JPH0931062A - Benzimidazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzimidazole compound expressed by a specific formula, having action suppressing foaming of macrophage and useful as an active ingredient for medicines used for preventing and/or treating arteriosclerosis. SOLUTION: This compound is expressed by formula I [Y is a single bond or S; Z is O, S or N-R<4> ; R<1> and R<2> are each H, a halogen, an alkyl, an aryl, an alkoxy, an aryloxy, an alkoxycarbonyl, etc.; R<3> and R<4> are each H, an alkyl, an acyl, sulfonyl, an alkoxycarbonyl, etc.; (n) and (m) are each 1-3; L is a 2-12C alkylene or a coupling group, containing one or two or more phenylene groups or ether groups and selected from an alkylene in which number of atoms constituting a bonding chain length is 4-12], e.g. 1-(2'-(5'-methylbenzimidazoylthio)-5-(2''- benzimidazoylthio)pentane. Furthermore, the compound is preferably obtained by using 2-mercaptobenzimidazole compound of formula II as a raw material compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzimidazole compound. More specifically, the present invention is a novel bis-type benzimidazole useful as an active ingredient of a drug used for treating or preventing hyperlipidemia or arteriosclerosis, an additive of a silver halide light-sensitive material, or a constituent of liquid crystal. It relates to compounds.

[0002]

2. Description of the Related Art With the increase in life expectancy in recent years, so-called adult diseases such as arteriosclerosis, hypertension and diabetes continue to increase. In particular, high-calorie and high-cholesterol diets are increasing, and hyperlipidemia and arteriosclerosis resulting therefrom are rapidly increasing, which is becoming a major social problem. Currently, the drugs used for drug therapy of hyperlipidemia and arteriosclerosis are symptomatically reducing blood cholesterol, and are not drugs that can be expected to degenerate the arteriosclerotic lesion itself. Arteriosclerosis is a lesion characterized by intimal thickening of blood vessels and lipid accumulation, and recent biochemical findings reveal that macrophage foaming plays a central role in the formation of atherosclerotic plaques. Has been done.
Therefore, by suppressing the macrophage foaming, the formation of atherosclerotic plaque is inhibited to prevent arteriosclerosis,
Alternatively, there is a possibility that arteriosclerotic lesions can be degenerated by curtailing arteriosclerotic lesions, but no drug having such an action has been heretofore known.

[0003]

An object of the present invention is to provide a compound which has an effect of suppressing foam formation of macrophages and is useful as an active ingredient of a drug used for the prevention and / or treatment of arteriosclerosis. It is in. Another object of the present invention is to provide a compound having the above-mentioned action and useful as an active ingredient of a prophylactic and / or therapeutic agent for hyperlipidemia.

[0004]

The inventors of the present invention have made diligent efforts to solve the above problems, and as a result, a novel benzimidazole compound represented by the following formula has an action of suppressing foam formation of macrophages. , It was found to be useful as an active ingredient of a prophylactic / therapeutic agent for arteriosclerosis and a prophylactic / therapeutic agent for hyperlipidemia. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula (I):

Embedded image (In the formula, Y represents a single bond or a sulfur atom; Z represents an oxygen atom, a sulfur atom, or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group. , Aryl group, alkoxy group, aryloxy group, alkoxycarbonyl group, carbamoyl group, sulfamoyl group, acylamino group, sulfonylamino group,
Represents a cyano group, a hydroxy group, or a nitro group; R ³ and
R ⁴ is independently a hydrogen atom, an alkyl group, an acyl group,
A sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group; n and m each independently represent an integer of 1, 2 or 3, and n or m is 2 or 3
, Respectively, two or three identical or different
Indicates that R ¹ or R ² is substituted on the benzene ring; L
Represents a alkylene group having 2 to 12 carbon atoms, or a linking group selected from alkylene groups having 1 to 2 or more phenylene groups or ether groups and having a linking chain length of 4 to 12 atoms; Is a sulfur atom, Z is NR ⁴ , n = m, and when R ³ and R ⁴ represent the same substituent, R ¹ and R ² represent the same substituent. ) Are provided). Furthermore, according to another aspect of the present invention, a hyperlipidemia-preventing / treating agent containing the above compound as an active ingredient, and an arteriosclerosis-preventing / treating agent; macrophage foaming inhibitor; arteriosclerotic lesion degeneration agent; arteriosclerosis Nest formation inhibitors; and cholesterol lowering agents are provided.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the above formula, Y represents a single bond or a sulfur atom. When Y represents a single bond, the carbon atom sandwiched by the two nitrogen atoms of the imidazole ring substituted by R ³ (the 2-position carbon of the benzimidazole ring) is directly bonded to the linking group L. Of these, Y is preferably a sulfur atom. Z represents an oxygen atom, a sulfur atom, or NR ^4, and the hetero-condensed ring containing Z is a benzoxazole, benzthiazole, or benzimidazole ring.

R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group,
Represents an aryloxy group, an alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylamino group, a sulfonylamino group, a cyano group, a hydroxy group, or a nitro group, and n and m each independently represent an integer of 1, 2, or 3 . R ¹ and R ² are independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acylamino group, a sulfonylamino group, or an alkoxycarbonyl group, preferably a hydrogen atom, a chlorine atom, a C _1-4 alkyl group, Particularly preferably, it is a C _1-4 alkoxy group. When Z is NR ^4, it is preferable that ^one of R ¹ and R ² is a hydrogen atom.

When n is 1, it means that one R ¹ is substituted at any position on the benzene ring, and when n is 2 or 3, it is 2 or 3 Rs, respectively. Indicates that ¹ is an arbitrary substitution on the benzene ring. When n is 2 or 3, a plurality of R ^1's may be the same or different. Similarly, when m is 1, it means that one R ² is substituted at any position on the benzene ring, and when n is 2 or 3, it is 2 or 3 R respectively. Indicates that ¹ is an arbitrary substitution on the benzene ring. When n is 2 or 3, a plurality of R ² may be the same or different. R ¹ and R ²
Are preferably substituted at the 5-position and / or the 6-position of the hetero-condensed ring containing the benzimidazole ring and Z, respectively.

Each substituent represented by R ¹ and R ² will be specifically described. As the halogen atom, any of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be used, preferably a fluorine atom or a chlorine atom. Atom, or bromine atom,
Particularly preferably, a chlorine atom can be used. The alkyl group may be a linear, branched or cyclic C _1-18 (carbon number 1
~ 18) alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert- butyl group, cyclopropyl group, cyclohexyl group, An n-octyl group, an n-dodecyl group, an n-octadecyl group, or the like can be used.
A linear, branched or cyclic C _1-8 alkyl group, more preferably a linear or branched C _1-4 alkyl group, particularly preferably a methyl group can be used.

As the halogenated alkyl group, 1 or 2
The above linear or branched or cyclic C _1-18 alkyl group substituted by the same or different halogen atoms, more preferably linear, branched or cyclic C _1-8 alkyl group, and more preferably direct. Chained or branched C _1-4 alkyl groups can be used. As the halogen atom, for example, a fluorine atom or a chlorine atom, more preferably a fluorine atom can be used. For example, a monochloromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group or the like can be used, and a trifluoromethyl group is particularly preferably used.

The aryl group may be substituted or unsubstituted.
C _6-14 aryl group (for example, a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, etc.), preferably a substituted or unsubstituted phenyl group, more preferably an unsubstituted phenyl group. Can be used. Examples of the substituent of the aryl group include the above-mentioned alkyl group, halogenated alkyl group, halogen atom, hydroxy group and the following alkoxy group.
The aryloxy group is 1 on the ring of the above aryl group.
A C _6-14 aryloxy group formed by substituting one hydrogen atom with an oxygen atom can be used, and for example, a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group or the like can be used. .

