JP2000119249A - Novel urea derivative having nitrogen-containing aromatic heterocyclic ring - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel N-containing aromatic heterocyclic compound that has excellent TNF-α production inhibitory action and is useful as a therapeutic agent for a variety of diseases, particularly autoimmune diseases, for example, rheumatoid arthritis. SOLUTION: This novel compound is represented by formula I (R1 is H, a lower alkyl, phenyl or the like; R2 is H, a lower alkyl, a cycloalkyl or the like; R3 and R4 are each H, a lower alkyl, a lower alkenyl, a cycloalkyl, phenyl or the like; R5 is H, a lower alkyl, hydroxy or the like; R6 is an aromatic hetero-cyclic ring having an N atom in its ring; and A1 and A2 are each a lower alkylene) or its salts, typically 1-(2-cyclohexylethyl)-1-(2-hydroxyethyl)-3-(4- pyridyl-methyl) urea. The compound of formula I is prepared by, for example, allowing a compound of formula II to condense with an amino alcohol derivative by using 1,1'-carbonyldiimidazole as a condensing agent and subjecting the product to the Mitshunobu reaction with a thiol derivative of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel urea derivative having an inhibitory effect on TNF-α production and useful as a therapeutic agent for various diseases, in particular, an autoimmune disease such as rheumatoid arthritis. is there.

[0002]

2. Description of the Related Art TNF-α (Tumor Necrosis Factor-
α: tumor necrosis factor) was discovered as a factor that induces hemorrhagic necrosis at a tumor site, but is now recognized as a cytokine that is widely involved in biological defense and immune mechanisms through inflammation. However, continuous and excessive production of TNF-α causes tissue damage and causes various diseases and causes exacerbation. Therefore, it has been reported that it is important to suppress the overproduction of TNF-α in a pathological condition where TNF-α is excessively produced (Yamazaki, Clinical Immunity, 27 , 1270, 199).
Five). Examples of the pathological conditions related to TNF-α include the above-mentioned literatures such as rheumatoid arthritis and systemic lupus erythematosus (SL).
E), cachexia, acute infection, allergy, fever, anemia,
Many disease states such as diabetes are mentioned.

[0003] It has been reported that TNF-α plays an important role in the development of autoimmune diseases such as rheumatoid arthritis and Crohn's disease (Andreas Eigler).
etal., Immunology Today, 18 , 487, 1997).

[0004] TNF-α is known to be involved in various diseases including autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and systemic lupus erythematosus, as reported in the above literatures and others. Compounds that inhibit its production or suppress its action are expected to be useful for the treatment of various diseases, and many studies have been made. A summary of these drug studies is described in the above literature (Yamazaki, Clinical Immunity, 27 , 127).
0, 1995, Andreas Eigler et al., Immunology Today,
18 , 487, 1997). Also recently, T
The proteolytic enzyme involved in the secretion of NF-α was found to be a metalloprotease, and a study on the inhibitory effect of a metalloprotease inhibitor on TNF-α production has also been reported (Tokuhei 9-508115).

[0005] Although various studies have been made on drugs having an inhibitory effect on TNF-α production as described above, focusing on the chemical structure of the drug, the compound of the present invention has the chemical structural characteristics. No drugs are known. The chemical structural feature of the compound of the present invention is that it has a urea structure as a basic structure and has a sulfur atom and a nitrogen-containing aromatic heterocycle in a side chain. Few studies have been reported on drugs having such a urea structure as a basic skeleton, and no specific report has been made on drugs having a sulfur atom in the side chain.

[0006]

As described above, there is no specific report on a compound having a urea structure as a basic structure and having a sulfur atom and a nitrogen-containing aromatic heterocyclic ring in a side chain. Research and its pharmacological effects, especially TNF
Research on the -α production inhibitory effect has been a very interesting issue.

[0007]

Means for Solving the Problems The present inventors have focused on a urea structure, which has hardly been studied for application to drugs,
Synthetic studies on new urea derivatives in which a sulfur atom was introduced into one side chain and a nitrogen-containing aromatic heterocyclic ring was introduced into the other side chain succeeded in creating many new compounds. Further, their pharmacological actions were studied, and they were found that these novel compounds have excellent TNF-α production inhibitory actions.

The present invention relates to a compound represented by the following general formula [I] or a salt thereof (hereinafter collectively referred to as the compound of the present invention unless otherwise specified) and a pharmaceutical composition containing them as an active ingredient.

[0009]

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[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl group or the following formula [II].

[0011]

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R ² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a carboxyl group or an ester thereof, and a non-aromatic having a sulfur atom in the ring linked to a sulfur atom adjacent to A ¹ It may form a heterocyclic ring.

R ³ and R ⁴ are the same or different and
It represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or a phenyl group. R ⁵ represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group.

R ⁶ represents an aromatic heterocyclic ring having a nitrogen atom in the ring.

A ¹ and A ² are the same or different,
Shows a lower alkylene group.

Each of the lower alkyl groups defined above is a cycloalkyl group, a cycloalkenyl group, an adamantyl group,
It may be substituted with a phenyl group, a halogen atom, a hydroxy group, a lower alkoxy group, or an aromatic or non-aromatic heterocyclic ring having a nitrogen atom in the ring.

Each of the phenyl groups defined above may be substituted with a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, a halogen atom, a nitro group, a carboxyl group or an ester thereof.

The aromatic or non-aromatic heterocycle having a nitrogen atom in the ring as defined above may be a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, a cycloalkyl group, a phenyl group, a halogen atom, a hydroxy group or It may be substituted with a lower alkoxy group. ]

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The groups defined above will be described in detail below.

The lower alkyl group means methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl,
It represents a straight-chain or branched alkyl having 1 to 8 carbon atoms such as isopentyl, isohexyl, t-butyl, 3,3-dimethylbutyl and the like.

The lower alkenyl group includes vinyl, allyl, 3
2-butenyl, 5-hexenyl, isopropenyl and the like;
Indicate straight or branched alkenyl having 8 carbon atoms.

The cycloalkyl group is a cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The cycloalkenyl group means cycloalkenyl having 3 to 8 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.

The lower alkoxy group means a straight or branched alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy and t-butoxy.

The halogen atom means fluorine, chlorine, bromine and iodine.

The lower alkylene group is a group having 1 to 8 carbon atoms such as methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, dimethylethylene, propylethylene, isopropylethylene, and methylpropylene. Represents a linear or branched alkylene.

The aromatic heterocycle having a nitrogen atom in the ring includes pyridine, pyrimidine, pyrrole, imidazole,
A monocyclic or condensed polycyclic aromatic heterocycle having one or two nitrogen atoms in the ring, such as oxazole, thiazole, quinoline, indole, benzimidazole, benzoxazole, and benzothiazole is shown.

A non-aromatic heterocyclic ring having a nitrogen atom in the ring is a non-aromatic heterocyclic ring having one or two nitrogen atoms in the ring, such as pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and homopiperazine. Shows a ring.

The non-aromatic heterocyclic ring having a sulfur atom in the ring refers to a non-aromatic heterocyclic ring containing one or two sulfur atoms in the ring, such as tetrahydrothiophene, thiolactone and dithiolane.

Esters are alkyl, benzyl or phenyl esters having 1 to 8 carbon atoms such as methyl, ethyl and propyl.

In the compound of the present invention, the thiol group, hydroxy group, non-aromatic heterocyclic ring or nitrogen atom of the aromatic heterocyclic ring may be protected by a protecting group.

The term "thiol-protecting group" means a group commonly used as a thiol-protecting group such as an acyl group or a substituted thio group.

More specifically, an acyl group such as a lower alkanoyl group, a phenylcarbonyl group, a thenoyl group and a nicotinoyl group; an ester group such as a lower alkoxycarbonyl group and a substituted lower alkoxycarbonyl group; a substituted thio group such as a lower alkylthio group and a phenylthio group A substituted carbamoyl group. The phenyl ring of the phenylcarbonyl group and the phenylthio group may be substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group.

Specific examples of preferred protecting groups for the thiol group include acyl groups such as acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group and tenoyl group;
Ester groups such as -butoxycarbonyl group and benzyloxycarbonyl group; and substituted thio groups such as ethylthio group, t-butylthio group and phenylthio group.

The hydroxy-protecting group means those commonly used as hydroxy-protecting groups such as an acyl group, a substituted lower alkyl group and a substituted silyl group. More specifically, an acyl group such as a formyl group, a lower alkanoyl group, a halogeno lower alkanoyl group, or a phenylcarbonyl group; an ester group such as a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group; an allyl group, a lower alkoxy lower alkyl group, or a substituted lower alkoxy group Substituted lower alkyl groups such as lower alkyl group, phenyl lower alkyl group, tetrahydropyranyl group and tetrahydrofuranyl group; and substituted silyl groups such as lower alkylsilyl group and phenylsilyl group. The phenyl ring of the phenylcarbonyl group, phenyl lower alkoxycarbonyl group, phenyl lower alkyl group and phenylsilyl group may be substituted with a halogen atom, lower alkyl group, lower alkoxy group or nitro group.

Specific examples of preferred protecting groups for the hydroxy group include acyl groups such as formyl group, acetyl group, pivaloyl group, monochloroacetyl group, trichloroacetyl group, trifluoroacetyl group and benzoyl group; methoxycarbonyl group and ethoxycarbonyl group. Ester group such as a group, isobutoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group; allyl group, methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, benzyl group, Substituted alkyl groups such as 4-methoxybenzyl group, trityl group, 2-tetrahydropyranyl group and 2-tetrahydrofuranyl group; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t
And substituted silyl groups such as -butyldiphenylsilyl group.

