Antifibrinolytics – All About Drugs

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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_0002 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

……………………..

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

………………………
http://www.google.com/patents/EP2417131A1?cl=en

Compounds of formula I- V may be prepared by the following route:Scheme A. Preparation of intermediatesMETHOD A

L C^O”

METHOD B

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

………………….

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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