WO2017042839A1

WO2017042839A1 - Novel eltrombopag salt and preparation thereof

Info

Publication number: WO2017042839A1
Application number: PCT/IS2016/050013
Authority: WO
Inventors: Nasir Ali Shafakat ALI; Vijay Hariprasad SHARMA; Ashutosh Vijay Joshi; Parven Kumar Luthra
Original assignee: Actavis Group PTC ehf
Current assignee: Actavis Group PTC ehf
Priority date: 2015-09-08
Filing date: 2016-09-08
Publication date: 2017-03-16
Anticipated expiration: 2018-03-08

Abstract

A eltrombopag tromethamine salt has been obtained and characterized. Pharmaceutical compositions comprising the elthrombopag tromethamine salt form can be used for treatment of diseases, including thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Process of preparing the elthrombopag tromethamine salt form is also provided.

Description

NOVEL ELTROMBOPAG SALT AND PREPARATION THEREOF

Field

The invention generally relates to a pharmaceutical compound, and more specifically an eltrombopag salt and the preparation thereof. The present invention also relates to methods of treatment, in particular the treatment of thrombocytopenia.

Introduction

Thrombocytopenia is a disorder in which there is an abnormally low amount of platelets. Thrombopoietin (TPO) has been shown to be the main humoral regulator in situations involving thrombocytopenia. In several studies TPO was shown to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Because platelets are necessary for blood clotting and when their numbers are low, a patient is at risk of death from catastrophic haemorrhage. TPO is thus considered to have potential useful applications in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. In addition, studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. Eltrombopag, also known as (Z)-3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-oxo-lH-pyrazol- 4(5H)-ylidene)hydrazinyl)-2'-hydroxybiphenyl-3-carboxylic acid, is a compound having the following chemical structure:

It is a small-molecule, non-peptide thrombopoitin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. Eltrombopag is marketed under the trade name Promacta® by GlaxoSmithKline and Ligand Pharmaceuticals as a bisethanolamine salt of the following chemical structure for the treatment of conditions leading to thrombocytopenia.

Eltrombopag is the first FDA approved small molecule drug in the hematopoietic growth factor field for the treatment of thrombocytopenia. Instead of competing with endogenous thrombopoietin (TPO) for the same binding site of TPO receptor, eltrombopag activates the TPO receptor interacts with the transmembrane domain of the TPO receptor, leading to increased platelet production by initiating signalling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.

Eltrombopag has been disclosed in U.S. Patent Nos. 7,332,481 and 7,160,870, as well as WO 01/89457; and in EP Patent No. 1,294,378. Eltrombopag bisethanolamine salt and eltrombopag olamine salt has been disclosed in WO 03/098992 and U.S. Patent No. 8,052,994, respectively.

Summary

The present invention provides a novel crystalline form of eltrombopag:

In particular, the present invention provides eltrombopag tromethamine salt and processes for preparing the novel salt form. Tromethamine (2-Amino-2-hydroxymethyl-propane-l,3-diol) is an organic amine proton acceptor, generally used as an alkalizer or emulsifying agent, biological buffer, as well as in the synthesis of surface-active agents and pharmaceuticals. It has been found that crystalline eltrombopag tromethamine salt as described herein has advantageous properties. In particular, eltrombopag tromethamine salt has HPLC purity more than 99.5%, it is non-hygroscopic, has a low content of residual solvent and is stable at ambient temperature for at least up to 9 months.

Novel eltrombopag salt form according to the invention has been characterized by powder X- ray diffraction (XRD) as shown in Figure 1 and Table 2 herein. Table 1 shows the main peaks as 2-theta values:

Table 1

Thus, the novel salt form according to the present invention can be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all 10 of X-ray diffraction peaks with 2-theta values of about 8.49°, about 12.5°, about 15.9°, about 18.09°, about 20.14°, about 20.82°, about 21.7°, about 22.48°, about 25.2° and/or about 26.12°.

The skilled person will appreciate that it may be useful to further characterize the compound by the presence of additional X-ray diffraction peaks. Thus, novel eltrombopag tromethamine according to the invention can also be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of the X-ray diffraction peaks having 2-theta values as indicated in Table 2 and/or as shown in Figure 1.

As used herein, the term "about" refers to a range of values + 10% of a specified value. For example, the phrase "about 95" includes ± 10% of 95 and 95 as such. It should be appreciated and is well known to the skilled person that the powder x-ray diffraction pattern can have 2- theta values that show a slight deviation from the above recited values. Thus, in one embodiment, eltrombopag tromethamine salt obtained or obtainable by the present invention can be characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0. Γ, 20.82+/- 0. Γ, 21.7+/- 0. Γ, 22.48+/- 0. Γ, 25.2+/- 0. Γ and/or 26.12+/- Ο. Γ.

