JPH10130240A - Inhibitor of icam-1-production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject pharmaceutical compound, capable of inhibiting the production of an ICMA-1 which is an intercellular adhesion molecule and useful as a therapeutic agent for various diseases concerned with the ICMA-1 such as chronic articular rheumatism. SOLUTION: The substitution reaction of a compound represented by formula I [R<1> is a 1-6C alkyl, a 3-6C cyclic alkyl, etc.; R<2> is H or a 1-6C alkylthio; R<3> is H, a halogen, a 1-6C alkyl, etc.; X is H or a halogen; X, is F, Cl, a 1-3C alkylsulfonyl, etc.; Y is OH, a group represented by the formula O-R<7> (R<7> is phenyl, acetoxymethyl, etc.); A is N or a group represented by the formula C-R<6> (R<6> is H, a halogen, etc.)] with a compound represented by formula II [R<4> is H or a 1-6C alkyl; R<5> is a halogen, a 1-36C alkyl, etc.; (m) is 2 or 3] is carried out to afford a compound represented by formula III. The reaction is advantageously conducted in the presence of an inorganic or an organic base, etc., in or without an inert solvent. The reactional temperature is usually ambient temperature to 200 deg.C, preferably within the range of 25-150 deg.C. the reactional time is 30min to 48hr and usually about 30min to 2hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to ICAM-1 (in
tercellular adhesion molecule-1) a production inhibitor, more specifically, inhibits the production of ICAM-1, a cell adhesion molecule, and inhibits inflammatory diseases such as rheumatoid arthritis, ischemic reperfusion injury of myocardium, bronchial asthma, glomerulus The present invention relates to a drug useful as a therapeutic agent for nephritis and the like.

[0002]

2. Description of the Related Art In vivo, cells having different functions are involved in maintaining homeostasis while interacting with each other. Adhesion molecules are molecules responsible for the adhesion between cells or between cells and extracellular matrix. Many adhesion molecules have been identified so far, and their functions have been clarified by using monoclonal antibodies. Adhesion molecules are classified into the selectin family, the immunoglobulin (Ig) superfamily, the integrin family, and the cadherin family.

[0003] The adhesion of activated leukocytes to vascular endothelial cells plays an important role in the development of the inflammatory response. It is known that the adhesion of leukocytes to vascular endothelial cells is responsive through several cell adhesion molecules.
ICAM-1 belonging to the selectin family and the Ig superfamily is one of those adhesion molecules,
A-1 (Leukocyte function-associated antigen-1)
Is used as a counter receptor, and its expression is a glycoprotein found in vascular endothelial cells, tracheal epithelial cells, activated leukocytes and the like. ICAM-1 expression is IL-1, TN
ICAM-1 plays an important role in the progression of inflammation because it is enhanced by inflammatory cytokines such as F and its expression is increased in local inflammation such as rheumatoid arthritis and autoimmune thyroid gland in humans. It is said that Also, from studies using monoclonal antibodies and various disease models, inhibition of ICAM-1 may be useful in the treatment of myocardial ischemia-reperfusion injury, airway hyperreactivity in asthma, arthritis, glomerulonephritis, etc. It has been reported.

[0004]

Accordingly, the present invention provides an I
By inhibiting CAM-1 production, ICAM-1
It is an object of the present invention to provide a medicament useful for the treatment of various diseases in which is involved.

[0005]

The present inventors have conducted intensive studies and as a result, have found that the compound represented by the following general formula (1) or a salt thereof strongly inhibits the production of ICAM-1;
The present inventors have found that the present invention is extremely useful for treating various diseases in which CAM-1 is involved, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1)

[0007]

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[Wherein, R ¹ is a linear or branched C _1-6 alkyl group which may have a substituent; a C _3-6 cyclic alkyl group which may have a substituent; Atom, C _1-6
An alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, a C _1-6 alkylthio group, a di (C _1-6 alkyl) amino-C _1-6 alkyl group,
_1-6 alkylamino-C _1-6 alkyl group, amino C _1-6 alkyl group, imidazolyl-C _1-6 alkyl group, pyrrolyl-C _1-6 alkyl group, (1,2,3-triazolyl-1
-Yl) -C _1-6 alkyl group, (1,2,3-triazolyl-2-yl) -C _1-6 alkyl group, (1,2,4-
A triazolyl-1-yl) -C _1-6 alkyl group, (1,
An aryl group optionally having as a substituent a group selected from the group consisting of a 2,4-triazolyl-4-yl) -C _1-6 alkyl group and a (1-morpholyl) -C _1-6 alkyl group; Or

