Deuterated N-phenylindazole amide compound, pharmaceutical composition and use thereof

Abstract

The present invention discloses a compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, a pharmaceutical composition and use. The compound of formula I provided by the present invention has a good therapeutic effect on diseases mediated by glucocorticoid receptor disorders, such as asthma, chronic obstructive pulmonary disease, etc.

Description

Technical Field

[0001] The present invention belongs to the field of innovative pharmaceutical chemistry and relates to an N-phenylindazole indazole amide compound, a pharmaceutical composition and an application thereof. Background Art

[0002] Glucocorticoids bind to the corresponding glucocorticoid receptors (GR), causing upstream and / or downstream gene transcription, regulating immune responses and energy metabolism. The regulatory effect of GR on "energy metabolism" is the cause of the side effects of traditional glucocorticoid receptor agonists (steroids), limiting the long-term use of this type of agonists. The new selective nonsteroidal glucocorticoid receptor modulators (SGRMs) have strong anti-inflammatory activity and reduce the side effects of energy metabolism regulation, which is significantly better than the earlier reported steroidal glucocorticoids and nonsteroidal glucocorticoids. AZD-5423 is a new selective glucocorticoid receptor modulator, which is currently in Phase II clinical research.

[0003]

[0004] Deuterated drugs refer to drugs in which some hydrogen atoms in the drug molecule are replaced with deuterium. Since the shape and volume of deuterium in the drug molecule are similar to those of hydrogen, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the CD bond is more stable than the CH bond, the CD bond of deuterated drugs is less likely to break during the chemical reaction, and its half-life will be extended. Since 2000, the deuterated strategy has been widely used in drug research. Summary of the invention

[0005] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, the structure of which is as follows:

[0006]

[0007] wherein R1, R2, R3 or R4 are independently selected from hydrogen or deuterium,

[0008] At the same time, at least one of R1, R2, R3 or R4 is deuterium.

[0009] In some embodiments, the compound is represented by any of the following structural formulas:

[0010]

[0011] The present invention provides a use of a compound as shown in formula I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a glucocorticoid receptor modulator.

[0012] The present invention provides use of a compound shown in I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and / or preventing a disease mediated by a glucocorticoid receptor.

[0013] The present invention provides use of a compound as shown in I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and / or preventing inflammatory diseases.

[0014] The present invention provides use of a compound as shown in I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and / or preventing asthma.

[0015] The present invention provides use of a compound as shown in I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and / or preventing chronic obstructive pulmonary disease.

[0016] The present invention provides a pharmaceutical composition, which contains a compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

[0017] In the pharmaceutical composition, the compound as shown in Formula I, or its pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate is used in a therapeutically effective amount.

[0018] The present invention provides use of a pharmaceutical composition in preparing a glucocorticoid receptor modulator.

[0019] The present invention provides use of a pharmaceutical composition in preparing a drug for treating and / or preventing a disease mediated by a glucocorticoid receptor.

[0020] The present invention provides use of a pharmaceutical composition in preparing a medicament for treating and / or preventing inflammatory diseases.

[0021] The present invention provides use of a pharmaceutical composition in preparing a medicine for treating and / or preventing asthma.

[0022] The present invention provides use of a pharmaceutical composition in preparing a medicament for treating and / or preventing chronic obstructive pulmonary disease.

[0023] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0024] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0025] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0026] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid (forming sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0027] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0028] The term "isomers" refers to compounds that have the same chemical formula but different arrangements of the atoms.

[0029] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0030] Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled with radioisotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0031] In addition to the form of salts, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I) is a prodrug within the scope and spirit of the present invention. For example, a carboxyl-containing compound can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally, because hydrolysis occurs mainly under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.

[0032] The positive and progressive effects of the present invention are:

[0033] (1) The compound of the present invention is a highly effective and selective non-steroidal glucocorticoid receptor modulator.

[0034] (2) The compounds of the present invention have good pharmacokinetic properties, significantly improved oral bioavailability and prolonged half-life.

