JPH05155882A - New imidazole derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new derivative, having a specific structure containing imidazole group, capable of exhibiting inhibiting actions on the production and/or secretion of interleukin-1 and useful as a therapeutic and a preventing agents for inflammatory diseases such as chronic rheumatic arthritis. CONSTITUTION:A new imidazole derivative, expressed by formula II [A is lower alkylene; B is aromatic hydrocarbon ring or thiophene ring; D is single bond, O, CO, CH(OR<5>) (R<5> is H or lower alkyl), C(=NOR<5>), CH(N(R<5>)2) or NR<5>; R<5> is H or halogen; R<2> is lower alkyl, lower alkenyl, (substituted)phenyl, (substituted)cycloalkyl, (substituted)thienyl, etc.; R<3> is heterocyclic ring having nitrogen atom; R<4> is H or lower alkyl], having inhibiting actions on the production and/or secretion of interleukin-1 and useful as a therapeutic agent, etc., for inflammatory diseases is obtained by heating and reacting a compound expressed by formula I (A, B, D, R<1>, R<2>, R<3> and R<4> are same as those described above) with ammonium acetate in a molar amount of 10-20 times based on the compound expressed by formula I without or in a solvent such as acetic acid at 100-150 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to interleukin-1.
(Hereinafter abbreviated as IL-1) A novel imidazole derivative having a production inhibitory action and / or a secretory inhibitory action. The compound of the present invention is effective as a therapeutic / prophylactic drug for inflammatory diseases.

[0002]

IL is a physiologically active protein produced and / or secreted from immunocompetent cells such as macrophages.
-1 is involved in maintaining homeostasis of the living body, but when its production or / and secretion is excessive, it induces abnormal immune response, inflammatory reaction, etc., and exerts an adverse effect on the living body. Particularly recently, strong IL-1 activity has been observed in the synovial fluid and the synovial tissue culture supernatant of patients with rheumatoid arthritis, and this IL-1 production is associated with the degree of bone destruction of affected joints and inflammation of synovial tissues. It has been reported that they correlate well [Arthritis & Rheumatism (Arthritis &
Rheum. ), 31, p. 480, 1988]. A compound having imidazole as a basic skeleton is disclosed in JP-A-62-
Japanese Patent No. 153286 discloses a compound in which a diaryl-substituted imidazole is condensed with a thiazole, pyrrole, thiazine or pyridine ring.
In 3782, these compounds are reported to also suppress IL-1 production. Also, WO88 / 011
67, IL of 4,5-diaryl-2-substituted imidazole derivatives in monocytes and / or macrophages
It has been reported to inhibit the production of -1.

[0003]

[Problems to be Solved by the Invention] As a therapeutic agent for inflammatory diseases, it is desirable to inhibit the production or / and secretion of IL-1, which is considered to be the causative agent. Further, treatment of inflammatory diseases requires long-term medication, and drugs with few side effects are desirable. Therefore, as a novel therapeutic agent for inflammatory diseases, the development of a compound that inhibits the production or / and secretion of IL-1 with less side effects is desired.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that a compound represented by the following formula [1] has an IL-1 production inhibitory action and / or a secretion inhibitory action. In addition to having the above, the present invention was completed by discovering that there are few side effects.

That is, the present invention uses the formula [1]

[Chemical 2]

(In the formula, A represents a lower alkylene group, and B
Represents an aromatic hydrocarbon ring or a thiophene ring, D represents a single bond, an oxygen atom, —CO—, —CH (OR ⁵ ) — (in the formula, R ⁵ represents a hydrogen atom or a lower alkyl group),
-C (= NOR ⁵⁾ - (wherein, R ⁵ are as defined above.), - CH (N ( R 5) 2) - ( wherein, R ⁵ are as defined above.) , Or —NR ⁵ — (wherein R
⁵ has the same meaning as above. ) Represents. R ¹ represents a hydrogen atom or a halogen atom. R ² represents a lower alkyl group, a lower alkenyl group, an optionally substituted phenyl group, an optionally substituted cycloalkyl group, or an optionally substituted thienyl group. Furthermore, the D
Is a single bond, R ² represents a lower alkoxy group or a hydroxy group. R ³ represents a heterocyclic group containing a nitrogen atom, and R ⁴ represents a hydrogen atom or a lower alkyl group.)
The present invention relates to an imidazole derivative represented by or an acid addition salt thereof.

In the above formula [1], the lower alkyl group is a straight chain or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl and 2-methylpropyl. , 1,1-dimethylethyl,
Examples include pentyl and hexyl.

Examples of the lower alkylene group include linear or branched C 1-6 carbon atoms such as methylene, methylethylene, ethylmethylene, ethylene, methylethylene, propylene, butylene, or pentylene.

Examples of the lower alkenyl group are linear or branched ones having 1 to 6 carbon atoms such as vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like can be mentioned.

Examples of the aromatic hydrocarbon ring include a benzene ring or a naphthalene ring having 10 or less carbon atoms.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

Examples of the lower alkoxy group include linear or branched C1-C6 methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethylethoxy, pentyloxy, hexyloxy and the like. Be done.

The substituent of the optionally substituted phenyl group or thienyl group is, for example, halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, thiol group, lower alkylthio group, lower alkylsulfinyl group, lower alkyl. Examples thereof include a sulfonyl group, an amino group, a substituted amino group, and a cyano group. Number of substituents is 1
There may be one or a plurality of the same or different.

