US 2016.0039810A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0039810 A1 FLYNN et al. (43) Pub. Date: Feb. 11, 2016 (54) A CRYSTALLINE FORM OF AN ANXIOLYTIC Publication Classification COMPOUND (51) Int. Cl. (71) Applicant: BIONOMICS LIMITED, Thebarton, C07D 47L/04 (2006.01) South Australia (AU) (52) U.S. Cl. (72) Inventors: Bernard Luke FLYNN, Donvale, CPC ........... C07D 471/04 (2013.01); C07B 2.200/13 Victoria (AU); Dharam PAUL, Flinders (2013.01) Park, South Australia (AU); Andrew John HARVEY, Goodwood, South Australia (AU) (57) ABSTRACT (73) Assignee: Bionomics Limited. Thebarton, South Australia (AU) A crystalline Form B of compound 1 can be used in pharma ceutically compositions. The pharmaceutical compositions (21) Appl. No.: 14/776,595 can be used in methods of treating a disease (e.g., a disease of (22) PCT Filed: May 14, 2013 the central nervous system). (86). PCT No.: PCT/AU2013AOOO497 1 S371 (c)(1), O O (2) Date: Sep. 14, 2015 H N Related U.S. Application Data 21 r (60) Provisional application No. 61/787,436, filed on Mar. S. Nul 15, 2013. N N (30) Foreign Application Priority Data N Apr. 12, 2013 (AU) ................................ 2O132O4159 Patent Application Publication Feb. 11, 2016 Sheet 1 of 10 US 2016/0039810 A1 20 O 3 10 20 30 40 2-Theta Scale, (Cu Kalpha Radiation) Figure 1 Patent Application Publication Feb. 11, 2016 Sheet 2 of 10 US 2016/0039810 A1 | s 3 3500 3000 2500 2000 500 1000 500 Wavenumber crit-1 Sampla Narro - - - - PP445 Figure 2 Patent Application Publication Feb. 11, 2016 Sheet 3 of 10 US 2016/0039810 A1 •••----|-------…–...--->~~~~£--~~~~~~~-----~-*<----------×=&**• ---------------….…….…~~~~~~~~~~~~~~~~~~~~--~~~~~£2------------------------ . ; Patent Application Publication Feb. 11, 2016 Sheet 4 of 10 US 2016/0039810 A1 sample RH 6 S. R o S S3 8 3 i 3 ge t 8 s : s sseu amge F. 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In general, Form B, and pharmaceutical compositions FIELD OF THE INVENTION thereof, are useful for treating or lessening the severity of a variety of diseases or disorders described herein (e.g., an 0001. The present invention relates generally to a crystal anxiety disorder). Form B is a stable crystalline hemihydrate line form of an anxiolytic compound and methods and uses of form of compound 1. Form B can be characterized using the crystalline form in therapy and to methods for preparing various techniques as described herein including, but not the crystalline form. limited to, X-ray powder diffraction, Raman spectroscopy, differential scanning calorimetry, dynamic vapor sorption, BACKGROUND OF THE INVENTION and thermogravimetric Fourier-transfor infrared thermo 0002 Polymorphism denotes the existence of more than gram. one crystal structure of a chemical entity. For any specific 0008 Also provided herein is a pharmaceutical composi chemical entity it is not readily predictable that it will exhibit tion comprising Form B of compound 1 and optionally an polymorphism. In the instance when the chemical entity is a additional ingredient selected from pharmaceutically accept drug, the ability of the chemical entity to exist in more than able carriers, diluents, and excipients. one crystal form can have a profound effect on the shelf life, 0009. Also provided herein are methods of treating vari solubility, formulation properties, and/or processing proper ous diseases, disorders, or conditions comprising administer ties of the drug. Furthermore, the biological action of the drug ing to a Subject Form B of compound 1, or a pharmaceutical can be affected by the polymorphism. Different crystalline composition thereofas described herein. forms can possess varying rates of uptake in the body, leading 0010 Also provided herein are uses of Form B of com to lower or higher biological activity than required. An undes pound 1, or a pharmaceutical composition thereof as ired polymorph may even show toxicity. Therefore the occur described herein for treating various diseases, disorders, or rence of an unknown polymorphic form during manufacture conditions. and processing of a drug can have a profound impact. 