Bosentan, represented by structural formula (I) and chemically named N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide, is an endothelin receptor antagonist. It is useful for the treatment of cardiovascular disorders such as hypertension, ischemia, vasospasm and angina pectoris and the marketed product, Tracleer®, is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with grade III functional status.

Bosentan was first described in U.S. Pat. No. 5,292,740. The preparation method involves coupling of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide and sodium ethylene glycolate in ethylene glycol at 100° C. However, one of the disadvantages of this process is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol. The removal of this impurity requires costly and laborious separation steps. To minimize the formation of this impurity a large excess of ethylene glycol is used which again is impractical on a large industrial scale. The process disclosed in patent application WO 01/55120 has overcome the above problems by using protected ethylene glycol for the reaction.
Polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. Polymorphic forms of a compound can be distinguished by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry. Additionally, the properties of polymorphic forms of the same active pharmaceutical ingredient are well known in the pharmaceutical art to have an effect on the manufacture of drug product compositions comprising the active pharmaceutical ingredient. For example, the solubility, stability, flowability, tractability and compressibility of the active pharmaceutical ingredient as well as the safety and efficacy of the drug product can be dependent on the crystalline from.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of the pharmaceutical product. It also adds to the choice that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.
USPTO Backgrounds
USPTO Backgrounds