Examples of the substituted amino group include monomethylamino, dimethylamino, monoethylamino, diethylamino, dipropylamino, 1-methylethylamino,
Alternatively, 1,1-dimethylethylamino and the like can be mentioned.

Examples of the lower alkylthio group include linear or branched C1-6 carbon atoms such as methylthio, ethylthio, propylthio, 2-methylethylthio, butylthio, pentylthio, and hexylthio.

The lower alkylsulfinyl group is a straight-chain or branched one having 1 to 6 carbon atoms, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl,
2-methylethylsulfinyl, butylsulfinyl,
Examples include pentylsulfinyl, hexylsulfinyl, and the like.

Examples of the lower alkylsulfonyl group include linear or branched ones having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2-methylethylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl. Be done.

The cycloalkyl group has a carbon number of 3 to
Eight, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. Examples of the substituent of the cycloalkyl group include a halogen atom, a lower alkyl group, a hydroxy group, an oxo group, a lower alkoxy group, an acyloxy group, an amino group, a substituted amino group, a hydroxyimino group, and a lower alkoxyimino group. .. The number of substituents may be one, or may be the same or different and may be plural.

The acyloxy group has, for example, 2 carbon atoms.
~ 7 acetoxy, benzoyloxy, cyclohexylcarbonyloxy and the like.

The lower alkoxyimino group is a straight-chain or branched one having 1 to 6 carbon atoms, for example, methoxyimino,
Examples thereof include ethoxyimino, propoxyimino, 1-methylethoxyimino, butoxyimino, 1,1-dimethylethoxyimino, pentyloxyimino, and hexyloxyimino.

Examples of the heterocyclic group containing a nitrogen atom include a heterocyclic group having 1 to 2 nitrogen atoms and having 5 to 9 carbon atoms, and specifically, for example, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 9-acridyl, 2-pyrazyl, 4-pyridazyl, 4-cinnolyl, 2-quinoxalyl, etc. Can be mentioned.

In the formula [1], the formula

[Chemical 3] (In the formula, A, B, D, R ¹ and R ² have the same meanings as described above.)

Specific examples of the group represented by: 1- (2-fluoro-4-biphenylyl) ethyl, 1
-(2-Fluoro-4-biphenylyl) -1-methylethyl, (2-fluoro-4-biphenylyl) methyl, 1- (3-benzoylphenyl) ethyl, 1- (4
-Isobutylphenyl) ethyl, 1- (4- (2-methylallyl) aminophenyl) ethyl, 1- (6-hydroxy-2-naphthyl) ethyl, 1- (6-methoxy-2)
-Naphthyl) ethyl, 1- (3-phenoxyphenyl)
Ethyl, 1- (5-benzoyl-2-thienyl) ethyl, 1- (4- (2-thenoyl) phenyl) ethyl, 1- (4- (2-oxocyclopentyl) methylphenyl) ethyl and the like can be mentioned.

The acid addition salt of the imidazole derivative represented by the above formula [1] includes, for example, pharmaceutically acceptable acid addition salts. Specific examples thereof include inorganic acids, organic acids and sulfonic acids. Salt can be mentioned. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. Examples of the organic acid include formic acid, acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, glutamic acid and the like. Examples of the sulfonic acid include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid and the like.

The compound of the present invention may have optical isomers or geometrical isomers depending on the substituents, and the present invention includes these isomers or a mixture. The invention also includes tautomers as well as all hydrates and crystal forms.

The compounds included in the present invention will be specifically listed below. 4- (1- (2-Fluoro-4-biphenylyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (3-pyridyl ) Imidazole 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (2-pyridyl) imidazole 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (2 -Pyrazyl) imidazole 4- (2-fluoro-4-biphenylyl) methyl-2
-(4-Pyridyl) imidazole

4- (1- (2-Fluoro-4-biphenylyl) -1-methyl-ethyl) -2- (4-pyridyl) imidazole 4- (1- (3-benzoylphenyl) ethyl) -2-
(4-Pyridyl) imidazole 4- (1- (3-benzoylphenyl) ethyl) -2-
(3-Pyridyl) imidazole 4- (1- (3-benzoylphenyl) ethyl) -2-
(2-Pyridyl) imidazole 4- (1- (3-benzoylphenyl) ethyl) -2-
(2-pyrazyl) imidazole

4- (1- (3-benzoylphenyl) ethyl) -2- (2-quinolyl) imidazole 4- (1- (3-benzoylphenyl) ethyl) -2-
(3-quinolyl) imidazole 4- (1- (3- (α-hydroxybenzyl) phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (3- (α-hydroxyiminobenzyl) phenyl) Ethyl) -2- (4-pyridyl) imidazole 4- (1- (3- (α-methoxyiminobenzyl) phenyl) ethyl) -2- (4-pyridyl) imidazole

4- (1- (3- (α-aminobenzylphenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (3- (α-methylaminobenzylphenyl) ethyl) -2- (4-Pyridyl) imidazole 4- (1- (3- (α-acetoxybenzylphenyl)
Ethyl) -2- (4-pyridyl) imidazole 4- (1- (4-isobutylphenyl) ethyl) -2-
(4-Pyridyl) imidazole 4- (1- (6-methoxy-2-naphthyl) ethyl)-
2- (4-pyridyl) imidazole