The protecting group for the nitrogen atom of the non-aromatic heterocyclic ring or the aromatic heterocyclic ring is a group commonly used as a protecting group for an amino group such as an acyl group, a substituted lower alkyl group and a substituted sulfonyl group.

More specifically, acyl groups such as formyl group, lower alkanoyl group, halogeno lower alkanoyl group and phenylcarbonyl group; lower alkoxycarbonyl group;
Ester groups such as substituted lower alkoxycarbonyl groups and phenoxycarbonyl groups; substituted lower alkyl groups such as allyl groups, phenyl lower alkyl groups and benzoyl lower alkyl groups; and substituted sulfonyl groups such as lower alkylsulfonyl groups and phenylsulfonyl groups. The phenyl ring of the phenylcarbonyl group, phenoxycarbonyl group, phenyl lower alkyl group, benzoyl lower alkyl group and phenylsulfonyl group may be substituted with a halogen atom, lower alkyl group, lower alkoxy group or nitro group.

Specific examples of preferred protecting groups for the nitrogen atom of the non-aromatic heterocyclic ring or the aromatic heterocyclic ring include a formyl group,
Acetyl group, trichloroacetyl group, trifluoroacetyl group, acyl group such as benzoyl group; methoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, Ester groups such as benzyloxycarbonyl group, diphenylmethoxycarbonyl group and phenoxycarbonyl group; substituted alkyl groups such as allyl group, benzyl group, trityl group and (4-methoxyphenyl) diphenylmethyl group; benzenesulfonyl group;
Substituted sulfonyl groups such as 4,6-trimethylbenzenesulfonyl group and toluenesulfonyl group are exemplified.

The salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts, and include salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, and organic acids such as acetic acid, fumaric acid, maleic acid and tartaric acid. And salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium. When the compound of the present invention has a geometric isomer or an optical isomer, those isomers are also included in the scope of the present invention. Incidentally, the compound of the present invention may be in the form of a hydrate.

Preferred examples of the compound of the present invention include a compound represented by the general formula [I] wherein each group is as follows or a salt thereof; (1a) R ¹ is hydrogen atom, lower alkyl Group or a general formula [I
I] represents a group wherein the lower alkyl group may be substituted with a phenyl group; and / or (2a) R ² is selected from a hydrogen atom, a lower alkyl group, a carboxyl group or an ester thereof. A group; and / or
Or (3a) a group in which R ² is bonded to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring selected from a tetrahydrothiophene ring or a thiolactone ring; and / or (4a) R ³ And R ⁴ are the same or different and are selected from a hydrogen atom or a lower alkyl group, wherein the lower alkyl group is a group selected from a cycloalkyl group, a cycloalkenyl group, an adamantyl group, a phenyl group, a pyridine ring or a piperidine ring. (5a) R ⁵ is a group which may be substituted, and wherein the phenyl group is further substituted with a group selected from a halogeno lower alkoxy group, a halogen atom, a carboxyl group or an ester thereof; It represents a group selected from hydrogen atom or a lower alkyl group; and / or (6a) R ⁶ is a pyridine ring, a pyrimidine ring, a pyrrole ring An aromatic heterocycle having a nitrogen atom selected from an imidazole ring, a thiazole ring, an indole ring, a benzimidazole ring or a benzothiazole ring in the ring, wherein the aromatic heterocycle may be substituted with a lower alkyl group Represents a group.

That is, in the compound represented by the general formula [I], the compound of the above (1a) or a salt thereof; in the compound represented by the general formula [I], the compound of the above (2a) or a salt thereof; In the compound represented by the general formula [I], the compound of the above (3a) or a salt thereof.-In the compound represented by the general formula [I], the compound of the above (4a) or a salt thereof. A compound represented by the above (5a) or a salt thereof, a compound represented by the general formula [I], a compound represented by the above (6a) or a salt thereof, and a compound represented by the general formula [I]: (1a) above,
A compound comprising two or more combinations of (2a), (3a), (4a), (5a) and (6a) or a salt thereof.

More preferred examples of the compound of the present invention include:
Examples of the compound represented by the general formula [I] include a compound wherein each group is as follows or a salt thereof; (1b) R ¹ represents a group selected from a hydrogen atom or a lower alkyl group; and / or (2b) R ² represents a hydrogen atom; and / or (3b) R ³ represents a lower alkyl group, wherein the lower alkyl group is a group selected from a cycloalkyl group, a cycloalkenyl group, an adamantyl group or a phenyl group. And (4b) R ⁴ represents a hydrogen atom; and / or (5b) R ⁵ represents a hydrogen atom. And / or (6b) R ⁶ represents a pyridine ring.

That is, in the compound represented by the general formula [I], the compound of the above (1b) or a salt thereof; in the compound represented by the general formula [I], the compound of the above (2b) or a salt thereof; In the compound represented by the general formula [I], the compound of the above (3b) or a salt thereof;-In the compound represented by the general formula [I], the compound of the above (4b) or a salt thereof. A compound represented by the above (5b) or a salt thereof, a compound represented by the general formula [I], a compound represented by the above (6b) or a salt thereof, and a compound represented by the general formula [I]: (1b) above,
A compound comprising two or more combinations of (2b), (3b), (4b), (5b) and (6b) or a salt thereof.

More preferred examples of the compound of the present invention include compounds represented by the general formula [I] wherein each group is as follows, or salts thereof: (1c) R ¹ is a hydrogen atom, methyl And / or (2c) R ² represents a group selected from a hydrogen atom, an isopropyl group or a methoxycarbonyl group; and / or (3c) R ² represents a group forming a 2-oxotetrahydrothiophene ring or a tetrahydrothiophene ring by bonding to a sulfur atom adjacent to A ¹ ; and / or (4c) R ³ represents a hydrogen atom, an isopentyl group, Cyclopentylethyl group, 2-cyclohexylethyl group, 2-cycloheptylethyl group, 2-cyclooctylethyl group, 2
-(Cyclohexen-1-yl) ethyl group, 1-adamantylmethyl group, 2- (1-adamantyl) ethyl group,
Phenethyl group, 2,2-diphenylethyl group, 3-phenylpropyl group, 4-fluorophenethyl group, 4- (ethoxycarbonyl) phenethyl group, 4- (trifluoromethoxy) phenethyl group, 2- (1-piperidyl) ethyl And / or (5c) R ⁴ represents a group selected from a hydrogen atom, a 2-cyclohexylethyl group or a phenethyl group; and / or (6c) R ⁵ represents a hydrogen atom or a methyl group; and / or (7c) R ⁶ is 1-pyrrolyl group, 1-imidazolyl group, 4-
(1-methylimidazolyl) group, 4- (2-methylthiazolyl) group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4- (1-methylpyridinium) group, 4-pyrimidinyl group, 3-indolyl A group selected from a group, a 2-benzimidazolyl group or a 2-benzothiazolyl group; and / or (8c) A ¹ represents an ethylene group or an isopropylethylene group; and / or (9c) A ² represents a methylene group, And a group selected from an ethylene group, a methylmethylene group, a propylene group, a tetramethylene group and a pentamethylene group.

That is, in the compound represented by the general formula [I], the compound of the above (1c) or a salt thereof. In the compound represented by the general formula [I], the compound of the above (2c) or a salt thereof. In the compound represented by the general formula [I], the compound of the above (3c) or a salt thereof.-In the compound represented by the general formula [I], the compound of the above (4c) or a salt thereof. A compound represented by the above (5c) or a salt thereof; a compound represented by the general formula [I]; a compound represented by the above (6c) or a salt thereof; a compound represented by the general formula [I]; A compound of the formula (7c) or a salt thereof, a compound of the general formula [I], a compound of the above (8c) or a salt thereof, a compound of the general formula [I], a compound of the above (9c) or The salt, In the compound represented by the beauty and general formula [I], the (1c),
(2c), (3c), (4c), (5c), (6c), (7c), (8c) and (9c)
Or a salt thereof, which is a combination of two or more of the above.

The most preferred examples of the compound of the present invention include:
Examples of the compound represented by the general formula [I] include a compound in which each group is as follows or a salt thereof; (1d) R ¹ represents a group selected from a hydrogen atom or a methyl group; and / or 2d) R ² represents a hydrogen atom; and / or (3d) R ³ is 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2- (cyclohexen-1-yl) ethyl group, 2- (1-adamantyl) ethyl group, a phenethyl group, 3-phenylpropyl shows the group or 4-fluoro pheneticillin group selected from methyl group; and / or (4d) R ⁴ represents a hydrogen atom; and / or (5d) R ⁵ is a hydrogen atom And / or (6d) R ⁶ represents a group selected from a 3-pyridyl group or a 4-pyridyl group; and / or (7d) A ¹ represents an ethylene group; and / or (8d) A ² is a methylene group, It represents a group selected from styrene group or a propylene group.

That is, in the compound represented by the general formula [I], the compound of the above (1d) or a salt thereof; in the compound of the general formula [I], the compound of the above (2d) or a salt thereof; In the compound represented by the general formula [I], the compound of the above (3d) or a salt thereof;-in the compound of the general formula [I], the compound of the above (4d) or a salt thereof; A compound represented by the above (5d) or a salt thereof; a compound represented by the general formula [I]; a compound represented by the above (6d) or a salt thereof; a compound represented by the general formula [I]; A compound of (7d) or a salt thereof; a compound of the general formula [I]; a compound of the above (8d) or a salt thereof; and a compound of the general formula [I];
A compound comprising two or more combinations of (2d), (3d), (4d), (5d), (6d), (7d) and (8d), or a salt thereof.

