KR20140071892A - Heterocyclic compounds - Google Patents

Abstract

The present invention relates to a novel heterocyclic compound or a pharmaceutically acceptable salt and a solvate thereof. In particular, the novel heterocyclic compound is an inhibitor of 11β-hydroxysteroid dehydrogenase1 and treats or prevents skin diseases. A pharmaceutical composition or a cosmetic composition containing the novel heterocyclic compound or the pharmaceutically acceptable salt and the solvate thereof is very useful for treating or preventing skin diseases.

Description

 The present invention relates to novel heterocyclic compounds,

The present invention relates to a novel heterocyclic compound, and more particularly to a novel heterocyclic compound or a pharmaceutically acceptable salt and solvate thereof for the treatment or prevention of a skin disease as an inhibitor of 11? -Hydroxysteroid dehydrogenase 1, ≪ / RTI >

The present invention also relates to a cosmetic composition comprising a novel heterocyclic compound or a pharmaceutically acceptable salt or solvate thereof.

Glucocorticoids (GC) are one of the steroid hormones in vivo and are secreted in response to a variety of stresses, such as physical and psychological stress.

In other words, glucocorticoids are secreted from the pituitary hypothalamo-pituitary-adrenal axis and induce various responses such as cell differentiation and cell proliferation and apoptosis.

Meanwhile, cortisol is a human in vivo glucocorticoid that binds to the GC receptor (GR) and regulates gene expression. Such cortisol is regulated in activity by two enzymes. 11? -Hydroxysteroid dehydrogenase type 1 enzyme (hereinafter referred to as 11? -HSD1) is an active form of cortisone, which is an inactive form, cortisol), whereas 11? -hydroxysteroid dehydrogenase type 2 (11? -hydroxysteroid dehydrogenase 2, hereinafter referred to as 11? -HSD2) converts cortisol back to cortisone.

11β-HSD1 is mainly present in liver, lung, adipose tissue, ovary and central nervous system, and 11b-HSD2 is known to be expressed in kidney, colon, glands and placenta.

It has recently been found that 11β-HSD1 is also expressed in epidermal keratinocyte, dermal fibroblast, and hair follicle root sheath, and their expression increases with age [Ana Tiganescu et al ,; 2011, Journal of Investigative Dermatology, 131, 30-36.].

11β-HSD1 is also expressed in sebaceous glands, and glucocorticoids are involved in 11β-HSD1 even when inducing adipogenesis. Inactivation of 11β-HSD1 in keratinocytes and dermal fibroblasts leads to cell death It is expected to regulate proliferation and be useful for skin barrier recovery, such as wound healing.

Therefore, studies on effective inhibitors of ll [beta] -HSDl are required.

2011, Journal of Investigative Dermatology, 131, 30-36.

The present invention provides a novel heterocyclic compound or a pharmaceutically acceptable salt and solvate thereof capable of inhibiting the activity of an excellent ll [beta] -HSDl.

Also provided is a pharmaceutical composition containing the above-mentioned novel heterocyclic compound or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and useful for the treatment or prevention of skin diseases.

Also provided is a cosmetic composition containing the novel heterocyclic compound or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

The present invention provides a heterocyclic compound represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof.

[Chemical Formula 1]

[In the above formula (1)

Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;

R ¹ or R ² are independently from each other hydrogen, amino, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, or (C 1 -C 7) alkylamino;

R is selected from the group consisting of hydrogen, halogen, cyano, amino, (CrC7) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, (C1-C7) alkoxy, or (C6-C12) aryloxy;

Ar is (C6-C12) arylene, (C3-C7) heterocycloalkylene or (C3-C12) heteroarylene;

Wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of said R ¹ or R ² and said alkyl, cycloalkyl, alkoxy and aryloxy of R are independently of each other selected from the group consisting of cyano, halogen, ) Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;

o or p independently of one another is an integer selected from 1 to 2.]

In the formula 1 according to an embodiment of the present invention, Ar may be selected from the following structures.

[In the above formula,

R ²¹ to R ²⁷ independently from each other are hydrogen, halogen, hydroxy, carboxy, cyano or (C 1 -C 7) alkyl;

A is NR ^12, and O or S, R ¹² is hydrogen or (C1-C7) alkyl;

l is an integer selected from 1 to 4;

m is an integer selected from 1 to 3;

and n is an integer selected from 1 to 6.]

Preferably, the heterocyclic compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt or solvate thereof may be a compound represented by the following formulas (2) to (4) or a pharmaceutically acceptable salt or solvate thereof .

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

 [In the formula (2)

Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;

A is NR ^21, and O or S, R ²¹ is hydrogen or (C1-C7) alkyl;

R ¹ or R ² are, independently of each other, hydrogen, an amine, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy or (C 1 -C 7) alkylamino;

R ⁷ or R ³¹ is hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7) heterocycloalkyl, (C 6 -C 12) ) Heteroaryl, (C1-C7) alkoxy or (C6-C12) aryloxy;

(C ¹ -C ⁷ ) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of the R ¹ or R ² and the R ⁷ is independently selected from the group consisting of cyano, halogen, Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;

o or p independently of one another is an integer selected from 1 to 2.]

Preferably, in the above formulas (2) to (5) according to an embodiment of the present invention, Z is NR ¹¹ and R ¹¹ is hydrogen or (C 1 -C 7) alkyl;

A is O or S;

R ¹ or R ² are, independently of each other, hydrogen, amino, hydroxy, halogen or (C 1 -C 7) alkyl;

R ⁷ or R ³¹ independently of one another can be hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 6 -C 12) aryl or cyano substituted (C 6 -C 12) aryl.

The heterocyclic compound of Formula 1 or pharmaceutically acceptable salts and solvates thereof may be exemplified as a heterocyclic compound selected from the following structures, or pharmaceutically acceptable salts and solvates thereof, but is not limited thereto .