4- (1- (6-hydroxy-2-naphthyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (2-methylallyl) aminophenyl) ethyl) -2- ( 4-Pyridyl) imidazole 4- (1- (5-benzoyl-2-thienyl) ethyl)
2- (4-Pyridyl) imidazole 4- (1- (5- (α-hydroxybenzyl) -2-thienyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (5- (α- Acetoxybenzyl) -2-thienyl) ethyl) -2- (4-pyridyl) imidazole

4- (1- (5- (α-hydroxyiminobenzyl) -2-thienyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (5- (α-methoxyiminobenzyl)- Two
-Thienyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (5- (α-aminobenzyl) -2-thienyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- ( 5- (α-methylaminobenzyl) -2-
Thienyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (3-phenoxyphenyl) ethyl) -2-
(4-pyridyl) imidazole

4- (1- (4- (2-thenoyl) phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (α-hydroxy-2-thenyl) phenyl) ethyl) 2- (4-Pyridyl) imidazole 4- (1- (4- (α-acetoxy-2-thenyl) phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (α- Hydroxyimino-2-enyl) phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (α-methoxyimino-2-thenyl))
Phenyl) ethyl) -2- (4-pyridyl) imidazole

4- (1- (4- (α-amino-2-thenyl) phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (α-methylamino-2-thenyl) ) Phenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (2-oxocyclopentyl) methylphenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (2-Hydroxycyclopentyl) methylphenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (2-acetoxycyclopentyl) methylphenyl) ethyl) -2- (4-pyridyl) imidazole

4- (1- (4- (2-hydroxyiminocyclopentyl) methylphenyl) ethyl) -2- (4
-Pyridyl) imidazole 4- (1- (4- (2-methoxyiminocyclopentyl) methylphenyl) ethyl) -2- (4-pyridyl)
Imidazole 4- (1- (4- (2-aminocyclopentyl) methylphenyl) ethyl) -2- (4-pyridyl) imidazole 4- (1- (4- (2-methylaminocyclopentyl))
Methylphenyl) ethyl) -2- (4-pyridyl) imidazole

The imidazole derivative represented by the above formula [1] can be produced, for example, by the following method. Method A

[Chemical 4] (In the formula, A, B, D, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.) The compound of the present invention represented by the formula [3] is, for example, JP-A-2
It is produced from the compound of the formula [2] according to the method described in JP-A-69477. That is, the compound of the formula [2] is added in a large excess, for example, 10 to 20 relative to the compound of the formula [2].
It can be produced by using double molar ammonium acetate and heating at 100 to 150 ° C. in the absence of solvent or in a solvent such as acetic acid.

Method B

[Chemical 5] (In the formula, R ⁵ represents an alkyl group, X represents a halogen atom or another leaving group, and A, B, D, R ¹ , R ² , and R ³ have the same meanings as described above.) Formula [ The compound of the present invention represented by [6] can be produced by reacting the compound represented by the formula [4] or a salt thereof with the compound of the formula [5] in the presence of a base in an inert solvent.
As the base used here, an inorganic base (for example, sodium hydride, potassium hydride, sodium amide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,
Potassium carbonate) or an organic base (eg, triethylamine). Further, as the inert solvent, for example, ether solvent, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, N, N-dimethylformamide, dimethylsulfoxide and the like can be used. Examples of the ether solvent include tetrahydrofuran, dioxane, diethyl ether and the like. Examples of the aromatic hydrocarbon solvent include toluene, xylene, benzene and the like. Examples of the halogen hydrocarbon solvent include 1,2-
Dichloroethane, dichloromethane, chloroform and the like can be mentioned. The reaction temperature is in the range of -20 to 100 ° C, preferably -10 to 50 ° C.

Method C

[Chemical 6] (In the formula, D ¹ represents —CO—, and D ² represents hydroxymethylene. A, B, R ¹ , R ² , R ³ , and R ⁴
Represents the same meaning as described above. The compound of the present invention represented by the formula [8] is a compound represented by the formula [7] or a salt thereof in a polar solvent, if necessary, in the presence of cerium trichloride, a reducing agent such as sodium borohydride. It can be produced by reduction by use. Examples of the polar solvent used here include alcohol solvents and water. Examples of the alcohol solvent include methanol and ethanol. The reaction temperature is −
20-100 degreeC, Preferably the range of -10-50 degreeC is mentioned.

Method D

[Chemical 7] (In the formula, D ³ represents acyloxymethylene. A,
B, D ² , R ¹ , R ² , R ³ and R ⁵ have the same meanings as described above. ) Expression

The compound of the present invention represented by [9] can be produced by reacting the compound represented by the formula [8] or a salt thereof with a corresponding acid halide or acid anhydride in a basic solvent. Examples of the basic solvent include pyridine and triethylamine. The reaction temperature is in the range of -20 to 100 ° C, preferably -10 to 50 ° C.

