KR101715449B1 - Compounds for treatment of inflammatory diseases - Google Patents

Abstract

The present invention relates to a compound for the treatment of inflammatory diseases, which is characterized by being a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
According to the present invention, it is possible to provide a compound which interacts with and interferes with the 5-LOX-pathway, in particular compounds having an inhibitory effect on arachidonate 5-lipoxygenase.

Description

[0001] The present invention relates to compounds for the treatment of inflammatory diseases,

The present invention relates to compounds for the treatment of inflammatory diseases.

The arachidonate 5-lipoxygenase (5-LOX, 5-LO, 5-lipoxygenase or Alox5) pathway mediates the production of major inflammatory mediators by inhibiting asthma, chronic obstructive lung It has been shown to play a major role in the pathophysiology of inflammatory diseases such as diseases (COPD), allergic rhinitis, atherosclerosis, atopic dermatitis and pain, and has also been reported to be involved in cancer and Alzheimer's disease.

The 5-LOX enzyme is required for the production of LTB4 (leukotriene B4), the primary chemotactic factor and leukocyte activator. LTB4 is mainly produced in neutrophilic leukocytes and macrophages, in which LTA4 is converted to LTB4 by the enzyme LTA4 hydrolase (hydrolytic enzyme). 5-LOX is also involved in the synthesis of LTC4, D4, and E4 (cysteinyl leukotriene; cys-LT), which are also potent organ exponential fusions and infectious agents. Cys-LT is also produced from LTA4, a 5-LOX metabolite of arachidonic acid (AA). LTC4 synthase, another enzyme present in some cells, including acidophilic leukocytes, basophilic leukocytes, and mast cells, binds glutathione with LTA4 to produce LTC4. LTC4 is further metabolized into LTD4 and LTE4. 5-LOX activity has also been shown to inhibit 5-hydroxyeicosatetraenoic acid (HETE) and 5-oxo-6,8,11,9-eicosatetraenoic acid (5-oxo ETE). Since 5-oxo-ETE has been shown to cause tissue eosinophilia, it can play a major role in asthma and other diseases.

The clinical significance of the leukotriene pathway in inflammatory airways disease has been demonstrated through the efficacy of various substances in the treatment of asthma and allergic rhinitis. Cys-LT receptor 1 antagonists (e.g., montelukast, zafirlukast and pranlukast) have been shown to be effective in asthma and allergic rhinitis, and the 5-LOX inhibitor Zileuton has been shown to be effective in treating asthma. 5-LOX inhibitors that block the production of cis-LTs and LTB4 have the potential to show improved efficacy over leukotriene receptor antagonists in the treatment of asthma and allergic rhinitis. 5-LOX inhibitors will block the pro-inflammatory activity of LTB4 and cis-LT as well as other leukotrienes such as 5-HETE and 5-oxo-ET. A meta-analysis of several clinical trials showed that zilutones had a higher forced expiratory volume in 1 (FEV1) effect in patients with severe asthma compared to cis-LT receptors appear.

The only commercially available 5-LOX inhibitor is zilutone, a redox hydroxyurea compound that chelates an important active site iron moiety in the 5-LOX enzyme. However, the efficacy of zileuton has not been adequately demonstrated due to the inconvenience of taking (for example, four times a day), suboptimal pharmacokinetic and pharmacodynamic profile, and the potential for hepatotoxicity. In addition, efforts to develop non-redox 5-LOX inhibitors have failed due to inadequate efficacy in the human body.

Therefore, there is a need for the development of more potent, non-hepatic 5-LOX inhibitors that may show better efficacy than zile ruton and cis-LT receptor antagonists.

It is an object of the present invention to provide a compound having anti-inflammatory activity and anti-5-LOX activity.

It is an object of the present invention to provide a compound which interacts with and interferes with the 5-LOX-pathway, in particular compounds having an inhibitory effect on arachidonate 5-lipoxygenase.

It is another object of the present invention to provide a compound that acts as an anti-inflammatory agent.

It is still another object of the present invention to provide a compound that is effective for inflammatory diseases, in particular a compound such as asthma, atherosclerosis, pain, COPD, allergic rhinitis, post-inflammatory infection, arthritis, dermatitis, allergies such as pain, hay fever, Diseases affecting the 5-LOX-pathway such as inflammatory bowel diseases such as immune diseases, Crohn's disease and the like, diseases associated with celiac disease, acne, and other pathologies of 5-LOX- pathway or cancer and / or Alzheimer's disease To provide an effective compound.