The present invention also provides a pharmaceutical composition containing, as an active ingredient, the heterocyclic compound of Formula 1 of the present invention or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of skin diseases.

In accordance with one embodiment of the present invention, the skin disease is selected from psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczematous dermatitis, photodermatitis, dermatitis dermatitis, herpes dermatitis, squamous cellulitis, Inflammatory bowel disease, arthritic or inflammatory eye disease, arthritis, rheumatoid arthritis, spondylitis, systemic sclerosis, dermatomyositis, multiple myositis, inflammatory muscle lesions, acquired immunodeficiency, leprosy, triceps, inflammatory bowel disease Disease, stress disorder or transplant rejection.

The present invention also provides a cosmetic composition comprising the heterocycle compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The novel heterocyclic compounds of the invention or pharmaceutically acceptable salts and solvates thereof act as inhibitors of good ll [beta] -HSDl.

In addition, the novel heterocyclic compounds of the present invention or pharmaceutically acceptable salts and solvates thereof act as an excellent inhibitor against 11? -HSD1 and can be useful for the treatment and prevention of skin diseases.

Also, the cosmetic composition of the present invention contains a novel heterocyclic compound having an excellent inhibitory effect on 11? -HSD1, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and thus it is possible to prevent and treat skin diseases.

1 is a graph showing inhibition of cortisol formation by the method according to Example 9 using the heterocyclic compound of the present invention,
2 is a graph showing inhibition of cortisol formation by the method according to Example 10 using the heterocyclic compound of the present invention,
FIG. 3 is a graph showing cytotoxicity according to the concentration of a heterocyclic compound according to Example 2 of the present invention,
4 is a graph showing cytotoxicity of the heterocyclic compound according to the concentration of the heterocyclic compound according to Example 4 of the present invention,
FIG. 5 is a graph showing cytotoxicity according to the concentration of a heterocyclic compound according to Example 5 of the present invention. FIG.

The present invention provides a heterocyclic compound represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof.

[Chemical Formula 1]

[In the above formula (1)

Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;

R ¹ or R ² are independently from each other hydrogen, amino, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, or (C 1 -C 7) alkylamino;

R is selected from the group consisting of hydrogen, halogen, cyano, amino, (CrC7) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, (C1-C7) alkoxy or (C6-C12) aryloxy;

Ar is (C6-C12) arylene, (C3-C7) heterocycloalkylene or (C3-C12) heteroarylene;

Wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of said R ¹ or R ² and said alkyl, cycloalkyl, alkoxy and aryloxy of R are independently of each other selected from the group consisting of cyano, halogen, ) Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;

o or p independently of one another is an integer selected from 1 to 2.]

The heterocyclic compound of the present invention has a structure in which thiophene, furan or pyrrole is fused to the pyridine ring, that is, pyrrolopyridine, thienopyridine or furopyridine, and has an excellent inhibitory effect on 11? -HSD1, N, S of thiophene fused to the pyridine ring, O of furan, N of pyrrole, and NH of sulfonamide are easily hydrogen-bonded to the 11? -HSD1 enzyme to inhibit the enzymatic activity, thereby preventing cortisone from being converted into activated cortisol .

In the formula 1 according to an embodiment of the present invention, Ar may be selected from the following structures.

[In the above formula,

R ²¹ to R ²⁷ independently from each other are hydrogen, halogen, hydroxy, carboxy, cyano or (C 1 -C 7) alkyl;

A is NR ^12, and O or S, R ¹² is hydrogen or (C1-C7) alkyl;

l is an integer selected from 1 to 4;

m is an integer selected from 1 to 3;

and n is an integer selected from 1 to 6.]

Preferably, the heterocyclic compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt or solvate thereof may be a compound represented by the following formulas (2) to (4) or a pharmaceutically acceptable salt or solvate thereof .

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

 [In the formula (2)

Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;

A is NR ^21, and O or S, R ²¹ is hydrogen or (C1-C7) alkyl;

R ¹ or R ² are independently from each other hydrogen, amino, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, or (C 1 -C 7) alkylamino;

R ⁷ or R ³¹ is hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7) heterocycloalkyl, (C 6 -C 12) ) Heteroaryl, (C1-C7) alkoxy or (C6-C12) aryloxy;

(C ¹ -C ⁷ ) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of the R ¹ or R ² and the R ⁷ is independently selected from the group consisting of cyano, halogen, Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;

o or p independently of one another is an integer selected from 1 to 2.]

Preferably, in the above formulas (2) to (5) according to an embodiment of the present invention, Z is NR ¹¹ and R ¹¹ is hydrogen or (C 1 -C 7) alkyl;

A is O or S;

R ¹ or R ² are, independently of each other, hydrogen, amino, hydroxy, halogen or (C 1 -C 7) alkyl;

R ⁷ or R ³¹ independently of one another can be hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 6 -C 12) aryl or cyano substituted (C 6 -C 12) aryl.

In particular, the structure of Formula 4 has the highest inhibitory activity and the activity is somewhat low. However, the following Formula 2 may be commercially preferable from the viewpoints of ease of synthesis and low production cost.

The heterocyclic compound of Formula 1 or pharmaceutically acceptable salts and solvates thereof may be exemplified as a heterocyclic compound selected from the following structures, or pharmaceutically acceptable salts and solvates thereof, but is not limited thereto .

