JPH0733767A - Thiochroman derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having high inhibiting actions on lipoxygenases and the synthesis of thromboxane A2, scavenging action, etc., on active oxygen radicals and useful for treating bronchial asthma, thrombosis, ischemic diseases, hepatitis, etc. CONSTITUTION:This compound is expressed by formula I [R<1> is H, an alkenyl, etc.; R<2> is H or protecting group of hydroxyl group; R<3> and R<4> are H, an aryl, etc.; R<5> is H or an alkyl; Q is a nitrogen-containing heterocyclic ring; (n) is 1-4], e.g. 3,4-dihydro-2-(1-imidazolyl)methyl-5,7,8-trimethyl-2H-benzo-1-thiopyra n-6- ol. The compound is obtained by reacting a compound expressed by formula II (R<6> is H or lower alkyl; R<7> is protecting group of hydroxyl group) with a reducing agent such as lithium aluminum hydride in an inert solvent such as THF, then reacting the resultant compound expressed by formula III with a halogenating agent or an organic sulfonyl halide, converting the compound expressed by formula III into a compound expressed by formula IV (X is halogen, alkylsulfonyloxy, etc.) and finally reacting the prepared compound expressed by formula IV with a nitrogen-containing heterocyclic compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiochroman derivative useful as a medicine or as an intermediate for the synthesis of a compound useful as a medicine, and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art In the development of various inflammatory diseases, leukotriene produced by the action of 5-lipoxygenase from arachidonic acid and thromboxane A ₂ produced by the action of cyclooxygenase are involved as important factors. Are known. In addition, it is known that active oxygen species are greatly involved in these diseases. Conventionally, it has been known that a chroman derivative having a substituent on the side chain exhibits a lipoxygenase inhibitory action, an antioxidant action, etc. [see JP-A-63-264476, JP-A-2-215778, etc.], and It is known that the thiochromancarboxylic acid amide derivative exhibits antihistamine action, lipoxygenase inhibitory action and the like [see JP-A-2-215779], but the activity is not always sufficient. A corresponding thiochroman derivative is also known for vitamin E, but its antioxidant effect is said to be weaker than that of vitamin E [H.
A. Zahalka et al., Journal of Organic Chemistry.
ic Chemistry), 53, 3789-37
45 (1988)]. Therefore, compounds having higher pharmacological activity, and further compounds having more pharmacological activity are desired.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel thiochroman derivative having a higher lipoxygenase inhibitory action, a thromboxane A ₂ synthesis inhibitory action, a reactive oxygen species scavenging action and the like, and a thiochroman derivative thereof which is acceptable as a pharmaceutical. Or a synthetic intermediate compound thereof. The present inventors have conducted extensive research to achieve this object, and surprisingly, the following general formula (I)
The thiochroman derivative represented by and a pharmaceutically acceptable salt thereof have an extremely high lipoxygenase inhibitory action,
The present invention has been completed by finding that the compound has a pharmacological action such as a thromboxane A ₂ synthesis inhibitory action or a scavenging action of active oxygen species, or an intermediate for the synthesis of compounds having these actions.

[0004]

The object of the present invention is to provide a compound of the general formula (I)

[0005]

[Chemical 2]

(In the formula, R ¹ represents a hydrogen atom, an alkyl group which may have a substituent or an alkenyl group which may have a substituent, and R ² represents a hydrogen atom or a protective group for a hydroxyl group. represents, R ³ and R ⁴ are a hydrogen atom, an optionally substituted alkyl group, which may have a substituent alkenyl group, an aryl group which may have an alkoxyl group or a substituted group Or R ³ and R ⁴ together represent a group represented by the formula —CH═CH—CH═CH—, R ⁵ represents a hydrogen atom or an alkyl group, and Q represents a nitrogen-containing heterocycle. A thiochroman derivative (hereinafter, referred to as thiochroman derivative (I)) or a pharmaceutically acceptable salt thereof (hereinafter, simply referred to as salt). To be achieved.