A 5- or 6-membered heteroaromatic monocyclic ring containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a heteroaromatic obtained by condensing a heterobenzene monocyclic ring with a benzene ring A heterocyclic substituent which is a condensed ring is shown, wherein the heterocyclic substituent is a halogen atom, C _1-6
It may have a substituent selected from the group consisting of an alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group:

R ² represents a hydrogen atom or a C _1-6 alkylthio group. This R ² and R ¹ may be integrated to form a cyclic structure containing a part of the quinolone skeleton. Preferably, the ring may contain a sulfur atom as a constituent atom of the ring, and the ring may have a C _1-6 alkyl group as a substituent. Alternatively, R ² and Y may be integrated so as to form a cyclic structure including a part of the quinolone skeleton:

R ³ represents a hydrogen atom, an amino group, a C _1-6 alkyl group or a C _1-6 alkoxyl group, wherein the amino group is a formyl group, a C _1-6 alkyl group, or a C _2-6 one or more groups selected from the group consisting _-6 acyl groups may have a substituent: R ⁴ represents a hydrogen atom or a C _1-6 alkyl group:

R ⁵ is selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group. A phenyl group which may have a substituent as a substituent; or contains one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,
A 5- or 6-membered heteroaromatic monocyclic ring or a heterocyclic condensed ring which is a condensed heteroaromatic condensed ring obtained by condensing a heteroaromatic condensed monocyclic ring with a benzene ring is represented by a halogen atom, C _{1 -6} alkyl group, a fluorine atom C _1-6 alkyl group having as a substituent, C _1-6 alkoxyl group, and C _1-6 which may have a substituent selected from the group consisting of an alkylthio group: X Represents a hydrogen atom or a halogen atom: A represents a nitrogen atom or a formula (2)

[0013]

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(Wherein, R ⁶ represents a hydrogen atom, a halogen atom, or a C
_{It represents a 1-6} alkyl group or a C _1-6 alkoxyl group which may have a halogen atom as a substituent.

This R ⁶ and the above R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton, but this ring has an oxygen atom or a sulfur atom as a ring constituent atom. This ring may further have a C _1-6 alkyl group as a substituent. )); M represents an integer of 2 or 3;
Hydroxyl group or formula (3):

[0016]

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(Wherein R ⁷ is phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2) -Oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, C _1-6 alkyl group, C _1-6
And a phenylalkyl group comprising an alkoxy-methyl group or a C _1-6 alkylene group and a phenyl group. )
The partial structure represented by is shown. ] Or a salt thereof as an active ingredient.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents of the compound represented by the general formula (1) having the ability to inhibit ICAM-1 production of the present invention are described below. In the present specification, for example, “C _1-6 ” indicates that the number of carbon atoms is 1 to 6.

The substituent R ¹ represents a linear or branched C _1-6 alkyl group, C _3-6 cyclic alkyl group, aryl group or heterocyclic substituent which may have a substituent. ,
Here, a linear or branched C _1-6 alkyl group and C
Examples of the substituent in the _1-6 cyclic alkyl group include a halogen atom and a hydroxyl group. Of these, a halogen atom is preferable, and a fluorine atom is particularly preferable. Also,
As the alkyl group, a methyl group and an ethyl group are preferable, and as the cyclic alkyl group, a cyclopropyl group is preferable. As the alkyl group having a substituent, a 2-fluoroethyl group, a 2-chloroethyl group and a 2,2,2-
A trichloroethyl group is preferable, and a 2-halogenocyclopropyl group is preferable as the cyclic alkyl group having a substituent.

