Source: http://www.google.com/patents/US8119680?dq=patent:3079728
Timestamp: 2017-10-21 21:45:59
Document Index: 712241393

Matched Legal Cases: ['Application No. 2525547', 'Application No. 04752297', 'Application No. 200507305', 'Application No. 2004247013', 'Application No. 2006', 'Application No. 4753', 'Application No. 04752297']

Patent US8119680 - α-Haloketone derivatives of imidazolyl-substituted aromatic compounds and ... - Google Patents
Novel compounds, compositions, and kits are provided. Methods of modulating Aβ levels, and methods of treating a disease associated with aberrant Aβ levels are also provided....http://www.google.com/patents/US8119680?utm_source=gb-gplus-sharePatent US8119680 - α-Haloketone derivatives of imidazolyl-substituted aromatic compounds and compounds prepared therefrom
Publication number US8119680 B2
Application number US 12/875,935
Also published as CA2525547A1, CA2525547C, CN102584813A, CN102584813B, EP1628666A2, EP1628666A4, EP1628666B1, US7244739, US7781442, US7799808, US8017629, US20050070538, US20070249833, US20070260058, US20100324032, US20100331551, WO2004110350A2, WO2004110350A3
Publication number 12875935, 875935, US 8119680 B2, US 8119680B2, US-B2-8119680, US8119680 B2, US8119680B2
Inventors Soan Cheng, Daniel D Comer, Long Mao, Guity P Balow, David Pleynet
Patent Citations (80), Non-Patent Citations (41), Referenced by (3), Classifications (29), Legal Events (3)
α-Haloketone derivatives of imidazolyl-substituted aromatic compounds and compounds prepared therefrom
US 8119680 B2
2-bromo thiazole (1 g, 6.1 mmol) was placed in a flask and toluene:EtOH (4:1, 80 mL:20 mL) was added prior to the addition of 4-acetylphenyl boronic acid (1.2 g, 7.32 mmol), sodium carbonate (2.16 g, 20.4 mmol), and water (3 mL). The reaction mixture was degassed by bubbling nitrogen through it for 30 min. Pd(PPh3)4 was subsequently added and the reaction mixture was heated at 80° C. for 17 h before it was allowed to cool to room temperature. EtOAc (3×100 mL) and water (100 mL) were added. The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered, and purified by column chromatography (120 g ISCO cartridge). Compound 1219 was isolated as a white powder (974 mg, 79%, mass for C11H9NOS, calculated: 203.3, observed: 204.2 [M+1]). Compound 1219 (204 mg, 1 mmol) was dissolved in 30% HBr in acetic acid (3 mL) before bromine (160 mg, 1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 6 h before it was poured onto ice-water, stirred for 10 min and the precipitate filtered. Compound 1221 was isolated as a yellow powder (257 mg, 92%, mass for C11H9BrNOS, calculated: 281.2, observed: 282.1 [M+1]).
Compound 29, diethyl-(4-methyl-3-nitrophenyl)-amine was prepared by dissolving 4-methyl-3-nitroaniline (25.0 g, 164.5 mmol) and ethyl bromide (44.8 g, 411.2 mmol) in DMF in a 350 mL glass bomb. A large stir bar and K2CO3 (56.75 g, 411.2 mmol) were added. The bomb was tightly capped and placed in an oil bath at 80° C. The mixture was then vigorously stirred for 40 h. The reaction was then cooled and uncapped, and the material was partitioned between EtOAc (400 mL) and water (300 mL). The water layer was then washed twice with EtOAc (150 mL) and the combined EtOAc layers were washed twice with water (500 mL) and once with brine (500 mL). The EtOAc layer was then dried over MgSO4, filtered and concentrated to a dark liquid. The product was purified by silica gel chromatography with 5% EtOAc/hexanes. Pure fractions were concentrated to yield compound 29 as an orange liquid (20.8 g, 61%). LC/MS: [M+H]+=209.1. C11H16N2O2=208.2. 1H NMR (CDCl3) 300 MHz δ1.16 (t, 6H, J=6.9 Hz), 2.44 (s, 3H), 3.35 (q, 4H, J=6.9 Hz), 6.76 (two d, 1H, J=3.0 Hz), 7.09 (two d, 1H, J=0.6 Hz), 7.25 (d, 1H, J=3.0 Hz).