In the present specification, each symbol means the following respectively. The alkyl group in the alkyl group which may have a substituent represented by R ¹ , R ³ and R ⁴ includes a methyl group, an ethyl group, a propyl group, an isopropyl group and t-
It is a linear or branched alkyl group such as a butyl group and an isoamyl group, and among them, a lower alkyl group having 5 or less carbon atoms is preferable. The alkenyl group in the alkenyl group which may have a substituent represented by R ¹ , R ³ and R ⁴ is a linear or branched alkenyl group such as vinyl group, allyl group, methallyl group and prenyl group. Among them, a lower alkenyl group having 5 or less carbon atoms is preferable. Examples of the substituent which these may have include a hydroxyl group which may be protected, a lower alkoxyl group, an amino group which may have a substituent, an optionally protected carboxyl group and an aryl group. Can be mentioned.

Examples of the protective group for the optionally protected hydroxyl group include acyl groups such as acetyl group, propionyl group, butanoyl group and benzoyl group; alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; aminocarbonyl group. And an aminocarbonyl group such as a dimethylaminocarbonyl group. As the lower alkoxyl group, a methoxy group, an ethoxy group,
Examples thereof include linear or branched alkoxyl groups such as a propoxy group, an isopropoxy group and a butoxy group, and among them, a lower alkoxyl group having 5 or less carbon atoms is preferable. The substituent of the amino group which may have a substituent includes a lower alkyl group such as a methyl group and an ethyl group;
Examples thereof include an acyl group such as an acetyl group and a benzoyl group, and the substituent may be mono-substituted or di-substituted. Specific examples of the amino group include a methylamino group, a dimethylamino group and an acetylamino group. Group, benzoylamino group and the like. As the protecting group for the optionally protected carboxyl group, a methyl group,
Examples thereof include lower alkyl groups such as ethyl group, propyl group and butyl group. Examples of the aryl group include a phenyl group, a naphthyl group, a p-methoxyphenyl group, a p-chlorophenyl group and the like. Examples of the protective group for the hydroxyl group represented by R ² include those mentioned above.

The alkoxyl group represented by R ³ and R ⁴ is
It is a straight-chain or branched-chain alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group, and among them, a lower alkoxyl group having 5 or less carbon atoms is preferable. The aryl group in the optionally substituted aryl group represented by R ³ and R ⁴ is preferably a phenyl group, and the aryl group optionally has a lower alkyl group or a lower alkoxyl group. ,
Examples thereof include a halogen atom and an optionally protected carboxyl group. Examples of the lower alkyl group include linear or branched alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a t-butyl group, and among them, a lower alkyl group having 4 or less carbon atoms. Is preferred. Examples of the lower alkoxyl group include the same ones as described above. Examples of the halogen atom include chlorine atom, bromine atom, iodine atom and the like. As the carboxyl group which may be protected, the same as those mentioned above can be mentioned.

The alkyl group represented by R ⁵ is a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, an isoamyl group, and the like. No more than 4 lower alkyl groups are preferred.

The nitrogen-containing heterocyclic group represented by Q may be a group containing at least one nitrogen atom as a hetero atom, preferably 1 to 4 nitrogen atoms, more preferably 1 to 4 nitrogen atoms.
It contains three nitrogen atoms. As the hetero atom, at least one hetero atom other than nitrogen atom (for example, oxygen atom, sulfur atom) may be contained. The nitrogen-containing heterocyclic group is preferably a 5-membered ring or 6-membered ring, and may be a 5-membered or 6-membered condensed ring. The heterocyclic group is
It may be substituted with a lower alkyl group as described above, an optionally substituted amino group, an optionally protected carboxyl group or the like. The nitrogen-containing heterocyclic group, specifically, imidazolyl group, pyridyl group, pyrrolidinyl group, piperidinyl group, morpholino group, triazolyl group, thiazolyl group, pyrazolyl group, pyrimidinyl group, pyrazinyl group,
Examples thereof include a triazinyl group and a pyrrolyl group, and among them, an imidazolyl group, a pyridyl group, a triazolyl group, a thiazolyl group and the like are preferable. n represents an integer of 1 to 4, preferably 1 or 2.

The thiochroman derivative (I) and its salt are prepared according to the following scheme.