One embodiment of the compound for the treatment of inflammatory diseases according to the present invention may be a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

(I)

In this formula,

n is 0 or 1;

X and Y are each independently CR ^a or N;

Z ¹ is -CH ₂ O, O or NH;

A is a residue selected from the following groups,

delete

R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;

R ^b is selected from the group consisting of hydrogen, fluorine, -CF ₃ , -OCF ₃ , -OCH ₃ , -CN and methyl groups;

R ^c is selected from the group consisting of hydrogen, fluorine, -CF ₃ and -OCH ₃ groups;

R ^d is selected from the group consisting of hydroxy, fluorine and-OCH ₃ groups;

R ^e is selected from the group consisting of hydrogen and -CF ₃ groups;

R ^f is selected from the group consisting of hydrogen, methyl and -OCH ₃ groups;

R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;

B is a residue selected from the following groups,

(O) NH, -C (O) CH _2, or SO (SO ₂ ) ₂ , wherein Z is CH ₂ O, O, NH, -CH ₂ , -CH ₂ CH ₂ , -C _2. )

R ² is selected from the group consisting of -CH ₂ CF ₃ , tertiary-butyl, cyclopropyl, cyclohexyl and groups:

R < ³ > is selected from the group consisting of hydrogen and a fluorine group;

R < ⁴ > is selected from the group consisting of hydrogen and a methyl group;

R ⁵ is hydrogen, _{fluorine, -CF 3, -NH 2, -NH} (CH 3), -NO 2, -OH, -CH 2 OH, -CH (CH 2 CH 3) OH, -C (CH 3 ) ₂ OH, -C (O) CH ₃ and -OCH ₃ Groups;

R ⁶ is hydrogen, -OH, -CH ₂ OH and -OCH ₃ Groups;

R ⁷ is selected from the group consisting of hydrogen and -CH ₂ OH groups;

R < ⁸ > is selected from the group consisting of hydrogen and a fluorine group;

R ⁹ is hydrogen, fluorine, and -OCH ₃ Groups;

R ¹⁰ is hydrogen, -OCF ₃ And a fluorine group;

R ¹¹ is selected from the group consisting of hydrogen, chlorine, and fluorine groups.

In addition, one embodiment of the compound for the treatment of inflammatory diseases of the present invention may be a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

≪

In this formula,

n is 0 or 1;

X and Y are each independently CR ^a or N;

Z ² is -CH ₂ , -C (O), -C (O) NH or -SO ₂ ;

R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;

R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;

R ¹² is selected from the group consisting of the following groups;

R ³ is selected from the group consisting of hydrogen and a fluorine group;

R < ⁴ > is selected from the group consisting of hydrogen and a methyl group;

R ⁵ is hydrogen, _{fluorine, -CF 3, -NH 2, -NH} (CH 3), -NO 2, -OH, -CH 2 OH, -CH (CH 2 CH 3) OH, -C (CH 3 ) ₂ OH, -C (O) CH ₃ and -OCH ₃ Groups;

R ⁶ is hydrogen, -OH, -CH ₂ OH and -OCH ₃ Groups;

R ⁷ is selected from the group consisting of hydrogen and -CH ₂ OH groups;

R < ⁸ > is selected from the group consisting of hydrogen and a fluorine group;

R ⁹ is hydrogen, -OH and -OCH ₃ Groups;

R ¹⁰ is hydrogen, -OCF ₃ And a fluorine group;

R < ¹¹ > is hydrogen, chlorine And a fluorine group.

In addition, one embodiment of the compound for the treatment of inflammatory diseases of the present invention may be a compound represented by the following general formula (III), a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.

(III)

In this formula,

n is 0 or 1;

X is CR < ^a > or N;

Z ³ is -CH ₂ , -CH ₂ CH ₂ , -C (O), -C (O) O, -C (O) NH, -C (O) CH ₂ or -SO ₂ ;

R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;

A < ^{1 >} is a residue selected from the following groups,

R ^b is selected from the group consisting of hydrogen, fluorine, -CF ₃ , -OCF ₃ , -OCH ₃ , -CN and methyl groups;

R ^c is selected from the group consisting of hydrogen, fluorine, -CF _3, and -OCF ₃ groups;

R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;

R ¹³ is selected from the group consisting of -CH ₂ CF ₃ , tertiary-butyl, cyclopropyl, cyclohexyl and groups:

R ¹⁰ is selected from the group consisting of hydrogen, -OCF _3, and fluorine groups;

delete

delete

delete

R ¹⁴ is hydrogen, -CF ₃ And -CH ₂ OH groups;

R ¹⁵ is selected from the group consisting of hydrogen and a fluorine group.

May include any one of the following formulas (1) to (133), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

The compound may have an inhibitory activity on an enzyme involved in an inflammatory pathway and the inflammatory pathway may be arachidonate 5-lipoxygenase, and the compound may be administered at a concentration of 0.001 to 50 μM, The IC ₅₀ for arachidonate 5-lipoxygenase is less than 1 μM, or the EC ₅₀ for the production of leukotriene B4 (LTB4) in rat arthritic leukocyte (RBL) or mouse whole blood (RWB) is at least one of less than 10 μM .

The compounds may also be used for the treatment of diseases selected from the group consisting of cancer, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, dermatitis, arthritis, atherosclerosis, allergies, autoimmune diseases, inflammatory bowel disease, inflammatory diseases and Alzheimer's disease , And the compound may further comprise a pharmaceutically acceptable carrier or excipient.

The daily dose of the compound may be from 0.01 mg to 1 g per kg of body weight.

According to the present invention, it is possible to provide a compound which interacts with and interferes with the 5-LOX-pathway, in particular compounds having an inhibitory effect on arachidonate 5-lipoxygenase.

In addition, compounds capable of anti-inflammatory activity can be provided.

In addition, compounds effective for inflammatory diseases, particularly autoimmune diseases such as asthma, atherosclerosis, pain, COPD, allergic rhinitis, post-inflammatory infection, allergies such as arthritis, dermatitis, pain, hay fever, lupus erythematosus, Pathogens of the 5-LOX-pathway, or diseases affecting the 5-LOX-pathway such as cancer and / or Alzheimer's disease, and the like. .

The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned can be clearly understood by those skilled in the art from the description of the claims.

Advantages and features of the present invention and methods for accomplishing the same will become apparent with reference to the embodiments described in detail below with reference to the accompanying synthetic methods. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. To fully disclose the scope of the invention to those skilled in the art, and the invention is only defined by the scope of the claims.

Unless defined otherwise, all terms (including technical and scientific terms) used herein may be used in a sense commonly understood by one of ordinary skill in the art to which this invention belongs. Also, commonly used predefined terms are not ideally or excessively interpreted unless explicitly defined otherwise.

Such compounds which competitively inhibit the specific binding of 5-LOX of the compounds according to the invention to the 5-LOX can also be referred to herein as " competitive inhibitory compounds ".

Hereinafter, the compound for treating inflammatory diseases of the present invention will be described in detail.

The present invention is a compound which can be used for the treatment of inflammatory diseases, which may be a compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

The compounds according to the present invention can competitively inhibit specific binding to arachidonate 5-lipoxygenase (5-LOX, 5-LO, 5-LOX, Alox 5).

In one embodiment, the compound inhibits the activity against enzymes involved in the inflammatory pathway, preferably arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO, 5-LOX, , And the concentration of the compound may be 0.001 to 50 [mu] M. Particularly preferably, at a concentration of 0.001 to 50 μM of said compound, the IC ₅₀ for said arachidonate 5-lipoxygenase is less than 1 μM or the rat basophilic leukocyte cells (RBL) or rat whole The EC ₅₀ for the production of leukotriene B4 (LTB4) of blood (RWB) may be at least one of less than 10 [mu] M.

Herein, terms such as " IC ₅₀ " and " EC ₅₀ " refer to the half-maximal inhibitory concentration of a compound for a given activity such as inhibition of the enzyme through the compound, ) And the half-maximal effective concentration, respectively. One example of an IC ₅₀ is the inhibitory median concentration of the compound relative to the activity of arachidonate 5-lipoxygenase. One example of an EC ₅₀ value is an effective concentration of the inhibitory median of the compound for the production and / or secretion of leukotriene B4 (LTB4) in cells such as rheumatoid leukocyte (RBL) or mouse whole blood (RWB) to be.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, acetate derived from acetic acid, acetoate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, Citrate derived from citrate, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from enantic acid, formate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycol Acid-derived glycolate, hydrochloric acid-derived hydrochloride, hydrobromic acid-derived hydrobromide, lactic acid-derived lactate, maleic acid-derived maleate, malonic acid-derived malonate, mandelic acid ≪ / RTI > derived from mandelate, methanesulfonic acid Naphthalene-2-sulphonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, perchloric acid derived perchlorate, phosphate derived from phosphoric acid, phthalate derived from phthalic acid, salicylic acid Derived salicylate, sorbate-derived sorbate, stearic acid-derived stearate, succinic acid-derived succinate, sulfate-derived sulfate, tartrate-derived tartrate, p-toluenesulfonic acid And non-toxic inorganic and organic acid addition salts such as toluene-p-sulfonate and the like. These salts can be formed through a process according to known techniques.

In addition, acids such as oxalic acid, which may not be regarded as pharmaceutically acceptable, can be used as mediators in obtaining the chemical compounds of the present invention and pharmaceutically acceptable acid addition salts for the treatment of inflammatory diseases have.

In yet another embodiment, each of the compounds according to one embodiment of the present invention may be used in the form of a free base for the treatment of inflammatory diseases.

Metal salts of the compounds of the present invention and alkali metal salts such as sodium salts of compounds containing a carboxyl group according to an embodiment of the present invention.

The compound according to one embodiment of the present invention may be provided in the form of unsolvated or solvated form together with a pharmaceutically acceptable solvent such as water, ethanol and the like. The solvated forms may be provided in hydrate form such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like. Generally, for purposes of the present invention, the solvated form is considered to be the same as the unsolvated form.

Inflammatory disease may be a disease associated with the pathway of arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO, 5-LOX, Allox 5). But are not limited to, asthma, allergic rhinitis, dermatitis, chronic obstructive pulmonary disease (COPD), post-inflammatory infection, arthritis, atherosclerosis, cancer, Alzheimer's disease.

The active metabolites, isomers and salts of the compounds according to one embodiment of the present invention, including the compounds of the present invention, can be conducted according to known pharmaceutical methods.

The compounds of the present invention which may be used in the treatment according to the present invention may be administered in the form of a raw chemical compound, but optionally the active ingredient in the form of a physiologically acceptable salt may be formulated as adjuvants, it is preferably introduced into the pharmaceutical composition along with excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical adjuvants. Salts of the compounds of the present invention may be in the anhydrous or solvated form.

In one embodiment of the present invention, it is preferred that the present invention provides a medicament comprising a compound, or a pharmaceutically acceptable salt or derivative thereof, which is usable according to the invention together with one or more pharmaceutically acceptable carriers.

The carrier may optionally further comprise other therapeutic or prophylactic ingredients. In addition, the carrier should be " acceptable " in terms of compatibility with the ingredients of the formulation and not deleterious to the receptor.

The medicament of the present invention can be administered orally, rectally, rectally, bronchially, nasally, topically, buccally, sublingually, by ball, transdermal, vaginal or parenteral (skin, subcutaneous, intramuscular, intraperitoneal, intravenous, Injection), or may be provided in a form suitable for suction or ventilation by powder and liquid aerosol particles or a release system. Suitable examples of sustained release systems are the semipermeable matrices of solid hydrophobic polymers comprising the compounds of the present invention, which may be in the form of particles, such as membranes or microcapsules.

Compounds that can be used in accordance with the present invention may be provided in the form of drugs and unit dosages, together with conventional adjuvants, carriers, or diluents. Such forms include solids, especially tablets, filled capsules, powders and pellets forms and liquids, especially aqueous and non-aqueous solutions, suspensions, emulsions, elixirs, and the like, for oral, rectal suppository and sterile injection solutions for parenteral use, And capsules filled with the material. Such drugs and unit dosage forms, etc., may include conventional ingredients in conventional proposals, whether with additional active compounds or principles, and such unit dosage forms are possible in any amount consistent with the desired daily dose.

The compounds which can be used according to the invention can be administered in a variety of oral and parenteral dosage forms. The following dosage forms may contain, as an active ingredient, a compound usable according to the invention, or a pharmaceutically acceptable salt of a compound usable according to the invention.

For preparing a medicament from a usable compound according to the present invention, the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

In powders, the carrier is a finely divided solid mixed with finely divided active ingredients. In tablets, the active ingredient is mixed with the carrier having the necessary binding force in suitable proportions and compacted to the desired shape and size. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax and cocoa butter.

The term " preparation " of the pharmaceutical formulations in the present invention includes preparing an active compound and an encapsulating material as a carrier to provide a capsule, wherein the active ingredient is covered by the carrier, There is an association. Likewise, there are also casinos and lozenges. Tablets, powders, capsules, pills, cachexia, rosin and the like may be used in solid form suitable for oral administration.

To prepare the suppository, the low melting point wax, such as a fatty acid glyceride or cocoa butter mixture, is first melted and then the active ingredient is uniformly dispersed by stirring. The molten homogeneous mixture is then poured into molds of convenient size and allowed to cool and allow to solidify.

Forms suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, as well as active ingredients such as known carriers. Materials prepared in liquid include solutions, suspensions, and emulsifiers such as water or water-propylene glycol solutions. For example, a substance prepared as a parenteral injection liquid is an aqueous polyethylene glycol solution.

Thus, compounds according to one embodiment of the present invention may be formulated for parenteral administration (e.g., bolus injection or continuous infusion). It can also be supplied in unit quantities of ampoules, packed syringes, small injections or multiple quantitative containers. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous delivery vehicles, and may contain materials such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained from aseptic isolation of sterile solid or lyophilisation of the solution, which may be constituted with a suitable medium, such as sterile distilled water, prior to use.

An aqueous solution suitable for oral use can be prepared by dissolving the active ingredient in water and then adding a suitable coloring agent, flavor, and thickening agent. Aqueous suspensions suitable for oral use are prepared by dispersing finely divided active ingredients in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents can do.

Also included are ready-to-use preparations in solid form which are converted to prepared preparations in liquid form by oral administration immediately prior to use. Such liquid forms include solutions, suspensions, and emulsifiers. The prepared materials may contain, in addition to active ingredients, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

In one embodiment of the present invention, the medicament is applied locally, totally or in combination of two routes.

The compounds of the present invention may be adjusted to include from 0.001% to 70% agent per weight of compound, preferably from 0.01% to 70% per weight of compound, more preferably from 0.1% To 70%. In one embodiment, the amount of compound suitable for administration may be from 0.01 mg to 1 g per kg of body weight.

Compositions suitable for administration include, in general, perfume-based active agents such as sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerol or sucrose or acacia; And rouge lozenges comprising an oral cleanser comprising the active ingredient in a suitable liquid carrier.

The solution or suspension may be administered directly to the nasal cavity by conventional means such as a dropper, pipette or spray. The compositions may be presented in single or multiple quantitative forms. When administering multiple doses with a dropper or pipette, the patient is achievable by administering a suitable predetermined amount of solution or suspension. In the case of spraying, it is achievable, for example, by metering atomising spray pumps.

In the case of administration to airways, a suitable propellant, such as chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, By means of an aerosol formulation in which the active ingredient is provided in a pressurized pack. The aerosol may also contain a surfactant such as lecithin. The quantification of the drug can be controlled by the provision of a metered valve.

Alternatively, the active ingredients may be provided in the form of a dry powder. A dry powder such as a powder mix of a compound on a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP), and the like. The powder carrier will form a gel in the nasal cavity. The powder composition may be provided in a unit dosage form capable of powder administration, for example, using an inhaler such as a capsule or cartridge made of gelatin or a blister pack.

In compositions intended for aerodynamic administration, including intranasal compositions, the compounds may generally have a small particle size of about 5 microns or less. Such a particle size is achievable by known means such as atomization.

If desired, compositions provided to provide sustained release of the active ingredient may be used.

The pharmaceutically prepared substance is preferably in unit dosage form. In this form, the prepared material is subdivided into unit quantities containing an appropriate amount of active ingredient. The unit dosage form can be a packaged ready-to-use material and the package includes a discrete amount of the prepared material, such as packaged tablets, capsules, vials or powders in an ampoule. In addition, the unit dosage form may be a capsule, tablet, cache or rosin itself, or may be packaged in a suitable number. Tablets or capsules for oral administration and liquid and sustained infusion for intravenous administration and continuous infusion are preferred compositions.

Example

Hereinafter, the present invention will be described in more detail with reference to the following examples.

<Synthesis of Compound>

The synthesis of the compounds described herein is accomplished by means described in the chemical literature, methods described herein, or a combination thereof.

The compounds described herein can be synthesized using standard synthetic techniques known to those skilled in the art, or a combination of methods described herein with methods known in the art. In addition, the solvents, temperatures, and other reaction conditions described herein may vary according to those skilled in the art. The starting materials used in the synthesis of the compounds described herein can be synthesized or synthesized by Aldrich Chemical Co. (Milwaukee, Wis.) Or Sigma Chemical Co. (St. Louis, Mo.), and the like.

The compounds described herein and other related compounds having other components can be synthesized using techniques and materials described herein as well as techniques and materials known to those skilled in the art. General methods for the preparation of the compounds described herein may be derived from reactions known in the art for the introduction of the various moieties found in the formulas provided in the present invention, May be modified to such an extent as would be appreciated by those skilled in the art.

In the examples, the compounds described in the present invention can be prepared using the synthetic scheme according to the following reaction schemes, and the compounds were synthesized by derivatization according to the methods of the following reaction schemes.

[Reaction 1] Synthesis of 3-aminopyrrolidine

A1 synthesis process

To a solution of 4-nitroaniline in methylene chloride (25 mL) was added 4-fluorophenylboronic acid (13.03 mmol), triethylamine (32.58 mmol) and copper (II) acetate (21.72 mmol). The resulting mixture was stirred at room temperature overnight. The insoluble solids were removed by filtration using celite and the filtered liquid was evaporated. The crude residue was purified by flash column chromatography to give A1.

A2 Composite Process

Methanol and methylene chloride (8 mL, 5: 3 ratio, v / v) followed by the addition of A1 (7.24 mmol), Pd / C (0.20 g) was added in, and the reaction mixture H ₂ And the mixture was stirred at room temperature for 4 hours. After the reaction was completed, insoluble residues were removed by filtration using celite, and the filtered liquid was concentrated in vacuo to produce A2.

A3 synthesis course

To a solution of A2 (0.59 mmol) in methylene chloride (6 mL) was added tert-butyl 3-oxopyrrolidine-1-carboxylate (0.53 mmol), sodium triacetoxyborohydride (1.07 mmol) 0.30 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was diluted with methylene chloride and washed with saturated Na ₂ CO ₃ and brine. The organic layer was dried over MgSO ₄ and concentrated. The crude residue was purified by flash column chromatography to yield A3.

A4 compositing course

A solution of A3 (0.47 mmol) in 4-dioxane (4 mL) was treated with HCl (4 M in 1,4-dioxane, 1.5 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, and then adjusting the pH with saturated Na ₂ CO ₃ (aq.) To 8 and extracted with methylene chloride (× 2). The organic phase was dried over anhydrous MgSO ₄ Concentration in vacuo yielded A4.

[Reaction 2] Coupling reaction of pyrrolidine with aldehyde

B2 synthesis process

Methylene chloride and methanol (5 mL, 3: 2 ratio, v / v ) (0.19 mmol), 1 H -indazole-3-carbaldehyde (0.23 mmol) and sodium triacetoxyborohydride (0.38 mmol) were added. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, The reaction mixture was diluted with methylene chloride, washed with brine and dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography to give B2.

[Reaction 3] Coupling reaction between sulfonyl chloride and pyrrolidine

C1  Synthesis process

Methylene chloride (2 mL) in the (S) - N 1- (4- flu-phenyl) - N 4- (pyrrolidin-3-yl) benzene-1,4-diamine (0.29 mmol) And triethylamine (0.59 mmol) in dichloromethane was added a solution of 4-fluorobenzenesulfonyl chloride (0.29 mmol) in methylene chloride (2 mL) at 0 &lt; 0 &gt; C. The reaction mixture was allowed to stir at room temperature and then stirred for 4 hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride, washed with brine and dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography to give C1.

[Reaction 4] coupling reaction of aniline with pyrrolidone

D1  Synthesis process

To a solution of N 1- (4-fluorophenyl) benzene-1,4-diamine in methylene chloride (3 mL) N a (0.25 mmol) solution of (4-fluorophenyl) -3-oxopyrrolidin-1-carboxamide (0.23 mmol), sodium triazole hydride (0.45 mmol) and acetic acid (0.5 mL) with the time signal setok . The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with methylene chloride and washed with brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography to give D1.

[Reaction Scheme 5] Coupling reaction between azetidine and acid

E1  Synthesis process

The indazole-3-carboxylic acid (0.25 mmol) solution, N 1- (azetidin-3-yl) - - 1 H in methylene chloride (2 mL) N 4- (4- fluorophenyl) benzene-1, 4- Diamine (0.34 mmol), 1-hydroxybenzotriazole-zolimonohydrate (0.12 mmol) and triethylamine (0.45 mmol) in DMF (10 mL) Was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo. The crude residue was purified by flash column chromatography to give E1.

[Reaction Scheme 6] Coupling reaction between pyridine chloride and pyrrolidine

F1 synthesis process

To a solution of methyl 2 - ((4- (pyrrolidin-3-ylamino) phenyl) amino) nicotinate (0.16 mmol) in N, N -dimethylformamide (1 mL) was added methyl 2-chloronitrate 0.16 mmol) and N, N -diisopropylethylamine (0.48 mmol) were added. The mixture was placed in a cavity of a microwave system apparatus and heated at 150 캜 for 30 minutes (150 W). After the reaction was complete, insoluble residues were removed by filtration using celite, and the filtered liquid was concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography to give F1.

F2 synthesis process

To a solution of F1 (0.089 mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (0.45 mmol) at 0 ° C and the reaction mixture was stirred for a further 30 min. After the reaction was complete, the reaction was quenched with water and insoluble solids were removed by filtration using celite. The filtered liquid was concentrated in vacuo and the resulting residue was purified by flash column chromatography to give F2.

[Reaction Scheme 7] Coupling reaction between pyrimidine chloride and azetidine

G1  Synthesis process

To a solution of N 1- (azetidin-3-yl) - N 4- (4- fluorophenyl) benzene-1,4-diamine (0.79 mmol) to the solution, 2-chloro-5-methoxypyrid limiter Dean (0.79 mmol), (0.08 mmol), palladium (II) acetate (0.04 mmol) and cesium carbonate (0.49 mmol) were added to the reaction mixture. The reaction mixture was stirred at 100 &lt; 0 &gt; C overnight. After the reaction was complete, the insoluble residue was filtered off and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography to give G1.

The compounds prepared in the above Schemes 1 to 7 were evaluated for inhibitory activity (IC ₅₀ , EC ₅₀ , tex ( ex vivo ).

Evaluation Method 1: 5- LOX  Activity of compounds against enzymes

The activity of the compounds for 5-LOX is judged by measuring the level of LTB ₄ (leukotriene B4) through the fluorescence method. The fluorescence method was performed as follows.

Fluorescence assays measuring 5-hydroperoxyeicosatetraenoic acid (5-HPETE) to quantify LTB ₄ levels were performed in a 384 well microplate format (Pufahl et al., (2007) Development of a Was introduced for high-throughput screening in the fluorescence-based enzyme assay of human 5-lipoxygenase. ANALYTICAL BIOCHEMISTRY 364, 204-12. For the non-specific cleavage of acetate groups in H ₂ DCFDA (2 ', 7'-dichlorodihydrofluorescein diacetate), human 5-LOX pressed insects Cell lysates (Cayman Cat # 60402) were incubated with H ₂ DCFDA (50 mM Tris-Cl per reaction, pH 7.5, 2 mM CaCl 2, 20 uM H ₂ DCFDA, 600 mU 5-LOX per reaction) for 5 minutes. The compound was incubated with the enzyme mixture for 5 minutes in a quantitative reaction system (0.5 nM to 10 uM) and the enzymatic reaction was initiated by adding ATP and arachidonic acid to final concentrations of 100 uM and 3 uM, respectively. After incubation for 5 minutes, the fluorescent material was measured using Spectramax M5 (molecular device, Ex / Em = 485 nm / 530 nm). All steps were performed at room temperature.

The evaluation results are shown in Table 1 below. In the following Table 1, the activity range indicated by +++ was measured at less than 1 uM, the ++ was measured at 1 to 10 uM, the + was measured at greater than 10 uM .

Evaluation Method 2: ELISA ( enzyme - linked immunosorbent assay )On by LTB ₄  Measure

(5-LOX) enzyme (Cayman, Cat # 60402) produced in insect cells was suspended in a culture buffer (50 mM Tris-Cl, pH 7.4, 2 mM CaCl ₂ , 0.1 mM ATP, % DMSO) for 5 min under RT conditions. The compounds were tested with a dose response of 0.5 nM to 10 uM. Enzyme reaction is started by the addition of arachidonic acid at a final concentration of 3uM, was terminated after incubation for 5 minutes at 25 ℃, the reaction was added to H ₂ O ₂ to a final concentration of 1mM. LTB ₄ levels were quantified using an LTB ₄ EIA kit (Cayman, Cat # 520111).

The evaluation results are shown in Table 2 below. In the following Table 2, the activity range indicated by +++ was measured at less than 1 uM, the ++ was measured at 1 to 20 uM, the + was measured at greater than 20 uM .

Evaluation Method 3: RBL (Murine basophilic leukemia cells) LTB4  Secretion analysis

The secretion assay of LTB4 in RBL (murine basophilic leukemia cells) was carried out as follows.

Rat basophilic platelet (RBL) cells (ATCC, Cat # CRL-2256) were maintained in EMEM (ATCC, Cat # 30-2003) supplemented with 15% FBS. The day before RBL assay, cells were seeded in 96-well plates at a concentration of 2 X 10 ⁴ cells per well Seeded. The medium was replaced with 100 ul of EMEM supplemented with 0.5% FBS followed by the addition of a quantitative reaction (5 nM to 100 uM). After 15 minutes of incubation at 37 ° C, arachidonic acid and calcium ionophore at final concentrations of 2.5 uM and 5 uM, respectively, were added. After an additional 10 min incubation at 37 ° C, the culture supernatant was transferred and quantification of LTB4 was performed with the leukotriene B4 EIA kit (Cayman, Cat # 520111) as instructed.

The evaluation results are shown in Table 3 below. In the following Table 3, the activity range indicated by +++ was measured at less than 10 uM, ++ was measured at 10 to 20 uM, and the mark + was measured at greater than 20 uM .

Evaluation Method 4: RWB  (rat whole blood ) In LTB4  Secretion analysis

The secretion assay of LTB4 in RBL (murine basophilic leukemia cells) was carried out as follows.

Sprague Dawley Blood from the posterior vena c of male rats (6-9 weeks of age) was collected in a vacuum vial coated with sodium herapine (Greiner bio-one, Cat # 455051). The blood was collected and diluted 1: 1 in RPMI (WelGene, Cat # LM 011-05). Diluted blood was sampled in 96 well plates (200 ul per well) and the compounds were added in a quantitative reaction for a desired concentration ranging from 2.5 nM to 50 uM. After preincubation at 37 占 폚 for 15 minutes, calcium ionophor (A23187) was added to a final concentration of 10 uM. After further incubation at 37 ° C for 10 min, LTB4 production was stopped by diluting the reaction mixture with ice cold PBS (1: 4 dilution). Cells were removed by centrifugation at 1000 xg for 10 minutes at 4O &lt; 0 &gt; C, supernatants were transferred and quantification of LTB4 was performed with the leukotriene B4 EIA kit (Cayman, Cat # 520111) according to the instructions.

The evaluation results are shown in Table 4 below. In the following Table 4, the activity range indicated by +++ was measured at less than 10 uM, the ++ was measured at 10 to 20 uM and the + was measured at greater than 20 uM .

Table 5 below shows the nuclear magnetic resonance values of the compounds of the formulas (1) to (133) by color, melting point, and ¹ H-NMR.

The scope of the rights is not limited to the above-described embodiments, but may be embodied in various forms of embodiments within the scope of the appended claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims (10)

A compound for the treatment of inflammatory diseases which is a compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof:
(I)

In this formula,
n is 0 or 1;
X and Y are each independently CR ^a or N;
Z ¹ is -CH ₂ O, O or NH;
A is a residue selected from the following groups,

R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;
R ^b is selected from the group consisting of hydrogen, fluorine, -CF ₃ , -OCF ₃ , -OCH ₃ , -CN and methyl groups;
R ^c is selected from the group consisting of hydrogen, fluorine, -CF ₃ and -OCH ₃ groups;
R ^d is selected from the group consisting of hydroxy, fluorine and-OCH ₃ groups;
R ^e is selected from the group consisting of hydrogen and -CF ₃ groups;
R ^f is selected from the group consisting of hydrogen, methyl and -OCH ₃ groups;
R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;
B is a residue selected from the following groups,

(O) NH, -C (O) CH _2, or SO (SO ₂ ) ₂ , wherein Z is CH ₂ O, O, NH, -CH ₂ , -CH ₂ CH ₂ , -C _2. )
R ² is selected from the group consisting of -CH ₂ CF ₃ , tertiary-butyl, cyclopropyl, cyclohexyl and groups:

R ³ is selected from the group consisting of hydrogen and a -Cl group;
R < ⁴ > is selected from the group consisting of hydrogen and a methyl group;
R ⁵ is hydrogen, _{fluorine, -CF 3, -NH 2, -NH} (CH 3), -NO 2, -OH, -CH 2 OH, -CH (CH 2 CH 3) OH, -C (CH 3 ) ₂ OH, -C (O) CH ₃ and -OCH ₃ groups;
R ⁶ is selected from the group consisting of hydrogen, -OH, -CH ₂ OH and -OCH ₃ groups;
R ⁷ is selected from the group consisting of hydrogen and -CH ₂ OH groups;
R &lt; ⁸ &gt; is selected from the group consisting of hydrogen and a fluorine group;
R ⁹ is selected from the group consisting of hydrogen, -OH and -OCH ₃ groups;
R ¹⁰ is selected from the group consisting of hydrogen, -OCF _3, and fluorine groups;
R &lt; ¹¹ &gt; is hydrogen, -Cl And a fluorine group. The method according to claim 1,
A compound for the treatment of inflammatory diseases which is a compound represented by the following formula (II), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof
&Lt;

In this formula,
n is 0 or 1;
X and Y are each independently CR ^a or N;
Z ² is -CH ₂ , -C (O), -C (O) NH or -SO ₂ ;
R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;
R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;
R ¹² is selected from the group consisting of the following groups;

R &lt; ³ &gt; is selected from the group consisting of hydrogen and a chlorine group;
R &lt; ⁴ &gt; is selected from the group consisting of hydrogen and a methyl group;
R ⁵ is hydrogen, _{fluorine, -CF 3, -NH 2, -NH} (CH 3), -NO 2, -OH, -CH 2 OH, -CH (CH 2 CH 3) OH, -C (CH 3 ) ₂ OH, -C (O) CH ₃ and -OCH ₃ groups;
R ⁶ is selected from the group consisting of hydrogen, -OH, -CH ₂ OH and -OCH ₃ groups;
R ⁷ is selected from the group consisting of hydrogen and -CH ₂ OH groups;
R &lt; ⁸ &gt; is selected from the group consisting of hydrogen and a fluorine group;
R ⁹ is selected from the group consisting of hydrogen, -OH and -OCH ₃ groups;
R ¹⁰ is selected from the group consisting of hydrogen, -OCF _3, and fluorine groups;
R ¹¹ is selected from the group consisting of hydrogen, chlorine, and fluorine groups.
The method according to claim 1,
A compound for the treatment of inflammatory diseases which is a compound represented by the following formula (III), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof
(III)

In this formula,
n is 0 or 1;
X is CR < ^a > or N;
Z ³ is -CH ₂ , -CH ₂ CH ₂ , -C (O), -C (O) O, -C (O) NH, -C (O) CH ₂ or -SO ₂ ;
R ^a is selected from the group consisting of hydrogen, fluorine, chlorine and methyl groups;
A &lt; ^{1 &gt;} is a residue selected from the following groups,

R ^b is selected from the group consisting of hydrogen, fluorine, -CF ₃ , -OCF ₃ , -OCH ₃ , -CN and methyl groups;
R ^c is selected from the group consisting of hydrogen, fluorine, -CF _3, and -OCF ₃ groups;
R ¹ is selected from the group consisting of hydrogen, fluorine, -OCH _3, and a methyl group;
R ¹³ is selected from the group consisting of -CH ₂ CF ₃ , tertiary-butyl, cyclopropyl, cyclohexyl and groups:

R ¹⁰ is selected from the group consisting of hydrogen, -OCF _3, and fluorine groups;
R ¹⁴ is selected from the group consisting of hydrogen, -CF ₃ and -CH ₂ OH groups;
R ¹⁵ is selected from the group consisting of hydrogen and a fluorine group.
4. The method according to any one of claims 1 to 3,
The compound is a compound for the treatment of inflammatory disease, which is any one of the following Chemical Formulas 1 to 133, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof

4. The method according to any one of claims 1 to 3,
The compound is a compound for treating an inflammatory disease having an inhibitory activity on an enzyme involved in inflammatory pathways
6. The method of claim 5,
The inflammatory pathway is an arachidonate 5-lipoxygenase, a compound for the treatment of inflammatory diseases
The method according to claim 6,
At a concentration of 0.001-50 μM of the compound, the IC ₅₀ for the arachidonate 5-lipoxygenase is less than 1 μM or the production of leukotriene B4 (LTB4) in rheumatoid leukocyte (RBL) or mouse whole blood (RWB) EC ₅₀ for the compound are at least one of inflammatory diseases of less than about 10μM
4. The method according to any one of claims 1 to 3,
The compounds are useful for the treatment of diseases selected from the group consisting of cancer, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, dermatitis, arthritis, atherosclerosis, allergies, autoimmune diseases, inflammatory bowel disease, inflammatory diseases and Alzheimer's disease Or &lt; RTI ID = 0.0 &gt;
A pharmaceutical composition for the treatment or prophylaxis of cancer, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, dermatitis, arthritis, atherosclerosis, or atherosclerosis, comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or excipient. , Allergies, autoimmune diseases, inflammatory bowel disease, inflammatory diseases and Alzheimer's disease.
4. The method according to any one of claims 1 to 3,
The daily dose of the compound is 0.01 mg to 1 g per kg of body weight.