As the alkoxy group, a linear, branched or cyclic C _1-18 alkoxy group can be used.
Methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, cyclohexoxy group, n-octyloxy group, n-dodecyloxy group, or n-octadecyl group An oxy group or the like can be used. Preferably, a linear, branched or cyclic C _1-8 alkoxy group, more preferably a linear or branched chain
A C _1-4 alkoxy group can be used, particularly preferably a methoxy group or an ethoxy group. The alkoxycarbonyl group, the linear, branched or cyclic C _1-18 alkoxy group, preferably a linear, branched or cyclic C _1-8 alkoxy group, more preferably a linear or branched C _1-4 A carbonyl group substituted with an alkoxy group can be used. For example, a methoxycarbonyl group, an ethoxycarbonyl group,
n-butoxycarbonyl, tert-butoxycarbonyl group,
An n-octyloxycarbonyl, n-dodecyloxycarbonyl, n-octadecyloxycarbonyl group or the like can be used, and preferably a methoxycarbonyl group or an ethoxycarbonyl group can be used.

As the carbamoyl group, a substituted or unsubstituted carbamoyl group can be used, and as the substituted carbamoyl group, a mono- or di-substituted carbamoyl group can be used. As the 1 or 2 substituents substituting the carbamoyl group, for example, the above C _1-18 alkyl group or the above C _6-14 aryl group can be used.
Alternatively, the total carbon number of the two substituents is, for example, 18 or less, preferably 12 or less, more preferably 6 or less. As the substituted carbamoyl group, for example, a methylcarbamoyl group, a diethylcarbamoyl group, an n-octylcarbamoyl group, an n-hexadecylcarbamoyl group, a phenylcarbamoyl group, or preferably a methylcarbamoyl group can be used.

A substituted or unsubstituted sulfamoyl group can be used as the sulfamoyl group, and a mono- or di-substituted sulfamoyl group can be used as the substituted sulfamoyl group. Substitution with sulfamoyl group 1
Or, as the two substituents, for example, the above C _1-18 alkyl group or the above C _6-14 aryl group can be used,
The total carbon number of these 1 or 2 substituents is, for example,
18 or less, preferably 12 or less, more preferably 6 or less. The substituted sulfamoyl group, for example, methylsulfamoyl group, diethylsulfamoyl group, n-octylsulfamoyl group, n-hexadecylsulfamoyl group, phenylsulfamoyl group, preferably a methylsulfamoyl group Etc. can be used.

[0015] The acyl group constituting the acylamino group, the above-mentioned C _1-18 alkylcarbonyl group in which the alkyl group is a carbonyl group substituted, halogenated alkylcarbonyl halide C _1-18 alkyl group as described above which has been substituted ,
Alternatively, it is possible to use an arylcarbonyl group or the like in which the above C _6-14 aryl group is substituted, and the number of carbon atoms of these alkyl group, halogenated alkyl group, or aryl group substituted with a carbonyl group is preferably 12 or less. , And more preferably 6 or less. As the acylamino group, for example, acetylamino group, trifluoroacetylamino group, propionylamino group, n-butanoylamino group, n-octanoylamino group, n-hexadecanoylamino group, or benzoylamino group, preferably acetyl An amino group or a propionylamino group can be used, particularly preferably a propionylamino group.

The sulfonyl group constituting the sulfonylamino group includes an alkylsulfonyl group which is a sulfonyl group substituted by the above C _1-18 alkyl group, and the above halogenated group.
A halogenated alkylsulfonyl group substituted with a C _1-18 alkyl group, or an arylsulfonyl group substituted with the above C _6-14 aryl group can be used, and these alkyl groups substituted with a sulfonyl group, halogenated The number of carbon atoms of the alkyl group or the aryl group is preferably 12 or less, more preferably 6 or less. Examples of the sulfonylamino group include a methanesulfonylamino group, a trifluoromethanesulfonylamino group, an ethanesulfonylamino group, an n-butanesulfonylamino group, an n-octanesulfonylamino group, an n-hexadecanesulfonylamino group, a benzenesulfonylamino group, Alternatively, a p-toluenesulfonylamino group, preferably a methanesulfonylamino group can be used.

R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, an acyl group, a sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group or a carbamoyl group.
The alkyl group represented by R ³ and R ⁴ is the above C _1-18 alkyl group, preferably a linear or branched chain of these, more preferably a linear or branched C _1-8 alkyl group,
Particularly preferably, a linear or branched C _1-4 alkyl group, and most preferably a methyl group can be used. The acyl group represented by R ³ and R ^4, the alkyl group C _1-18 alkyl group described above is a carbonyl group substituted, halogenated alkylcarbonyl halide C _1-18 alkyl group as described above is substituted, Alternatively, an arylcarbonyl group substituted with the above C _6-14 aryl group can be used.

Examples of the sulfonyl group represented by R ³ and R ^4, the alkyl halide alkylsulfonyl group C _1-18 alkyl group described above is a sulfonyl group substituted, halogenated C _1-18 alkyl group as described above was substituted A sulfonyl group, or
It is possible to use an arylsulfonyl group or the like substituted with the above C _6-14 aryl group, and as the alkoxycarbonyl group, the above C _1-18 alkoxy group, preferably a C _1-8 alkoxy group, and more preferably a linear chain. Alternatively, a carbonyl group substituted with a branched chain C _1-4 alkoxy group can be used. As the carbamoyl group and the sulfamoyl group, the substituted or unsubstituted carbamoyl group and sulfamoyl group described above can be used, respectively. R ³
As R ⁴ and R ⁴ , independently, a hydrogen atom, a linear or branched C _1-5 alkyl group, or a linear or branched C _1-4 alkylcarbonyl group is preferable, and R ³ and R ⁴ are hydrogen atoms. Is particularly preferable.

In the above formula (I), L represents a linking group, and the linking group contains a C _2-12 alkylene group, or one or more phenylene groups or ether groups, and the number of atoms constituting the linking chain length. Is selected from 4 to 12 alkylene groups. These alkylene groups may be substituted with other substituents,
The alkylene group may be linear or branched. C
_{As the 2-12} alkylene group, for example, ethylene group, 1,4
-Butylene group, 1,5-pentylene group, 1,6-hexylene group,
A 1,10-decylene group or the like can be used. Preferably a linear or branched C _4-12 alkylene group, more preferably a linear or branched C _4-11 alkylene group, still more preferably a linear C _4-8 alkylene group, particularly preferably C _{5-. 6} alkylene groups can be used.

When L contains one or more phenylene groups or ether groups, the number of carbon atoms or oxygen atoms (which are referred to as atoms constituting the linking chain length) constituting the chain portion of the linking chain is 4 to The number is 12 (however, in the case of a phenylene group, the number of atoms is 4). The phenylene group has one or more other same or different substituents, for example, the substituents described for R ¹ above (such as an alkyl group, a halogenated alkyl group, a halogen atom, an alkoxy group, or a hydroxy group). May be.

Examples of the linking group containing phenylene include alkylene groups such as 1,4-xylylene, 1,3-xylylene, 1,2-xylylene and 2-ethylene-4-phenylmethyl group.
Examples thereof include a phenylene-alkylene group, and examples of the linking group containing an ether group include an ethylylene oxyethyl group and an ethyleneoxyethoxyethyl group. L is preferably a C _4-8 alkylene group or an ethyleneoxyethyl group, and particularly preferably a C _5-6 alkylene group. In the compound of the present invention, the two partial structures linked by the linking group L (in the formula (I), the partial structure on the right side and the partial structure on the left side across L) are not the same, and further, When Y is a sulfur atom, Z is NR ⁴ , n = m, and R ³ and R ⁴ are the same substituent, R ¹ and R ² are the same substituent. There is no such thing. More preferably, when Y is a sulfur atom, Z is NR ⁴ , and n is m, R ¹ and R ² are the same substituents, and R ³ and R ^{4 are}
Are not the same substituent.

The above compounds of the present invention are capable of forming acid addition salts and, if R ¹ and / or R ² are hydroxy groups, base addition salts. Both of these acid addition salts and base addition salts are included in the scope of the present invention. Further, when R ¹ and / or R ² is a hydroxy group, it may exist as a Zwitter type compound in the molecule, and such a compound is also included in the scope of the present invention. Examples of the acid addition salt include mineral salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, and p-
Organic acid salts such as toluene sulfonate, methane sulfonate, oxalate, tartrate, malate and citrate can be mentioned. Examples of the base addition salt include metal salts such as sodium salt, potassium salt, magnesium salt or calcium salt, as well as ammonium salt and triethylamine salt.