Method E

[Chemical 8] (In the formula, D ⁴ represents hydroxyiminomethylene or alkoxyiminomethylene. A, B, D ¹ , R ¹ ,
R ² , R ³ and R ⁴ have the same meanings as described above. The compound of the present invention represented by the formula [10] can be produced by treating the compound represented by the formula [7] or a salt thereof with hydroxylamine hydrochloride or alkoxylamine hydrochloride in a polar solvent. Examples of the polar solvent used here include alcohol solvents and water. Examples of the alcohol solvent include methanol and ethanol. Examples of the reaction temperature include room temperature to the boiling point of the solvent.

Method F

[Chemical 9] (In the formula, D ⁵ represents aminomethylene or alkylaminomethylene. A, B, D ¹ , R ¹ , R ² , R ³ ,
And R ⁴ have the same meaning as described above. The compound of the present invention represented by the formula [11] is obtained by reductive amination of the compound represented by the formula [7] or a salt thereof with sodium cyanoborohydride in the presence of ammonia or an alkylamine in an alcohol solvent. It can be manufactured. Examples of the alcohol solvent include methanol and ethanol. As the reaction temperature,
The range of 0 degreeC-room temperature is mentioned.

The compound represented by the formula [1] obtained by the above various methods can be purified by a conventional method such as silica gel column chromatography or recrystallization. As a developing solvent for purification by silica gel chromatography, for example, chloroform-methanol system,
Examples thereof include ethyl acetate-hexane system, ethyl acetate-alcohol (ethanol, 2-propanol, methanol, etc.). Examples of the solvent for purification by recrystallization include methanol, ethanol, alcohol solvents such as 2-propanol, esters such as ethyl acetate, ether solvents such as diethyl ether, aromatic hydrocarbon group solvents such as toluene,
These mixed solvents etc. are mentioned. In the case of purification by recrystallization, it can be purified by forming an acid addition salt such as hydrochloride, if necessary.

The optically active substance included in the present invention can be produced by a usual method. A mixture of optical isomers is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol, etc.), and an optically active acid (for example, L-tartaric acid, D-tartaric acid, D-camphoric acid, L-
Examples thereof include mandelic acid, L-pyroglutamic acid, D-10-camphorsulfonic acid, D-quinic acid, L-malic acid and dibenzoyl-L-tartaric acid. ) Is added to form a salt. The temperature at which the salt is formed may be in the range of room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once heat the solvent to around the boiling point. Before collecting the precipitated salt by filtration, it can be cooled if necessary to improve the yield. The amount of the optically active acid used is in the range of 0.5 to 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, the obtained crystal can be recrystallized in a crystallization solvent (for example, an alcohol solvent) to obtain a highly pure optically active salt. If necessary, the optically active substance can be obtained as a free form by treating the obtained salt with a base by a conventional method.

The starting compound represented by the formula [2] can be produced by the following method.

[Chemical 10] (In the formula, A, B, D, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described above.) The compound represented by the formula [2] is represented by the formula [12]. Α
It can be produced by reacting an aminoketone hydrochloride with a compound represented by the formula [13] in an organic solvent or in the absence of a solvent in the presence of a base. Examples of the base include organic amines such as triethylamine, pyridine and diisopropylamine. Examples of the organic solvent include halogenated hydrocarbon solvents such as dichloromethane and chloroform,
An ether solvent such as tetrahydrofuran or dioxane,
Aromatic hydrocarbon solvents such as benzene and toluene, N, N-
Examples thereof include dimethylformamide and dimethylsulfoxide. The reaction temperature may be in the range of -20 ° C to the boiling point of the solvent.

[Chemical 11] (In the formula, A, B, D, R ¹ , R ² and R ⁵ have the same meanings as described above.) The compound represented by the formula [15] is the α-aminoketone hydrochloric acid represented by the formula [14]. After protecting the salt with a suitable acetal, if necessary the ketone, and then for example, the journal of Organic Chemistry (J. Org.
m. ), 35, page 1912, 1970. That is, after protecting an amino group with a t-butoxycarbonyl (Boc) group and the like by a conventional method, it is reacted with an alkyl halide in N, N-dimethylformamide in the presence of silver oxide and then with a mineral acid such as hydrochloric acid. A compound represented by the formula [15] can be produced by deprotection [acetal and B
For protection and deprotection of the oc group, for example, Protective Groups in Organic Synthesis (Protective Groups in Org) is used.
anic Synthesis), pp. 116 and 23
Page 2, John Wiley & Sons (John Wiley
& Sons), 1981].

[Chemical 12] (In the formula, A, B, D, R ¹ and R ² have the same meanings as described above.)

The compound represented by the formula [14] is represented by Angewante Chemie, 8
Vol. 3, pp. 358, 1971, and is produced in 3 steps from the compound of formula [16]. In the first step, the compound of formula [16] is treated with thionyl chloride by a conventional method to produce an acid chloride, and in the second step, the acid chloride is added in tetrahydrofuran at 0 to 10 ° C. at a ratio of 1: 1.
The oxazole compound is prepared by treatment with potassium tert-butoxide and methyl isocyanoacetate or ethyl isocyanoacetate in excess of 1.5 to 3 equivalents of acid chloride in a molar ratio of, and conventional purification. In the third step, the oxazole compound can be hydrolyzed with hydrochloric acid or hydrochloric acid-alcohol at room temperature to reflux temperature to produce a hydrochloride of the compound of the formula [14]. Formulas [5], [13], and [16]
The compound represented by is a compound known per se or can be synthesized by a known synthetic method. For example, 2- (2
-Fluoro-4-biphenylyl) acetic acid is disclosed in JP-A-48 / 48
It can be synthesized according to the method described in JP-A-32866.

