CARBOXY SUBSTITUTED GLUCOCORTICOID RECEPTOR AGONISTS
20230227493 · 2023-07-20
Inventors
Cpc classification
International classification
Abstract
The present invention provides a compound of Formula I:
##STR00001##
wherein R.sup.1 is H, halogen, C1-C3 alkyl, or C1-C3 alkoxy; R.sup.2 is H or halogen; and X is O, OCH.sub.2, or CH.sub.2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof is useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis, and lupus nephritis.
Claims
1-24. (canceled)
25. A method of preparing a compound of the Formula I: ##STR00056## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is H, halogen, C1-C3 alkyl, or C1-C3 alkoxy; R.sup.2 is H or halogen; and X is O, OCH.sub.2, or CH.sub.2, the method comprising: reacting a compound of structure 1 ##STR00057## with an aldehyde of structure 2 ##STR00058## wherein R.sup.3 is hydrogen or an alkyl group.
26. The method of claim 25, wherein the compound of structure 1 is a compound of structure 1a ##STR00059## .
27. The method of claim 25, wherein the compound of the Formula I is a compound of Formula Ib ##STR00060## .
28. The method of claim 25, wherein the compound of the Formula I is a compound of Formula Ic ##STR00061## .
29. The method of claim 25, comprising the steps of (a) creating a suspension by suspending the compound of structure 1 and the compound of structure 2 in a suitable organic solvent; (b) cooling the suspension to about -10° C.; (c) treating the suspension with a suitable acid; and (d) allowing the suspension to warm to room temperature and allowing said suspension to stir.
30. The method of claim 29, wherein the suitable organic solvent is acetonitrile and the suitable acid is perchloric acid.
31. The method of claim 25, wherein the compound of Formula I is: ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## .
Description
[0055] The compounds of the present invention, or salts thereof, may be readily prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the preparations and examples below. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention, or salts thereof. 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 unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The following preparations, examples, and assays further illustrate the invention, but should not be construed to limit the scope of the invention in any way.
##STR00018##
[0056] In Scheme 1, the compound of structure 1 is reacted with an aldehyde of structure 2 wherein R.sup.3 is hydrogen or a suitable alkyl group, such as a tert-butyl or methyl, under conditions well known to one of ordinary skill in the art to provide the compound of Formula I.
[0057] More specifically, as shown in Scheme 1A below, the compound of structure 1a is reacted with an aldehyde of structure 2 wherein R.sup.3 is hydrogen or a suitable alkyl group, such as a tert-butyl or methyl, under conditions well known to one of ordinary skill in the art to provide the compounds of Formula Ib and Formula Ic.
##STR00019##
[0058] For example, about 1.1 equivalents of the compound of structure 1a and about 1 equivalent of a compound of structure 2 wherein R.sup.3 is hydrogen or a suitable alkyl group, such as a tert-butyl group, are suspended in a suitable organic solvent, such as acetonitrile. The suspension is cooled to about -10° C. and then treated with about 5 equivalents of a suitable acid, such as perchloric acid (70% in water). The reaction mixture is then warmed to room temperature and allowed to stir for about 1 hour. Additional organic solvents may be added, such as acetonitrile and dimethylformamide, and the mixture is allowed to stir for about 2 additional hours. The reaction is then quenched using standard conditions, such as with saturated aqueous sodium bicarbonate and the products are isolated using standard techniques well known in the art, such as extraction with a suitable organic solvent, such as methylene chloride:isopranol (9:1), drying the organic extracts over magnesium sulfate, filtering, and concentration under vacuum to provide the crude product mixture. This crude mixture can be purified and the products of Formula Ib and Formula Ic separated using techniques well know in the art, such as chromatography, for example reverse phase chromatography with a suitable eluent, such as 2:1 10 mM ammonium bicarbonate water + 5% methanol:acetonitrile.