The aryl group which may have a substituent is not particularly limited as long as it is a substituent derived from various aromatic hydrocarbon compounds, and the number of substituents on these aryl groups is as follows. One or more substituents may be present, and when there are a plurality of substituents, they may be all composed of the same species, or may be a mixture of a plurality of species. Further, these substituents may be present at any position on the aryl group. Examples of the substituent on the aryl group include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, a C _1-6 alkylthio group, a di ( C _1-6 alkyl) amino-C _1-6 alkyl group, C _1-6 alkylamino-C _1-6 alkyl group, C _1-6 aminoalkyl group, imidazolyl-C _1-6
An alkyl group, a pyrrolyl-C _1-6 alkyl group, (1,2,
3-triazolyl-1-yl) -C _{1 -6} alkyl group,
(1,2,3-triazolyl-2-yl) -C _1-6 alkyl group, (1,2,4-triazolyl-1-yl) -C
_1-6 alkyl group, (1,2,4-triazolyl-4-yl) -C _1-6 alkyl group, and (1-morpholyl)
-C _1-6 alkyl group and the like. Among them, a halogen atom is preferably a chlorine atom or a fluorine atom,
_{The 1-6} alkyl group may be linear, branched or cyclic. Also, C _1-6 alkyl group having a fluorine atom as a substituent, C _1-6 alkoxyl group, C _1-6 alkylthio group, a di (C _1-6 alkyl) amino -C _1-6 alkyl group, C _{1- 6} alkylamino-C _1-6 alkyl group, C _1-6
Aminoalkyl group, imidazolyl-C _1-6 alkyl group,
Pyrrolyl-C _1-6 alkyl group, (1,2,3-triazolyl-1-yl) -C _1-6 alkyl group, (1,2,3-
Triazolyl-2-yl) -C _1-6 alkyl group, (1,
2,4-triazolyl-1-yl) -C _1-6 alkyl group, (1,2,4-triazolyl-4-yl) -C _1-6
Similarly, the alkyl group and the respective alkyl moieties of the (1-morpholyl) -C _1-6 alkyl group may be linear, branched or cyclic. The two alkyl groups in the di (C _1-6 alkyl) amino-C _1-6 alkyl group may be the same or different.

As the C _1-6 alkyl group having a fluorine atom as a substituent, a linear C _1-6 alkyl group having a fluorine atom is preferred. The number of fluorine atoms to be substituted is not particularly limited, but may be one in which all hydrogen atoms are substituted from monosubstitution, for example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trimethyl group, And a fluoromethyl group.

Di (C _1-6 alkyl) amino-C _1-6 alkyl group, C _1-6 alkylamino-C _1-6 alkyl group, C _1-6
Aminoalkyl group, imidazolyl-C _1-6 alkyl group,
Pyrrolyl-C _1-6 alkyl group, (1,2,3-triazolyl-1-yl) -C _1-6 alkyl group, (1,2,3-
Triazolyl-2-yl) -C _1-6 alkyl group, (1,
2,4-triazolyl-1-yl) -C _1-6 alkyl group, (1,2,4-triazolyl-4-yl) -C _1-6
In the alkyl group and the (1-morpholyl) -C _1-6 alkyl group, each substituent may be on any carbon atom of the alkyl group, but is more preferably on the terminal carbon atom of the alkyl group. . The alkyl moiety of these substituents is most preferably a methyl group.
_1-6 alkyl) aminomethyl group, C _1-6 alkylamino methyl group, aminomethyl group, imidazolylmethyl group, and the like as an example.

The aryl group in the aryl group which may have a substituent includes a phenyl group and a naphthyl group, with a phenyl group being preferred.

In the aryl group which may have a substituent,
More preferred are, for example, a fluorine atom, a chlorine atom, a halogen atom such as a bromine atom, a C _1-6 alkyl group,
And a phenyl group which may be substituted by 1 to 3 substituents selected from the group of C _1-6 alkoxyl group and the like. Among these, a phenyl group, a 2-fluorophenyl group and a 4-fluorophenyl group are exemplified. And a 2,4-difluorophenyl group are particularly preferred.

The heterocyclic substituent is a 5- or 6-membered heteroaromatic monocyclic ring containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a heteroaromatic ring thereof. A heterocyclic substituent is a heteroaromatic condensed ring in which an aromatic condensed monocyclic ring and a benzene ring are condensed. Thienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group, benzoxazolyl group, benzothiazolyl group, benzoimidazolyl group and the like.

These heterocyclic substituents include a halogen atom,
C _1-6 alkyl group, C having a fluorine atom as a substituent
_It may have a substituent selected from the group consisting of a _1-6 alkyl group, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group. Specific examples of the substituent on the heterocyclic substituent include those corresponding to the specific examples of the substituent used for R ¹ described above. Also,
The substituents on these heterocyclic substituents may be one or more, and when there are a plurality of substituents, they may be the same or different.

In the general formula (1), R ² is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
¹ and R ² include a nitrogen atom to which R ¹ is bonded and a carbon atom to which R ² is bonded, and are integrated so as to form a cyclic structure including a part of the quinolone skeleton which is a mother nucleus. It may be. The ring thus formed may contain a sulfur atom as a ring constituent atom, and the ring may further comprise a C
_It may have a _1-6 alkyl group as a substituent. The ring formed here may be any ring having a size of 4 to 6 members, and furthermore, this ring may be saturated, partially saturated or unsaturated.