The substituents comprising the "alkyl", "alkoxy" and other "alkyl" moieties described in this invention include all straight-chain or branched forms, wherein C ₁ -C ₇ alkyl is methyl, ethyl, n-pentyl, n-hexyl, n-heptyl, C ₁ -C ₇ alkoxy is methoxy, ethoxy, n-butyl, Propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexyloxy, C ₃ -C ₇ cycloalkyl is cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, and C ₆ -C ₁₂ aryl includes phenyl, naphthyl, biphenyl, anthryl and the like. The 5-membered or 7-membered heterocycle includes both aliphatic heterocycles and heteroaryls, in particular heterocycloalkyl, that is, the aliphatic heterocycle may be morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, Pyridyl, pyrrolidonyl, piperidinyl, oxazolidinonyl, thiazolidinonyl, heteroaryl includes furyl, thiophenyl, pyrrolyl, pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl Monocyclic heteroaryl such as isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, Benzothiazolyl, benzoisothiazolyl, benzooxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, , Quinolyl, isoquinolyl, Tease carbonyl, quinazolinyl, quinolinyl met my match yet, and the like carbonyl quinoxalinyl, carbazolyl, phenanthridine each optionally substituted, aryl, polycyclic heteroaryl such as benzo-dioxide solril.

"Heterocycloalkyl" in the present invention means an alicyclic ring containing oxygen, sulfur or nitrogen in the ring as a hetero atom, and the number of heteroatoms is 1-4, preferably 1-2. Cycloalkyl in heterocycloalkyl is preferably monocycloalkyl or bicycloalkyl, including those in which an aromatic cyclic aryl or heteroaryl is fused.

The synthesis of the heterocyclic compound represented by the formula (1) or pharmaceutically acceptable salts and solvates thereof is not particularly limited, and examples of the synthetic reaction schemes are shown below and are prepared through similar or already known organic reactions .

[Reaction Scheme]

[In the above reaction formula,

R, R ¹ , R ² , o, p and Ar are the same as defined in the above formula (1), and X is halogen.

Hereinafter, the present invention will be described in detail by way of the following examples, but the present invention is not limited to these examples.

[Example 1] Preparation of compound S001

One H - pyrrolo [2,3-b] pyridin-6-amine

(12.3 g, 42.5 mmol) and dimethyl sulfate (4.5 ml, 46.3 mmol) were suspended in anhydrous acetonitrile under a nitrogen atmosphere and 55-60 Lt; 0 > C for 14 hours. The reaction mixture was transferred to a sealed tube and cooled to 0-4 < 0 > C and ammonia solution (7M, 100 ml) was slowly added to methanol. The reaction mixture was stirred at < RTI ID = 0.0 > 50-55 C < / RTI > The solvent of the reaction mixture was distilled off and the residue was extracted with dichloromethane (100 ml) and 10% potassium carbonate aqueous solution (25 ml). The aqueous layer was further extracted three times with dichloromethane (50 ml). The organic layers were collected, washed once with a 10% aqueous solution of potassium carbonate, saturated brine, and once with water, dried over anhydrous magnesium sulfate, filtered and the solvent of the filtrate was distilled off. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 2) to give the title compound as a yellow crystalline solid (2.5 g, yield 44.6%).

N- (1 H - pyrrolo [2,3-b] pyridin-6-yl) - [1,1'-biphenyl] -4-sulfonamide

To a solution of 1 H -pyrrolo [2,3-b] pyridin-6-amine (266 mg, 2 mmol) in pyridine (10 ml) was added [1,1'-biphenyl] Chloride (500 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 2) to give the title compound as a white solid (500 mg, 71.6% yield).

MS (ESI pos ion) m / z: 350 (MH < + >). Calc'd exact mass for C19H15N3O2S: 349.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.45 (br s, 1H), 10.78 (br s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.85 - 7.82 (m, 3H), 7.69 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.43-7.40 (m, 1H), 7.26-7.25 , ≪ / RTI > 1H), 6.32 (dd, J = 3.6 Hz, 1.8 Hz, 1H).

[Example 2] Preparation of compound S002

Preparation of 4'-cyano- [1,1'-biphenyl] -4-sulfonic acid

To a solution of 4-biphenylcarbonitrile (1.56 g, 8.72 mmol) in dichloromethane (30 ml) was added chlorosulfonic acid (1.17 ml, 1.74 mmol) at -14 ° C. The reaction temperature was maintained at -10 ° C, and the mixture was stirred for 1 hour and then at 8-10 ° C for 6 hours. Triethylamine (2.43 ml, 1.74 mmol) was added to the reaction mixture while maintaining the temperature at 12 占 폚 and stirred for 15 minutes. The black solid disappeared and the white solid remained. Water (10 ml) was added to the suspension, stirred for 10 minutes and concentrated. To this residue was added aqueous sodium hydroxide (20 ml, 15%) and concentrated in vacuo to half of the total volume. To the mixture was added concentrated hydrochloric acid until pH = 7 and water was added until the total volume was 20 ml. Saturated brine (20 ml) was added and stirred for 10 min. The resulting solid was collected by filtration, and vacuum dried to obtain 2.5 g. The following reaction was carried out without further purification.

Preparation of 4'-cyano- [1,1'-biphenyl] -4-sulfonyl chloride

(1.5 g, 5.8 mmol) and phosphorus oxychloride (25 ml) was stirred at reflux for 16 hours. An excess of ice water was added to the reaction mixture and the resulting precipitate was extracted with dichloromethane. All the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 8) to give the title compound as a white solid (500 mg, 31.2% yield).

4'-cyano-N- (1 H - pyrrolo [2,3-b] pyridin-6-yl) - [1,1'-biphenyl] -4-sulfonamide

In pyridine (10 ml) 4'- cyano- [1,1'-biphenyl] -4-sulfonyl chloride (70 mg, 0.5 mmol) 1 H dissolved in a solution-pyrrolo [2,3-b] Pyridin-6-amine (140 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 2) to give the title compound (67.8 mg, 67.8% yield) as a white solid. .

MS (ESI pos ion) m / z: 375 (MH < + >). Calc'd exact mass for C20H14N4O2S: 374.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.45 (br s, 1H), 10.84 (br s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.95 - 7.90 (m, 6H), 7.85 (d, J = 8.4 Hz, 1H), 7.26-7.25 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.33 (dd, J = 3.6 Hz, 1.8 Hz, 1H).

