KR20050007056A - Pharmaceutical composition for inhibition of 5-lipoxygenase - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for inhibition of 5-lipoxygenase is provided, which pharmaceutical composition inhibits formation of leukotrienes, so that it can be useful for prevention and treatment of leukotriene-associated disease such as asthma. CONSTITUTION: The pharmaceutical composition for inhibition of 5-lipoxygenase comprises a compound of formula (1), wherein X is CH or nitrogen; Y is sulfur or oxygen; R1 is hydrogen, lower alkyl, halogen, nitro, cyano, amino, lower dialkylamino, hydroxy, lower alkoxy, hydroxy lower alkyl, or lower alkanoyl; R2 is one selected from formulas (i) to (v); R3 is hydrogen, lower alkyl; R4 is a benzene ring containing R5, R6, R7, R8 and R9; the R5, R6, R7, R8 and R9 are the same or different, and hydrogen, lower alkyl, halogenated lower alkyl, halogen, nitro, cyano, amino, lower dialkylamino, mercapto, lower alkyl mercapto, halogenated lower alkyl mercapto, phenyl azo, lower alkylphenyl azo, lower alkanoyl, hydroxy, lower alkoxy or hydroxy lower alkyl; R10 is hydrogen or lower alkyl; R11 is hydrogen, lower alkyl, halogen, mercapto or lower alkyl mercapto; and R12 is hydrogen, lower alkyl, halogen, nitro, cyano, amino, lower dialkylamino, lower alkanoyl, hydroxy, lower alkoxy, or hydroxy lower alkyl.

Description

Pharmaceutical composition for 5-lipoxygenase inhibition {PHARMACEUTICAL COMPOSITION FOR INHIBITION OF 5-LIPOXYGENASE}

The present invention is a pharmaceutical used for the inhibition of 5-lipoxygenase containing a compound represented by the following formula (1) as an active ingredient, in particular for the prevention, treatment and treatment of leukotriene-related diseases such as asthma. To a red composition.

Lucotriene is an oxidized polyunsaturated fatty acid with a large number of bioactivity, one of the inflammatory mediators that exhibits a variety of bioactivity, metabolized in several steps from arachidonic acid released from the cell membrane by calcium action Biosynthesis as a class of substances.

First, as a first step, an unstable epoxide intermediate, leukotriene A ₄ (LTA ₄ ), is produced from the arachidonic acid by the action of 5-lipoxygenase, and the leukotrienes A ₄ pass through two pathways, respectively. Leukotrien B ₄ and leukotrien C ₄ , D ₄ , E ₄ .

Rucotriene B ₄ (LTB ₄ ) produced through the first pathway is a bioactive compound produced by hydration by the hydrolase of LTA ₄ . The compound exhibits chemotaxis to inflammatory cells such as polymorphonuclear leukocytes and causes degranulation and aggregation of inflammatory cells. Lucotriene B ₄ also increases vascular permeability, forming edema.

Of the second base coat Li generated by the path yen C _4, D ₄ and E _4, LTC ₄ is generated and glutathione are added to the epoxide LTA ₄ by LTC ₄ synthase, the peptide portion of these LTC ₄ Metabolic changes result in LTD ₄ and LTE ₄ . These three rucotrienes are major components of the slow reaction substance of hypersensitivity and affect urgent hypersensitivity. These compounds also cause contraction of smooth muscle, increase mucus secretion and increase vascular permeation.

The biological effects of leukotrienes play an important role in asthma, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, bronchitis, allergic rhinitis, psoriasis, skin diseases, arthritis, inflammatory bowel disease, sepsis, cardiomyopathy It is known to be associated with a variety of cardiopulmonary diseases, including cardiac hypersensitivity, cerebrovascular spasms, and ischemia.

Of these, asthma is the most reliable evidence that leukotrienes play a pivotal role, so the focus of most leukotrienes research is in this area.

In particular, LTC ₄ and LTD ₄ have a very strong bronchial contraction action to the human airway, is known to be 1000 times more powerful than histamine. These compounds strongly promote mucosal secretion and increase capillary permeability in the human airways. These results can be seen by showing a high level of leukotrienes in the body fluids of asthma patients and a close correlation between the content and the severity of the disease.

5-lipoxygenase, on the other hand, is restricted to neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, and B lymphocytes. To be distributed. On the other hand, LTA ₄ hydrolase and LTC ₄ synthase are widely distributed in more diverse tissues.

