CN116283781A

CN116283781A - Deuterated N-phenyl indazole amide compound, pharmaceutical composition and application

Info

Publication number: CN116283781A
Application number: CN202211645583.4A
Authority: CN
Inventors: 孟祥杰; 张超; 杨琨琨
Original assignee: Yaokang Zhongtuo Jiangsu Pharmaceutical Technology Co ltd Beijing Branch
Current assignee: Yaokang Zhongtuo Jiangsu Pharmaceutical Technology Co ltd Beijing Branch
Priority date: 2022-12-16
Filing date: 2022-12-16
Publication date: 2023-06-23

Abstract

The invention discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, a pharmaceutical composition and application. The compound shown in the formula I provided by the invention has good therapeutic effect on diseases mediated by glucocorticoid receptor disorder, such as asthma, chronic obstructive pulmonary disease and the like.

Description

Deuterated N-phenyl indazole amide compound, pharmaceutical composition and application

Technical Field

The invention belongs to the field of innovative pharmaceutical chemistry, and relates to an N-phenyl indazole amide compound, a pharmaceutical composition and application.

Background

Glucocorticoids bind to the corresponding Glucocorticoid Receptor (GR), causing transcription of upstream and/or downstream genes, regulating immune response and energy metabolism. The regulatory role of GR in "energy metabolism" is responsible for the side effects of traditional glucocorticoid receptor agonists (steroids), limiting the long-term use of such agonists. The novel selective non-Steroidal Glucocorticoid Receptor Modulators (SGRMs) have stronger anti-inflammatory activity, and reduce the side effects on energy metabolism regulation, which are obviously superior to the steroid glucocorticoids and non-steroid glucocorticoids reported earlier. AZD-5423 is a novel selective glucocorticoid receptor modulator, is currently in the phase II clinical research stage,

deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Because the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction of the deuterated drug, and the half-life period of the deuterated drug is prolonged. Since 2000, deuteration strategies have been widely used in drug research.

Disclosure of Invention

The invention provides a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:

wherein R is ₁ 、R ₂ 、R ₃ Or R is ₄ Independently selected from the group consisting of hydrogen and deuterium,

at the same time, R ₁ 、R ₂ 、R ₃ Or R is ₄ At least one of which is deuterium.

In some embodiments, the compound is represented by any one of the following structural formulas:

the invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing glucocorticoid receptor modulators.

The invention provides application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing medicines for treating and/or preventing glucocorticoid receptor mediated diseases.

The invention provides application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing medicines for treating and/or preventing inflammatory diseases.

The invention provides application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing medicines for treating and/or pre-asthma.

The invention provides an application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing medicines for treating and/or preventing chronic obstructive pulmonary disease.

The invention provides a pharmaceutical composition, which contains a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.

In the pharmaceutical composition, the compound shown in the formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective in treatment.

The invention provides an application of a pharmaceutical composition in preparing glucocorticoid receptor modulators.

The invention provides a use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prophylaxis of glucocorticoid receptor mediated diseases.

The invention provides an application of a pharmaceutical composition in preparing a medicament for treating and/or preventing inflammatory diseases.

The invention provides application of a pharmaceutical composition in preparing a medicament for treating and/or pre-treating asthma.

The invention provides a use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prophylaxis of chronic obstructive pulmonary disease.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may 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 formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, 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, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.

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

Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (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 its conversion product from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in the body, they are useful for therapeutic dosing of the compounds of the inventionIs described. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

The invention has the positive progress effects that:

(1) The compound is a high-efficiency selective non-steroidal glucocorticoid receptor modulator.

(2) The compound has good pharmacokinetic property, remarkably improves the oral bioavailability and prolongs the half life.

(3) The compound has good therapeutic effect on asthma and chronic obstructive pulmonary disease.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1: synthesis of Compound I-1

Step one: synthesis of Compound b

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 0deg.C, reacted for 30min at 0deg.C, then warmed to 15deg.C and reacted for 16h. After the reaction was completed, the reaction mixture was diluted with DCM, washed with 1M diluted hydrochloric acid, 10% sodium bicarbonate solution, saturated brine, filtered and concentrated. The reaction residue was dissolved in THF (20 mL), nitrogen-protected, the reaction cooled to 10-15deg.C and a solution of isopropyl magnesium chloride in tetrahydrofuran (2M, 5mL,10 mmol) was slowly added dropwise. After completion of the dropwise addition, a tetrahydrofuran solution (1M, 20mL,20 mmol) of compound e was slowly added dropwise to the above solution. Slowly heating to 20deg.C, adding 20% acetic acid aqueous solution, extracting with ethyl acetate (20 mL×3), mixing organic phases, washing with saturated sodium bicarbonate solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain crude product of compound b. Beating with n-hexane and methyl tert-butyl ether, suction filtration, collecting filter cake, and vacuum drying to obtain compound b (4.7 g, 83%). MS (EsI, m/z): 283 (M) ⁺ +1).

