagonism and scavenging of reactive oxygen species, and has extremely low toxicity and side effects. Therefore, the compound of the present invention (
1) Thrombosis, heart, and lungs in mammals (mice, rats, rabbits, dogs, monkeys, humans, etc.). Ischemic diseases caused by contraction or traction of arterial vascular smooth muscle in the brain and kidneys (e.g. myocardial infarction, stroke). Nephritis, pulmonary failure, bronchial asthma, psoriasis, inflammation, immediate allergies, arteriosclerosis, atherosclerosis, fatty liver,
Hepatitis, cirrhosis, hypersensitivity pneumonitis, immunodeficiency, reactive oxygen species (
superoxide, hydroxyl radical, lipid peroxide, etc.)
Antithrombotic agents are expected to have therapeutic and preventive effects on various diseases such as circulatory system diseases (myocardial infarction, stroke, nephritis, etc.) and carcinogenesis caused by damage to living tissues, enzymes, cells, etc. As a medicine such as an antiangiological agent, an anti-asthma agent, an anti-allergy agent, a psoriasis treatment agent, a heart, brain, and circulatory system improving agent, a nephritis treatment agent, an active oxygen scavenger, an anticancer agent, and an arachidonic acid cascade substance regulation improvement agent. Useful. The compounds of the present invention have low toxicity and can be used as is or in pharmaceutical compositions mixed with known pharmaceutically acceptable carriers, excipients, etc. [e.g., tablets, capsules (including soft capsules and microcapsules), liquid preparations, injections] It can be safely administered orally or parenterally as a drug or suppository. Dosage is subject to administration. Although it varies depending on the route of administration and symptoms, for example,
When orally administered to adult patients with thrombosis, a single dose is usually about 0.1 mg/kg to 20 mg/kg body weight, preferably 0.2 mg/kg to 10 m
It is convenient to administer about 1 to 3 g/kg body weight per day. The compound represented by the general formula (1) according to the present invention can be produced by irradiating the compound represented by the general formula [wherein each symbol has the same meaning as above] with light in the presence of oxygen. can. This reaction advantageously proceeds in organic solvents such as alcohols such as methanol and ethanol, ethers such as dimethyl ether, diethyl ether, dioxane and tetrahydrofuran, and ketones such as acetone. Approximately 240 nanometers (nm) to 400μ for light irradiation
A photoexcitation beam containing wavelengths up to m is used. A preferable wavelength is the n→π absorption wavelength derived from the quinone carbonyl group of the quinone derivative (II), that is, from 290r+m to 350 μm. Examples of the light source include a halogen lamp, a tungsten lamp, a fluorescent lamp, and a single light. This reaction advantageously proceeds in the presence of a basic substance such as triethylamine or pyridine. Air is sufficient oxygen. The reaction temperature is usually -20°C to 50°C, preferably 0°C to room temperature. This reaction proceeds in the following three-step reaction. Compound (n) first undergoes an intramolecular redox reaction by light irradiation and changes into hydroquinone derivative (1), and hydroquinone derivative (III) undergoes oxidation in the presence of air and oxygen to become quinone derivative (IV). Then, the quinone derivative (IV) undergoes a photo-ring closure reaction and changes into the benzofuran derivative (1). As described above, this photoreaction includes an intramolecular redox reaction and a photocyclization reaction due to light. Therefore, either quinone derivative (II) or (■) can be used in the production of benzofuran derivatives. The benzofuran derivative (1) thus produced can be isolated and collected by known separation and purification means (eg, chromatography, crystallization method). The compound represented by formula (II) is disclosed in JP-A-61-
44840 and Japanese Patent Application No. 62-21516. For example, it can be produced by using the following reaction steps.