The compound of the present invention may have one or more asymmetric carbon atoms depending on the kind of R ^{1 to} R ⁴ . In such cases, there may be one or more asymmetric carbon-based optical isomers and two or more asymmetric carbon-based diastereoisomers, but any optical form in pure form. Both isomers or diastereoisomers are included within the scope of the invention. Further, a mixture of arbitrary optical isomers in an arbitrary ratio, a racemate, a mixture of arbitrary diastereoisomers in an arbitrary ratio, and the like are also included in the scope of the present invention. Further, it goes without saying that any hydrate or solvate of the compound of the present invention in free form or salt form is also included in the scope of the present invention.

In a preferred embodiment of the present invention, (a) Y is a single bond or a sulfur atom; Z is an oxygen atom, a sulfur atom or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom or a halogen. Atom, alkyl group, halogenated alkyl group, aryl group, alkoxy group, alkoxycarbonyl group, sulfamoyl group, acylamino group, sulfonylamino group, cyano group, hydroxy group, or nitro group; R ³ and R ⁴ are each independently Hydrogen atom, alkyl group,
Or an acyl group; n and m are each independently 1 or 2; L is an alkylene group having 4 to 11 carbon atoms, or 1 or 2 or more ether groups, and the number of atoms constituting the connecting chain length is The above compound which is a linking group selected from 5 to 8 alkylene groups;

(B) Y is a single bond or a sulfur atom; Z is an oxygen atom, a sulfur atom, or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, C _1-4 alkyl. Base,
Halogenated C _1-4 alkyl group, phenyl group, C _1-4 alkoxy group, C _1-4 alkoxycarbonyl group, C _1-4 alkylsulfamoyl group, C _1-4 alkylcarbonylamino group, C _1-4
An alkylsulfonylamino group, a cyano group, a hydroxy group, or a nitro group; R ³ and R ⁴ each independently represent a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group; n and m Are each independently 1 or 2;
L is an alkylene group having 4 to 11 carbon atoms, or 1 or 2 or more ether groups, and the number of atoms constituting the connecting chain length is 5
~ 8 above-mentioned compound which is a linking group selected from alkylene groups;

(C) Y is a single bond or a sulfur atom; R ¹ is a hydrogen atom, a halogen atom, a C _1-4 alkyl group, or a nitro group; n is 1 or 2, and R ² is hydrogen. Atom, halogen atom, C _1-4 alkyl group, halogenated C _1-4 alkyl group,
Phenyl group, C _1-4 alkoxy group, C _1-4 alkoxycarbonyl group, C _1-4 alkylsulfamoyl group, C _1-4 alkylcarbonylamino group, C _1-4 alkylsulfonylamino group, cyano group, or A hydroxy group; m is 1 or 2
R ³ is a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group; Z is an oxygen atom, a sulfur atom, or NR ⁴ (R ⁴ is a hydrogen atom, C _1-4 alkyl A group or a C _1-4 alkylcarbonyl group); L is an alkylene group having 4 to 11 carbon atoms, or 1 or 2 or more ether groups, and the number of atoms constituting the connecting chain length is 5 to 8 A compound which is a linking group selected from the alkylene groups of

(D) The compound of (c) above, wherein
A compound in which R ² is a hydrogen atom when Y represents a single bond; (e) The compound of (c) or (d) above, wherein L contains one or more ether groups and is linked. When the chain length is an alkylene group having 5 to 8 atoms, Y
Is a sulfur atom; (f) In the compound of (e) above, R ¹ is a halogen atom; n is 1 or 2; R ² is a halogen atom; m
Is 1 or 2; (g) In the compound of (e) above, R ¹ is a halogen atom; n is 1 or 2; R ² is a halogen atom; m
Is 2; and (h) R ¹ and R ² are each in the 5-position of the hetero-fused ring and / or
There is provided each of the above compounds which is a 6-position substituent.

In these compounds, R ¹ and / or R ²
The halogen atom represented by is a chlorine atom, a C _1-4 alkyl group is a methyl group, a halogenated C _1-4 alkyl group is a trifluoromethyl group, and a C _1-4 alkoxy group is a methoxy group or an ethoxy group. And the C _1-4 alkoxycarbonyl group is an ethoxycarbonyl group, the C _1-4 alkylsulfamoyl group is a methylsulfamoyl group, the C _1-4 alkylcarbonylamino group is an ethylcarbonylamino group, , A C _1-4 alkylsulfonylamino group is a methylsulfonylamino group; the C _1-4 alkyl group represented by R ³ and / or R ⁴ is a methyl group, and the C _1-4 alkylcarbonyl group is an ethylcarbonyl group. And the number of atoms constituting the linking chain length is 5 to 8 including 1 or 2 or more ether groups represented by L.
The compound in which the alkylene group of is an ethylylene oxyethyl or ethyleneoxy ethoxyethyl group is a particularly preferable compound as the compound of the present invention. Of the compounds of the present invention, particularly preferable compounds are exemplified below, but the scope of the present invention is not limited to these compounds.

[0029]

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[Chemical 6]

[Chemical 7]

The compound of the present invention can be produced, for example, from the readily available starting compound (II) according to the scheme shown below by a reaction well known to those skilled in the art. Specific methods for these methods are described in detail in the Examples herein,
Those skilled in the art can easily produce the compound of the present invention by referring to the following general description and examples and appropriately modifying or altering these methods (scheme) Wherein R ¹ , R ² , R ³ , n, m, Z, Y, and L are as described above, and X ₁ represents a halogen atom or a leaving group for a nucleophilic substitution reaction such as an alkyl or arylsulfonyloxy group. , X ₂ represents the leaving group, the carboxyl group, or the alkoxycarbonyl group).

Embedded image

Among the 2-mercaptobenzimidazole compounds (II) used for the production of the compound of the formula (IV), known compounds can be produced by the methods described in respective references, but new compounds are , Generally O
It can be produced by the method described in rg. Syn. Col. Vol.4, p.569. In addition, some of the compounds are commercially available as reagents. Compound (II) as a linking group reagent
Compound (IV) can be produced by reacting with (X ₁ -LX ₂ : III) (step 1). The above reaction is, for example,
Ethanol, acetonitrile, acetone, ethyl acetate,
Dimethylformamide (DMF), tetrahydrofuran (TH
It is generally carried out in a general organic solvent such as F).

If necessary, the reaction may be carried out in the presence of a base catalyst such as sodium hydroxide, potassium carbonate, triethylamine or sodium ethylate as a deoxidizing agent, but it is heated in alcohol in the absence of a catalyst. By doing so, the reaction proceeds well. When a base is used, the reaction temperature may be appropriately selected according to the type of substrate compound or solvent, but is usually 0 to 150 ° C, preferably 20 to 100 ° C. When the reaction is carried out in alcohol in the absence of a catalyst, about 50 to 120 ° C is suitable.

When both X ₁ and X ₂ are leaving groups, an excessive amount of compound (I) relative to compound (II) is used to suppress side reactions.
It is preferable to use II). Usually double to 10
A double amount may be used, but preferably a 4-fold to 10-fold amount can be used. In general, unreacted compound (I
II) can be recovered after the reaction is completed. On the other hand, when X ₂ is a carboxyl group or an alkoxycarbonyl group, almost equimolar amount of compound (III) to compound (II) should be used in order to suppress side reactions. For example, it is preferable to use 0.8 to 1.2 times mol, preferably 0.95 to 1.1 times mol of compound (III) with respect to compound (II). When X ₂ is a carboxyl group, it can be isolated by neutralizing the carboxylic acid compound (IV) formed after the reaction and collecting the precipitated crystals or extracting it with an organic solvent.

When X ₂ is a chlorine atom, a bromine atom, or a leaving group such as a p-toluenesulfonyloxy group, the compound (IV) is reacted with a 2-mercaptoazole compound (V) to give Compound of the invention (compound of formula-2 in the scheme)
Can be manufactured (step 2). Compound (V) used as a reaction reagent in step 2 can be generally produced by a known method (Org. Syn. Col. Vol., 4, p. 569), and some of the compounds are commercially available. It is also possible to obtain goods. The reaction between compound (IV) and compound (V) can be carried out according to the conditions of the above step 1.