Therefore, in the case of drugs that can selectively inhibit the action of 5-lipoxygenase enzyme, it seems that the biosynthesis of leukotrienes can be more effectively blocked in the early stage, so that it can be used as an effective therapeutic agent for inflammatory reaction or asthma.

Looking at the recent research trend related to the present invention, a) inhibition of 5-lipoxygenase, b) inhibition of 5-lipoxygenase activating protein (FLAP), c) peptidyl rucotriene ( LTD ₄ ) Receptor antagonists (e.g. montelukast, pranlukast, zafirlukast), d) The development of LTB ₄ receptor antagonists is a great effort.

Recently, zileuton and E6080 are drugs for the purpose of inhibiting 5-lipoxygenase, and A-61443, BW-755c, A-63162, MK-886, MK-591, WY-50,295, Substances such as ZD5138 are in the process of being developed as 5-lipoxygenase inhibitors and are in clinical trials.

Gilluton, a drug synthesized by Abbott Laboratories, was received by the US Food and Drug Administration (FDA) in July 1997 and is the first commercially available drug to treat asthma with 5-lipoxygenase inhibitory activity. E6080 also inhibits the release of LTB ₄ and LTC ₄ as a selective, orally potent 5-lipoxygenase inhibitor developed by Eisai Co. Ltd. of Japan.

Therefore, the treatment of 5-lipoxygenase inhibitors that effectively inhibit the biosynthesis of leukotrienes will be more effective in the treatment of diseases such as asthma and other inflammatory diseases in which leukotrienes play a major role, and thus the development of such therapeutic agents is urgently needed. It is requested.

It is an object of the present invention to provide a 5-lipoxygenase inhibitory use of a pharmaceutical composition comprising the compound represented by the formula (1) as an active ingredient, in particular a novel use as an agent for the prevention, treatment and treatment of asthma.

The present invention provides a pharmaceutical composition for inhibiting 5-lipoxygenase comprising a compound represented by the following formula (1) or a pharmacologically acceptable addition salt thereof as an active ingredient.

Throughout this specification, the meanings of the symbols used in the formula (1) are as follows.

X is CH or nitrogen atom, Y is sulfur atom or oxygen atom, R ₁ is hydrogen atom, lower alkyl group, halogen atom, nitro group, cyano group, amino group, lower dialkylamino group, hydroxyl group, lower alkoxy group, hydroxy lower group An alkyl group or a lower alkanoyl group.

In addition, R ₂ may be one of the groups defined in the following items (i) to (v).

(i) formula

In the formula, R ₃ means a hydrogen atom, a lower alkyl group, etc., R ₄ is a formula Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, Lower alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group.

(ii) equation

Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same as in (i) above.

(iii) equation

In the above formula, R ₁₀ is a hydrogen atom or a lower alkyl group.

(iv) equation

In the formula, R ₁₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a mercapto group, or a lower alkyl mercapto group.

(v) expression

In the formula, R ₁₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, or a lower dialkylamino group, a lower alkanoyl group, a hydroxyl group, a lower alkoxy group, or a hydroxy lower alkyl group.

Preferred compounds include the following.

R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkanoyl group, or the like; R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, a lower group Alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group.

R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkanoyl group, or the like; R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, a lower group Alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group.

R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a lower alkanoyl group, or the like; A is an expression Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, Lower alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group). Wherein R ₁₀ is a hydrogen atom or a lower alkyl group Wherein R ₁₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a mercapto group, a lower alkyl mercapto group or the like R ₁₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, or a lower dialkylamino group, a lower alkanoyl group, a hydroxyl group, a lower alkoxy group, or a hydroxy lower alkyl group. It may be one selected from the group.

In the formulas (1) to (4) of the present invention, used in the definition of R ₁ , R ₃ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and R ₁₂ Lower alkyl group term refers to a straight or branched chain alkyl group consisting of 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl, Tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-1-metalpropyl and 1-ethyl-2-methylpropyl groups. Among them, methyl, ethyl, propyl and isopropyl groups are preferable.

The term “halogen atom” used in the definitions of R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₁ , and R ₁₂ refers to fluorine, chlorine, bromine, and iodine, among which fluorine, Chlorine is preferred.