[0028] In the general formula (1), R ³ represents a hydrogen atom, an amino group, represents a C _1-6 alkyl group or a C _{1 -6} alkoxy group, an amino group of which formyl groups, C _{1 -6}
It may be substituted by one or more substituents selected from the group consisting of an alkyl group, a C _2-5 acyl group, and a halogen atom. Here, the C _1-6 alkyl group includes a linear or branched one. Preferred are a methyl group, an ethyl group, a normal propyl group and an isopropyl group. The alkyl moiety of the alkoxyl group may be the same as the alkyl group used for R ³ .

In the general formula (1), R ⁴ represents a hydrogen atom or a C _1-6 alkyl group. The C _1-6 alkyl group may be a straight-chain or branched chain, and may be a methyl group, An ethyl group, a normal propyl group or an isopropyl group is preferred.

In the general formula (1), R ⁵ represents a nitro group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group substituted by a fluorine atom, a C _1-6 alkoxyl group and a C _1-6 alkoxyl group. _{It represents a} phenyl group or a heterocyclic substituent which may be substituted by a substituent selected from the group consisting of _1-6 alkylthio groups. Here, the heterocyclic substituent may be either monocyclic or bicyclic. The monocyclic heterocyclic substituent has a 5- or 6-membered aromatic ring containing one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Examples include a substituent derived from a heterocyclic compound. Examples of the bicyclic heterocyclic substituent include a substituent derived from a bicyclic, aromatic heterocyclic compound formed by condensing the above monocyclic heterocyclic compound and a benzene ring. For example, pyrrolyl group, imidazolyl group, pyrazolyl, pyridyl group,
Examples include pyridazinyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group, benzoxazolyl group, benzothiazolyl group, and benzoimidazolyl group. Further, the heterocyclic group may have the same substituent as the phenyl group, and the number of substituents on the phenyl group or the heterocyclic group may be one or more. When there are groups, they may be the same or different. Further, these substituents may be present at any position on the phenyl group or the heterocyclic ring.

The halogen atom is a chlorine atom
And a fluorine atom or a fluorine atom is preferable. _1-6The alkyl group is
It may be straight or branched, but is preferably
Methyl, ethyl, normal propyl and isop
It is a ropyl group. Al having a fluorine atom as a substituent
The alkyl group is preferably a straight-chain alkyl group. Also replace
The number of fluorine atoms is not particularly limited.
Hydrogen atoms may be substituted, specifically,
Oromethyl group, difluoromethyl group, trifluoromethyl
And a 2,2,2-trifluoromethyl group and the like.
You.

X is a halogen atom or a hydrogen atom. In the case of a halogen atom, a fluorine atom is preferable, and among these, a fluorine atom or a hydrogen atom is preferable.

A is a nitrogen atom or formula (2):

[0034]

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[0035] Although (R ⁶ is as defined above) is a partial structure represented by, when A is a partial structure of formula (2), R ⁶
Is a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally having a halogen atom as a substituent, or a C _1-6 alkoxyl group optionally having a halogen atom as a substituent. Here, the halogen atom is preferably a chlorine atom or a fluorine atom, particularly preferably a fluorine atom. C which may have a halogen atom as a substituent
_{As the} halogen atom in the _1-6 alkyl group or C _1-6 alkoxyl group, a fluorine atom or a chlorine atom is preferable, and a fluorine atom is particularly preferable. As an alkyl group or an alkoxyl group having a fluorine atom as a substituent,
A linear alkyl group or alkoxyl group is preferred.
The number of fluorine atoms on such an alkyl group or alkoxyl group is not particularly limited, but may be mono-substituted to perfluoro-substituted. Specifically, a fluoroalkyl group such as a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group; a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, And fluoroalkoxy groups such as fluoromethoxy group and 2,2,2-trifluoroethoxy group. Further, R ⁶ and R ¹ include a nitrogen atom to which R ¹ is bonded and a carbon atom to which R ⁶ is bonded, and are saturated and partially saturated including a part of the quinolone skeleton which is a mother nucleus. Alternatively, they may be integrated so as to form a 7-membered ring from an unsaturated 4-membered ring, and this ring may be an oxygen atom,
The ring may contain a nitrogen atom or a sulfur atom as a constituent atom of the ring, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.