When X ₂ is a carboxyl group or an alkoxycarbonyl group, the compound (IV) is reacted with an o-phenylenediamine compound (VI) to give a compound of the present invention (formula-3 in the scheme). The compound) can be produced. As the compound (VI), a commercially available product can be easily obtained, and the condensation ring closure reaction of the compound (IV) and the compound (VI) can be generally performed in the presence of an acid catalyst. Examples of the acid catalyst include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or
Organic sulfonic acids such as p-toluene sulfonic acid can be preferably used. The reaction can be carried out in the absence of a solvent or in the presence of water or various organic solvents. The molar ratio of the compound (VI) to the compound (IV) is preferably 0.8 to 1.2, 0.9
The range of 5 to 1.1 is particularly preferred. The acid catalyst may be used in a range of about 0.1 to 10 times, preferably 1 to 5 times the mol of the compound (IV).

In the above reaction, when R ³ is a hydrogen atom, the starting compound (II) or the compound of formula-2 or formula-3 is subjected to alkylation or acylation to give another compound of the present invention. It can be manufactured. The alkylation is
In the above-mentioned general organic solvent, a basic catalyst such as sodium hydroxide, potassium carbonate, triethylamine or sodium ethylate is used as a deoxidizing agent to react with a reactive alkylating agent such as alkyl halide or alkyl tosylate. Just do it. The reaction temperature may be appropriately selected depending on the kind of the substrate compound and the solvent, but it is generally suitable to carry out at a temperature of about 0 to 100 ° C, preferably about 20 to 60 ° C.

The acylation reaction may generally be carried out by reacting with a corresponding acid halide in the presence of a base catalyst (eg, potassium carbonate, triethylamine, pyridine etc.) as a deoxidizing agent in a usual inert solvent. . As the inert solvent, for example, acetonitrile, ethyl acetate, THF, DMF, dimethylacetamide (DMAc) or the like can be used, but when DMF, DMAc, acetonitrile or the like having strong polarity is used, even in the absence of a base catalyst. The reaction proceeds. The acid halide is preferably used in an amount about 1.8 to 2.4 times the molar amount of the substrate compound, and the reaction temperature can be about 30 to 150 ° C, preferably about 50 to 100 ° C.

The compound of the present invention has an action of strongly suppressing foam formation of macrophages involved in the formation of arteriosclerotic lesions in arteriosclerosis, and is useful as a drug for the prevention and / or treatment of arteriosclerosis. It is useful as an active ingredient or an active ingredient of a preventive and / or therapeutic agent for hyperlipidemia by lowering blood cholesterol. Therefore, according to another aspect of the present invention, a prophylactic and / or therapeutic agent for arteriosclerosis and a prophylactic and / or therapeutic agent for hyperlipidemia containing the above compound as an active ingredient are provided.

Without being bound to any particular theory, when foamed macrophages enter the arterial wall, they trigger the abnormal proliferation of smooth muscle in the arterial wall, causing arteriosclerosis. Known to be (S
chaffner, T. et al., Amer. J. Pathol., 110, pp.57-
73, 1980; Gerrity, RG, Amer. J. Pathol. 103, pp.
181-190, 1981). The medicament of the present invention directly suppresses the formation of arteriosclerotic plaque and enables degeneration of arteriosclerotic plaque by suppressing foam formation of macrophages involved in the formation of arteriosclerotic plaque. Therefore, the medicament of the present invention is useful for treating and / or preventing arteriosclerosis and hyperlipidemia caused by various causes.

The dosage form of the above-mentioned medicament of the present invention is not particularly limited, and it can be administered orally or parenterally. As the drug of the present invention, the compound of the above formula (I) which is the active ingredient may be used as it is, but usually, the compound of the formula which is the active ingredient is used.
If necessary, pharmacologically and pharmaceutically acceptable additives should be added to the compound of (I) to provide a formulation in a form well known to those skilled in the art. Examples of preparations suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups. Examples of preparations suitable for parenteral administration include injection. Preparations, drops, suppositories, inhalants, transdermal absorbents, transmucosal absorbents, patches, and the like. Examples of pharmacologically and pharmaceutically acceptable additives include excipients,
Disintegrant or disintegration aid, binder, lubricant, coating agent, pigment, diluent, base, solubilizer or dissolution aid,
An isotonicity agent, a pH adjuster, a stabilizer, a propellant, an adhesive and the like can be used.

For example, for a formulation suitable for oral administration, transdermal or transmucosal administration, as a pharmacologically or pharmaceutically acceptable additive, for example, glucose, lactose, D-mannitol, starch, or crystals. Excipients such as cellulose;
Disintegrators or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; hydroxypropylmethylcellulose , Coating agents such as sucrose, polyethylene glycol or titanium oxide; petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water,
Alternatively, a base such as hard fat can be used. In addition, propellants such as CFCs, diethyl ether, or compressed gas; adhesives such as sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene, polybutene; additives for formulations such as cotton cloth or plastic cloth base cloth. It may be used to produce a formulation.

Formulations suitable for injection or infusion include, for example, solubilizers or solubilizers that can form an aqueous or injection-soluble injection such as distilled water for injection, physiological saline, and propylene glycol; glucose, chloride. Isotonic agents such as sodium, D-mannitol, glycerin; inorganic acids, organic acids,
Pharmaceutical additives such as pH adjusters such as inorganic bases or organic bases may be added.

The dose of the drug of the present invention is not particularly limited, and may be appropriately selected depending on the administration form, the purpose of treatment and / or prevention, the age, body weight, symptoms of the patient and the like. For example, in the case of intravenous administration, about 10 to 400 mg, preferably about 10 to 100 mg, of the active ingredient per day for an adult may be administered. The amount of the active ingredient is about 10 to 800 mg, preferably 10 to 800 mg.
About 300 mg may be used. The drug of the present invention may be administered once or in several divided doses per day, and the administration period can be arbitrarily determined according to the age of the patient, the degree of improvement in symptoms, and the like.

[0044]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. In the examples, compounds with compound numbers are
It corresponds to the numbers of the compounds exemplified in the structural formulas above as particularly preferred compounds of the present invention.

Example 1: Synthesis of 5- (2'-benzimidazoylthio) pentyl bromide 2-mercaptobenzimidazole (6.0 g) and 1,5-dibromopentane (60 g) were dissolved in ethanol (50 ml) and heated under reflux for 6 hours. did. After distilling off the solvent under reduced pressure, 50 ml of ethyl acetate and 50 ml of hexane were added to the residue and digested to obtain about 12 g of a solid matter. 100 ml of water was added to this solid and the mixture was neutralized with an aqueous sodium hydroxide solution. The precipitated oil solution was extracted with ethyl acetate, washed with water and concentrated. The residue was separated by silica gel column chromatography (silica gel 220 g, solvent: chloroform) to obtain 8.7 g of crude crystals.
The crude crystals were recrystallized from ethanol to give the title compound 7.8
got g. Melting point 126-127 ℃ Elemental analysis Calculated as C ₁₂ H ₁₅ N ₂ SBr: C, 48.15; H, 5.05; N, 9.36 (%) Found: C, 47.98; H, 5.11; N, 9.21 (%)

Example 2: Synthesis of 1- (2 '-(5'-methylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 1) 5- (2'-Benz (Imidazoylthio) Pentyl bromide
0.57 g and 2-mercapto-5-methylbenzimidazole
0.36 g was dissolved in 5 ml of ethanol and heated under reflux for 8 hours. After cooling, the reaction solution was neutralized with an aqueous sodium hydroxide solution, and the precipitated oily matter was extracted with ethyl acetate. After washing with water, the solvent was distilled off under reduced pressure, and the obtained oil was separated and purified by silica gel column chromatography. The obtained crude purified product was crystallized from ethyl acetate to obtain 0.52 g of the title compound. Mp 163-165 ° C. Elemental Analysis C ₂₀ H ₂₂ N ₄ S ₂ Calculated: C, 62.79; H, 5.80 ; N, 14.65 (%) Found: C, 62.58; H, 5.71 ; N, 14.51 (%)

