In an effort to remove residual palladium from a drug
candidate
prepared by palladium-catalyzed indolization, many
treatments
were examined. The most effective treatment was to
precipitate
palladium from solution using
2,4,6-trimercapto-s-triazine
(TMT), which reduced palladium levels from 600−650 ppm
to
20−60 ppm in an isolated indole intermediate.
Subsequent
crystallizations routinely afforded active pharmaceutical
ingredient with <1 ppm of palladium. TMT treatment
should
prove useful to reduce the concentration of residual
palladium
in other reactions.
Development of an efficient and scalable process for the human immunodeficiency virus (HIV) protease inhibitor BMS-232632 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucinyl]-amino}-4(S)-hydroxy-6-phenyl-2-azahexane, is described. The key step in the synthesis of the intermediate N-1-(tert-butyloxycarbonyl)-N-2-[4-(pyridin-2-yl)benzylidene]hydrazone (11) was the Pd-mediated coupling of boronic acid 9 with 2-bromopyridine. An efficient procedure was developed for the chemoselective reduction of hydrazone 11 to hydrazine carbamate 4 (6) was prepared stereoselectively from chiral diol 10. The subsequent union of 4 and 6 followed by coupling with N-methoxycarbonyl-L-tert-leucine provided the free base BMS-232632 in high yield. Evaluation of a variety of salts and identification of bisulfate salt 19 with enhanced bioavailability are also described.
. The key intermediate N-(tert-butyloxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxy-butane
Autoreactive B cell-derived antibodies
form immune complexes that
likely play a pathogenic role in autoimmune diseases. In systemic
lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid
cells and induce proinflammatory cytokine production by monocytes
and NETosis by neutrophils. Bruton’s tyrosine kinase (BTK)
is a non-receptor tyrosine kinase that signals downstream of Fc receptors
and plays a transduction role in antibody expression following B cell
activation. Given the roles of BTK in both the production and sensing
of autoreactive antibodies, inhibitors of BTK kinase activity may
provide therapeutic value to patients suffering from autoantibody-driven
immune disorders. Starting from an in-house proprietary screening
hit followed by structure-based rational design, we have identified
a potent, reversible BTK inhibitor, BIIB068 (1), which
demonstrated good kinome selectivity with good overall drug-like properties
for oral dosing, was well tolerated across preclinical species at
pharmacologically relevant doses with good ADME properties, and achieved
>90% inhibition of BTK phosphorylation (pBTK) in humans.
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
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