JPH07112978A - Agent for treating and preventing disease related to lipoperoxide - Google Patents

Abstract

PURPOSE:To obtain a novel compound having a lipoperoxide production- inhibiting action and useful for preventing and treating diseases relating to lipoperoxide. CONSTITUTION:A compound of formula I (X, Y are H, hydroxyl, a halogen, lower alkyl; Z is hydroxyl, hydroxysulfonyloxy; R<1> is an alkyl or phenyl which may be substituted with one or more of halogens OH, CN, a lower alkyl groups), e.g. 4-(4-hydroxybenxyl)-5-methyl-1,2-dithiol-3-thione. The compound of formula I is obtained by hydrolyzing a compound of formula II (R<4> is a lower alkyl) with an acidic reagent such as hydrobromic acid. The diseases relating to the lipoperoxide includes arteriosclerosis, pulmonary diseases, digestive organ diseases, hepatic diseases, cardiac diseases, cerebrovascular diseases, inflammation, autoimmune diseases, shock, disseminated intravascular coagulation syndromes, dermatosis, ophthalmic diseases, diabetes, cancers, renal diseases, iron anaphylaxis, pancreatitis, and those due to the toxicities of antibiotics and carcinostatic agents.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 1,2-dithiol-3-thione derivative, a method for producing the same, and a therapeutic and prophylactic agent for diseases involving lipid peroxide containing these compounds as an active ingredient. Is.

[0002]

2. Description of the Related Art At present, it is becoming clear that lipid peroxides are closely associated with various diseases. For example, arteriosclerosis, lung disease, digestive organ disease, liver disease, heart disease, cerebrovascular disease, inflammation, autoimmune disease, shock, disseminated intravascular coagulation syndrome, skin disease, eye disease, diabetes, cancer, renal disease,
Iron hypersensitivity, pancreatitis, toxicity of antibiotics and carcinostatics, etc. are mentioned as related diseases, and it is thought that lipid peroxidation reaction by reactive oxygen species and various free radicals is involved in the onset and deterioration of the disease state. There is. Regarding heart disease, ischemic heart disease such as myocardial infarction has been rapidly increasing in recent years. Reperfusion therapy has come to be widely used as a treatment method, and effective results have been obtained. On the other hand, even if resumption of blood flow is obtained by this treatment method, severe arrhythmia such as ventricular fibrillation,
Hemorrhagic infarction, no-reflow phenomeno
It has been reported that new injuries such as n, so-called reperfusion injury occur (J. Clin. Invest., 7).
6, 1713, 1985). As a mechanism of this reperfusion injury, involvement of active oxygen and lipid peroxide is considered. Further, reperfusion injury is considered to occur during heart surgery and organ transplantation, and is currently of interest.

[0003]

An object of the present invention is to provide a novel drug which is useful for treating and preventing a disease involving lipid peroxide.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive research on compounds having an inhibitory action on lipid peroxide formation for the purpose of developing drugs that act effectively for the treatment and prevention of these diseases. As a result, they have found that the novel compound of the present invention or a salt thereof has excellent effects and are useful as a medicine, and completed the present invention. That is, the present invention has the general formula (1)

[0005]

[Chemical 10] (In the formula, X and Y each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and Z
Represents a hydroxyl group or a hydroxysulfonyloxy group, R ¹ represents an alkyl group or a compound represented by the general formula (2)
1]

[0006]

[Chemical 11] (In the formula, R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an acetyl group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group.) Is a group that is ) Or a salt thereof, and a therapeutic or prophylactic agent for a disease involving lipid peroxide, which comprises the compound or a salt thereof as an active ingredient.

Arznemittel-For
sch, 13, 2, 130 (1963), 5- (4-hydroxyphenyl) -1,2-dithiol as a 1,2-dithiol-3-thione derivative having a hydroxyphenyl group or a hydroxysulfonyloxyphenyl group. Although -3-thione and 5- (4-hydroxysulfonyloxyphenyl) -1,2-dithiol-3-thione are described, these compounds are different from the compounds of the present invention, and they are It is only described as a metabolite.

Next, the compounds of the present invention represented by the general formula (1) will be explained. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The lower alkyl group is an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group,
Examples thereof include n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group. The alkyl group is a linear, branched or cyclic alkyl group having 1 to 9 carbon atoms, such as a lower alkyl group described above, a pentyl group, an isopentyl group, a tert-pentyl group, Examples thereof include neopentyl group, cyclopentyl group, hexyl group, isohexyl group, cyclohexyl group, heptyl group, isoheptyl group, 4-methylcyclohexyl group, octyl group, isooctyl group, nonyl group and isononyl group. The lower alkoxy group is an alkoxy group having 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an allyloxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. A group etc. can be mentioned.
Examples of the lower alkoxy moiety of the lower alkoxycarbonyl group include the same lower alkoxy moieties having 1 to 4 carbon atoms as those of the above lower alkoxy group. The compounds of the present invention are specifically illustrated in Table-1 [Table 1] to Table-8 [Table 23], but it goes without saying that the present invention is not limited thereto.

[0009]

[Table 1] Table-1 ──────────────────────────────────── Compound R ¹ Z number ────────── ──────────────────────────── 1 CH ₃ OH 2 C ₂ H ₅ OH 3 n-C ₃ H ₇ OH 4 iso-C _{3 H 7 OH 5 n-C 4} H 9 OH 6 iso-C 4 H 9 OH 7 sec-C 4 H 9 OH 8 tert-C 4 H 9 OH 9 n-C 5 H 11 OH 10 iso-C 5 H 11 OH 11 neo-C ₅ H ₁₁ OH 12 tert-C ₅ H ₁₁ OH 13 cyclopentenyl OH 14 n-C ₆ H ₁₃ OH 15 iso-C ₆ H ₁₃ OH 16 cyclohexyl OH 17 n-C ₇ H ₁₅ OH

[0010]

TABLE 2 _{18 iso-C 7 H 15 OH} 19 4-methylcyclohexyl OH 20 n-C 8 H 17 OH 21 iso-C 8 H 17 OH 22 n-C 9 H 19 OH 23 iso-C 9 H 19 OH 24 _{CH 3 OSO 3 H 25 C 2} H 5 OSO 3 H 26 n-C 3 H 7 OSO 3 H 27 iso-C 3 H 7 OSO 3 H 28 n-C 4 H 9 OSO 3 H 29 iso-C 4 H 9 OSO ₃ H 30 sec-C ₄ H ₉ OSO ₃ H 31 tert-C ₄ H ₉ OSO ₃ H 32 n-C ₅ H ₁₁ OSO ₃ H 33 iso-C ₅ H ₁₁ OSO ₃ H 34 neo-C ₅ H _{11 OSO 3 H 35 tert-C 5} H 11 OSO 3 H 36 cyclopentyl OSO 3 H 37 n-C 6 H 13 OSO 3 H 38 iso-C 6 H 13 OSO 3 H 39 cyclohexyl OSO 3 H 4 _{n-C 7 H 15 OSO 3} H 41 iso-C 7 H 15 OSO 3 H 42 4-methylcyclohexyl OSO 3 H 43 n-C 8 H 17 OSO 3 H 44 iso-C 8 H 17 OSO 3 H

[0011]

[Table 3] 45 n-C ₉ H ₁₉ OSO ₃ H 46 iso-C ₉ H ₁₉ OSO ₃ H ─────────────────────────── ──────────

[0012]