The term “lower dialkylamino group” used in the definitions of R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₂ means a lower dialkylamino group derived from the lower alkyl group described above. Dimethylamino groups are preferred.

The term "lower alkoxy group" used in the definitions of R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₂ means a straight or branched chain alkoxy group composed of 1 to 6 carbon atoms. Is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tertiary pentyloxy, 1- Methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, hexyloxy group and the like. Among them, methoxy and ethoxy groups are preferable.

The term “hydroxy lower alkyl group” used in the definitions of R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , and R ₁₂ refers to a lower alkyl group and a lower alkyl group described above composed of 1 to 6 carbon atoms. Functional groups consisting of hydroxy groups linked to any of the carbon atoms, in particular hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl groups.

The term “lower alkanoyl group” used in the definitions of R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R _9, and R ₁₂ refers to a lower alkyl group of 1 to 6 carbon atoms. It refers to a functional group formed by linking to, and in particular, formyl, acetyl, propionyl, butyryl, vareryl, isovaleryl, and pivaloyl groups are preferable.

The term "halogenated lower alkyl group" used in the definitions of R ₅ , R ₆ , R ₇ , R ₈ and R ₉ is a halogen element described above in which part or all of hydrogen of the lower alkyl group described above composed of 1 to 6 carbon atoms is mentioned. Mean substituted group, and methyl fluoride group, methyl chloride group, ethyl fluoride group and ethyl chloride group are particularly preferable.

The term "lower alkyl mercapto group" used in the definitions of R ₅ , R ₆ , R ₇ , R ₈ and R ₉ refers to a lower alkyl group composed of 1 to 6 carbon atoms in which hydrogen is connected to the sulfur of the mercapto group instead of hydrogen. Group, and especially a methyl mercapto group and an ethyl mercapto group are preferable.

The term "halogenated lower alkyl mercapto group" used in the definition of R ₅ , R ₆ , R ₇ , R ₈ and R _{9 means that} the lower alkyl group described above consisting of 1 to 6 carbon atoms is connected to sulfur of the mercapto group instead of hydrogen. The lower alkyl group refers to a group in which part or all of the hydrogen of the lower alkyl group is substituted with the above-described halogen element, and in particular, methyl fluoride mercapto group, methyl chloride mercapto group, ethyl fluoride mercapto group, and ethyl chloride mercapto group are preferable.

The term "lower alkylphenyl azo group" used in the definitions of R ₅ , R ₆ , R ₇ , R ₈ and R ₉ refers to a phenyl group having two or more substituted phenyl groups and a phenyl group having a lower alkyl group of 1 to 6 carbon atoms. It means group comprised as an azo group, Especially a tolyl azo group and ethylphenyl azo group are preferable.

The pharmacologically acceptable salts mentioned above include the therapeutically active non-toxic acid addition salts which the compounds of formula (1) can form.

These salts may conveniently be used in the form of a base of the compound of formula (1) with suitable acids, for example inorganic acids such as hydrochloric acid (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like; Or for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p It can be obtained by treatment with organic acids such as, but not limited to, toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamonic acid and the like.

In addition, the above pharmacologically acceptable salts include solvates and salts thereof that the compound of formula (1) can form. Such solvates include hydrates, alcoholates and the like.

The composition for inhibiting 5-lipoxygenase of the present invention can be usefully used as a prophylactic, therapeutic or therapeutic adjuvant for diseases related to leukotriene activity because of its 5-lipoxygenase inhibitory effect.

Specifically, the disease includes asthma, whooping cough, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, sepsis, myocardial ischemia, heart hypersensitivity, cerebrovascular spasm, ischemia and allergic rhinitis. It includes a variety of inflammatory diseases, including.

The 5-lipoxygenase inhibitory pharmaceutical composition of the present invention may be prepared in unit dosage form by formulation with a pharmaceutically acceptable carrier or excipient, or may be prepared by incorporation into a multi-dose container, and may be prepared once or several times. It can be administered orally, parenterally or topically.

As used herein, the term “parenteral” includes, without limitation, subcutaneous, intravenous, arterial or infusion techniques. The term "topical" also includes inhalation spray and rectal administration, as well as administration by conventional routes such as mucous membranes and skin of the mouth and nose.