##STR00020##
PREPARATION 1
Tert-Butyl 4-[(3-Fluoro-4-Formyl-Phenyl)Methyl]Benzoate
[0059] ##STR00021##
[0060] To a 20 mL sealed tube was added (3-fluoro-4-formyl-phenyl)boronic acid (10 g, 60 mmol), tert-butyl 4-(bromomethyl)benzoate (18 g, 66 mmol), potassium carbonate (27 g, 200 mmol), tetrakis(triphenylphosphene)palladium(0) (2.1 g, 1.8 mmol), and THF (100 mL):water (40 mL). The reaction was heated to 95° C. After 1 h, the reaction was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude residue. The residue was purified by normal phase purification (silica gel), eluting with 9:1 hexanes:ethyl acetate to give the title compound (18.7 g, 86% yield). ES/MS m/z 257.0 (M-tBu-H).
[0061] The following compound in Table 1 was prepared in a manner essentially analogous to the procedure described in Preparation 1.
TABLE-US-00001 Prep. No. Name Structure ES/MS (m/z) (M+H) 2 tert-butyl 3-(3-fluoro-4-formylbenzyl)benzoate
PREPARATION 3
4-[Fluoro-4-Formyl-Phenyl)Methyl]Benzoic Acid
[0062] ##STR00023##
[0063] tert-Butyl 4-[(3-fluoro-4-formyl-phenyl)methyl]benzoate (16 g, 51 mmol, preparation 1) was dissolved in DCM (300 mL) and cooled to 0° C. Trifluoroacetic acid (150 mL) was added dropwise and the reaction was warmed to room temperature. After 1 h, the reaction was concentrated in vacuo and the off-white solid was triturated with diethyl ether/hexanes. The resulting solid was collected by filtration and dried in a vacuum oven to provide the title compound (13.1 g, 96% yield). ES/MS m/z 257.0 (M-H).
##STR00024##
PREPARATION 4
4-Formylphenoxy)Benzoic Acid
[0064] ##STR00025##
[0065] To a microwave vial were added 4-fluorobenzaldehyde (0.63 g, 5.0 mmol), methyl 4-hydroxybenzoate (0.81 g, 5.3 mmol), DMF (15 mL), and potassium carbonate (0.83 g, 6.0 mmol). The reaction was microwaved at 150° C. for 1 h and cooled to rt. The solution was partitioned between EtOAc and water. The organic layer was isolated, washed with saturated aq. sodium chloride (2×), saturated aq NaHCO.sub.3, dried over MgSO.sub.4, filtered, and was concentrated to a colorless oil. To the crude oil, hexanes (50 mL) were added to yield a white semi-solid. It was then sonicated, chilled to 0° C., and suction filtered to isolate a white solid. The white solid was washed with hexanes and dried under vacuum.
[0066] The white solid was dissolved in methanol (8 mL), and sodium hydroxide in water (5 M, 2 mL) was added. The solution was heated to 50° C. for 2 h. The reaction was cooled to rt, diluted with water (10 mL), and acidified to pH 4 with 5 N aq HCl. A white solid was collected via suction filtration, washed with water, and further dried under vacuum to give the title compound (790 mg, 84% yield). MS m/z 241.0 (M-H).
[0067] The following compound in Table 2 was prepared in a manner essentially analogous to the procedure described in Preparation 4.
TABLE-US-00002 Prep. No. Name Structure ES/MS (m/z) (M-H) 5 3-(4-formylphenoxy)benzoic acid
PREPARATION 6
6-BromoFluoro-3-Methoxy-Benzaldehyde
[0068] ##STR00027##
[0069] Two reactions were carried out in parallel. To a solution of 4-bromo-2-fluoro-1-methoxybenzene (250 g, 1.2 mol) in THF (1500 mL) was added LDA (2 M, 730 mL) slowly at -78° C. over 30 min. After an additional 30 min, DMF (140 mL, 1.8 mol) was added at -78° C. slowly over 30 min. After 1 h, the two reactions were combined and the mixture was diluted with aq citric acid (2000 mL) and extracted with EtOAc (1500 mL × 2). The combined organic layers were washed with saturated aq sodium chloride (1000 mL) and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (1000 mL) at rt over 12 h to give the title compound (382 g, 67% yield). ES/MS m/z 233.9 (M+H).