The compound of the present invention represented by the above formula [1] and salts thereof can be administered orally or parenterally when it is used as a medicine. That is, it can be orally administered in a commonly used dosage form such as tablets, capsules, syrups and suspensions, or in the form of liquid solutions such as solutions, emulsions and suspensions. Things can be administered parenterally in the form of injections. It may also be administered rectally in the form of suppositories. Also, the above suitable dosage forms can be produced by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection form, acceptable buffers, solubilizers, isotonic agents and the like can be added.
The dose and the number of doses vary depending on the symptoms, age, body weight, and administration form, but in general, for adults, about 1 to 1000 mg, preferably 3 to 500 mg is orally administered daily.
In the case of injection, 0.1 to 500 mg, preferably 3 to
50 mg can be administered once or in several divided doses.

[0046]

FUNCTION AND EFFECT OF THE INVENTION The compound [1] of the present invention was found to inhibit IL-1 production or / and secretion in an experiment using rat macrophages. Therefore, it is effective as a therapeutic or preventive drug for inflammatory diseases. That is,
Diseases with elevated levels of IL-1 in blood and tissues (rheumatoid arthritis, osteoarthritis, psoriasis, human immunodeficiency virus infection, acquired immunodeficiency syndrome, bacterial infection, dyspnea, pneumoconiosis, alcoholic cirrhosis) , Chronic hepatitis B, burns, sarcoidosis, tuberculoma, Aschoff nodule,
Application of the compound of the present invention in rheumatoid nodules, obstructive jaundice, Behcet's disease, osteomalacia, insulin-dependent diabetes mellitus, inflammatory bowel disease, Kawasaki disease, etc., or surgical treatment (organ transplantation, artificial dialysis, bypass surgery, etc.) Is extremely useful in terms of treating and preventing inflammation.

[0047]

EXAMPLES The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to them. Example 1

[Chemical 13] 3- (2-fluoro-4-biphenylyl) -1- (4
-Pyridylcarbonyl) amino-2-butanone 731
mg (2.02 mmol) and ammonium acetate (7
The mixture of g) was heated at 140-150 ° C for 4 hours.
The reaction mixture was made basic with a 1 M aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by a medium pressure silica gel column chromatogram and hydrochloric acid-chlorinated with hydrochloric acid-isopropanol to give the desired 4- (1- (2-fluoro-4) -4.
347 mg (44%) of -biphenylyl) ethyl) -2- (4-pyridyl) imidazole hydrochloride was obtained. Melting point 234-235 ° C

Example 2

[Chemical 14] 3- (3-benzoylphenyl) -1- (4-pyridylcarbonyl) amino-2-butanone 10.0 g (2
6.9 mmol) and ammonium acetate (100 g)
The mixture was heated at 140-150 ° C for 2 hours. After basifying the reaction mixture with aqueous sodium hydroxide,
It was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by a medium pressure silica gel column chromatogram and hydrochloric acid-chlorinated with hydrochloric acid-isopropanol to obtain the desired 4- (1- (3-benzoylphenyl)). 5.64 g (49%) of ethyl) -2- (4-pyridyl) imidazole hydrochloride was obtained. Melting point 133-136 ° C

Example 3

[Chemical 15] In the same manner as in Example 1, 3- (2-fluoro-4-)
Biphenylyl) -1- (3-pyridylcarbonyl) amino-2-butanone gives the desired 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (3-pyridyl) imidazole hydrochloride. It was Melting point 226-228 ° C

Example 4

[Chemical 16] In the same manner as in Example 1, 3- (2-fluoro-4-)
Biphenylyl) -1- (2-pyridylcarbonyl) amino-2-butanone gives the desired 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (2-pyridyl) imidazole hydrochloride. It was Melting point 161-163 ° C

Example 5

[Chemical 17] In the same manner as in Example 1, 3- (2-fluoro-4-)
From biphenylyl) -1- (2-pyrazylcarbonyl) amino-2-butanone, the desired 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (2-pyrazyl) imidazole hydrochloride was obtained. Obtained. Melting point 117-119 ° C

Example 6

[Chemical 18] In the same manner as in Example 1, 3- (2-fluoro-4-)
Biphenylyl) -3-methyl-1- (4-pyridylcarbonyl) amino-2-butanone yields the desired 4- (1-
(2-Fluoro-4-biphenylyl) -1-methylethyl) -2- (4-pyridyl) imidazole hydrochloride was obtained. Melting point 195-200 ° C

Example 7

[Chemical 19] In the same manner as in Example 1, 3- (2-fluoro-4-)
Biphenylyl) -1- (4-pyridylcarbonyl) amino-2-propanone provides the desired 4- (2-fluoro-).
4-Biphenylyl) methyl-2- (4-pyridyl) imidazole hydrochloride was obtained. Melting point 226-228 ° C

Example 8

[Chemical 20] In the same manner as in Example 1, 3- (4-isobutylphenyl) -1- (4-pyridylcarbonyl) amino-2-
The desired 4- (1- (4-isobutylphenyl) ethyl) -2- (4-pyridyl) imidazole hydrochloride was obtained from butanone. Melting point 202-204 ° C