[Table 4] Table-2 ──────────────────────────────────── Compound R ¹ X Z number ───────── _{──────────────────────────── 1 CH 3 H 2-OH} 2 C 2 H 5 H 2-OH 3 n-C 3 H _{7 H 2-OH 4 n-} C 6 H 13 H 2-OH 5 n-C 9 H 19 H 2-OH 6 CH 3 4-OH 2-OH 7 n-C 3 H 7 4-OH 2-OH 8 _{n-C 6 H 13 4-} OH 2-OH 9 CH 3 4-Cl 2-OH 10 n-C 3 H 7 4-Cl 2-OH 11 n-C 6 H 13 4-Cl 2-OH 12 CH 3 _{4-CH 3 2-OH 13} n-C 3 H 7 4-CH 3 2-OH 14 n-C 6 H 13 4-CH 3 2-OH 15 CH 3 H 3-OH 16 C 2 H 5 H 3- OH 17 n-C ₃ H ₇ H 3-OH

[0013]

TABLE 5 _{18 n-C 6 H 13 H} 3-OH 19 n-C 9 H 19 H 3-OH 20 CH 3 4-OH 3-OH 21 n-C 3 H 7 4-OH 3-OH 22 n _{-C 6 H 13 4-OH 3} -OH 23 CH 3 5-OH 3-OH 24 n-C 3 H 7 5-OH 3-OH 25 n-C 6 H 13 5-OH 3-OH 26 CH 3 4 -F 3-OH 27 n-C 3 H 7 4-F 3-OH 28 n-C 6 H 13 4-F 3-OH 29 CH 3 4-Cl 3-OH 30 n-C 3 H 7 4-Cl 3-OH 31 n-C ₆ H ₁₃ 4-Cl 3-OH 32 CH ₃ 4-Br 3-OH 33 n-C ₃ H ₇ 4-Br 3-OH 34 n-C ₆ H ₁₃ 4-Br 3- _{OH 35 CH 3 4-I 3} -OH 36 n-C 3 H 7 4-I 3-OH 37 n-C 6 H 13 4-I 3-OH 38 CH 3 4-CH 3 3-OH 3 _{n-C 3 H 7 4-} CH 3 3-OH 40 n-C 6 H 13 4-CH 3 3-OH 41 CH 3 4-C 2 H 5 3-OH 42 n-C 3 H 7 4-C 2 _{H 5 3-OH 43 n-} C 6 H 13 4-C 2 H 5 3-OH 44 CH 3 3-F 4-OH

[0014]

[Table 6] _{45 n-C 3 H 7 3} -F 4-OH 46 n-C 6 H 13 3-F 4-OH 47 CH 3 3-Cl 4-OH 48 n-C 3 H 7 3-Cl 4 _{-OH 49 n-C 6 H 13} 3-Cl 4-OH 50 CH 3 3-Br 4-OH 51 n-C 3 H 7 3-Br 4-OH 52 n-C 6 H 13 3-Br 4-OH 53 CH ₃ 3-I 4-OH 54 n-C ₃ H ₇ 3-I 4-OH 55 n-C ₆ H ₁₃ 3-I 4-OH 56 CH ₃ 3-CH ₃ 4-OH 57 n-C _{3 H 7 3-CH 3 4-} OH 58 n-C 6 H 13 3-CH 3 4-OH 59 CH 3 3-C 2 H 5 4-OH 60 n-C 3 H 7 3-C 2 H 5 4- OH 61 n-C ₆ H ₁₃ 3-C ₂ H ₅ 4-OH 62 CH ₃ H 2-OSO ₃ H 63 C ₂ H ₅ H 2-OSO ₃ H 64 n-C ₃ H ₇ H 2-OSO ₃ H 65 n- _{6 H 13 H 2-OSO 3} H 66 n-C 9 H 19 H 2-OSO 3 H 67 CH 3 4-Cl 2-OSO 3 H 68 n-C 3 H 7 4-Cl 2-OSO 3 H 69 n _{-C 6 H 13 4-Cl 2} -OSO 3 H 70 CH 3 4-CH 3 2-OSO 3 H 71 n-C 3 H 7 4-CH 3 2-OSO 3 H

[0015]

Table 7 _{72 n-C 6 H 13 4} -CH 3 2-OSO 3 H 73 CH 3 H 3-OSO 3 H 74 C 2 H 5 H 3-OSO 3 H 75 n-C 3 H 7 H 3- _{OSO 3 H 76 n-C 6} H 13 H 3-OSO 3 H 77 n-C 9 H 19 H 3-OSO 3 H 78 CH 3 4-Cl 3-OSO 3 H 79 n-C 3 H 7 4-Cl _{3-OSO 3 H 80 n-} C 6 H 13 4-Cl 3-OSO 3 H 81 CH 3 4-CH 3 3-OSO 3 H 82 n-C 3 H 7 4-CH 3 3-OSO 3 H 83 n _{-C 6 H 13 4-CH 3} 3-OSO 3 H 84 CH 3 3-Cl 4-OSO 3 H 85 n-C 3 H 7 3-Cl 4-OSO 3 H 86 n-C 6 H 13 3-Cl _{4-OSO 3 H 87 CH 3} 3-CH 3 4-OSO 3 H 88 n-C 3 H 7 3-CH 3 4-OSO 3 H 89 n-C 6 H 13 3-CH 3 4 OSO ₃ H ────────────────────────────────────

[0016]

[Table 8] Table-3 ──────────────────────────────────── Compound R ¹ X Y number ───────── _{──────────────────────────── 1 CH 3 2-OH 6} -OH 2 n-C 3 H 7 2-OH 6-OH _{3 n-C 6 H 13 2} -OH 6-OH 4 CH 3 3-OH 5-OH 5 n-C 3 H 7 3-OH 5-OH 6 n-C 6 H 13 3-OH 5-OH 7 CH ₃ 2-F 6-F 8 n-C ₃ H ₇ 2-F 6-F 9 n-C ₆ H ₁₃ 2-F 6-F 10 CH ₃ 3-F 5-F 11 n-C ₃ H ₇ 3 -F 5-F 12 n-C 6 H 13 3-F 5-F 13 CH 3 2-Cl 6-Cl 14 n-C 3 H 7 2-Cl 6-Cl 15 n-C 6 H 13 2-Cl _{6-Cl 16 CH 3 3-} Cl 5-Cl 17 n-C 3 H 7 3-Cl 5-C l

[0017]

Table 9 18 n-C ₆ H ₁₃ 3-Cl 5-Cl 19 CH ₃ 2-Br 6-Br 20 n-C ₃ H ₇ 2-Br 6-Br 21 n-C ₆ H ₁₃ 2-Br 6 _{-Br 22 CH 3 3-Br 5} -Br 23 n-C 3 H 7 3-Br 5-Br 24 n-C 6 H 13 3-Br 5-Br 25 CH 3 2-I 6-I 26 n-C ₃ H ₇ 2-I 6-I 27 n-C ₆ H ₁₃ 2-I 6-I 28 CH ₃ 3-I 5-I 29 n-C ₃ H ₇ 3-I 5-I 30 n-C ₆ H ₁₃ 3-I 5-I 31 CH ₃ 2-CH ₃ 6-CH ₃ 32 n-C ₃ H ₇ 2-CH ₃ 6-CH ₃ 33 n-C ₆ H ₁₃ 2-CH ₃ 6-CH ₃ 34 CH _{3 3-CH 3 5-CH} 3 35 n-C 3 H 7 3-CH 3 5-CH 3 36 n-C 6 H 13 3-CH 3 5-CH 3 37 CH 3 3-C 2 H 5 5- C ₂ H ₅ 38 n-C ₃ H _{7 3-C 2 H 5 5-} C 2 H 5 39 n-C 6 H 13 3-C 2 H 5 5-C 2 H 5 40 CH 3 3- (n-C 3 H 7) 5- (n-C ₃ H ₇ ) 41 n-C ₃ H ₇ 3- (n-C ₃ H ₇ ) 5- (n-C ₃ H ₇ ) 42 n-C ₆ H ₁₃ 3- (n-C ₃ H ₇ ) 5- _{(n-C 3 H 7)} 43 CH 3 3- (iso-C 3 H 7) 5- (iso-C 3 H 7) 44 n-C 3 H 7 3- (iso-C 3 H 7) 5- (iso-C ₃ H ₇₎