PREPARATION 7
2-Fluoro-3-Methoxy-6-Methyl-Benzaldehyde
[0070] ##STR00028##
[0071] Three reactions were carried out in parallel. 6-Bromo-2-fluoro-3-methoxybenzaldehyde (120 g, 5.3 mol, see Preparation 6), methylboronic acid (47 g, 7.9 mol), Pd(dppf)Cl.sub.2 (12 g, 0.02 mol), and Cs.sub.2CO.sub.3 (340 g, 1.1 mol) were added in dioxane (600 mL) and water (120 mL). The mixture was stirred at 120° C. After 12 h, the three reactions were combined and the mixture was diluted with saturated aq NH.sub.4Cl solution (1000 mL) and extracted with MTBE (1500 mL × 2). The combined organic layers were washed with saturated aq sodium chloride (1000 mL) and concentrated under reduced pressure to give a residue. The residue was purified by normal phase chromatography, eluting with 40:1 petroleum ether: EtOAc to give the title compound (180 g, 59% yield). ES/MS m/z 169.3 (M+H).
PREPARATION 8
2-Fluoro-3-Hydroxy-6-Methyl-Benzaldehyde
[0072] ##STR00029##
[0073] 2-Fluoro-3-methoxy-6-methyl-benzaldehyde (175 g, 1.0 mol, see Preparation 7) was added into DCM (1050 mL), and BBr.sub.3 (200 mL, 2.1 mol) was added slowly into the solution at 0° C. The reaction was stirred at rt. After 1 h, the mixture was diluted with saturated aq sodium bicarbonate (1000 mL) until pH=7-8 and was then extracted with MTBE (1500 mL × 2). The combined organic layers were washed with saturated aq sodium chloride (1000 mL) and concentrated under reduced pressure to give the title compound (110 g, 68% yield). ES/MS m/z 154.9 (M+H).
##STR00030##
[0074] Wherein G is methyl or methoxy.
[0075] Wherein J is methyl or tert-butyl.
PREPARATION 9
Tert-Butyl 3-((2-Fluoro-3-Formyl-4-Methylphenoxy)Methyl)Benzoate
[0076] ##STR00031##
[0077] A mixture of 2-fluoro-3-hydroxy-6-methyl-benzaldehyde (300 mg, 1.9 mmol, see preparation 8), tert-butyl 3-(bromomethyl)benzoate (500 mg, 1.8 mmol), and cesium carbonate (1.2 g, 3.7 mmol) in DMF (6 mL) was stirred at rt overnight. The mixture was diluted with EtOAc and water. The organic solution was washed with three portions water, one portion saturated aq sodium chloride, dried over Na.sub.2SO.sub.4, filtered, and evaporated to give the crude residue. The residue was purified by normal phase purification, eluting with 9:1 hexanes:ethyl acetate to give the title compound (250 mg, 40% yield). MS m/z 362.0 (M+NH.sub.4.sup.+).
[0078] The following compounds in Table 3 were prepared in a manner essentially analogous to the procedure described in Preparation 9.
TABLE-US-00003 Prep. No. Name Structure ES/MS (m/z) (M+H) 10 tert-butyl 3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl) benzoate
PREPARATION 13
Tert-Butyl 2-Fluoro-4-Methoxyphenoxydiphenylsilane
[0079] ##STR00035##
[0080] To a solution of 2-fluoro-4-methoxyphenol (25 g, 180 mmol) in DMF (350 mL 0.5 M) was added imidazole (18 g, 260 mmol) and tert-butylchlorodiphenylsilane (55 mL, 200 mmol). The reaction was stirred for 18 h at rt. The combined organic extracts were washed with water and saturated aq sodium chloride, dried over Na.sub.2SO.sub.4, filtered, and concentrated to a crude residue. The residue was purified by normal phase purification, eluting with 5:1 hexanes:ethyl acetate to give the title compound (67 g, 93% yield). .sup.1H NMR (399.8 MHz, d.sub.6-DMSO) δ 7.67-7.65 (m, 4H), 7.51-7.44 (m, 6H), 6.82 (dd, J= 2.9, 12.7 Hz, 1H), 6.59 (t, J= 9.4 Hz, 1H), 6.47 (ddd, J= 9.0, 3.0, 1.4 Hz, 1H), 3.64 (s, 3H), 1.06 (s, 9H).
