AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jun 232014
 

Abstract Image

AZD 6564

ACS Med. Chem. Lett., 2014, 5 (5), pp 538–543
DOI: 10.1021/ml400526d

SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf

NMR PG 16/32 AS ABOVE

Figure imgf000012_0002R1 = 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

……………………..

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

Abstract Image

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

Starting from (2R,4S),methyl 2,neopentyl,4,(3,oxo,2,3,dihydroisoxazol,5,
yl)piperidine,1,
carboxylate (0.8 g, 2.7 mmol) and following the procedure described in 15, Step8
the title
compound was obtained (0.44 g, 69 %):
1H NMR (600 MHz, DMSO,d6) δ 0.92 (s, 9H), 1.11 –1.34 (m, 3H), 1.35 – 1.46 (m, 1H), 1.79 – 1.98 (m, 2H), 2.65 – 2.93 (m, 3H),
3.03 – 3.14 (m,1H), 5.74 (s, 1H);13C NMR (101 MHz, CH4,d4) δ 177.39, 174.72, 95.42, 54.83, 49.32, 45.50,
37.13, 34.75, 31.19, 30.07, 28.06;
[α]20D+43.8 (MeOH/H2O 1:1, c = 1); HRMS calculated for[C13H23N2O2]+: 239.1759; found: 239.1753
Compounds of formula I- V may be prepared by the following route:Scheme A. Preparation of intermediatesMETHOD A

Figure imgf000015_0001

O

L C^O”

 

Figure imgf000015_0002

METHOD B

O

Figure imgf000015_0003

 

Figure imgf000015_0004

METHOD C

 

Figure imgf000016_0001

METHOD D

RIB(OR)2

 

Figure imgf000016_0002

X = Cl, Br

 

Figure imgf000016_0003

METHOD E

Figure imgf000017_0001

METHOD F

Figure imgf000017_0002

METHOD G

 

Figure imgf000018_0001

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

Figure imgf000019_0001
Figure imgf000019_0002

°Y J ‘relative

Figure imgf000019_0003

………………….

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.

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463
GLENMARK SCIENTIST ,  INDIA
web link
http://anthonycrasto.jimdo.com/

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