DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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AZD 6564
SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
NMR PG 16/32 AS ABOVE
R1 = NEOPENTYL R2=H
5-[(2R,4S)-2-(2,2-Dimethylpropyl)piperidin-4-yl]-1,2-oxazol-3(2H)-one
5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
238.326
C13 H22 N2 O2
Antifibrinolytics
AstraZeneca (Innovator)
SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
NMR PG 16 0F 32
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Discovery of the fibrinolysis inhibitor AZD6564, acting via interference of a protein – Protein interaction
ACS Med Chem Lett 2014, 5(5): 538
http://pubs.acs.org/doi/abs/10.1021/ml400526d
A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein–protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.
SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf
Step 9: 5,((2R,4S),2,Neopentylpiperidin,4,yl)isoxazol,3(2H),one
O
L C^O”
METHOD B
O
METHOD C
METHOD D
RIB(OR)2
X = Cl, Br
METHOD E
METHOD F
METHOD G
R1 = 1-methyl-1 H-tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl
Scheme B. Formation of 5-isoxazol-3-ones
°Y I ‘relative
°Y J ‘relative
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http://www.google.com/patents/EP2417131A1?cl=en
Example 14
5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
Step 1 : Cis-methyl 2-neopentyl-4-(3-oxo-23-dihvdroisoxazol-5-yl)piperidine-l-carboxylate The compound was prepared as described in Example 1, Step 2 starting from cis-methyl 4-(3- ethoxy-3-oxopropanoyl)-2-neopentylpiperidine-l -carboxylate (2.68 g, 8.19 mmol) which resulted in cis-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (1.60 g, 66 %) : IH NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.18 (dd, IH), 1.45 (dd, IH), 1.80 – 1.92 (m, 2H), 1.97 – 2.17 (m, 2H), 2.94 – 3.02 (m, IH), 3.11 – 3.23 (m, IH), 3.71 (s, 3H), 3.88 – 3.99 (m, IH), 4.22 – 4.32 (m, IH), 5.72 (s, IH); m/z (MH+) 297.
Step 2: (2R,4S)-Methyl 2-neopentyl-4-(3-oxo-2,3-dihvdroisoxazol-5-yl)piperidine-l- carboxylate
Following the procedure described in Example 1, Step 3, racemic cis-methyl 2-neopentyl-4- (3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l -carboxylate (1.60 g, 5.4 mmol) was subjected to chiral separation using Chiralcel IC mobile phase heptane/IP A/FA 60/40/0.1 which resulted in (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l-carboxylate (0.8 g, 2.7 mmol).
Step 3: 5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one
5 Starting from (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (0.8 g, 2.7 mmol) and following the procedure described in Example 1, Step 4 the title compound was obtained (0.44 g, 69 %): 1H NMR (600 MHz, DMSO-d6) δ 0.89 (s, 9H), 1.18 (m, 2H), 1.50 (m, 2H), 1.82-1.90 (m, 2H), 2.70-2.85 (m, 3H), 3.08 (m, IH), 5.71 (s, IH). [α]20 D +43.8 (MeOH/H2O 1:1, c = 1); HRMS calculated for [C13H23N2O2]+: 239.1759; found: 10 239.1753.
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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
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