JPH09227561A - Xanthine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound consisting of a specific xanthine derivative, effective for inhibiting the activity of a transcription factor NFκB and useful e.g. as an agent for the prevention and treatment of diseases to which the NFκB activity inhibiting action is effective, e.g. autoimmune diseases, inflammatory diseases and AIDS. SOLUTION: This compound is a new xanthine derivative (or its salt) expressed by formula I [W is a 5 to 7-membered heterocyclic group containing; N, having oxo group and optionally condensed with an aromatic ring; Y is single bond, a lower alkylene which may have CO group in the chain or on the chain terminal, etc.; L is a lower alkylene; R<1> and R<2> are each H or a lower alkyl; R<3> and R<4> are each H, a lower alkyl, an aryl or a (substituted)lower alkanoyl]. It has an activity-inhibiting action on transcription factor NFκB and is useful e.g. as an agent for the prevention and treatment of autoimmune diseases, inflammatory diseases, viral diseases, etc. The compound can be produced by reacting a compound of formula II or its salt with a xanthine compound expressed by formula III (Q<1> is a reactive residue) or its salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel xanthine derivative. Further, the present invention relates to a pharmaceutical composition comprising such a xanthine derivative as an active ingredient, more specifically, an NFκB activity inhibitor, an expression inhibitor of a gene having an NFκB recognition sequence, or an NFκB activity inhibitory action. Relates to a prophylactic / therapeutic agent for a disease.

[0002]

2. Description of the Related Art Gene expression is controlled by a transcriptional regulatory factor which is a DNA binding protein that recognizes a specific nucleotide sequence on the gene. NFκB, which is known as one of the transcriptional regulatory factors, is present in the nuclear extract of antibody-producing cells and has been identified as a factor that binds to the enhancer of the immunoglobulin κ light chain (Igκ) gene. The NFκB-binding sequence on the genome consists of about 10 bases and is found in various genes as well as immunoglobulin genes. Genes of inflammatory cytokines such as tumor necrosis factor and cell adhesion factors are included in these gene groups. It has been clarified that NFκB is involved in the induction of the expression of these genes, and is involved in the control of biological defense reaction and the pathogenesis of inflammatory diseases. NFκB is composed of a complex of Rel family subunits represented by p50 and p65 proteins. Usually a regulatory subunit in the cytoplasm
Exists in association with IκB protein. When a certain stimulus is given to cells, IκB is modified and NFκB is released from the complex and activated. NFκB thus activated translocates into the nucleus and binds to a specific base sequence on genomic DNA.

Conventionally, as a substance that inhibits the transcriptional activity of NFκB, an NFκB-binding protein has been disclosed in European Patent Publication No. 584238. In addition, non-steroidal drugs, aspirin and sodium salicylate, have been shown to inhibit NFκB activity at high concentrations (Kopp, E. et al., Science, vol.265, p956, 1994).
). In addition, the steroid drug dexamethasone
It has been reported that it induces the production of NFκB and thereby inhibits the activation of NFκB (Scheinman, RI et al.,
Science, 270, 283, 1 995; Auphan, N. et al., Scie
nce, vol.270, p286, 1995). During inflammation, various cytokines are released in the living body by receiving various external stimuli. Conventional drugs antagonize the binding of mediators such as histamine to the receptor, and inhibit metabolic enzymes such as lipoxygenase or cyclooxygenase in the arachidonic acid cascade, thereby inhibiting histamine, leukotriene B4 or prostaglandin E2. It suppresses the expression of inflammatory mediators such as. However, with these non-steroidal drugs, the effect is expected to be a symptomatic treatment, and it cannot be said to be sufficient as a fundamental treatment. Also,
It has been reported that long-term administration causes side effects. On the other hand, although steroid drugs are effective, they have strong side effects, and there is a problem that they cannot be administered for a long time. In particular, inflammatory diseases such as autoimmune diseases often become chronic, require long-term medical treatment, and there is a strong demand for a fundamental therapeutic drug with few side effects. Further, the substance disclosed in European Patent Publication No. 584238 is unstable in vivo due to a protein and has various obstacles when administered as a drug.

[0004]

DISCLOSURE OF THE INVENTION The present invention aims to provide a novel xanthine derivative having an activity of inhibiting the transcription factor NFκB and a pharmaceutical composition containing the compound as an active ingredient in order to establish a fundamental therapy for inflammatory diseases. It is what

[0005]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0006]

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[Wherein W is a 5- to 7-membered heterocyclic group containing at least a nitrogen atom as a hetero atom, having at least an oxo group as a substituent and optionally condensed with an aromatic ring, and Y is a single bond] A lower alkylene group, a lower alkenylene group or a lower alkynylene group, which may be present by hand, or in which a CO group may be interposed or present at both ends,
Z is a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may have a CO group interposed or may be present at both ends, L is a lower alkylene group, and R ¹ and R ² are the same or different and are a hydrogen atom or a lower atom. Represents an alkyl group, or represents a lower alkylene group which is bonded to each other at a terminal thereof, and R ³ and R ⁴ are the same or different and each is a hydrogen atom,
A lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkanoyl group which may be substituted with a lower alkoxy group. However, in W, when the bond of the heterocyclic group is from the nitrogen atom constituting the heterocycle, Y is not a single bond. ] The xanthine derivative shown by these or its pharmacologically acceptable salt. The present invention is also a pharmaceutical composition comprising the xanthine derivative [I] or a pharmacologically acceptable salt thereof as an active ingredient, and more specifically, an activity inhibitor of NFκB and expression of a gene having an NFκB recognition sequence. It is an inhibitor and a preventive / therapeutic agent for diseases for which the activity of inhibiting NFκB activity is effective.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound [I] of the present invention,
Examples of W include a 5- to 7-membered heterocyclic group which contains at least a nitrogen atom as a hetero atom, has at least an oxo group as a substituent, and which may be condensed with a substituted or unsubstituted benzene ring. . More preferable W is as follows:

[0009]

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(However, ring A is a 5- to 7-membered heterocyclic ring which contains a nitrogen atom as a hetero atom, has an oxo group as a substituent, and may have a substituted or unsubstituted aryl group as a substituent. And ring B represents a substituted or unsubstituted Penzen ring.). Preferred ring A may contain a nitrogen atom as a hetero atom and may further contain a hetero atom other than the nitrogen atom selected from a nitrogen atom, an oxygen atom or a sulfur atom, and has an oxo group as a substituent. Examples thereof include a 5- to 7-membered heterocyclic ring which may have a substituted or unsubstituted aryl group as a substituent. Further, in the ring B, examples of the substituent on the benzene ring include a lower alkyl group, a lower alkoxy group and a halogen atom.