Example 9

[Chemical 21] In the same manner as in Example 1, 3- (6-hydroxy-2)
The target 4- (1- (6-hydroxy-2-naphthyl) ethyl) -2- (4-pyridyl) imidazole hydrochloride was obtained from -naphthyl) -1- (4-pyridylcarbonyl) amino-2-butanone. .. Melting point 190-195 ° C

Example 10

[Chemical formula 22] 4- (1- (3-benzoylphenyl) ethyl) -2-
(4-pyridyl) imidazole hydrochloride 233 mg (5
47 μmol) in chloroform (20 ml) and 1M
The mixture was distributed in an aqueous sodium hydroxide solution (20 ml), the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (5 ml), sodium borohydride (20.6 mg, 547 μmol) was added thereto, and the mixture was stirred at room temperature for 4 hours.
Stir for hours. The reaction mixture was acidified with 1M hydrochloric acid, basified with a 1M aqueous sodium hydroxide solution, and concentrated under reduced pressure. The obtained residue was partitioned between chloroform and water, the organic layer was dried over sodium sulfate and concentrated under reduced pressure, the residue was purified by a medium pressure silica gel column chromatogram, and then hydrochloric acid-isopropanol was added to give the desired 4- (1- (3-
(Α-Hydroxybenzylphenyl) ethyl) -2-
195 mg of (4-pyridyl) imidazole hydrochloride (8
3%) was obtained. Melting point 123-125 ° C

Reference Example 1

[Chemical formula 23] 600 mg (2.04 mmol) 3- (2-fluoro-4-biphenylyl) -2-oxobutylamine hydrochloride
And isonicotinic acid chloride hydrochloride 545 mg (3.
06 mmol) in a methylene chloride (10 ml) suspension,
With stirring under ice cooling, 516 mg of triethylamine (5.10 m)
(mol) and the mixture was stirred for 2 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a medium-pressure silica gel column chromatogram, and the target 3- (2-fluoro-4-biphenylyl) -1- (4-pyridylcarbonyl) amino-2-butanone 731 mg (99
%) Was obtained. 1H-NMR (CDCl3) δ ppm: 1.54 (3
H, d, J = 6.93 Hz), 3.92 (1H, q, J
= 6.93 Hz), 4.27-4.46 (2H, m),
7.02 (1H, bs), 7.04-7.13 and
7.34-7.63 (total8H, m), 7.6
1-7.63 (2H, m), 8.75 (2H, d, J =
5.28Hz)

Reference Example 2

[Chemical formula 24] 3- (3-benzoylphenyl) -2-oxobutylamine hydrochloride 19.0 g (62.5 mmol) and isonicotinic acid chloride hydrochloride 16.7 g (93.8 mm)
Ol) in a methylene chloride (150 ml) suspension under ice cooling with stirring, and 15.8 g (156 mmo) of triethylamine.
1) was added dropwise and the mixture was stirred for 2 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a medium-pressure silica gel column chromatogram to obtain 22.2 g (95%) of the target 3- (3-benzoylphenyl) -1- (4-pyridylcarbonyl) amino-2-butanone. .. 1H-NMR (CDCl3) δ ppm: 1.55 (3
H, d, J = 7.26 Hz), 3.98 (1H, q,
J = 7.26 Hz), 4.25-4.37 (2H,
m), 7.02 (1H, bs), 7.45-7.82.
(11H, m), 8.66 (2H, dd, J = 1.65
Hz and 4.29 Hz).

Reference Example 3

[Chemical 25] By the same method as in Reference Example 1, 3- (2-fluoro-4)
-Biphenylyl) -2-oxobutylamine hydrochloride and nicotinic acid chloride hydrochloride yielded the desired 3- (2-fluoro-4-biphenylyl) -1- (3-pyridylcarbonyl) amino-2-butanone. .. 1H-NMR (CDCl3) δ ppm: 1.54 (3
H, d, J = 6.93 Hz), 4.28-4.46 (2
H, m), 7.02-7.17 (3H, m), 7.33.
-7.58 (7H, m), 8.10 (1H, dt, J =
1.98 Hz and 7.92 Hz), 8.73 (1
H, dd, 1.65 Hz).

Reference Example 4

[Chemical formula 26] By the same method as in Reference Example 1, 3- (2-fluoro-4)
-Biphenylyl) -2-oxobutylamine hydrochloride and picolinic acid chloride hydrochloride gave the desired 3- (2-fluoro-4-biphenylyl) -1- (2-pyridylcarbonyl) amino-2-butanone. .. 1H-NMR (CDCl3) δ ppm: 1.53 (3
H, d, 6.93 Hz), 3.93 (1H, q, 6.9)
3 Hz), 4.37 (2H, dd, 1.98 Hz, 4.
95 Hz), 7.05-7.14 and 7.34-7.
55 (9H, m), 7.80-7.88, 8.12-
8.16 and 8.57-8.65 (4H, m).