The compounds of the present invention include the compounds of the above preferred examples, the more preferred examples, the further preferred examples, the most preferred examples described above, and salts thereof, in which a thiol group, a hydroxy group, a non-aromatic heterocycle or an aromatic heterocycle is used. A compound in which a nitrogen atom is protected by a protecting group or a salt thereof may be used. In a compound or a salt thereof in which a thiol group is protected with a protecting group, R ¹ is a protecting group for a thiol group. Particularly, a compound in which a thiol group is protected by an acetyl group or a salt thereof is preferable.

A typical synthetic route of the compound of the present invention is shown on the next page.

[0051]

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The compound [I] of the present invention can be synthesized by various synthetic routes as shown in the above reaction scheme.
This synthesis method is shown below for each route. However,
These routes exemplify typical routes and do not show all methods, and a detailed synthesizing method will be described in an embodiment described later.

Route A) [III] → [IV] → [I] Route B) [III] → [V] → [IV] → [I] Route C) [III] → [I]

The method of synthesizing these routes will be described in more detail below.

Route A)

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The compound [III] is reacted with the amino alcohol derivative [VI] in the presence of a condensing agent (for example, 1,1'-carbonyldiimidazole [VII]) to obtain a compound represented by the formula [IV]. Next, the compound [IV] is condensed with the thiol derivative [VIII] using the Mitsunobu reaction to obtain the compound [I] of the present invention.

Route B)

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The compound of the formula [V] is reacted with the compound of the formula [IX] in the presence of a condensing agent (for example, 1,1'-carbonyldiimidazole [VII]). Then, the compound [V] is deprotected with TBAF (tetra-n-butylammonium fluoride) to obtain a compound [IV]. Hereinafter, the compound [I] of the present invention is obtained in the same manner as in Route A.

Route C)

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The compound [III] is reacted with the compound represented by the formula [X] in the presence of a condensing agent (eg, 1,1'-carbonyldiimidazole [VII]) to give the compound [I] of the present invention.
Get.

In the above synthesis method, when the reactant has a thiol group, a hydroxy group or an amino group in the molecule, those groups may be protected with an appropriate protecting group if necessary. The protecting group can be removed by a conventional method after the reaction. When the reactant has a carboxyl group in the molecule, the carboxyl group may be esterified as necessary, and the ester may be converted to a carboxylic acid by hydrolysis or the like.

When R ² is linked to a sulfur atom adjacent to A ¹ to form a thiolactone ring in the compound of the present invention, this compound can be synthesized by the following method other than the above route. That is, when R ² represents a carboxyl group and R ¹ represents a hydrogen atom in the formula [I], the thiolactone ring can also be synthesized by condensing those groups.

The compound obtained by the above method can be converted into the above-mentioned salts by a conventional method.

The chemical structural feature of the compound of the present invention is that the compound has a urea structure as a basic structure and has a sulfur atom on one side chain and a nitrogen-containing aromatic heterocycle on the other side chain. Few studies have been reported on drugs having such a urea structure as a basic skeleton, and no specific report has been made on drugs having a sulfur atom in the side chain. When limiting to the study of drugs having an inhibitory effect on TNF-α production, which is the object of the present invention, no drug having a chemical structure similar to that of the compound of the present invention is known at all.

The present inventors have enthusiastically studied synthesis of compounds having a urea structure as a basic structure, which has hardly been studied as a drug in the past. Excellent T compound
The present inventors have found that they have an inhibitory effect on NF-α production, and completed the present invention. In the compound of the present invention, even when the sulfur atom in the side chain remains bonded to various groups (represented by R ¹ in the formula [I], except for a hydrogen atom), the form of SH (in the formula [I]) R ¹ is represented by a hydrogen atom).
When R ¹ serves as a protective group for the SH group, the bond as the protective group is subjected to hydrolysis or the like, and finally the SH
In some cases, the shape may be effective. When a carboxylic acid ester is contained in the molecule, the effect is exhibited even when the ester remains as it is, but the ester bond sometimes undergoes hydrolysis or the like, and eventually becomes a carboxylic acid form, and the effect may be exhibited. Furthermore, when the molecule contains a group that is converted into a free hydroxy group or amino group, those groups may be administered while being protected with an appropriate protecting group, or administered after removing those protecting groups. You may.

In order to examine the usefulness of the compound of the present invention, the inhibitory effect of the compound of the present invention on TNF-α production was examined. The details will be shown in the section on pharmacological tests below, but TNF induced by lipopolysaccharide (LPS) stimulation
As a result of examining the inhibitory effect on the release of -α in vivo, the compound of the present invention showed an excellent TNF-α production inhibitory effect.

The production of TNF-α is closely related to the development of autoimmune diseases such as rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus, cachexia, acute infection, allergy, fever, anemia, diabetes and the like. It is known that compounds that inhibit the production, such as the compounds of the present invention, are expected to be useful for treating a wide variety of diseases.

The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, etc., and can be formulated using widely used techniques. For example, tablets, capsules, granules, oral preparations such as powders, lactose, crystalline cellulose, starch, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, hydroxypropylcellulose, polyvinylpyrrolidone, etc. , A disintegrating agent such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, and silicone resin, and a film agent such as a gelatin film may be added as necessary.

The dose of the compound of the present invention can be appropriately selected depending on the condition, age, dosage form, etc., and usually 0.1 to 5000 mg, preferably 1 to 1000 mg per day for oral preparations.
g may be administered once or in several divided doses.

The production examples, preparation examples, and results of pharmacological tests of the compounds of the present invention are shown below. These examples are for better understanding of the present invention, and do not limit the scope of the present invention. Absent.

[0071]

EXAMPLES [Production Examples] Reference Example 1 3- (4-pyridyl) propylamine (Reference compound 1-
1)

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N- [3- (4-pyridyl) propyl] phthalimide (799 mg) and hydrazine monohydrate (6
00 mg) in methanol (15 ml) and heat to reflux for 4 hours. After cooling, the reaction solution is concentrated under reduced pressure, and chloroform is added to the residue. The organic layer was washed with a saturated aqueous solution of sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (Reference compounds 1-1 and 36).
6 mg).

(Reference compound 1-1) IR (Film, cm ^-1 ) 3359, 2932, 285
9,1602,1558,1416,1219,106
9,994,893,835,798,755

Using the same method as in Reference Example 1, the following compound is obtained.

(RS) -1- (4-pyridyl) ethylamine (Reference compound 1-2)

3- (2-pyridyl) propylamine (Reference compound 1-3) IR (Film, cm ^-1 ) 2980, 2935, 170
7,1592,1110

3- (3-pyridyl) propylamine (Reference compound 1-4) IR (Film, cm ^-1 ) 3362, 3284, 293
1,858,1575,1478,1423

3- (1-pyrrolyl) propylamine (Reference compound 1-5) IR (Film, cm ^-1 ) 3368, 3295, 309
7,2931,2868,1500,1449,135
2,1280,1090,1060

(2-Methyl-4-thiazolyl) methylamine (Reference compound 1-6) IR (Film, cm ^-1 ) 3363, 3290, 292
2,2849,1600,1525,1478,144
0,1185,1125

5- (4-pyridyl) pentylamine (Reference compound 1-7) IR (Film, cm ^-1 ) 3350, 2932, 285
8, 1603, 1536, 1484, 1416, 139
1,1316,1220,804

(4-pyrimidinyl) methylamine (Reference compound 1-8) IR (Film, cm ^-1 ) 3362, 1658, 164
1,1586,1551,1389

Reference Example 2 N- (2-cyclohexylethyl)-(4-pyridyl)
Methylamine (Reference compound 2-1)

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2-cyclohexylethyl bromide (1.50
g) in ethanol (16 ml), 4-picolylamine (1.00 g), anhydrous potassium carbonate (1.32 g)
And sodium iodide (3.49 g) were added, and the mixture was refluxed for 17 hours while stirring. Water is added to the reaction solution, and extracted with ether. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain the title compound (Reference compound 2-1, 0.68 g).

Using the same method as in Reference Example 2, the following compound is obtained.

N-phenethyl-3- (4-pyridyl)
Propylamine (Reference compound 2-2) IR (Film, cm ^-1 ) 3025, 2933, 160
2,1495,1453,1415

Reference Example 3 4- (4-pyridyl) butylamine (Reference compound 3-
1)

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Under a nitrogen atmosphere, lithium aluminum hydride (370 mg) was added to anhydrous ether (14 m
l) and a solution of 4- (4-pyridyl) butyronitrile (705 mg) in anhydrous ether (10 ml) is added dropwise. Stir at room temperature for 2.5 hours. Under ice-cooling, anhydrous sodium sulfate is added to the reaction solution, and water (0.5 ml) is added dropwise. Then, tetrahydrofuran is added, and the insoluble matter is filtered. The filtrate is concentrated under reduced pressure to obtain the title compound (Reference compound 3-1, 827 mg).

(Reference compound 3-1) IR (Film, cm ^-1 ) 3284, 3068, 302
4,2932,2858,1602,1557,145
8,1415,1219,1069,993,804,
752

Reference Example 4 2- (aminomethyl) benzothiazole hydrochloride (Reference compound 4-1)

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1) 2-phenyl-4,5-dihydro-
To a solution of 1,3-oxazol-5-one (1.8 g) in acetic acid (14 ml) was added 2-aminothiophenol (1.
2 ml) and stir for 1 hour while heating to 40 ° C. Water is added to the reaction solution, and the precipitate is collected by filtration to obtain 2- (benzoylaminomethyl) benzothiazole (0.75 g) as crystals.