0011. Also provided herein are uses of Form B of com 0003. It is therefore important to be able to understand and pound 1, or a pharmaceutical composition thereof as control polymorphism. Predicting any possible polymorphs described herein in the manufacture of a medicament for for a drug can diminish the possibility of contamination dur treating various diseases, disorders, or conditions. ing a drugs manufacture or storage by other polymorphic forms. DEFINITIONS 0004 Also, understanding which crystal structures are 0012. The term “solvate” refers to forms of a compound possible in some cases allows researchers to maximize the (e.g., compound 1) that are associated with a solvent, usually desired properties of a compound, Such as Solubility, formu by a solvolysis reaction. This physical association may lation properties, processing properties, and shelflife. Under include hydrogen bonding. Conventional solvents include standing these factors early in the development of a new drug water, methanol, ethanol, acetic acid, DMSO, THF, diethyl may mean a more active, more stable, or more cheaply manu ether, and the like. In certain embodiments, Solvates are factured drug. formed using Class 3 solvents. Categories of solvents are defined in, for example, the International Conference on Har SUMMARY OF THE INVENTION monization of Technical Requirements for Registration of 0005 U.S. Pat. No. 8,293,737, the entirety of which is Pharmaceuticals for Human Use (ICH), "Impurities: Guide incorporated herein by reference, describes certain 18-naph lines for Residual Solvents, Q3C(R3), (November 2005). A thyridin-4(1H)-one compounds which are useful as anxi compound may be prepared, e.g., in crystalline form, and may olytic agents. Such compounds include 1-ethyl-6-(indan-2- be solvated. Suitable solvates include pharmaceutically ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4- acceptable solvates and further include both stoichiometric one (compound 1). Solvates and non-stoichiometric Solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorpo rated in the crystal lattice of a crystalline solid. “Solvate encompasses both solution-phase and isolable Solvates. Rep resentative Solvates includehydrates, ethanolates, and metha nolates. 0013 The term “hydrate.” refers to a compound (e.g., compound 1) which is associated with water. Typically, the r number of the water molecules contained in a hydrate of a compound is in a definiteratio to the number of the compound molecules in the hydrate. Hydrates include both stoichiomet croc ric hydrates and non-stoichiometric hydrates. Therefore, a hydrate of a compound may be represented, for example, by 0006 Compound 1 possesses anxiolytic activity without the general formula R.XH2O, wherein R is the compound and sedative side effects and therefore represents an attractive wherein X is a number greater than 0. A given compound may alternative to the 1,4-benzodiazepine class of anxiolytics form more than one type of hydrates, including, e.g., mono Such as diazepam. hydrates (Stoichiometric, X is 1), lower hydrates (non-sto 0007. A polymorph of compound 1 has been discovered ichiometric, X is a number greater than 0 and Smaller than 1, and named Form B, and compositions thereof, are useful as e.g., hemihydrates (R.0.5H2O)), and polyhydrates (non-sto US 2016/0039810 A1 Feb. 11, 2016 ichiometric, X is a number greater than 1, e.g., dihydrates 0019. As used herein, the terms “in combination' and (R.2H2O) and hexahydrates (R.6H2O)). “co-administration can be used interchangeably to refer to 0014. It is also to be understood that compounds that have the use of more than one therapy (e.g., one or more prophy the same molecular formula but differ in the nature or lactic and/or therapeutic agents). The use of the terms does sequence of bonding of their atoms or the arrangement of not restrict the order in which therapies (e.g., prophylactic their atoms in space are termed "isomers’. and/or therapeutic agents) are administered to a subject. 0015 The term “polymorphs' refers to a crystalline form 0020. As used herein, the terms “treatment,” “treat, and of a compound (e.g., compound 1), or a hydrate or Solvate “treating refer to reversing, alleviating, delaying the onset thereof, in a particular crystal packing arrangement. All poly of or inhibiting the progress of a "pathological condition” morphs have the same elemental composition. The term (e.g., a disease, disorder, or condition, or one or more signs or “crystalline, as used herein, refers to a solid state form which symptoms thereof). In some embodiments, treatment may be consists of orderly arrangement of structural units. Different administered after one or more signs or symptoms have devel crystalline forms of the same compound, or a hydrate, or oped or have been observed.