[0018]

TABLE 10 _{45 n-C 6 H 13 3-} (iso-C 3 H 7) 5- (iso-C 3 H 7) 46 CH 3 3- (n-C 4 H 9) 5- (n-C _{4 H 9) 47 n-C} 3 H 7 3- (n-C 4 H 9) 5- (n-C 4 H 9) 48 n-C 6 H 13 3- (n-C 4 H 9) 5- _{(n-C 4 H 9)} 49 CH 3 3- (iso-C 4 H 9) 5- (iso-C 4 H 9) 50 n-C 3 H 7 3- (iso-C 4 H 9) 5- _{(iso-C 4 H 9)} 51 n-C 6 H 13 3- (iso-C 4 H 9) 5- (iso-C 4 H 9) 52 CH 3 3- (sec-C 4 H 9) 5- _{(sec-C 4 H 9)} 53 n-C 3 H 7 3- (sec-C 4 H 9) 5- (sec-C 4 H 9) 54 n-C 6 H 13 3- (sec-C 4 H _{9) 5- (sec-C 4} H 9) 55 CH 3 3- (tert-C 4 H 9 _{5- (tert-C 4 H 9} ) 56 n-C 3 H 7 3- (tert-C 4 H 9) 5- (tert-C 4 H 9) 57 n-C 6 H 13 3- (tert-C ₄ H ₉ ) 5- (tert-C ₄ H ₉ ) ────────────────────────────────────

[0019]

[Table 11] Table-4 ──────────────────────────────────── Compound R ¹ X Y number ───────── _{──────────────────────────── 1 CH 3 2-Cl 6} -Cl 2 n-C 3 H 7 2-Cl 6-Cl _{3 n-C 6 H 13 2} -Cl 6-Cl 4 CH 3 3-Cl 5-Cl 5 n-C 3 H 7 3-Cl 5-Cl 6 n-C 6 H 13 3-Cl 5-Cl 7 CH ₃ 2-CH ₃ 6-CH ₃ 8 n-C ₃ H ₇ 2-CH ₃ 6-CH ₃ 9 n-C ₆ H ₁₃ 2-CH ₃ 6-CH ₃ 10 CH ₃ 3-CH ₃ 5-CH ₃ 11 n-C ₃ H ₇ 3-CH ₃ 5-CH ₃ 12 n-C ₆ H ₁₃ 3-CH ₃ 5-CH ₃ ───────────────────── ────────────────

[0020]

[Table 12] Table-5 ──────────────────────────────────── Compound R ² R ³ Z number ──────── ───────────────────────────── 1 H H 2-OH 2 4-OH H 2-OH 3 4-F H 2- OH 4 4-Cl H 2-OH 5 3-Cl 4-Cl 2-OH 6 4-CH ₃ H 2-OH 7 3-CH ₃ 4-CH ₃ 2-OH 8 4-CH ₃ OH 2-OH _{9 H H 2-OSO 3 H} 10 4-OH H 2-OSO 3 H 11 4-F H 2-OSO 3 H 12 4-Cl H 2-OSO 3 H 13 3-Cl 4-Cl 2-OSO 3 H _{14 4-CH 3 H 2-} OSO 3 H 15 3-CH 3 4-CH 3 2-OSO 3 H 16 4-CH 3 O H 2-OSO 3 H 17 H H 3-OH

[0021]

Table 13 18 4-OH H 3-OH 19 4-F H 3-OH 20 4-Cl H 3-OH 21 3-Cl 4-Cl 3-OH 22 4-CH ₃ H 3-OH 23 3- CH ₃ 4-CH ₃ 3-OH 24 4-CH ₃ OH 3-OH 25 H H 3-OSO ₃ H 26 4-OH H 3-OSO ₃ H 27 4-F H 3-OSO ₃ H 28 4- _{Cl H 3-OSO 3 H 29} 3-Cl 4-Cl 3-OSO 3 H 30 4-CH 3 H 3-OSO 3 H 31 3-CH 3 4-CH 3 3-OSO 3 H 32 4-CH 3 O _{H 3-OSO 3 H 33 H} H 4-OH 34 4-OH H 4-OH 35 4-F H 4-OH 36 4-Cl H 4-OH 37 3-Cl 4-Cl 4-OH 38 4-Br H 4-OH 39 4-I H 4-OH 40 4-NO ₂ H 4-OH 41 4-CN H 4-OH 42 4-CH 3 CO H 4-OH 43 4-CH 3 H 4-OH 44 3-CH 3 4-CH 3 4-OH

[0022]

Table 14 45 4-C ₂ H ₅ H 4-OH 46 4-CH ₃ OH 4-OH 47 3-CH ₃ O 4-CH ₃ O 4-OH 48 4-C ₂ H ₅ OH 4- _{OH 49 4-CH 3 OCO H} 4-OH 50 4-C 2 H 5 OCO H 4-OH 51 H H 4-OSO 3 H 52 4-OH H 4-OSO 3 H 53 4-F H 4-OSO 3 H 54 4-Cl H 4- OSO 3 H 55 3-Cl 4-Cl 4-OSO 3 H 56 4-Br H 4-OSO 3 H 57 4-I H 4-OSO 3 H 58 4-NO 2 H 4 _{-OSO 3 H 59 4-CN H} 4-OSO 3 H 60 4-CH 3 CO H 4-OSO 3 H 61 4-CH 3 H 4-OSO 3 H 62 3-CH 3 4-CH 3 4-OSO 3 _{H 63 4-C 2 H 5} H 4-OSO 3 H 64 4-CH 3 O H 4-OSO 3 H 65 3-CH ₃ O 4-CH ₃ O 4-OSO ₃ H 66 4-C ₂ H ₅ OH 4-OSO ₃ H 67 4-CH ₃ OCOH 4-OSO ₃ H 68 4-C ₂ H ₅ OCO H 4-OSO ₃ H ────────────────────────────────────

[0023]

[Table 15] Table-6 ──────────────────────────────────── Compound R ² X Z number ───────── ──────────────────────────── 1 H 4-OH 2-OH 2 4-OH 4-OH 2-OH 3 4-F 4-OH 2-OH 4 4-Cl 4-OH 2-OH 5 4-CH ₃ 4-OH 2-OH 6 4-CH ₃ O 4-OH 2-OH 7 H 4-Cl 2-OH 8 4- OH 4-Cl 2-OH 9 4-F 4-Cl 2-OH 10 4-Cl 4-Cl 2-OH 11 4-CH ₃ 4-Cl 2-OH 12 4-CH ₃ O 4-Cl 2-OH 13 H 4-CH ₃ 2-OH 14 4-OH 4-CH ₃ 2-OH 15 4-F 4-CH ₃ 2-OH 16 4-Cl 4-CH ₃ 2-OH 17 4-CH ₃ 4-CH ₃ 2-OH

[0024]