Reference Example 5

[Chemical 27] By the same method as in Reference Example 1, 3- (2-fluoro-4)
-Biphenylyl) -2-oxobutylamine hydrochloride and 2-pyrazinecarboxylic acid chloride, the desired 3-
(2-Fluoro-4-biphenylyl) -1- (2-pyrazylcarbonyl) amino-2-butanone was obtained. 1H-NMR (CDCl3) δ ppm: 1.54 (3
H, d, 6.93 Hz), 3.93 (1H, q, 6.9)
3Hz), 4.38 (2H, dd, 2.64Hz an
d 4.95 Hz), 7.03-7.16 and 7.3.
4-7.57 (8H, m), 8.35-8.47 (1
H, bs), 8.56-8.57 (1H, m), 8.7.
6 (1H, d, 2.31Hz), 9.36 (1H, d,
1.32 Hz).

Reference Example 6

[Chemical 28] By the same method as in Reference Example 1, 3- (2-fluoro-4)
-Biphenylyl) -3-methyl-2-oxobutylamine hydrochloride and isonicotinic acid chloride hydrochloride, the desired 3- (2-fluoro-4-biphenylyl) -3-
Methyl-1- (4-pyridylcarbonyl) amino-2-
I got butanone. 1H-NMR (CDCl3) δ ppm: 1.64 (6
H, s), 4.27 (2H, d, 4.29 Hz), 7.
00-7.16 and 7.34-7.55 (9H,
m), 7.63 (2H, dd, 1.65Hz and
4.62 Hz), 8.75 (2H, d, 5.94H
z).

Reference Example 7

[Chemical 29] By the same method as in Reference Example 1, 3- (2-fluoro-4)
-Biphenylyl) -2-oxopropylamine hydrochloride and isonicotinic acid chloride hydrochloride, the desired 3-
(2-Fluoro-4-biphenylyl) -1- (4-pyridylcarbonyl) amino-2-propanone was obtained. 1H-NMR (CDCl3) δ ppm: 3.85 (2
H, s), 4.44 (2H, d, 4.62 Hz), 7.
05-7.20 and 7.30-7.55 (8H, m)
7.64 (2H, dd, 1.65Hz, 4.29H
z), 8.75 (2H, d, 5.94Hz).

Reference Example 8

[Chemical 30] In the same manner as in Reference Example 1, the desired 3- (4-isobutylphenyl) -1- (4-pyridyl) was obtained from 3- (4-isobutylphenyl) -2-oxobutylamine hydrochloride and isonicotinic acid chloride hydrochloride. Carbonyl) amino-2-butanone was obtained. 1H-NMR (CDCl3) δ ppm: 0.88an
d 0.91 (6H, s), 1.49 (3H, d, 6.9)
3Hz), 1.75-1.95 (1H, m), 2.45
(2H, d, 7.26Hz), 3. 84 (1H, q,
6.83), 4.20-4.40 (2H, m), 7.0.
0 (1H, bs), 7.14 (4H, s), 7.61
(2H, dd, 1.65Hz, 4.62Hz), 8.7
4 (2H, d, 6.27Hz).

Reference Example 9

[Chemical 31] By the same method as in Reference Example 1, 3- (6-hydroxy-
The desired 3- (6-hydroxy-2-naphthyl) -1- (4-pyridylcarbonyl) amino-2-butanone was obtained from 2-naphthyl) -2-oxobutylamine hydrochloride and isonicotinic acid chloride hydrochloride. .. 1H-NMR (CDCl3) δ ppm: 1.57 (3
H, d, 6.93 Hz), 3.99 (1H, q, 6.9)
3 Hz), 4.25-4.43 (2H, m), 7.03
-7.27 and 7.59-7.68 (9H, m),
8.74 (2H, dd, 1.65Hz, 4.62H
z).

Reference Example 10

[Chemical 32] Flurbiprofen 70.0 g (287 mmol) was dissolved in toluene 300 ml, and thionyl chloride 85.
3 g (717 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. The operation of concentrating the solvent under reduced pressure, further adding toluene and concentrating under reduced pressure was repeated to obtain an acid chloride of flurbiprofen. Then potassium tert-butoxide
To a suspension of 66.4 g (574 mmol) of tetrahydrofuran (300 ml), a solution of ethyl isocyanoacetate 68.4 (574 mmol) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling, followed by the above-mentioned acid of flurbiprofen. After adding a solution of chloride in tetrahydrofuran (100 ml) dropwise, the mixture was stirred at 10 ° C.
The mixture was stirred below for 2 hours. The solvent was concentrated under reduced pressure, 17.3 g (287 mmol) of acetic acid and water were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatogram to give 5- (1- (2-fluoro-4-biphenylyl)).
Ethyl) -4-ethoxycarbonyloxazole was obtained. This was stirred in 600 ml of 6M hydrochloric acid at 95 to 100 ° C. for 4 hours. The reaction solution was allowed to stand overnight at room temperature, 100 ml of toluene was added thereto, and the mixture was stirred in an ice bath, and the precipitated crystals were collected by filtration, washed with toluene and dried to obtain the desired 3- (2-fluoro). -4-Biphenylyl) -2-oxo-1-butylamine hydrochloride as white crystals 44.8
g (53%) was obtained. Melting point 176-177 ° C