Y is a hydroxyl group or formula (3):

[0037]

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Is a substituent having the structure shown by
⁷ is a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole -4-ylmethyl group, 3-acetoxy-2-oxobutyl group, C _1-6 alkyl group, C _1-6 alkoxy-methyl group,
And a substituent selected from the group consisting of a phenylalkyl group comprising a C _1-6 alkylene group and a phenyl group.

When A is a partial structure represented by the formula (2), in R ³ and R ⁶ of the formula (1), R ³ is a hydrogen atom, an amino group, a hydroxyl group or a C _1-6 alkyl group.
Preferred combinations are those in which R ⁶ is selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group and a halogenomethoxyl group. A more preferred combination is a case where R ³ is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and R ⁶ is a methyl group, a methoxyl group, a difluoromethoxyl group, a trifluoromethyl group, or a hydrogen atom.

Preferred examples of the compound represented by the formula (1) used as an active ingredient in the inhibitor of ICAM-1 production of the present invention include a compound represented by the following formula (4) or (5) or a salt thereof. No.

[0041]

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The compound of the formula (1) can be produced, for example, according to the following reaction formula.

[0043]

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Wherein X ′ is a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a C _1-3 alkylsulfonyl group, or an arylsulfonyl group such as a benzenesulfonyl group and a toluenesulfonyl group. And Y ′ is the same as Y in formula (1) or in formula (8):

[0045]

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(Wherein R ⁸ and R ⁹ represent a fluorine atom or a lower alkylcarbonyloxy group), and are R ¹ , R ² , R ³ , R ^3
4 , R ⁵ , m, X and A are the same as described above]

That is, it can be produced by reacting the compound represented by the general formula (6) with the compound represented by the formula (7) or an acid addition salt thereof.

When Y 'is a C _1-6 alkyl group, C _2-7 alkoxymethyl group, C _1-6 alkylene group or phenyl group, conversion to the corresponding carboxylic acid is carried out by hydrolysis of a usual carboxylic acid ester. When deprotection is required, the protecting group can be removed under appropriate conditions corresponding to the protecting group to obtain the target compound represented by the formula (1).

In the compound of the formula (6), when Y 'is a compound represented by the formula (8), the compound is subjected to a substitution reaction with the compound of the formula (7) and then treated with an acidic or basic compound. It can be converted to the corresponding carboxylic acid.

The substitution reaction between the compound of the formula (6) and the compound of the formula (7) can be carried out without solvent or in an inert solvent. Here, as the inert solvent, for example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water,
3-methoxybutanol and the like can be mentioned. Alternatively, these solvents may be used as a mixture.

The reaction can be carried out usually at room temperature to 200 ° C., preferably at 25 ° C. to 150 ° C. The reaction time is 30 minutes to 48 hours, usually 30 minutes to
It is completed in about 2 hours.

The reaction may be carried out with an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine, 1,8-diazabicycloundecene and the like. It is advantageous to work in the presence of an organic basic compound.

The compound of the formula (1) may exist as diastereomers, but when the compound of the present invention is administered to humans or animals, it is preferable to administer the compound consisting of a single diastereomer. The term “consisting of a single diastereomer” includes not only the case where no other diastereomer is contained, but also the case where it is chemically pure. It means that other diastereomers may be included as long as they have no effect.

The term "stereochemically single" means that when a compound or the like contains an asymmetric carbon atom and there are a plurality of kinds which are mutually isomers, one of them is one of them. It means that it is composed only of In this case, the “unity” is also considered in the same manner as described above.

The compound (1) may be in a free form, or as an acid addition salt of an inorganic acid or an organic acid or a salt of a carboxyl group. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, or acetate, methanesulfonate, and benzene. Organic acid salts such as sulfonate, toluene sulfonate, citrate, maleate, fumarate, lactate and the like can be mentioned.

Examples of the salt of the carboxyl group include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N salt.
-Methylglucamine salt, tris- (hydroxylmethyl) aminomethane salt and the like.

The free form, acid addition salt and carboxyl group salt of compound (1) may exist as hydrates.

On the other hand, the compounds of the present invention in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. When used as a synthetic intermediate here, for example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, phenyl esters, and the like are preferable.

When used as a prodrug,
Esters which are easily cleaved in the living body to produce a free form of carboxylic acid are preferred, and include, for example, acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-yne Preferred are oxoalkyl esters such as danyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and 3-acetoxy-2-oxobutyl ester.

