Vinyl-aryl derivatives for inflammation and immune-related uses
a technology of aryl derivatives and aryl derivatives, which is applied in the field of bioactive chemical compounds, can solve the problems of inert antigenic stimulation, tissue damage, and agents that inhibit il-2 production, and achieve the effect of modulating activity
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[0112]The invention relates to compounds and pharmaceutical compositions that are particularly useful for immunosuppression or to treat or prevent inflammatory conditions, immune disorders, and allergic disorders.
[0113]In one embodiment, the invention relates to compounds of structural formula (I):
[0114]or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:[0115]X1 and X2 are, independently, CH or N;[0116]one of X3 or X6 is NR29, and the other is CH2, CHR2, or C(R2)2;[0117]L is a linker selected from the group consisting of —NHCH2—, —CH2NH—, —NR5—C(O)—, —C(O)—NR5—, —NR5—C(S)—, —C(S)—NR5—, —NR5—C(NR8)—, —C(NR8)—NR5—, —NR5C(S)NR5—, —NR5C(NR8)NR5—, or —NR5CRaRbNR5—;[0118]Y is a substituted phenyl, provided that Y is not substituted with —NHC(O)R30;[0119]R1 is H or a substituent;[0120]R2, for each occurrence is, independently, a substituent, provided that R2 is not ═O or ═C(R28)2;[0121]R4 is a substituent;[0122]Ra and Rb, for each occurrence, are indepen...
example 1
Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate
[0328]
[0329]Compound A (31 mg, 0.074 mmol) was dissolved in methylene chloride (2 mL) at room temperature. Ethyl chloroformate (14 μl, 2 eq) was added to the solution and it was heated to 110° C. in the microwave for 1 hour. The solvent was removed and the crude mixture was flashed with ethyl acetate / hexane to produce 28.4 mg (97% yield) of Compound 12.
[0330]1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.1 Hz, 2H), 7.36-7.48 (m, 1H), 7.19 (d, J=8.1 Hz, 2H), 6.997 (t, J=8.1 Hz, 1H), 4.00-4.20(m, 3H), 3.59-3.63 (m, 1H), 2.17-2.20 (m, 3H), 1.63 (s, 3H), 1.26 (t, J=6.3 Hz, 3H) ppm.
[0331]ESMS calcd. (C22H22F2N2O3): 400.2; found: 401.2. (M+H).
example 2
methyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-(thiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (B) and methyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (C)
[0332]
[0333]N-(4-(4-bromopyridin-3-yl)phenyl)-2,6-difluorobenzamide (e). To a solution of 4-Bromopyridine hydrochloride (500 mg, 2.57 mmol) in THF (15 mL) was added LDA (2.0 N, 2.6 mL, 5.2 mmol) at −78° C. After 30 min, the solution of ZnCl2 (1 M in ether, 3.1 mL, 3.1 mmol) in THF (5 mL) was added slowly. The cold bath was removed and the solution was allowed to warm up room temperature. To this solution was added Pd(PPh3)4 (50 mg) and compound d (370 mg, 1.03 mmol). The solution was heated at 65° C. for 2 hrs before it was diluted with EtOAc (20 mL) and H2O (10 mL). The organic phase was collected, dried and concentrated. Column chromatography afforded Compound e (210 mg, 21%). 1H NMR (300 MHz, (CD3)2SO) δ 10.99 (s, 1H), 8.52 (s, 1H), 8.40 (d, J=5.4 Hz, 1H), 7.84-7.78 (m, 3H), 7.63-7...
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