[0035] (3) The compounds of the present invention have good therapeutic effects on asthma and chronic obstructive pulmonary disease. DETAILED DESCRIPTION

[0036] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0037] Example 1: Synthesis of Compound I-1

[0038]

[0039] Step 1: Synthesis of compound b

[0040] Compound a (3.8 g, 20 mmol) was dissolved in DCM (40 mL), CDI (4.9 g, 30 mmol) and N, O-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol) were added to the above solution at 0 ° C, and the reaction was carried out at 0 ° C for 30 min, then the temperature was raised to 15 ° C and the reaction was carried out for 16 h. After the reaction was completed, DCM was added to dilute the reaction solution, washed with 1M dilute hydrochloric acid, 10% sodium bicarbonate solution, saturated brine, filtered and concentrated. The reaction residue was dissolved in THF (20 mL), nitrogen was protected, the reaction solution was cooled to 10-15 ° C, and a tetrahydrofuran solution of isopropyl magnesium chloride (2M, 5 mL, 10 mmol) was slowly added dropwise. After the addition was completed, a tetrahydrofuran solution of compound e (1M, 20 mL, 20 mmol) was slowly added dropwise to the above solution. The temperature was slowly raised to 20°C, 20% acetic acid aqueous solution was added to the reaction solution, and ethyl acetate was used for extraction (20 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound b. The product was slurried with n-hexane and methyl tert-butyl ether, filtered, and the filter cake was collected and dried in vacuo to obtain compound b (4.7 g, 83%). MS (EsI, m / z): 283 (M + +1).

[0041] Step 3: Synthesis of compound c

[0042] Compound b (4.7 g, 16.7 mmol) was dissolved in toluene, isopropanol (10 g, 167 mmol) and aluminum isopropoxide (700 mg, 3.4 mmol) were added to the above solution, the reaction solution temperature was raised to 50°C, and the reaction was stirred for 15 h. After the reaction was completed, it was cooled to room temperature, 1M HCl and water were added to the reaction solution, and ethyl acetate was extracted (20 mL×3), the organic phases were combined, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound c (2.0 g, 66%). MS (ESI, m / z): 185 (M + +1).

[0043] Step 3: Synthesis of compound d

[0044] A suspension of raw material c (1.84 g, 10 mmol), N,N-dimethylaminoglycine (515 mg, 5 mmol), CuI (57 mg, 0.3 mmol) and CsCO3 (9.8 g, 30 mmol) in butyronitrile (40 mL) was placed in a sealed tube, heated to 110°C and stirred for 30 min. A solution of compound f (3.4 g, 10 mmol) in butyronitrile (4 mL) was added to the above suspension, sealed, and reacted at 110°C for 20 h. After the reaction was completed, it was cooled to room temperature, water was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound d (1.9 g, 50%). MS (ESI, m / z): 395 (M + +1).

[0045] Step: Synthesis of Compound I-1

[0046] Compound d (395 mg, 1 mmol) and g (69 μL, 1 mmol) were dissolved in anhydrous DCM (3 mL), HATU (382 mg, 1.5 mmol) and DIPEA (0.6 mL, 3 mmol) were added to the above solution, and stirred at room temperature for 2.5 h. After the reaction was completed, water was added to the reaction solution, and DCM was extracted (5 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound I-1 (319 mg, 65%). 1 H NMR (500 MHz, DMSO-d6) δ 7.67(d, J=1.9Hz, 1H), 7.61(s, 1H), 7.60-7.53(m, 2H), 7.46-7.37(m, 3H), 7 .30 (t, J=7.8Hz, 1H), 7.14 (dq, J=7.9, 1.1Hz, 1H), 7.07 (dd, J=8.5, 1.9Hz, 1 H), 7.00 (q, J=1.1Hz, 1H), 6.90-6.79 (m, 2H), 5.35 (dt, J=4.7, 0.9Hz, 1H), 4 .40 (dqd, J=8.6, 6.3, 4.9Hz, 1H), 1.29 (d, J=6.2Hz, 3H). MS (ESI, m / z): 491 (M + 1).