A preferred specific example of W is:

[0012]

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[However, X ^a , X ^b , X ^c , X ^d and X ^e each independently represent an oxygen atom, a sulfur atom, an imino group or a methylene group, and Ar ^a , Ar ^b , Ar ^c , Ar ^d And Ar ^f each independently represent a hydrogen atom or a substituted or unsubstituted aryl group, and T represents a hydroxyl group or a lower alkanoyloxy group. ] The group shown by these is mentioned.

Here, the preferred X ^a is a sulfur atom. Preferred X ^b is a sulfur atom. Preferred X ^c is a sulfur atom or an oxygen atom. Preferred X ^d is a sulfur atom. Preferred X ^e is a sulfur atom. Ar ^a , Ar ^b , Ar ^c ,
In Ar ^d and Ar ^f , the substituent on the aryl group is
Examples thereof include a lower alkyl group, a lower alkoxy group and a halogen atom. Preferred Ar ^a is a hydrogen atom or an aryl group which may be substituted with a group selected from a halogen atom or a lower alkoxy group. Of these, the case where Ar ^a is a lower alkoxy group-substituted phenyl group is preferable. Preferred Ar ^b is a hydrogen atom or an aryl group which may be substituted with a group selected from a halogen atom or a lower alkoxy group. Of these, Ar ^b is preferably a halogen atom-substituted phenyl group. Preferred Ar ^c is a hydrogen atom or an aryl group which may be substituted with a group selected from a halogen atom or a lower alkoxy group. Of these, it is preferable that Ar ^c is a hydrogen atom or a halogen atom-substituted phenyl group. Preferred Ar ^d is a hydrogen atom or an aryl group which may be substituted with a group selected from a halogen atom or a lower alkoxy group. Of these, Ar ^d is preferably a hydrogen atom. Preferred Ar ^f is a hydrogen atom or an aryl group which may be substituted with a group selected from a halogen atom or a lower alkoxy group. Of these, Ar ^f is preferably a hydrogen atom. In the substituents on the aryl group of Ar ^a , Ar ^b , Ar ^c , Ar ^d and Ar ^f , the halogen atom is preferably a chlorine atom and the lower alkoxy group is preferably a methoxy group. Preferred T is a lower alkanoyloxy group. Of these, it is preferable that T is an acetyloxy group.

In compound [I], preferred Y is a single bond. Another preferable Y is the formula —Y ¹ —Y ¹ —CO— —CO—Y ¹ — [wherein Y ¹ represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group. ] Of these, formula -Y ¹ -Y ¹ -CO- [wherein the symbols have the same meanings as described above]. ] The group shown by these is preferable. Here, as Y ¹ , a lower alkylene group is preferable, and a methylene group, an ethylene group, or a trimethylene group is particularly preferable.

Preferred Z is of the formula --Z ¹ --Z ¹ --CO--CO--Z ^1- [wherein Z ¹ represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group. ] It is a group shown by. Further, preferable Z is represented by the formula: —Z ¹ — [where the symbols have the same meaning as described above. ] The group shown by these is mentioned. Here, as Z ¹ , a lower alkylene group is preferable, and a methylene group, an ethylene group, or a trimethylene group is particularly preferable.

Preferred R ¹ and R ² are those which are bonded to each other at the terminals to form a lower alkylene group. Further, preferred R ³ and R ⁴ are the same or different and each is a hydrogen atom or a lower alkyl group. Particularly preferred R ³ is a methyl group, and particularly preferred R ⁴ is a methyl group or an isobutyl group. Furthermore, the expression

[0018]

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[However, the symbols have the same meanings as described above. ] A specific example of the group represented by the above is a 1,4-piperazinediyl group.

Specific preferred examples of the compound [I] include:
The following general formulas [Ia], [Ib], [Ic],
The novel xanthine derivatives represented by [Id], [Ie] and [If] can be mentioned.

[0021]

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[Wherein X ^a is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^a is a hydrogen atom, or a substituted or unsubstituted aryl group, T is a hydroxyl group, or a lower alkanoyloxy group, and Y is a CO group. Represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group, which may be present either on the both sides or at both ends, and the other symbols have the same meanings as described above. ]

[0023]

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[Wherein X ^b is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^b is a hydrogen atom, or a substituted or unsubstituted aryl group, and Y is a CO group interposed or present at both ends. Optionally represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group,
Other symbols have the same meaning as described above. ]

[0025]

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[Wherein X ^c is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^c is a hydrogen atom, or a substituted or unsubstituted aryl group, and Y is present with a CO group interposed or at both ends. Optionally represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group,
Other symbols have the same meaning as described above. ]

[0027]

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[Wherein, X ^d is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^d is a hydrogen atom, or a substituted or unsubstituted aryl group, Y is a single bond, or a CO group is present or both ends are present. Represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may be present in the above, and the other symbols have the same meanings as described above. ]

[0029]

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[Wherein, X ^e is an oxygen atom, a sulfur atom, an imino group, or a methylene group, and Y is a lower alkylene group, a lower alkenylene group, or a lower alkynylene, which may have a CO group interposed or at both ends. Represents a group,
Other symbols have the same meaning as described above. ]

[0031]

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[Wherein Ar ^f represents a hydrogen atom or a substituted or unsubstituted aryl group, Y represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may have a CO group or may be present at both ends. The other symbols have the same meanings as described above. In compound [Ia] to compound [If], preferred examples of the meaning of each symbol in the general formula are as already described in the description of compound [I].