Table 16 18 4-CH ₃ O 4-CH ₃ 2-OH 19 H 4-OH 3-OH 20 4-OH 4-OH 3-OH 21 4-F 4-OH 3-OH 22 4-Cl 4 -OH 3-OH 23 4-CH ₃ 4-OH 3-OH 24 4-CH ₃ O 4-OH 3-OH 25 H 5-OH 3-OH 26 4-OH 5-OH 3-OH 27 4-F. 5-OH 3-OH 28 4-Cl 5-OH 3-OH 29 4-CH ₃ 5-OH 3-OH 30 4-CH ₃ O 5-OH 3-OH 31 H 4-Cl 3-OH 32 4- OH 4-Cl 3-OH 33 4-F 4-Cl 3-OH 34 4-Cl 4-Cl 3-OH 35 4-CH ₃ 4-Cl 3-OH 36 4-CH ₃ O 4-Cl 3-OH _{37 H 4-CH 3 3-} OH 38 4-OH 4-CH 3 3-OH 39 4-F 4-C _{3 3-OH 40 4-Cl} 4-CH 3 3-OH 41 4-CH 3 4-CH 3 3-OH 42 4-CH 3 O 4-CH 3 3-OH 43 H 3-Cl 4-OH 44 4 -OH 3-Cl 4-OH

[0025]

Table 17 45 4-F 3-Cl 4-OH 46 4-Cl 3-Cl 4-OH 47 4-CH ₃ 3-Cl 4-OH 48 4-CH ₃ O 3-Cl 4-OH 49 H 3 -CH ₃ 4-OH 50 4-OH 3-CH ₃ 4-OH 51 4-F 3-CH ₃ 4-OH 52 4-Cl 3-CH ₃ 4-OH 53 4-CH ₃ 3-CH ₃ 4- OH 54 4-CH ₃ O 3-CH ₃ 4-OH 55 H 4-Cl 2-OSO ₃ H 56 4-OH 4-Cl 2-OSO ₃ H 57 4-F 4-Cl 2-OSO ₃ H 58 4 _{-Cl 4-Cl 2-OSO 3} H 59 4-CH 3 4-Cl 2-OSO 3 H 60 4-CH 3 O 4-Cl 2-OSO 3 H 61 H 4-CH 3 2-OSO 3 H 62 4 -OH 4-CH ₃ 2-OSO ₃ H 63 4-F 4-CH ₃ 2-OSO ₃ H 64 4-Cl 4- CH ₃ 2-OSO ₃ H 65 4-CH ₃ 4-CH ₃ 2-OSO ₃ H 66 4-CH ₃ O 4-CH ₃ 2-OSO ₃ H 67 H 4-Cl 3-OSO ₃ H 68 4-OH _{4-Cl 3-OSO 3 H} 69 4-F 4-Cl 3-OSO 3 H 70 4-Cl 4-Cl 3-OSO 3 H 71 4-CH 3 4-Cl 3-OSO 3 H

[0026]

Table 18 72 4-CH ₃ O 4-Cl 3-OSO ₃ H 73 H 4-CH ₃ 3-OSO ₃ H 74 4-OH 4-CH ₃ 3-OSO ₃ H 75 4-F 4-CH ₃ 3-OSO ₃ H 76 4-Cl 4-CH ₃ 3-OSO ₃ H 77 4-CH ₃ 4-CH ₃ 3-OSO ₃ H 78 4-CH ₃ O 4-CH ₃ 3-OSO ₃ H 79 H 3 _{-Cl 4-OSO 3 H 80 4} -OH 3-Cl 4-OSO 3 H 81 4-F 3-Cl 4-OSO 3 H 82 4-Cl 3-Cl 4-OSO 3 H 83 4-CH 3 3- _{Cl 4-OSO 3 H 84 4} -CH 3 O 3-Cl 4-OSO 3 H 85 H 3-CH 3 4-OSO 3 H 86 4-OH 3-CH 3 4-OSO 3 H 87 4-F 3- CH ₃ 4-OSO ₃ H 88 4-Cl 3-CH ₃ 4-OSO ₃ H 89 4-CH ₃ 3-CH ₃ 4- OSO ₃ H 90 4-CH ₃ O 3-CH ₃ 4-OSO ₃ H ───────────────────────────────── ────

[0027]

[Table 19] Table-7 ──────────────────────────────────── Compound R ² X Y number ───────── ──────────────────────────── 1 H 2-OH 6-OH 2 4-OH 2-OH 6-OH 3 4-Cl 2-OH 6-OH 4 4-CH ₃ 2-OH 6-OH 5 4-CH ₃ O 2-OH 6-OH 6 H 3-OH 5-OH 7 4-OH 3-OH 5-OH 8 4- Cl 3-OH 5-OH 9 4-CH ₃ 3-OH 5-OH 10 4-CH ₃ O 3-OH 5-OH 11 H 2-Cl 6-Cl 12 4-OH 2-Cl 6-Cl 13 4 -Cl 2-Cl 6-Cl 14 4-CH 3 2-Cl 6-Cl 15 4-CH 3 O 2-Cl 6-Cl 16 H 3-Cl 5-Cl 17 4-OH 3-Cl 5-Cl

[0028]

Table 20 18 4-Cl 3-Cl 5-Cl 19 4-CH ₃ 3-Cl 5-Cl 20 4-CH ₃ O 3-Cl 5-Cl 21 H 2-CH ₃ 6-CH ₃ 22 4- OH 2-CH ₃ 6-CH ₃ 23 4-Cl 2-CH ₃ 6-CH ₃ 24 4-CH ₃ 2-CH ₃ 6-CH ₃ 25 4-CH ₃ O 2-CH ₃ 6-CH ₃ 26 H 3-CH ₃ 5-CH ₃ 27 4-OH 3-CH ₃ 5-CH ₃ 28 4-Cl 3-CH ₃ 5-CH ₃ 29 4-CH ₃ 3-CH ₃ 5-CH ₃ 30 4-CH ₃ O 3-CH ₃ 5-CH ₃ 31 H 3-C ₂ H ₅ 5-C ₂ H ₅ 32 4-Cl 3-C ₂ H ₅ 5-C ₂ H ₅ 33 4-CH ₃ 3-C ₂ H _{5 5-C 2 H 5 34 H} 3- (n-C 3 H 7) 5- (n-C 3 H 7) 35 4-Cl 3- (n-C 3 H 7) 5- (n-C 3 H ₇₎ 36 4-CH _{3 - (n-C 3 H 7} ) 5- (n-C 3 H 7) 37 H 3- (iso-C 3 H 7) 5- (iso-C 3 H 7) 38 4-Cl 3- (iso- _{C 3 H 7) 5- (iso} -C 3 H 7) 39 4-CH 3 3- (iso-C 3 H 7) 5- (iso-C 3 H 7) 40 H 3- (n-C 4 H _{9) 5- (n-C 4} H 9) 41 4-Cl 3- (n-C 4 H 9) 5- (n-C 4 H 9) 42 4-CH 3 3- (n-C 4 H 9 _{) 5- (n-C 4 H} 9) 43 H 3- (iso-C 4 H 9) 5- (iso-C 4 H 9) 44 4-Cl 3- (iso-C 4 H 9) 5- ( iso-C ₄ H ₉₎

[0029]