【Effect of the invention】

The novel benzofuran derivative according to the present invention improves the metabolism of polyunsaturated fatty acids, particularly regulates the biosynthesis of arachidonic acid cascade substances (prostaglandins), inhibits the inactivation of synthetic enzymes, inhibits 5-lipoxygenase, and thromboxane A1. Synthetic enzyme inhibition, etc.) and active oxygen species scavenging effect, and is used as a medicine to improve the functions of the heart, brain, lungs, kidneys, etc. and their circulatory system disorders, as an anti-asthma agent, an anti-allergy agent, and an anti-inflammatory agent. Useful. Experimental Example 15 - Lipoxygenase inhibition effect on RBL-1 cells (rat basophilic leukemi
acells) I O' MCM (mast c
The test solution (MOMO, 5-, arachidonic acid 50 ug, quinone compound (final concentration 10 μM,
1 μM, 0.1 μM)) and incubated at 37°C for 20
The reaction was carried out for minutes. After the reaction, ethanol 4- was added and the mixture was thoroughly mixed, and then left at room temperature for 10 minutes. The mixture was then centrifuged (2000 rpm) for 10 minutes to separate the supernatant. This supernatant was dried under reduced pressure. 0.5-m of 60% water-containing methanol solution was added to the concentrate. 100 μg of this solution was subjected to high performance liquid chromatography, and 5-HETE (5-hydroxy-ei
cosatetraenoic acid) was quantified. The absorption of 5-HETE at 237 nm was measured using an ultraviolet absorption monitor. 5-HETE production inhibition rate (I
E)(1-b/a)X100. a is the peak height or peak area value when the test compound is not included,
b represents the peak height or peak area value when the test compound is included.