Compound 29 (20.8 g, 100.0 mmol) was dissolved in MeOH: CH2Cl2 and cooled to 0° C. in an ice bath. NiCl2.6H2O (4.0 g, 16.8 mmol) and NaBH4 (11.0 g, 297.3 mmol) were added in 1 g portion over 90 min. TLC confirmed reaction completion. The solvent was removed under reduced pressure and the material was re-suspended in CH2Cl2 (500 mL) and silica gel. The solvent was then removed under reduced pressure until material appeared as a loose grey powder. The powder was placed into a funnel and generously washed with EtOAc (500 mL). The resulting solution was concentrated to a yellow liquid which was purified on a silica gel column eluted with 30% EtOAc/hexanes. Pure fraction were combined and concentrated under reduced pressure to yield compound 30 as a light purple liquid (15.3 g, 85%). LC/MS: [M+H]+=179.2. C16\8N2=178.2. 1H NMR (CDCl3) 300 MHz δ1.13 (t, 6H, J=6.9 Hz), 2.04 (s, 3H), 3.27 (q, 4H, J=6.9 Hz), 3.51 (broad s, 2H), 6.05 (d, 1H, J=2.4 Hz), 6.11 (two d, 1H, J=2.4 Hz), 6.86 (d, 1H, J=8.1 Hz).
To a solution of 2,5-dimethyl-benzene-1,4-diamine (30 mmol, 4.1 g) in 40 mL THF, boc anhydride (33 mmol, 72 g) and TEA (45 mmol, 6.26 mL) were added respectively. After stirring at room temperature overnight, the reaction mixture was concentrated to remove THF, and the residue was re-dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×80 mL). The organic layers were combined and dried over Na2SO4. After removal of the solvent, the crude product was purified by using flash chromatography (5-50% ethyl acetate/hexane) to give the title compound 40 (over 90% yield).
2-methyl-5-bromoaniline (10.8 g, 58.4 mmol) and benzoyl isothiocyanate (9.5 g, 58.4 mmol) were combined in acetone and heated to reflux for 30 min. The reaction was allowed to cool and then poured into stirring ice water. The mixture was stirred for 15 min, and then formed a precipitate, which was filtered and air dried within vacuum for 1 h. The resulting yellow powder was then suspended in a 5% NaOH aqueous solution and stirred for 18 h at 80° C. The reaction was allowed to cool and then poured into stirring ice water (400 ml). After stirring on ice for 1 h, the resulting white solid was vacuum filtered and air vacuum filter dried for 1 h, to yield compound 51 as a white solid (10.1 g, 71%). LC/MS: [M−H]−=244.1. C8H9BrN2S=245.1. 1H NMR (DMSO-d6) 300 MHz δ 2.14 (s, 3H), 7.17 (d, 1H, J=8.4 Hz), 7.31 (d. 1H, J=7.8 Hz) 7.45 (s, 1H), 9.24 (broad s, 1H).
The following {4-[6-(4-methyl-imidazol-1-yl)-pyridin-3-yl]-thiazol-2-yl}-(2-methyl-5-pyrrol-1-yl-phenyl)-amine and representative analogs thereof were prepared in a similar procedure as described above. Generally, 0.1 mmol of 32 was dissolved in 1 ml DMF solution with various alpha bromoketone derivatives (sec “bromoketone” column of Table 4 below). The reaction was stirred at 70° C. for 6 h. After cooling to room temperature, the reaction mixture was purified by reversed phase HPLC using acetonitrile/water/TFA gradient and C18 stationary phase. The product was isolated and then concentrate to give the title compound as a TFA salt.
0.028 g = 67 % yield [M + 1]+ = 420 C20H20Cl2N4S = 419
0.024 g = 60% yield. [M + 1]+ = 395 C21H22N4O2S = 394.50
0.034 g = 92% yield. [M + 1]+ = 381 C21H24N4OS = 380.50
0.026 g = 65% yield. [M + 1]+ = 409 C22H24N4O2S = 408.53.
0.026 g = 60% yield [M + 1]+ = 443 C26H26N4OS = 442.55
Compound 1204 (500 mg, 1.26 mmol) was placed in anhydrous DMF (7 mL) under an atmosphere of nitrogen prior to addition of NaH (35 mg of 95% powder, 1.38 mmol). After stirring at room temperature for 10 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.38 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours before careful addition of water (50 mL) and EtOAc (3×50 mL). The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, and filtered. Removal of the solvent in vacuo gave compound 25 as a yellow oil, which solidified upon standing (530 mg). 1H NMR (300 MHz, DMSO. δ in ppm) −0.07 (s, 9H), 0.93 (t, J=7.8 Hz, 2H), 3.69 (t, J=7.5 Hz, 2H), 5.32 (s, 2H), 7.11 (s, 1H), 7.44-7.50 (m, 3H), 7.65 (d, J=6.3 Hz, 2H), 7.68 (d, J=5.7 Hz, 2H), 7.78 (d, J=0.9 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 8.30 (s, 1H). Expected mass spectrometry=527; observed=528 [M+1].