The compound [I] has optical isomers based on an asymmetric carbon atom, and the present invention includes both such isomers and mixtures thereof.

The compound [I] which is the active ingredient of the present invention is
It may be orally administered in the form of tablets, powders, granules, capsules, syrups, etc., or suppositories, injections,
Although it may be parenterally administered as an external preparation, a drip, etc., it is preferably administered as an oral preparation. The dose varies depending on the type of disease, degree of symptoms, age, weight, sex of patient, etc., but when administered to humans as an oral preparation, for example, 0.001 to 20 mg / kg, preferably 0.01 to 15 mg / kg
It is kg, and more preferably 0.1 to 10 mg / kg can be administered once a day or in divided doses.

The preparation for oral / parenteral administration is manufactured by a conventional method using a conventional pharmaceutically acceptable carrier. That is, when preparing a solid preparation for oral use, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then the tablet is prepared by a conventional method. , Coated tablets, granules, powders, capsules, etc.
As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide and the like can be used. As a binder,
For example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic,
Tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Calcium citrate, dextrin, pectin and the like can be used. As the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like can be used. As the colorant, any one can be used as long as it is usually allowed to be added to a medicine. As the flavoring agent, cocoa powder, peppermint brain, aromatic acid, peppermint oil, Borneolum, cinnamon powder and the like can be used. These tablets and granules may be coated with sugar, gelatin, or any other coating as required. In addition, antiseptics, antioxidants and the like can be added if necessary.

In the case of preparing injections, drip infusions, etc., if necessary, the active ingredient may contain a pH adjusting agent, a buffering agent and a stabilizing agent.
An agent, a solubilizer, etc. are added, and if necessary, freeze-drying or the like is performed to prepare a subcutaneous / muscular / intravenous injection or an instillation by a conventional method.

According to the present invention, compound [I] or a pharmaceutically acceptable salt thereof has the general formula [II]

[0038]

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[However, the symbols have the same meanings as described above. ] The compound or its salt shown by the following general formula [II
I]

[0040]

[Chemical 21]

[However, Q ¹ represents a reactive residue, and other symbols have the same meanings as described above. ] It can manufacture by making it react with the compound shown by these, or its salt, and making it into the pharmacologically acceptable salt if desired.

The compound [I] or a pharmacologically acceptable salt thereof has the general formula [IV]

[0043]

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[However, Q ² represents a reactive residue, and other symbols have the same meanings as described above. ] The compound or its salt shown by the following general formula [V]

[0045]

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[However, the symbols have the same meanings as described above. ] It can manufacture by making it react with the compound shown by these, or its salt, and making it into the pharmacologically acceptable salt if desired.

Compound [II] or a salt thereof and compound [II]
The reaction with I] or a salt thereof can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. In the compound [III], Q ¹ is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an alkylsulfonyloxy group such as a methylsulfonyloxy group, a phenylsulfonyloxy group or a tosyloxy group, which is substituted or unsubstituted. Typical reactive residues include alkanoyloxy groups such as phenylsulfonyloxy group and acetyloxy group. In addition, the general formula [II
When Z in I] is a group represented by the formula: —CO—Z ¹ — (wherein Z ¹ has the same meaning as described above), Q ¹ is a hydroxyl group, a methoxy group, or ethoxy. A lower alkoxy group such as a group can be used. As the deoxidizing agent, for example, any of those usually usable as the deoxidizing agent such as alkali metal hydroxide, alkali metal carbonate, and trialkylamine can be preferably used. Also,
Compound [II] can also be used as a deoxidizing agent.
Examples of the solvent include dimethylformamide, dimethylsulfoxide, dioxane, ethers such as tetrahydrofuran, hydrocarbons such as toluene, ketones such as acetone, nitriles such as acetonitrile, esters such as ethyl acetate, chloroform and the like. Halogenated hydrocarbons and lower alcohols such as ethanol can be used. The reaction is carried out at room temperature to under heating, for example, 10 to 140.
Suitably proceeds at ° C.

Compound [IV] or a salt thereof and compound [V]
Alternatively, the reaction with a salt thereof is carried out in the same manner as the reaction between the compound [II] or a salt thereof and the compound [III] or a salt thereof, in a suitable solvent, in the presence or absence of a deoxidizing agent. can do. In this case, the same Q ² as Q ¹ can be used as Q ² in the compound [IV]. Therefore, even when Y in the general formula [IV] is a group represented by the formula: —Y ¹ —CO— (wherein Y ¹ has the same meaning as described above), Q ² is a hydroxyl group. Alternatively, a lower alkoxy group such as a methoxy group and an ethoxy group can be used.

Examples of the salt of compound [II] or compound [V] include inorganic acids such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate and phosphate. Addition salts; organic acid addition salts such as oxalates, fumarates, maleates, tartrates, phthalates and methanesulfonates can be mentioned. Even if these salts are used, the reaction is suitable. proceed. In addition, examples of the salt of compound [III] or compound [IV] include the above-mentioned inorganic acid addition salt and organic acid addition salt.

The compound [I] thus obtained can be converted into a pharmacologically acceptable salt thereof, if necessary. For example, the compound [I] can be easily treated with an acid to form a pharmacologically acceptable acid addition salt. can do. Examples of such acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate and phosphate; oxalate and fumarate. Examples thereof include organic acid addition salts such as acid salts, maleates, tartrates, phthalates and methanesulfonates.

Since the above-mentioned reaction of the present invention proceeds without racemization, the desired product can also be obtained as an optically active substance by using an optically active starting material compound as a starting material.