[0013]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
Q and n are as defined above, R ⁶ represents a hydrogen atom or a lower alkyl group, R ⁷ represents a protective group for a hydroxyl group, X represents a reaction of a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or the like. Represents a sexual group.
As R ⁶ , the lower alkyl group may be the same as the above. With respect to R ⁷ , examples of the protective group for the hydroxyl group include the same groups as described above. ) That is, the thiochromancarboxylic acid derivative (II) is used as a raw material and a reducing agent such as lithium aluminum hydride is reacted in an inert solvent such as tetrahydrofuran to obtain a corresponding thiochroman alcohol derivative (III), and then the alcohol Reaction of the derivative (III) with a halogenating agent in the presence or absence of an organic amine, or with an organic sulfonyl halide in the presence of an organic base such as pyridine, to give a halide or sulfonate. To the reactive compound (IV), reacting the reactive compound (IV) with the nitrogen-containing heterocyclic compound itself or its anion, and deprotecting or protecting it as necessary.
The thiochroman derivative may also be prepared by a method in which the reactive compound (IV) is not isolated, such as a method in which the thiochroman alcohol derivative (III) and the nitrogen-containing heterocyclic compound itself are reacted with triphenylphosphine in carbon tetrachloride. (I) can be obtained.

The reaction of the reactive derivative (IV) with the nitrogen-containing heterocyclic compound itself or its anion may be carried out without solvent or preferably in an inert solvent such as dioxane, tetrahydrofuran, toluene, dimethylformamide or the like. it can. When the reactive derivative (IV) is reacted with the nitrogen-containing heterocyclic compound itself such as imidazole, pyrrole or pyrazole, it can be carried out in the temperature range of room temperature to 150 ° C. in the presence or absence of a base, and When reacted with an anion of a nitrogen-containing heterocyclic compound such as 1-imidazolyl potassium or 3-pyridyl lithium, it is usually -78.
It can be carried out in the range of ℃ to 70 ℃. The thiochromancarboxylic acid derivative (II) is tetrahedron.
Letters (Tetrahedoron Letters), Vol. 27, No. 25,
2817 (1986) and JP-A-2-21248.
It is manufactured according to the method described in JP-A-3.

The salt of the thiochroman derivative (I) includes
There is no particular limitation so long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochlorides and sulfates; salts with organic acids such as acetates, citrates and succinates. The salt of the thiochroman derivative (I) is produced from the thiochroman derivative (I) by a method known per se.

Isolation of the thiochroman derivative (I) or a salt thereof from the reaction mixture can be carried out by a conventional method. For example, water is added to the reaction solution and extracted with ethyl acetate or the like.
After washing the extract with water, it is dried, concentrated under reduced pressure, and separated and purified by recrystallization or chromatography,
A thiochroman derivative (I) or a salt thereof can be obtained.

With respect to R ¹ , R ² , R ³ and R ⁴ in the general formula (I), the thiochroman derivative (I) and salts thereof in which none of the groups have a protecting group are generally used in horses including humans. It has pharmacological actions such as thromboxane A ₂ biosynthesis inhibitory action, 5-lipoxygenase inhibitory action and active oxygen species scavenging action on animals such as bovine, dog, guinea pig and mouse. It is higher than the chroman compound. Therefore, the compound is used for treating diseases caused by at least one of thromboxane A ₂ , leukotriene, reactive oxygen species, etc.
It is useful as a preventive agent. Specific examples of such diseases include bronchial asthma, thrombosis, and ischemic diseases (for example,
Stroke, myocardial infarction, etc.), nephritis, lung failure, psoriasis, allergic disease, anaphylactic shock, arteriosclerosis, fatty liver, hepatitis, cirrhosis, autoimmune disease (eg, rheumatism, arthritis, etc.), cancer, brain contusion, spinal cord Brain, lungs, etc.
Examples include diseases of the kidney, liver, joints, skin, and the like.

When the thiochroman derivative (I) of the present invention and its salt are used as the above-mentioned pharmaceuticals, pharmacologically acceptable additives (for example, carrier, excipient, diluent, etc.) and the like are required pharmaceutically. It can be orally or parenterally administered as a pharmaceutical composition in the form of powder, granules, tablets, capsules, syrups, injections and the like by appropriately mixing with the ingredients. An effective amount of thiochroman derivative (I) and its salt is added to the above-mentioned preparation. The dose varies depending on the administration route, symptoms, weight of the patient, age, etc., but when administered orally to an adult patient, for example, 1 to 100
0 mg / human / day, especially 5-100 mg / human / day 1
It is desirable to administer the drug in 1 to several times a day. In the case of intravenous administration, 0.1-100 g / human / day, especially 1
It is desirable to administer ˜50 mg / human / day divided into 1 to several times a day.

[0020]

The present invention will be described below with reference to examples.
The present invention is not limited to these examples.