PREPARATION 14
2-Fluoro-3-Hydroxy-6-Methoxybenzaldehyde
[0081] ##STR00036##
[0082] tert-Butyl 2-fluoro-4-methoxyphenoxydiphenylsilane (56 g, 150 mmol, see Preparation 13) was dissolved in 50 mL toluene and concentrated under vacuum for 18 h. The dried solid was dissolved in THF (500 mL) and cooled to -80° C. n-Butyllithium (100 mL, 170 mmol) was added rapidly to the cooled solution with a large bore cannula. After 1.5 h, DMF (25 mL, 320 mmol) was added to the solution and the ice bath was removed. After 30 min, 5 N aq HCl (35 mL) was added to the reaction, then tetrabutylammonium fluoride (1 M in THF, 185 mL, 185 mmol) was added. After 2.5 h, the organic layer was evaporated, acidified with 5 N aq HCl, and partitioned between ethyl acetate and water (500 mL). The combined organic extracts were washed with water and saturated aq sodium chloride, dried over MgSO.sub.4, filtered, and concentrated to a crude residue. The residue was purified by normal phase purification, eluting with 1:1 hexanes:ethyl acetate to give the title compound (22 g, 88% yield). MS m/z 170.8 (M+H).
##STR00037##
[0083] Wherein G is methyl or methoxy.
PREPARATION 15
2-(Fluoro-3-Formyl-4-Methoxyphenoxy)Methyl)Benzoic Acid
[0084] ##STR00038##
[0085] To a solution of methyl 2-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)benzoate (230 mg, 0.73 mmol) in MeOH (2 mL, 49 mmol) and THF (2 mL) was added LiOH (1.6 mL, 1.6 mmol, 1 M in water). The mixture was stirred overnight. The solvent was evaporated. The residue was diluted with water and the pH was adjusted to 6 with HCl (0.32 mL, 1.6 mmol, 5 M in water). The solid was collected by vacuum filtration and washed with water. The solid was left on the filter to dry under suction for 5 h to give the title compound (210 mg, 94% yield). MS m/z 305.0 (M+H).
[0086] The following compound was prepared in a manner essentially analogous to the procedure described in Preparation 15.
TABLE-US-00004 Prep. No. Chemical Name Structure ES/MS (m/z) (M+H) 16 2-((2-fluoro-3 -formyl-4-methylphenoxy)methyl)benzoic acid
EXAMPLE 1
4-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)Benzoic Acid (Isomer 1)
[0087] ##STR00040##
[0088] Perchloric acid (70% in water, 1.7 mL, 5 equiv.) was added to a suspension 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 (1.5 g, 4.1 mmol, also referred to as “16alpha-hydroxyprednisolone”) and 4-[(3-fluoro-4-formylphenyl)methyl]benzoic acid (1.00 g, 3.87 mmol, Preparation 3) in acetonitrile (20 mL) at -10° C. and was warmed to rt. After 1 h, additional acetonitrile (40 mL) and DMF (2 mL) were added to the suspension at rt. After 2 h, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with 9:1 methylene chloride:isopropanol. The organic layers were combined; dried over magnesium sulfate; filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography, eluting with 2:1 10 mM ammonium bicarbonate water + 5% methanol:acetonitrile to give the title compound, isomer 1, peak 1 (1.48 g, 62% yield). ES/MS m/z 617.5 (M+H). .sup.1H NMR (400.13 MHz, d.sub.6-DMSO) δ 7.83 (d, J= 8.2 Hz, 2H), 7.50 (t, J= 7.8 Hz, 1H), 7.32-7.27 (m, 3H), 7.14-7.11 (m, 2H), 6.16 (dd, J= 1.8, 10.1 Hz, 1H), 5.93 (s, 1H), 5.60 (s, 1H), 4.94 (d, J= 4.9 Hz, 1H), 4.89-4.72 (m, 1H), 4.48 (d, J= 19.5 Hz, 1H), 4.30-4.24 (m, 1H), 4.21-4.16 (m, 1H), 4.00 (s, 2H), 2.38-2.36 (m, 1H), 2.08 (s, 3H), 1.82-1.67 (m, 5H), 1.39 (s, 3H), 1.07-0.96 (m, 2H), 0.86 (s, 3H).
