Carboxy substituted glucocorticoid receptor agonists
12162905 ยท 2024-12-10
Assignee
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. 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.
2. The method of claim 1, wherein the compound of structure 1 is a compound of structure 1a ##STR00059##
3. The method of claim 1, wherein the compound of the Formula I is a compound of Formula Ib ##STR00060##
4. The method of claim 1, wherein the compound of the Formula I is a compound of Formula Ic ##STR00061##
5. The method of claim 1, comprising the steps of (a) creating a suspension by suspending the compound of structure 1 and the compound of structure 2 in acetonitrile; (b) cooling the suspension to about 10 C.; (c) treating the suspension with perchloric acid; and (d) allowing the suspension to warm to room temperature and allowing said suspension to stir.
6. The method of claim 1, wherein the compound of Formula I is: ##STR00062## ##STR00063## ##STR00064##
Description
Example 1
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)benzoic acid (isomer 1)
(1) ##STR00040##
(2) 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-formyl-phenyl)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). 1H NMR (400.13 MHz, d.sub.6-DMSO) 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-(3-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)
(3) ##STR00041##
(4) 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). 1H NMR (400.13 MHz, d.sub.6-DMSO) 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-((2-Fluoro-3-((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)-4-methylphenoxy)methyl)benzoic acid
(5) ##STR00042##
(6) 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). 1H NMR (399.80 MHZ, d.sub.6-DMSO): 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-((2-Fluoro-3-((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)-4-methylphenoxy)methyl)benzoic acid
(7) ##STR00043##
(8) 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).
(9) .sup.1H NMR (399.80 MHz, DMSO): 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).
(10) 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: A. C18 column using eluent 10 mM NH.sub.4HCO.sub.3 in water+5% MeOH:ACN B. C18 column using eluent 0.1% FA in water:ACN C. Chiral SFC using Chiralcel OJ-H eluting with MeOH+0.5% DMEA:CO.sub.2
(11) TABLE-US-00005 TABLE 5 Purification method and ES/MS aldehyde Ex. (m/z) starting No. Structure (M + H) material 5
Structural Assignment by NMR
(12) ##STR00055##
(13) 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.
(14) hGR CoActivator Recruitment Assay
(15) 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 M dexamethasone.
(16) 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.