Reference Example 11

[Chemical 33] 5- (3- (α, α-ethylenedioxybenzyl) phenyl) propionic acid (50.0 g, 168 mmol) was dissolved in toluene (500 ml), and thionyl chloride (60.0) was added.
g (504 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. The operation of concentrating the solvent under reduced pressure, further adding toluene and concentrating under reduced pressure was repeated to obtain an acid chloride. Next, 28.3 g (252 mm) of potassium tert-butoxide
ol) in tetrahydrofuran (250 ml),
Under ice cooling, 28.5 g of ethyl isocyanoacetate (2
A solution of 52 mmol) in tetrahydrofuran (60 ml) was added dropwise, followed by a solution of the above acid chloride in tetrahydrofuran (100 ml), and the mixture was added to 1 part.
The mixture was stirred at 0 ° C or lower for 2 hours. The solvent was concentrated under reduced pressure, 10.2 g (168 mmol) of acetic acid and water were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatogram to give 5- (1- (3- (α, α-ethylenedioxybenzyl) phenyl) ethyl) -4-. Ethoxycarbonyl oxazole was obtained. This was stirred in 200 ml of 6M hydrochloric acid at 95 to 100 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was repeatedly recrystallized from ethyl acetate-ethanol to give the desired 3- (3-benzoylphenyl) -2-oxo-1-butylamine hydrochloride as white crystals. 0 g (64%) was obtained. Melting point 152-153 ° C

Reference Example 12

[Chemical 34] In the same manner as in Reference Example 10, 2- (2-fluoro-4-)
The target 3- (2-fluoro-4-biphenylyl) -3-methyl-2-oxo-1-butylamine hydrochloride was obtained from biphenylyl) -2-methylpropionic acid. 1H-NMR (DMSO-d6) δ ppm: 1.55
(6H, s), 3.95 (2H, s), 7.24-7.
59 (8H, m), 8.16 (2H, bs).

Reference Example 13

[Chemical 35] In the same manner as in Reference Example 10, 2- (2-fluoro-4-)
The desired 3- (2-fluoro-4-biphenylyl) -2-oxo-1-propylamine hydrochloride was obtained from biphenylyl) acetic acid. 1H-NMR (DMSO-d6) δ ppm: 3.99.
(2H, s), 4.06 (2H, s), 7.15-7.
57 (8H, m), 8.27 (2H, bs).

Reference Example 14

[Chemical 36] In the same manner as in Reference Example 10, the target 3- (4-isobutylphenyl) -2-oxo-1- was obtained from ibuprofen.
Butylamine hydrochloride was obtained. Melting point 183-184 ° C

Reference Example 15

[Chemical 37] The target 3- (4-isobutylphenyl) -2-oxo-1-butylamine hydrochloride was obtained from naproxen in the same manner as in Reference Example 10. Melting point 244-245 ° C

Reference Example 16

[Chemical 38] 20.0 g (78.7 mmol) of ketoprofen was dissolved in benzene (500 ml), 48.8 g (787 mmol) of ethylene glycol and 2.0 g of p-toluenesulfonic acid were added thereto, and Dean-Stark was added.
The mixture was heated under reflux for 5 hours while being dehydrated using the above apparatus. The reaction mixture was washed with 1M aqueous sodium hydroxide solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (250 ml), 10% aqueous potassium hydroxide solution (250 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours.
Stir vigorously. The reaction mixture was concentrated under reduced pressure to remove methanol, the resulting aqueous layer was diluted with water, acidified with 2M hydrochloric acid, and then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was recrystallized from toluene-hexane to give the desired 2- (3- (α, α-ethylenedioxybenzyl) phenyl) propionic acid as 1
Obtained 9.5 g (83%).

Reference Example 17

[Chemical Formula 39] Flurbiprofen 10.0 g (40.9 mmol)
N, N-dimethylformamide (120 ml) solution of 60% sodium hydride 3.60 g (90.0 mm)
ol) was added, and 12.8 g (90.
(2 mmol) was added dropwise, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by a medium pressure silica gel column chromatogram to obtain the desired 2- (2-fluoro-4-).
White crystals of methyl biphenylyl) -2-methylpropionate were obtained. Dissolve this in 30 ml of ethanol,
A solution of sodium hydroxide (4.3 g, 108 mmol) in water (3 ml) was added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 6.26 g (59%) of a target pale yellow crystal of 2- (2-fluoro-4-biphenylyl) -2-methylpropionic acid. Melting point 167-168 ° C

Claims (1)

[Claims] 1. A formula [1]: (In the formula, A represents a lower alkylene group, B represents an aromatic hydrocarbon ring or a thiophene ring, D is a single bond, an oxygen atom, —CO—, —CH (OR ⁵ ) — (in the formula, R ⁵ Represents a hydrogen atom or a lower alkyl group), -C (= NOR
⁵ )-(wherein R ⁵ has the same meaning as described above), -C
H (N (R ⁵⁾ ₂₎ - represents a (wherein, R ⁵ are as defined above.) - (wherein, R ⁵ are as defined above.), Or -NR ^5. R ¹ represents a hydrogen atom or a halogen atom. R ² represents a lower alkyl group, a lower alkenyl group, an optionally substituted phenyl group, an optionally substituted cycloalkyl group, or an optionally substituted thienyl group. Further, when D represents a single bond, R ² represents a lower alkoxy group or a hydroxy group. R ³ represents a heterocyclic group containing a nitrogen atom, and R ⁴ represents a hydrogen atom or a lower alkyl group), or an imidazole derivative or an acid addition salt thereof.