Avatrombopag

 

Avatrombopag, also known as AKR-501, YM477, AS 1670542 or E5501, is a novel orally-active thrombopoietin (TPO) receptor agonist. AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects.  AKR-501 may be useful in the treatment of patients with thrombocytopenia. (source: Eur J Haematol. 2009 Apr;82(4):247-54).

Avatrombopag is a thrombopoietin receptor (c-Mpl) agonist in phase III clinical evaluation at Eisai for the oral treatment of chronic immune thrombocytopenia (idiopathic thrombocytopenia purpura) and for the treatment of thrombocytopenia associated with liver diseases. Phase II studies are ongoing for the treatment of thrombocytopenia during antiviral therapy (inhibition and maintenance) with Interferon for hepatitis C.

The drug candidate may hold potential in treating thrombocytopenia of diverse etiologies, including idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia of myelodysplastic syndromes (MDS), in combination with or as a substitute for platelet transfusion.

AKR-501, a novel, small-molecule thrombopoietin mimetic being investigated for the treatment of thrombocytopenia. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture AKR-501. AKR-501 is an investigational thrombopoietin receptor agonist that, based on preclinical studies, increases platelet production by stimulating megakaryocytic proliferation and differentiation. Eisai is currently conducting Phase II clinical trials of AKR-501 in the United States as a potential treatment for idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia associated with liver diseases (TLD), and has confirmed proof of concept in the clinical studies for ITP. In addition, Eisai will explore the compound’s potential as a treatment for chemotherapy-induced thrombocytopenia (CIT).

E-5501 stimulates the production of thrombopoietin (TPO), a glycoprotein hormone that stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets. The drug candidate was originally developed at Yamanouchi, and development responsibilities were passed to AkaRx when it was formed in 2005 as a spin-off following the creation of Astellas Pharma subsequent to the merger of Yamanouchi Pharmaceutical and Fujisawa Healthcare.

In 2007, MGI Pharma was granted a license to E-5501 for the treatment of thrombocytopenia. Eisai eventually gained the rights to the product as results of its acquisition of MGI Pharma. In 2010, Eisai acquired AkaRx. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture E-5501. In 2011, orphan drug designation was assigned by the FDA for the treatment of idiopathic thrombocytopenic purpura.

E5501 (or AKR-501 or YM477) is a small molecule agonist c-Mpl, orally available. It is in clinical trials for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). It acts as an agonist of the thrombopoietin receptor active orally, mimicking its biological effect. Thrombocytopenic purpura The is the idiopathic consequence of a low number of platelets (thrombocytopenia) of unknown cause. A very low platelets can even lead to purpura (bruises), or bleeding diathesis.

February 2012: A Phase III, multicenter, randomized, double-blind, controlled against placebo, parallel group, with an open-label extension phase to assess the efficacy and safety of combined oral E5501 to standard treatment for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia, is underway.

January 2010: Eisai Inc. announced its successful acquisition of the biopharmaceutical company, AkaRx Inc. Following this acquisition, AkaRx became a wholly owned subsidiary of Eisai Inc. Eisai now owns the worldwide exclusive rights to develop , marketing and manufacture AKR-501.

October 2009: Eisai Research Institute of Boston, Inc. (established in 1987) and Eisai Medical Research Inc. (established in 2002) were merged into Eisai Inc. 2005: AkaRx was founded as a spin-out of the merger of Yamanouchi Pharmaceutical Company Ltd. and Fujisawa Pharmaceutical Company Ltd. to form Astellas Pharma Inc. AKR-501 was discovered by Yamanouchi and was licensed to AkaRx as part of the foundation of the company in 2005.

In a Phase I trial in healthy volunteers, 10 mg of AKR-501 for 14 days, increased platelet count by 50%.AKR-501 was well tolerated in both studies, mono- and multi-dose. No adverse effects were reported, even at the highest doses.

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Patent

WO 2004029049

Espacenet

Compound A is a compound of the present invention has the following chemical structure.

That is, compounds useful as a platelet 增多 agent according to the present invention A, as well as medicaments for the Compound A as an active ingredient, in particular increasing platelets agents and Z or thrombocytopenia treating agent.

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PATENT

WO 2003062233

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JP 2014144916/WO 2013018362

https://www.google.co.in/patents/WO2013018362A1?cl=en

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid as expressed by the following chemical formula (hereinafter referred to as “Compound X”) and pharmaceutically acceptable salts are known to have excellent thrombocytosis effects (patent literature 1, patent literature 2).

[Formula 1]

Patent literature 1 discloses a hydrochloride of compound X as example 16 (hereinafter referred to as “compound X hydrochloride”).

Furthermore, patent literature 2 discloses a maleic acid salt of compound X that has endothermic peaks near 198 degree C and 271 degree C in thermo gravimetric analysis (hereinafter referred to as “maleic acid salt of compound X”). However, patent literature 2 neither discloses nor suggests that the maleic acid salt of compound X exhibits crystal polymorphism.

On the other hand, compounds exhibiting crystal polymorphism demonstrate entirely different effects regardless of being the same compound, because various physical properties including physicochemical properties differ depending on the crystalline form. In pharmaceutical products in particular, if compounds that have different functional effects are expected to have the same effect, a different functional effect than expected will occur, which is thought to induce unexpected circumstances, and therefore there is demand for supply of a drug substance with constant quality. Therefore, when a compound which has crystal polymorphism is used as a medicine, one type of crystal of that compound must always be constantly provided in order to ensure constant quality and constant effects that are required of the medicine.

Under the aforementioned conditions, from the perspective of supplying a drug substance for medicines, there is a need for compound X or crystals of pharmaceutically acceptable salts thereof, which can ensure constant quality and constant effects and which can be stably supplied in mass production such as industrial production or the like, as well as for establishment of a manufacturing method thereof.