Mp 139.5-142.0 ° C IR (KBr, cm ^-1 ) 3270, 1639, 153
6,1522,1317

2) 2- (benzoylaminomethyl) benzothiazole (750 mg) in dioxane (10 m
1) Concentrated hydrochloric acid (5.8 ml) is added to the solution, and the mixture is refluxed for 40 hours while stirring. The reaction solution is concentrated under reduced pressure. Under ice-cooling, 4N aqueous sodium hydroxide solution (20 ml) was added to the residue.
To pH 10 or higher, and extracted with chloroform.
The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is dissolved in methanol (10 ml), and thereto is added a 4N hydrogen chloride ethyl acetate solution (1.4 ml) under ice-cooling. After concentration under reduced pressure, the precipitate was collected by filtration and the title compound (Reference compound 4-1, 486 mg)
Get.

(Reference compound 4-1) mp 250 ° C. or higher IR (KBr, cm ⁻¹ ) 3063, 1502, 143
6,1358,1084

Reference Example 5 2- (t-butyldimethylsiloxy) ethylamine (Reference compound 5-1)

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In a solution of 2-aminoethanol (2.0 ml) in anhydrous methylene chloride (65 ml), t-butyldimethylchlorosilane (5.4 g) and imidazole (2.
7 g) and stir at room temperature overnight. A 5% aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (Reference Compound 5-
1, 6.0 g).

(Reference compound 5-1) IR (Film, cm ^-1 ) 2929, 2857, 147
2,1256,1107,836,777

Reference Example 6 N- (2-hydroxyethyl) -2- [4- (trifluoromethoxy) phenyl] ethylamine hydrochloride (Reference compound 6-1)

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In a solution of 4- (trifluoromethoxy) phenethylamine (1.47 g) in ethanol (22 ml), 2-bromoethanol (0.77 ml), anhydrous potassium carbonate (1.40 g) and sodium iodide (2.54 g) were added.
g) and heat to reflux overnight with stirring. After cooling,
The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is extracted with ether. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography, and then ethyl acetate (0.1 m
l), and thereto is added a 4N hydrogen chloride dioxane solution (0.65 ml) under ice cooling. The precipitate is collected by filtration to give the title compound (Reference Compound 6-1, 437 mg) as crystals.

(Reference compound 6-1) mp 101.0-115.0 ° C. IR (KBr, cm ⁻¹ ) 3409, 2959, 245
8,1592,1514,1158

The following compounds were obtained in the same manner as in Reference Example 6.

N- (2-hydroxyethyl) -2-
[4- (Ethoxycarbonyl) phenyl] ethylamine hydrochloride (Reference compound 6-2) mp 147.5-153.0 ° C IR (KBr, cm ^-1 ) 3406, 2967, 279
4,2459,1715,1613,1578,144
8,1416,1368,1309,1284,118
2,1128,1110,1063,1020,85
2,782,760,702

N- [2- (t-butyldimethylsiloxy) ethyl] -2- (1-piperidyl) ethylamine (Reference compound 6-3) IR (Film, cm ^-1 ) 2934, 2855, 281
0, 1464, 1256, 1138, 1089, 83
6,776

2-cyclohexyl-N- (2-tetrahydrothienylmethyl) ethylamine hydrochloride (Reference compound 6-4) mp 190 ° C. IR (KBr, cm ⁻¹ ) 2925, 2852, 278
7,2596,1595,1477,1450

Reference Example 7 2-cyclooctyl-N- (2-hydroxyethyl) ethylamine hydrochloride (Reference compound 7-1)

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Under a nitrogen atmosphere, lithium aluminum hydride (358 mg) was added to anhydrous ether (22 m
l) and suspended in N- (2-hydroxyethyl) cyclooctylacetic acid amide (998 mg) in anhydrous ether (8 m
l) The solution is added dropwise. Stir at room temperature overnight. Under ice-cooling, ethyl acetate and 0.1 N hydrochloric acid are added to the reaction solution until no foaming occurs. Then, the mixture is made basic by adding a 4N aqueous sodium hydroxide solution, and extracted with ether. The organic layer is washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is dissolved in ether (0.5 ml), and thereto is added a 4N solution of hydrogen chloride in ethyl acetate (0.75 ml) under ice-cooling. The precipitate was collected by filtration to give the title compound (Reference compound 7-1, 500 mg)
Is obtained as crystals.

(Reference compound 7-1) mp 130 ° C. IR (KBr, cm ⁻¹ ) 3374, 2918, 285
2,1591,1446

Reference Example 8 4- (aminomethyl) quinoline (Reference compound 8-1)

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4-quinolinecarboxaldehyde (2.
0 g) in methanol (50 ml) was added with ammonium acetate (9.8 g) and stirred at room temperature for 3 hours. Furthermore,
Add sodium cyanoborohydride (1.0 g) and add 4 g
Stir for 0 minutes. The reaction solution is poured into water and concentrated under reduced pressure.
The concentrate is extracted with chloroform. The organic layer is extracted by adding 1N hydrochloric acid. The hydrochloric acid extract is made alkaline by the addition of a 4N aqueous sodium hydroxide solution, and then extracted with chloroform. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound (Reference compound 8-1, 0.14 g).

(Reference compound 8-1) IR (Film, cm ^-1 ) 3289, 1595, 151
1,1464,1316

Example 1 1- (2-Cyclohexylethyl) -1- (2-hydroxyethyl) -3- (4-pyridylmethyl) urea (Compound 1-1)

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Under a nitrogen atmosphere, 1,1'-carbonyldiimidazole (3.60 g) was added to 4- (aminomethyl) pyridine (2.00 g) in anhydrous tetrahydrofuran (62 m
l) Dissolve in solution and stir at room temperature for 10 minutes. N- (2-Hydroxyethyl) -2-cyclohexylethylamine hydrochloride (4.64 g) is added to the reaction solution, and the mixture is refluxed for 2 hours. Under ice-cooling, chloroform was added to the reaction solution for extraction. The organic layer was treated with a 10% aqueous sodium hydrogen carbonate solution, water,
The extract is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain the title compound (Compound 1-1, 5.09 g).

(Compound 1-1) mp 143.0-145.5 ° C. IR (KBr, cm ⁻¹ ) 3332, 2922, 285
0, 1624, 1537, 1443, 1407, 137
2,1072

Using the same method as in Example 1, the following compound is obtained.

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- [2- (4-pyridyl) ethyl] urea (Compound 1-2) IR (Film, cm ^-1 ) 3325,2922,285
0, 1627, 1537, 1448, 1415, 136
5,1269,1053

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- [3- (4-pyridyl) propyl] urea (Compound 1-3) IR (Film, cm ^-1 ) 3340, 2922, 285
0,1621,1538,1442,1422,140
4,1373,1294,1249,1222,107
5,1061

1- (2-cyclohexylethyl) -1
-(2-hydroxyethyl) -3-[(RS) -1-
(4-pyridyl) ethyl] urea (compound 1-4) IR (Film, cm ^-1 ) 3307, 2923, 285
0, 1632, 1532, 1449, 1409, 124
2,1051

1- (2-cyclopentylethyl) -1
-(2-hydroxyethyl) -3- (4-pyridylmethyl) urea (compound 1-5) mp 122.7-125.5 ° C IR (KBr, cm ^-1 ) 3342, 2942, 286
5,1623,1535,1405,1367,126
6,1236,1077

1- [2- (1-adamantyl) ethyl] -1- (2-hydroxyethyl) -3- (4-pyridylmethyl) urea (compound 1-6)

1- (2-hydroxyethyl) -1-isopentyl-3- (4-pyridylmethyl) urea (compound 1-7) IR (Film, cm ^-1 ) 3327, 2955, 286
9,1631,1606,1563,1535,146
8,1416,1366,1237,1066,756

1- (2-hydroxyethyl) -1-phenethyl-3- (2-pyridylmethyl) urea (compound 1-8) IR (Film, cm ^-1 ) 3338, 2928, 163
2,1597,1571,1537,1478,143
7,1273,1048,751,701

1- (2-hydroxyethyl) -1-phenethyl-3- (3-pyridylmethyl) urea (compound 1-9) IR (Film, cm ^-1 ) 3330, 1626, 153
6,1428,1044

1- (2-hydroxyethyl) -1-phenethyl-3- (4-pyridylmethyl) urea (compound 1-10) mp 98.1-99.5 ° C. IR (KBr, cm ⁻¹ ) 3347 , 3031,292
4,2862,1622,1530,1451,142
2,1364,1276,1223,1078,100
2,794,771,746,696

1- (2-hydroxyethyl) -1-phenethyl-3- [2- (2-pyridyl) ethyl] urea (compound 1-11)

1- (2-hydroxyethyl) -1-phenethyl-3- [2- (3-pyridyl) ethyl] urea (compound 1-12) IR (Film, cm ^-1 ) 3325, 2930, 162
8,1538,1235,1049,1030,753

1- (2-hydroxyethyl) -1-phenethyl-3- [2- (4-pyridyl) ethyl] urea (compound 1-13) IR (Film, cm ^-1 ) 3329, 2930, 162
5,1537,1496,1453,1416,136
5,1273,1233,701