Compound 1210 was dissolved in DMF (5 ml) and aqueous 2 M HCl (5 ml), and stirred at room temperature for 1.5 hours. The product was then purified by reverse-phase HPLC. Pure fractions were combined and concentrated to dryness under reduced pressure. The resulting material was dissolved in CH2Cl2 (250 ml) and washed 2×saturated NaHCO3 (100 mL) and 1×brine (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 1211 as a white solid (free base) (0.610 g, 51%). LC/MS: [M+H]+=418.5. C24H27C5S=417.5.
Compound 1211 (free base) (0.610 g, 1.46 mmol) was partially dissolved in MeOH (2 ml). 2M HCl/Et2O (1.46 ml, 2.92 mmol) was then added and the solution cleared. The solution was concentrated down to a minimal volume using a stream of nitrogen gas. Et2O (5 ml) was then added and the compound was triturated to a white solid, which was washed with 2×Et2O (5 ml) and dried with a stream of nitrogen. The material was then re-dissolved in dry EtOH (1.5 ml) with gentle heating. The mixture was allowed to cool and the compound crystallized. The crystals were collected on a filter and washed with 2×Et2O (1 ml) and dried in vacuo to yield the dihydrochloride salt as an off-white solid (0.320 g, 26%). LC/MS: [M+1]+=418.5. C24H27N5S.2HCl=490.5. 1H NMR (DMSO-d6) 300 MHz δ1.09-1.36 (6H, t, J=6.9 Hz), 2.34 and 2.36 (6H, two s), 3.51 (4H, broad s), 7.42 (2H, t, J=8.4 Hz), 7.57 (1H, s), 7.79 (2H, d, J=9.0 Hz), 8.07 (1H, t, J=1.2 Hz), 8.19 (2H, d, J=9.0 Hz), 8.57 (1H, s), 9.69 (1H, d, J=1.8 Hz), 9.68 (1H, s).
N*3*-[4-(4-bromo-phenyl)-thiazol-2-yl]-N*1*,N*1*-diethyl-4-meth-benzene-1,3-diamine (104 mg, 0.25 mmol) (1215a) was placed in a flask and toluene:EtOH (4:1, 12 mL:3 mL) were added prior to the addition of 3-furyl boronic acid (34 mg, 0.30 mmol), sodium carbonate (80 mg, 0.75 mmol) and water (1 mL). The reaction mixture was degassed by bubbling nitrogen through it for 30 min. Pd(PPh3)4 (29 mg, 0.025 mmol) was subsequently added and the reaction mixture was heated at 80° C. for 17 h before it was allowed to cool to room temperature. EtOAc (3×100 mL) and water (100 mL) were added. The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered, and purified by column chromatography (40 g ISCO cartridge). The title compound was isolated as a yellow powder (40 mg, 40%, mass for C24H25N3O5S, calculated: 403.5, observed: 404.1 [M+1]).
Following overnight coating with the capture antibody at 4° C., the assay plates were blocked with 50 μl of 1% BSA/TBS, Fraction V (Sigma, St. Louis, Mo.). Assay plates containing cells were washed three times with 50 μl of TBS/0.1% Tween-20, and then supernatant from the wells of the tissue culture plates was transferred to the antibody-coated plates (20 μl of supernatant was added to plates coated with Aβ42-selective antibody, and 10 μl of supernatant was added to plates coated with Aβ40-selective antibody). The assay plates were incubated with cell supernatant for 2 hours at room temperature. Plates were then washed three times with 50 μi of TBS/0.1% Tween-20. After washing, wells were incubated with 25 of anti-Aβ1-12 conjugated to alkaline phosphatase (˜0.5 μg/ml in 1% TBS) for 2.5 hours at room temperature. Wells were washed three times with 50 μl of TBS/0.1% Tween-20 and 25 μl of CDP-Star chemiluminescence substrate (i, Inc.) was added and incubated for 20 minutes at room temperature. Luminescence was quantified on an Analyst HT (Molecular Devices Corp.).
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U.S. Classification 514/399, 548/341.1
International Classification A61K31/415, A61K31/425, A61K31/40, A61K31/53, A61K31/505, A61K31/497, A61K31/535, C07D277/42, C07D417/04, C07D417/14, C07D277/04, A61K31/50, C07D417/10, C07D413/00, C07D233/54, A61K, C07D417/12
Cooperative Classification C07D277/42, C07D417/04, C07D417/10, C07D417/12, C07D417/14
European Classification C07D417/12, C07D277/42, C07D417/10, C07D417/14, C07D417/04