The pharmaceutical composition may be in solid, semisolid or liquid dosage form (e.g. in the form of tablets, capsules, pills, powders, suppositories, solutions, elixirs, syrups, suspensions, creams, sugar-containing tablets, pastes and sprays) Can be. As is known in the art, the route of administration of the 5-lipoxygenase inhibitors described herein is selected according to the type of composition to be used. In general, it is preferred to use unit dosage forms of the inhibitors described herein to facilitate the treatment and administration of the correct dose of the active compound. In general, compounds having a therapeutic effect of the present invention are present in a dosage form that is sufficient to provide a desired level of concentration, i.e., a concentration level ranging from about 0.5 to about 90% by weight relative to the total composition weight.

The particular route of administration and dosage will depend on the individual's state of health or pathological findings, etc., but in general, for oral administration, an amount of about 10 mg to about 1000 mg per day is administered in single or multiple dose form. For parenteral administration, a dose of about 5 mg to 800 mg per day is administered in single or multidose form. In some cases, amounts below the above range may be more appropriate, in other cases, larger amounts may be used without causing harmful or toxic side effects. It is desirable to.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may contain various disintegrants such as starch, preferably potato or tapioca starch, alginic acid and certain silicate complexes, polyvinyl pyrrolidone, It can be used with binders such as sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are sometimes very useful for tableting. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules. Preferred materials related to this include high molecular weight polyethylene glycols as well as lactose or lactose. If oral administration of an aqueous suspending agent or elixir is desired, the essential active ingredients contained therein are various sweetening or flavoring agents, colorants or pigments and, if desired, emulsifying and / or suspending agents as well as water, ethanol, propylene glycol, It can be used in combination with diluents such as glycerin and various similar mixtures.

For parenteral administration, various substances can be used as carriers, adjuvants and vehicles in the compositions of the present invention as useful in the pharmaceutical sector. Injections, such as oily solutions, suspensions or emulsions, may be formulated by known techniques using the necessary suitable dispersing or wetting agents and suspending agents. Sterile injectables may also be used, for example, sterile nonpyrogenic or parenterally acceptable non-toxic diluents or solvents such as 1,3-butanediol. Other acceptable vehicles and solvents that may be used include 5% Textose Injection, Ringer's Injection and Sodium Chloride Injection. Sterile, nonvolatile oils are also commonly used as solvents or suspending media. Any mixed nonvolatile oil may be used for this purpose, including synthetic mono-, di- or triglycerides. Fatty acids such as oleic acid may also be used in the preparation of injectable compositions.

Suppositories for rectal administration of the pharmaceutical composition of the present invention may be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter, polyethylene glycol, etc., which is solid at room temperature but liquid at body temperature and thus melts in the rectum to release the drug.

In addition, the composition containing the above-described active ingredient may be administered locally, and for this purpose, it is preferable to administer the cream, salves, jelly, paste, ointment, or the like according to standard pharmaceutical practice.

Various synthetic methods may be used to prepare the compound of Formula (1) as an active ingredient of the pharmaceutical composition of the present invention. Some of these methods are described by schemes (1) and (2).

Other compounds that make up the active ingredient of the pharmaceutical compositions of the present invention may also be prepared from the same methods as described below or by methods known in the art using appropriate starting materials.

Scheme 1

In the above scheme, R ₁ is as defined in formula (1) above, R is the same as each definition of R ₅ , R ₆ , R ₇ , R ₈ and R ₉ in formula (1) above, 1 The substituents described above mean R ′ means a lower alkyl group (the definition is the same as that used in the above formulas (1) to (4)).

In the structure of the compound constituting the active ingredient of the pharmaceutical composition of the present invention, in the case of containing an amino bridge (-NR _3- , R ₃ is a hydrogen atom or a lower alkyl group), the production method schematically shown in Scheme (1) It can be prepared by.

In more detail, the thiourea-based intermediate is synthesized by selecting 2-aminophenol and isothiocyanate as appropriate starting materials according to the desired final compound and reacting in an appropriate organic solvent (I).

Based on 1 equivalent of 2-aminophenol compounds in said reaction (I), 1-1.5 equivalent can be used for an isothiocyanate compound, and 1-1.2 equivalent is preferable.

The reaction temperature may be room temperature or more, but the reaction is preferably performed at room temperature, and the reaction time may be about 1 hour to 24 hours or more, but it is preferable to react for 12 hours or more.