Compound (1) has an inhibitory action on ICAM-1 production and inhibits various cell adhesions.
As a therapeutic agent for diseases caused by cell adhesion based on CAM-1, for example, inflammatory diseases such as rheumatoid arthritis and arthritis, ischemia-reperfusion injury of myocardium, bronchial asthma, glomerulonephritis, rejection at the time of organ transplantation, etc. Useful.

When compound (1) is used as an ICAM-1 production inhibitor, the dosage varies depending on the age, sex, symptoms, etc. of the patient, but is in the range of 20 mg to 1 g, preferably 200 mg to 600 mg per day per adult. Is preferred.
In this case, the daily dose may be administered once a day or divided into 2 to 4 times, and the daily dose may exceed the above-mentioned amount if necessary.

The ICAM-1 production inhibitor containing the compound (1) is not particularly limited in its administration method and dosage form, and may be used in the preparation of various commonly used preparations in accordance with its administration method. What should I do?

Examples of oral preparations include tablets, powders,
Examples include granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions.

As an injection, after the solution is stored in a container, it may be prepared as a solid preparation by freeze-drying or the like before use, and a stabilizer, a preservative, and a solubilizing agent may be used as necessary. Also, it may be stored in a container for each dose,
Also, multiple doses may be stored in the same container.

Examples of external preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.

Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants And the like can be selected and mixed as needed to form a formulation.

Examples of the liquid preparation include solutions, suspensions, and emulsions, and may contain a suspending agent, an emulsifier, and the like as additives.

[0068]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Synthesis Example 1 1-Cyclopropyl-8-difluoromethoxy-1,4
-Dihydro-6-fluoro-7- [4- (4-pyridyl) -1-piperazinyl] -4-oxoquinoline-3-
carboxylic acid

[0070]

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1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-6,7-difluoro-4-oxoquinoline-3-carboxylic acid (165.5 mg, 0.5
0 mmol), 1- (4-pyridyl) piperazine (808
g, 4.95 mmol) and pyridine (10 ml).
After heating and stirring at 05-110 ° C for 24 hours, the mixture was dried under reduced pressure.

Chloroform was added to the residue, and extracted with a 1N aqueous sodium hydroxide solution. The aqueous layer was adjusted to pH 7.4 with hydrochloric acid, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative TLC (developing solvent) to obtain 24 mg of the title compound as yellow crystals.

Melting point: 250 ° C. Elemental analysis: C ₂₃ H ₂₁ F ₃ N ₄ O ₄ .1.75 H ₂ O Calculated: C, 54.60; H, 4.88; N, 11.81 Analysis : C, 54.71; H, 4.85; N, 11.07

Synthesis Example 2 8-Difluoromethoxy-1,4-dihydro-1-ethyl-fluoro-7- (2-methoxyphenyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid

[0075]

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8-difluoromethoxy-1,4-dihydro-1-ethyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid (7.00 g, 21.9 mmol),
1- (2-methoxyphenyl) piperazine (6.32)
g, 32.9 mmol), triethylamine (30 ml) and acetonitrile (300 ml), and the mixture was heated under reflux for 23 hours and then dried under reduced pressure.

The residue was dissolved in chloroform (500 ml), washed with a 10% aqueous citric acid solution (2 × 200 ml) and saturated saline (2 × 200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. 7. The residue is recrystallized from ethanol.
01 g (74%) of the title compound were obtained as yellow crystals.

Melting point: 216-231 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J
= 7.4Hz), 3.22 (4H, m, -CH 2 - ×
2), 3.22 (4H, m , -CH 2 - × 2), 3.5
_{6 (4H, m, -CH 2} - × 2), 3.91 (3H,
_{s, -OCH 3), 4.70 (} 2H, q, J = 7.4H
z), 6.70 (1H, t, J = 74.7 Hz), 6.
89-7.09 (4H, m, aromatic H),
8.14 (1H, d, J = 12 Hz, H-5), 8.6
6 (1H, s, H- 2) Elemental _{analysis; C 24 H 24 F 3 N} 3 O 5 Calculated: C, 58.65; H, 4.92 ; N, 8.55 Analytical values: C, 58 .59; H, 4.94; N, 8.41

Synthesis Example 3 1-Cyclopropyl-1,4-dihydro-6-fluoro-8-difluoromethoxy-7- [4- (2-pyrimidyl) -1-piperazinyl] -4-oxoquinoline-3-
carboxylic acid

[0080]

Embedded image

1-cyclopropyl-1,4-dihydro-
6,7-difluoro-8-difluoromethoxy-4-oxoquinoline-3-carboxylic acid (331 mg, 1.0 mmol
l), 1- (2-pyrimidyl) piperazine (328 mg,
2.0 mmol), triethylamine (279 ml, 2.0 mm
ol) and acetonitrile (20 ml) were mixed and heated at reflux for 16 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration.
Recrystallization from ethanol gave the title compound as colorless crystals.