[Example 3] Preparation of compound S003

N- (1 H -Pyrrolo [2,3-b] pyridin-6-yl) -2-oxooxazolidin-3-sulfonamide

Chloroethanol (0.67 ml, 0.01 mol) was slowly added at 0 ° C to a mixed solution of chlorosulfonyl isocyanate (0.87 ml, 0.01 mol) dissolved in dichloromethane (100 ml). The reaction mixture was stirred at 0 < 0 > C for 1.5 h and then 1 H -pyrrolo [2,3-b] pyridin- 6- amine (1.33 g, 0.01 mol) and triethylamine (4.2 mmol) in dichloromethane ml, 0.03 mol) was slowly added thereto while keeping the reaction temperature at 5 ° C. The temperature of the reaction mixture was slowly raised to room temperature and stirred for 24 hours. The reaction was concentrated and the residue was washed with a small amount of dichloromethane and filtered to give the title compound (1.3 g, 46% yield) as a white solid.

4'-cyano-N- (1 H -Pyrrolo [2,3-b] pyridin-6-yl) -4-phenyl (piperidinyl)

Acetonitrile (10 ml) to N- (1 H - pyrrolo [2,3-b] pyridin-6-yl) -2-oxo-oxazolidin-3-sulfonamide (0.635 g, 2.25 mmol) and 4- (0.5 g, 2.25 mmol) and diisopropylethylamine (0.29 g, 2.24 mmol) were dissolved in a sealed test tube and sealed. Electromagnetic waves were applied at 110 ° C And reacted for 0.5 hour. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (ethyl acetate: petroleum ether = 2: 3) to give the title compound (0.35 mg, 41% yield).

MS (ESI pos ion) m / z: 382 (MH < + >). Calc'd exact mass for C19H19N5O2S: 381.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.48 (br s, 1H), 10.20 (br s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.31-7.29 (m, 3H), 6.88 (d, J = 7.8 Hz, 1H), 6.38 2.92 (m, 2H), 2.96-2.94 (m, 1H), 1.74-1.72 (m, 2H), 1.54-1.47 (m, 2H).

[Example 4] Preparation of compound S004

Preparation of 1- (4-chlorophenylthio) propan-2-one

Potassium carbonate (19.1 g, 0.138 mol) was added to a mixed solution of 4-chlorobenzeneethiol (10.0 g, 0.069 mol) and 1-chloropropan-2-one (16.6 g, 0.18 mol) in acetone (150 ml) And the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, the inorganic salts were removed by filtration, and the filtrate was collected and the solvent was removed by vacuum distillation. The residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen sulfite solution, dried over anhydrous sodium sulfate, filtered, and the filtrate solvent was removed by vacuum distillation. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 20) to give the title compound (7.32 g, 52.8% yield).

5-chloro-3-methylbenzo [ b ] Thiophene

A mixture of 1- (4-chlorophenylthio) propan-2-one (7.32 g, 0.069 mol) and polyphosphoric acid (7.32 g) was added to chlorobenzene (73.2 ml) and refluxed for 19 hours. The reaction mixture was filtered and the filtrate was removed by vacuum distillation to give the title compound (3.0 g, 45% yield). The following reaction was carried out without further purification.

Potassium 5-chloro-3-methylbenzo [ b ] Thiophene-2-sulfonate

A mixture of 5-chloro-3-methylbenzo [ b ] thiophene (2.0 g, 0.011 mol), acetic anhydride (3.33 ml) and concentrated sulfuric acid (0.64 ml) was added to ethyl acetate (28 ml) Lt; / RTI > The reaction mixture was diluted with ethyl acetate and washed with a small amount of water. All the organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved again in ethyl acetate and a solution of potassium acetate (1.11 g) in ethanol (8.4 ml) was added to form a potassium salt. When some precipitate was formed, a further solution of potassium acetate (1.11 g) in ethanol (8.4 ml) was added and washed by addition of ether (555 ml). All precipitates were collected by filtration and vacuum dried to give the title compound (3.4 g, 100% yield).

5-chloro-3-methylbenzo [ b ] Thiophene-2-sulfonyl chloride

A suspension of potassium 5-chloro-3-methylbenzo [ b ] thiophene-2-sulfonate (3.4 g, 0.011 mol) in phosphorus oxychloride (150 ml) was stirred at 60 ° C for 12 hours. The excess phosphoryl chloride was removed by vacuum distillation and the residue was purified by silica gel chromatography (dichloromethane) to give the title compound (1.7 g, 50.3% yield).

5-Chloro-3-methyl-N- (1 H - pyrrolo [2,3-b] pyridin-6-yl) benzo [b] thiophene-

Pyridin-5-chloro-in (10 ml) -3- methyl-benzo [b] thiophene-2-sulfonyl chloride in a mixed solution was added (1.5 g, 5.3 mmol) 1 H - pyrrolo [2,3-b] Pyridine-6-amine (0.91 g, 6.8 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 8) to obtain the title compound (270 mg, 13.4% yield) as a white solid. .

MS (ESI pos ion) m / z: 378 (MH < + >). Calc'd exact mass for C16H12ClN3O2S2: 377.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.43 (br s, 1H), 11.21 (br s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.26-7.25 , 6.34-6.33 (m, 1H), 2.59 (s, 3H).

[Example 5] Preparation of compound S005

Preparation of sodium 5-chloronaphthalene-2-sulfonate

5-Aminonaphthalene-2-sulfonic acid (6 g, 0.027 mol) was dissolved in water (15 ml) at which sodium hydroxide (1.2 g, 0.03 mol) was added. The reaction mixture was acidified by the addition of concentrated hydrochloric acid (15 ml) and diazotized by addition of an aqueous solution of sodium nitrite (2.1 g, 0.03 mol) in water (3 ml) at 0 ° C. To the other flask was added a solution prepared by dissolving copper chloride (3.0 g) in hydrochloric acid (15 ml) while taking care of nitrogen gas evolution. The reaction mixture was stirred for 24 hours. A small amount of insoluble material was filtered off and the filtrate was made into sodium sulfonate form using salt (5 g). The resulting solid was collected by filtration and dried in vacuo at 50 [deg.] C to give the title compound (15 g).