Step three: synthesis of Compound c

Compound b (4.7 g,16.7 mmol) was dissolved in toluene, and to the above solution were added isopropanol (10 g,167 mmol) and aluminum isopropoxide (700 mg,3.4 mmol), the temperature of the reaction mixture was raised to 50℃and the reaction was stirred for 15 hours. After the reaction was completed, it was cooled to room temperature, 1M HCl and water were added to the reaction mixture, extraction was performed with ethyl acetate (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 give compound c (2.0 g, 66%). MS (ESI, m/z): 185 (M) ⁺ +1).

Step three: synthesis of Compound d

Starting material c (1.84 g,10 mmol), N-dimethylaminoglycine (515 mg,5 mmol), cuI (57 mg,0.3 mmol) and CsCO ₃ A suspension of (9.8 g,30 mmol) of butyronitrile (40 mL) was placed in the vialHeating to 110deg.C, and stirring for 30min. A solution of compound f (3.4 g,10 mmol) in butyronitrile (4 mL) was added to the suspension, and the mixture was sealed and reacted at 110℃for 20h. After the completion of the reaction, the mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound d (1.9 g, 50%). MS (ESI, m/z): 395 (M) ⁺ +1).

The steps are as follows: synthesis of Compound I-1

Compound d (399mg, 1 mmol) and g (69. Mu.L, 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 2.5h. After the completion of the reaction, water was added to the reaction mixture, the mixture was extracted with DCM (5 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give Compound I-1 (319 mg, 65%). ¹ H NMR(500MHz，DMSO-d ₆ )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，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)，1.29(d，J＝6.2Hz，3H).MS(ESI，m/z)：491(M ⁺ 1).

Example 2: synthesis of Compound I-2

Synthesis of Compound 1 As in example 1, only the raw material e was replaced with

And (3) obtaining the product.

Step one: synthesis of Compound 2

To a solution of Compound 1 (229 mg,0.47 mmol) in N, N-dimethylformamide (15 mL) was added potassium hydroxide (105.5 mg,1.88 mmol) and elemental iodine (239 mg,0.94 mmol), and the mixture was reacted at room temperature for 3 hoursTLC monitored the completion of the reaction, quenched by the addition of saturated sodium sulfite solution, the aqueous phase extracted with ethyl acetate (10 mL. Times.2), washed with water (20 mL. Times.2), dried over anhydrous sodium sulfate with saturated brine (20 mL), and purified by column chromatography to give iodo compound 2 (135 mg, 47%). MS (ESI, m/z): 614 (M) ⁺ +1).

Step two: synthesis of Compound I-1

To a deuterated acetic acid solution (4 mL) of compound 2 (110 mg,0.18 mmol) was added sodium acetate (49 mg,0.36 mmol), and the reaction was completed for 2 hours at room temperature, and the reaction was completed by TLC, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound I-1 (31 mg, 35%). ¹ H NMR(500MHz，DMSO-d ₆ )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)，7.00(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).

Example 3: synthesis of Compound I-3

The synthesis was as in example 2, and the starting compound 1 was replaced with the compound I-1. ¹ H NMR(500MHz，DMSO-d ₆ )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)，7.00(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)：492(M ⁺ +1).

Example 4: glucocorticoid receptor affinity assay

Detection of test Compounds against the sugar skin Using Fluorescence Polarization (FP) technique based on the commercial kit from Panvera/Invitrogen (article number P2893)Binding of the plasma hormone receptor. For specific procedures, reference is made to the kit instructions and to the experimental methods disclosed in WO 2008/076048. A solution of test compound in DMSO (1. Mu.L) and a solution of control in DMSO (1. Mu.L) were added to a black polystyrene 384-well plate. 0% control is 100% DMSO and 100% control is 10. Mu.M dexamethasone. Background solution (background solution) (8 μl; assay buffer 10×, stabilizing peptide, DTT and ice cold MQ water) was added to the bottom well (the background well). GS Red solution (7. Mu.L; assay buffer 10×, stabilizing peptide, DTT, GS Red and ice cold water) was added to all wells except background wells. GR solution (7. Mu.L; assay buffer 10X, stabilizing peptide, DTT, GR and ice-cold water) was added to all wells. The plates were sealed and incubated at room temperature for 2 hours in the dark. The plates were read in an analytical plate reader (excitation wavelength 530nm, emission wavelength 590nm, and dichroic mirror wavelength 561 nm). Calculation of IC using XLfit model 205 ₅₀ Values.

TABLE 1 binding Capacity of test Compounds to glucocorticoid receptor

Names of Compounds	GRhuFL_FP_v2 average IC ₅₀ (nM)
		I-1	1.7
I-2	1.6
		I-3	1.62
AZD-5423	4.2

As shown in Table 1, the binding capacity of the compounds I-1 to I-3 to glucocorticoid receptor was superior to that of the positive control AZD-5423.

Example 5: cell pharmacodynamic assay

Inhibition of cellular transcriptional activity (Cellular transrepression assay, TR): human bronchopulmonary carcinoma cells ChaGo K1 (ATCC: HTB 168) were transfected with TPA Response Element (TRE) -LacZ construct (5 Xtrel-LacZ). Before 3-5 h of the test compound, 10ng/ml PMA stimulated ChaGo K1 cells, followed by 24h of incubation with the test compound. Inhibition of transcriptional activity by the test compounds was calculated using inhibition of PMA stimulated trel-LacZ activity as a standard. PMA stimulated trel-LacZ activity was inhibited, resulting in a decrease in beta-galactosidase activity, and was assayed in a fluorometric assay system using 4-Methylumbelliferyl beta-D-galactoside as substrate. Dexamethasone 1000nm was used as 100% control and DMSO 0.1% was used as background control.

Primary human PBMCs were isolated from fresh venous blood drawn from healthy donors. Mice isolate PBMCs from blood of female Wistar rats. Heparinized blood was centrifuged using a ficol-paque Plus (GE Healthcare) density gradient, and then the obtained PBMC cells were purified by lysing erythrocytes. Inoculating 20 ten thousand cells/hole into a 96 round bottom micro-pore plate by adopting an RPMI 1640 culture medium, adding a compound to be tested, and incubating for 45 minutes at 37 ℃; then, 0.5ng/ml LPS was added to the 96-well plate and incubation was continued for 18 hours at 37℃in humidified atmosphere. The plate is centrifuged to form cells, and the supernatant is collected without cells. ELISA method for quantifying the amount of TNF alpha produced.

TABLE 2 cytopharmacodynamic test results of test compounds

Names of Compounds	TR(IC ₅₀ nM)	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

As shown in Table 2, the compounds I-1 to I-3 significantly inhibited the transcriptional activity of the human bronchopulmonary carcinoma cell transcription factor AP-1 and the production of LPS-induced TNFa in PBMC cells, and were superior to the positive control AZD-5423.

Example 6: test compound pharmacokinetic property detection

Male SD rats were selected for oral (10 mg/kg) or intravenous (2 mg/kg) administration, 5min,15min,30min,1h,2h,4h,8h,10h,24h after the administration, blood was continuously taken from the ocular fundus venous plexus and placed in an EP tube containing heparin, centrifuged, and upper plasma was taken for LC-MS/MS analysis, and pharmacokinetic parameters were calculated using WinNonlin software according to the blood concentration-time data obtained from the test, and oral bioavailability was calculated.

The research result shows that the oral bioavailability of AZD-54230 in rats is 25%, and the half-life period is 3.5h; and the oral bioavailability of the compound I-1 is improved to 65%, and the half life is prolonged to 7.2h.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structure:

2. The compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, wherein the compound is represented by any of the following structural formulas:

3. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or adjuvant.

4. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the preparation of a glucocorticoid receptor modulator.

5. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the manufacture of a medicament for the treatment and/or prophylaxis of a glucocorticoid receptor mediated disease.

6. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory diseases.

7. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the manufacture of a medicament for the treatment and/or prophylaxis of asthma.

8. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, in the manufacture of a medicament for the treatment and/or prophylaxis of chronic obstructive pulmonary disease.