Compound [IV] which is a starting material compound of the present invention
Can be manufactured, for example, as follows.
That is, in the compound [IV], the compound in which the bond of the heterocyclic group in W is from a nitrogen atom forming the heterocycle is represented by the general formula [VI] WH [VI] [where the symbol is It has the same meaning as above. And a compound represented by], general formula [VII] Q ^{3-Y-Q 2} (VII) [where, Q ³ than Q ² a halogen atom, an alkylsulfonyloxy group or a substituted or unsubstituted phenylsulfonyloxy group It represents a highly reactive one, and other symbols have the same meanings as described above. ] The compound shown by
It can be produced by reacting. Also, Y
The compound [IV] in which is a single bond can be produced by treating the compound [VI] with a halogenating agent (for example, sulfuryl chloride). Further, the compound [IV] in which the bond of the heterocyclic group in W is from the carbon atom constituting the heterocycle and Y is not a single bond is a compound [VI] obtained by converting the compound [VI] into an organometallic compound (for example, n -Butyllithium), the carbanion compound obtained by
(1) General formula [VIII] Q ⁴ -Y ¹ -Q ⁵ [VIII] [wherein Q ⁴ is a halogen atom, an alkylsulfonyloxy group or a substituted or unsubstituted phenylsulfonyloxy group, and Q ⁵ is a protected hydroxyl group. The other symbols have the same meanings as described above. ] By reacting with a compound represented by
After removing the hydroxyl-protecting group of Q ⁵ , the resulting compound is treated with a halogenating agent (eg, thionyl chloride), a sulfonylating agent (eg, alkylsulfonyl chloride, substituted or unsubstituted phenylsulfonyl chloride), or the like, or (2) General formula [IX] Q ⁴ —Y ¹ —CH ₂ —Q ⁵ [IX] [where the symbols have the same meanings as described above. ] After removing the protective group for the hydroxyl group of Q ⁵ by reacting with the compound represented by the above, the obtained compound is oxidized and further treated with a halogenating agent, a condensing agent (for example, dicyclohexylcarbodiimide), or (3) General formula [X] OHC-Y ¹ -Q ⁵ [X] [where the symbols have the same meaning as described above. ] After being reacted with the compound represented by the formula (1), the resulting compound is oxidized, then the protective group for the hydroxyl group is removed, and further treated with a halogenating agent, a sulfonylating agent or the like.

Starting compound [II] is compound [IV]
And the general formula [XI]

[0054]

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[R ¹¹ and R ²¹ are the same or different and each represent a hydrogen atom or a lower alkyl group, or are bonded to each other at the terminals to represent a lower alkylene group, and one of Q ⁶ and Q ⁷ is a hydrogen atom or an amino group. Represents a protective group for the group, and the other represents a hydrogen atom. ] With a compound represented by
If desired, it can be produced by removing the amino-protecting group. Further, the compound [II] is produced by first reacting the compound [XI] with the compound [VII], and then reacting the product with the compound [VI], and optionally removing the protecting group of the amino group. You can also

The starting compound [V] can be produced by reacting the compound [III] with the compound [XI], and then optionally removing the amino-protecting group. In addition, the general formula [Va]

[0057]

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(Where the symbols have the same meanings as defined above), the compound [XI] and the compound of the general formula Q ¹ -Z-Q ⁸ [XII] (wherein Q ⁸ is a halogen atom or alkylsulfonyl) An oxy group or a substituted or unsubstituted phenylsulfonyloxy group having a higher reactivity than Q ¹ and other symbols have the same meanings as those described above. Product and General Formula [XIII]

[0059]

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(Where the symbols have the same meanings as above), the compound can also be produced by reacting with a compound represented by the above and removing the amino-protecting group, if desired.

Among the compounds [III], the compounds of the general formula [III
-A]

[0062]

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The compound represented by (where the symbols have the same meaning as described above) can be produced by reacting the compound [XII] with the compound [XIII].

In the synthesis of the above raw material compounds,
In addition to those specifically indicated, a protecting group can be introduced into the compound to be subjected to each reaction and the protecting group can be appropriately removed by a conventional method, if necessary.

In the present invention, the lower alkyl group means one having 1 to 6 carbon atoms, preferably one having 1 to 4 carbon atoms. The lower alkoxy group means one having 1 to 6 carbon atoms, preferably one having 1 to 4 carbon atoms. What is a lower alkanoyl group?
It means one having 2 to 7 carbon atoms, preferably one having 2 to 5 carbon atoms. A lower alkylene group is
It means one having 1 to 6 carbon atoms, preferably one having 1 to 4 carbon atoms. The lower alkenylene group means one having 2 to 6 carbon atoms, preferably 2 carbon atoms.
~ 4 means. The lower alkynylene group means one having 2 to 6 carbon atoms, preferably one having 2 to 4 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group, and a phenyl group is particularly preferable.
Examples of the aralkyl group include a benzyl group and a phenethyl group. Examples of the aromatic ring include a benzene ring and a naphthalene ring, and a benzene ring is particularly preferable. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Experimental Example 1 Transfection Experiment A plasmid (p (kB) 4-neo-Luc) was prepared in which an oligonucleotide having four NF-kB binding sequences (GGGGACTTTCC) ligated was incorporated upstream of the firefly luciferase gene (Luc). did. This plasmid was transfected into a human uterine cervix cancer-derived cell line HeLa using the calcium phosphate method to obtain a cell line HeLa-kB6 which stably expresses this plasmid. This cell line was stimulated with TNF-α (10 ng / ml) for 5 hours in the presence or absence of the test compound (30 μM). For intracellular luciferase activity, luciferase assay kit, Piccagene (trademark: Toyo Ink) and chemiluminescence measuring device, Lumat (MicroLumant LB96P,
Trademark: Berthold Japan KK). Table 1 shows the inhibition rate of luciferase activity in the presence of the test compound.

[0067]

[Table 1]

Experimental Example 2 Phytohemagglutinin in human T cell line Jurkat
Effect of (PHA) Stimulation on Interleukin 2 (IL-2) Production Jurkat cells were stimulated with PHA (10 μg / ml) for 24 hours in the presence or absence of a test compound (10 μM). The obtained Jurkat cell culture supernatant was added to a mouse cytotoxic T cell line CTLL-2 that proliferates in an IL-2 dependent manner,
After 3 hours [3H] -thymidine (18.5 kBq) was added. After 24 hours, the radioactivity incorporated into CTLL-2 cells was measured with a matrix 96 beta ray counter (made by Packard). Table 2 shows the IL-2 production suppression rate in the presence of the test compound.