【Experimental result】

As shown in Table 1, the results showed a strong effect of inhibiting the production of 5-HETE. Experimental Example 2 Inhibition of lipid peroxide production in rat brain homogenate Method: A male SD rat (12 weeks old) was subjected to exsanguination under bendoparbital anesthesia, and then brain tissue was removed. Brain tissue was homogenized in phosphate buffer (pH 7,4) and
% homogenate. 3 of the same homogenate
After reacting at 7°C for 1 hour, Ohkawa et al.
Biochemistry), 95, 351,
The amount of lipid peroxide produced was measured by the thiobarbic acid method as described in [1979]. Test compound is 5%
It was added to the homogenate before the reaction to give a final concentration of 10''M.
The results are shown in Table 2 as % inhibition rate compared with the DMSO) addition group. As shown in Table 2 of the experimental results, the lipid peroxide production reaction was strongly suppressed. Table 2 Example 1 (Compound No. 1) Propylene was added to a solution of 4-(3,5,6-drimethyl-1,4-benzoquinon-2-yl)-4-phenylbutyric acid (1,0 g) in ethanol (1,0n2). Light (manufactured by Ushio Electric,
JCD 100-650LL) was irradiated for 4 hours. During this time, the temperature of the reaction solution was maintained at 10 to 40° C. while stirring. After the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to give 2-(5-hydroxy-4,6,7-)dimethyl-3-phenyl-benzo[b
Cotlan-2-yl)acetic acid (0.66 g, 68%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Table 39.
It is shown in Table 4. According to this example, compound numbers 2 to 5.
7-8, 10-14, 16-17, 19-2 were produced. Example 2 (Compound No. 6) A solution of 2.3.5-trimethyl-6-(l-phenylhebutyl)-1,4-benzoquinone (0.32 g) in methanol (320 ete) was irradiated with promelite for 4 hours. . During this time, the temperature of the reaction solution was maintained at 10 to 40° C. while stirring. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with isopropyl ether/hexane (1:2) to obtain 5-
Hydroxy-4,6°7-drimethyl-2-benzene-3-phenyl-benzo[blfuran (0.31 g, 96
%) was obtained. Physical properties and nuclear magnetic resonance spectrum data are shown in Tables 3 and 4.
It was shown to. According to this example, compound number 9゜15.1
8 was produced. Example 3 (Compound No. 1) Pyridine ( 1,66g)
was added and irradiated with promlite for 6 hours. During this time, the reaction temperature was maintained at 10 to 40° C. and the reaction was carried out while stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and ethyl acetate and ethyl acetate were added to the residue.
Extract by adding IN hydrochloric acid. The ethyl acetate layer was taken out, washed with water, washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residue was recrystallized from isopropyl ether to obtain Compound No. 1 (4.90 g, 75%). Physical properties and nuclear magnetic resonance spectrum data are shown in Tables 3 and 4.
It was shown to. Compound No. 8 was produced according to this example. Example 4 (Compound No. 9) Methyl 7-(3,5,6-1limethyl-1,4-benzoquinon-2-yl)-7-phenylhebutanoate (0,5
A solution of 0 g) in methanol/ethyl acetate (1:1×50−) was irradiated with promelite for 3 hours. During this time, the temperature of the reaction solution was maintained at 10 to 40° C. while stirring (light irradiation was stopped midway and in order to confirm the intermediate). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, sequentially eluting with isopropyl ether/hexane (1:1) and then with isopropyl ether to obtain 7-(3,5,6-drimethyl-1. Methyl 4-hydroquinon-2-yl)-7-phenyl-6-heptenoate (o, 20 g) was obtained. Oily substance. Nuclear magnetic resonance spectrum (in deuterated chloroform): δ 1.4-1.8 (
411), 1.90 (3H), 1.9-2.4 (4
H), 2.21 (6H), 3.63 (3H), 4
．． 53(LH)', 4.83(IH), 6.48(
01), 7.26 (511). This hydroquinone compound (0.18 g) was dissolved in tetrahydrofuran (2d), a 1M aqueous ferric chloride solution (ltRl) was added under light, and the mixture was stirred at room temperature for 20 minutes. Tetrahydrofuran was distilled off under reduced pressure, and ethyl acetate was added to the residue for extraction. The ethyl acetate layer was washed with brine, dried (magnesium sulfate), and the solvent was distilled off. The residue was subjected to silica gel column chromatography under the protection of light, eluted with isopropyl ether, and purified to give 7-(3,5,6-)dimethyl-1,4-benzoquinon-2-yl)-7-phenyl-
Methyl 6-heptenoate (0.16 g) was obtained. Oily substance. Nuclear magnetic resonance spectrum (in deuterochloroform): δ1.4
~1.8 (4H), 1.9~2.1 (2H), 1.
92 (3H), 2.00 (3B), 2.06 (3I
I), 2.27 (2H), 3.63 (3H), 6
．． 17(18), 7.23(5H). This quinone body (0.14g) was mixed with methanol (70Ml).
and irradiated with promlite for 3 hours. After the reaction was completed, methanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with isopropyl ether to obtain Compound No. 9 (0.14 g). The physical properties and nuclear magnetic resonance spectrum data are shown in Tables 3 and 4. 2.51 (2B), 2.78 (2H), 4.11 (2B
), 4.84 (LH). 2.60 (2H), 3.97 (2H), 4.88 (21
+), 5.07 (IH). (3H), 2.23 (3H), 2.41 (3H), 2.
57(28), 4.412.42(3)1), 2.60
(2H), 3.61 (3H), 4.47 (LH). 7J4 (511) 10 1.20 (3H), 1.5-1.8 (48
), 1.91 (3+1), 2.22 (211) 2.2
6 (311), 2.41 (311), 2.60 (2H)
, 4.08 (2H), 4.482.34 (3H), 2.
54 (2H), 6.60 (LH), 7.13 (IH),
7.22.27 (3H), 2.43 (3H), 2.60
(21+), 4.07 (LH), 4.562.2-2.
5 (4H), 2.39 (:3H), 2.59 (2H),
3.32 (21+) 3.56 (2H), 4.16 (11
1), 4.67 (IH), 7.1-7.42, 40 (3
H), 2.60 (2+1), ? , o7 (2t
l), 7.26 (2n), 7, 812.41 (3
H), 2.59 (21+), 3.62 (311), 4.
51(III), 7.0(3)1), 2.40(3)1
), 2.59 (211), 7.21 (211), 7J7
(2H), 7.86 (21+) 2.38 (3B), 2.40 (38), 2.60 (2B
), 7.19 (4H), 7.642.38 (38), 2
．． 40 (3H), 2.59 (2H), 3.60 (31m
), 4.60 (3B), 2.27 (2H), 2.42 (
3H), 2.59 (2H), 7J5”DMso-d, medium measurement

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom, a methyl group, or a methoxy group, or R^1 and R^2
are bonded to each other and R^1 and R^2 form -CH=CH-CH=
CH-, R^3 is an optionally substituted aromatic ring group, R^4 is a hydrogen atom, a methyl group, an optionally substituted hydroxymethyl group, which may be amidated or esterified. Z represents a carboxyl group, Z represents a -C≡C- group or a bond, m represents an integer from 0 to 10, and n represents an integer from 0 to 5. ] A benzofuran derivative represented by