At this time, the organic solvent used is methanol, ethanol, ether, etc., methanol is most preferred.

The progress of the reaction can be confirmed by using thin-layer chromatography, and after the reaction (I), the thiourea compound as an intermediate is obtained in most cases as a precipitate.

In the next step, the target compound is synthesized by adding an acid to the obtained thiourea compound to induce a ring closure reaction (II).

First, an acid capable of sufficiently dissolving it is added to a predetermined amount of the thiourea compound. At this time, the reaction temperature is maintained at 100 ℃ to reflux temperature, the reaction, preferably at a reflux temperature. The reaction time may be from about 1 hour to 24 hours or more, but 12 hours or more is preferred.

The acid used in the reaction (II) may be trifluoroacetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid and the like, but trifluoroacetic acid or phosphoric acid is preferred, and trifluoroacetic acid is most preferred.

When the reaction is completed, the acid is removed by the method known in the art (for example, vacuum distillation when trifluoroacetic acid is used) to obtain the desired final compound (II).

Furthermore, the compound in which the lower alkyl group (R ') is substituted for hydrogen of the above-mentioned amino bridge structure can be easily prepared through substitution reactions known in the art (III, III').

Scheme 2

In the above scheme, R ₁ and X are as defined in the above formula (1), and Q is a resin as a solid support. And A is the same as defined in the above formula (4).

Among the compounds constituting the active ingredient of the pharmaceutical composition of the present invention, compounds having no amino bridge (-NR _3- , R ₃ is a hydrogen atom or a lower alkyl group) are schematically represented in Scheme (2). It may be prepared by a manufacturing method.

Hereinafter, the manufacturing method will be described in detail.

It is possible to use traditional solution phase synthesis methods to obtain the final compound, but more desirable results can be obtained when using solid-phase synthesis.

According to the solid phase synthesis method, any resin that can be easily selected by those skilled in the art may be used as the solid support, and in particular, 2-chlorotrityl chloride resin or 4-methoxytrityl chloride resin may be used. desirable.

First, one of the starting materials, 2-aminobenzenethiol compound, is bound to a solid support, such as 2-chlorotrityl chloride resin, through a thiol group. The resin used at this time is preferably used after swelling in an appropriate organic solvent, for example, methylene chloride, for several minutes.

An amide-based intermediate is synthesized by reacting the 2-aminobenzenethiol compound to which the resin is bound and the benzoyl chloride compound as another starting material (I). The reaction (I) may proceed for 1 to 7 hours at 0 ° C. to 50 ° C., preferably at room temperature for 2 to 5 hours.

The combined resin can be separated by a mixture of methylene chloride of trifluoroacetic acid or triethylsilane, preferably a mixture of methylene chloride of trifluoroacetic acid and triethylsilane (II).

The amide-based intermediate separated from the resin gives the desired final compound by inducing ring closure in a solution in which dithiothreitol is dissolved in a suitable organic solvent such as dimethylformamide or methanol (III).

When describing the specific compound (1-25) and the preparation method of the active ingredient of the pharmaceutical composition of the present invention are as follows.

Compound 1-3

Preparation of Compound 1

2-hydroxy-3-aminopyridine (70 mg, 0.64 mmol) and phenyl isothiocyanate (100 μl, 0.83 mmol) were reacted with methanol as a solvent at room temperature for one day, and then the precipitate was washed with methanol to obtain a solid phase. N- (2-hydroxypyridino) -N'-phenylthiourea is obtained. Trifluoroacetic acid was added to the obtained compound (39.2 mg, 0.16 mmol) and refluxed for one day, followed by distillation under reduced pressure to remove trifluoroacetic acid, followed by column chromatography (ethyl acetate-hexane 3: 1 v / v). Obtain 2-phenyl aminopyridinothiazole in solid phase.

Method for preparing compounds 2 and 3

From the appropriate starting materials for each compound, compounds 2 and 3 are obtained according to the process for preparing compound 1.

Compound 4-11

Preparation of Compound 4

2-aminophenol (100 mg, 0.92 mmol) and 4-phenylazophenyl isothiocyanate (139 μl, 0.92 mmol) are stirred for 1 day at room temperature with methanol as solvent. After the reaction, the precipitate is filtered off and washed with a small amount of ether to give a solid N- (2-hydroxyphenyl) -N'-phenylazophenyl thiourea. Trifluoroacetic acid was added to the obtained compound (100 mg, 0.41 mmol) and refluxed for one day, followed by distillation under reduced pressure to remove trifluoroacetic acid, followed by column chromatography (ethyl acetate-hexane 3: 1 v / v). Obtain 4-phenylazophenyl aminobenzoxazole (compound 1) in the solid phase.