[0069]

[Table 2]

[0070]

EXAMPLES Specific representative examples of the present invention will be given below, but the present invention is not limited to these.

Example 1 2- (4-chlorophenyl) -4- (3-piperazinopropyl) -2,3-dihydro-1,4-benzothiazin-3-one 4.00 g and 1,3-dimethyl- 8- (3
A suspension of 1.10 g of -bromopropyl) xanthine in 60 ml of acetone is heated to reflux for 17.5 hours. The insoluble material is removed by filtration, the solvent of the filtrate is evaporated, the obtained residue is dissolved in ethyl acetate, washed with water and saturated brine, and dried. After the solvent was distilled off, the resulting residue was subjected to silica gel column chromatography [chloroform-methanol (20: 1)].
Was purified as a colorless crystalline solid to give 1,3-dimethyl-8- {3- [4- (3- (2- (4-chlorophenyl) -2,3-dihydro-3-oxo-1,4- 1.66 g (73%) of benzothiazin-4-yl) propyl) piperazino] propyl} xanthine are obtained. This is dissolved in ethanol, treated with hydrochloric acid-ethanol solution, and then the solvent is distilled off. The residue is recrystallized from methanol-ether to give the corresponding dihydrochloride dihydrate. mp:
-220 degreeC (decomposition), Mass (m / z): 621 (M +).

Example 2-20 In the same manner as in Example 1, the compounds shown in Table 3 below were obtained from the corresponding starting compounds.

[0073]

[Table 3]

[0074]

[Table 4]

[0075]

[Table 5]

Example 21 2- (4-chlorophenyl) -4- (3-chloropropyl) -2,3-dihydro-1,4-benzothiazine-3
-One and 1,3-dimethyl-8- (3-piperazinopropyl) xanthine were treated similarly to the method described in Example 1 to give 1,3-dimethyl-8- {3- [4- (3-
(2- (4-chlorophenyl) -2,3-dihydro-3
-Oxo-1,4-benzothiazin-4-yl) propyl) piperazino] propyl} xanthine is obtained. The physicochemical properties of this product were consistent with those of the target product of Example 1.

Example 22 2. (2-Chlorophenyl) -4- (3-piperazinopropyl) -2,3-dihydro-1,4-benzothiazin-3-one 2.60 g and 1,3-dimethyl- 7- (3
1.60 g of -chloropropyl) xanthine is dissolved in 30 ml of acetone, 1.70 g of potassium carbonate and 1.80 g of sodium iodide are added, and the mixture is heated under reflux for 24 hours. The insoluble matter is filtered off and the solvent is distilled off. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer was further washed with water and saturated brine, dried, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography [chloroform-methanol (20: 1)] to give 1 as a colorless crystalline solid. , 3-dimethyl-7-
{3- [4- (3- (2- (4-chlorophenyl)-
3.24 g (84%) of 2,3-dihydro-3-oxo-1,4-benzothiazin-4-yl) propyl) piperazino] propyl} xanthine are obtained. This is dissolved in ethanol, an equimolar amount of fumaric acid is added, and recrystallized from ethanol to obtain the corresponding fumarate monohydrate. mp: 182-189 ° C (decomposition), Mass (m / z): 6
21 (M +).

Example 23 2- (4-chlorophenyl) -4- (2-piperazinoethyl) -2,3-dihydro-1,4-benzothiazine-
2.40 g of 3-one and 1,3-dimethyl-7- (3-
Chloropropyl) xanthine (1.58 g) was used in Example 2.
The same treatment as described in 2 was performed to obtain 1,3-dimethyl-7- {3- [4- (2- (2-
(4-chlorophenyl) -2,3-dihydro-3-oxo-1,4-benzothiazin-4-yl) ethyl) piperazino] propyl} xanthine 3.44 g (92%)
Is obtained. Further, the same treatment as in Example 22 is carried out to obtain the corresponding fumarate hemihydrate.
mp: 172-175 ° C (decomposition), Mass (m / z): 607
(M +).

Reference Example 1 2- (4-chlorophenyl) -2,3-dihydro-1,
4-benzothiazin-3 (4H) -one 20.00 g
4.66 g of 96% potassium hydroxide is added to a solution of dimethylsulfoxide in 290 ml and the mixture is stirred at room temperature for 30 minutes. Then 1-bromo-3-chloropropane 14.
Add 85 g and stir at room temperature for 5 hours. The reaction solution is water 8
Pour into 00 ml and extract with ethyl acetate. The ethyl acetate layer is washed with water and saturated brine, dried and the solvent is evaporated. The obtained residue is purified by silica gel column chromatography [ethyl acetate-hexane (1: 5)] to give 2- (4-chlorophenyl) -4- as colorless crystals.
(3-chloropropyl) -2,3-dihydro-1,4-
20.62 g of benzothiazin-3-one are obtained (mp: 82.5-85 ° C). To this oily substance, 275 ml of dimethyl sulfoxide was added and dissolved, and 25.21 g of piperazine and 17.55 g of sodium iodide were further dissolved.
And stirred at room temperature for 19 hours. 200 ml of saturated aqueous sodium hydrogencarbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saturated brine, dried and the solvent is evaporated. The obtained residue was subjected to alumina column chromatography [chloroform-methanol (1
0: 1)] to give 2- (4 as a pale yellow oil.
-Chlorophenyl) -4- (3-piperazinopropyl)
22.52 g (77% in total) of 2,2,3-dihydro-1,4-benzothiadi-3-one are obtained. Mass (m /
z): 401 (M +).

Reference Example 2-7 In the same manner as in Reference Example 1, the compounds shown in Table 4 below were obtained from the corresponding starting compounds.