[Table 21] _{45 4-CH 3 3- (iso} -C 4 H 9) 5- (iso-C 4 H 9) 46 H 3- (sec-C 4 H 9) 5- (sec-C 4 H 9 ) 47 4-Cl 3- (sec-C ₄ H ₉ ) 5- (sec-C ₄ H ₉ ) 48 4-CH ₃ 3- (sec-C ₄ H ₉ ) 5- (sec-C ₄ H ₉ ). _{49 H 3- (tert-C 4} H 9) 5- (tert-C 4 H 9) 50 4-Cl 3- (tert-C 4 H 9) 5- (tert-C 4 H 9) 51 4-CH _{3 3- (tert-C 4 H} 9) 5- (tert-C 4 H 9) ───────────────────────────── ───────

[0030]

[Table 22] Table-8 ──────────────────────────────────── Compound R ² X Y number ───────── ──────────────────────────── 1 H 2-Cl 6-Cl 2 4-OH 2-Cl 6-Cl 3 4-Cl 2-Cl 6-Cl 4 4-CH ₃ 2-Cl 6-Cl 5 4-CH ₃ O 2-Cl 6-Cl 6 H 3-Cl 5-Cl 7 4-OH 3-Cl 5-Cl 8 4- Cl 3-Cl 5-Cl 9 4-CH ₃ 3-Cl 5-Cl 10 4-CH ₃ O 3-Cl 5-Cl 11 H 2-CH ₃ 6-CH ₃ 12 4-OH 2-CH ₃ 6- CH ₃ 13 4-Cl 2-CH ₃ 6-CH ₃ 14 4-CH ₃ 2-CH ₃ 6-CH ₃ 15 4-CH ₃ O 2-CH ₃ 6-CH ₃ 16 H 3-CH ₃ 5-CH ₃ 17 4-OH _{3-C 3} 5-CH ₃

[0031]

Table 23 18 4-Cl 3-CH ₃ 5-CH ₃ 19 4-CH ₃ 3-CH ₃ 5-CH ₃ 20 4-CH ₃ O 3-CH ₃ 5-CH ₃ 21 H 3-C ₂ H ₅ 5-C ₂ H ₅ 22 4-Cl 3-C ₂ H ₅ 5-C ₂ H ₅ 23 4-CH ₃ 3-C ₂ H ₅ 5-C ₂ H ₅ 24 H 3- (n-C ₃ H _{7) 5- (n-C 3} H 7) 25 4-Cl 3- (n-C 3 H 7) 5- (n-C 3 H 7) 26 4-CH 3 3- (n-C 3 H 7 _{) 5- (n-C 3 H} 7) 27 H 3- (iso-C 3 H 7) 5- (iso-C 3 H 7) 28 4-Cl 3- (iso-C 3 H 7) 5- ( _{iso-C 3 H 7) 29} 4-CH 3 3- (iso-C 3 H 7) 5- (iso-C 3 H 7) 30 H 3- (n-C 4 H 9) 5- (n-C ₄ H ₉ ) 31 4-Cl 3- (n-C ₄ H ₉ ) 5- (n-C ₄ H ₉ ) 32 4-CH ₃ 3- (n-C ₄ H ₉ ) 5- (n-C ₄ H ₉ ) 33 H 3- (iso-C ₄ H ₉ ) 5- (iso-C ₄ H ₉ ) 344 _{-Cl 3- (iso-C 4 H} 9) 5- (iso-C 4 H 9) 35 4-CH 3 3- (iso-C 4 H 9) 5- (iso-C 4 H 9) 36 H 3 _{- (sec-C 4 H 9} ) 5- (sec-C 4 H 9) 37 4-Cl 3- (sec-C 4 H 9) 5- (sec-C 4 H 9) 38 4-CH 3 3- _{(sec-C 4 H 9)} 5- (sec-C 4 H 9) 39 H 3- (tert-C 4 H 9) 5- (tert-C 4 H 9) 40 4-Cl 3- (tert-C ₄ H ₉ ) 5- (tert-C ₄ H ₉ ) 41 4-CH ₃ 3- (tert-C ₄ H ₉ ) 5- (tert-C ₄ H ₉ ) ─────────── ───────────── ─────────────

The salt of the compound of the general formula (1) may be any pharmaceutically acceptable salt, for example, inorganic salts such as lithium, sodium, potassium, calcium and aluminum, ammonia, trimethylamine, triethylamine, Examples thereof include salts with organic amines such as piperidine and morpholine, or amino acids.

Next, a typical method for producing the compound of the present invention is shown below. Among the compounds represented by the general formula (1), the compound in which Z is a hydroxyl group can be prepared by the method represented by the general formula (3) by any one of [Production Process 1] and [Production Process 2] as shown below. ) [Chemical 12]

[0034]

[Chemical 12] (In the formula, X and Y each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and R
¹ is an alkyl group or general formula (2)

[0035]

[Chemical 13] (In the formula, R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an acetyl group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group.) Is a group that is
R ⁴ represents a lower alkyl group. ) Can be produced by acid-hydrolyzing the compound represented by the formula (1), and for example by a method such as [Production Process 3]. [Manufacturing Process 1] General Formula (5) [Chemical Formula 14]

[0036]

[Chemical 14] (In the formula, X, Y, R ¹ and R ⁴ have the same meanings as described above.) The ketone represented by the general formula (6)

[0037]

[Chemical 15] (In the formula, R ⁵ is a lower alkyl group having 1 to 4 carbon atoms,
W ¹ represents a halogen atom or an ester residue of sulfuric acid or sulfonic acid. ) Or general formula (7)

[0038]

[Chemical 16] (In the formula, W ¹ has the same meaning as described above, and V represents an alkylene group having 2 to 4 carbon atoms.),
General formula (8) [Chemical formula 17]

[0039]

[Chemical 17] (In the formula, X, Y, R ¹ and R ⁴ are as defined above, and R ⁶ is
It represents a lower alkyl group having 1 to 4 carbon atoms or an alkylene group having 2 to 4 carbon atoms in which R ^{6 are} linked together. First, the compound represented by the formula (1) is prepared. Then, the compound of the general formula (3) can be produced by reacting this with phosphorus pentasulfide. The first stage reaction is usually carried out in a solvent such as benzene, toluene, xylene. The reaction temperature is -20 ° C to 100 ° C, and the reaction time is several hours to 24 hours. Examples of suitable bases used include metal alkoxides such as sodium hydride, sodium methoxide, sodium ethoxide, and sodium tert-amyloxide. The second step reaction is usually carried out at a temperature from room temperature to 200 ° C. using an organic solvent inert to phosphorus pentasulfide, such as a solvent such as benzene, toluene, xylene, pyridine or chlorobenzene. The reaction time is several tens of minutes to 12 hours. The phosphorus pentasulfide used in this reaction is about 1 to 5 times mol, preferably 1 to 3 times mol, of the ketone. The compound represented by the general formula (5) can be produced, for example, by reacting an acid chloride with a Grignard reagent. [Manufacturing Process 2] General Formula (9) [Chemical Formula 18]

[0040]

[Chemical 18] (In the formula, X, Y, R ¹ and R ⁴ have the same meanings as described above, and R ⁷ represents a lower alkyl group having 1 to 4 carbon atoms.) Phosphorus sulfide or Lawesson's reagent (ie 2,4-bis (4
The compound of the general formula (3) can be produced by cyclizing with -methoxyphenyl) -1,3-dithia-2,4-diphosphethane-2,4-disulfide). The thionation agent used in this reaction is about 1 to 5 times mol, preferably 1 to 3 times mol, of 3-oxoester. Note that phosphorus pentasulfide and Lawesson's reagent may be simultaneously used in any ratio, and powdered sulfur may be added to the reaction mixture. The powdered sulfur used is about 0.5 to 5 times the molar amount of 3-oxoester. As the solvent used in the reaction, an organic solvent which is inert to the thionating agent, for example, a solvent such as benzene, toluene, xylene, pyridine or chlorobenzene is used, and the temperature is from room temperature to 20.
It is carried out at a temperature of 0 ° C. The reaction time is from tens of minutes to 12
The 3-oxoester of general formula (9) is
[Chemical 19]

[0041]

[Chemical 19] (In the formula, R ¹ and R ⁷ are as defined above.)
Oxo ester and general formula (11)

[0042]

[Chemical 20] (Wherein X, Y and R ⁴ have the same meanings as described above, W ² represents a halogen atom, or an ester residue of sulfuric acid or sulfonic acid) in the presence of a suitable base. Can be manufactured. The reaction is carried out in an ether such as acetone or diethyl ether, or a solvent such as benzene, toluene, xylene, dimethylformamide or dimethylsulfoxide. The reaction temperature is from -10 ° C to the boiling point of the solvent, and the reaction time is from several hours to 48 hours. Suitable bases to be used include sodium hydride, metal alcoholates such as sodium methoxide and sodium ethoxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal iodides such as sodium iodide and potassium iodide. Can be mentioned.

