Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III

Edoxaban, DU-176b

Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery

for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642  Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825,  see s[pecific page 2808 for description  ie 14/31 of pdf

WO 2010071121, http://www.google.com/patents/WO2010071121A1

WO 2007032498

N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

NOV20, 2013

Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.

The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx

Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.^[1]

In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.^[2]

Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).

Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement^[3] (phase III early results compare well to enoxaparin^[4]), and for stroke prevention in patients with atrial fibrillation^[5][6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.

A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.^[7]

1.  “First market approval in Japan for LIXIANA (Edoxaban)”. Press Release. Daiichi Sankyo Europe GmbH. 2011-04-22.
2.  Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (September 2008). “DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles”. J. Thromb. Haemost. 6 (9): 1542–9. doi:10.1111/j.1538-7836.2008.03064.x. PMID 18624979.
3.  Raskob, G.; Cohen, A. T.; Eriksson, B. I.; Puskas, D.; Shi, M.; Bocanegra, T.; Weitz, J. I. (2010). “Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement”. Thrombosis and Haemostasis 104 (3): 642–649. doi:10.1160/TH10-02-0142.PMID 20589317. edit
4.  “Phase III Trial Finds Edoxaban Outclasses Enoxaparin in Preventing Venous Thromboembolic Events”. 8 Dec 2010.
5.  Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (September 2010). “Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation”. Thromb. Haemost. 104 (3): 633–41. doi:10.1160/TH10-01-0066.
6.  Edoxaban versus Warfarin in Patients with Atrial Fibrillation Robert P. Giugliano, M.D., Christian T. Ruff, M.D., M.P.H., Eugene Braunwald, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Jonathan L. Halperin, M.D., Albert L. Waldo, M.D., Michael D. Ezekowitz, M.D., D.Phil., Jeffrey I. Weitz, M.D., Jindřich Špinar, M.D., Witold Ruzyllo, M.D., Mikhail Ruda, M.D., Yukihiro Koretsune, M.D., Joshua Betcher, Ph.D., Minggao Shi, Ph.D., Laura T. Grip, A.B., Shirali P. Patel, B.S., Indravadan Patel, M.D., James J. Hanyok, Pharm.D., Michele Mercuri, M.D., and Elliott M. Antman, M.D. for the ENGAGE AF-TIMI 48 InvestigatorsDOI: 10.1056/NEJMoa1310907
7.  “Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism”. N. Engl. J. Med. August 2013. doi:10.1056/NEJMoa1306638. PMID 23991658.
8. WO 03/000657 pamphlet WO 03/000680 pamphlet WO 03/016302 pamphlet WO 04/058715 pamphlet WO 05/047296 pamphlet WO 07/032498 pamphlet WO 08/129846 pamphlet WO 08/156159 pamphlet
9. J Am Chem Soc 1978, 100(16): 5199

Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274

• N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate represented by the following formula (A) (hereinafter, also referred to as compound A) :
• 

  
• is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases (Patent Literature 1 to 8).
• For example, a method comprising mixing the free form of compound A represented by the following formula (B) (hereinafter, also referred to as compound B):
• 
• with p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, followed by crystallization from aqueous ethanol, is known as a method for obtaining compound A (Patent Literature 1 to 8). These literature documents do not make any mention about adding p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate in a stepwise manner in the step of obtaining compound A from compound B.

Citation ListPatent Literature

• • Patent Literature 1: International Publication No. WO 03/000657
  • Patent Literature 2: International Publication No. WO 03/000680
  • Patent Literature 3: International Publication No. WO 03/016302
  • Patent Literature 4: International Publication No. WO 04/058715
  • Patent Literature 5: International Publication No. WO 05/047296
  • Patent Literature 6: International Publication No. WO 07/032498
  • Patent Literature 7: International Publication No. WO 08/129846
  • Patent Literature 8: International Publication No. WO 08/156159

SIMILAR

OTHER SALTS

Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C₂₄H₃₀ClN₇O₄S · HCl
Molecular Weight: 584.52 g.mol^-1

Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.

The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:

formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.