Method for preparing compound 5 to 11

Compounds 5 to 11 are obtained according to the process for preparing compound 4 from the appropriate starting materials for each compound.

Compound 12-25

Compound 23

Compound 24

Compound 25

Preparation of Compound 12

1 g (1.66 mmol / g, 1 equiv) of 2-chlorotrityl chloride resin was swollen in methylene chloride for 3-5 minutes, followed by 1.162 mmol (0.202 ml, 0.7 equiv) of N, N-diisopropylethylamine And 1.66 mmol (0.178 ml, 1 equiv) of 2-aminobenzenethiol, and then the mixture is stirred slowly at room temperature for 3 hours. The resin is then filtered and washed with methylene chloride / methanol / N, N-diisopropylethylamine (85: 10: 5 v / v / v) liquid.

200 mg of 2-chlorotrityl resin (0.332 mmol / g of 2-aminobenzenethiol loading rate) in which 2-aminobenzenethiol is bound through its thiol group was obtained from 5-6 ml of N, N-dimethylformamide. After suspension, 0.996 mmol (0.116 ml, 3 equiv) of benzoyl chloride and 0.996 mmol (0.173 ml, 3 equiv) of N, N-diisopropylethylamine were added thereto, and the mixture was stirred at room temperature for 3 hours. The resin is then filtered and washed with 50 ml of N, N-dimethylformamide and 50 ml of methylene chloride. The remaining resin on the filter is treated with 20% of a solution of acetate / methylene chloride and 20ml of 5% triethylene silane / methylene chloride with 65% of trifluoro. The filtrate obtained from the above process was concentrated in vacuo to an oily residue and then in 10 ml of dimethylformamide / methanol (9: 1 v / v) containing 0.2 mmol (0.031 g) of dithiothreitol. Dissolve and leave for 3 hours at room temperature. Next, the mixture was extracted with ether or ethyl acetate, and the obtained extract was washed with water, dried and concentrated in vacuo to give compound 12.

Synthesis of Compounds 13-25

Compounds 13 to 25 are obtained according to the process for preparing compound 12 from the appropriate starting materials for each compound.

Hereinafter, the present invention will be described in detail with reference to the following examples, whereby the scope of the present invention is not limited. It is also evident that various other aspects, modifications and equivalents that will be readily made by those skilled in the art without departing from the spirit of the invention or the scope of the claims are included in the invention.

Example

The inhibitory activity test for 5-lipoxygenase of Compounds (1) of the present invention was carried out via the method described below.

Bone marrow collected from BALB / cJ mice was enriched in 50% enriched medium (100 units / ml penicillin, 100 mg / ml streptomycin, 10 mg / ml gentamycin, 2 mM L-glutamic acid, 0.1 mM non-essential). RPMI 1640 containing amino acid, 10% fetal calf serum) and 50% WEHI-3 cell conditioned medium as a source of interleukin-3 were incubated for 10 weeks. At about 4 weeks after starting the culture, more than 98% bone marrow-derived mast cells were identified.

The bone marrow-derived mast cells obtained above were suspended in an enriched medium at a concentration of 1 × 10 ⁶ cells / ml, the test compound was mixed to a concentration of 2.5 μg / ml, and then cultured in a CO ₂ incubator at 37 ° C. for 30 minutes. It was. Next, centrifuged (4 ° C., 120 × g, 20 minutes) of the culture to which 100 ng / ml bone marrow cell proliferation factor (SCF) was added to the medium, and the LTC ₄ enzyme immunoassay kit (LTC) was obtained from the supernatant. The amount of free LTC ₄ was measured using a ₄ enzyme immunoassay kit (Cayman Chemical, Ann Arbor, USA).

Dimethyl sulfoxide (DMSO) was used as a solvent of the test compound, and the cell proliferation factor was recombined using a baculovirus expression system in insect cells.

The 5-lipoxygenase inhibitory activity of the compounds of the present invention is measured by the above method, and the results are shown in Table (1).

Each test compound used in the activity test is the compound 1 to 25 described above.