The 3-oxoester represented by the general formula (10) is described in, for example, J. Org. Chem. , 43, 20
87 (1978) and J. Chem. Soc. , 24
07 (1963), ordinary conditions of Claisen condensation, and the like.

[Production Step 3] As a reagent used for acid hydrolysis of the compound represented by the general formula (3), hydrogen bromide, hydrogen iodide, red phosphorus, trifluoroacetic acid, hydrochloric acid, pyridine hydrochloride, pyridine odor Examples thereof include hydrohalides, boron trichloride, boron tribromide, boron triiodide, aluminum chloride, aluminum bromide, magnesium iodide etherate, lithium iodide and the like. The reaction is carried out without a solvent or in a solvent such as water, acetic anhydride, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, pyridine, collidine, and dimethylformamide at a temperature of -10 ° C to 250 ° C for a reaction time of several tens. It is carried out from 10 minutes to 10 hours. Among the compounds represented by the general formula (1), the compound in which Z is a hydroxysulfonyloxy group can be prepared by, for example, a method such as [Production process 3].
1]

[0045]

[Chemical 21] (In the formula, X, Y and R ¹ have the same meanings as described above.) The compound can be produced by producing the compound and subjecting it to a sulfuric acid esterification by a method such as [Production Process 4].

[Production Step 4] Examples of the reagent used for the sulfuric acid esterification of the compound represented by the general formula (4) include sulfur trioxide and sulfur trioxide complex. The sulfur trioxide complex is a complex with a Lewis acid such as ether, amine or sulfide, and is N, N-dimethylformamide / sulfur trioxide complex, dioxane / sulfur trioxide complex, pyridine / sulfur trioxide complex, triethylamine / trioxide. Examples thereof include sulfur complexes and trimethylamine / sulfur trioxide complexes. The reaction is preferably carried out in the presence of a base such as a tertiary amine, an alkali metal, an alkaline earth metal or an organic acid salt thereof, but a base is required when using a tertiary amine-sulfur trioxide complex. Not. The amount of sulfur trioxide or sulfur trioxide complex used for the compound represented by the general formula (4) is 1.5 to 5 molar equivalents, preferably 2.0 to 3.5 molar equivalents. When a base is used, it is used in an amount of 1.5 to 5 molar equivalents, preferably 2.0 to 3.5 molar equivalents, based on the compound represented by the general formula (4). As the solvent, benzene, toluene, xylene, n-butyl alcohol, iso-butyl alcohol, tert-
Examples thereof include butyl alcohol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and 1,3-dimethyl-2-imidazolidinone. The reaction temperature is in the range of 0 ° C. to the boiling point of the solvent, and the reaction time is several minutes to 10 hours.

The compound of the general formula (1) of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization or column chromatography. Also,
The compound represented by the general formula (1) of the present invention includes metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and aluminum hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, trimethylamine, It can be produced as a salt by a conventional treatment with organic amines such as triethylamine, piperidine and morpholine, ammonium hydroxide, ammonia or an ion exchange resin.

The compound represented by the general formula (1) or a salt thereof of the present invention can be used as a tablet, granule, powder or suspension by using a commonly used pharmaceutical carrier, excipient or other additive. ,
It can be administered as an oral administration agent such as a capsule or a syrup, or a parenteral administration agent such as an injection, a suppository, an isotonic solution for infusion, or the like. For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid or the like is used as the adsorbent, and corn starch, lactose, calcium phosphate, magnesium stearate or the like is used as the excipient. In addition, when preparing an injection, if necessary, a pH adjusting agent, a buffer,
A stabilizer, a preservative, a solubilizer, etc. are added, and the preparation is administered. The dose is appropriately adjusted depending on the administration route, the weight of the patient, the age, the symptoms and the like. For example, in patients with myocardial infarction, immediately after emergency hospitalization, before surgery for recanalization of the blocked coronary artery,
It is preferable to continuously infuse intravenously during the operation and for several hours after the operation, and to combine frequent single administrations depending on the urgency. Single dose is 0.1 to 50 per adult
0 mg, continuous administration is administered at a rate of 0.1 to 100 mg per minute.

[0049]

EXAMPLES The production examples and evaluation examples of the present invention are described below, but the present invention is not limited thereto. Production Example 1 4- (4-hydroxybenzyl) -5-methyl-1,2
-Production of dithiol-3-thione (Compound No. 1 in Table-1) (1) Synthesis of 1,1-bis (methylthio) -2- (4-methoxybenzyl) -1-buten-3-one tert 4.27 g of carbon disulfide and 4- (4-methoxyphenyl) in a solution of sodium tert-amyloxide in benzene (60 ml) prepared from 9.90 g amyl alcohol and 4.49 g sodium hydride (about 60% oily). ) -2-butanone 10.00 g of the mixture,
The temperature was lowered at 10 ° C for 1.2 hours. After stirring at room temperature for 5 hours, the reaction mixture was kept at 0 to 5 ° C., and 16.24 g of methyl iodide was appropriately added over 1 hour. After stirring at room temperature for 2.5 hours, 100 ml of water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the concentrated residue was purified by column to obtain 11.37 g of the desired product. 1H NMR (CDCl ₃ , δ) 2.14 (3H, s) 2.32 (3H,
s) 2.36 (3H, s) 3.78 (3H,
s) 3.90 (2H, s) 6.82 (2H,
d) 7.07 (2H, d) (2) 4- (4-methoxybenzyl) -5-methyl-
Synthesis of 1,2-dithiol-3-thione Heat-refluxed phosphorus pentasulfide 8.06 g of o-xylene (8
0 ml) suspension, 1,1-bis (methylthio) -2
A solution of 4.37 g of-(4-methoxybenzyl) -1-buten-3-one in o-xylene (12 ml) was added dropwise. After refluxing for 15 minutes and cooling to room temperature, 50 ml of diethyl ether was added. The insoluble matter was removed by vacuum filtration, and the filtrate was washed with water, a 1% aqueous sodium hydroxide solution, and saturated brine in this order. The organic layer is dried over anhydrous magnesium sulfate,
The concentrated residue was column purified to obtain 3.17 g of the desired product. 1H NMR (CDCl ₃ , δ) 2.45 (3H, s) 3.77 (3H,
s) 4.04 (2H, s) 6.80 (2H, s)
d) 7.12 (2H, d) (3) 4- (4-hydroxybenzyl) -5-methyl-
Synthesis of 1,2-dithiol-3-thione In 5.00 g of pyridine hydrochloride melted at 200 ° C., 4
-(4-Methoxybenzyl) -5-methyl-1,2-dithiol-3-thione (1.00 g) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ether. Then, the organic layer was washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The organic layer was concentrated to dryness to obtain 0.64 g of the desired product. 1H NMR (CDCl ₃ , δ) 2.48 (3H, s) 3.97 (2H,
s) 6.69 (2H, d) 6.99 (2H,
d)

