Glucocorticoid receptor agonist and immunoconjugates thereof
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embodiment (emb) 1
[0647]A compound having Formula I-a:
(SM-L-Q)n-A1 I-a
or a pharmaceutically acceptable salt or solvate thereof, wherein:
[0648]A1 is an anti-tumor necrosis factor (TNF) alpha protein; L is a linker; Q is a heterobifunctional group or heterotrifunctional group; or Q is absent; n is 1-10; and SM is a radical of a glucocorticosteroid.
Emb 2
[0649]The compound of Emb 1, or a pharmaceutically acceptable salt or solvate thereof, wherein SM is a monovalent radical of a glucocorticosteroid.
Emb 3
[0650]The compound of Emb 2, or a pharmaceutically acceptable salt or solvate thereof, wherein SM is a monovalent radical of a glucocorticosteroid selected from the group consisting of:
wherein the sulfur, oxygen, or nitrogen atom is attached directly or indirectly to the C- or D-ring of the glucocorticosteroid, and R is C1-4 alkyl.
Emb 4
[0651]The compound of Emb 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the sulfur, oxygen, or nitrogen atom is attached directly or indirectly to t...
example 1
of (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminophenoxy)phenyl)-2,6b-difluoro-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
Step 1: Synthesis of tert-butyl (4-(4-formylphenoxy)phenyl)carbamate
[0950]
[0951]To a solution of tert-butyl (4-hydroxyphenyl)carbamate (10 g, 47.8 mmol) and 4-fluorobenzaldehyde (11.86 g, 96 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (39.6 g, 287 mmol). The mixture was stirred at 90° C. for 5 hours. One additional vial was set up as described above. All two reaction mixtures were combined and diluted with DCM (300 mL), then extracted with water (3×100 mL). The organic layer was washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with PE:EtOAc=30:1 to 5:1) to obtain the target compound (20 g, 63.8 mmol, 66.7% yield) as a ye...
example 2
of (2S,6aS,6bR,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-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
Step 1: Synthesis of 4-(bromomethyl)benzaldehyde
[0954]
[0955]Diisobutylaluminum hydride (153 mL, 153 mmol, 1 M in toluene) was added drop-wise to a 0° C. solution of 4-(bromomethyl)benzonitrile (20 g, 102 mmol) in toluene (400 mL over 1 hour Two additional vials were set up as described above. All three reaction mixtures were combined. The mixture solution was added 10% aqueous HCl (1.5 L). The mixture was extracted with DCM (3×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with PE / EtOAc=10 / 1) to obtain the target compound (50 g, yield 82%) as white solid. 1H NMR (400 MHz, chloroform-d) δ 10.02 (s, 1H), 7.91-7.82 (m, 2H), 7.56 (d, J...
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