Melting point: 267-273 ° C. 1H-NMR (CDCl ₃ ) δ: 1.18-1.12.
(2H, m, -CH (CH 2) 2), 1.26-1.30
(2H, m, -CH (CH 2) 2), 3.53-3.57
_{(2H, m, -CH 2 -} × 2), 4.06-4.07
_{(4H, m, -CH 2 -} × 2), 6.85 (1H, t,
J = 4.5 Hz, pirimidine H-5),
7.22 (1H, t, J = 73.5 Hz, -CH
F ₂ ), 8.11 (1H, d, J = 12 Hz, H−
5), 8.57 (2H, d, J = 12 Hz, pirim
idine H-4,5), 8.94 (1H, s, H-
2) Elemental _{analysis; C 22 H 20 F 3 N} 5 O 4 Calculated: C, 55.58; H, 4.24 ; N, 14.73 analysis: C, 55.29; H, 4.02 N, 14.65;

Example 1 ICAM-1 Production Inhibition Ability Test ICAM-1 Production Inhibition Test: Human umbilical vein endothelial cells (H
UBEC) was seeded at a rate of 8 × 10 ³ cells, and 3% in the presence of 5% CO _2.
Pre-cultured at 7 ° C for 48 hours. 48 hours later, each well
Human-TNFα and each of the test compounds having the structures shown below were subjected to final concentrations of 1000 U / ml and 0.05, respectively.
Add 50 μl each to 0.5, 5 μg / ml.
The cells were further cultured at 37 ° C for 4 hours in the presence of% CO ₂ . Hank's Balanced Salt Solution containing 0.1% BSA
After washing 5 times with (HBSS), 100 μl of a mouse anti-human ICAM-1 antibody adjusted to 1 μg / ml was added to each well and reacted at room temperature for 45 minutes. After completion of the reaction, the cells were washed five times with HBSS containing 0.1% BSA, and a 3000-fold diluted solution of peroxidase-labeled mouse Ig was added to each well in an amount of 100 μl / well, followed by further reaction at room temperature for 90 minutes.
After washing the cells 5 times with HBSS containing 0.1% BSA, 100 μl of ABTS was added as a reaction substrate to each well,
The reaction was performed at room temperature for 20 minutes. The reaction was stopped by adding 50 μl of a 1% SDS solution to each well. After the reaction was stopped, the color development ratio of the solution in each well was measured at an absorption wavelength of 405 nm using an absorbance meter. The results are shown in FIG. The benzothiophene derivative used as Comparative Product 1 in this test was Boshelli, DH, Kramer, JB, Conn.
or, DT, Lesch, ME, Schrier, DJ, Ferin, M.
A. & Wright, CD: J. Med. Chem. 37: 717-718, 199
4, which is known to have ICAM-1 production inhibitory ability.

[0084]

Embedded image

<Results> ICAM- of two quinolone compounds (product 1 of the present invention (compound prepared in Synthesis Example 2) and product 2 of the present invention (compound prepared in Synthesis Example 3)) and benzothiophene derivative (comparative product 1) 1 In the production inhibition test,
The products 1 and 2 of the present invention exhibited a strong inhibitory effect. FIG.
As shown in FIG.
5%, about 50% at 0.1 μg / ml, about 75 at 5 μg / ml
%, A strong inhibitory effect was observed. In addition, be of comparative product 1
The ICAM-1 inhibitory effect of the nzothiophene derivative was almost equivalent to the value described in the literature, and the validity of the test was confirmed. In addition,
Although no results are shown, none of the three samples showed any activity of inhibiting the binding of ICAM-1 to the receptor (LFA-1). Based on the above results, the product of the present invention shows a strong inhibitory effect on ICAM-1 production.
It is useful as a therapeutic agent for many diseases involving AM-1.

Formulation Example 1 (Capsule):

[Table 1]

Formulation Example 2 (Solution):

[Table 2] Compound of Synthesis Example 2 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl parahydroxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100 g

[0088]

EFFECT OF THE INVENTION The ICAM-1 production inhibitor of the present invention has a strong ICAM-1 production inhibitory activity, and is associated with inflammatory diseases such as rheumatoid arthritis, ischemic reperfusion injury of myocardium, in which ICAM-1 is involved. It is useful for treating various diseases such as bronchial asthma and glomerulonephritis.