1- (2-hydroxyethyl) -1-phenethyl-3- [3- (2-pyridyl) propyl] urea (compound 1-14) IR (Film, cm ^-1 ) 3338,3026,292
9,1625,1597,1496,751

1- (2-hydroxyethyl) -1-phenethyl-3- [3- (3-pyridyl) propyl] urea (compound 1-15) IR (Film, cm ^-1 ) 3327, 2929, 163
2,1537,1496,1479,1454,123
4

1- (2-hydroxyethyl) -1-phenethyl-3- [3- (4-pyridyl) propyl] urea (compound 1-16) IR (Film, cm ^-1 ) 3327, 2931, 162
7, 1539, 1496, 1452, 1414, 136
7,1272,1234,1067,752,702

1- (2-hydroxyethyl) -1-
(3-Phenylpropyl) -3- [3- (4-pyridyl) propyl] urea (Compound 1-17) IR (Film, cm ^-1 ) 3325, 2931, 162
6,1607,1539,1271,1238,105
2,753,700

1- (4-fluorophenethyl) -1-
(2-Hydroxyethyl) -3- [3- (4-pyridyl) propyl] urea (Compound 1-18) IR (Film, cm ^-1 ) 3329, 2931, 162
7, 1607, 1540, 1509, 756

1- (2-hydroxyethyl) -3-
[3- (4-pyridyl) propyl] -1- [4- (trifluoromethoxy) phenethyl] urea (compound 1-1
9) IR (Film, cm ^-1 ) 3328, 2932, 162
8, 1540, 1510, 1262, 759

1- [4- (ethoxycarbonyl) phenethyl] -1- (2-hydroxyethyl) -3- [3-
(4-pyridyl) propyl] urea (compound 1-20) IR (Film, cm ^-1 ) 3330, 2932, 171
4,1609,1538,1446,808,765

1- (2-cyclohexylethyl) -1
-(2-hydroxyethyl) -3- [3- (1-pyrrolyl) propyl] urea (compound 1-21) mp 88.2-89.1 ° C IR (KBr, cm ^-1 ) 3332, 3239, 292
1,846,1616,1540,1504,148
2,1444,1406,1343,1319,127
7, 1256, 1238, 1219, 1094

1- (2-hydroxyethyl) -3-
[2- (1-Imidazolyl) ethyl] -1-phenethylurea (Compound 1-22) IR (Film, cm ^-1 ) 3114, 1626, 153
7,1454,1232

1- (2-cyclohexylethyl) -1
-(2-hydroxyethyl) -3-[(2-methyl-4
-Thiazolyl) methyl] urea (Compound 1-23) IR (Film, cm ^-1 ) 3332, 2921, 285
0, 1629, 1534, 1447, 1406

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- [4- (4-pyridyl) butyl] urea (Compound 1-24) IR (Film, cm ^-1 ) 3324, 2923, 285
1,1626,1607,1538,1448,141
5,1372,1315,1269,1055,100
3,753

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- [5- (4-pyridyl) pentyl] urea (Compound 1-25) IR (Film, cm- ¹ ) 3332, 2923, 285
2,1624,1539,1448,1416,137
3,1270,1055,754

1- (2-cycloheptylethyl) -1
-(2-hydroxyethyl) -3- (4-pyridylmethyl) urea (compound 1-26) mp 124.0-130.5 ° C IR (KBr, cm ^-1 ) 3343, 3038, 292
2,2850,1622,1608,1534,149
6,1458,1302,794,769

1- (2-cyclooctylethyl) -1
-(2-hydroxyethyl) -3- (4-pyridylmethyl) urea (compound 1-27) mp 130.0-131.5 ° C IR (KBr, cm ^-1 ) 3782, 3686, 363
6,3341,2921,2852,1711,162
3,1608,1534,1497,1449,142
0,1302,1272,787,768

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- (4-pyrimidinylmethyl) urea (Compound 1-28) IR (Film, cm ^-1 ) 3350, 2922, 285
1,1633,1585,1538,1448,140
9,1387,1355

1- (2-cyclohexylethyl) -1
-(2-hydroxyethyl) -3- [2- (1-methyl-4-imidazolyl) ethyl] urea (compound 1-2
9)

1- (2-cyclohexylethyl) -1
-(2-hydroxyethyl) -3- [2- (3-indolyl) ethyl] urea (compound 1-30) mp 147.5-149.0 ° C IR (KBr, cm ^-1 ) 3229, 2922, 161
0,1557,1230,1060,751

1- (2-benzimidazolylmethyl)
-3- (2-Cyclohexylethyl) -3- (2-hydroxyethyl) urea (compound 1-31) mp 163.2-165.2 ° C (decomposition) IR (KBr, cm ^-1 ) 3154, 2917, 285
1,1617,1554,1441

1- (2-benzothiazolylmethyl)-
3- (2-cyclohexylethyl) -3- (2-hydroxyethyl) urea (Compound 1-32) IR (Film, cm ^-1 ) 3323, 2922, 163
4,1536,1448,1410

1- (2-cyclohexylethyl) -1
-(2-Hydroxyethyl) -3- (4-quinolylmethyl) urea (Compound 1-33) IR (Film, cm ^-1 ) 3319, 2922, 285
1,1633,1538,1242

1- [2- (1-adamantyl) ethyl] -1- (2-hydroxyethyl) -3- [3- (1
-Imidazolyl) propyl] urea (compound 1-34) mp 111-125 ° C IR (KBr, cm ^-1 ) 3378, 3216, 311
7,2899,2845,1626,1596,154
2,1482,1450,1409

Example 2 1- [2- (t-butyldimethylsiloxy) ethyl]-
1- [2- (1-cyclohexenyl) ethyl] -3-
(4-pyridylmethyl) urea (compound 2-1)

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Under a nitrogen atmosphere, 4- (aminomethyl) pyridine (0.73 g) and 1,1'-carbonyldiimidazole (1.23 g) were added to anhydrous tetrahydrofuran (1
2 ml) and stir at room temperature for 30 minutes. N- [2- (t-Butyldimethylsiloxy) ethyl] -2- (1-cyclohexenyl) ethylamine (1.88 g) is added to the reaction solution, and the mixture is heated under reflux for 1.5 hours. After cooling, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (compounds 2-1 and 3.01).
g).

(Compound 2-1) IR (Film, cm ^-1 ) 3350, 2928, 285
6,1633,1601,1563,1530,147
2,1414

Using the same method as in Example 2, the following compound is obtained.

1- [2- (t-butyldimethylsiloxy) ethyl] -1- [2- (1-piperidyl) ethyl]
-3- (4-Pyridylmethyl) urea (compound 2-2) IR (Film, cm ^-1 ) 3342, 2932, 285
5,2803,1644,1536,1471,125
6,1104,836,776

1- [2- (t-butyldimethylsiloxy) ethyl] -1- [2- (4-pyridyl) ethyl]-
3- [3- (4-Pyridyl) propyl] urea (Compound 2-3) IR (Film, cm ^-1 ) 3351, 2930, 285
7, 1634, 1603, 1535, 1470, 141
5,1363,1252,1103,928,836
779

1- [2- (t-butyldimethylsiloxy) ethyl] -3- (2-cyclohexylethyl) -3
-(4-pyridylmethyl) urea (compound 2-4)

Example 3 1- [2- (1-Cyclohexenyl) ethyl] -1-
(2-hydroxyethyl) -3- (4-pyridylmethyl) urea (compound 3-1)

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Under a nitrogen atmosphere, 1- [2- (t-butyldimethylsiloxy) ethyl] -1- [2- (1-cyclohexenyl) ethyl] -3- (4-pyridylmethyl) urea (compound 2-1) 3.01 g) and tetrafluoride-
A 1 M solution of n-butylammonium in tetrahydrofuran (8.0 ml) was added to anhydrous tetrahydrofuran (18 ml).
And stir at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate and chloroform. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, and the title compound (compound 3
-1, 1.58 g).

(Compound 3-1) mp 117.0-118.0 ° C. IR (KBr, cm ⁻¹ ) 3347, 2925, 162
2,1531,1420,1403,1365

Using the same method as in Example 3, the following compound is obtained.

1- (2-hydroxyethyl) -1-
[2- (1-Piperidyl) ethyl] -3- (4-pyridylmethyl) urea (Compound 3-2) IR (Film, cm ^-1 ) 3316, 2935, 163
6,1531,1470,1415,1362,127
2,1042,755

.1- (2-hydroxyethyl) -1-
[2- (4-pyridyl) ethyl] -3- [3- (4-pyridyl) propyl] urea (compound 3-3)

1- (2-cyclohexylethyl) -3
-(2-Hydroxyethyl) -1- (4-pyridylmethyl) urea (Compound 3-4) IR (Film, cm ^-1 ) 3349, 2922, 285
0, 1628, 1536, 1447, 1415, 126
6

Example 4 1- [2- (acetylthio) ethyl] -1- (2-cyclohexylethyl) -3- (4-pyridylmethyl) urea (compound 4-1)

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In a nitrogen atmosphere, 1- (2-cyclohexylethyl) -1- (2-hydroxyethyl) -3- (4-
Pyridylmethyl) urea (Compound 1-1, 550 mg)
And triphenylphosphine (944 mg) are dissolved in anhydrous tetrahydrofuran (4 ml), and the mixture is stirred under sodium chloride-ice cooling for 30 minutes. While maintaining the liquid temperature at 5 ° C. or lower, diisopropyl azodicarboxylate (0.
71 ml) and then thioacetic acid (0.26 ml) are added dropwise. After stirring for 15 minutes, a 10% aqueous sodium hydrogen carbonate solution (30 ml) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to give the title compound (compound 4-1).
Get.