Example 3: Synthesis of 1- (2 '-(5'-chlorobenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 2) 0.61 g of the title compound was obtained from 0.6 g of-(2'-benzimidazoylthio) pentyl bromide and 0.37 g of 5-chloro-2-mercaptobenzimidazole (crystallization from ethyl acetate-acetonitrile), melting point 160-163 ° C Element Analysis Calculated as C ₁₉ H ₁₉ N ₄ S ₂ Cl: C, 56.63; H, 4.75; N, 13.91 (%) Found: C, 56.49; H, 4.60; N, 13.71 (%)

Example 4: Synthesis example of 1- (2- (5'-chlorobenzimidazoyl) -thio) -5- (2 "-(5" -methylbenzimidazoyl) -thio) pentane (Compound 3) In the same manner as in 1-, 5- (2- (5'-methylbenzimidazoyl) -thio) pentyl bromide was synthesized from 2-mercapto-5-methylbenzimidazole and 1,5-dibromopentane. In the same manner as in Example 3, the title compound (0.6 g) was obtained from the obtained 5- (2- (5'-methylbenzimidazoyl) -thio) pentyl bromide (0.63 g) and 5-chloro-2-mercaptobenzimidazole (0.37 g). (Crystallization from ethanol-acetonitrile). Mp 174-175 ° C. Elemental Analysis _{C 20 H 21 N 4 S 2} Cl Calculated: C, 57.60; H, 5.08 ; N, 13.44 (%) Found: C, 57.44; H, 5.14 ; N, 13.58 (% )

Example 5: Synthesis of 1- (2 '-(5'-methoxybenzimidazoyl) -thio) -5- (2 "-(5" -methylbenzimidazoyl) -thio) pentane (Compound 4) As in Example 4, 5- (2 '-(5'-methylbenzimidazoyl) -thio) pentyl bromide 0.63 g and 2-mercapto
0.75 g of the title compound was obtained from 0.36 g of -5-methoxybenzimidazole (crystallized from ethyl acetate). Mp 170-171 ° C. Elemental Analysis C ₂₁ H ₂₄ N ₄ 0S ₂ Calculated: C, 61.13; H, 5.86 ; N, 13.58 (%) Found: C, 60.98; H, 5.74 ; N, 13.42 (%)

Example 6: 1- (2'-benzimidazoylthio) -5-
Synthesis of (2 "-(5" -methoxybenzimidazoyl) -thio) pentane (Compound 5) In the same manner as in Example 2, 0.9 g of 5- (2'-benzimidazoylthio) pentyl bromide and 2-mercapto-5 were prepared. -0.89 g of the title compound was obtained from 0.57 g of methoxybenzimidazole (wax-like substance).

Example 7: 1- (2'-benzimidazoylthio) -5-
Synthesis of (2 "-(5" -hydroxybenzimidazoyl) -thio) pentane (Compound 6) Compound 5 (0.34 g) was dissolved in 2 ml of hydrobromic acid and 2 ml of water and heated under reflux for 16 hours. The reaction solution was neutralized with an aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with water, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol-ethyl acetate to give the title compound (0.18 g). Melting point 112-114 ° C Elemental analysis Calculated as C ₁₉ H ₂₀ N ₄₀ S ₂ : C, 59.35; H, 5.24; N, 14.57 (%) Actual value: C, 59.21; H, 5.12; N, 14.39 (%)

Example 8: 1- (2'-Benzimidazoylthio) -5-
(2 "-(5" -methanesulfonylaminobenzimidazoyl)-
Synthesis of (thio) pentane (Compound 7) In the same manner as in Example 2, 5- (2'-benzimidazolylthio) pentyl bromide 0.3 g and 2-mercapto-5-methanesulfonylaminobenzimidazole 0.28 g
0.32 g was obtained (crystallized from ethyl acetate-acetonitrile). Mp 141-143 ° C. Elemental Analysis _{C 20 H 23 N 5 0 2} S 3 Calculated: C, 52.03; H, 5.02 ; N, 15.18 (%) Found: C, 51.84; H, 4.98 ; N, 15.09 ( %)

Example 9: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-(5" -propionylaminobenzimidazoyl) -thio) pentane (Compound 8) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 2-mercapto- 5-Methanesulfonylaminobenzimidazole 0.22 g
0.23 g was obtained (wax-like substance).

Example 10: Synthesis of 1- (2 '-(5'-ethoxycarbonylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 9) 5- (2'-benzimidazoylthio) pentyl bromide 0.3 g and 2-mercapto-5-ethoxycarbonylbenzimidazole 0.22 g
4 g was obtained (crystallized from ethyl acetate-acetonitrile). Mp 155-156 ° C. Elemental Analysis _{C 22 H 24 N 4 0 2} S 2 Calculated: C, 59.97; H, 5.49 ; N, 12.72 (%) Found: C, 59.73; H, 5.38 ; N, 12.58 ( %)

Example 11: Synthesis of 1- (2 '-(5', 6'-dimethylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound Example 10) In the same manner, 0.54 g of the title compound was obtained from 0.6 g of 5- (2′-benzimidazolylthio) pentyl bromide and 0.35 g of 2-mercapto-5,6-dimethylbenzimidazole (crystallized from ethyl acetate-acetonitrile). mp 150-153 ° C. elemental analysis C ₂₁ H ₂₄ N ₄ S ₂ calculated: C, 63.60; H, 6.10 ; N, 14.13 (%) Found: C, 63.36; H, 6.02 ; N, 14.32 (%)

Example 12: Synthesis of 1- (2 '-(5', 6'-dichlorobenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 11) Similar to Example 2. And 5- (2'-benzimidazoylthio) pentyl bromide (0.6 g) and 5,6-dichloro-2-mercapto-
0.72 g of the title compound was obtained from 0.44 g of benzimidazole (crystallized from acetonitrile). Melting point 167-169 ℃ Elemental analysis C ₁₉ H ₁₈ N ₄ S ₂ Cl ₂ Calculated value: C, 52.17; H, 4.15; N, 12.81 (%) Actual value: C, 52.03; H, 4.01; N, 12.62 ( %)

Example 13: Synthesis of 6- (2'-benzimidazolylthio) hexyl bromide In the same manner as in Example 1, 2-mercaptobenzimidazole 3.0
5.0 g of the title compound from g and 1,4-dibromohexane 24.4 g
Was obtained (crystallized from ethyl acetate-hexane).

Example 14: Synthesis of 1- (2 '-(5', 6'-dichlorobenzimidazoyl) -thio) -6- (2 "-benzimidazoylthio) hexane (Compound Example 12) Similarly, 6- (2'-benzimidazoylthio) hexyl bromide 0.31 g and 5,6-dichloro-2-mercapto-
0.32 g of the title compound was obtained from 0.22 g of benzimidazole (crystallized from ethyl acetate-chloroform). Mp 287-230 ° C. Elemental Analysis _{C 20 H 20 N 4 S 2} Cl 2 Calculated: C, 53.21; H, 4.47 ; N, 12.41 (%) Found: C, 53.07; H, 4.22 ; N, 12.12 ( %)

Example 15: Synthesis of 8- (2'-benzimidazolylthio) octyl bromide 2-Mercaptobenzimidazole 1.5 as in Example 1.
From g and 1,8-dibromooctane 13.6 g, the title compound 2.6 g
Was obtained (crystallized from ethyl acetate-hexane).