[0047] Example 2: Synthesis of Compound I-2

[0048]

[0049] The synthesis of compound 1 was as in Example 1, except that raw material e was replaced by That's it.

[0050] Step 1: Synthesis of compound 2

[0051] Potassium hydroxide (105.5 mg, 1.88 mmol) and iodine (239 mg, 0.94 mmol) were added to a solution of compound 1 (229 mg, 0.47 mmol) in N, N-dimethylformamide (15 mL), and the mixture was reacted at room temperature for 3 hours. The reaction was complete after monitoring by TLC. A saturated sodium sulfite solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL*2), washed with water (20 mL*2), washed with saturated salt (20 mL), dried over anhydrous sodium sulfate, and separated and purified by column chromatography to obtain iodinated compound 2 (135 mg, 47%). MS (ESI, m / z): 614 (M + +1).

[0052] Step 2: Synthesis of Compound I-1

[0053] Sodium acetate (49 mg, 0.36 mmol) was added to a deuterated acetic acid solution (4 mL) of compound 2 (110 mg, 0.18 mmol) and the mixture was added dropwise over 2 hours. The mixture was reacted at room temperature for 24 hours. The reaction was complete when detected by TLC. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound I-1 (31 mg, 35%). 1 H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J=1.9Hz, 1H), 7.60-7.53 (m, 2H), 7.46-7.37 (m, 3H), 7.30 (t, J=7.8 Hz, 1H), 7.14 (dq, J=7.9, 1.1Hz, 1H), 7.07 (dd, J=8.5, 1.9Hz, 1H), 7.00 (q, J =1.1Hz, 1H), 6.90-6.79 (m, 2H), 5.35 (dt, J = 4.7, 0.9Hz, 1H), 4.40 (dqd, J = 8 .6, 6.3, 4.9Hz, 1H), 3.77 (s, 3H), 1.29 (d, J=6.2Hz, 3H). MS (ESI, m / z): 489 (M + +1).

[0054] Example 3: Synthesis of Compound I-3

[0055]

[0056] The synthesis is as shown in Example 2, except that the raw material compound 1 is replaced by compound I-1. 1H NMR (500 MHz, DMSO-d6) δ 7.67(d, J=1.9Hz, 1H), 7.60-7.53(m, 2H), 7.46-7.37(m, 3H), 7.30(t, J= 7.8Hz, 1H), 7.14 (dq, J=7.9, 1.1Hz, 1H), 7.07 (dd, J=8.5, 1.9Hz, 1H), 7.0 0 (q, J=1.1Hz, 1H), 6.90-6.79 (m, 2H), 5.35 (dt, J=4.7, 0.9Hz, 1H), 4.40 (dqd, J=8.6, 6.3, 4.9Hz, 1H), 1.29 (d, J=6.2Hz, 3H). MS (ESI, m / z): 492 (M + +1).

[0057] Example 4: Glucocorticoid receptor affinity detection test

[0058] The binding of the test compound to the glucocorticoid receptor was detected by fluorescence polarization (FP) technology based on a commercial kit from Panvera / Invitrogen (article number P2893). The specific operation steps refer to the kit instructions and the experimental method disclosed in WO2008 / 076048. The DMSO solution (1 μL) of the test compound and the DMSO solution (1 μL) of the control were added to a black polystyrene 384-well plate. The 0% control was 100% DMSO, and the 100% control was 10 μM dexamethasone. The background solution (8 μL; assay buffer 10×, stabilizing peptide, DTT, and ice-cold MQ water) was added to the background well. GS Red solution (7 μL; assay buffer 10×, stabilizing peptide, DTT, GS Red, and ice-cold water) was added to all wells except the background well. GR solution (7 μL; assay buffer 10×, stabilizing peptide, DTT, GR, and ice-cold water) was added to all wells. The plate was sealed and incubated at room temperature in the dark for 2 hours. The plate was read in an Analyst plate reader (excitation wavelength 530 nm, emission wavelength 590 nm, and dichroic mirror wavelength 561 nm). IC was calculated using XLfit model 205. 50 value.