[0081]

[Table 6]

Reference Example 7 2- (4-chlorophenyl) -2,3-dihydro-1,
4-benzothiazin-3 (4H) -one 15.20 g
To 274 ml of the dimethylsulfoxide solution of 96%, 21.36 g of 96% potassium hydroxide was added, and the mixture was stirred at room temperature for 30 minutes. Then 1-bromo-2-chloroethane 35.
Add 33 g and stir at room temperature for 5 hours. Water
Pour into 800 ml and extract with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried, and the solvent was distilled off to obtain 13.00 g of a yellow crystal residue (m
p: 155-158 ° C). Then, 55.66 g of piperazine and p-toluenesulfonic acid monohydrate were added to the residue.
Add 0.41 g and heat at 160 ° C. for 4 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution, and the ethyl acetate layer is separated. The ethyl acetate layer is further washed with water (3 times) and saturated saline, and then dried. The solvent was evaporated, and the obtained residue was purified by alumina column chromatography [chloroform-methanol (10: 1)] to give 2- (4-chlorophenyl) -4- (2- as a brown oily substance.
15.80 g (74%) of piperazinoethyl) -2,3-dihydro-1,4-benzothiazin-3-one are obtained. Mass (m / z): 387 (M +).

Reference Example 8 2- (4-chlorophenyl) -2,3-dihydro-1,
4-benzothiazin-3 (4H) -one 7.04 g,
Ethyl bromoacetate 5.12 g, potassium carbonate 8.82
A mixture of g and 70 ml of acetone is heated to reflux for 3 hours. The insoluble matter is filtered off and the solvent is distilled off. The obtained residue is dissolved in 40 ml of ethanol and cooled with ice. 1 in this
20 ml of 0% sodium hydroxide aqueous solution is added dropwise, and after completion of the addition, the mixture is stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, chloroform and water were added, and the pH was adjusted with concentrated hydrochloric acid under ice cooling.
2-3, and separate the chloroform layer. The chloroform layer is washed with water and saturated brine and dried, the solvent is evaporated, and the obtained residue is treated with isopropyl ether to give pale yellow crystals. Then, the crystals are mixed with tetrahydrofuran 50
Dissolve in ml, and at room temperature, carbonyldiimidazole
4.10 g are added little by little, and after the addition, the mixture is stirred at the same temperature for 1.5 hours. This solution is added dropwise to a solution of 9.90 g of piperazine in 100 ml of tetrahydrofuran at room temperature over 30 minutes, and after completion of the addition, the mixture is stirred at the same temperature for 45 minutes. The solvent is distilled off, ethyl acetate is added to the residue, washed with water and saturated saline and dried, and then the solvent is distilled off. The residue was purified by alumina column chromatography [chloroform-methanol (20: 1)] and crystallized with ethyl acetate to give 2- (4-chlorophenyl) -4 as colorless crystals.
-(Piperazinocarbonylmethyl) -2,3-dihydro-1,4-benzothiazin-3-one 7.99 g (7
8%) is obtained. mp: 187.5-188.5 ° C.

Reference Example 9 2,3-dihydro-1,4-benzothiazine-3 (4
H) -one 8.00 g methylene chloride 80 ml suspension is cooled with ice water. In this, sulfuryl chloride 6.5
4 g is added dropwise over 25 minutes. After the dripping is completed, 2 at the same temperature
After stirring for a period of time, the precipitate was collected by filtration and washed with a small amount of methylene chloride to give the corresponding 2-chloro compound as colorless crystals.
19 g (85%) are obtained (mp: ˜199 ° C. (decomposition)). Next, 7.75 g of this 2-chloro compound was added to piperazine 16.70 g of dimethyl sulfoxide 200.
After being added to the ml solution over 5 minutes, the mixture is stirred at room temperature for a further 18 hours. Volatile components are distilled off under reduced pressure,
The obtained residue is treated with chloroform and the insoluble matter is filtered off. After evaporating the solvent of the filtrate, water and ethyl acetate are added to the obtained residue, and the aqueous layer is separated. The water in the aqueous layer was distilled off, and the resulting residue was purified by alumina column chromatography [chloroform-methanol (10: 1)] to give 2-piperazino-2,3-dihydro-1,4 as a pale yellow crystalline solid. -Benzothiazin-3 (4H) -one 4.6
2 g (48%) are obtained. Mass (m / z): 249 (M
+).

Reference Example 10 (1) A mixture of 50.00 g of 2,2'-dithiosalicylic acid and 270 ml of thionyl chloride was refluxed under heating for 4 hours. After distilling off excess thionyl chloride, the resulting crystal residue was treated with hexane and washed to obtain 2,2 'as light brown crystals.
52.30 g (93%) of dithiosalicyl chloride are obtained. mp: 140-150 ° C.

(2) 2,2'-dithiosalicyl chloride 5
2.30 g is suspended in 330 ml dioxane and cooled with ice water. 50 ml of concentrated aqueous ammonia is added dropwise thereto. After completion of dropping, the reaction solution is left at room temperature for 2 hours, diluted with 100 ml of dioxane and 900 ml of water, and stirred overnight at room temperature. The precipitate is filtered, washed with water, and dried by blowing air to quantitatively obtain 2,2′-dithiosalicylic acid amide as colorless crystals (mp: ˜244 ° C.). Next, 700 ml of this 2,2'-dithiosalicylic acid amide was added to water.
Then, 37.14 g of sodium hydrosulfite and 57.50 g of sodium carbonate are added, and the mixture is heated under reflux for 1 hour. The reaction solution is ice-cooled and adjusted to pH 1-2 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and air-dried to give 28.40 g of thiosalicylic acid amide as pale yellow crystals.
(61%) is obtained. mp: 138-140 ° C.

(3) Thiosalicylic acid amide 15.00
g and p-chlorobenzaldehyde (13.76 g) are suspended in 250 ml of ethanol, 40 ml of 20% hydrochloric acid-ethanol is added, and the mixture is heated to 60 ° C. for 2 hours. The reaction solution is ice-cooled, the precipitate is collected by filtration, and washed with ethanol. The crystals were suspended in 75 ml of dimethylformamide and heated at 120 ° C.
The mixture is heated and stirred for 15 minutes to dissolve the crystals. After leaving this solution at room temperature overnight, the precipitate was collected by filtration and washed with dimethylformamide, tetrahydrofuran and ether in this order to give 2- (4-chlorophenyl) -2,3-dihydro-1,3-as colorless crystals. Benzothiazin-4-one 15.1
3 g (56%) are obtained. mp: 230-231 ° C.