(Compound 4-1) IR (Film, cm ^-1 ) 3348, 2922, 285
0,1692,1633,1602,1531,141
3,1358,1294,1223,1134,110
8

Using the same method as in Example 4, the following compound is obtained.

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [2- (4-
Pyridyl) ethyl] urea (compound 4-2) IR (Film, cm ^-1 ) 3351, 923, 285
0,1772,1711,1633,1538,143
4,1394,755,720

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [3- (4-
Pyridyl) propyl] urea (compound 4-3) mp 70 ° C IR (KBr, cm ^-1 ) 3346, 3066, 302
7,2923,2840,1705,1627,160
4,1540,1485,1455,1442,142
4,1416,1403,1358,1314,129
4,1264,1245,1225,1186,116
7,1144,1119

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [1- (4-
Pyridyl) ethyl] urea (compound 4-4) IR (Film, cm ^-1 ) 2976, 2922, 285
0,1727,1690,1632,1600,152
6,1448,1407,1374,1296,122
0,1135,1107

1- [2- (acetylthio) ethyl]-
1- (2-cyclopentylethyl) -3- (4-pyridylmethyl) urea (compound 4-5) IR (Film, cm ^-1 ) 3349, 2946, 169
2,1632,1602,1531,1414,129
5,1135

1- [2- (acetylthio) ethyl]-
1- [2- (1-adamantyl) ethyl] -3- (4-
Pyridylmethyl) urea (compound 4-6)

1- [2- (acetylthio) ethyl]-
1-Isopentyl-3- (4-pyridylmethyl) urea (compound 4-7) IR (Film, cm ^-1 ) 3350, 2955, 287
0,1693,1633,1601,1563,153
1,1468,1415,1357,1296,123
7,1137,948

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- (2-pyridylmethyl) urea (compound 4-8) IR (Film, cm ^-1 ) 3383,2930,168
8, 1636, 1593, 1532, 1436, 135
5,1137,752

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- (3-pyridylmethyl) urea (compound 4-9) IR (Film, cm ^-1 ) 3370, 2930, 168
9,1633,1536,1290

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- (4-pyridylmethyl) urea (compound 4-10) IR (Film, cm ^-1 ) 3360, 3026, 293
0,1690,1633,1602,1562,153
3,1496,1454,1415,1357,129
1,1224,1136,951,751,701

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [2- (2-pyridyl) ethyl]
Urea (compound 4-11)

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [2- (3-pyridyl) ethyl]
Urea (compound 4-12) IR (Film, cm ^-1 ) 3390, 1688, 163
3,1535,1479,1136,752

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [2- (4-pyridyl) ethyl]
Urea (compound 4-13) IR (Film, cm ^-1 ) 3390, 1685, 163
6,1604,1534,1497,1416,135
6,1291,1221,1136,752,701

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [3- (2-pyridyl) propyl] urea (compound 4-14) IR (Film, cm ^-1 ) 3399, 3062, 293
1,1682,1633,1568,1537,147
6,751

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [3- (3-pyridyl) propyl] urea (compound 4-15) IR (Film, cm ^-1 ) 3391, 2930, 168
8, 1632, 1536, 1479, 1290, 113
5

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [3- (4-pyridyl) propyl] urea (compound 4-16) IR (Film, cm ^-1 ) 3391, 293, 168
8,1632,1603,1536,1497,145
3,1415,1356,1290,1220,113
6,994,952,751,701

1- [2- (acetylthio) ethyl]-
1- (3-phenylpropyl) -3- [3- (4-pyridyl) propyl] urea (compound 4-17) IR (Film, cm ^-1 ) 3391, 293, 168
8,1632,1537,1496,1415,129
4,1219,952,753,700

1- [2- (acetylthio) ethyl]-
1- (4-Fluorophenethyl) -3- [3- (4-pyridyl) propyl] urea (compound 4-18) IR (Film, cm ^-1 ) 3392,2933,168
6,1636,1603,1509,1220

1- [2- (acetylthio) ethyl]-
3- [3- (4-pyridyl) propyl] -1- [4-
(Trifluoromethoxy) phenethyl] urea (compound 4-19) IR (Film, cm ^-1 ) 3394, 2935, 169
0,1634,1604,1536,1261

1- [2- (acetylthio) ethyl]-
1- [4- (ethoxycarbonyl) phenethyl] -3-
[3- (4-pyridyl) propyl] urea (compound 4-
20) IR (Film, cm ^-1 ) 3396, 2933, 171
4,1690,1608,1534,1415,76
5,706

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [3- (1-
Pyrrolyl) propyl] urea (compound 4-21) IR (Film, cm ^-1 ) 3366, 2923, 285
0, 1690, 1632, 1533, 1447, 140
4,1355,1282,1218,1136,109
0

1- [2- (acetylthio) ethyl]-
3- [2- (1-Imidazolyl) ethyl] -1-phenethylurea (compound 4-22) IR (Film, cm ^-1 ) 3387, 2937, 168
8,1640,1537,1289

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3-[(2-methyl-4-thiazolyl) methyl] urea (compound 4-2
3)

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [4- (4-
Pyridyl) butyl] urea (compound 4-24) IR (Film, cm ^-1 ) 3350, 2922, 285
1,1690,1632,1603,1534,144
8, 1414, 1355, 1293, 1219, 113
7,951,754

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [5- (4-
Pyridyl) pentyl] urea (compound 4-25) IR (Film, cm ^-1 ) 3354, 2924, 285
2,1689,1633,1536,1448,141
5,1356,1293,1218,1136,993

1- [2- (acetylthio) ethyl]-
1- (2-cycloheptylethyl) -3- (4-pyridylmethyl) urea (compound 4-26)

1- [2- (acetylthio) ethyl]-
1- (2-cyclooctylethyl) -3- (4-pyridylmethyl) urea (compound 4-27) IR (Film, cm ^-1 ) 3350, 2919, 285
4,1693,1633,1602,1563,153
1,1446,1415,755

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- (4-pyrimidinylmethyl) urea (compound 4-28) IR (Film, cm ^-1 ) 3369, 2922, 285
0, 1691, 1632, 1582, 1530, 144
8,1386,1353

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [2- (1-
Methyl-4-imidazolyl) ethyl] urea (compound 4
−29) IR (Film, cm ⁻¹ ) 3350, 2922, 285
0,1692,1639,1536,1448,140
7, 1355, 1295, 1226, 1137, 95
1,753

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [2- (3-
Indolyl) ethyl] urea (compound 4-30) IR (Film, cm ^-1 ) 3400,3256,292
3,2850,1683,1633,1537,145
4,743

1- [2- (acetylthio) ethyl]-
3- (2-benzimidazolylmethyl) -1- (2-cyclohexylethyl) urea (compound 4-31) IR (Film, cm ^-1 ) 3338, 2923, 285
1,1693,1633,1537,1446,129
6,1272,751

1- [2- (acetylthio) ethyl]-
3- (2-benzothiazolylmethyl) -1- (2-cyclohexylethyl) urea (compound 4-32) IR (Film, cm ^-1 ) 3361, 922, 168
9,1639,1533

1- [2- (acetylthio) ethyl]-
1- [2- (1-cyclohexenyl) ethyl] -3-
(4-pyridylmethyl) urea (compound 4-33)

1- [2- (acetylthio) ethyl]-
1- [2- (1-Piperidyl) ethyl] -3- (4-pyridylmethyl) urea (Compound 4-34) IR (Film, cm ^-1 ) 3350, 2934, 285
1,803,1691,1649,1600,153
0,1414,1355,1274,1114,99
4,952,758

1- [2- (acetylthio) ethyl]-
1- [2- (4-pyridyl) ethyl] -3- [3- (4
-Pyridyl) propyl] urea (compound 4-35) IR (Film, cm ^-1 ) 3391, 2931, 168
8,1632,1603,1537,1416,135
7,1294,1220,1136

1- [2- (acetylthio) ethyl]-
3- (2-cyclohexylethyl) -3- (4-pyridylmethyl) urea (compound 4-36) IR (Film, cm ^-1 ) 3350, 2922, 285
0, 1693, 1633, 1601, 1531, 141
4,1252,1135

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- (4-quinolylmethyl) urea (compound 4-37)

1- [2- (acetylthio) ethyl]-
1- [2- (1-adamantyl) ethyl] -3- [3-
(1-imidazolyl) propyl] urea (compound 4-3
8) IR (Film, cm ^-1 ) 3392, 3109, 290
2,2845,1690,1633,1534,144
9,1405

Example 5 1- (2-Cyclohexylethyl) -1- [2- (methylthio) ethyl] -3- [3- (4-pyridyl) propyl)] urea (Compound 5-1)

Embedded image

Under a nitrogen atmosphere, 4- (3-aminopropyl) pyridine (Reference compound 1-1, 101 mg) and 1,1'-carbonyldiimidazole (131 mg) were suspended in anhydrous tetrahydrofuran (10 ml), and the suspension was added at room temperature for 30 minutes. Stir for minutes. Add 2-cyclohexyl-N
-[2- (methylthio) ethyl] ethylamine (149
mg) and heated to reflux for 2 hours. Water is added to the reaction mixture under ice cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The resulting oil is purified by silica gel column chromatography,
The title compound (Compound 5-1, 212 mg) is obtained.