[0059] Table 1 Binding ability of the tested compounds to glucocorticoid receptor

[0060] Compound Name <![CDATA[GRhuFL_FP_v2 average IC 50 (nM)]]> I-1 1.7 I-2 1.6 I-3 1.62 AZD-5423 4.2

[0061] As shown in Table 1, compounds I-1 to I-3 have better binding abilities to glucocorticoid receptor than the positive control AZD-5423.

[0062] Example 5: Cellular pharmacodynamics testing

[0063] Cellular transrepression assay (TR): Human bronchial lung cancer cells ChaGo K1 (ATCC: HTB168) were transfected with TPA response element (TRE)-LacZ construct (5×trel-LacZ). ChaGo K1 cells were stimulated with 10ng / ml PMA 3-5h before adding the test compound, and then the test compound was added and incubated for 24 hours. The inhibition of trel-LacZ activity stimulated by PMA was used as the standard to calculate the inhibitory effect of the test compound on transcriptional activity. The trel-LacZ activity stimulated by PMA was inhibited, resulting in a decrease in β-galactosidase activity, which was analyzed in a fluorescence analysis system using 4-Methylumbelliferyl β-D-galactoside as a substrate. Dexamethasone 1000nm was used as the 100% control, and DMSO 0.1% was used as the background control.

[0064] Primary human PBMCs were isolated from fresh venous blood drawn from healthy donors. PBMCs were isolated from the blood of female Wistar rats. Heparinized blood was purified by density gradient centrifugation using Ficol-Paque Plus (GE Healthcare), and the erythrocytes were lysed and purified. The cells were plated at 200,000 cells / well in 96-well round-bottom microplates using RPMI 1640 medium, and the test compounds were added and incubated at 37°C for 45 minutes; then, 0.5 ng / ml LPS was added to the 96-well plates and incubated for another 18 hours at 37°C in a humidified atmosphere. The plates were centrifuged to pellet the cells, and the cell-free supernatant was collected. TNFα production was quantified by ELISA.

[0065] Table 2 Cellular pharmacodynamic test results of the tested compounds

[0066] Compound Name <![CDATA[TR(IC 50 nM)]]> <![CDATA[HPBMC(IC 50 nM)]]> I-1 0.025 0.14 I-2 0.027 0.15 I-3 0.028 0.16 AZD-5423 0.066 0.38

[0067] As shown in Table 2, compounds I-1 to I-3 significantly inhibited the transcriptional activity of transcription factor AP-1 in human bronchial lung cancer cells and the production of TNFa induced by LPS in PBMC cells, and were superior to the positive control AZD-5423.

[0068] Example 6: Detection of pharmacokinetic properties of test compounds

[0069] Male SD rats were selected and the drug was administered orally (10 mg / kg) or intravenously (2 mg / kg). At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration, blood was continuously collected from the retinal venous plexus and placed in EP tubes containing heparin. The blood was centrifuged and the upper plasma was collected for LC-MS / MS analysis. Based on the blood drug concentration-time data obtained from the test, WinNonlin software was used to calculate the pharmacokinetic parameters and the oral bioavailability.

[0070] The results showed that the oral bioavailability of AZD-54230 in rats was 25% and the half-life was 3.5h; while the oral bioavailability of compound I-1 was increased to 65% and the half-life was extended to 7.2h.

[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is represented by any of the following structural formulas: 。 2. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2 in the preparation of a glucocorticoid receptor modulator.

4. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 2, in the preparation of a medicament for treating and / or preventing a disease mediated by a glucocorticoid receptor.

5. A method according to claim 4, wherein the disease mediated by the glucocorticoid receptor for treating and / or preventing the disease is an inflammatory disease.

6. A method according to claim 4, wherein the disease mediated by the glucocorticoid receptor is asthma.

7. A use according to claim 4, wherein the disease mediated by glucocorticoid receptor is chronic obstructive pulmonary disease.

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