Example 16: Synthesis of 1- (2 '-(5', 6'-dichlorobenzimidazoyl) -thio) -8- (2 "-benzimidazoylthio) octane (Compound 13) Similar to Example 2. 8- (2'-benzimidazoylthio) octyl bromide 0.37 g and 5,6-dichloro-2-mercapto-
0.36 g of the title compound was obtained from 0.22 g of benzimidazole (crystallized from ethanol-water). Mp 176-178 ° C. Elemental Analysis _{C 22 H 24 N 4 S 2} Cl 2 Calculated: C, 55.11; H, 5.05 ; N, 11.69 (%) Found: C, 54.98; H, 4.88 ; N, 11.43 ( %)

Example 17: 1- (2 '-(5', 6'-dichlorobenzimidazoyl) -thio) -5- (2 "-(5" -methylbenzimidazoyl) -thio) pentane (Compound 14 In the same manner as in Example 2, 0.32 g of 5- (2 '-(5'-methylbenzimidazoyl) -thio) pentyl bromide and 0.24 g of 5,6-dichloro-2-mercaptobenzimidazole were prepared. Was obtained (crystallization from acetonitrile). Mp 161-165 ° C. Elemental Analysis _{C 20 H 20 N 4 S 2} Cl 2 Calculated: C, 53.21; H, 4.47 ; N, 12.41 (%) Found: C, 53.10; H, 4.29 ; N, 12.21 ( %)

Example 18: 1- (2 '-(5', 6'-Dichlorobenzimidazoyl) -thio) -5- (2 "-(5", 6 "-dimethylbenzimidazoyl) -thio) pentane Synthesis of (Compound 15) In the same manner as in Example 1, 2-mercapto-5,6-dimethylbenzimidazole (5.34 g) and 1,5-dibromopentane (34.5 g) were converted into 5- (2 '-(5', 6'-dimethylbenz (Imidazoyl) -thio)
6.6 g of pentyl bromide was obtained. Furthermore, in the same manner as in Example 2, represented by 0.65 g of 5- (2 '-(5', 6'-dimethylbenzimidazolyl) -thio) pentyl bromide and 0.44 g of 5,6-dichloro-2-mercapto-benzimidazole Compound
0.72 g was obtained (crystallized from acetonitrile). Mp 171-173 ° C. Elemental Analysis _{C 21 H 22 N 4 S 2} Cl 2 Calculated: C, 54.19; H, 4.76 ; N, 12.04 (%) Found: C, 54.03; H, 4.57 ; N, 12.11 ( %)

Example 19: Synthesis of 1- (2 '-(5'-chloro-6'-trifluoromethylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 16) In the same manner as in Example 2, 0.39 g of 5- (2'-benzimidazolylthio) pentyl bromide and 0.26 g of 5-chloro-2-mercapto-6-trifluoromethylbenzimidazole were used to obtain 0.29 g of the title compound (wax-like substance). ).

Example 20: Synthesis of 1- (2 '-(5'-cyanobenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 17) 0.2 g of the title compound was obtained from 0.3 g of-(2'-benzimidazolylthio) pentyl bromide and 0.16 g of 5-cyano-2-mercaptobenzimidazole (crystallized from ethyl acetate-acetonitrile), melting point 152-154 ° C Element analysis C ₂₀ H ₁₉ N ₅ S ₂ calculated: C, 61.04; H, 5.22 ; N, 17.80 (%) Found: C, 59.96; H, 5.10 ; N, 17.64 (%)

Example 21: Synthesis of 4- (2'-benzimidazolylthio) butyl chloride 2-Mercaptobenzimidazole 6.2 as in Example 1.
g and 1,4-chlorobromobutane 10.3 g
g was obtained (wax-like).

Example 22: Synthesis of 1- (2 '-(5'-methylbenzimidazoyl) -thio) -4- (2 "-benzimidazoylthio) butane (Compound 18) 0.03 g of the title compound was obtained from 0.33 g of-(2'-benzimidazolylthio) butyl chloride and 0.24 g of 5-methyl-2-mercaptobenzimidazole (crystallization from methanol-water), melting point 204-206 ° C Elemental analysis Calculated as C ₁₉ H ₂₀ N ₄ S ₂ : C, 61.92; H, 5.47; N, 15.21 (%) Measured value: C, 61.78; H, 5.34; N, 15.10 (%)

Example 23: Synthesis of 1- (2 '-(5'-methylbenzimidazoyl) -thio) -6- (2 "-benzimidazoylthio) hexane (Compound 19) 0.33 g of-(2'-benzimidazoylthio) hexyl bromide and 0.16 g of 5-methyl-2-mercapto-benzimidazole gave 0.33 g of the title compound (crystallized from ethyl acetate), melting point 202-204 ° C Elemental analysis Calculated as C ₂₁ H ₂₄ N ₄ S ₂ : C, 63.60; H, 6.16; N, 14.13 (%) Actual value: C, 63.42; H, 6.09; N, 14.01 (%)

Example 24: Synthesis of 1- (2 '-(5'-methylbenzimidazoyl) -thio) -8- (2 "-benzimidazoylthio) octane (Compound 20) 0.36 g of-(2'-benzimidazoylthio) octyl bromide and 0.16 g of 5-methyl-2-mercapto-benzimidazole were obtained to give 0.36 g of the title compound (crystallized from ethyl acetate-hexane), melting point 101-103 ° C. elemental analysis C ₂₃ H ₂₈ N ₄ S ₂ calculated: C, 65.05; H, 6.65 ; N, 13.20 (%) Found: C, 64.87; H, 6.41 ; N, 13.34 (%)

Example 25: Synthesis of 2- (2- (2-p-toluenesulfonyloxy) -ethoxy) -ethylmercaptobenzimidazole 3.1 g 2-mercaptobenzimidazole and 8.3 g diethylene glycol di-p-tosylate in acetonitrile The mixture was heated to reflux for 18 hours. After distilling off the solvent under reduced pressure, the residue was separated by silica gel column chromatography to obtain 2.4 g of the title compound (wax-like).

Example 26: Synthesis of 2- (2- (2- (2 '-(5'-methylbenzimidazole) -thio) -ethoxy) -ethylmercaptobenzimidazole (Compound 21) -(2- (2-p-Toluenesulfonyloxy) -ethoxy) -ethylmercaptobenzimidazole
0.38 g and 2-mercapto-5-methylbenzimidazole
0.21 g of the title compound was obtained from 0.17 g. Melting point 130-131 ° C Elemental analysis Calculated as C ₁₉ H ₂₀ N ₄ OS ₂ Calcd: C, 59.35; H, 4.96; N, 14.57 (%) Found: C, 59.12; H, 4.72; N, 14.32 (%)

Example 27: Synthesis of 2- (2- (2- (2-p-toluenesulfonyloxy) -ethoxy) -ethoxy) -ethylmercaptobenzimidazole 3.1 g 2-mercaptobenzimidazole and triethyleneglycol di- 9.6 g of p-tosylate was heated under reflux in acetonitrile for 18 hours. After the solvent was distilled off under reduced pressure, the title compound was collected by silica gel column chromatography 3.3 g
Was obtained (wax-like).

Example 28: Synthesis example of 2- (2- (2- (2- (2 '-(5'-methylbenzimidazole) -thio) -ethoxy) -ethoxy) -ethylmercaptobenzimidazole (Compound 22) 1- (2- (2- (2-p-toluenesulfonyloxy) -ethoxy) -ethoxy) -ethylmercaptobenzimidazole 0.43 g and 2-mercapto-5-methylbenzimidazole 0.17 g 0.33 g mp 119-122 ° C. elemental analysis to obtain a _{C 21 H 24 N 4 O 2} S 2 calculated: C, 58.85; H, 5.64 ; N, 13.08 (%) Found: C, 58.59; H, 5.45 ; N, 12.89 (%)

Example 29: 1- (2 '-(1'-methyl-5'-methylsulfamoylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane (Compound 23) In the same manner as in Synthesis Example 2, 0.32 g of 5- (2'-benzimidazolylthio) pentyl bromide and 0.26 g of 2-mercapto-1-methyl-5-methylsulfamoylbenzimidazole were used to obtain 0.22 g of the title compound ( . ethyl acetate - crystallized from acetonitrile) melting point 139-140 ° C. elemental analysis _{C 21 H 25 N 5 O 2} S 3 calculated: C, 53.03; H, 5.30 ; N, 14.73 (%) Found: C, 52.92 ; H, 5.13; N, 14.61 (%)

Example 30: 1- (2 '-(1'-methyl-5'-methylsulfamoylbenzimidazoyl) -thio) -5- (2 "-(1-propionyl) benzimidazoyl) -thio ) Pentane (compound
25) Synthesis of 1- (2 '-(1'-methyl-5'-methylsulfamoylbenzimidazoyl) -thio) -5- (2 "-benzimidazoylthio) pentane 0.1 g dimethylacetamide 0.3 ml Dissolved in a mixture of 0.5 ml of acetonitrile and 0.1 ml of triethylamine, and slowly added 0.04 ml of propionyl chloride at 45 ° C. After stirring for 4.5 hours, water was added and the mixture was extracted with ethyl acetate. Purified by silica gel column chromatography, ethyl acetate
-Crystallization from acetonitrile gave the title compound 0.04 g. Mp 91-93 ° C. Elemental analysis _{C 24 H 29 N 5 O 3} S 3 Calculated: C, 54.21; H, 5.50 ; N, 13.17 (%) Found: C, 54.11; H, 5.32 ; N, 13.02 ( %)

Example 31: Synthesis of ethyl 6- (2-benzimidazolethio) caproate 6.3 g of 2-mercaptobenzimidazole and 7.8 g of 6-bromocaproic acid were dissolved in 35 ml of ethanol and heated under reflux for 12 hours. After cooling, water was added to the reaction solution, and the pH was adjusted to 8 with an aqueous sodium carbonate solution. The precipitated crystals are collected by filtration,
After drying, 11.2 g of the title compound was obtained.