Example number IC ₅₀ (μM) Example number IC ₅₀ (μM) One 9.52 14 11.04 2 10.27 15 1.54 3 1.58 16 4.32 4 6.28 17 9.30 5 8.91 18 2.50 6 1.21 19 4.16 7 12.61 20 5.27 8 4.50 21 2.76 9 0.95 22 2.49 10 28.37 23 6.11 11 23.88 24 5.55 12 7.26 25 2.92 13 11.22

The numbers in the examples in the table above correspond to the numbers of the aforementioned compounds.

As described above, the compound of formula (1) of the present invention can be used to regulate the activity of leukotrienes in vivo or in vitro because of its superior 5-lipoxygenase inhibitory activity, Diseases related to activity such as asthma, pertussis, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, sepsis, myocardial ischemia, heart hypersensitivity, cerebrovascular spasm, ischemia, allergic rhinitis It can be usefully used as a prophylactic, therapeutic and therapeutic aid for various inflammatory diseases, including.

Claims (9)

5-lipoxygenase inhibition pharmaceutical composition comprising the compound represented by the following formula (1) as an active ingredient. <Formula 1> Wherein X is CH or nitrogen atom, Y is sulfur atom or oxygen atom, R ₁ is hydrogen atom, lower alkyl group, halogen atom, nitro group, cyano group, amino group, lower dialkylamino group, hydroxyl group, lower alkoxy group, hydroxide Roxy lower alkyl group or lower alkanoyl group. R ₂ is one selected from the groups defined in the following items (i) to (v). (i) formula In the formula, R ₃ means a hydrogen atom, a lower alkyl group, R ₄ is a formula Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, Lower alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group. (ii) equation Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same as defined in (i) above. (iii) equation Wherein R ₁₀ is a hydrogen atom or a lower alkyl group. (iv) equation Wherein R ₁₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a mercapto group, or a lower alkyl mercapto group. (v) expression Wherein R ₁₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a lower alkanoyl group, a hydroxyl group, a lower alkoxy group, or a hydroxy lower alkyl group. The method of claim 1, wherein the disease caused by the activity of 5-lipoxygenase, namely asthma, whooping cough, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, gout, rheumatoid arthritis, sepsis, cardiomyopathy, A pharmaceutical composition for the prevention, treatment and treatment of diseases including cardiac hypersensitivity, cerebrovascular spasm, ischemia, allergic rhinitis. The pharmaceutical composition of claim 2, wherein the disease is asthma. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is represented by the following formula (2). <Formula 2> R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, or a lower alkanoyl group; R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, a lower group Alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is represented by the following formula (3). <Formula 3> R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, or a lower alkanoyl group; R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, a lower group Alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is represented by the following formula (4). <Formula 4> R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, or a lower alkanoyl group; A is an expression Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, Lower alkyl mercapto group, halogenated lower alkyl mercapto group, phenyl azo group, lower alkylphenyl azo group, lower alkanoyl group, hydroxyl group, lower alkoxy group, or hydroxy lower alkyl group) Wherein R ₁₀ is a hydrogen atom or a lower alkyl group Wherein R ₁₁ is a hydrogen atom, a lower alkyl group, a halogen atom, a mercapto group, or a lower alkyl mercapto group R ₁₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, or a lower dialkylamino group, a lower alkanoyl group, a hydroxyl group, a lower alkoxy group, or a hydroxy lower alkyl group. It is one selected from. The method according to claim 4, wherein R ₁ is a hydrogen atom or a lower alkyl group, R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, characterized in that each of the hydrogen atom, lower alkyl group or halogen atom Pharmaceutical composition. The method of claim 5, wherein R ₁ is a hydrogen atom, a lower alkyl group, a halogen atom, or a nitro group, R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different, each hydrogen atom, lower alkyl group Or a phenyl azo group. The compound of claim 6, wherein R ₁ is a hydrogen atom or a lower alkyl group, wherein A is Wherein R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a lower dialkylamino group, a mercapto group, Lower alkyl mercapto group, halogenated lower alkyl mercapto group or lower alkoxy group) Wherein R ₁₁ is a hydrogen atom, a lower alkyl group, a halogen element, a mercapto group, or a lower alkyl mercapto group Wherein R ₁₂ is a hydrogen atom, a lower alkyl group or a halogen atom.