EXAMPLE 2
4-Fluoro-4-((6aR,6bS,7S,8aS,8bS,10S,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)Benzoic Acid (Isomer 2)
[0089] ##STR00041##
[0090] From Example 1, the residue was purified by reverse phase chromatography, eluting with 2:1 10 mM ammonium bicarbonate water + 5% methanol:acetonitrile to give the title compound, isomer 2, peak 2 (122 mg, 5% yield). ES/MS m/z 617.4 (M+H). .sup.1H NMR (400.13 MHz, d.sub.6-DMSO) δ 7.84 (d, J= 8.2 Hz, 2H), 7.33-7.29 (m, 3H), 7.21 (t, J= 7.8 Hz, 1H), 7.11-7.05 (m, 2H), 6.27 (s, 1H), 6.19-6.16 (m, 1H), 5.94 (s, 1H), 5.30 (d, J= 6.4 Hz, 1H), 4.83-4.79 (m, 1H), 4.31 (s, 1H), 4.19 (d, J= 19.1 Hz, 1H), 4.03-3.98 (m, 3H), 2.37-2.30 (m, 1H), 2.08-2.02 (m, 3H), 1.87-1.77 (m, 5H), 1.39 (s, 3H), 1.26-1.14 (m, 1H), 1.08-1.02 (m, 1H), 0.87 (s, 3H).
EXAMPLE 3
3-(Fluoro-3-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-Hydroxy-8b-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)-4-Methylphenoxy)Methyl)Benzoic Acid
[0091] ##STR00042##
[0092] To a suspension 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 (290 mg, 0.77 mmol, also referred to as “16alpha-hydroxyprednisolone”) and tert-butyl 3-[(2-fluoro-3-formyl-4-methyl-phenoxy)methyl]benzoate (250 mg, 0.7375 mmol) in ACN (7 mL) at -10° C., was added perchloric acid (320 uL, 3.7 mmol, 70 mass% in water) dropwise. The reaction was stirred at -10° C. for 2 h. The reaction was poured into a rapidly stirring flask containing saturated aq. NaHCO.sub.3. The mixture was stirred for 5 min and then extracted with 10% IPA/DCM (3×). The combined organic extracts were washed with brine, dried with Na.sub.2SO.sub.4, filtered, and concentrated to give a crude residue. The residue was purified by reverse phase chromatography, eluting with 10 mM NaHCO.sub.3 water + 5% MeOH:ACN to give a mixture of diastereomers. The mixture was subjected to chiral SFC chromatography using Chiralpak AS-H eluting with 35 % EtOH (w/ 0.5% DMEA):65% CO.sub.2 to give the title compound (190 mg, 40% yield). MS m/z 647.2 (M+H). .sup.1H NMR (399.80 MHz, d.sub.6-DMSO): δ 7.97 (s, 1H), 7.88 (d, J= 7.7 Hz, 1H), 7.58 (d, J= 7.5 Hz, 1H), 7.45 (t, J= 7.7 Hz, 1H), 7.32 (d, J= 10.0 Hz, 1H), 7.17 (t, J= 8.5 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 6.16 (dd, J= 1.8, 10.1 Hz, 1H), 5.94 (s, 1H), 5.61 (s, 1H), 5.21 (s, 2H), 4.96 (d, J= 5.7 Hz, 1H), 4.81-4.81 (m, 1H), 4.47 (d, J= 19.4 Hz, 1H), 4.31 (s, 1H), 4.20 (d, J= 19.5 Hz, 1H), 3.47-3.41 (m, 1H), 2.30 (s, 4H), 2.18-2.14 (m, 2H), 1.86-1.75 (m, 3H), 1.64 (td, J= 13.2, 5.8 Hz, 1H), 1.40 (s, 3H), 1.26-1.16 (m, 2H), 0.90-0.85 (m, 3H).