Reference Example 11 (±) -cis-2- (4-methoxyphenyl) -3-
Acetoxy-5- (2- (4- (benzyloxycarbonyl) piperazino) ethyl) -2,3-dihydro-1,
5-Benzothiazepin-4 (5H) -one 17.07
g is dissolved in 29 ml of acetic acid and cooled with ice. In this 3
58 ml of 0% hydrogen bromide-acetic acid solution was added, and the mixture was stirred at room temperature for 7 hours.
Stir for 0 minutes. Add 800 ml of ether to the reaction mixture,
Stir for 1 hour. The precipitate is filtered off and washed several times with ether. The crystals obtained are dissolved in 50 ml of water and made alkaline with concentrated aqueous ammonia. This is extracted with ethyl acetate, the ethyl acetate layer is washed with water and saturated brine, and then dried. The residue obtained by distilling off the solvent was dissolved in ethanol, 2.73 g of oxalic acid was added, and recrystallized from ethanol to obtain (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- (. 2- (piperazino) ethyl) -2,3-dihydro-1,5-benzothiazepine-
13.22 g (82) of 4 (5H) -one oxalate.
%) Is obtained (mp: 200-204 ° C. (decomposition)).
The corresponding free form can be obtained by treating the oxalate salt with ethyl acetate and an aqueous solution of sodium hydrogen carbonate, and then treating the mixed solution according to a usual extraction and washing method.

Reference Example 12 1,3-Dimethyl-8- (3-bromopropyl) xanthine 1.17 g, N-benzylpiperazine 1.60
g, 1.17 g of sodium iodide, 20 ml of acetone
The mixture is heated to reflux for 17 hours. The insoluble matter is filtered off and the solvent is distilled off. Ethyl acetate and aqueous sodium hydrogen carbonate solution are added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer is washed with water and saturated brine and dried, and the solvent is evaporated. The obtained residue is purified by silica gel column chromatography [chloroform-methanol (20: 1)] to give pale yellow crystals (mp: 152-154 ° C). Next, this crystal was dissolved in 20 ml of methanol to obtain 10% P
Add 100 mg of d-C and carry out catalytic reduction to 1 under 5 atm.
Do it for 3.5 hours. After completion of the reaction, the catalyst is filtered off and the solvent is distilled off to obtain a colorless crystalline solid. Silica gel-preparative TLC [chloroform-methanol-
Concentrated aqueous ammonia (100: 10: 1)] to obtain 73 mg (6%) of 1,3-dimethyl-8- (3-piperazinopropyl) xanthine as a colorless crystalline solid. Mass (m / z): 306 (M +).

Reference Example 13 Theophylline 15.00 g, 1-bromo-3-chloropropane 15.73 g, potassium carbonate 13.90 g
A mixture of 100 ml of dimethylformamide in 3 is stirred at room temperature for 3 days. The reaction solution is diluted with 300 ml of chloroform and the insoluble matter is filtered off. The solvent is distilled off, chloroform and water are added to the residue, and the chloroform layer is separated. Further, after washing with water and saturated saline and drying, the solvent is distilled off. The obtained crystal residue is washed with ether to obtain 20.35 g (95%) of 1,3-dimethyl-7- (3-chloropropyl) xanthine as colorless crystals. mp: 11
5-120 ° C.

[0091]

INDUSTRIAL APPLICABILITY The xanthine derivative of the present invention represented by the general formula [I] inhibits the transcription of the DNA having the NFκB recognition sequence by inhibiting the activation of the transcription factor NFκB. Therefore, if the gene has the NFκB recognition sequence,
It is possible to effectively inhibit the expression of a protein corresponding to the gene. That is, the xanthine derivative [I] is TNF, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL- 8), Granulocyte colony stimulating factor (GC
SF), interferon β (INF-β) and other cytokines, as well as cell adhesion factors ICAM-1, VCAM-1 and ELAM-
1, or nitric oxide synthase, major histocompatibility complex (MHC) class I, MHC class II, β2 microglobulin, immunoglobulin light chain, serum amyloid A,
Genes of angiotensinogen, complement B, complement C4 protein, c-myc gene which is one of the oncogenes, human immunodeficiency virus (HIV), simian virus 40 (SV40), cytomegalo Virus (CM
By suppressing the expression of viral genes such as V) and adenovirus, biosynthesis of proteins corresponding to these genes can be suppressed, and related diseases can be prevented or treated.

Therefore, the compound [I] is effective for treating rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Behcet's disease, periarteritis nodosa, ulcerative colitis, active chronic hepatitis, glomerulonephritis and the like. Various autoimmune diseases such as osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis, lung disease with granulomas, various intractable diseases in which inflammatory symptoms are the basis of the pathology, Endotoxin shock, sepsis, inflammatory bowel disease,
Glucuria, acute myeloblastic leukemia, pneumonia, heart transplant, encephalomyelitis, anorexia, acute hepatitis, chronic hepatitis, drug-induced liver injury, alcoholic hepatitis, viral hepatitis, jaundice, cirrhosis, liver failure , Atrial myxoma, Castleman syndrome, multiple myeloma, rennelt T lymphoma, mesangial proliferative nephritis, renal cell carcinoma, cytomegalovirus pneumonia, cytomegalovirus retinopathy, adenovirus cold, adenovirus It is effective in treating and preventing diseases such as pool fever, adenovirus ophthalmitis and AIDS.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 31/55 ABE A61K 31/55 ABE C07D 473/04 C07D 473/04

Claims (20)