(Compound 5-1) IR (Film, cm ^-1 ) 3346, 2922, 285
1,1627,1535,1447,1415,129
4,1221

Using the same method as in Example 5, the following compound is obtained.

1- (2-cyclohexylethyl) -1
-[2- (methylthio) ethyl] -3- (4-pyridylmethyl) urea (compound 5-2) mp 65.5-67.3 ° C IR (KBr, cm ^-1 ) 3331, 923, 163
0,1600,1534,1413

1-[(2RS) -2- (benzylthio) -3-methylbutyl] -1-phenethyl-3- [3
-(4-pyridyl) propyl)] urea (compound 5-
3) IR (Film, cm ^-1 ) 3350, 3062, 302
6,2957,2868,1628,1603,153
0, 1495, 1453, 1415, 1383, 136
4,1297,1242,1220

1- (2-cyclohexylethyl) -3
-(4-pyridylmethyl) -1-[(2RS) -2-tetrahydrothienyl] methylurea (compound 5-4) mp 95.2-96.5 ° C IR (KBr, cm ^-1 ) 3301, 925, 285
1,1626,1602,1563,1522,144
5,1412

1-[(3RS) -2-oxo-3-tetrahydrothienyl] -3-phenethyl-3- [3-
(4-pyridyl) propyl] urea (compound 5-5) IR (Film, cm ^-1 ) 2939, 1704, 163
3,1530,1305,1220

1,1,1 '-[(1R, 1'R) -1,
1'-bis (methoxycarbonyl) -2,2 '-(dithio) diethyl] -3,3'-bis [3- (4-pyridyl) propyl] -3,3'-diphenethyldiurea (compound 5-6 )

Example 6 1-[(R) -2- (acetylthio) -1- (methoxycarbonyl) ethyl] -3-phenethyl-3- [3-
(4-pyridyl) propyl] urea (compound 6-1)

Embedded image

Under a nitrogen atmosphere, 1,1 '-[(1R, 1'
R) -1,1'-bis (methoxycarbonyl) -2,
2 '-(dithio) diethyl] -3,3'-bis [3-
(4-pyridyl) propyl] -3,3'-diphenethyldiurea (Compound 5-6, 1.01 g) was added to acetone (1
0 ml), water (2.5 ml) and tri-
Add n-butylphosphine (0.69 ml) and stir at room temperature for 4.5 hours. Under a nitrogen atmosphere, triethylamine (0.44 ml) and acetic anhydride (0.30 m
l) and stir at room temperature for 20 minutes. The reaction solution is concentrated under reduced pressure, and the residue is acidified with 1N hydrochloric acid. The aqueous layer washed with ether is made weakly basic by adding a 1N aqueous sodium hydroxide solution under ice-cooling, and then extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound (compound 6-1; 0.50
g).

(Compound 6-1) [α] _D ²⁰ -40.9 ° (c = 1.0, methanol) IR (Film, cm ⁻¹ ) 2950, 1744, 169
3,1643,1524,1204,1136

Example 7 1- (2-Cyclohexylethyl) -1- (2-mercaptoethyl) -3- [3- (4-pyridyl) propyl]
Urea (compound 7-1)

Embedded image

In a nitrogen atmosphere, 1- (2-cyclohexylethyl) -1- (2- (acetylthio) ethyl) -3-
[3- (4-pyridyl) propyl)] urea (compound 4
-3, 200 mg) in methanol (1.0 ml) and then a 1N aqueous sodium hydroxide solution (0.5 ml).
And stirred at room temperature for 20 minutes. The reaction solution is adjusted to pH 7 by adding 1N hydrochloric acid. After concentration under reduced pressure, a 10% aqueous sodium hydrogen carbonate solution (300 ml) is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to give the title compound (Compound 7-1)
Get.

Using the same method as in Example 7, the following compound is obtained.

1- (2-mercaptoethyl) -1-phenethyl-3- [2- (4-pyridyl) ethyl] urea (compound 7-2)

Example 8 1- [2- (acetylthio) ethyl] -1- (2-cyclohexylethyl) -3- (4-pyridylmethyl) urea hydrochloride (Compound 8-1)

Embedded image

In a nitrogen atmosphere, 1- [2- (acetylthio) ethyl] -1- (2-cyclohexylethyl) -3
-(4-pyridylmethyl) urea (compounds 4-1 and 65
To a solution of 4 mg) in chloroform (4 ml) is added a 4N solution of hydrogen chloride in ethyl acetate (0.45 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure, and ether was added. The precipitate is collected by filtration to give the title compound (compound 8-1, 384 mg) as crystals.

(Compound 8-1) mp 145.0-147.0 ° C IR (KBr, cm ^-1 ) 3285, 2923, 285
1,428,1692,1637,1605,153
0, 1498, 1407, 1367, 1298, 113
8,784

Using the same method as in Example 8, the following compound was obtained.

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3- [3- (4-
Pyridyl) propyl] urea hydrochloride (compound 8-2) IR (Film, cm ^-1 ) 3350, 2923, 285
1,1690,1637,1536,1448,137
4,1296,1246,1137,754

1- [2- (acetylthio) ethyl]-
1- (2-cyclopentylethyl) -3- (4-pyridylmethyl) urea hydrochloride (compound 8-3) mp 151.4-152.6 ° C. IR (KBr, cm ⁻¹ ) 3271, 948, 286
4,2428,1689,1637,1606,152
6,1498,1407,1367,1138,786

1- [2- (acetylthio) ethyl]-
1- [2- (1-adamantyl) ethyl] -3- (4-
Pyridylmethyl) urea hydrochloride (compound 8-4) IR (KBr, cm ^-1 ) 3348, 2901, 284
6,2614,1694,1643,1605,152
2,1450,1401,1346,1292,127
8,1224,1133

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- (4-pyridylmethyl) urea
Hydrochloride (compound 8-5) mp 167.0-168.0 ° C. (decomposition) IR (KBr, cm ⁻¹ ) 3273, 2429, 209
5,1988,1698,1636,1608,152
6,1499,1408,1367,1302,128
8,1224,1135,1018,1003,78
3,754,706

1- [2- (acetylthio) ethyl]-
1-phenethyl-3- [3- (4-pyridyl) propyl] urea fumarate (compound 8-6) mp 110.1-115.0 ° C IR (KBr, cm ^-1 ) 3384, 2926, 254
0, 2162, 1713, 1671, 1618, 154
0, 1507, 1380, 1285, 1264, 116
8,988

1- [2- (acetylthio) ethyl]-
1- (2-cyclohexylethyl) -3-[(2-methyl-4-thiazolyl) methyl] urea hydrochloride (compound 8-7) mp 121.0-124.6 ° C IR (KBr, cm ^-1 ) 3302 , 2923, 285
2,2426,1690,1642,1603,153
1,1450,1408,1305

1- [2- (acetylthio) ethyl]-
1- (2-cycloheptylethyl) -3- (4-pyridylmethyl) urea hydrochloride (compound 8-8) mp 138.3-140.8 ° C IR (KBr, cm ^-1 ) 3286, 2924, 285
3,2436,2091,1990,1693,163
6,1605,1526,1498,1446,140
6,1367,1300,784

1- [2- (acetylthio) ethyl]-
3- (2-benzothiazolylmethyl) -1- (2-cyclohexylethyl) urea hydrochloride (compound 8-9) mp 120.3-125.4 ° C IR (KBr, cm ^-1 ) 3270, 2922, 169
4,1637,1518,1442,1293

1- [2- (acetylthio) ethyl]-
1- [2- (1-cyclohexenyl) ethyl] -3-
(4-pyridylmethyl) urea hydrochloride (Compound 8-1
0) mp 165.0-167.0 ° C (decomposition) IR (KBr, cm ^-1 ) 3280, 3085, 292
6,2424,2093,1696,1637,152
5,1407,1366,1295,1137,102
0,784

1- (2-cyclohexylethyl) -1
-(2-Mercaptoethyl) -3- [3- (4-pyridyl) propyl] urea hydrochloride (Compound 8-11) IR (Film, cm ^-1 ) 3333,2922,285
0, 1634, 1532, 1447, 1294, 122
0

Example 9 4- [3- [2- (acetylthio) ethyl] -iodide
3- (2-cyclohexylethyl) ureidomethyl]-
1-methylpyridinium (compound 9-1)

Embedded image

1- [2- (acetylthio) ethyl] -1
Methyl iodide (0.13 ml) is added to a solution of-(2-cyclohexylethyl) -3- (4-pyridylmethyl) urea (compound 4-1 and 370 mg) in acetone (2 ml). After stirring overnight, the mixture was concentrated under reduced pressure, and the precipitate was collected by filtration.
The title compound (Compound 9-1, 386 mg) is obtained as crystals.

(Compound 9-1) mp 34.5-60.0 ° C IR (KBr, cm ^-1 ) 3327, 2921, 284
9,1689,1632,1521,1447,140
8, 1368, 1296, 1236, 1182, 113
6,945,748

[Formulation Examples] General formulation examples of oral and injection preparations of the compound of the present invention are shown below.

1) Tablet Formulation 1 In 100 mg of the present compound 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

The tablets having the above formulation are coated with 2 mg of a coating agent (eg, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, or silicone resin) to obtain a target coated tablet (tablets having the following formulation) The same). Also, by appropriately changing the amounts of the compound of the present invention and additives, desired tablets can be obtained.

2) Capsule Formulation 1 Compound of the present invention in 150 mg 5 mg Lactose 145 mg in 150 mg

A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.