EXAMPLE 4
3-(Fluoro-3-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-7-Hydroxy-8b-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)-4-Methylphenoxy)Methyl)Benzoic Acid
[0093] ##STR00043##
[0094] Chiral SFC purification described in Example 3 gave the title compound as the second diastereomer (61 mg, 13% yield). MS m/z 647.3 (M+H). .sup.1H NMR (399.80 MHz, DMSO): δ 7.97 (s, 1H), 7.87 (d, J= 7.7 Hz, 1H), 7.59 (d, J= 7.7 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.34-7.32 (m, 1H), 7.17-7.13 (m, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.34 (s, 1H), 6.18 (dd, J= 1.9, 10.0 Hz, 1H), 5.95 (s, 1H), 5.31 (d, J= 6.7 Hz, 1H), 5.22-5.15 (m, 2H), 4.78 (d, J= 2.6 Hz, 1H), 4.32 (d, J= 18.9 Hz, 2H), 4.02 (d, J= 19.0 Hz, 1H), 3.17 (s, 1H), 2.40-2.39 (m, 2H), 2.22 (s, 3H), 2.11-2.08 (m, 2H), 1.91-1.86 (m, 2H), 1.40 (s, 3H), 1.31-1.19 (m, 3H), 0.88 (s, 3H).
[0095] The following compounds listed in Table 5 were prepared in a manner essentially analogous to the method described in Examples 3 and 4 utilizing the corresponding aldehyde starting material as indicated in the table. Purification of final products was performed essentially by the following methods: [0096] A. C18 column using eluent 10 mM NH.sub.4HCO.sub.3 in water + 5% MeOH:ACN [0097] B. C18 column using eluent 0.1% FA in water:ACN [0098] C. Chiral SFC using Chiralcel OJ-H eluting with MeOH + 0.5% DMEA:CO.sub.2
TABLE-US-00005 Ex. No. Structure ES/MS (m/z) (M+H) Purification method and aldehyde starting material 5
##STR00055##
[0099] Two dimensional through-space ROE NMR analysis of acetal isomers consistently gave a cross peak for H22 (acetal) and H16 in the R configuration. Alternatively, H22 in the S configuration consistently gave about 1 ppm larger shift. All other compounds were assigned essentially by the same method.
Hgr CoActivator Recruitment Assay
[0100] The activity of glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR Coactivator Assay from Life Technologies (A15899). The compounds were acoustically transferred to an assay plate in a 3-fold 10-point serial dilution with a top concentration of 200 nM. Ten microliters of a 2× solution of GR-LBD was added to the compound plate and incubated for 10 min. Then ten microliters of a 2× solution of Fluoresein-SRC1-4 and Tb labelled anti-GST antibody was added to the plate. The plate was incubated in the dark for two hours and then read on an Envision plate reader, with excitation at 340 nm and emission at 520 nm (Fluorescein) and 490 nm (Terbium). The emission ratio of 520/490 was analyzed in Genedata. To obtain percent activity, the data was compared to a negative control of DMSO and positive control of 4 .Math.M dexamethasone.
[0101] Following the procedure as essentially described above, the compound of Example 1 provided a relative IC.sub.50 of 2.14 nM, the compound of Example 2 provided a relative IC.sub.50 of 4.50 nM, and the compounds of Examples 3-9, 11, 12, 14, and 15 each provided a relative IC.sub.50 of less than 200 nM. Examples 10 and 13 each provided a relative IC.sub.50 greater than 200 nM.