[Claims] 1. A compound of the general formula [I] [Wherein, W is a 5- to 7-membered heterocyclic group containing at least a nitrogen atom as a hetero atom, at least an oxo group as a substituent, and an aromatic ring may be condensed, and Y is a single bond. Or a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may have a CO group interposed or present at both ends, and Z is a lower alkylene group which may have a CO group present or present at both ends. An alkylene group, a lower alkenylene group or a lower alkynylene group, L is a lower alkylene group, R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, or are bonded to each other at the ends to represent a lower alkylene group, R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group,
It represents a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkanoyl group which may be substituted with a lower alkoxy group. However, in W, when the bond of the heterocyclic group is from the nitrogen atom constituting the heterocycle, Y is not a single bond. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 2. W contains at least a nitrogen atom as a hetero atom, at least an oxo group as a substituent, and a substituted or unsubstituted benzene ring may be condensed.
The compound according to claim 1, which is a 7-membered heterocyclic group. 3. W is of the formula: (However, ring A represents a 5- to 7-membered heterocyclic ring which contains a nitrogen atom as a hetero atom, has an oxo group as a substituent, and may have a substituted or unsubstituted aryl group as a substituent, B is a group represented by a substituted or unsubstituted benzene ring.) The compound according to claim 1. 4. W is of the formula: [However, X ^a , X ^b , X ^c , X ^d, and X ^e each independently represent an oxygen atom, a sulfur atom, an imino group, or a methylene group, and Ar ^a , Ar ^b , Ar ^c , Ar ^d, and Ar ^f Each independently represent a hydrogen atom or a substituted or unsubstituted aryl group, and T represents a hydroxyl group or a lower alkanoyloxy group. ] The compound of Claim 1 which is one group selected from the group shown by these. 5. A compound represented by the general formula [Ia]: [Wherein X ^a is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^a is a hydrogen atom, or a substituted or unsubstituted aryl group, T is a hydroxyl group, or a lower alkanoyloxy group, and Y is a CO group or A lower alkylene group, a lower alkenylene group or a lower alkynylene group which may be present at either of the both ends, Z is a lower alkylene group, a lower alkenylene group or a lower which may be present at either of the two ends by a CO group. Alkynylene group,
R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkanoyl group which may be substituted with a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 6. A compound represented by the general formula [Ib]: [However, X ^b is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^b is a hydrogen atom, or a substituted or unsubstituted aryl group, and Y is a CO group interposed or present at both ends. A lower alkylene group, a lower alkenylene group or a lower alkynylene group, Z is a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may have a CO group interposed or may be present at both ends, R ³ and R ⁴ are the same Or, it represents a lower alkanoyl group which may be substituted with a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 7. A compound represented by the general formula [Ic]: [Wherein X ^c is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^c is a hydrogen atom, or a substituted or unsubstituted aryl group, and Y is a CO group, which may be present or present at both ends. A lower alkylene group, a lower alkenylene group or a lower alkynylene group, Z is a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may have a CO group interposed or may be present at both ends, R ³ and R ⁴ are the same Or, it represents a lower alkanoyl group which may be substituted with a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 8. A compound represented by the general formula [Id]: [However, X ^d is an oxygen atom, a sulfur atom, an imino group, or a methylene group, Ar ^d is a hydrogen atom, or a substituted or unsubstituted aryl group, Y is a single bond, and a CO group is present at either or both ends. Optionally lower alkylene group, lower alkenylene group or lower alkynylene group, Z is CO
A lower alkylene group, a lower alkenylene group or a lower alkynylene group, which may be interposed or present at both ends, R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group. Represents a lower alkanoyl group which may be substituted with a group, an aryl group, an aralkyl group, or a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 9. A compound represented by the general formula [Ie]: [Wherein X ^e is an oxygen atom, a sulfur atom, an imino group, or a methylene group, and Y is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, which may be present with a CO group interposed or at both ends, Z Is a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may be present with a CO group interposed or at both ends, R ³ and R ⁴ being the same or different, a hydrogen atom, a lower alkyl group, a lower alkenyl group, It represents a lower alkynyl group, an aryl group, an aralkyl group, or a lower alkanoyl group which may be substituted with a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 10. A compound represented by the general formula [If]: [Wherein Ar ^f is a hydrogen atom or a substituted or unsubstituted aryl group, Y is a lower alkylene group, a lower alkenylene group or a lower alkynylene group which may be present with a CO group interposed or at both ends, and Z is CO A lower alkylene group, a lower alkenylene group or a lower alkynylene group, which may be interposed or present at both ends, R ³ and R ⁴ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group. Represents a lower alkanoyl group which may be substituted with a group, an aryl group, an aralkyl group, or a lower alkoxy group. ] The xanthine derivative shown by these, or its pharmacologically acceptable salt. 11. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient. 12. A pharmaceutical composition comprising the compound according to claim 2 as an active ingredient. 13. A pharmaceutical composition comprising the compound according to claim 3 as an active ingredient. 14. A pharmaceutical composition comprising the compound according to claim 4 as an active ingredient. 15. The method according to claim 1, which is an NFκB activity inhibitor.
The pharmaceutical composition according to 1, 12, 13 or 14. 16. Tumor necrosis factor (TNF), interleukin-1, and interleukin based on NFκB activity inhibitory action.
-2, interleukin-6, interleukin-8, granulocyte colony stimulating factor, interferon β, cell adhesion factors ICAM-1 and VCAM-1 and ELAM-1, nitrite oxide synthase, major histocompatibility complex class I, major histocompatibility complex class II, β2 microglobulin, immunoglobulin light chain, serum amyloid A, angiotensino
Gene, an inhibitor of gene expression of one or more substances selected from the group consisting of gene, complement B, complement C4, c-myc, human immunodeficiency virus, simian virus 40, cytomegalovirus and adenovirus. The pharmaceutical composition according to claim 11, 12, 13 or 14. 17. A preventive / therapeutic agent for diseases for which the activity of inhibiting the activity of NFκB is effective. 18. The pharmaceutical composition according to claim 11, 12, 13 or 14 which is a prophylactic / therapeutic agent for inflammatory diseases. 19. The pharmaceutical composition according to claim 11, 12, 13 or 14 which is a prophylactic / therapeutic agent for autoimmune diseases. 20. The pharmaceutical composition according to claim 11, 12, 13 or 14 which is a prophylactic / therapeutic agent for viral diseases.