Reference Example 1 [(3,4-Dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-
Synthesis of thiopyran-2-yl) methanol] Under a nitrogen atmosphere, a solution prepared by suspending 3 g of lithium aluminum hydride in 500 ml of tetrahydrofuran was added to 3,4-
Dihydro-6-hydroxy-5,7,8-trimethyl-
18 g of 2H-benzo-1-thiopyran-2-carboxylic acid
Was dissolved in 300 ml of tetrahydrofuran and added dropwise. After the dropping, the reaction solution was heated under reflux for 1 hour, cooled, and then water diluted with tetrahydrofuran was added dropwise. Then, diluted hydrochloric acid was added, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried and concentrated, and the obtained residue was suspended in ethyl acetate and filtered to give crystals. The filtrate was purified by silica gel column chromatography and combined with the above crystals and had the following physical properties (3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-yl). ) 12 g of methanol
Obtained. NMR spectrum (400 MHz, CDCl ₃ ) δ 1.68-1.83 (m, 1H), 2.16 (s, 3)
H), 2.19 (s, 3H), 2.29 (s, 3H),
2.55-2.69 (m, 1H), 2.81-2.93
(M, 1H), 3.40 (m, 1H), 3.59 (d
d, 1H), 3.71 (dd, 1H), 4.55 (b
r. s, 1H)

Reference Example 2 [(Synthesis of (3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzo-1-thiopyran-2-yl) methanol]] In Reference Example 1, Instead of 3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-carboxylic acid, 3,4-dihydro-
6-hydroxy-2,5,7,8-tetramethyl-2H
By carrying out the reaction and separation and purification in the same manner as in Reference Example 1 except that -benzo-1-thiopyran-2-carboxylic acid was used, the following physical properties were obtained (3,4-dihydro-6-hydroxy-2,5). , 7,8-Tetramethyl-2H-benzo-1-thiopyran-2-yl) methanol 11.5
g was obtained. FD mass spectrum [M] ⁺ 252

Reference Example 3 [2- (3,4-dihydro-6-
Hydroxy-5,7,8-trimethyl-2H-benzo-
Synthesis of 1-thiopyran-2-yl) ethanol] In Reference Example 1, instead of 3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-carboxylic acid. , (3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-yl) acetic acid are used, and the reaction and separation / purification are performed in the same manner as in Reference Example 1. Thus, 2- (3,4-dihydro-6- having the following physical properties is obtained.
Hydroxy-5,7,8-trimethyl-2H-benzo-
11.5 g of 1-thiopyran-2-yl) ethanol was obtained. FD mass spectrum [M] ⁺ 252

Reference Example 4 Synthesis of [(3,4-dihydro-6-hydroxy-5- (2-propenyl) -7- (1-methylethyl) -2H-benzo-1-thiopyran-2-yl) methanol ] In Reference Example 1, 3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-carboxylic acid was replaced with 3,4-dihydro-
6-hydroxy-5- (2-propenyl) -7- (1-
Methylethyl) -2H-benzo-1-thiopyran-2-
By carrying out the reaction and separation and purification in the same manner as in Reference Example 1 except that methyl carboxylate was used, (3,4-dihydro-6-hydroxy-5- (2-propenyl) -7- (having the following physical properties was obtained. 1-methylethyl) -2H-benzo-
11.5 g of 1-thiopyran-2-yl) methanol was obtained. NMR spectrum (400 MHz, CDCl ₃ ) δ 1.66-1.83 (m, 1H), 2.17 (s, 3)
H), 2.2 (s, 3H), 2.28 (s, 3H),
2.55-2.69 (m, 1H), 2.8-2.93
(M, 1H), 3.33-3.46 (m, 1H), 3.
59 (dd, 1H), 3.71 (dd, 1H), 4.5
2 (br.s, 1H)

Reference Example 5 [2- (3,4-dihydro-6-
Hydroxy-5,7,8-trimethyl-2H-benzo-
Synthesis of 1-thiopyran-2-yl) ethyl p-toluenesulfonate] 2- (3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1 obtained in Reference Example 3 −
2.52 g of thiopyran-2-yl) ethanol and 0.85 g of pyridine are dissolved in 200 ml of methylene chloride,
1.95 g of p-toluenesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature overnight. The obtained reaction solution is washed with water, dried,
After concentrating and then purifying by silica gel column chromatography, 2- (3,4-) having the following physical properties is obtained.
Dihydro-6-hydroxy-5,7,8-trimethyl-
2H-benzo-1-thiopyran-2-yl) ethyl p
-3.1 g of toluene sulphonate were obtained. FD mass spectrum [M] ⁺ 406