Preparation of 5-chloronaphthalene-2-sulfonyl chloride

A mixture of phosphorus oxychloride (20 ml) and sodium 5-chloronaphthalene-2-sulfonate (5 g) was stirred at 80 ° C for 4 hours. The excess phosphoryl chloride was removed by vacuum distillation and the residue was diluted with dichloromethane (100 ml), filtered through silica gel and the filtrate solvent was distilled in vacuo to give the title compound as a brown solid (1.6 g). The following reaction was carried out without further purification.

5-Chloro-N- (1 H - pyrrolo [2,3-b] pyridin-6-yl) -naphthalene-2-sulfonamide

To a solution of 5-chloronaphthalene-2-sulfonyl chloride in pyridine (10 ml) was added 1 H -pyrrolo [2,3-b] pyridine-6-amine (1.0 g) Respectively. The reaction was terminated by TLC and the reaction mixture was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 1) to give the title compound (220 mg, overall 7.0% yield).

MS (ESI pos ion) m / z: 358 (MH < + >). Calc'd exact mass for C17H12ClN3O2S: 357.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.42 (br s, 1H), 10.94 (br s, 1H), 8.75 (d, J = 1.2 Hz, 1H), 8.31 (d, J = 9.0 Hz, (D, J = 8.4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.14 1H), 7.65-7.63 (m, 1H), 7.24-7.23 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.30-6.

[Example 6] Preparation of compound S006

2- (1 H - pyrrolo [2,3-b] pyridin-6-yl) isoindoline-1,3-dione

Phthalic anhydride (0.90 g, 6.1 mmol) was added to a solution of 1 H -pyrrolo [2,3-b] pyridin-6-amine (0.8 g, 6.0 mmol) in glacial acetic acid (10 ml) Lt; / RTI > The solvent of the reaction was removed by vacuum distillation and the residue was neutralized by slow addition of aqueous sodium bicarbonate solution until the bubbling ceased. The resulting solid was collected by filtration, washed with water and dried in vacuo to give the title compound (1.4 g, 78.7% yield).

2- (1-methyl-1 H - pyrrolo [2,3-b] pyridin-6-yl) isoindoline-1,3-dione

To a solution of 2- (1 H- pyrrolo [2,3-b] pyridin-6-yl) isoindoline-1,3-dione (1.4 g, 5.3 mmol) in dimethylformamide (30 ml) Sodium hydride (60% over mineral oil, 0.26 g, 6.5 mmol) was added slowly. The mixture was stirred for 30 minutes and then a solution of iodomethane (1.51 g, 10.64 mmol) in dimethylformamide (10 ml) was added. After stirring at room temperature for 3 hours, sodium hydride (60% over mineral oil, 0.13 g, 3.3 mmol) and iodomethane (0.75 g, 5.3 mmol) were further added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. All the organic matter was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 5) to give the title compound (0.23 g, 15.6% yield).

1-methyl-1 H - pyrrolo [2,3-b] pyridin-6-amine

Absolute ethanol 2-on (25 ml) - a 1, 3-dione (0.23 g, 0.83 mmol) in turn (1-methyl -1 H-pyrrolo [2,3-b] pyridin-6-yl) was added isopropyl Was added hydrazine hydrate (0.20 g, 4.00 mmol), and the mixture was stirred under reflux for 3 hours. The solvent of the reaction mixture was removed by vacuum distillation, the residue was dissolved in water and extracted twice with dichloromethane. All organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound as a white solid (0.12 g, 98.4% yield).

4-Cyano-N- (1-methyl-1 H - pyrrolo [2,3-b] pyridine-b-yl) biphenyl-4-sulfonamide

In pyridine (15 ml) 4'- cyano- [1,1'-biphenyl] -4-sulfonyl chloride (0.28 g, 1.01 mmol) dissolved in the here in 1-methyl -1 H-pyrrolo [2, 3-b] pyridin-6-amine (0.12 g, 0.82 mmol), which was stirred for 3 hours at room temperature. The reaction was terminated by TLC and the reaction mixture was concentrated. The residue was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1: 5) to give the title compound (0.20 g, 63.5% yield).

MS (ESI pos ion) m / z: 389 (MH < + >). Calc'd exact mass for C21H16N4O2S: 388.

^{1 H-NMR (600MHz, DMSO} -d 6): 10.99 (br s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.96 - 7.91 (m, 6H), 7.83 (d, J = 8.4 Hz , 7.27 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.32 (d, J = 3.0 Hz, 1H), 3.70 (s, 3H).

[Example 7] Preparation of compound S007

4-chloro-1 H - pyrrolo [2,3-b] pyridine N-oxide The preparation of methachlorobenzoic acid salt

Ethyl acetate in the meta (150ml) - chloroperoxybenzoic acid (11.36 g, 65.8 mmol) is added and at 0 ℃ here 4-chloro -1 H - pyrrolo [2,3-b] pyridine (5.0 g, 32.9 mmol ) And the mixture was stirred at 0 ° C for 2 hours. The resulting solid was collected by filtration and then vacuum dried to give the title compound (10.6 g, 100% yield).