3) Injection Formulation 1 Compound of the present invention in 10 ml 10 to 100 mg sodium chloride 90 mg sodium hydroxide (or hydrochloric acid) qs sterile purified water qs

A desired injection can be obtained by appropriately changing the mixing ratio of the compound of the present invention and additives.

[Pharmacological test] The method of McGeehan et al. (Nature,
370 , 558-561 (1994)), the inhibitory effect on TNF-α production induced by lipopolysaccharide (LPS) stimulation was examined in an in vivo test.

As test animals, female rats weighing about 200 g and around 8 weeks of age (5 rats per group) were used. An LPS solution (1 m) was prepared by dissolving LPS derived from Salmonella in physiological saline.
g / ml) was prepared. The test compound was dissolved or uniformly suspended in a 1% aqueous methylcellulose solution to obtain a test compound preparation.

Rats were treated with the above LPS solution (0.5 ml / k
g) was administered subcutaneously. Immediately after LPS administration, a test compound preparation solution (including 5 ml / kg and 10 mg / kg test compound) was orally administered. Two hours after LPS administration, blood was collected from the abdominal aorta and centrifuged at 3000 rpm for 10 minutes at 4 ° C. The TNF-α level in the obtained plasma was measured using a rat TNF-α-specific ELISA kit. In addition,
In the LPS-non-administered group (control), TNF was present in plasma.
-Α production was not observed.

The TNF-α production inhibition rate of the test compound was as follows:
It was determined by the following equation.

[0246] A: TNF-α level in plasma of test compound non-administration group B: TNF-α level in plasma of test compound administration group

(Results) Table 1 shows the inhibition rate (%) of TNF-α production by oral administration of 10 mg / kg.

[0248]

[Table 1]

[0249]

As described above, the compound of the present invention has an excellent TNF-α production inhibitory action, and is useful for autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and systemic lupus erythematosus. Obviously, it has wide pharmaceutical use as a therapeutic agent for sexual diseases, cachexia, acute infections, allergies, fever, anemia, diabetes and the like.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/426 A61K 31/426 31/428 31/428 31/4402 31/4402 31/4406 31/4406 31/4409 31 / 4409 31/4436 31/4436 31/47 31/47 31/505 31/505 A61P 3/10 A61P 3/10 29/00 29/00 37/00 37/00 43/00 111 43/00 111 C07D 209 / 16 C07D 209/16 213/36 213/36 213/38 213/38 215/12 215/12 233/64 105 233/64 105 235/14 235/14 239/26 239/26 277/28 277/28 277/64 277/64 333/32 333/32 409/12 409/12 // C07F 7/18 C07F 7/18 A (72) Inventor Masakazu Ban 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka Santen (72) Inventor Hiroshi Suhara 3-9-19 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka

Claims (12)

[Claims] 1. A compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl group or the following formula [II]. Embedded image R ² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group,
It represents a phenyl group, a carboxyl group or an ester thereof, and may be linked to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocycle having a sulfur atom in the ring. R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or a phenyl group. R ⁵ represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group. R ⁶ represents an aromatic heterocyclic ring having a nitrogen atom in the ring. A ¹ and A ² are the same or different,
Shows a lower alkylene group. Each lower alkyl group defined above is a cycloalkyl group, cycloalkenyl group, adamantyl group, phenyl group, halogen atom, hydroxy group, lower alkoxy group, aromatic or non-aromatic heterocycle having a nitrogen atom in the ring. It may be substituted. Each of the phenyl groups defined above may be substituted with a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, a halogen atom, a nitro group, a carboxyl group or an ester thereof. The aromatic or non-aromatic heterocycle having a nitrogen atom defined above in the ring is a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, a cycloalkyl group, a phenyl group, a halogen atom, a hydroxy group or a lower alkoxy group. May be substituted. ] 2. An aromatic heterocycle having a nitrogen atom in the ring, wherein the aromatic heterocycle is a pyridine ring, a pyrimidine ring, a pyrrole ring, an imidazole ring, an oxazole ring, a thiazole ring, a quinoline ring, an indole ring, a benzimidazole ring, a benzoxazole ring or a benzoxyl ring. A non-aromatic heterocyclic ring having a nitrogen atom selected from a thiazole ring, a non-aromatic heterocyclic ring having a nitrogen atom selected from a piperidine ring, a morpholine ring, a piperazine ring or a homopiperazine ring, and a non-aromatic heterocyclic ring having a sulfur atom in the ring is tetrahydrothiophene The compound according to claim 1, which is selected from a ring or a thiolactone ring, or a salt thereof. Wherein 1) R ¹ is a hydrogen atom, it is selected from a lower alkyl group or the following formula [II], a lower alkyl group group which may be substituted with a phenyl group of the; and /
Or 2) R ² represents a group selected from a hydrogen atom, a lower alkyl group, a carboxyl group or an ester thereof; and / or
Or 3) a group in which R ² is linked to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring selected from a tetrahydrothiophene ring or a thiolactone ring; and / or 4) R ³ and R ⁴ is the same or different and is selected from a hydrogen atom or a lower alkyl group, and the lower alkyl group is substituted with a group selected from a cycloalkyl group, a cycloalkenyl group, an adamantyl group, a phenyl group, a pyridine ring or a piperidine ring. And the phenyl group is a group which may be substituted with a group selected from a halogeno lower alkoxy group, a halogen atom, a carboxyl group or an ester thereof; and / or 5) R ⁵ is a hydrogen atom or And / or 6) R ⁶ represents a pyridine ring, a pyrimidine ring, or a pillow. A heterocyclic ring having a nitrogen atom selected from a ring, an imidazole ring, a thiazole ring, an indole ring, a benzimidazole ring or a benzothiazole ring in the ring, wherein the aromatic heterocycle is substituted with a lower alkyl group. The compound according to claim 1, or a salt thereof. 4) R ¹ represents a group selected from a hydrogen atom or a lower alkyl group; and / or 2) R ² represents a hydrogen atom; and / or 3) R ³ represents a lower alkyl group. A group in which the lower alkyl group may be substituted with a group selected from a cycloalkyl group, a cycloalkenyl group, an adamantyl group or a phenyl group, and the phenyl group may be substituted with a halogen atom; And / or 4) R ⁴ represents a hydrogen atom; and / or 5) R ⁵ represents a hydrogen atom; and / or 6) R ⁶ represents a pyridine ring; Wherein 1) R ¹ is a hydrogen atom, a methyl group, a benzyl group or the following formula represents a group selected from [II]; and / or ## STR4 ## 2) R ² represents a group selected from a hydrogen atom, an isopropyl group or a methoxycarbonyl group; and / or 3) R ² linked to a sulfur atom adjacent to A ¹ to form a 2-oxotetrahydrothiophene ring or tetrahydrothiophene represents a group to form a ring; and / or 4) R ³ is a hydrogen atom, an isopentyl group, 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2-cycloheptylethyl group, 2-cyclooctyl ethyl, 2
-(Cyclohexen-1-yl) ethyl group, 1-adamantylmethyl group, 2- (1-adamantyl) ethyl group,
Phenethyl group, 2,2-diphenylethyl group, 3-phenylpropyl group, 4-fluorophenethyl group, 4- (ethoxycarbonyl) phenethyl group, 4- (trifluoromethoxy) phenethyl group, 2- (1-piperidyl) ethyl And / or a group selected from a 2- (4-pyridyl) ethyl group; and / or 5) R ⁴ represents a group selected from a hydrogen atom, a 2-cyclohexylethyl group or a phenethyl group; and / or 6 ) R ⁵ represents a hydrogen atom or a methyl group; and / or 7) R ⁶ is 1-pyrrolyl group, 1-imidazolyl group, 4-
(1-methylimidazolyl) group, 4- (2-methylthiazolyl) group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4- (1-methylpyridinium) group, 4-pyrimidinyl group, 3-indolyl And a group selected from a 2-benzimidazolyl group and a 2-benzothiazolyl group; and / or 8) A ¹ represents an ethylene group or an isopropylethylene group; and / or 9) A ² represents a methylene group or an ethylene group. A compound selected from the group consisting of, methylmethylene group, propylene group, tetramethylene group and pentamethylene group; 6) R ¹ represents a group selected from a hydrogen atom or a methyl group; and / or 2) R ² represents a hydrogen atom; and / or 3) R ³ represents a 2-cyclopentylethyl group, A group selected from a 2-cyclohexylethyl group, a 2- (cyclohexen-1-yl) ethyl group, a 2- (1-adamantyl) ethyl group, a phenethyl group, a 3-phenylpropyl group and a 4-fluorophenethyl group; And / or 4) R ⁴ represents a hydrogen atom; and / or 5) R ⁵ represents a hydrogen atom; and / or 6) R ⁶ represents a group selected from a 3-pyridyl group or a 4-pyridyl group. ; and / or 7) a ¹ represents an ethylene group; and / or 8) a ² is methylene group, a group selected from an ethylene or propylene group; a compound according to claim 1 wherein Other salts thereof. 7. The compound according to claim 1, or a salt thereof, wherein the thiol group, hydroxy group, non-aromatic heterocycle or aromatic heterocycle has a nitrogen atom protected by a protecting group. Or its salts. 8. The compound according to claim 7, wherein the thiol group is protected with an acetyl group, or a salt thereof. 9. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof as an active ingredient. 10. A TNF-α production inhibitor comprising the compound according to claim 1 or a salt thereof as an active ingredient. 11. A therapeutic agent for an autoimmune disease comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient. 12. An antirheumatic agent comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient.