Novel glucocorticoid receptor agonist

Abstract

The present invention relates to a compound of formula I: TIFF2024510775000043.tif35170 [Wherein, R is hydrogen, -P(=O)(OH)2, TIFF2024510775000044.tif21170 or a pharma- ceutically acceptable salt thereof, wherein the compounds of formula I or a pharma- ceutically acceptable salt thereof are useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and inflammatory bowel disease.

Description

Technical Field

[0001] The present disclosure provides compounds that are glucocorticoid receptor agonists and are useful for the treatment of autoimmune and inflammatory diseases such as atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions.

[0002] Atopic dermatitis is a chronic, pruritic, recurrent, and remitting inflammatory skin disease that frequently occurs in children but also affects many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or subcutaneous injectable biologics known as dupilumab. Despite the progress made in the treatment of atopic dermatitis, there remains a significant need for new compounds for the treatment of atopic dermatitis as well as other inflammatory and autoimmune diseases.

[0003] WO 2017 / 210471 discloses certain glucocorticoid receptor agonists and their immune complexes useful for treating autoimmune or inflammatory diseases. WO 2018 / 089373 discloses novel steroids, their protein complexes, and methods of treating diseases, disorders, and conditions including administering the steroids and complexes.

[0004] The present invention provides certain novel compounds that are glucocorticoid receptor agonists. The present invention further provides certain novel compounds that are prodrugs of glucocorticoid receptor agonists. Additionally, the present invention provides certain novel compounds that are glucocorticoid receptor agonists useful for the treatment of autoimmune and inflammatory diseases such as atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis.

[0005] Thus, in one embodiment, the present invention provides a compound of formula I:

[0006] [ka] [Wherein, R is hydrogen, -P(=O)(OH)2,

[0007] [ka] or a pharma- ceutically acceptable salt thereof.

[0008] In one embodiment, R is hydrogen.

[0009] In one embodiment, R is -P(=O)(OH).

[0010] In one embodiment, R is

[0011] [ka] It is.

[0012] In one embodiment, R is

[0013] [ka] It is.

[0014] In one embodiment, R is

[0015] [ka] It is.

[0016] In certain embodiments, the present invention provides a compound of formula Ia:

[0017] [Chemical formula] [wherein, R is hydrogen, -P(=O)(OH)2,

[0018] [Chemical formula] and is] a compound, or a pharmaceutically acceptable salt thereof is provided.

[0019] In certain embodiments, the present invention relates to formula Ib:

[0020] [Chemical formula] [wherein, R is hydrogen, -P(=O)(OH)2,

[0021] [Chemical formula] and is] a compound, or a pharmaceutically acceptable salt thereof is provided.

[0022] In certain embodiments, the present invention relates to formula Ic:

[0023] [Chemical formula] [wherein, R is hydrogen, -P(=O)(OH)2,

[0024] [Chemical formula] and is] a compound, or a pharmaceutically acceptable salt thereof is provided.

[0025] In one embodiment, the present invention also provides a method for treating an inflammatory disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating atopic dermatitis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention further provides a method for treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention further provides a method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating systemic lupus erythematosus in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, the present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory diseases. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of atopic dermatitis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of lupus nephritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of systemic erythematosus.

[0027] In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating inflammatory diseases. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating atopic dermatitis. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating rheumatoid arthritis. In one embodiment, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating inflammatory bowel disease. In one embodiment, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating lupus nephritis. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating systemic erythematosus.

[0028] In one embodiment, the present invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention further provides a process for preparing a pharmaceutical composition comprising mixing a compound of formula I or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention also encompasses novel intermediates and processes for the synthesis of compounds of formula I.

[0029] As used herein, the terms "treating," "treatment," or "treat" include suppressing, delaying, preventing, or improving the progression or severity of an existing symptom or disorder.

[0030] As used herein, the term "patient" refers to a mammal, particularly a human.

[0031] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the present invention or a pharmaceutically acceptable salt thereof that, when administered to a patient singly or in multiple doses, provides the desired effect to a patient being diagnosed or treated.

[0032] The effective amount can be determined by one of ordinary skill in the art using known techniques and by observing results obtained under similar circumstances. When determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including the type of patient; the patient's height, age, and general health; the particular disease or disorder involved; the degree or involvement or severity of the disease or disorder; the response of the individual patient; the particular compound being administered; the mode of administration; the bioavailability characteristics of the preparation being administered; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances, but are not limited thereto.

[0033] As used herein, it is understood that formula I encompasses formula Ia, formula Ib, and formula Ic, and all references herein to formula I should be read as including formula Ia, formula Ib, and formula Ic.

[0034] The compounds of the present invention can be formulated as pharmaceutical compositions administered by any route that makes the compound biologically available, including topical administration. Further, the compounds of the present invention can be formulated as antibody drug conjugates (ADCs), and certain compounds of Formula I are recognized by those skilled in the art as the payload portion of an ADC. Such ADCs are administered by injection, particularly subcutaneous injection. Further, a compound of the present invention having a hydroxy group capped at C21, wherein R is -P(=O)(OH)2

[0035]

Chemical Formula

[0036] Pharmaceutically acceptable salts of Formula I are included within the scope of the present invention. Pharmaceutically acceptable salts of the compounds of the present invention, such as the compounds of Formula I, can be formed by reacting the appropriate free base of the compound of the present invention with an appropriate pharmaceutically acceptable acid under standard conditions well known in the art in a suitable solvent such as diethyl ether. See, for example, Berge, S.M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0037] Certain abbreviations are defined as follows. "DMSO" refers to dimethyl sulfoxide, "DCM" refers to methylene chloride or dichloromethane, "g" refers to gram, "rt" refers to room temperature, "g" refers to gram, "hr" or "hrs" refers to hour, "mg" refers to milligram, "min" refers to minute, "mL" refers to milliliter, "mol" refers to mole, "mmol" refers to millimole, "nm" refers to nanometer, "ES / MS" refers to electrospray mass spectrometry, and "m / z" refers to mass-to-charge ratio equivalent in mass spectrometry.

[0038] The compounds of the present invention or salts thereof may be readily prepared by various procedures known to those skilled in the art, some of which are described in the following preparations and examples. Those skilled in the art will recognize that the specific synthetic steps for each of the described routes can be combined in different ways to prepare the compounds of the present invention or salts thereof, or can be combined with steps from different schemes. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. All substituents are as defined previously unless otherwise indicated. Reagents and starting materials are readily available to those skilled in the art. The following preparations, examples, and assays further illustrate the present invention but should in no way be construed as limiting the scope of the present invention.

[0039] Preparation 1 tert-Butyl N-[4-[(3-fluoro-4-formyl-phenyl)methyl]phenyl]carbamate

[0040]

Chemical formula

[0041] Preparation 2 (2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0042]

Chem.

[0043] Preparation 3 (2R,3R,4S,5S,6S)-2-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5-indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0044]

Chem.

[0045] Preparation 4 9H-Fluoren-9-ylmethyl N-[4-[(3-fluoro-4-formyl-phenyl)methyl]phenyl]carbamate

[0046]

Chem.

[0047] Preparation 5 (4-(3-Fluoro-4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamic acid (9H-fluoren-9-yl)methyl

[0048] [Chemical Structure] A solution of N-[4-[(3-fluoro-4-formyl-phenyl)methyl]phenyl])carbamic acid 9H-fluoren-9-ylmethyl (1.5 g, 2.9 mmol, see Preparation 4) and (8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one (1.3 g, 3.5 mmol) in acetonitrile at 0 °C (15 mL, 290 mmol) was added dropwise with perchloric acid (70% in water, 1.3 mL, 17 mmol). The reaction mixture was stirred at 0 °C for 30 minutes and then warmed to room temperature over 6 hours. The reaction mixture was poured into 30 mL of saturated aqueous sodium hydrogen carbonate. The crude solution was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (50 mL) and water (30 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (silica gel) eluting with 9:1 dichloromethane:methanol to give the title compound (1.5 g, 61% yield). ES / MS m / z 810.3 (M+H).

[0049] Preparation 6 (4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-8b-(2-((di-tert-butoxyphosphoryl)oxy)acetyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-10-yl)-3-fluorobenzyl)phenyl)carbamic acid (9H-fluoren-9-yl)methyl

[0050] [Chemical formula] 1H - Tetrazole (520 mg, 7.3 mmol) and N - di - tert - butoxyphosphanyl - N - ethyl - ethanamine (1.9 g, 7.1 mmol) were added all at once to a solution of (4 - (3 - fluoro - 4 - ((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS) - 7 - hydroxy - 8b - (2 - hydroxyacetyl) - 6a,8a - dimethyl - 4 - oxo - 2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b - dodecahydro - 1H - naphtho[2’,1’:4,5]indeno[1,2 - d][1,3]dioxol - 10 - yl)benzyl)phenyl)carbamic acid (9H - fluoren - 9 - yl)methyl (650 mg, 0.75 mmol, see Preparation 5) in dimethylformamide (7 mL, 90 mmol) at room temperature under a nitrogen atmosphere. After 3 hours, the reaction was cooled to 0 °C, hydrogen peroxide (1.9 g, 7.5 mmol) was added, and the reaction was warmed to room temperature over 4 hours. The reaction was quenched by the addition of sodium thiosulfate (10 mL), poured into water (15 mL), and extracted three times with ethyl acetate (25 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by normal - phase chromatography (silica gel) eluting with 1:1 petroleum ether:ethyl acetate to give the title compound (250 mg, 33% yield). ES / MS m / z 1002.3 (M + H).

[0051] Preparation 7 Phosphate = 2 - ((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS) - 10 - (4 - (4 - aminobenzyl) - 2 - fluorophenyl) - 7 - hydroxy - 6a,8a - dimethyl - 4 - oxo - 1,2,4,6a,6b,7,8,8a,11a,12,12a,12b - dodecahydro - 8bH - naphtho[2’,1’:4,5]indeno[1,2 - d][1,3]dioxol - 8b - yl) - 2 - oxoethyl = di - tert - butyl

[0052] [Chemical Structure] (4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-8b-(2-((Di-tert-butoxyphosphoryl)oxy)acetyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-10-yl)-3-fluorobenzyl)phenyl)carbamic acid (9H-fluoren-9-yl)methyl (250 mg, 0.25 mmol, see Preparation 6) was dissolved in acetonitrile (4 mL, 76 mmol), and piperidine (200 μL, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The crude solution was concentrated under reduced pressure to give a residue. The residue was taken up in 10 mL of petroleum ether and stirred for 2 hours. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (165 mg, yield 77%). ES / MS m / z 780.3 (M+H).

[0053] Preparation 8 (2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0054]

Chemical Structure

[0055] Example 1 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)-2-fluorophenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one (isomer 1)

[0056]

Chem.

[0057] Example 1 (Additional Preparation) (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one Perchloric acid (70% w / w in water, 12 mL, 140 mmol, 3.5 equiv) was added dropwise to a cold (0 - 3 °C) slurry of (8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one (15.00 g, 39.85 mmol) and tert-butyl N-[4-[(3-fluoro-4-formyl-phenyl)methyl]phenyl]carbamate (13.12 g, 39.85 mmol, see Preparation 1) in acetonitrile (750 mL, 589 g, 50 volumes, 360 equiv, 14.34 mol). After 10 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours. Solid NaHCO3 (16.8 g, 200 mmol) was added portionwise to adjust the pH to neutral. After stirring for 1 hour, the mixture was filtered and washed with 50 mL of acetonitrile. The clear solution was then treated all at once with a solution of (R)-anisophosphine (10.84 g, 39.85 mmol) in methanol (325 mL) and treated with about 5 mg of salt. The mixture was stirred at ambient temperature for 16 hours, the resulting suspension was filtered, washed with acetonitrile (3 × 50 mL), and dried under vacuum at 45 °C to give 17.8 g of (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)-2-fluorophenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one-(R)-anisophosphine salt as a white solid (52% yield).

[0058] Solid HPLC-MS showed 1.69 min at 215 / 242 nm (corrected for anisophosphine peak at 0.68), 95.5 / 96 area % a / a (desired isomer), 1.75 min, 1.3 / 1.4 area % a / a (undesired isomer).

[0059] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one-(R)-anisophosphonium salt (20 g, 23 mmol) and a mixture of 200 mL of DCM and 200 mL of saturated aqueous NaHCO3 were stirred vigorously until all solids had dissolved (generally overnight). Next, the layers were separated and the aqueous layer was extracted with 2 × 50 mL of DCM. The combined organic phases were washed with 2 × 50 mL of saturated NaCl, dried over anhydrous Na2SO4, and concentrated under vacuum at 45 °C to give 12.5 g of the title compound as a white solid (91% yield). HPLC purity: 96.6% at 215 nm, 96.9% at 242 nm. ES / MS m / z 588.2 (M+1). Q-NMR (9.5 mg of the product + 3.0 mg of TCNB (MW 260.89). Purity 90% w / w. Residual DCM 1% w / w. 1 H NMR(500.11MHz,CDCl3)δ 0.95(s,3H);1.20-1.03(m,2H),1.44-1.37(m,4H),1.84-1.56(m,3H),1.97-1.90(m,1H),2.25-2.00(m,3H),2.38-2.29(m,1H),2.62-2.50(m,1H),3.08-2.90(m,1H),3.68-3.47(m,1H),3.82(s,2H),4.32-4.23(d,1H),4.49(m,1H),4.65-4.58(d,1H),5.08-5.03(d,1H),5.63(s,1H),6.00(s,1H),6.27-6.23(d,J=8.3Hz,1H),6.60(d,J=8.3Hz,2H),6.99-6.82(m,3H),7.23-7.16(m,1H),7.35(t,J=7.7Hz,1H).