4-chloro-1 H - pyrrolo [2,3-b] pyridin-6-amine

Under nitrogen atmosphere with acetonitrile (10 ml) with 4-chloro -1 H - pyrrolo [2,3-b] pyridine-N- oxide, meta-chloro benzoic acid (1.62 g, 5.0 mmol) and dimethyl sulfate (0.69 g, 5.5 mmol) was stirred at 55 to 60 ° C for 14 hours. The reaction mixture was transferred to a closed reactor and cooled to 0 to 4 ° C, followed by slow addition of ammonia solution (25 ml, 14 M) in methanol. The reaction mixture was sealed and reacted at 50 ° C for 4 hours with an electromagnetic wave. The reaction was cooled to room temperature, the solvent was removed by vacuum distillation and the residue was layered between dichloromethane (10 ml) and 10% aqueous sodium carbonate solution (2.5 ml). The aqueous layer was extracted three times with dichloromethane (50 ml), and the organic layers were combined and washed with 10% aqueous sodium carbonate solution (10 ml), saturated brine (10 ml), and water. All organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Purification of the residue on silica gel chromatograph gave the title compound (0.57 g, 68% yield).

4-methyl-1 H - pyrrolo [2,3-b] pyridin-6-amine

4-dioxane H -1 to (7 ml) - pyrrolo [2,3-b] pyridin-6-amine was added (100 mg, 0.6 mmol), and where methyl boronic acid (72 mg, 1.2 mmol) in , Tetrakis triphenylphosphine palladium (0) (10 mg, 0.009 mmol), potassium carbonate (248 mg, 1.8 mmol) and water (1.8 ml). The reaction mixture was reacted at 160 캜 for 2 hours under an atmosphere of nitrogen by injecting electromagnetic waves. The catalyst of the mixture was filtered off and the filtrate was layered between dichloromethane (40 ml) and water (20 ml). All the organic layers were dried over anhydrous magnesium sulfate, and the filtrate was concentrated after filtration. The residue was purified by HPLC to give the title compound (23 mg, 26% yield).

4'-cyano-N- (4-methyl-1 H - pyrrolo [2,3-b] pyridine-b-yl) - [1,1'-biphenyl] -4-sulfonamide

4-sulfonyl chloride (0.208 g, 0.75 mmol) was dissolved in pyridine (10 ml), and 4-methyl- 1H -pyrrolo [ 3-b] pyridin-6-amine (0.11 g, 0.75 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by TLC and the reaction mixture was concentrated and the residue was purified by silica gel chromatography to obtain the title compound (0.1 g, 33.0% yield).

MS (ESI pos ion) m / z: 389 (MH < + >). Calc'd exact mass for C21H16N4O2S: 388.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.39 (br s, 1H), 10.76 (br s, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.95 - 7.89 (m, 6H), 7.20 (br s, 1 H), 6.70 (s, 1 H), 6.37 (br s, 1 H), 2.41 (s, 3 H).

[Example 8] Preparation of compound S008

2-methyl-1 H - pyrrolo [2,3-b] pyridine N-oxide

Dichloromethane (20ml) in 2-methyl -1 H - pyrrolo [2,3-b] pyridine (1.50 g, 11.35 mmol) was added and where the meta of dichloromethane (20ml) at 0 ℃ - chloroperoxybenzoic acid (2.95 g, 17.09 mmol) in dichloromethane (20 ml) was added to the solution, and the mixture was stirred at room temperature for 2.5 hours. Then, a solution of meta-chloroperoxybenzoic acid Stir for 24 hours. Insoluble solids in the reaction mixture were filtered off and the filtrate collected and concentrated in vacuo. This residue was subjected to the next reaction without further purification.

2-methyl-1 H - pyrrolo [2,3-b] pyridin-6-amine

Dimethyl sulfate (2 ml) was added to a suspension of 2-methyl- 1H -pyrrolo [2,3-b] pyridine N-oxide in anhydrous acetonitrile (50 ml) under a nitrogen atmosphere, Stir for 24 hours. The reaction mixture was cooled to room temperature and ammonia solution (20 ml, 14 M) in methanol was added slowly. The reaction mixture was sealed and reacted at 65 ° C for 8 hours with an electromagnetic wave. The solvent of the reaction mixture was removed by vacuum distillation, and the residue was layered between ethyl acetate and 10% aqueous sodium carbonate solution. The organic layers were combined and washed with water and saturated brine. All the organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (0.12 g).

4'- Cyano -N- (2- methyl -One H - Pyrrolo [2,3-b] pyridine -b-yl) -biphenyl-4- Sulfonamide  Produce

Pyridin-4'-cyano-a (15 ml) - [1,1'- biphenyl] -4-sulfonyl chloride (0.31 g, 1.12 mmol) was added and 2-methyl -1 H here-pyrrolo [2 , 3-b] pyridin-6-amine (0.13 g, 0.88 mmol) was added and stirred at room temperature for 24 hours. The reaction was terminated by TLC and the reaction mixture was concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.1 g).

MS (ESI pos ion) m / z: 389 (MH < + >). Calc'd exact mass for C21H16N4O2S: 388.

^{1 H-NMR (600MHz, DMSO} -d 6): 11.28 (br s, 1H), 10.71 (br s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.95 - 7.89 (m, 6H), 7.68 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.01 (s, 1H), 2.30 (s, 3H).

The pharmacological assay method for evaluating the activity of 11β-HSD1 as an inhibitor by using the heterocyclic compound according to the present invention is not limited. However, the effect of inhibiting the cortisol formation of the heterocyclic compounds according to the embodiment of the present invention Respectively.

This pharmacological analysis was also carried out with the heterocyclic compound according to the present invention or a pharmacologically acceptable salt thereof.

[Example 9] Inhibition of cortisol production of 11? -HSD1

Human liver microsomes with 11β-HSD1 were used to inhibit cortisol formation of the compounds.

Human liver microsomes (Invitrogen / Gibco) in which human 11? -HSD1 was present were diluted in MES buffer (20 mM MES (2- (N-morpholino) ethanesulfonic acid), 5 mM EDTA (Ethylenediaminetetraacetic acid) Subsequently, 200 uM NADPH (Nicotinamide adenine dinucleotide phosphate) and 160 nM cortisone were added to 20 ug microsome. In order to confirm the inhibitory effect of the compounds on cortisol formation, the respective compounds were treated together at the concentration. After incubation for 2 hours at room temperature, the amount of cortisol produced was measured using the manufacturer's anti-cortisol antibody (Cisbio).

  compound IC ₅₀ (uM) S001 8.166 S002  0.4544 S003 5.138 S004 0.2284 S005 0.9391 S006  26.70 S007 18.70 S008 28.91

[Example 10] Inhibition of cortisol production of 11? -HSD1

 Purified 11 [beta] -HSDl was used to confirm the inhibitory effect of the compounds on cortisol formation.