[Brief description of the drawings]

FIG. 1 is a diagram showing the color development ratio at an absorption wavelength of 405 nm of each compound after reaction in Example 1.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 ABG A61K 31/535 ABG 31/55 ABN 31/55 ABN C07D 471/04 114 C07D 471/04 114A // C07D 401 / 12 213 401/12 213 239 239

Claims (3)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a linear or branched C _1-6 alkyl group which may have a substituent; a C _3-6 cyclic alkyl group which may have a substituent; _1-6 alkyl group, C _1-6 alkyl group having a fluorine atom as a substituent, C _1-6 alkoxyl group, C _1-6 alkylthio group, di (C _1-6 alkyl) amino-C _1-6 alkyl group , C _1-6 alkylamino-C _1-6 alkyl group, amino C _1-6 alkyl group, imidazolyl-C _1-6
An alkyl group, a pyrrolyl-C _1-6 alkyl group, (1,2,
3-triazolyl-1-yl) -C _1-6 alkyl group,
(1,2,3-triazolyl-2-yl) -C _1-6 alkyl group, (1,2,4-triazolyl-1-yl) -C
_1-6 alkyl group, (1,2,4-triazolyl-4-yl) -C _1-6 alkyl group and (1-morpholyl) -
An aryl group optionally having a substituent selected from the group consisting of a C _1-6 alkyl group; or a 5-membered or 1- or 2-membered heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom A heterocyclic substituent is a 6-membered heteroaromatic monocyclic ring or a heteroaromatic condensed ring obtained by condensing the heteroaromatic monocyclic ring with a benzene ring. The heterocyclic substituent is a halogen atom, a C _1-6 alkyl. group, a fluorine atom C _1-6 alkyl group having as a substituent, C _1-6 alkoxyl group, and C _1-6 which may have a substituent selected from the group consisting of alkylthio radicals: R
² represents a hydrogen atom or a C _1-6 alkylthio group, and this R ² and the above R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton. The ring may contain a sulfur atom as a constituent atom of the ring, and the ring may have a C _1-6 alkyl group as a substituent. Further, R ² and Y may be integrated so as to form a cyclic structure including a part of the quinolone skeleton: R 2
³ represents a hydrogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxyl group, and a halogen atom. Among them, the amino group is a formyl group, a C _1-6 alkyl group, and a C _2-6 group. _It may have one or more groups selected from the group consisting of ₆ acyl groups as substituents: R ⁴ represents a hydrogen atom or a C _1-6 alkyl group: R ⁵ represents a halogen atom, C _{1- 6} alkyl groups, C _1-6 alkyl groups having a fluorine atom as a substituent, C _1-6 alkoxyl groups, and C 6
_A phenyl group optionally having a substituent selected from the group consisting of _1-6 alkylthio groups; or a 5-membered or 6-membered atom containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A heteroaromatic condensed ring in which a condensed heteroaromatic monocyclic ring or a condensed heteroaromatic monocyclic ring and a benzene ring are condensed, and the heterocyclic substituent is a halogen atom, a C _1-6 alkyl group. ,
A C _1-6 alkyl group having a fluorine atom as a substituent,
_It may have a substituent selected from the group consisting of a _1-6 alkoxyl group and a C _1-6 alkylthio group: X represents a hydrogen atom or a halogen atom: A represents a nitrogen atom or a formula (2) Embedded image (Wherein, R ⁶ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group _optionally having a halogen atom as a substituent,
Or C which may have a halogen atom as a substituent
_{1-6 represents an} alkoxyl group. This R ⁶ and the above R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton, but this ring may contain an oxygen atom or a sulfur atom as a ring constituent atom. This ring may further have a C _1-6 alkyl group as a substituent. )), M represents an integer 2 or 3, and Y represents a hydroxyl group or a formula (3): (In the formula, R ⁷ represents a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo- 1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-
Oxobutyl group, C _1-6 alkyl group, C _1-6 alkoxy-
It represents a phenylalkyl group composed of a methyl group or a C _1-6 alkylene group and a phenyl group. The partial structure represented by the parentheses is shown. ] Or a salt thereof as an active ingredient. 2. The ICA according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (4).
M-1 production inhibitor. Embedded image 3. The ICA according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (5).
M-1 production inhibitor. Embedded image