Eltrombopag tromethamine salt obtained or obtainable by the present invention can be additionally characterized by at least one of X-ray diffraction peaks with 2-theta values 4.54+/- 0. Γ, 5.64+/- 0. Γ, 10.00+/- 0. Γ, 11.51+/- 0. Γ, 14.12+/- 0. Γ, 16.70+/- 0. Γ, 18.83+/- 0. Γ, 24.04+/- 0. Γ, 27.82+/- 0. Γ, 30.22+/- 0. Γ, 33.90+/- 0. Γ, 38.40+/- 0. Γ or 42.01+/- Ο. Γ.

In one embodiment, crystalline eltrombopag tromethamine salt can be characterized by the X- ray diffraction peaks with 2 theta values of 8.49+/- 0. Γ, 12.5+/- 0. Γ, 15.9+/- 0. Γ, 18.09+/- 0. Γ, 20.14+/- 0. Γ, 20.82+/- 0. Γ, 21.7+/- 0. Γ, 22.48+/- 0. Γ, 25.2+/- 0. Γ and 26.12+/- 0.1°.

Eltrombopag tromethamine according to the invention can also be characterized by the X-ray diffraction peaks with 2 theta values of 8.49°, 12.5°, 15.9°, 18.09°, 20.14°, 20.82°, 21.7°, 22.48°, 25.2° and 26.12°.

Eltrombopag tromethamine may optionally also have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2, and/or a differential scanning calorimetric (DSC) thermogram with an endothermic peak at about 136.9+/-3°C or a differential scanning calorimetric thermogram as depicted in Fig. 3. The term "substantially similar" as used herein means an analytical spectrum, such as XRD pattern, 1H- MR spectrum, FT-IR spectrum, Raman spectrum, TGA thermogram, DSC thermogram etc., which resembles the reference spectrum to a great degree in both the peak locations and their intensity.

In one embodiment, the eltrombopag tromethamine according to the invention is characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0.1°, 20.82+/- 0.1°, 21.7+/- 0.1°, 22.48+/- 0.1°, 25.2+/- 0.1° and/or 26.12+/- 0.1°; and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/-3°C.

In another embodiment, eltrombopag tromethamine according to the invention is characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49°, 12.5°, 15.9°, 18.09°, 20.14°, 20.82°, 21.7°, 22.48°, 25.2° and 26.12°; and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9°C. The crystalline eltrombopag tromethamine compound of the invention can be synthesized from readily available starting materials, such as eltrombopag as described below in the Examples. Alternatively, methods known in the art for preparing eltrombopag can be employed. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. It will be appreciated that while specific process conditions (i.e. crystallization temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. In some instances, reactions or crystallizations were conducted at room temperature and no actual temperature measurement was taken.

It is understood that room temperature can be taken to mean a temperature within the range commonly associated with the ambient temperature in a laboratory environment, and will typically be in the range of about 25°C to about 50°C. In other instances, reactions or crystallizations were conducted at room temperature and the temperature was actually measured and recorded.

The starting material can be readily prepared from commercially available eltrombopag or other starting materials and reagents using the procedures that are well known in the art, for example as described in U.S. Patent Nos. 7,332,481 and 7,160,870 or examples provided herein.

Generally, the crystallization is conducted in a suitable solvent, including tetrahydrofuran, ethyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, dioxane, diethyl ether, diary 1 ether and the like, or mixtures thereof, by an addition of tromethamine. Crystallization can be done by commonly used techniques such as solvent evaporation; slow cooling of the solution, solvent/ non-solvent, diffusion, vapour diffusion and sublimation. Upon completion of the crystallization, the crystalline compound can be isolated from the reaction mixture by any conventional means such as precipitation, concentration, centrifugation and the like. The molar ratios described in the methods of the invention can be readily determined by various methods available to those skilled in the art. In one embodiment, tromethamine can be added to the solution of eltrombopag in tetrahydrofuran to form crystalline, which is then filtered, washed and dried.

The present invention also provides a pharmaceutical composition comprising eltrombopag tromethamine and optionally a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable" refers to a material that is not biologically or otherwise unacceptable when used in the invention. For example, the term "pharmaceutically acceptable excipient" refers to a material that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration. In another aspect, the present invention also provides a method of treating thrombocytopenia comprising administering a therapeutically effective amount of eltrombopag tromethamine, preferably eltrombopag tromethamine characterized in the present application, such as eltrombopag tromethamine salt characterized by the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0. Γ, 20.82+/- 0. Γ, 21.7+/- 0. Γ, 22.48+/- 0. Γ, 25.2+/- 0. Γ and 26.12+/- 0. Γ. Eltrombopag tromethamine for the treatment of thrombocytopenia may optionally also have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2, and/or a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/-3°C or a differential scanning calorimetric thermogram as depicted in Fig. 3. The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a patient in need thereof, i.e., the amount of drug needed to obtain the desired therapeutic effect. For example, an "effective amount" according to the present invention may be the amount needed to activate TPO receptor.