Purified human 11β-HSD1 protein (Origene) was diluted in MES buffer (20 mM MES, 5 mM EDTA, pH 6.0) and then 10 μl of 11β-HSD1 protein was added with 500 μM NADPH and 200 nM cortisone. In order to confirm the inhibitory effect of the compounds on cortisol formation, the respective compounds were treated together at the concentration. After incubation for 2 hours at room temperature, the amount of cortisol produced was measured using the manufacturer's anti-cortisol antibody (Cisbio).

  compound IC ₅₀ (uM) S001 3.699 S002  0.8213 S003 2.396 S004 0.3396 S005 1.179 S006 2.246 S007 2.198 S008 3.021

The heterocyclic compounds of the present invention or pharmaceutically acceptable salts and solvates thereof inhibit the ability of ll [beta] -HSDl to produce cortisol. Human liver microsomes in the presence of ll [beta] -HSDl convert cortisone to cortisol in the presence of NADPH, but the heterocyclic compounds of the invention inhibit this cortisol production. As shown in Table 1, it can be confirmed that the IC50 value inhibits the function of 11? -HSD1 in the order of S004, S002, and S005 when the concentration is below 1 uM. In addition, it has been confirmed that the cotisol to cotisol conversion of the purified 11? -HSD1 protein is also inhibited by the compounds of the present invention. As shown in Table 2, the functions of 11? -HSD1 are inhibited in the order of S004, S002 and S005.

[Example 11] Evaluation of cytotoxicity of the heterocyclic compound according to the present invention

In order to evaluate the cytotoxicity of the compounds of this invention and cultured in the first day of Human keratinocyte (HaCaT) a 96 well plate in 10% FBS (Fetal bovine serum) with DMEM (Dulbecco's modified Eagle's medium ) contained in 5x10 ³ Number of cell culture medium . After 24 hours, the cells were treated with S002, S004, and S005 compounds (0-50 uM) and cultured for 12 hours in an incubator (37 ° C, 5% CO ₂ ). To confirm the number of living cells, 10 μl of MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, Sigma) was added to the medium. After culturing at 37 ° C for 4 hours, the medium was removed, and then 100 ul of DMSO (Dimethyl sulfoxide) was added thereto to confirm that it was violet. Then, the wavelength was measured at 570 nm on a spectroscope.

As shown in FIG. 3 to FIG. 5, it was confirmed that there was no toxicity of the compound in human keratinocyte (HaCaT) cells. That is, when the present compound is toxic to a cell, the cell is killed and the MTT measurement value should be decreased. However, as shown in FIG. 3, FIG. 4 and FIG. 5, These results indicate that the compound of the present invention has no toxicity to human keratinocytes and is harmless to the skin when used in humans.

[Example 12]

Wound healing experiments were performed using 7-week-old female BALB / C mice. Each group consisted of 8 animals. The skin of the incision area was completely removed and sterilized with alcohol and povidone. The skin was removed in a size of 1cm in width and 1cm in the area where hair was removed. In order to prevent the skin around the incision from spreading, a thread was used at the corner to connect the skin to the surrounding skin. Control group 1% DMSO and treated group were pf-915275 (N- (6-Amino-2-pyridinyl) -4'-cyano- [1,1'-biphenyl] -4- sulfonamide) is used. Compounds S002 and S005 of the present invention were used to measure the presence or absence of wound healing effects. The concentration of each sample was set at 1 mM. The material was applied 20 [mu] l each, and then applied with a tegadum (manufacturer: 3M). On top of that, we used the filter paper to draw the exact size of the incision. The drug was applied once every two days while replacing the tegadum. The value of wound healing recovery rate of each sample was compared with that of the control group, and the value is shown in Table 3 below.

Wound healing times bokyul (in%) Control group Pf-915275 S002 S005 Day 0 0 0 0 0 Day 2 19.1 14.2 17.8 31.1 Day 5 46.3 54.8 53.5 55.0 Day 7 61.2 69.6 69.8 74.3

As shown in Table 3, the heterocyclic compounds S002 and S005 of the present invention had higher wound healing recovery ability than the control group, and showed almost the same or higher wound healing recovery ability than the treatment group Pf-915275, -HSD1 function and inhibit the conversion of cotisone to cotisol, showing high wound healing or resilience without cytotoxicity.

The pharmaceutical composition comprising the heterocyclic compound represented by the general formula (1) according to the present invention or a pharmaceutically acceptable salt and solvate thereof is useful for the treatment and / or prophylaxis of psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczematous dermatitis, , Rheumatoid arthritis, arthritis, rheumatoid arthritis, spondylitis, systemic sclerosis, dermatomyositis, dermatomyositis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, Can be used for the treatment or prevention of inflammatory diseases including multiple myositis, inflammatory muscle lesions, acquired immune deficiency syndrome, leprosy, triceps, inflammatory bowel disease, stressful disease or graft rejection.

The pharmaceutical composition comprising the heterocyclic compound represented by the formula (1) or the pharmaceutically acceptable salts and solvates thereof according to the present invention is useful for the treatment and / or prophylaxis of psoriatic atopic dermatitis, contact dermatitis, eczematous dermatitis, , Seborrhoeic dermatitis, herpes dermatitis, squamous cellulitis, scleroderma, dermatomyositis.

The heterocyclic compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to the present invention may also be useful as a cosmetic composition containing the same as an active ingredient.

For use as a pharmaceutical composition, the salt of the heterocycle compound of formula (I) will be a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts of the compounds of the invention include, for example, pharmaceutically acceptable acids such as hydrochloric, sulfuric, methanesulfonic, fumaric, maleic, succinic, acetic, benzoic, citric, Acid addition salts that may be formed by mixing a solution of a compound of the present invention with a solution of an acid or phosphoric acid. In addition, when the compounds of the present invention have an acidic moiety, such as carboxy, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; And salts formed with suitable organic ligands, such as quaternary ammonium salts.

In the present invention, the pharmaceutical composition may contain 0.001 to 90% by weight, more preferably 0.001 to 50% by weight, of the heterocyclic compound of formula (I) according to the present invention as an active ingredient.

The present invention includes within its scope solvates of the heterocyclic compounds of formula (1). Such solvates may be dissolved in conventional organic solvents such as hydrocarbon solvents such as benzene or toluene; Chlorinated solvents such as chloroform or dichloromethane; Alcoholic solvents such as methanol, ethanol or isopropanol; Ethereal solvents such as diethyl ether or tetrahydrofuran; Or an ester solvent such as ethyl acetate.

The pharmaceutical compositions comprising the heterocyclic compounds of formula (I) or pharmaceutically acceptable salts and solvates thereof of the present invention can be administered by any suitable route, for example, (for example in the form of tablets or capsules) Orally; Parenteral administration (e. G., Intravenous administration); (E.g., in the treatment of inflammatory or obstructive airways disease); (E.g., in the treatment of allergic rhinitis); (E.g., in the treatment of atopic dermatitis); Or in the rectum (for example, in the treatment of inflammatory bowel disease).

The present invention also provides a pharmaceutical composition comprising a heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier. The composition may contain co-therapeutic agents, for example, anti-inflammatory, bronchodilatory or antihistamine drugs. Such compositions may be prepared using conventional diluents or excipients and techniques known in the art of pharmacy. Thus, oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, for example patches. The composition for inhalation may constitute an aerosol or other atomizable or dry powder formulation.

Claims (8)

A heterocyclic compound represented by the following formula (1) or a pharmaceutically acceptable salt and solvate thereof:
[Chemical Formula 1]

[In the above formula (1)
Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;
R ¹ or R ² are independently from each other hydrogen, amino, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, or (C 1 -C 7) alkylamino;
R is selected from the group consisting of hydrogen, halogen, cyano, amino, (CrC7) alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, (C1-C7) alkoxy or (C6-C12) aryloxy;
Ar is (C6-C12) arylene, (C3-C7) heterocycloalkylene or (C3-C12) heteroarylene;
Wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of said R ¹ or R ² and said alkyl, cycloalkyl, alkoxy and aryloxy of R are independently of each other selected from the group consisting of cyano, halogen, ) Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;
o or p independently of one another is an integer selected from 1 to 2.] The method according to claim 1,
Lt; RTI ID = 0.0 > Ar < / RTI > is selected from the following structures: or a pharmaceutically acceptable salt and solvate thereof.

[In the above formula,
R ²¹ to R ²⁷ independently from each other are hydrogen, halogen, hydroxy, carboxy, cyano or (C 1 -C 7) alkyl;
A is NR ^12, and O or S, R ¹² is hydrogen or (C1-C7) alkyl;
l is an integer selected from 1 to 4;
m is an integer selected from 1 to 3;
and n is an integer selected from 1 to 6.] The method according to claim 1,
Wherein the formula 1 is a heterocyclic compound represented by the following formulas 2 to 4, or a pharmaceutically acceptable salt or solvate thereof.
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[In the formula (2)
Z is NR < ¹¹ >, O or S, and R < ¹¹ > is hydrogen or (C1-C7) alkyl;
A is NR ^21, and O or S, R ²¹ is hydrogen or (C1-C7) alkyl;
R ¹ or R ² are independently from each other hydrogen, amino, hydroxy, halogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy, or (C 1 -C 7) alkylamino;
R ⁷ or R ³¹ is hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7) heterocycloalkyl, (C 6 -C 12) ) Heteroaryl, (C1-C7) alkoxy or (C6-C12) aryloxy;
(C ¹ -C ⁷ ) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy and aryloxy of the R ¹ or R ² and the R ⁷ is independently selected from the group consisting of cyano, halogen, Alkyl, (C6-C12) aryl, (C3-C12) heteroaryl, 5 to 7 membered heterocycloalkyl;
o or p independently of one another is an integer selected from 1 to 2.] The method of claim 3,
In formulas (2) to (5)
Z is a NR ^11, R ¹¹ is hydrogen or (C1-C7) alkyl;
A is O or S;
R ¹ or R ² are, independently of each other, hydrogen, amino, hydroxy, halogen or (C 1 -C 7) alkyl;
R ⁷ or R ³¹ is independently selected from the group consisting of hydrogen, halogen, cyano, amino, (C 1 -C 7) alkyl, (C 6 -C 12) aryl, Acceptable salts and solvates. 5. The method of claim 4,
(2) to (5) are heterocyclic compounds selected from the following structures or pharmaceutically acceptable salts and solvates thereof

A pharmaceutical composition for the treatment or prevention of inflammatory diseases, comprising a heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or solvate thereof. The method according to claim 6,
Inflammatory diseases include psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczematous dermatitis, dermatitis dermatitis, dermatitis dermatitis, herpes dermatitis, herpes dermatitis, squamous cellulitis, scleroderma, gingivitis, pemphigus, vesicular epidermolysis, , Allergic conjunctivitis, degenerative or inflammatory eye diseases, arthritis, rheumatoid arthritis, spondylitis, systemic sclerosis, dermatomyositis, multiple myositis, inflammatory muscle lesions, acquired immunodeficiency syndrome, lupus, tricepsychosis, inflammatory bowel disease, Or a pharmaceutically acceptable salt thereof. A cosmetic composition comprising a heterocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt and solvate thereof.

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