Example 32: Synthesis of 2- (5- (2'-benzimidazolylthio) pentyl) -benzimidazole (compound 27) 6- (2-Benzimidazolethio) ethyl caproate 0.8
8 g and o-phenylenediamine 0.34 g were melt | dissolved in concentrated hydrochloric acid 1 ml and water 2 ml, and it heated and refluxed for 20 hours under nitrogen stream.
After cooling, 3 ml of water was added to the reaction solution, and the precipitate was collected by filtration.
The obtained precipitate was suspended in water-methanol 1: 1 and an aqueous sodium hydroxide solution was added so as to maintain pH8. The precipitated crystals were collected by filtration and washed with water-containing methanol until it became neutral to obtain 0.88 g of the title compound. Melting point 313-316 ° C Elemental analysis Calculated as C ₁₉ H ₂₀ N ₄ S: C, 67.82; H, 5.99; N, 16.66 (%) Actual value: C, 67.65; H, 5.72; N, 16.52 (%)

Example 33: Synthesis of 1-propionyl-2- (5- (2 '-(1-propionylbenzimidazolyl) -thio) pentyl) -benzimidazole (Compound 24) 5- (2'-benzimidazoylthio)
Pentyl) -benzimidazole from 0.2 g
0.17 g was obtained. Melting point 142-145 ° C Elemental analysis Calculated as C ₂₅ H ₂₈ N ₄ O ₂ S: C, 66.93; H, 6.29; N, 12.49 (%) Actual value: C, 66.76; H, 6.11; N, 12.22 (% )

Example 34: Synthesis of 1-methyl-2- (5- (2 '-(1-methylbenzimidazolyl) -thio) pentyl) -benzimidazole (Compound 26) 2- (5- (2'- 0.2 g of benzimidazoylthio) pentyl) -benzimidazole was dissolved in 2 ml of dimethylformamide, 0.18 g of potassium carbonate and 0.3 g of methyl iodide were added, and the mixture was stirred at 40 ° C. for 14 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. After washing with water, the solvent was distilled off under reduced pressure, and crystallization from acetonitrile gave the title compound (0.03 g). Melting point 118-120 ℃ Elemental analysis Calculated as C ₂₁ H ₂₄ N ₄ S: C, 69.19; H, 6.64; N, 15.31 (%) Actual value: C, 69.03; H, 6.41; N, 15.23 (%)

Example 35: Synthesis of 2- (5- (2'-benzimidazolylthio) pentyl) -5,6-dimethylbenzimidazole (Compound 28) 6- (2-Benzimidazolethiol was prepared in the same manner as in Example 32. ) 0.70 g of the title compound was obtained from 0.88 g of ethyl caproate and 0.43 g of 4,5-dimethyl-o-phenylenediamine (crystallized from ethyl acetate-acetonitrile). Melting point 211-214 ° C Elemental analysis Calculated as C ₂₁ H ₂₄ N ₄ S: C, 69.19; H, 6.64; N, 15.31 (%) Actual value: C, 69.11; H, 6.48; N, 15.12 (%)

Example 36: Synthesis of 2- (5- (2'-benzimidazolylthio) pentyl) -5,6-dichlorobenzimidazole (Compound 28) In the same manner as in Example 32, 6- (2-benzimidazolethio) ) 0.93 g of the title compound was obtained from 0.88 g of ethyl caproate and 0.56 g of 4,5-dichloro-o-phenylenediamine (crystallization from ethyl acetate-acetonitrile). Melting point 194-196 ℃ Elemental analysis Calculated as C ₁₉ H ₁₈ N ₄ SCl ₂ : C, 56.30; H, 4.48; N, 13.83 (%) Actual value: C, 56.24; H, 4.37; N, 13.69 (%)

Example 37: 2- (5- (2'-Benzimidazolylthio) pentyl) -5-nitrobenzimidazole (Compound 2
Synthesis of 9) In the same manner as in Example 32, 0.50 g of the title compound was obtained from 0.88 g of ethyl 6- (2-benzimidazolethio) caproate and 0.48 g of 4-nitro-o-phenylenediamine (from ethyl acetate-acetonitrile). Crystallization). Melting point 184-185 ° C Elemental analysis Calculated as C ₁₉ H ₁₉ N ₅ O ₂ S: C, 59.82; H, 5.02; N, 18.36 (%) Found: C, 59.59; H, 4.98; N, 18.44 (% )

Example 38: Synthesis of 2- (7- (2'-benzimidazolylthio) heptyl) -benzimidazole (Compound 31) 2-Mercaptobenzimidazole 3.1 as in Example 31
Ethyl 8- (2-benzimidazolethio) octanoate (6.4 g) was obtained from g and 4.46 g of 8-bromooctanoic acid. Then, in the same manner as in Example 32, 0.98 g of ethyl 8- (2-benzimidazolethio) octanoate and 0.34 g of o-phenylenediamine
The title compound (0.70 g) was obtained from the above. Melting point 263-264 ℃ Elemental analysis Calculated as C ₂₁ H ₂₄ N ₄ S: C, 69.19; H, 6.64; N, 15.37 (%) Actual value: C, 69.03; H, 6.48; N, 15.21 (%)

Example 39: Synthesis of 2- (11- (2'-benzimidazolylthio) undecyl) -benzimidazole (Compound 32) 2-Mercaptobenzimidazole 3.1 as in Example 31
Ethyl 12- (2-benzimidazolethio) dodecanoate (6.4 g) was obtained from g and 5.3 g of 12-bromododecanoic acid. Then, in the same manner as in Example 32, 1.13 g of ethyl 11- (2-benzimidazolethio) dodecanoate and 0.34 g of o-phenylenediamine
The title compound (0.70 g) was obtained from the above. Melting point 206-208 ℃ Elemental analysis Calculated as C ₂₅ H ₃₂ N ₄ S: C, 71.39; H, 7.67; N, 13.32 (%) Found: C, 71.22; H, 7.41; N, 13.19 (%)

Example 40: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-benzothiozoylthio) pentane (Compound 33) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 2-mercaptobenzothiazole
0.2 g of the title compound was obtained from 0.17 g (crystallized from acetonitrile). Mp 124-125 ° C. Elemental Analysis C ₁₉ H ₁₉ N ₃ S ₃ Calculated: C, 59.19; H, 4.97 ; N, 10.90 (%) Found: C, 59.31; H, 4.75 ; N, 10.70 (%) Compound 36 was similarly synthesized.

Example 41: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-(5" -chlorobenzothiazoyl) -thio) pentane (Compound 34) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 5-chloro-2 -0.38 g of the title compound was obtained from 0.20 g of mercaptobenzothiazole (crystallization from acetonitrile). Melting point 125-127 ℃ Elemental analysis Calculated as C ₁₉ H ₁₈ N ₃ S ₃ Cl: C, 54.33; H, 4.32; N, 10.01 (%) Found: C, 54.11; H, 4.12; N, 10.12 (% )

Example 42: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-(6" -ethoxybenzothiozoyl) -thio) pentane (Compound 35) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 6-ethoxy-2 were prepared. -0.38 g of the title compound was obtained from 0.21 g of mercaptobenzothiazole (crystallization from acetonitrile). Mp 122-124 ° C. Elemental Analysis C ₂₁ H ₂₃ N ₃ OS ₃ Calculated: C, 58.71; H, 5.40 ; N, 9.78 (%) Found: C, 58.54; H, 5.32 ; N, 9.65 (%)

Example 43: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-benzoxazoylthio) pentane (Compound 37) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 0.15 g of 2-mercaptobenzoxazole were added to give the title compound 0.1 g. Melting point 128-130 ℃ Elemental analysis Calculated as C ₁₉ H ₁₉ N ₃ OS ₂ : C, 61.76; H, 5.18; N, 11.38 (%) Found: C, 61.49; H, 5.02; N, 11.21 (%) Similarly, compound 38 was synthesized.