Reference Example 6 [3,4-dihydro-2- (2-
Synthesis of iodoethyl) -5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol] 2- (3,4-dihydro-6-hydroxy-5,7,8 obtained in Reference Example 5 -Trimethyl-2H-benzo-1-
Thiopyran-2-yl) ethyl p-toluenesulfonate (406 mg) was dissolved in dimethylformamide (5 ml), sodium iodide (450 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution is poured into water, extracted with ethyl acetate, the extract is washed with water, dried and concentrated, and the resulting residue is purified by silica gel column chromatography to give 3,4-dihydro-2 having the following physical properties. -(2-Iodoethyl) -5,7,8-trimethyl-2H-benzo-1-
324 mg of thiopyran-6-ol was obtained. FD mass spectrum [M] ⁺ 362

Example 1 [3,4-dihydro-2- (1-
Imidazolyl) methyl-5,7,8-trimethyl-2H
-Synthesis of benzo-1-thiopyran-6-ol] (3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1-thiopyran-2-yl)
1 g of methanol was dissolved in a mixed solvent of 50 ml of carbon tetrachloride and 150 ml of chloroform, 1.2 g of triphenylphosphine and 1.5 g of imidazole were added, and
Heated to reflux for hours. After concentrating the reaction solution, by purifying the residue by silica gel column chromatography,
510 mg of 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol having the following physical properties was obtained. NMR spectrum (400 MHz, CDCl ₃ ) δ 1.60-1.75 (m, 1H), 2.18 (s, 3)
H), 2.20 (s, 3H), 2.24 (s, 3H),
2.56-2.70 (m, 1H), 2.80-2.92
(M, 1H), 3.50 (m, 1H), 4.10 (d,
2H), 5.32 (br.s, 1H), 6.98 (s.
1H), 7.09 (s, 1H), 7.52 (s, 1H)

Example 2 [3,4-dihydro-2- (1-
Imidazolyl) methyl-5,7,8-trimethyl-2H
-Synthesis of Benzo-1-thiopyran-6-ol Hydrochloride] 3,4-Dihydro-2- (1-imidazolyl) methyl-
1.1 g of 5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol was dissolved in 100 ml of ethanol, and hydrogen chloride gas was blown therein under ice cooling. The reaction solution was concentrated, the residue was washed with diethyl ether, and dried to give 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-1-thiopyran-. 1.13 g of 6-ol hydrochloride was obtained. NMR spectrum (400 MHz, DMSO-d6)? 1.53-1.7 (m, 1H), 2.09 (s, 9)
H), 2.0-2.2 (m, 1H), 2.5-2.61.
(M, 1H), 2.73-2.86 (m, 1H), 3.
38 (br.s, 1H), 3.79 (m, 1H), 4.
30 (dd, 1H), 4.45 (dd, 1H), 7.7
2 (s, 1H), 7.84 (s, 1H), 9.20
(S, 1H)

Example 3 [3,4-dihydro-2- (1-
Imidazolyl) methyl-5,7,8-trimethyl-2H
-Synthesis of benzo-1-thiopyran-6-yl monosuccinate] 3,4-dihydro-2- (1-imidazolyl) methyl-
0.5 g of 5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol was dissolved in 5 ml of pyridine, 0.21 g of succinic anhydride was added, and the mixture was heated under reflux overnight. 0.1 g of succinic anhydride was added and heated to reflux for one day, and 0.2 g of succinic anhydride was added and heated to reflux for one day. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with 1N hydrochloric acid.
The precipitated crystals are filtered, washed with water, dried, and recrystallized from ethanol to give the following physical properties 3,
4-dihydro-2- (1-imidazolyl) methyl-5
7,8-Trimethyl-2H-benzo-1-thiopyran-
0.15 g of 6-yl monosuccinate was obtained. NMR spectrum (400 MHz, DMSO-d6)? 1.51-1.67 (m, 1H), 1.96 (s, 3)
H), 1.98 (s, 3H), 2.12 (s, 3H),
2.0-2.15 (m, 1H), 2.53-2.64
(M, 3H), 2.72-2.90 (m, 3H), 3.
62-3.75 (m, 1H), 4.1-4.3 (m, 2)
H), 6.92 (s, 1H), 7.27 (s, 1H),
7.70 (s, 1H)