Production Example 2 5-hexyl-4- (4-hydroxybenzyl) -1,
Production of 2-dithiol-3-thione (Compound No. 14 in Table-1) (1) Synthesis of ethyl 3-oxononanoate Org. Chem. , 43, 2087
It was synthesized by the method described in (1978). Meldrum's acid 2
To a solution of 2.49 g of methylene chloride (25 ml), 25.00 g of enanthate chloride was added dropwise at 0 ° C over 5 minutes, and 24.19 g of pyridine was added dropwise over 30 minutes. After stirring at the same temperature for 1 hour and at room temperature for 2 hours, the reaction mixture was washed with 0.5N hydrochloric acid and water in this order. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness, and the solid obtained was dissolved in ethanol 350.
Dissolved in ml. After refluxing this ethanol solution for 3 hours, the concentrated residue of the reaction mixture was purified by column to obtain the target compound 2
1.44 g was obtained. 1H NMR (CDCl ₃ , δ) 0.88 (3H, t) 1.24-1.36
(9H, m) 1.56-1.68 (2H, m) 2.53 (2H,
t) 3.43 (2H, s) 4.20 (2H,
q) (2) Synthesis of ethyl 2- (4-methoxybenzyl) -3-oxononanoate Sodium hydride (about 60%, oily) 4.00 g DM
A solution of 18.02 g of ethyl 3-oxononanoate in DMF (50 ml) was added dropwise to the F (200 ml) suspension under ice cooling. After stirring at room temperature for 40 minutes, a solution of 4-methoxybenzyl chloride (14.09 g) in DMF (20 ml) was added dropwise at the same temperature. After stirring at 80 ° C. for 6 hours, DMF was distilled off and the residue was dissolved in chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and the concentrated residue was column purified to obtain 12.12 g of the desired product. 1H NMR (CDCl ₃ , δ) 0.86 (3H, t) 1.12-1.28
(11H, m) 2.19 (1H, t) 3.14 (2H,
t) 3.75 (2H, d) 3.77 (3H,
s) 4.13 (2H, q) 6.78 (2H,
d) 7.02 (2H, d) (3) 5-hexyl-4- (4-methoxybenzyl)-
Synthesis of 1,2-dithiol-3-thione 12.60 g of refluxed phosphorus pentasulfide, pyridine (20 m
l) In suspension, 2- (4-methoxybenzyl) -3-
Ethyl oxononanoate 12.12 g of pyridine (10 m
l) The solution was added dropwise. After stirring at the same temperature for 2 hours, the reaction mixture was returned to room temperature and poured into water. After extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the concentrated residue was purified by column to obtain 2.65 g of the desired product. 1H NMR (CDCl ₃ , δ) 0.87 (3H, t) 1.21-1.36
(6H, m) 1.57-1.64 (2H, m) 2.79 (2H,
t) 3.77 (3H, s) 4.06 (2H,
s) 6.79 (2H, d) 7.10 (2H,
d) (4) 5-hexyl-4- (4-hydroxybenzyl)
Synthesis of -1,2-dithiol-3-thione In 30.00 g of pyridine hydrochloride melted at 200 ° C,
5-hexyl-4- (4-methoxybenzyl) -1,2
-4.50 g of dithiol-3-thione was added, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with chloroform. Subsequently, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue of the organic layer was purified by column and then recrystallized (hexane / ethyl acetate) to obtain 3.50 g of the desired product. 1H NMR (CDCl ₃ , δ) 0.88 (3H, t) 1.29 (6H,
m) 1.61 (2H, m) 2.78 (2H,
t) 4.05 (2H, s) 4.74 (1H,
s) 6.72 (2H, d) 7.05 (2H,
d)

Production Example 3 4- (4-hydroxybenzyl) -5-phenyl-1,
Preparation of 2-Dithiol-3-thione (Compound No. 33 in Table-5) (1) Synthesis of ethyl 2- (4-methoxybenzyl) benzoylacetate 2.00 g of sodium hydride (about 60%, oily) DM
To the F (50 ml) solution, under ice-cooling, 10.00 g of ethyl benzoyl acetate and 7 m of 4-methoxybenzyl chloride were added.
1 was added. After stirring at room temperature for 3 hours, the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the concentrated residue was column purified to obtain 14.00 g of the desired product. 1H NMR (CDCl ₃ , δ) 1.12 (3H, t) 3.25-3.28
(2H, m) 3.75 (3H, s) 4.06-4.13
(2H, m) 4.58 (1H, t) 6.79 (2H,
d) 7.14 (2H, d) 7.42-7.46
(2H, m) 7.54-7.57 (1H, m) 7.94-7.96
(2H, m) (2) 4- (4-methoxybenzyl) -5-phenyl-
Synthesis of 1,2-dithiole-3-thione 14.00 g of refluxing phosphorus pentasulfide, pyridine (200 m
l) Into the suspension, 14.00 g of ethyl 2- (4-methoxybenzyl) benzoyl acetate was added dropwise. After stirring at the same temperature for 6 hours, the reaction mixture was pre-purified by a column. Next, the obtained oily substance was dissolved in ethyl acetate and washed with 2N hydrochloric acid and water. The organic layer is dried over anhydrous magnesium sulfate, and the concentrated residue is subjected to column purification to obtain 6.20 g of the desired product.
Got 1H NMR (CDCl ₃ , δ) 3.75 (3H, s) 4.00 (2H,
s) 6.72 (2H, d) 6.91 (2H,
d) 7.34-7.37 (2H, m) 7.43-7.53.
(3H, m) (3) Synthesis of 4- (4-hydroxybenzyl) -5-phenyl-1,2-dithiol-3-thione 4 in 7.00 g of pyridine hydrochloride melted at 200 ° C.
-(4-Methoxybenzyl) -5-phenyl-1,2-
Dithiol-3-thione (2.00 g) was added, and the mixture was added at the same temperature to
Stir for hours. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with chloroform. Subsequently, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue of the organic layer was purified by column to obtain 1.70 g of the desired product. 1H NMR (DMSO-d ₆ , δ) 3.93 (2H, s) 6.62 (2H,
d) 6.77 (2H, d) 7.42 (2H,
m) 7.51 (3H, m) 8.82 (1H,
s)

Production Example 4 4- (4-hydroxysulfonyloxybenzyl) -5
-Phenyl-1,2-dithiol-3-thione Preparation of trimethylammonium (trimethylammonium salt of compound No. 51 of Table-5) 4- (4-hydroxybenzyl) -5-phenyl-1,
DMF (5 ml) of 2-dithiol-3-thione (790 mg) and sulfur trioxide trimethylamine complex salt (500 mg)
The solution was stirred at 60 ° C. for 4 hours. After the reaction was completed, the residue obtained by concentrating the reaction mixture was sludged with ethanol-ether to obtain 760 mg of the desired product. 1H NMR (DMSO-d ₆ , δ) 2.84 (9H, s) 3.97 (2H,
s) 6.86 (2H, d) 7.07 (2H,
d) 7.44 (2H, m) 7.53 (3H,
m)

Evaluation Example 1 Lipid Peroxide Production Inhibitory Action Method: Male SD rats (7 to 10 weeks old) were exsanguinated under pentobarbital anesthesia and the brain was removed. Brain tissue was homogenized with phosphate buffer under ice-cooling, 5% homogenate was incubated at 37 ° C for 60 minutes, and the amount of malondialdehyde (MDA) produced was determined by measuring the absorbance at 535 nm by the thiobarbituric acid method. It was measured. From the amount of MDA (a) and the control value (b) (the amount of MDA when the test drug was not added), the lipid peroxide production inhibitory rate was calculated by the following formula. Lipid peroxide production inhibition rate (%) = 100 × (b−a) / b The test compound was added before incubation. Results: Table 9 [Table 24] shows the inhibitory effect on lipid peroxide production in rat brain homogenates. Table-9
All of these compounds inhibited the production of lipid peroxide with a high inhibition rate.