Example 44: 1- (2'-Benzimidazoylthio) -5-
Synthesis of (2 "-(5" -phenylbenzoxazoyl) -thio) pentane (Compound 39) In the same manner as in Example 2, 0.3 g of 5- (2'-benzimidazoylthio) pentyl bromide and 2-mercapto-5 were prepared. -0.2 g of phenylbenzoxazole was obtained to obtain 0.2 g of the title compound (crystallized from ethyl acetate-acetonitrile). Mp 100-102 ° C. Elemental Analysis C ₂₅ H ₂₃ N ₃ OS ₂ Calculated: C, 67.38; H, 5.20 ; N, 9.43 (%) Found: C, 67.45; H, 5.08 ; N, 9.23 (%)

Example 45: Inhibitory effect of macrophage foaming by the compound of the present invention The effect of the compound of the present invention to suppress macrophage foaming which triggers arteriosclerosis was examined by an in vitro test using mouse peritoneal macrophages. . A 15-week-old female ICR mouse (manufactured by Japan SLC) was excised from the neck by exsanguination, and then Hanks buffer (Nippon Pharmaceutical Co., Ltd.) was intraperitoneally injected.
The buffer solution was collected immediately after the abdomen was blown, and 1,000 rp was collected.
Peritoneal macrophages were collected by centrifugation at m. for 5 minutes. Then, the collected macrophages were suspended in GTI medium (manufactured by Wako Pure Chemical Industries, Ltd.) and seeded on a 24-well microplate. After culturing at 37 ° C. under 5% CO ₂ for 2 hours, the medium was changed to Davenco modified Eagle MEM medium (manufactured by Nippon Pharmaceutical Co., Ltd.). Furthermore, after culturing at 37 ° C and 5% CO ₂ for 16 hours,
The following test compound and liposome were added.

1) Test compound: DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) 2) Liposome: PC / PS / DCP / CHOL = 50/50/10/75 (nmol) PC: Phosphatidylcholine (Funakoshi) PS): phosphatidylserine (manufactured by Funakoshi); DCP: dicetyl phosphate (manufactured by Funakoshi); CHOL: cholesterol (manufactured by Sigma) After culturing at 37 ° C and 5% CO ₂ for 16 hours, chloroform is added. The lipid fraction was extracted with methanol. The extracted lipid fraction was dissolved in isopropyl alcohol, and the produced cholesterol ester (CE) was quantified using the enzyme luminescence method. The production rate of cholesterol ester was calculated as the ratio when the control without drug was set to 100%. Cytotoxicity was examined under the microscope from changes in cell morphology. The results are shown in Table 1 below (wherein the compound numbers correspond to the compound numbers of the invention described in the above examples).

[0091]

[Table 1]

From the above results, the compound of the present invention markedly suppressed the production rate of cholesterol ester without showing cytotoxicity to macrophages, and markedly caused foaming of macrophages, which is a direct trigger for the development of arteriosclerosis. It is clear that it can be suppressed to.

[0093]

The compound of the present invention is useful as an active ingredient of a prophylactic / therapeutic agent for hyperlipidemia and a prophylactic / therapeutic agent for arteriosclerosis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 417/12 235 C07D 417/12 235 // (C07D 413/12 235: 28 263: 58) ( C07D 417/12 235: 28 277: 74)

Claims (14)

[Claims] 1. The following formula: (In the formula, Y represents a single bond or a sulfur atom; Z represents an oxygen atom, a sulfur atom, or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group. A group, an aryloxy group, an alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylamino group, a sulfonylamino group, a cyano group, a hydroxy group, or a nitro group; R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, Represents an acyl group, a sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group; n and m each independently represent an integer of 1, 2 or 3, and when n or m represents 2 or 3, Two or three identical or different R ¹ or R ² are substituted on the benzene ring; L is an alkylene group having 2 to 12 carbon atoms, or 1 or 2 4 or more phenylene groups or ether groups containing 4 or more atoms constituting the link chain length
Represents a linking group selected from 12 alkylene groups;
Y is a sulfur atom, Z is NR ⁴ , and n = m,
And when R ³ and R ⁴ represent the same substituent, R ¹ and
R ² does not represent the same substituent). 2. Y is a single bond or a sulfur atom; Z is an oxygen atom, a sulfur atom or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group or an alkyl halide. Group, aryl group, alkoxy group, alkoxycarbonyl group, sulfamoyl group, acylamino group,
A sulfonylamino group, a cyano group, a hydroxy group, or a nitro group; R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, or an acyl group; n and m each independently represent 1 or 2; L is a alkylene group having 4 to 11 carbon atoms, or a linking group selected from alkylene groups having 1 to 2 or more ether groups and having a chain length of 5 to 8 and forming a linking chain length. Compound. 3. Y is a single bond or a sulfur atom; Z is an oxygen atom, a sulfur atom or NR ⁴ ; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group. , Halogenated C _1-4 alkyl group, phenyl group, C _1-4 alkoxy group, C _1-4 alkoxycarbonyl group, C _1-4 alkylsulfamoyl group, C _1-4 alkylcarbonylamino group, C _{1- 4} alkylsulfonylamino group, cyano group, hydroxy group,
Or a nitro group; R ³ and R ⁴ are each independently a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group; n and m are each independently 1 or 2; L Is an alkylene group having 4 to 11 carbon atoms or 1 to 2 or more ether groups, and the number of atoms constituting the connecting chain length is 5 to 8
The compound according to claim 1, which is a linking group selected from the alkylene groups of 4. Y is a single bond or a sulfur atom; R ¹ is a hydrogen atom, a halogen atom, a C _1-4 alkyl group, or a nitro group; n is 1 or 2, and R ² is a hydrogen atom. , Halogen atom, C _1-4 alkyl group, halogenated C _1-4 alkyl group, phenyl group, C _1-4 alkoxy group, C _1-4 alkoxycarbonyl group, C _1-4 alkylsulfamoyl group, C _{1 -4} alkylcarbonylamino group, C _1-4 alkylsulfonylamino group,
A cyano group or a hydroxy group; m is 1 or 2; R ³ is a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group; Z is an oxygen atom, a sulfur atom, or N-
R ⁴ (R ⁴ represents a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group); L is an alkylene group having 4 to 11 carbon atoms, or 1 or 2 or more ether groups. The compound according to claim 1, which is a linking group selected from alkylene groups having 5 to 8 atoms, which comprises a linking chain length. 5. The compound according to claim 4, wherein R ² is a hydrogen atom when Y represents a single bond. 6. The method according to claim 4 or 5, wherein when L is an alkylene group containing 1 or 2 or more ether groups and having a connecting chain length of 5 to 8 atoms, Y is a sulfur atom. Compound of. 7. R ¹ is a halogen atom; n is 1 or 2
The compound according to claim 6, wherein R ² is a halogen atom; and m is 1 or 2. 8. The compound according to claim 7, wherein m is 2. 9. A prophylactic / therapeutic agent for hyperlipidemia, which comprises the compound according to any one of claims 1 to 3 as an active ingredient. 10. A prophylactic / therapeutic agent for hyperlipidemia, which comprises the compound according to any one of claims 4 to 8 as an active ingredient. 11. An agent for preventing or treating arteriosclerosis, which comprises the compound according to any one of claims 1 to 3 as an active ingredient. 12. An agent for preventing or treating arteriosclerosis, which comprises the compound according to any one of claims 4 to 8 as an active ingredient. 13. A cholesterol lowering agent comprising the compound according to any one of claims 1 to 3 as an active ingredient. 14. A cholesterol lowering agent comprising the compound according to any one of claims 4 to 8 as an active ingredient.