Example 4 [3,4-dihydro-2- (2-
Synthesis of (1-imidazolyl) ethyl) -5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol] 2- (3,4-dihydro-6-hydroxy-5,7,8
-Trimethyl-2H-benzo-1-thiopyran-2-yl) ethyl p-toluenesulfonate 406 mg and imidazole 200 mg were heated under reflux in toluene overnight. The reaction solution is washed successively with aqueous sodium hydrogen carbonate, water and brine, dried and concentrated, and the residue obtained is purified by silica gel column chromatography to give the following physical properties 3,4
-Dihydro-2- (2- (1-imidazolyl) ethyl)
182 mg of -5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol was obtained. FD mass spectrum [M] ⁺ 302

Example 5 [3,4-dihydro-2- (1-
Synthesis of Imidazolyl) methyl-2,5,7,8-tetramethyl-2H-benzo-1-thiopyran-6-ol] In Example 1, (3,4-dihydro-6-hydroxy-5,7,8) Instead of 1 g of -trimethyl-2H-benzo-1-thiopyran-2-yl) methanol, (3,4
-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzo-1-thiopyran-2-yl) methanol was used in the same manner as in Example 1 except that 1.06 g was used for the reaction, separation and purification. By carrying out, 3,4-dihydro-2- (1-imidazolyl) methyl-2,5,7,8-tetramethyl-2H-benzo-1- having the following physical properties
0.34 g of thiopyran-6-ol was obtained. FD mass spectrum [M] ⁺ 302

Example 6 [3,4-dihydro-2- (1-
Imidazolyl) methyl-5- (2-propenyl) -7-
Synthesis of (1-methylethyl) -2H-benzo-1-thiopyran-6-ol] In Example 1, (3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-benzo-1 -Thiopyran-2-yl) methanol 2 g instead of 1 g
(3,4-dihydro-6-hydroxy-5- (2-propenyl) -7- (1-methylethyl) -2H-benzo-
1-Thiopyran-2-yl) methanol 3,4-dihydro-2 having the following physical properties was obtained by carrying out the reaction and separation and purification in the same manner as in Example 1 except that 1.17 g was used.
-(1-Imidazolyl) methyl-5- (2-propenyl) -7- (1-methylethyl) -2H-benzo-1-
0.54 g of thiopyran-6-ol was obtained. FD mass spectrum [M] ⁺ 328 NMR spectrum (400 MHz, CDCl ₃ ) δ 1.21 (d, 3H), 1.23 (d, 3H), 1.6
3-1.8 (m, 1H), 2.1-2.44 (m, 1
H), 2.58-2.72 (m, 1H), 2.77-
2.9 (m, 1H), 3.09-3.22 (m, 1
H), 3.45 (d, 2H), 3.48-3.58.
(M, 1H), 4.11 (d, 2H), 5.0 (dd,
1H), 5.1 (dd, 1H), 5.27 (br.s,
1H), 5.87-6.03 (m, 1H), 6.9.
(S, 1H), 6.99 (s, 1H), 7.1 (s, 1)
H), 7.52 (s, 1H)

Test Example 1 (5-lipoxygenase inhibitory action) Ochi et al.'S method (Journal of Biological Chemistry, 25
RBL-1 in accordance with Volume 8, page 5754 (1983)).
Using cells, the inhibitory effect of 5-lipoxygenase was evaluated by the reduction of 5-hydroxyeicosatetraenoic acid (5-HETE) production. As a test compound of the present invention 3,
4-dihydro-2- (1-imidazolyl) methyl-5
7,8-Trimethyl-2H-benzo-1-thiopyran-
6-ol (Invention Compound 1) and the corresponding chroman compound 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-
Using 1-pyran-6-ol (control compound 1), the 50% inhibitory concentration of each was determined. The results are shown in Table 1.