The term "treating" or "treatment" as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), that includes one or more of the following: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient. Preferably, the patient is with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The term "patient" is intended to include those mammals, such as humans, that are in need of treatment or disease prevention, that are presently being treated for disease prevention or treatment of a specific disease or medical condition, as well as test subjects in which compounds of the invention are being evaluated or being used in an assay, for example an animal model. All other terms used herein are intended to have their ordinary meaning as understood by those of ordinary skill in the art to which they pertain.

Brief Description of the Drawings Figure 1 shows structural analysis of eltrombopag tromethamine by X-ray diffraction (XRD), as obtained according to the invention.

Figure 2 shows an Infrared Spectrum (IR) of eltrombopag tromethamine, as obtained by according to the invention.

Figure 3 shows results of Differential Scanning Calorimetry (DSC) of eltrombopag tromethamine, as obtained according to the invention.

Examples

The above features along with additional details of the invention, are described further in the examples below, which are intended to further illustrate the invention but are not intended to limit its scope in any way.

Example 1: Preparation of eltrombopag tromethamine salt

To the solution of eltrombopag (5g) in tetrahydrofuran (150ml) tromethamine (2.9g) was added and precipitate formed and was stirred for two to six hours. Product was filtered and washed with tetrahydrofuran (20ml). After drying 7.2g (92%) of eltrombopag tromethamine was obtained.

Figure 1 and Table 2 shows results of structural analysis of the final product by powder X-ray diffraction (XRD). Table 2

Figure 2 shows an Infrared Spectrum (IR) of the eltrombopag tromethamine, as obtained by the above process. Figure 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t- butyl amine salt, as obtained by the above process.

Claims

1. Crystalline eltrombopag tromethamine salt.

2. Crystalline eltrombopag tromethamine salt characterized by at least one of the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0. Γ, 20.14+/- 0. Γ, 20.82+/- 0. Γ, 21.7+/- 0. Γ, 22.48+/- 0. Γ, 25.2+/- 0. Γ and/or 26.12+/- Ο. Γ.

3. Crystalline eltrombopag tromethamine salt characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/-3°C.

4. Crystalline eltrombopag tromethamine salt characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49+/- 0. Γ, 12.5+/- 0. Γ, 15.9+/- 0. Γ, 18.09+/- 0. Γ, 20.14+/- 0. Γ, 20.82+/- 0. Γ, 21.7+/- 0. Γ, 22.48+/- 0. Γ, 25.2+/- 0. Γ and/or 26.12+/- 0. Γ; and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9+/- 3°C.

5. Crystalline eltrombopag tromethamine salt characterized by (i) at least one of the X-ray diffraction peaks with 2 theta values of 8.49°, 12.5°, 15.9°, 18.09°, 20.14°, 20.82°, 21.7°, 22.48°, 25.2° and 26.12° and (ii) a differential scanning calorimetric thermogram with an endothermic peak at about 136.9°C.

6. A pharmaceutical composition comprising eltrombopag tromethamine salt and optionally at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 6 comprising eltrombopag tromethamine salt according to any one of the claims 1 to 5.

8. A method of treating thrombocytopenia comprising administering a therapeutically effective amount of eltrombopag tromethamine salt.

9. The method of claim 8, comprising administering a therapeutically effective amount of an eltrombopag tromethamine salt according to any one of the claims 1 to 5.

10. A method of treating thrombocytopenia comprising administering a therapeutically effective amount of a crystalline eltrombopag tromethamine salt, wherein the crystalline eltrombopag tromethamine salt is characterized by at least one of the X-ray diffraction peaks with 2 theta values of 8.49+/- 0.1°, 12.5+/- 0.1°, 15.9+/- 0.1°, 18.09+/- 0.1°, 20.14+/- 0.1°, 20.82+/- 0.1°, 21.7+/- 0.1°, 22.48+/- 0.1°, 25.2+/- 0.1° and/or 26.12+/- 0.1°.

11. Crystalline eltrombopag tromethamine salt according to any one of the claims 1 to 5 for se as a medicament.

12. Crystalline eltrombopag tromethamine salt according to any one of the claims 1 to 5 for se in the treatment of thrombocytopenia.

13. The use of crystalline eltrombopag tromethamine salt according to any one of the claims 1 to 5 in the manufacture of a medicament for the treatment of thrombocytopenia.