[0060] Example 2 (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one (isomer 2)

[0061]

Chem.

[0062] Example 3 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-8b-(2-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0063]

Chem.

[0064] Example 4 (2S,3S,4S,5R,6R)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0065]

Chem.

[0066] Example 5 Phosphate=Dihydrogen=2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl

[0067]

Chem.

[0068] Example 6 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-Aminobenzyl)-2-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-8b-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0069]

Chemical Structure

[0070] hGR Core Activator Recruitment Assay The activity of the glucocorticoid compound was measured using the LanthaScreen TR-Fret GR co-activator assay (A15899) from Life Technologies. The compound was transferred to the assay plate by acoustic dispensing at a maximum concentration of 200 nM with 10-point serial dilutions in triplicate. A 2-fold solution of 10 microliters of GR-LBD was added to the compound plate and incubated for 10 minutes, after which a 2-fold solution of 10 microliters of fluorescein-SRC1-4 label and Tb-labeled anti-GST antibody was added to the plate. The plate was incubated in the dark for 2 hours and then read on an Envision plate reader that was excited at 340 nm and emitted light at 520 nm (fluorescein) and 490 nm (terbium). The luminescence ratio of 520 / 490 was analyzed with Genedata. To obtain the activity ratio, the data was compared to the negative control of DMSO and the positive control of 4 μM dexamethasone.

[0071] Essentially following the above procedure, the compound of Example 1 had a relative IC of 2.07 nM 50 and the compound of Example 2 had a relative IC of 13.1 nM 50 . The present invention includes the following aspects. <1> Formula:

Chemical formula

Chemical formula

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Chem.

Chem.

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Chem.

Claims

1. Formula: 【Chemical 1】 [wherein, R is hydrogen, -P(=O)(OH) ２ , 【Chemical 2】 ] of the compound or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein R is hydrogen.

3. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein R is -P(=O)(OH) ２ .

4. R is 【Chemical 3】 The compound or a pharmaceutically acceptable salt thereof according to Claim 1.

5. R is 【Chemical 4】 The compound or a pharmaceutically acceptable salt thereof according to Claim 1.

6. R is 【Chemical 5】 The compound or a pharmaceutically acceptable salt thereof according to Claim 1.

7. The compound is 【Chemical 6】 The compound or a pharmaceutically acceptable salt thereof according to Claim 1.

8. The compound is 【Chemical 7】 The compound or a pharmaceutically acceptable salt thereof according to Claim 7.

9. 【Chemical 8】 The compound according to Claim 8.

10. The compound is [Chemical Formula 9] The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

11. [Chemical Formula 10] The compound according to claim 10.

12. The compound is [Chemical Formula 11] The compound or a pharmaceutically acceptable salt thereof according to claim 6.

13. [Chemical Formula 12] The compound according to claim 12.

14. The compound is [Chemical Formula 13] The compound or a pharmaceutically acceptable salt thereof according to claim 1.

15. The compound is [Chemical Formula 14] The compound or a pharmaceutically acceptable salt thereof according to claim 3.

16. The compound is [Chemical Formula 15] The compound or a pharmaceutically acceptable salt thereof according to claim 5.

17. A pharmaceutical composition for use in a method of treating atopic dermatitis in a patient, The pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, The method comprises administering to a patient in need of such treatment an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16. A pharmaceutical composition.

18. A pharmaceutical composition for use in a method of treating systemic lupus erythematosus in a patient, wherein said pharmaceutical composition comprises a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and said method comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition.

19. A pharmaceutical composition for use in a method of treating rheumatoid arthritis in a patient, wherein said pharmaceutical composition comprises a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and said method comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition.

20. A pharmaceutical composition for use in a method of treating lupus nephritis in a patient, wherein said pharmaceutical composition comprises a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and said method comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition.

21. A pharmaceutical composition for use in a method of treating inflammatory bowel disease in a patient, wherein said pharmaceutical composition comprises a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and said method comprises administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition.

22. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in therapy.

23. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment of atopic dermatitis.

24. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment of systemic lupus erythematosus.

25. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment of lupus nephritis.

26. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis.

27. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease.

28. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating atopic dermatitis.

29. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating systemic lupus erythematosus.

30. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating lupus nephritis.

31. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating rheumatoid arthritis.

32. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating inflammatory bowel disease.

33. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

34. A process for preparing a pharmaceutical composition, the process comprising mixing the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.

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