[0034]

[Table 1]

Test Example 2 (Inhibition of thromboxane synthase) Test tubes 1 and 2 had 50 mM Tris-0.1 M NaC.
l buffer solution (pH 7.5) 100 μl and solvent dimethylsulfoxide 2 μl, and test tubes 3 and 4 were 10-fold diluted with human platelet microsomes (200 μl) as enzyme solution.
μg / ml) 100 μl and dimethyl sulfoxide 2
10 μl of a 10-fold diluted human platelet microsome (200 μg / ml), which is an enzyme solution, in test tubes 5 and 6
0 μl and 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-
2 μl of a dimethyl sulfoxide solution of 1-thiopyran-6-ol (invention compound 1) was placed in test tubes 7 and 8 at a 10-fold dilution of human platelet microsomes (2) which is an enzyme solution.
00 μg / ml) 100 μl and the chroman compound 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-1-pyran-6-ol corresponding to the invention compound 1 (control) After adding 2 μl of a dimethyl sulfoxide solution of the compound 1) and stirring, 22
Incubated for 3 minutes in a -25 ° C shaking bath. After adding ₂ μl of a prostaglandin H ₂ acetone solution (50 μg / ml) to each test tube and stirring,
Incubated in a shaking bath at 22-25 ° C for 3 minutes. Then 10 μl of ferrous chloride aqueous solution (6.
3 mg / ml) was added to stop the reaction, and the mixture was allowed to stand at room temperature for 15 minutes and then cooled with ice. 3000 r.p.m. at 4.degree. p.
m. The thromboxane B ₂ produced in the supernatant was diluted 10-fold and measured by radioimmunoassay. Test tube 3 with test tubes 1 and 2 as blanks
The inhibition rate of the amount of thromboxane B ₂ produced was calculated by using Controls 4 and 4. The results are shown in Table 2.

[0036]

[Table 2]

Test Example 3 (Anti-asthma Action) Anti-ovalbumin rabbit serum was passively sensitized by intravenous administration to the forearm of Hartley guinea pigs (body weight 238-278 g). The drug was sprayed into the nasal cavity and oral cavity after 24 hours. Five minutes after drug administration, a 2% physiological saline solution of the antigen ovalbumin was sprayed and inhaled using an ultrasonic nebulizer, and the presence or absence of anaphylaxis symptoms was observed for 10 minutes after the transition. Whether or not anaphylactic symptoms are induced is determined by Suzuki's method (“Allergy Experimental Method (1), Protein / Nucleic Acid / Enzyme, Special Issue”, Volume 14, 580).
Page (1969)), and the rollover time and lethality time were also measured. In addition, as a test compound, 3,4-dihydro-2- (1-imidazolyl) methyl-5,7,8-trimethyl-2H-benzo-1-thiopyran-6-ol (invention compound 1) of the present invention and a control Beclomethasone propionate (control compound 2) was used as a drug. The results are shown in Tables 3, 4, and 5.

[0038]

[Table 3]

[0039]

[Table 4]

[0040]

[Table 5]

From these test results, the thiochroman derivative (I) and salts thereof of the present invention have higher lipoxygenase inhibitory activity or thromboxane synthase inhibitory activity than the corresponding chroman compound, and are equivalent to steroids. Since it has a high anti-anaphylactic effect, it is useful as a therapeutic agent for diseases such as leukotriene, thromboxane A ₂ and reactive oxygen species, such as heart, brain, lung, kidney, liver, joint and skin. It was confirmed. Further, it was confirmed that the thiochroman derivative (I) of the present invention has low toxicity in a toxicity test.

[0042]

EFFECTS OF THE INVENTION Since the compounds of the present invention have pharmacological actions such as lipoxygenase inhibitory action, thromboxane A ₂ synthesis inhibitory action and active oxygen species scavenging action, the involvement of leukotriene, thromboxane A ₂ , active oxygen species, etc. It is expected to be effective in treating diseases such as heart, brain, lung, kidney, liver, joint and skin.

Front page continued (72) Inventor Manzo Shiono 1 2045 Sakata, Kurashiki City, Okayama Prefecture Kuraray Co., Ltd.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents a hydrogen atom, an alkyl group which may have a substituent or an alkenyl group which may have a substituent, and R ² represents a hydrogen atom or a protective group of a hydroxyl group,
R ³ and R ⁴ are a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent,
It represents an alkoxyl group or an aryl group which may have a substituent, or R ³ and R ⁴ together form a compound represented by the formula:
It represents a group represented by CH = CH-CH = CH-, R 5 represents a hydrogen atom or an alkyl group, Q represents a nitrogen-containing heterocyclic group, n is an integer of from 1 4. ) The thiochroman derivative shown by these or its pharmaceutically acceptable salt.