The crystals of compound X maleic acid salt disclosed in patent literature 2 (hereinafter referred to as “compound X maleic acid salt A type crystals”) cannot be isolated as compound X maleic acid salt A type crystals when scaled up for mass production using the method disclosed in example 1 of patent literature 2, and therefore must be isolated in a different crystal form. (This other crystal form is referred to as “compound X maleic acid salt B type crystals”). Therefore, the compound X maleic acid salt A type crystals have a possibility that the crystal form will morph depending on the scale of production, and is clearly inappropriate as a drug substance for medicines which require constant quality and constant effects.

Preparation Example 1: Manufacture of Compound X Maleic Acid Salt B Type Crystal
310 mL of a 1 M aqueous solution of sodium hydroxide at room temperature was added to a mixture of 70.0 g of the ethyl ester of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid and 1.2 L of ethanol, the insoluble matter was filtered out, and then washed with 200 mL of ethanol. The reaction solution was stirred for 90 minutes at 60 degree C. After cooling to room temperature, 1.4 L of an aqueous solution containing 24.11 g of maleic acid was added to the solution obtained, and then the precipitate was collected by filtering.

The same operation was repeated and when combined with the previously obtained precipitate, 136.05 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid was obtained.

18.9 g of maleic acid and 2.1 L of 80% ethanol water were added to 88.90 g of the carboxylic acid obtained, and the solution was stirred for one hour at room temperature and for another hour at 100 degree C. After cooling to room temperature and further cooling with ice, the precipitated solid was filtered out to obtain 87.79 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.

6.84 g of maleic acid was added to 231 g of the crude product containing the crude product obtained above and those manufactured in a similar manner, dissolved in 5.5 L of 80% ethanol water, and then the precipitated solid was collected by filtering to obtain 203 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 1: Manufacture of Compound X Maleic Acid Salt C Type Crystals (1)
1.52 L of ethanol, 0.38 L of water, and 15.7 g of maleic acid were added to 78.59 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, and heated while stirring. After cooling to room temperature and further cooling with ice, the precipitated solid was collected by filtering to obtain 71.60 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.

296 mg of maleic acid was added to 10.0 g of the crude product obtained, dissolved in 60 mL of acetone, 60 mL of DMSO, and 30 mL of water, and then the precipitated solids were collected to obtain 8.41 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 2: Manufacture of Compound X Maleic Acid Salt C Type Crystals (2)
A mixture containing 80.1 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 580 mL of DMSO, 580 mL of acetone, 17.2 g of maleic acid, and 290 mL of water was stirred at 69 degree C. The insoluble matter was filtered out, washed with a mixture of 32 mL of DMSO, 32 mL of acetone, and 16 mL of water, and then the filtrate was cooled and the precipitate was collected by filtering. Washing was successively performed using 150 mL of water, 80 mL of acetone, 650 mL of water, and 80 mL of acetone, followed by drying, to obtain 70.66 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 3: Manufacture of Compound X Maleic Acid Salt C Type Crystals (3)
A mixture containing 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 100 L of DMSO, 100 L of acetone, 4.29 kg of maleic acid, and 50 L of water is stirred at 65 degree C, and then the insoluble matter is filtered out and washed with a mixture of 8 L of DMSO, 8 L of acetone, and 4 L of water, and then the filtrate is cooled, the precipitate is collected by filtering, successively washed using 40 L of acetone, 100 L of water, and 40 L of acetone, and then dried to obtain approximately 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

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REFERENCES

Garabet, L.; Ghanima, W.; Lee, S.; Mowinckel, M.C.; Liebman, H.; Jonassen, C.M.; Bussel, J.; Sandset, P.M.
Thrombopoietin receptor agonists do no not cause coagulation activation: In patients with immune thrombocytopenia
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO311-MON

Terrault, N.; Hassanein, T.; Joshi, S.; Lake, J.R.; Sher, L.S.; Vargas, H.E.; McIntosh, J.W.; Tang, S.; Jenkins, T.
Once-daily oral avatrombopag (E5501) prior to elective surgical or diagnostic procedures in patients with chronic liver disease and thrombocytopenia: Results from a phase 2, randomized, double-blind, placebo-controlled study (study 202)
63rd Annu Meet Am Assoc Study Liver Dis (November 9-13, Boston) 2012, Abst

​​Thiophenyl Triazol-3-one Derivatives As Smooth Muscle relaxers: US6613786 (2003) Priority: US20010336865P, Nov. 2, 2001 (Bristol-Myers Squibb CO, US)

Preparation Of Avatrombopag: 2-Acylaminothiazole derivative or salt thereof: EP1466912 (2004) Priority: JP20020010413, 18 Jan. 2002 (Yamanouchi Pharma Co Ltd, Japan)

Synthesis And Use Of MSE Framework-Type Molecular Sieves: US2009318696 (2009) Priority: US20080214631 20 Jun. 2008 (Exxon Mobil, US).

5,6-Dichloro-Nicotinic Acid Production By Reacting 6-Hydroxy-Nicotinic Acid With Acid Chloride Reacting With Chlorine Products, Then With Acid Chloride And Hydrolysing Products: CH664754 (1988) Priority: CH19850002692, 25 Jun. 1985 (Lonza AG, Switzerland).

David J. Kuter, New Thrombopoietic Growth Factors, Lymphoma and Myeloma Clinical Journal Volume 9, Supplement 3, S347-S356

///////E 5501, AKR 501, Phase III, eisai, Avatrombopag, y 477, orphan drug, ym 477, AS 1670542, Yamanouchi Pharma Co Ltd,  Japan