[0054]

[Table 24] Table-9 Inhibitory effect on lipid peroxide production in rat brain homogenate ───────────────────── Number of production example Inhibition rate (%) ── ─────────────────── 1 100 4 100 ────────────────────── The concentration of each compound is 10 ^-4 M, the number of experiments is n = 2

Evaluation Example 2 Reperfusion-induced arrhythmia inhibitory method Method: Male SD rats (8-12 weeks old) were anesthetized with pentobarbital, and thoracotomy was performed under artificial respiration. The left anterior descending coronary artery was ligated for 5 minutes and reperfused for 10 minutes. Standard limb II lead electrocardiograms were recorded to investigate the occurrence of ventricular arrhythmias. The test compound was intravenously administered 5 minutes before the coronary artery occlusion. In addition, Arznemittel-Forsc
Formula (12) described in h, 13, 2, 130 (1963).
[Chemical formula 22]

[0056]

[Chemical formula 22] 5- (4-hydroxyphenyl) -1,2-represented by
Dithiol-3-thione and formula (13)

[0057]

[Chemical formula 23] The same evaluation was performed for the trimethylammonium salt of 5- (4-hydroxysulfonyloxyphenyl) -1,2-dithiol-3-thione represented by Results: After ligating the left anterior descending coronary artery for 5 minutes and performing reperfusion, ventricular extrasystole, arrhythmia such as tachycardia (VT) and fibrillation (VF) occur. Table 10 [Table 25] shows the incidence and mortality of ventricular fibrillation in the control group and the test compound administration group. The compound of formula (12) and the compound of formula (13) are
It did not reduce the incidence of ventricular fibrillation and did not reduce mortality. On the other hand, the compound of Production Example No. 1 suppressed the incidence of ventricular fibrillation and decreased the mortality rate.

[0058]

[Table 25] Table-10 Rat coronary artery occlusion-effects on ventricular arrhythmia during reperfusion ─────────────────────────────── ───── Production dose Ventricular fibrillation incidence rate Mortality number (mg / kg) Ventricular fibrillation Mortality / Experimental cases (%) Occurrence population / Experimental cases (%) ───── ────────────────────────────── Control group 63/93 (67.7) 57/93 (61.3) 11 0.0 2/6 (33.3) 2/6 (33.3) Compound of formula (12) 3.0 2/2 (100.0) 2/2 (100.0) Compound of formula (13) 1 0.0 4/6 (66.7) 4/6 (66.7) ───────────────────────────────── ───

Evaluation Example 3 Inhibitory action of deviation of enzyme in myocardial cells after ischemia reperfusion Method: Male SD rats (7 to 12 weeks old) were anesthetized with pentobarbital, and thoracotomy was performed under artificial respiration. The left anterior descending coronary artery was ligated for 20 minutes and reperfused for 2 hours. At the end of the experiment, the heart was removed and the left ventricle was separated. The left ventricle was homogenized and the activity of creatine phosphokinase remaining in the ventricle was measured. The test compound was intravenously administered 5 minutes before the coronary artery occlusion. Table-11 [Table 26] shows the difference in the creatine phosphokinase (CPK) activity remaining in the non-ischemic region and the ischemia-reperfusion region in the left ventricle. Results: The compound of Production Example No. 1 suppressed the escape of creatine phosphokinase from cardiomyocytes due to ischemia-reperfusion and decreased the mortality rate.

[0060]

[Table 26] Table-11 ──────────────────────────────────── Manufacturing Example Dose CPK activity ( U / mg protein) Mortality number (mg / kg) Non-ischemic region-Ischemic reperfusion region (%) ──────────────────────── ───────────── Control group 1.33 ± 0.16 (n = 45) 53.1 1 1.0 0.45 ± 0.26 (n = 7) 41.7 ─ ─────────────────────────────────── The values in the table represent mean ± standard error. n indicates the number of experimental examples.

[0061]

INDUSTRIAL APPLICABILITY Since the compound represented by the general formula (1) of the present invention or a salt thereof has an inhibitory action on lipid peroxide production, it is useful as a therapeutic agent or prophylactic agent for diseases associated with lipid peroxide. is there.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/385 ABX 9454-4C ACD 9454-4C ACJ 9454-4C ACS 9454-4C ACV 9454-4C ADA 9454-4C ADN 9454-4C (72) Inventor Akihito Kanematsu 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor, Kazuya Sakakui, 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical (72) Inventor Mitsuhiro Mori 1900-1 Togo, Mobara, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Tatsuro Sugawara 1900 1900 Togo, Mobara City, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Shu Yuasa 1 Mitsui Toatsu Chemical Co., Ltd., 1900, Togo, Mobara-shi, Chiba Prefecture (72) Inventor Koichi Kawai 1 1900 Togo, Morihara-shi, Mobara City, Chiba Prefecture

Claims (7)

[Claims] 1. General formula (1) [Chemical formula 1] (In the formula, X and Y each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and Z
Represents a hydroxyl group or a hydroxysulfonyloxy group, R ¹ represents an alkyl group or the general formula (2) [Chemical Formula 2] (In the formula, R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an acetyl group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group.) Is a group that is ) Or a salt thereof. 2. In the general formula (1), Z is hydroxy.
R group and R ¹Is an alkyl group.
Or a salt thereof. 3. In the general formula (1), Z is hydroxy.
R group and R ¹Is represented by the general formula (2) [Chemical Formula 3](In the formula, R², R³Is the same as above. Group represented by
The compound or salt thereof according to claim 1, which is 4. The compound according to claim 1, wherein Z is a hydroxysulfonyloxy group in the general formula (1), or a salt thereof. 5. General formula (3) [Chemical formula 4] (In the formula, X and Y each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and R
⁴ represents a lower alkyl group, R ¹ represents an alkyl group or a compound represented by the general formula (2) [Chemical Formula 5] (In the formula, R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an acetyl group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group.) Is a group that is ) The compound represented by the formula (1) is acid-hydrolyzed. (In the formula, X, Y and R ¹ are the same as above. Z is a hydroxyl group.). 6. General formula (4) [Chemical formula 7] (In the formula, X and Y each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and R
¹ is an alkyl group or general formula (2) [Chemical Formula 8] (In the formula, R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an acetyl group, a lower alkyl group, a lower alkoxy group or a lower alkoxycarbonyl group.) Is a group that is ) Is treated with sulfur trioxide or a sulfur trioxide complex, the compound represented by the general formula (1) [Chemical Formula 9] (In the formula, X, Y and R ¹ are the same as described above. Z is a hydroxysulfonyloxy group.). 7. A therapeutic agent and a preventive agent for a disease associated with lipid peroxide, which comprises, as an active ingredient, a compound selected from the compounds according to claims 1 to 4 or salts thereof.